@article {818, title = {A genomic strategy for precision medicine in rare diseases: integrating customized algorithms into clinical practice.}, journal = {J Transl Med}, volume = {23}, year = {2025}, month = {2025 Jan 20}, pages = {86}, abstract = {

BACKGROUND: Despite the use of Next-Generation Sequencing (NGS) as the gold standard for the diagnosis of rare diseases, its clinical implementation has been challenging, limiting the cost-effectiveness of NGS and the understanding, control and safety essential for decision-making in clinical applications. Here, we describe a personalized NGS-based strategy integrating precision medicine into a public healthcare system and its implementation in the routine diagnosis process during a five-year pilot program.

METHODS: Our approach involved customized probe designs, the generation of virtual panels and the development of a personalized medicine module (PMM) for variant prioritization. This strategy was applied to 6500 individuals including 6267 index patients and 233 NGS-based carrier screenings.

RESULTS: Causative variants were identified in 2061 index patients (average 32.9\%, ranging from 12 to 62\% by condition). Also, 131 autosomal-recessive cases could be partially genetically diagnosed. These results led to over 5000 additional studies including carrier, prenatal and preimplantational tests or pharmacological and gene therapy treatments.

CONCLUSION: This strategy has shown promising improvements in the diagnostic rate, facilitating timely diagnosis and gradually expanding our services portfolio for rare diseases. The steps taken towards the integration of clinical and genomic data are opening new possibilities for conducting both retrospective and prospective healthcare studies. Overall, this study represents a major milestone in the ongoing efforts to improve our understanding and clinical management of rare diseases, a crucial area of medical research and care.

}, keywords = {Algorithms, Female, Genomics, High-Throughput Nucleotide Sequencing, Humans, Precision Medicine, rare diseases}, issn = {1479-5876}, doi = {10.1186/s12967-025-06069-2}, author = {M{\'e}ndez-Vidal, Cristina and Bravo-Gil, Nereida and Perez-Florido, Javier and Marcos-Luque, Irene and Fern{\'a}ndez, Raquel M and Fernandez-Rueda, Jose Luis and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Mart{\'\i}n-S{\'a}nchez, Marta and Fern{\'a}ndez-Su{\'a}rez, Elena and Mena, Marcela and Carmona, Rosario and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {817, title = {Metatranscriptomic analysis reveals gut microbiome bacterial genes in pyruvate and amino acid metabolism associated with hyperuricemia and gout in humans.}, journal = {Sci Rep}, volume = {15}, year = {2025}, month = {2025 Mar 22}, pages = {9981}, abstract = {

Several pathologies with metabolic origin, such as hyperuricemia and gout, have been associated with the gut microbiota taxonomic profile. However, there is no evidence of which bacterial genes are being expressed in the gut microbiome, and of their potential effects on hyperuricemia and gout. We sequenced the RNA of 26 fecal samples from 10 healthy normouricemic controls, 10 with asymptomatic hyperuricemia (AH), and six gout patients. The coding sequences were mapped to KEGG orthologues (KO). We compared the expression levels using generalized linear models and validated the expression of four KO in a larger sample by qRT-PCR. A distinct genetic expression pattern was identified among groups. AH individuals and gout patients showed an over-expression of KOs mainly related to pyruvate metabolism (Log2foldchange > 23, p-adj <= 3.56 {\texttimes} 10), the pentose pathway (Log2foldchange > 24, p-adj < 1.10 {\texttimes} 10) and purine metabolism (Log2foldchange > 22, p-adj < 1.25 {\texttimes} 10). AH subjects had lower expression of KO related to glycine metabolism (Log2foldchange=-18, p-adj < 1.72 {\texttimes} 10) than controls. Gout patients had lower expression (Log2foldchange=-22.42, p-adj < 3.31 {\texttimes} 10) of a KO involved in phenylalanine biosynthesis, in comparison to controls and AH subjects. The over-expression seen for the KO related to pyruvate metabolism and the pentose pathway in gout patients{\textasciiacute} microbiome was validated. There is a differential gene expression pattern in the gut microbiome of normouricemic individuals, AH subjects and gout patients. These differences are mainly located in metabolic pathways involved in acetate precursors and bioavailability of amino acids.

}, keywords = {Adult, Aged, Amino Acids, Bacteria, Case-Control Studies, Feces, Female, Gastrointestinal Microbiome, Gene Expression Profiling, Genes, Bacterial, Gout, Humans, Hyperuricemia, Male, Middle Aged, Pyruvic Acid, Transcriptome}, issn = {2045-2322}, doi = {10.1038/s41598-025-93899-1}, author = {Mart{\'\i}nez-Nava, Gabriela Ang{\'e}lica and Altamirano-Molina, Efren and V{\'a}zquez-Mellado, Janitzia and Casimiro-Soriguer, Carlos S and Dopazo, Joaquin and Lozada-P{\'e}rez, Carlos and Herrera-L{\'o}pez, Br{\'\i}gida and Mart{\'\i}nez-G{\'o}mez, Laura Edith and Mart{\'\i}nez-Armenta, Carlos and Guido-G{\'o}mora, Dafne Lissete and Valle-Guti{\'e}rrez, Sarah{\'\i} and Suarez-Ahedo, Carlos and Camacho-Rea, Mar{\'\i}a Del Carmen and Mart{\'\i}nez-Garc{\'\i}a, Mireya and Guti{\'e}rrez-Esparza, Guadalupe and Amezcua-Guerra, Luis M and Zamudio-Cuevas, Yessica and Mart{\'\i}nez-Flores, Karina and Fern{\'a}ndez-Torres, Javier and Burguete-Garc{\'\i}a, Ana I and Orbe-Orihuela, Yaneth Citlalli and Lagunas-Mart{\'\i}nez, Alfredo and M{\'e}ndez-Salazar, Eder Orlando and Francisco-Balderas, Adriana and Palacios-Gonz{\'a}lez, Berenice and Pineda, Carlos and L{\'o}pez-Reyes, Alberto} } @article {816, title = {Characterization of the Common Genetic Variation in the Spanish Population of Navarre.}, journal = {Genes (Basel)}, volume = {15}, year = {2024}, month = {2024 May 04}, abstract = {

Large-scale genomic studies have significantly increased our knowledge of genetic variability across populations. Regional genetic profiling is essential for distinguishing common benign variants from disease-causing ones. To this end, we conducted a comprehensive characterization of exonic variants in the population of Navarre (Spain), utilizing whole genome sequencing data from 358 unrelated individuals of Spanish origin. Our analysis revealed 61,410 biallelic single nucleotide variants (SNV) within the Navarrese cohort, with 35\% classified as common (MAF > 1\%). By comparing allele frequency data from 1000 Genome Project (excluding the Iberian cohort of Spain, IBS), Genome Aggregation Database, and a Spanish cohort (including IBS individuals and data from Medical Genome Project), we identified 1069 SNVs common in Navarre but rare (MAF <= 1\%) in all other populations. We further corroborated this observation with a second regional cohort of 239 unrelated exomes, which confirmed 676 of the 1069 SNVs as common in Navarre. In conclusion, this study highlights the importance of population-specific characterization of genetic variation to improve allele frequency filtering in sequencing data analysis to identify disease-causing variants.

}, keywords = {Cohort Studies, Exome, Female, Gene Frequency, Genetic Variation, Genetics, Population, Genome, Human, Humans, Male, Polymorphism, Single Nucleotide, Spain, Whole Genome Sequencing}, issn = {2073-4425}, doi = {10.3390/genes15050585}, author = {Maillo, Alberto and Huergo, Estefania and Apell{\'a}niz-Ruiz, Mar{\'\i}a and Urrutia-Lafuente, Edurne and Miranda, Mar{\'\i}a and Salgado, Josefa and Pasalodos-Sanchez, Sara and Delgado-Mora, Luna and Teijido, {\'O}scar and Goicoechea, Ibai and Carmona, Rosario and Perez-Florido, Javier and Aquino, Virginia and L{\'o}pez-L{\'o}pez, Daniel and Pe{\~n}a-Chilet, Maria and Beltran, Sergi and Dopazo, Joaquin and Lasa, I{\~n}igo and Beloqui, Juan Jos{\'e} and Alonso, {\'A}ngel and Gomez-Cabrero, David} } @article {810, title = {drexml: A command line tool and Python package for drug repurposing.}, journal = {Comput Struct Biotechnol J}, volume = {23}, year = {2024}, month = {2024 Dec}, pages = {1129-1143}, abstract = {

We introduce drexml, a command line tool and Python package for rational data-driven drug repurposing. The package employs machine learning and mechanistic signal transduction modeling to identify drug targets capable of regulating a particular disease. In addition, it employs explainability tools to contextualize potential drug targets within the functional landscape of the disease. The methodology is validated in Fanconi Anemia and Familial Melanoma, two distinct rare diseases where there is a pressing need for solutions. In the Fanconi Anemia case, the model successfully predicts previously validated repurposed drugs, while in the Familial Melanoma case, it identifies a promising set of drugs for further investigation.

}, issn = {2001-0370}, doi = {10.1016/j.csbj.2024.02.027}, author = {Esteban-Medina, Marina and de la Oliva Roque, V{\'\i}ctor Manuel and Herr{\'a}iz-Gil, Sara and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin and Loucera, Carlos} } @article {805, title = {Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches.}, journal = {Front Immunol}, volume = {14}, year = {2024}, month = {2023}, pages = {1282859}, abstract = {

INTRODUCTION: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing.

METHODS: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors.

RESULTS: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19.

DISCUSSION: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies.

}, keywords = {Computer Simulation, COVID-19, drug repositioning, Humans, SARS-CoV-2, Systems biology}, issn = {1664-3224}, doi = {10.3389/fimmu.2023.1282859}, author = {Niarakis, Anna and Ostaszewski, Marek and Mazein, Alexander and Kuperstein, Inna and Kutmon, Martina and Gillespie, Marc E and Funahashi, Akira and Acencio, Marcio Luis and Hemedan, Ahmed and Aichem, Michael and Klein, Karsten and Czauderna, Tobias and Burtscher, Felicia and Yamada, Takahiro G and Hiki, Yusuke and Hiroi, Noriko F and Hu, Finterly and Pham, Nhung and Ehrhart, Friederike and Willighagen, Egon L and Valdeolivas, Alberto and Dugourd, Aur{\'e}lien and Messina, Francesco and Esteban-Medina, Marina and Pe{\~n}a-Chilet, Maria and Rian, Kinza and Soliman, Sylvain and Aghamiri, Sara Sadat and Puniya, Bhanwar Lal and Naldi, Aur{\'e}lien and Helikar, Tom{\'a}{\v s} and Singh, Vidisha and Fern{\'a}ndez, Marco Fari{\~n}as and Bermudez, Viviam and Tsirvouli, Eirini and Montagud, Arnau and No{\"e}l, Vincent and Ponce-de-Leon, Miguel and Maier, Dieter and Bauch, Angela and Gyori, Benjamin M and Bachman, John A and Luna, Augustin and Pi{\~n}ero, Janet and Furlong, Laura I and Balaur, Irina and Rougny, Adrien and Jarosz, Yohan and Overall, Rupert W and Phair, Robert and Perfetto, Livia and Matthews, Lisa and Rex, Devasahayam Arokia Balaya and Orlic-Milacic, Marija and Gomez, Luis Cristobal Monraz and De Meulder, Bertrand and Ravel, Jean Marie and Jassal, Bijay and Satagopam, Venkata and Wu, Guanming and Golebiewski, Martin and Gawron, Piotr and Calzone, Laurence and Beckmann, Jacques S and Evelo, Chris T and D{\textquoteright}Eustachio, Peter and Schreiber, Falk and Saez-Rodriguez, Julio and Dopazo, Joaquin and Kuiper, Martin and Valencia, Alfonso and Wolkenhauer, Olaf and Kitano, Hiroaki and Barillot, Emmanuel and Auffray, Charles and Balling, Rudi and Schneider, Reinhard} } @article {811, title = {Genotypic characterization and antimicrobial susceptibility of human isolates in Southern Spain.}, journal = {Microbiol Spectr}, volume = {12}, year = {2024}, month = {2024 Oct 03}, pages = {e0102824}, abstract = {

is the main cause of bacterial gastroenteritis and a public health problem worldwide. Little information is available on the genotypic characteristics of human in Spain. This study is based on an analysis of the resistome, virulome, and phylogenetic relationship, antibiogram prediction, and antimicrobial susceptibility of 114 human isolates of from a tertiary hospital in southern Spain from October 2020 to June 2023. The isolates were sequenced using Illumina technology, and a bioinformatic analysis was subsequently performed. The susceptibility of isolates to ciprofloxacin, tetracycline, and erythromycin was also tested. The resistance rates for each antibiotic were 90.3\% for ciprofloxacin, 66.7\% for tetracycline, and 0.88\% for erythromycin. The fluoroquinolone resistance rate obtained is well above the European average (69.1\%). CC-21 ( = 23), ST-572 ( = 13), and ST-6532 ( = 13) were the most prevalent clonal complexes (CCs) and sequence types (STs). In the virulome, the , and genes were detected in all the isolates. A prevalence of 20.1\% was obtained for the genes and , which are related to the pathogenesis of Guillain-Barr{\'e} syndrome (GBS). The prevalence of the main antimicrobial resistance markers detected were CmeABC (92.1\%), RE-cmeABC (7.9\%), the T86I substitution in (88.9\%), (72.6\%) (65.8\%), and (17.1\%). High antibiogram prediction rates (>97\%) were obtained, except for in the case of the erythromycin-resistant phenotype. This study contributes significantly to the knowledge of genomics for the prevention, treatment, and control of infections caused by this pathogen.IMPORTANCEDespite being the pathogen with the greatest number of gastroenteritis cases worldwide, remains a poorly studied microorganism. A sustained increase in fluoroquinolone resistance in human isolates is a problem when treating infections. The development of whole genome sequencing (WGS) techniques has allowed us to better understand the genotypic characteristics of this pathogen and relate them to antibiotic resistance phenotypes. These techniques complement the data obtained from the phenotypic analysis of isolates. The zoonotic transmission of through the consumption of contaminated poultry supports approaching the study of this pathogen through "One Health" approach. In addition, due to the limited information on the genomic characteristics of in Spain, this study provides important data and allows us to compare the results with those obtained in other countries.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Anti-Bacterial Agents, Campylobacter Infections, Campylobacter jejuni, Child, Child, Preschool, Ciprofloxacin, Drug Resistance, Bacterial, Erythromycin, Female, Genotype, Humans, Infant, Male, Microbial Sensitivity Tests, Middle Aged, Phylogeny, Spain, Tetracycline, Young Adult}, issn = {2165-0497}, doi = {10.1128/spectrum.01028-24}, author = {Fern{\'a}ndez-Palacios, Pablo and Gal{\'a}n-S{\'a}nchez, F{\'a}tima and Casimiro-Soriguer, Carlos S and Jurado-Tarifa, Estefan{\'\i}a and Arroyo, Federico and Lara, Mar{\'\i}a and Chaves, J Alberto and Dopazo, Joaquin and Rodriguez-Iglesias, Manuel A} } @article {807, title = {HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study.}, journal = {Cell Mol Life Sci}, volume = {81}, year = {2024}, month = {2024 May 17}, pages = {219}, abstract = {

HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.

}, keywords = {Animals, Antineoplastic Agents, Alkylating, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, HMGA1a Protein, Humans, Leiomyosarcoma, Mice, Prognosis, Sarcoma, Signal Transduction, TOR Serine-Threonine Kinases, Trabectedin, Xenograft Model Antitumor Assays}, issn = {1420-9071}, doi = {10.1007/s00018-024-05250-y}, author = {Moura, David S and Mondaza-Hernandez, Jose L and Sanchez-Bustos, Paloma and Pe{\~n}a-Chilet, Maria and Cordero-Varela, Juan A and Lopez-Alvarez, Maria and Carrillo-Garcia, Jaime and Martin-Ruiz, Marta and Romero-Gonzalez, Pablo and Renshaw-Calderon, Marta and Ramos, Rafael and Marcilla, David and Alvarez-Alegret, Ramiro and Agra-Pujol, Carolina and Izquierdo, Francisco and Ortega-Medina, Luis and Martin-Davila, Francisco and Hernandez-Leon, Carmen Nieves and Romagosa, Cleofe and Salgado, Maria Angeles Vaz and Lavernia, Javier and Bagu{\'e}, Silvia and Mayodormo-Aranda, Empar and Alvarez, Rosa and Valverde, Claudia and Martinez-Trufero, Javier and Castilla-Ramirez, Carolina and Gutierrez, Antonio and Dopazo, Joaquin and Hindi, Nadia and Garcia-Foncillas, Jesus and Martin-Broto, Javier} } @article {808, title = {The Iberian Roma Population Variant Server (IRPVS).}, journal = {J Genet Genomics}, year = {2024}, month = {2024 Mar 26}, issn = {1673-8527}, doi = {10.1016/j.jgg.2024.03.006}, author = {Mavillard, Fabiola and Perez-Florido, Javier and Ortuno, Francisco M and Valladares, Amador and {\'A}lvarez-Villegas, Miren L and Rold{\'a}n, Gema and Carmona, Rosario and Soriano, Manuel and Susarte, Santiago and Fuentes, Pilar and L{\'o}pez-L{\'o}pez, Daniel and Nu{\~n}ez-Negrillo, Ana Mar{\'\i}a and Carvajal, Alejandra and Morgado, Yolanda and Arteaga, Daniel and Ufano, Rosa and Mir, Pablo and Gamella, Juan F and Dopazo, Joaquin and Paradas, Carmen and Cabrera-Serrano, Macarena} } @article {813, title = {The integrated genomic surveillance system of Andalusia (SIEGA) provides a One Health regional resource connected with the clinic.}, journal = {Sci Rep}, volume = {14}, year = {2024}, month = {2024 Aug 19}, pages = {19200}, abstract = {

The One Health approach, recognizing the interconnectedness of human, animal, and environmental health, has gained significance amid emerging zoonotic diseases and antibiotic resistance concerns. This paper aims to demonstrate the utility of a collaborative tool, the SIEGA, for monitoring infectious diseases across domains, fostering a comprehensive understanding of disease dynamics and risk factors, highlighting the pivotal role of One Health surveillance systems. Raw whole-genome sequencing is processed through different species-specific open software that additionally reports the presence of genes associated to anti-microbial resistances and virulence. The SIEGA application is a Laboratory Information Management System, that allows customizing reports, detect transmission chains, and promptly alert on alarming genetic similarities. The SIEGA initiative has successfully accumulated a comprehensive collection of more than 1900 bacterial genomes, including Salmonella enterica, Listeria monocytogenes, Campylobacter jejuni, Escherichia coli, Yersinia enterocolitica and Legionella pneumophila, showcasing its potential in monitoring pathogen transmission, resistance patterns, and virulence factors. SIEGA enables customizable reports and prompt detection of transmission chains, highlighting its contribution to enhancing vigilance and response capabilities. Here we show the potential of genomics in One Health surveillance when supported by an appropriate bioinformatic tool. By facilitating precise disease control strategies and antimicrobial resistance management, SIEGA enhances global health security and reduces the burden of infectious diseases. The integration of health data from humans, animals, and the environment, coupled with advanced genomics, underscores the importance of a holistic One Health approach in mitigating health threats.

}, keywords = {Animals, Drug Resistance, Bacterial, Genome, Bacterial, Genomics, Humans, One Health, Virulence Factors, Whole Genome Sequencing}, issn = {2045-2322}, doi = {10.1038/s41598-024-70107-0}, author = {Casimiro-Soriguer, Carlos S and Perez-Florido, Javier and Robles, Enrique A and Lara, Mar{\'\i}a and Aguado, Andrea and Rodr{\'\i}guez Iglesias, Manuel A and Lepe, Jose A and Garc{\'\i}a, Federico and P{\'e}rez-Alegre, M{\'o}nica and And{\'u}jar, Elo{\'\i}sa and Jim{\'e}nez, Victoria E and Camino, Lola P and Loruso, Nicola and Ameyugo, Ulises and Vazquez, Isabel Mar{\'\i}a and Lozano, Carlota M and Chaves, J Alberto and Dopazo, Joaquin} } @article {804, title = {The mechanistic functional landscape of retinitis pigmentosa: a machine learning-driven approach to therapeutic target discovery.}, journal = {J Transl Med}, volume = {22}, year = {2024}, month = {2024 Feb 06}, pages = {139}, abstract = {

BACKGROUND: Retinitis pigmentosa is the prevailing genetic cause of blindness in developed nations with no effective treatments. In the pursuit of unraveling the intricate dynamics underlying this complex disease, mechanistic models emerge as a tool of proven efficiency rooted in systems biology, to elucidate the interplay between RP genes and their mechanisms. The integration of mechanistic models and drug-target interactions under the umbrella of machine learning methodologies provides a multifaceted approach that can boost the discovery of novel therapeutic targets, facilitating further drug repurposing in RP.

METHODS: By mapping Retinitis Pigmentosa-related genes (obtained from Orphanet, OMIM and HPO databases) onto KEGG signaling pathways, a collection of signaling functional circuits encompassing Retinitis Pigmentosa molecular mechanisms was defined. Next, a mechanistic model of the so-defined disease map, where the effects of interventions can be simulated, was built. Then, an explainable multi-output random forest regressor was trained using normal tissue transcriptomic data to learn causal connections between targets of approved drugs from DrugBank and the functional circuits of the mechanistic disease map. Selected target genes involvement were validated on rd10 mice, a murine model of Retinitis Pigmentosa.

RESULTS: A mechanistic functional map of Retinitis Pigmentosa was constructed resulting in 226 functional circuits belonging to 40 KEGG signaling pathways. The method predicted 109 targets of approved drugs in use with a potential effect over circuits corresponding to nine hallmarks identified. Five of those targets were selected and experimentally validated in rd10 mice: Gabre, Gabra1 (GABARĪ±1 protein), Slc12a5 (KCC2 protein), Grin1 (NR1 protein) and Glr2a. As a result, we provide a resource to evaluate the potential impact of drug target genes in Retinitis Pigmentosa.

CONCLUSIONS: The possibility of building actionable disease models in combination with machine learning algorithms to learn causal drug-disease interactions opens new avenues for boosting drug discovery. Such mechanistically-based hypotheses can guide and accelerate the experimental validations prioritizing drug target candidates. In this work, a mechanistic model describing the functional disease map of Retinitis Pigmentosa was developed, identifying five promising therapeutic candidates targeted by approved drug. Further experimental validation will demonstrate the efficiency of this approach for a systematic application to other rare diseases.

}, keywords = {Animals, Mice, Retinitis pigmentosa, Signal Transduction}, issn = {1479-5876}, doi = {10.1186/s12967-024-04911-7}, author = {Esteban-Medina, Marina and Loucera, Carlos and Rian, Kinza and Velasco, Sheyla and Olivares-Gonz{\'a}lez, Lorena and Rodrigo, Regina and Dopazo, Joaquin and Pe{\~n}a-Chilet, Maria} } @article {809, title = {Molecular and phylogenetic characterization of the monkeypox outbreak in the South of Spain.}, journal = {Health Sci Rep}, volume = {7}, year = {2024}, month = {2024 Mar}, pages = {e1965}, abstract = {

BACKGROUND AND AIM: Until the May 2022 Monkeypox (MPXV) outbreak, which spread rapidly to many non-endemic countries, the virus was considered a viral zoonosis limited to some African countries. The Andalusian circuit of genomic surveillance was rapidly applied to characterize the MPXV~outbreak in the South of Spain.

METHODS: Whole genome sequencing was used to obtain the genomic profiles of samples collected across the south of Spain, representative of all the provinces of Andalusia. Phylogenetic analysis was used to study the relationship of the isolates and the available sequences of the 2022 outbreak.

RESULTS: Whole genome sequencing of a total of 160 MPXV~viruses from the different provinces that reported cases were obtained. Interestingly, we report the sequences of MPXV~viruses obtained from two patients who died. While one of the isolates bore no noteworthy mutations that explain a potential heightened virulence, in another patient the second consecutive genome sequence, performed after the administration of tecovirimat, uncovered a mutation within the A0A7H0DN30 gene, known to be a prime target for tecovirimat in its Vaccinia counterpart. In general, a low number of mutations were observed in the sequences reported, which were very similar to the reference of the 2022 outbreak (OX044336), as expected from a DNA virus. The samples likely correspond to several introductions of the circulating MPXV~viruses from the last outbreak. The virus sequenced from one of the two patients that died presented a mutation in a gene that bears potential connections to drug resistance. This mutation was absent in the initial sequencing before treatment.

}, issn = {2398-8835}, doi = {10.1002/hsr2.1965}, author = {Casimiro-Soriguer, Carlos S and Perez-Florido, Javier and Lara, Mar{\'\i}a and Camacho-Martinez, Pedro and Merino-Diaz, Laura and Pupo-Ledo, Inmaculada and de Salazar, Adolfo and Fuentes, Ana and Vi{\~n}uela, Laura and Chueca, Natalia and Martinez-Martinez, Luis and Lorusso, Nicola and Lepe, Jose A and Dopazo, Joaquin and Garc{\'\i}a, Federico} } @article {815, title = {Mutational landscape of risk variants in comorbid depression and obesity: a next-generation sequencing approach.}, journal = {Mol Psychiatry}, year = {2024}, month = {2024 May 28}, abstract = {

Major depression (MD) and obesity are complex genetic disorders that are frequently comorbid. However, the study of both diseases concurrently remains poorly addressed and therefore the underlying genetic mechanisms involved in this comorbidity remain largely unknown. Here we examine the contribution of common and rare variants to this comorbidity through a next-generation sequencing (NGS) approach. Specific genomic regions of interest in MD and obesity were sequenced in a group of 654 individuals from the PISMA-ep epidemiological study. We obtained variants across the entire frequency spectrum and assessed their association with comorbid MD and obesity, both at variant and gene levels. We identified 55 independent common variants and a burden of rare variants in 4 genes (PARK2, FGF21, HIST1H3D and RSRC1) associated with the comorbid phenotype. Follow-up analyses revealed significantly enriched gene-sets associated with biological processes and pathways involved in metabolic dysregulation, hormone signaling and cell cycle regulation. Our results suggest that, while risk variants specific to the comorbid phenotype have been identified, the genes functionally impacted by the risk variants share cell biological processes and signaling pathways with MD and obesity phenotypes separately. To the best of our knowledge, this is the first study involving a targeted sequencing approach toward the study of the comorbid MD and obesity. The framework presented here allowed a deep characterization of the genetics of the co-occurring MD and obesity, revealing insights into the mutational and functional profile that underlies this comorbidity and contributing to a better understanding of the relationship between these two disabling disorders.

}, issn = {1476-5578}, doi = {10.1038/s41380-024-02609-2}, author = {P{\'e}rez-Guti{\'e}rrez, Ana M and Carmona, Rosario and Loucera, Carlos and Cervilla, Jorge A and Guti{\'e}rrez, Blanca and Molina, Esther and L{\'o}pez-L{\'o}pez, Daniel and Perez-Florido, Javier and Zarza-Rebollo, Juan Antonio and L{\'o}pez-Isac, Elena and Dopazo, Joaquin and Martinez-Gonzalez, Luis Javier and Rivera, Margarita} } @article {812, title = {Shared germline genomic variants in two patients with double primary gastrointestinal stromal tumours (GISTs).}, journal = {J Med Genet}, volume = {61}, year = {2024}, month = {2024 Sep 24}, pages = {927-934}, abstract = {

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are prevalent mesenchymal tumours of the gastrointestinal tract, commonly exhibiting structural variations in and genes. While the mutational profiling of somatic tumours is well described, the genes behind the susceptibility to develop GIST are not yet fully discovered. This study explores the genomic landscape of two primary GIST cases, aiming to identify shared germline pathogenic variants and shed light on potential key players in tumourigenesis.

METHODS: Two patients with distinct genotypically and phenotypically GISTs underwent germline whole genome sequencing. CNV and single nucleotide variant (SNV) analyses were performed.

RESULTS: Both patients harbouring low-risk GISTs with different mutations ( and ) shared homozygous germline pathogenic deletions in both and genes. CNV analysis revealed additional shared pathogenic deletions in other genes such as . No particular pathogenic SNV shared by both patients was detected.

CONCLUSION: Our study provides new insights into germline variants that can be associated with the development of GISTs, namely, and deep deletions. Further functional validation is warranted to elucidate the precise contributions of identified germline mutations in GIST development.

}, keywords = {DNA Copy Number Variations, Female, Gastrointestinal Neoplasms, Gastrointestinal Stromal Tumors, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-kit, Receptor, Platelet-Derived Growth Factor alpha, Whole Genome Sequencing}, issn = {1468-6244}, doi = {10.1136/jmg-2024-110109}, author = {Moura, David S and L{\'o}pez L{\'o}pez, Daniel and di Lernia, Davide and Martin-Ruiz, Marta and Lopez-Alvarez, Maria and Ramos, Rafael and Merino, Jose and Dopazo, Joaquin and Lopez-Guerrero, Jose and Mondaza-Hernandez, Jose L and Romero, Pablo and Hindi, Nadia and Garcia-Foncillas, Jesus and Martin-Broto, Javier} } @book {798, title = {Cell-Level Pathway Scoring Comparison with~a~Biologically Constrained Variational Autoencoder}, series = {Lecture Notes in Computer Science. Computational Methods in Systems Biology}, volume = {14137}, year = {2023}, pages = {62 - 77}, publisher = {Springer Nature Switzerland}, organization = {Springer Nature Switzerland}, address = {Cham}, isbn = {978-3-031-42696-4}, issn = {0302-9743}, doi = {10.1007/978-3-031-42697-110.1007/978-3-031-42697-1_5}, url = {https://link.springer.com/chapter/10.1007/978-3-031-42697-1_5}, author = {Gundogdu, Pelin and Pay{\'a}-Milans, Miriam and Alamo-Alvarez, Inmaculada and Nepomuceno-Chamorro, Isabel A. and Dopazo, Joaquin and Loucera, Carlos} } @article {770, title = {A Comprehensive Analysis of 21 Actionable Pharmacogenes in the Spanish Population: From Genetic Characterisation to Clinical Impact.}, journal = {Pharmaceutics}, volume = {15}, year = {2023}, month = {2023 Apr 19}, abstract = {

The implementation of pharmacogenetics (PGx) is a main milestones of precision medicine nowadays in order to achieve safer and more effective therapies. Nevertheless, the implementation of PGx diagnostics is extremely slow and unequal worldwide, in part due to a lack of ethnic PGx information. We analysed genetic data from 3006 Spanish individuals obtained by different high-throughput (HT) techniques. Allele frequencies were determined in our population for the main 21 actionable PGx genes associated with therapeutical changes. We found that 98\% of the Spanish population harbours at least one allele associated with a therapeutical change and, thus, there would be a need for a therapeutical change in a mean of 3.31 of the 64 associated drugs. We also identified 326 putative deleterious variants that were not previously related with PGx in 18 out of the 21 main PGx genes evaluated and a total of 7122 putative deleterious variants for the 1045 PGx genes described. Additionally, we performed a comparison of the main HT diagnostic techniques, revealing that after whole genome sequencing, genotyping with the PGx HT array is the most suitable solution for PGx diagnostics. Finally, all this information was integrated in the Collaborative Spanish Variant Server to be available to and updated by the scientific community.

}, issn = {1999-4923}, doi = {10.3390/pharmaceutics15041286}, author = {N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Pita, Guillermo and Pe{\~n}a-Chilet, Maria and L{\'o}pez-L{\'o}pez, Daniel and Zamora, Jorge and Rold{\'a}n, Gema and Herr{\'a}ez, Bel{\'e}n and Alvarez, Nuria and Alonso, Mar{\'\i}a Rosario and Dopazo, Joaquin and Gonz{\'a}lez-Neira, Anna} } @article {771, title = {Crosstalk between Metabolite Production and Signaling Activity in Breast Cancer.}, journal = {Int J Mol Sci}, volume = {24}, year = {2023}, month = {2023 Apr 18}, abstract = {

The reprogramming of metabolism is a recognized cancer hallmark. It is well known that different signaling pathways regulate and orchestrate this reprogramming that contributes to cancer initiation and development. However, recent evidence is accumulating, suggesting that several metabolites could play a relevant role in regulating signaling pathways. To assess the potential role of metabolites in the regulation of signaling pathways, both metabolic and signaling pathway activities of Breast invasive Carcinoma (BRCA) have been modeled using mechanistic models. Gaussian Processes, powerful machine learning methods, were used in combination with SHapley Additive exPlanations (SHAP), a recent methodology that conveys causality, to obtain potential causal relationships between the production of metabolites and the regulation of signaling pathways. A total of 317 metabolites were found to have a strong impact on signaling circuits. The results presented here point to the existence of a complex crosstalk between signaling and metabolic pathways more complex than previously was thought.

}, issn = {1422-0067}, doi = {10.3390/ijms24087450}, author = {Cubuk, Cankut and Loucera, Carlos and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {769, title = {A crowdsourcing database for the copy-number variation of the Spanish population.}, journal = {Hum Genomics}, volume = {17}, year = {2023}, month = {2023 Mar 09}, pages = {20}, abstract = {

BACKGROUND: Despite being a very common type of genetic variation, the distribution of copy-number variations (CNVs) in the population is still poorly understood. The knowledge of the genetic variability, especially at the level of the local population, is a critical factor for distinguishing pathogenic from non-pathogenic variation in the discovery of new disease variants.

RESULTS: Here, we present the SPAnish Copy Number Alterations Collaborative Server (SPACNACS), which currently contains copy number variation profiles obtained from more than 400 genomes and exomes of unrelated Spanish individuals. By means of a collaborative crowdsourcing effort whole genome and whole exome sequencing data, produced by local genomic projects and for other purposes, is continuously collected. Once checked both, the Spanish ancestry and the lack of kinship with other individuals in the SPACNACS, the CNVs are inferred for these sequences and they are used to populate the database. A web interface allows querying the database with different filters that include ICD10 upper categories. This allows discarding samples from the disease under study and obtaining pseudo-control CNV profiles from the local population. We also show here additional studies on the local impact of CNVs in some phenotypes and on pharmacogenomic variants. SPACNACS can be accessed at: http://csvs.clinbioinfosspa.es/spacnacs/ .

CONCLUSION: SPACNACS facilitates disease gene discovery by providing detailed information of the local variability of the population and exemplifies how to reuse genomic data produced for other purposes to build a local reference database.

}, issn = {1479-7364}, doi = {10.1186/s40246-023-00466-8}, author = {L{\'o}pez-L{\'o}pez, Daniel and Rold{\'a}n, Gema and Fernandez-Rueda, Jose L and Bostelmann, Gerrit and Carmona, Rosario and Aquino, Virginia and Perez-Florido, Javier and Ortuno, Francisco and Pita, Guillermo and N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Gonz{\'a}lez-Neira, Anna and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {796, title = {Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis.}, journal = {Cell Rep}, volume = {42}, year = {2023}, month = {2023 Jun 13}, pages = {112640}, abstract = {

The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2023.112640}, author = {Pellegrinelli, Vanessa and Figueroa-Ju{\'a}rez, Elizabeth and Samuelson, Isabella and U-Din, Mueez and Rodriguez-Fdez, Sonia and Virtue, Samuel and Leggat, Jennifer and Cubuk, Cankut and Peirce, Vivian J and Niemi, Tarja and Campbell, Mark and Rodriguez-Cuenca, Sergio and Dopazo, Joaquin and Carobbio, Stefania and Virtanen, Kirsi A and Vidal-Puig, Antonio} } @article {766, title = {Detection of High Level of Co-Infection and the Emergence of Novel SARS CoV-2 Delta-Omicron and Omicron-Omicron Recombinants in the Epidemiological Surveillance of Andalusia.}, journal = {Int J Mol Sci}, volume = {24}, year = {2023}, month = {2023 Jan 26}, abstract = {

Recombination is an evolutionary strategy to quickly acquire new viral properties inherited from the parental lineages. The systematic survey of the SARS-CoV-2 genome sequences of the Andalusian genomic surveillance strategy has allowed the detection of an unexpectedly high number of co-infections, which constitute the ideal scenario for the emergence of new recombinants. Whole genome sequence of SARS-CoV-2 has been carried out as part of the genomic surveillance programme. Sample sources included the main hospitals in the Andalusia region. In addition to the increase of co-infections and known recombinants, three novel SARS-CoV-2 delta-omicron and omicron-omicron recombinant variants with two break points have been detected. Our observations document an epidemiological scenario in which co-infection and recombination are detected more frequently. Finally, we describe a family case in which co-infection is followed by the detection of a recombinant made from the two co-infecting variants. This increased number of recombinants raises the risk of emergence of recombinant variants with increased transmissibility and pathogenicity.

}, issn = {1422-0067}, doi = {10.3390/ijms24032419}, author = {Perez-Florido, Javier and Casimiro-Soriguer, Carlos S and Ortuno, Francisco and Fernandez-Rueda, Jose L and Aguado, Andrea and Lara, Mar{\'\i}a and Riazzo, Cristina and Rodriguez-Iglesias, Manuel A and Camacho-Martinez, Pedro and Merino-Diaz, Laura and Pupo-Ledo, Inmaculada and de Salazar, Adolfo and Vi{\~n}uela, Laura and Fuentes, Ana and Chueca, Natalia and Garc{\'\i}a, Federico and Dopazo, Joaquin and Lepe, Jose A} } @article {768, title = {Editorial: Critical assessment of massive data analysis (CAMDA) annual conference 2021.}, journal = {Front Genet}, volume = {14}, year = {2023}, month = {2023}, pages = {1154398}, issn = {1664-8021}, doi = {10.3389/fgene.2023.1154398}, author = {{\L}abaj, Pawe{\l} P and Dopazo, Joaquin and Xiao, Wenzhong and Kreil, David P} } @article {801, title = {Evaluation of a combined detection of SARS-CoV-2 and its variants using real-time allele-specific PCR strategy: an advantage for clinical practice.}, journal = {Epidemiol Infect}, volume = {151}, year = {2023}, month = {2023 Nov 24}, pages = {e201}, abstract = {

This study aimed to assess the ability of a real-time reverse transcription polymerase chain reaction (RT-PCR) with multiple targets to detect SARS-CoV-2 and its variants in a single test. Nasopharyngeal specimens were collected from patients in Granada, Spain, between January 2021 and December 2022. Five allele-specific RT-PCR kits were used sequentially, with each kit designed to detect a predominant variant at the time. When the Alpha variant was dominant, the kit included the HV69/70 deletion, E and N genes. When Delta replaced Alpha, the kit incorporated the L452R mutation in addition to E and N genes. When Omicron became dominant, L452R was replaced with the N679K mutation. Before incorporating each variant kit, a comparative analysis was carried out with SARS-CoV-2 whole genome sequencing (WGS). The results demonstrated that RT-PCR with multiple targets can provide rapid and effective detection of SARS-CoV-2 and its variants in a single test. A very high degree of agreement (96.2\%) was obtained between the comparison of RT-PCR and WGS. Allele-specific RT-PCR assays make it easier to implement epidemiological surveillance systems for effective public health decision making.

}, keywords = {Alleles, COVID-19, COVID-19 Testing, Humans, Real-Time Polymerase Chain Reaction, SARS-CoV-2, Sensitivity and Specificity}, issn = {1469-4409}, doi = {10.1017/S095026882300184X}, author = {Chaves-Blanco, Luc{\'\i}a and de Salazar, Adolfo and Fuentes, Ana and Vi{\~n}uela, Laura and Perez-Florido, Javier and Dopazo, Joaquin and Garc{\'\i}a, Federico} } @article {800, title = {Evidence of the association between increased use of direct oral anticoagulants and a reduction in the rate of atrial fibrillation-related stroke and major bleeding at the population level (2012-2019).}, journal = {Med Clin (Barc)}, year = {2023}, month = {2023 Nov 20}, abstract = {

BACKGROUND: The introduction of direct-acting oral anticoagulants (DOACs) has shown to decrease atrial fibrillation (AF)-related stroke and bleeding rates in clinical studies, but there is no certain evidence about their effects at the population level. Our aim was to assess changes in AF-related stroke and major bleeding rates between 2012 and 2019 in Andalusia (Spain), and the association between DOACs use and events rates at the population level.

METHODS: All patients with an AF diagnosis from 2012 to 2019 were identified using the Andalusian Health Population Base, that provides clinical information on all Andalusian people. Annual ischemic and hemorrhagic stroke, major bleeding rates, and used antithrombotic treatments were determined. Marginal hazard ratios (HR) were calculated for each treatment.

RESULTS: A total of 95,085 patients with an AF diagnosis were identified. Mean age was 76.1{\textpm}10.2 years (49.7\% women). An increase in the use of DOACs was observed throughout the study period in both males and females (p<0.001). The annual rate of ischemic stroke decreased by one third, while that of hemorrhagic stroke and major bleeding decreased 2-3-fold from 2012 to 2019. Marginal HR was lower than 0.50 for DOACs compared to VKA for all ischemic or hemorrhagic events.

CONCLUSIONS: In this contemporary population-based study using clinical and administrative databases in Andalusia, a significant reduction in the incidence of AF-related ischemic and hemorrhagic stroke and major bleeding was observed between 2012 and 2019. The increased use of DOACs seems to be associated with this reduction.

}, issn = {1578-8989}, doi = {10.1016/j.medcli.2023.10.008}, author = {Loucera, Carlos and Carmona, Rosario and Bostelmann, Gerrit and Mu{\~n}oyerro-Mu{\~n}iz, Dolores and Villegas, Rom{\'a}n and Gonzalez-Manzanares, Rafael and Dopazo, Joaquin and Anguita, Manuel} } @article {767, title = {Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging.}, journal = {Commun Biol}, volume = {6}, year = {2023}, month = {2023 Mar 08}, pages = {250}, abstract = {

ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.

}, issn = {2399-3642}, doi = {10.1038/s42003-023-04625-4}, author = {Sola-Garc{\'\i}a, Alejandro and C{\'a}liz-Molina, Mar{\'\i}a {\'A}ngeles and Espadas, Isabel and Petr, Michael and Panadero-Mor{\'o}n, Concepci{\'o}n and Gonz{\'a}lez-Mor{\'a}n, Daniel and Mart{\'\i}n-V{\'a}zquez, Mar{\'\i}a Eugenia and Narbona-P{\'e}rez, {\'A}lvaro Jes{\'u}s and L{\'o}pez-Noriega, Livia and Mart{\'\i}nez-Corrales, Guillermo and L{\'o}pez-Fern{\'a}ndez-Sobrino, Ra{\'u}l and Carmona-Marin, Lina M and Mart{\'\i}nez-Force, Enrique and Yanes, Oscar and Vinaixa, Maria and L{\'o}pez-L{\'o}pez, Daniel and Reyes, Jos{\'e} Carlos and Dopazo, Joaquin and Mart{\'\i}n, Franz and Gauthier, Benoit R and Scheibye-Knudsen, Morten and Capilla-Gonz{\'a}lez, Vivian and Mart{\'\i}n-Montalvo, Alejandro} } @article {775, title = {microRNAs-mediated regulation of insulin signaling in white adipose tissue during aging: Role of caloric restriction.}, journal = {Aging Cell}, year = {2023}, month = {2023 Jul 04}, pages = {e13919}, abstract = {

Caloric restriction is a non-pharmacological intervention known to ameliorate the metabolic defects associated with aging, including insulin resistance. The levels of miRNA expression may represent a predictive tool for aging-related alterations. In order to investigate the role of miRNAs underlying insulin resistance in adipose tissue during the early stages of aging, 3- and 12-month-old male animals fed ad libitum, and 12-month-old male animals fed with a 20\% caloric restricted diet were used. In this work we demonstrate that specific miRNAs may contribute to the impaired insulin-stimulated glucose metabolism specifically in the subcutaneous white adipose tissue, through the regulation of target genes implicated in the insulin signaling cascade. Moreover, the expression of these miRNAs is modified by caloric restriction in middle-aged animals, in accordance with the improvement of the metabolic state. Overall, our work demonstrates that alterations in posttranscriptional gene expression because of miRNAs dysregulation might represent an endogenous mechanism by which insulin response in the subcutaneous fat depot is already affected at middle age. Importantly, caloric restriction could prevent this modulation, demonstrating that certain miRNAs could constitute potential biomarkers of age-related metabolic alterations.

}, issn = {1474-9726}, doi = {10.1111/acel.13919}, author = {Corrales, Patricia and Martin-Taboada, Marina and Vivas-Garc{\'\i}a, Yurena and Torres, Lucia and Ramirez-Jimenez, Laura and Lopez, Yamila and Horrillo, Daniel and Vila-Bedmar, Rocio and Barber-Cano, Eloisa and Izquierdo-Lahuerta, Adriana and Pe{\~n}a-Chilet, Maria and Mart{\'\i}nez, Carmen and Dopazo, Joaquin and Ros, Manuel and Medina-Gomez, Gema} } @article {764, title = {Polystyrene nanoplastics affect transcriptomic and epigenomic signatures of human fibroblasts and derived induced pluripotent stem cells: Implications for human health.}, journal = {Environ Pollut}, year = {2023}, month = {2022 Dec 09}, pages = {120849}, abstract = {

Plastic pollution is increasing at an alarming rate yet the impact of this pollution on human health is poorly understood. Because human induced pluripotent stem cells (hiPSC) are frequently derived from dermal fibroblasts, these cells offer a powerful platform for the identification of molecular biomarkers of environmental pollution in human cells. Here, we describe a novel proof-of-concept for deriving hiPSC from human dermal fibroblasts deliberately exposed to polystyrene (PS) nanoplastic particles; unexposed hiPSC served as controls. In parallel, unexposed hiPSC were exposed to low and high concentrations of PS nanoparticles. Transcriptomic and epigenomic signatures of all fibroblasts and hiPSCs were defined using RNA-seq and whole genome methyl-seq, respectively. Both PS-treated fibroblasts and derived hiPSC showed alterations in expression of ESRRB and HNF1A genes and circuits involved in the pluripotency of stem cells, as well as in pathways involved in cancer, inflammatory disorders, gluconeogenesis, carbohydrate metabolism, innate immunity, and dopaminergic synapse. Similarly, the expression levels of identified key transcriptional and DNA methylation changes (DNMT3A, ESSRB, FAM133CP, HNF1A, SEPTIN7P8, and TTC34) were significantly affected in both PS-exposed fibroblasts and hiPSC. This study illustrates the power of human cellular models of environmental pollution to narrow down and prioritize the list of candidate molecular biomarkers of environmental pollution. This knowledge will facilitate the deciphering of the origins of environmental diseases.

}, issn = {1873-6424}, doi = {10.1016/j.envpol.2022.120849}, author = {Stojkovic, Miodrag and Ortu{\~n}o Guzm{\'a}n, Francisco Manuel and Han, Dongjun and Stojkovic, Petra and Dopazo, Joaquin and Stankovic, Konstantina M} } @article {774, title = {Rapid degeneration of iPSC-derived motor neurons lacking Gdap1 engages a mitochondrial-sustained innate immune response.}, journal = {Cell Death Discov}, volume = {9}, year = {2023}, month = {2023 Jul 01}, pages = {217}, abstract = {

Charcot-Marie-Tooth disease is a chronic hereditary motor and sensory polyneuropathy targeting Schwann cells and/or motor neurons. Its multifactorial and polygenic origin portrays a complex clinical phenotype of the disease with a wide range of genetic inheritance patterns. The disease-associated gene GDAP1 encodes for a mitochondrial outer membrane protein. Mouse and insect models with mutations in Gdap1 have reproduced several traits of the human disease. However, the precise function in the cell types affected by the disease remains unknown. Here, we use induced-pluripotent stem cells derived from a Gdap1 knockout mouse model to better understand the molecular and cellular phenotypes of the disease caused by the loss-of-function of this gene. Gdap1-null motor neurons display a fragile cell phenotype prone to early degeneration showing (1) altered mitochondrial morphology, with an increase in the fragmentation of these organelles, (2) activation of autophagy and mitophagy, (3) abnormal metabolism, characterized by a downregulation of Hexokinase 2 and ATP5b proteins, (4) increased reactive oxygen species and elevated mitochondrial membrane potential, and (5) increased innate immune response and p38 MAP kinase activation. Our data reveals the existence of an underlying Redox-inflammatory axis fueled by altered mitochondrial metabolism in the absence of Gdap1. As this biochemical axis encompasses a wide variety of druggable targets, our results may have implications for developing therapies using combinatorial pharmacological approaches and improving therefore human welfare. A Redox-immune axis underlying motor neuron degeneration caused by the absence of Gdap1. Our results show that Gdap1 motor neurons have a fragile cellular phenotype that is prone to degeneration. Gdap1 iPSCs differentiated into motor neurons showed an altered metabolic state: decreased glycolysis and increased OXPHOS. These alterations may lead to hyperpolarization of mitochondria and increased ROS levels. Excessive amounts of ROS might be the cause of increased mitophagy, p38 activation and inflammation as a cellular response to oxidative stress. The p38 MAPK pathway and the immune response may, in turn, have feedback mechanisms, leading to the induction of apoptosis and senescence, respectively. CAC, citric acid cycle; ETC, electronic transport chain; Glc, glucose; Lac, lactate; Pyr, pyruvate.

}, issn = {2058-7716}, doi = {10.1038/s41420-023-01531-w}, author = {Le{\'o}n, Marian and Prieto, Javier and Molina-Navarro, Mar{\'\i}a Micaela and Garcia-Garcia, Francisco and Barneo-Mu{\~n}oz, Manuela and Ponsoda, Xavier and S{\'a}ez, Rosana and Palau, Francesc and Dopazo, Joaquin and Izpisua Belmonte, Juan Carlos and Torres, Josema} } @article {799, title = {Real-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments.}, journal = {Virol J}, volume = {20}, year = {2023}, month = {2023 Oct 06}, pages = {226}, abstract = {

PURPOSE: Despite the extensive vaccination campaigns in many countries, COVID-19 is still a major worldwide health problem because of its associated morbidity and mortality. Therefore, finding efficient treatments as fast as possible is a pressing need. Drug repurposing constitutes a convenient alternative when the need for new drugs in an unexpected medical scenario is urgent, as is the case with COVID-19.

METHODS: Using data from a central registry of electronic health records (the Andalusian Population Health Database), the effect of prior consumption of drugs for other indications previous to the hospitalization with respect to patient outcomes, including survival and lymphocyte progression, was studied on a retrospective cohort of 15,968 individuals, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020.

RESULTS: Covariate-adjusted hazard ratios and analysis of lymphocyte progression curves support a significant association between consumption of 21 different drugs and better patient survival. Contrarily, one drug, furosemide, displayed a significant increase in patient mortality.

CONCLUSIONS: In this study we have taken advantage of the availability of a regional clinical database to study the effect of drugs, which patients were taking for other indications, on their survival. The large size of the database allowed us to control covariates effectively.

}, issn = {1743-422X}, doi = {10.1186/s12985-023-02195-9}, author = {Loucera, Carlos and Carmona, Rosario and Esteban-Medina, Marina and Bostelmann, Gerrit and Mu{\~n}oyerro-Mu{\~n}iz, Dolores and Villegas, Rom{\'a}n and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {772, title = {SigPrimedNet: A Signaling-Informed Neural Network for scRNA-seq Annotation of Known and Unknown Cell Types.}, journal = {Biology (Basel)}, volume = {12}, year = {2023}, month = {2023 Apr 10}, abstract = {

Single-cell RNA sequencing is increasing our understanding of the behavior of complex tissues or organs, by providing unprecedented details on the complex cell type landscape at the level of individual cells. Cell type definition and functional annotation are key steps to understanding the molecular processes behind the underlying cellular communication machinery. However, the exponential growth of scRNA-seq data has made the task of manually annotating cells unfeasible, due not only to an unparalleled resolution of the technology but to an ever-increasing heterogeneity of the data. Many supervised and unsupervised methods have been proposed to automatically annotate cells. Supervised approaches for cell-type annotation outperform unsupervised methods except when new (unknown) cell types are present. Here, we introduce SigPrimedNet an artificial neural network approach that leverages (i) efficient training by means of a sparsity-inducing signaling circuits-informed layer, (ii) feature representation learning through supervised training, and (iii) unknown cell-type identification by fitting an anomaly detection method on the learned representation. We show that SigPrimedNet can efficiently annotate known cell types while keeping a low false-positive rate for unseen cells across a set of publicly available datasets. In addition, the learned representation acts as a proxy for signaling circuit activity measurements, which provide useful estimations of the cell functionalities.

}, issn = {2079-7737}, doi = {10.3390/biology12040579}, author = {Gundogdu, Pelin and Alamo, Inmaculada and Nepomuceno-Chamorro, Isabel A and Dopazo, Joaquin and Loucera, Carlos} } @article {795, title = {Visualization of automatically combined disease maps and pathway diagrams for rare diseases.}, journal = {Front Bioinform}, volume = {3}, year = {2023}, month = {2023}, pages = {1101505}, abstract = {

Investigation of molecular mechanisms of human disorders, especially rare diseases, require exploration of various knowledge repositories for building precise hypotheses and complex data interpretation. Recently, increasingly more resources offer diagrammatic representation of such mechanisms, including disease-dedicated schematics in pathway databases and disease maps. However, collection of knowledge across them is challenging, especially for research projects with limited manpower. In this article we present an automated workflow for construction of maps of molecular mechanisms for rare diseases. The workflow requires a standardized definition of a disease using Orphanet or HPO identifiers to collect relevant genes and variants, and to assemble a functional, visual repository of related mechanisms, including data overlays. The diagrams composing the final map are unified to a common systems biology format from CellDesigner SBML, GPML and SBML+layout+render. The constructed resource contains disease-relevant genes and variants as data overlays for immediate visual exploration, including embedded genetic variant browser and protein structure viewer. We demonstrate the functionality of our workflow on two examples of rare diseases: Kawasaki disease and retinitis pigmentosa. Two maps are constructed based on their corresponding identifiers. Moreover, for the retinitis pigmentosa use-case, we include a list of differentially expressed genes to demonstrate how to tailor the workflow using omics datasets. In summary, our work allows for an ad-hoc construction of molecular diagrams combined from different sources, preserving their layout and graphical style, but integrating them into a single resource. This allows to reduce time consuming tasks of prototyping of a molecular disease map, enabling visual exploration, hypothesis building, data visualization and further refinement. The code of the workflow is open and accessible at https://gitlab.lcsb.uni.lu/minerva/automap/.

}, issn = {2673-7647}, doi = {10.3389/fbinf.2023.1101505}, author = {Gawron, Piotr and Hoksza, David and Pi{\~n}ero, Janet and Pe{\~n}a-Chilet, Maria and Esteban-Medina, Marina and Fernandez-Rueda, Jose Luis and Colonna, Vincenza and Smula, Ewa and Heirendt, Laurent and Ancien, Fran{\c c}ois and Grou{\`e}s, Valentin and Satagopam, Venkata P and Schneider, Reinhard and Dopazo, Joaquin and Furlong, Laura I and Ostaszewski, Marek} } @article {762, title = {Assessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival.}, journal = {Viruses}, volume = {14}, year = {2022}, month = {2022 Aug 27}, abstract = {

OBJECTIVES: More than two years into the COVID-19 pandemic, SARS-CoV-2 still remains a global public health problem. Successive waves of infection have produced new SARS-CoV-2 variants with new mutations for which the impact on COVID-19 severity and patient survival is uncertain.

METHODS: A total of 764 SARS-CoV-2 genomes, sequenced from COVID-19 patients, hospitalized from 19th February 2020 to 30 April 2021, along with their clinical data, were used for survival analysis.

RESULTS: A significant association of B.1.1.7, the alpha lineage, with patient mortality (log hazard ratio (LHR) = 0.51, C.I. = [0.14,0.88]) was found upon adjustment by all the covariates known to affect COVID-19 prognosis. Moreover, survival analysis of mutations in the SARS-CoV-2 genome revealed 27 of them were significantly associated with higher mortality of patients. Most of these mutations were located in the genes coding for the S, ORF8, and N proteins.

CONCLUSIONS: This study illustrates how a combination of genomic and clinical data can provide solid evidence for the impact of viral lineage on patient survival.

}, keywords = {COVID-19, Genome, Viral, Humans, mutation, Pandemics, Phylogeny, SARS-CoV-2}, issn = {1999-4915}, doi = {10.3390/v14091893}, author = {Loucera, Carlos and Perez-Florido, Javier and Casimiro-Soriguer, Carlos S and Ortuno, Francisco M and Carmona, Rosario and Bostelmann, Gerrit and Mart{\'\i}nez-Gonz{\'a}lez, L Javier and Mu{\~n}oyerro-Mu{\~n}iz, Dolores and Villegas, Rom{\'a}n and Rodr{\'\i}guez-Ba{\~n}o, Jes{\'u}s and Romero-G{\'o}mez, Manuel and Lorusso, Nicola and Garcia-Le{\'o}n, Javier and Navarro-Mar{\'\i}, Jose M and Camacho-Martinez, Pedro and Merino-Diaz, Laura and Salazar, Adolfo de and Vi{\~n}uela, Laura and Lepe, Jose A and Garc{\'\i}a, Federico and Dopazo, Joaquin} } @article {751, title = {Discovering potential interactions between rare diseases and COVID-19 by combining mechanistic models of viral infection with statistical modeling.}, journal = {Hum Mol Genet}, year = {2022}, month = {2022 Jan 12}, abstract = {

Recent studies have demonstrated a relevant role of the host genetics in the COVID-19 prognosis. Most of the 7000 rare diseases described to date have a genetic component, typically highly penetrant. However, this vast spectrum of genetic variability remains yet unexplored with respect to possible interactions with COVID-19. Here, a mathematical mechanistic model of the COVID-19 molecular disease mechanism has been used to detect potential interactions between rare disease genes and the COVID-19 infection process and downstream consequences. Out of the 2518 disease genes analyzed, causative of 3854 rare diseases, a total of 254 genes have a direct effect on the COVID-19 molecular disease mechanism and 207 have an indirect effect revealed by a significant strong correlation. This remarkable potential of interaction occurs for more than 300 rare diseases. Mechanistic modeling of COVID-19 disease map has allowed a holistic systematic analysis of the potential interactions between the loss of function in known rare disease genes and the pathological consequences of COVID-19 infection. The results identify links between disease genes and COVID-19 hallmarks and demonstrate the usefulness of the proposed approach for future preventive measures in some rare diseases.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddac007}, author = {L{\'o}pez-S{\'a}nchez, Macarena and Loucera, Carlos and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {763, title = {Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions.}, journal = {Int J Mol Sci}, volume = {23}, year = {2022}, month = {2022 Aug 04}, abstract = {

Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.

}, keywords = {Bone Neoplasms, Endoglin, Humans, Matrix Metalloproteinase 14, Proteomics, Receptors, Growth Factor, Sarcoma, Ewing, Signal Transduction}, issn = {1422-0067}, doi = {10.3390/ijms23158657}, author = {Puerto-Camacho, Pilar and Diaz-Martin, Juan and Olmedo-Pelayo, Joaqu{\'\i}n and Bolado-Carrancio, Alfonso and Salguero-Aranda, Carmen and Jord{\'a}n-P{\'e}rez, Carmen and Esteban-Medina, Marina and Alamo-Alvarez, Inmaculada and Delgado-Bellido, Daniel and Lobo-Selma, Laura and Dopazo, Joaquin and Sastre, Ana and Alonso, Javier and Gr{\"u}newald, Thomas G P and Bernabeu, Carmelo and Byron, Adam and Brunton, Valerie G and Amaral, Ana Teresa and de Alava, Enrique} } @article {754, title = {Incidence and Prevalence of Children{\textquoteright}s Diffuse Lung Disease in Spain.}, journal = {Arch Bronconeumol}, volume = {58}, year = {2022}, month = {2022 Jan}, pages = {22-29}, abstract = {

BACKGROUND: Children{\textquoteright}s diffuse lung disease, also known as children{\textquoteright}s Interstitial Lung Diseases (chILD), are a heterogeneous group of rare diseases with relevant morbidity and mortality, which diagnosis and classification are very complex. Epidemiological data are scarce. The aim of this study was to analyse incidence and prevalence of chILD in Spain.

METHODS: Multicentre observational prospective study in patients from 0 to 18 years of age with chILD to analyse its incidence and prevalence in Spain, based on data reported in 2018 and 2019.

RESULTS: A total of 381 cases with chILD were notified from 51 paediatric pulmonology units all over Spain, covering the 91.7\% of the paediatric population. The average incidence of chILD was 8.18 (CI 95\% 6.28-10.48) new cases/million of children per year. The average prevalence of chILD was 46.53 (CI 95\% 41.81-51.62) cases/million of children. The age group with the highest prevalence were children under 1 year of age. Different types of disorders were seen in children 2-18 years of age compared with children 0-2 years of age. Most frequent cases were: primary pulmonary interstitial glycogenosis in neonates (17/65), neuroendocrine cell hyperplasia of infancy in infants from 1 to 12 months (44/144), idiopathic pulmonary haemosiderosis in children from 1 to 5 years old (13/74), hypersensitivity pneumonitis in children from 5 to 10 years old (9/51), and scleroderma in older than 10 years old (8/47).

CONCLUSIONS: We found a higher incidence and prevalence of chILD than previously described probably due to greater understanding and increased clinician awareness of these rare diseases.

}, issn = {1579-2129}, doi = {10.1016/j.arbres.2021.06.001}, author = {Torrent-Vernetta, Alba and Gaboli, Mirella and Castillo-Corull{\'o}n, Silvia and Mond{\'e}jar-L{\'o}pez, Pedro and Sanz Santiago, Ver{\'o}nica and Costa-Colomer, Jordi and Osona, Borja and Torres-Borrego, Javier and de la Serna-Bl{\'a}zquez, Olga and Bell{\'o}n Alonso, Sara and Caro Aguilera, Pilar and Gimeno-D{\'\i}az de Atauri, {\'A}lvaro and Valenzuela Soria, Alfredo and Ayats, Roser and Martin de Vicente, Carlos and Velasco Gonz{\'a}lez, Valle and Moure Gonz{\'a}lez, Jos{\'e} Domingo and Canino Calder{\'\i}n, Elisa Mar{\'\i}a and Pastor-Vivero, Mar{\'\i}a Dolores and Villar {\'A}lvarez, Mar{\'\i}a {\'A}ngeles and Rovira-Amigo, Sandra and Iglesias Serrano, Ignacio and D{\'\i}ez Izquierdo, Ana and de Mir Messa, In{\'e}s and Gartner, Silvia and Navarro, Alexandra and Baz-Red{\'o}n, Noelia and Carmona, Rosario and Camats-Tarruella, N{\'u}ria and Fern{\'a}ndez-Cancio, M{\'o}nica and Rapp, Christina and Dopazo, Joaquin and Griese, Matthias and Moreno-Gald{\'o}, Antonio} } @article {749, title = {Integrating pathway knowledge with deep neural networks to reduce the dimensionality in single-cell RNA-seq data.}, journal = {BioData Min}, volume = {15}, year = {2022}, month = {2022 Jan 03}, pages = {1}, abstract = {

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) data provide valuable insights into cellular heterogeneity which is significantly improving the current knowledge on biology and human disease. One of the main applications of scRNA-seq data analysis is the identification of new cell types and cell states. Deep neural networks (DNNs) are among the best methods to address this problem. However, this performance comes with the trade-off for a lack of interpretability in the results. In this work we propose an intelligible pathway-driven neural network to correctly solve cell-type related problems at single-cell resolution while providing a biologically meaningful representation of the data.

RESULTS: In this study, we explored the deep neural networks constrained by several types of prior biological information, e.g. signaling pathway information, as a way to reduce the dimensionality of the scRNA-seq data. We have tested the proposed biologically-based architectures on thousands of cells of human and mouse origin across a collection of public datasets in order to check the performance of the model. Specifically, we tested the architecture across different validation scenarios that try to mimic how unknown cell types are clustered by the DNN and how it correctly annotates cell types by querying a database in a retrieval problem. Moreover, our approach demonstrated to be comparable to other less interpretable DNN approaches constrained by using protein-protein interactions gene regulation data. Finally, we show how the latent structure learned by the network could be used to visualize and to interpret the composition of human single cell datasets.

CONCLUSIONS: Here we demonstrate how the integration of pathways, which convey fundamental information on functional relationships between genes, with DNNs, that provide an excellent classification framework, results in an excellent alternative to learn a biologically meaningful representation of scRNA-seq data. In addition, the introduction of prior biological knowledge in the DNN reduces the size of the network architecture. Comparative results demonstrate a superior performance of this approach with respect to other similar approaches. As an additional advantage, the use of pathways within the DNN structure enables easy interpretability of the results by connecting features to cell functionalities by means of the pathway nodes, as demonstrated with an example with human melanoma tumor cells.

}, issn = {1756-0381}, doi = {10.1186/s13040-021-00285-4}, author = {Gundogdu, Pelin and Loucera, Carlos and Alamo-Alvarez, Inmaculada and Dopazo, Joaquin and Nepomuceno, Isabel} } @article {759, title = {Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus.}, journal = {Sci Rep}, volume = {12}, year = {2022}, month = {2022 Jul 02}, pages = {11219}, abstract = {

Systemic lupus erythematosus (SLE) is the prototype of an autoimmune disease. Belimumab, a monoclonal antibody targets BAFF, is the only biologic approved for SLE and active lupus nephritis. BAFF is a cytokine with a key-regulatory role in the B cell homeostasis, which acts by binding to three receptors: BAFF-R, TACI and BCMA. TACI and BCMA also bind APRIL. Many studies reported elevated soluble BAFF and APRIL levels in the sera of SLE patients, but other questions about the role of this system in the disease remain open. The study aimed to investigate the utility of the cytokine levels in serum and urine as biomarkers, the role of non-functional isoforms, and the association of gene variants with the disease. This case-control study includes a cohort (women, 18-60~years old) of 100 patients (48\% with nephritis) and 100 healthy controls. We used ELISA assays to measure the cytokine concentrations in serum (sBAFF and sAPRIL) and urine (uBAFF and uAPRIL); TaqMan Gene Expression Assays to quantify the relative mRNA expression of Ī”BAFF, Ī²APRIL, and ĪµAPRIL, and next-generation sequencing to genotype the cytokine (TNFSF13 and TNFSF13B) and receptor (TNFRSF13B, TNFRSF17 and TNFRSF13C) genes. The statistical tests used were: Kruskal-Wallis (qualitative variables), the Spearman Rho coefficient (correlations), the Chi-square and SKAT (association of common and rare genetic variants, respectively). As expected, sBAFF and sAPRIL levels were higher in patients than in controls (p <= 0.001) but found differences between patient subgroups. sBAFF and sAPRIL significantly correlated only in patients with nephritis (r = 0.67, p <= 0.001) and Ī²APRIL levels were lower in patients with nephritis (p = 0.04), and Ī”BAFF levels were lower in patients with dsDNA antibodies (p = 0.04). Rare variants of TNFSF13 and TNFRSF13B and TNFSF13 p.Gly67Arg and TNFRSF13B p.Val220Ala were associated with SLE. Our study supports differences among SLE patient subgroups with diverse clinical features in the BAFF/APRIL pathway. In addition, it suggests the involvement of genetic variants in the susceptibility to the disease.

}, issn = {2045-2322}, doi = {10.1038/s41598-022-15549-0}, author = {Ortiz-Aljaro, Pilar and Montes-Cano, Marco Antonio and Garc{\'\i}a-Lozano, Jos{\'e}-Ra{\'u}l and Aquino, Virginia and Carmona, Rosario and Perez-Florido, Javier and Garc{\'\i}a-Hern{\'a}ndez, Francisco Jos{\'e} and Dopazo, Joaquin and Gonz{\'a}lez-Escribano, Mar{\'\i}a Francisca} } @article {752, title = {Towards a metagenomics machine learning interpretable model for understanding the transition from adenoma to colorectal cancer.}, journal = {Sci Rep}, volume = {12}, year = {2022}, month = {2022 Jan 10}, pages = {450}, abstract = {

Gut microbiome is gaining interest because of its links with several diseases, including colorectal cancer (CRC), as well as the possibility of being used to obtain non-intrusive predictive disease biomarkers. Here we performed a meta-analysis of 1042 fecal metagenomic samples from seven publicly available studies. We used an interpretable machine learning approach based on functional profiles, instead of the conventional taxonomic profiles, to produce a highly accurate predictor of CRC with better precision than those of previous proposals. Moreover, this approach is also able to discriminate samples with adenoma, which makes this approach very promising for CRC prevention by detecting early stages in which intervention is easier and more effective. In addition, interpretable machine learning methods allow extracting features relevant for the classification, which reveals basic molecular mechanisms accounting for the changes undergone by the microbiome functional landscape in the transition from healthy gut to adenoma and CRC conditions. Functional profiles have demonstrated superior accuracy in predicting CRC and adenoma conditions than taxonomic profiles and additionally, in a context of explainable machine learning, provide useful hints on the molecular mechanisms operating in the microbiota behind these conditions.

}, issn = {2045-2322}, doi = {10.1038/s41598-021-04182-y}, author = {Casimiro-Soriguer, Carlos S and Loucera, Carlos and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {726, title = {A comprehensive database for integrated analysis of omics data in autoimmune diseases.}, journal = {BMC Bioinformatics}, volume = {22}, year = {2021}, month = {2021 Jun 24}, pages = {343}, abstract = {

BACKGROUND: Autoimmune diseases are heterogeneous pathologies with difficult diagnosis and few therapeutic options. In the last decade, several omics studies have provided significant insights into the molecular mechanisms of these diseases. Nevertheless, data from different cohorts and pathologies are stored independently in public repositories and a unified resource is imperative to assist researchers in this field.

RESULTS: Here, we present Autoimmune Diseases Explorer ( https://adex.genyo.es ), a database that integrates 82 curated transcriptomics and methylation studies covering 5609 samples for some of the most common autoimmune diseases. The database provides, in an easy-to-use environment, advanced data analysis and statistical methods for exploring omics datasets, including meta-analysis, differential expression or pathway analysis.

CONCLUSIONS: This is the first omics database focused on autoimmune diseases. This resource incorporates homogeneously processed data to facilitate integrative analyses among studies.

}, keywords = {Autoimmune Diseases, Computational Biology, Databases, Factual, Humans}, issn = {1471-2105}, doi = {10.1186/s12859-021-04268-4}, author = {Martorell-Marug{\'a}n, Jordi and L{\'o}pez-Dom{\'\i}nguez, Ra{\'u}l and Garc{\'\i}a-Moreno, Adri{\'a}n and Toro-Dom{\'\i}nguez, Daniel and Villatoro-Garc{\'\i}a, Juan Antonio and Barturen, Guillermo and Mart{\'\i}n-G{\'o}mez, Adoraci{\'o}n and Troule, Kevin and G{\'o}mez-L{\'o}pez, Gonzalo and Al-Shahrour, F{\'a}tima and Gonz{\'a}lez-Rumayor, V{\'\i}ctor and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin and Saez-Rodriguez, Julio and Alarc{\'o}n-Riquelme, Marta E and Carmona-S{\'a}ez, Pedro} } @article {736, title = {COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.}, journal = {Mol Syst Biol}, volume = {17}, year = {2021}, month = {2021 10}, pages = {e10387}, abstract = {

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.

}, keywords = {Antiviral Agents, Computational Biology, Computer Graphics, COVID-19, Cytokines, Data Mining, Databases, Factual, Gene Expression Regulation, Host Microbial Interactions, Humans, Immunity, Cellular, Immunity, Humoral, Immunity, Innate, Lymphocytes, Metabolic Networks and Pathways, Myeloid Cells, Protein Interaction Mapping, SARS-CoV-2, Signal Transduction, Software, Transcription Factors, Viral Proteins}, issn = {1744-4292}, doi = {10.15252/msb.202110387}, author = {Ostaszewski, Marek and Niarakis, Anna and Mazein, Alexander and Kuperstein, Inna and Phair, Robert and Orta-Resendiz, Aurelio and Singh, Vidisha and Aghamiri, Sara Sadat and Acencio, Marcio Luis and Glaab, Enrico and Ruepp, Andreas and Fobo, Gisela and Montrone, Corinna and Brauner, Barbara and Frishman, Goar and Monraz G{\'o}mez, Luis Crist{\'o}bal and Somers, Julia and Hoch, Matti and Kumar Gupta, Shailendra and Scheel, Julia and Borlinghaus, Hanna and Czauderna, Tobias and Schreiber, Falk and Montagud, Arnau and Ponce de Leon, Miguel and Funahashi, Akira and Hiki, Yusuke and Hiroi, Noriko and Yamada, Takahiro G and Dr{\"a}ger, Andreas and Renz, Alina and Naveez, Muhammad and Bocskei, Zsolt and Messina, Francesco and B{\"o}rnigen, Daniela and Fergusson, Liam and Conti, Marta and Rameil, Marius and Nakonecnij, Vanessa and Vanhoefer, Jakob and Schmiester, Leonard and Wang, Muying and Ackerman, Emily E and Shoemaker, Jason E and Zucker, Jeremy and Oxford, Kristie and Teuton, Jeremy and Kocakaya, Ebru and Summak, G{\"o}k{\c c}e Ya{\u g}mur and Hanspers, Kristina and Kutmon, Martina and Coort, Susan and Eijssen, Lars and Ehrhart, Friederike and Rex, Devasahayam Arokia Balaya and Slenter, Denise and Martens, Marvin and Pham, Nhung and Haw, Robin and Jassal, Bijay and Matthews, Lisa and Orlic-Milacic, Marija and Senff Ribeiro, Andrea and Rothfels, Karen and Shamovsky, Veronica and Stephan, Ralf and Sevilla, Cristoffer and Varusai, Thawfeek and Ravel, Jean-Marie and Fraser, Rupsha and Ortseifen, Vera and Marchesi, Silvia and Gawron, Piotr and Smula, Ewa and Heirendt, Laurent and Satagopam, Venkata and Wu, Guanming and Riutta, Anders and Golebiewski, Martin and Owen, Stuart and Goble, Carole and Hu, Xiaoming and Overall, Rupert W and Maier, Dieter and Bauch, Angela and Gyori, Benjamin M and Bachman, John A and Vega, Carlos and Grou{\`e}s, Valentin and Vazquez, Miguel and Porras, Pablo and Licata, Luana and Iannuccelli, Marta and Sacco, Francesca and Nesterova, Anastasia and Yuryev, Anton and de Waard, Anita and Turei, Denes and Luna, Augustin and Babur, Ozgun and Soliman, Sylvain and Valdeolivas, Alberto and Esteban-Medina, Marina and Pe{\~n}a-Chilet, Maria and Rian, Kinza and Helikar, Tom{\'a}{\v s} and Puniya, Bhanwar Lal and Modos, Dezso and Treveil, Agatha and Olbei, Marton and De Meulder, Bertrand and Ballereau, Stephane and Dugourd, Aur{\'e}lien and Naldi, Aur{\'e}lien and No{\"e}l, Vincent and Calzone, Laurence and Sander, Chris and Demir, Emek and Korcsmaros, Tamas and Freeman, Tom C and Aug{\'e}, Franck and Beckmann, Jacques S and Hasenauer, Jan and Wolkenhauer, Olaf and Wilighagen, Egon L and Pico, Alexander R and Evelo, Chris T and Gillespie, Marc E and Stein, Lincoln D and Hermjakob, Henning and D{\textquoteright}Eustachio, Peter and Saez-Rodriguez, Julio and Dopazo, Joaquin and Valencia, Alfonso and Kitano, Hiroaki and Barillot, Emmanuel and Auffray, Charles and Balling, Rudi and Schneider, Reinhard} } @article {701, title = {CSVS, a crowdsourcing database of the Spanish population genetic variability.}, journal = {Nucleic Acids Res}, volume = {49}, year = {2021}, month = {2021 01 08}, pages = {D1130-D1137}, abstract = {

The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variability worldwide. CSVS is also part of the GA4GH Beacon network. CSVS can be accessed at: http://csvs.babelomics.org/.

}, keywords = {Alleles, Chromosome Mapping, Crowdsourcing, Databases, Genetic, Exome, Gene Frequency, Genetic Variation, Genetics, Population, Genome, Human, Genomics, Humans, Internet, Precision Medicine, Software, Spain}, issn = {1362-4962}, doi = {10.1093/nar/gkaa794}, author = {Pe{\~n}a-Chilet, Maria and Rold{\'a}n, Gema and Perez-Florido, Javier and Ortuno, Francisco M and Carmona, Rosario and Aquino, Virginia and L{\'o}pez-L{\'o}pez, Daniel and Loucera, Carlos and Fernandez-Rueda, Jose L and Gallego, Asunci{\'o}n and Garcia-Garcia, Francisco and Gonz{\'a}lez-Neira, Anna and Pita, Guillermo and N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Santoyo-L{\'o}pez, Javier and Ayuso, Carmen and Minguez, Pablo and Avila-Fernandez, Almudena and Corton, Marta and Moreno-Pelayo, Miguel {\'A}ngel and Morin, Mat{\'\i}as and Gallego-Martinez, Alvaro and Lopez-Escamez, Jose A and Borrego, Salud and Anti{\v n}olo, Guillermo and Amigo, Jorge and Salgado-Garrido, Josefa and Pasalodos-Sanchez, Sara and Morte, Beatriz and Carracedo, {\'A}ngel and Alonso, {\'A}ngel and Dopazo, Joaquin} } @article {743, title = {Deciphering Genomic Heterogeneity and the Internal Composition of Tumour Activities through a Hierarchical Factorisation Model}, journal = {Mathematics}, volume = {9}, year = {2021}, month = {Jan-11-2021}, pages = {2833}, doi = {10.3390/math9212833}, url = {https://www.mdpi.com/2227-7390/9/21/2833https://www.mdpi.com/2227-7390/9/21/2833/pdf}, author = {Carbonell-Caballero, Jos{\'e} and L{\'o}pez-Qu{\'\i}lez, Antonio and Conesa, David and Dopazo, Joaquin} } @article {720, title = {A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin.}, journal = {Mol Oncol}, volume = {15}, year = {2021}, month = {2021 12}, pages = {3691-3705}, abstract = {

Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.

}, issn = {1878-0261}, doi = {10.1002/1878-0261.12996}, author = {Moura, David S and Pe{\~n}a-Chilet, Maria and Cordero Varela, Juan Antonio and Alvarez-Alegret, Ramiro and Agra-Pujol, Carolina and Izquierdo, Francisco and Ramos, Rafael and Ortega-Medina, Luis and Martin-Davila, Francisco and Castilla-Ramirez, Carolina and Hernandez-Leon, Carmen Nieves and Romagosa, Cleofe and Vaz Salgado, Maria Angeles and Lavernia, Javier and Bagu{\'e}, Silvia and Mayodormo-Aranda, Empar and Vicioso, Luis and Hern{\'a}ndez Barcel{\'o}, Jose Emilio and Rubio-Casadevall, Jordi and de Juan, Ana and Fia{\~n}o-Valverde, Maria Concepcion and Hindi, Nadia and Lopez-Alvarez, Maria and Lacerenza, Serena and Dopazo, Joaquin and Gutierrez, Antonio and Alvarez, Rosa and Valverde, Claudia and Martinez-Trufero, Javier and Martin-Broto, Javier} } @article {724, title = {Genome-scale mechanistic modeling of signaling pathways made easy: A bioconductor/cytoscape/web server framework for the analysis of omic data}, journal = {Computational and Structural Biotechnology Journal}, volume = {19}, year = {2021}, month = {Jan-01-2021}, pages = {2968 - 2978}, issn = {20010370}, doi = {10.1016/j.csbj.2021.05.022}, url = {https://linkinghub.elsevier.com/retrieve/pii/S2001037021002038}, author = {Rian, Kinza and Hidalgo, Marta R. and Cubuk, Cankut and Falco, Matias M. and Loucera, Carlos and Esteban-Medina, Marina and Alamo-Alvarez, Inmaculada and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {717, title = {Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system developmentAbstractBackgroundResultsConclusionsGraphic abstract}, journal = {Clinical Epigenetics}, volume = {13}, year = {2021}, month = {Jan-12-2021}, issn = {1868-7075}, doi = {10.1186/s13148-021-01040-6}, url = {http://link.springer.com/article/10.1186/s13148-021-01040-6/fulltext.html}, author = {Villalba-Benito, Leticia and L{\'o}pez-L{\'o}pez, Daniel and Torroglosa, Ana and Casimiro-Soriguer, Carlos S. and Luz{\'o}n-Toro, Berta and Fern{\'a}ndez, Raquel Mar{\'\i}a and Moya-Jim{\'e}nez, Mar{\'\i}a Jos{\'e} and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {744, title = {Highly accurate whole-genome imputation of SARS-CoV-2 from partial or low-quality sequences.}, journal = {Gigascience}, volume = {10}, year = {2021}, month = {2021 12 02}, abstract = {

BACKGROUND: The current SARS-CoV-2 pandemic has emphasized the utility of viral whole-genome sequencing in the surveillance and control of the pathogen. An unprecedented ongoing global initiative is producing hundreds of thousands of sequences worldwide. However, the complex circumstances in which viruses are sequenced, along with the demand of urgent results, causes a high rate of incomplete and, therefore, useless sequences. Viral sequences evolve in the context of a complex phylogeny and different positions along the genome are in linkage disequilibrium. Therefore, an imputation method would be able to predict missing positions from the available sequencing data.

RESULTS: We have developed the impuSARS application, which takes advantage of the enormous number of SARS-CoV-2 genomes available, using a reference panel containing 239,301 sequences, to produce missing data imputation in viral genomes. ImpuSARS was tested in a wide range of conditions (continuous fragments, amplicons or sparse individual positions missing), showing great fidelity when reconstructing the original sequences, recovering the lineage with a 100\% precision for almost all the lineages, even in very poorly covered genomes (<20\%).

CONCLUSIONS: Imputation can improve the pace of SARS-CoV-2 sequencing production by recovering many incomplete or low-quality sequences that would be otherwise discarded. ImpuSARS can be incorporated in any primary data processing pipeline for SARS-CoV-2 whole-genome sequencing.

}, keywords = {Genome, Viral, Phylogeny, SARS-CoV-2, Whole Genome Sequencing}, issn = {2047-217X}, doi = {10.1093/gigascience/giab078}, author = {Ortuno, Francisco M and Loucera, Carlos and Casimiro-Soriguer, Carlos S and Lepe, Jose A and Camacho Martinez, Pedro and Merino Diaz, Laura and de Salazar, Adolfo and Chueca, Natalia and Garc{\'\i}a, Federico and Perez-Florido, Javier and Dopazo, Joaquin} } @article {725, title = {Implementing Personalized Medicine in COVID-19 in Andalusia: An Opportunity to Transform the Healthcare System.}, journal = {J Pers Med}, volume = {11}, year = {2021}, month = {2021 May 26}, abstract = {

The COVID-19 pandemic represents an unprecedented opportunity to exploit the advantages of personalized medicine for the prevention, diagnosis, treatment, surveillance and management of a new challenge in public health. COVID-19 infection is highly variable, ranging from asymptomatic infections to severe, life-threatening manifestations. Personalized medicine can play a key role in elucidating individual susceptibility to the infection as well as inter-individual variability in clinical course, prognosis and response to treatment. Integrating personalized medicine into clinical practice can also transform health care by enabling the design of preventive and therapeutic strategies tailored to individual profiles, improving the detection of outbreaks or defining transmission patterns at an increasingly local level. SARS-CoV2 genome sequencing, together with the assessment of specific patient genetic variants, will support clinical decision-makers and ultimately better ways to fight this disease. Additionally, it would facilitate a better stratification and selection of patients for clinical trials, thus increasing the likelihood of obtaining positive results. Lastly, defining a national strategy to implement in clinical practice all available tools of personalized medicine in COVID-19 could be challenging but linked to a positive transformation of the health care system. In this review, we provide an update of the achievements, promises, and challenges of personalized medicine in the fight against COVID-19 from susceptibility to natural history and response to therapy, as well as from surveillance to control measures and vaccination. We also discuss strategies to facilitate the adoption of this new paradigm for medical and public health measures during and after the pandemic in health care systems.

}, issn = {2075-4426}, doi = {10.3390/jpm11060475}, author = {Dopazo, Joaquin and Maya-Miles, Douglas and Garc{\'\i}a, Federico and Lorusso, Nicola and Calleja, Miguel {\'A}ngel and Pareja, Mar{\'\i}a Jes{\'u}s and L{\'o}pez-Miranda, Jos{\'e} and Rodr{\'\i}guez-Ba{\~n}o, Jes{\'u}s and Padillo, Javier and T{\'u}nez, Isaac and Romero-G{\'o}mez, Manuel} } @article {711, title = {Mechanistic modeling of the SARS-CoV-2 disease map.}, journal = {BioData Min}, volume = {14}, year = {2021}, month = {2021 Jan 21}, pages = {5}, abstract = {

Here we present a web interface that implements a comprehensive mechanistic model of the SARS-CoV-2 disease map. In this framework, the detailed activity of the human signaling circuits related to the viral infection, covering from the entry and replication mechanisms to the downstream consequences as inflammation and antigenic response, can be inferred from gene expression experiments. Moreover, the effect of potential interventions, such as knock-downs, or drug effects (currently the system models the effect of more than 8000 DrugBank drugs) can be studied. This freely available tool not only provides an unprecedentedly detailed view of the mechanisms of viral invasion and the consequences in the cell but has also the potential of becoming an invaluable asset in the search for efficient antiviral treatments.

}, issn = {1756-0381}, doi = {10.1186/s13040-021-00234-1}, author = {Rian, Kinza and Esteban-Medina, Marina and Hidalgo, Marta R and Cubuk, Cankut and Falco, Matias M and Loucera, Carlos and Gunyel, Devrim and Ostaszewski, Marek and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {741, title = {Mutational Characterization of Cutaneous Melanoma Supports Divergent Pathways Model for Melanoma Development.}, journal = {Cancers (Basel)}, volume = {13}, year = {2021}, month = {2021 Oct 18}, abstract = {

According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being . The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included , , , and . We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.

}, issn = {2072-6694}, doi = {10.3390/cancers13205219}, author = {Mill{\'a}n-Esteban, David and Pe{\~n}a-Chilet, Maria and Garc{\'\i}a-Casado, Zaida and Manrique-Silva, Esperanza and Requena, Celia and Ba{\~n}uls, Jos{\'e} and Lopez-Guerrero, Jose Antonio and Rodr{\'\i}guez-Hern{\'a}ndez, Aranzazu and Traves, V{\'\i}ctor and Dopazo, Joaquin and Vir{\'o}s, Amaya and Kumar, Rajiv and Nagore, Eduardo} } @article {723, title = {Phylogenetic Analysis of the 2020 West Nile Virus (WNV) Outbreak in Andalusia (Spain)}, journal = {Viruses}, volume = {13}, year = {2021}, month = {Jan-05-2021}, pages = {836}, doi = {10.3390/v13050836}, url = {https://www.mdpi.com/1999-4915/13/5/836 }, author = {Casimiro-Soriguer, Carlos S. and Perez-Florido, Javier and Fernandez-Rueda, Jose L. and Pedrosa-Corral, Irene and Guillot-Sulay, Vicente and Lorusso, Nicola and Martinez-Gonzalez, Luis Javier and Navarro-Mar{\'\i}, Jose M. and Dopazo, Joaquin and Sanbonmatsu-G{\'a}mez, Sara} } @article {745, title = {Real world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients.}, journal = {Sci Rep}, volume = {11}, year = {2021}, month = {2021 12 03}, pages = {23380}, abstract = {

COVID-19 is a major worldwide health problem because of acute respiratory distress syndrome, and mortality. Several lines of evidence have suggested a relationship between the vitamin D endocrine system and severity of COVID-19. We present a survival study on a retrospective cohort of 15,968 patients, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020. Based on a central registry of electronic health records (the Andalusian Population Health Database, BPS), prescription of vitamin D or its metabolites within 15-30~days before hospitalization were recorded. The effect of prescription of vitamin D (metabolites) for other indication previous to the hospitalization was studied with respect to patient survival. Kaplan-Meier survival curves and hazard ratios support an association between prescription of these metabolites and patient survival. Such association was stronger for calcifediol (Hazard Ratio, HR = 0.67, with 95\% confidence interval, CI, of [0.50-0.91]) than for cholecalciferol (HR = 0.75, with 95\% CI of [0.61-0.91]), when prescribed 15~days prior hospitalization. Although the relation is maintained, there is a general decrease of this effect when a longer period of 30~days prior hospitalization is considered (calcifediol HR = 0.73, with 95\% CI [0.57-0.95] and cholecalciferol HR = 0.88, with 95\% CI [0.75, 1.03]), suggesting that association was stronger when the prescription was closer to the hospitalization.

}, keywords = {Calcifediol, COVID-19, Female, Humans, Kaplan-Meier Estimate, Male, Retrospective Studies, Spain, Survival Analysis, Vitamin D}, issn = {2045-2322}, doi = {10.1038/s41598-021-02701-5}, author = {Loucera, Carlos and Pe{\~n}a-Chilet, Maria and Esteban-Medina, Marina and Mu{\~n}oyerro-Mu{\~n}iz, Dolores and Villegas, Rom{\'a}n and L{\'o}pez-Miranda, Jos{\'e} and Rodr{\'\i}guez-Ba{\~n}o, Jes{\'u}s and T{\'u}nez, Isaac and Bouillon, Roger and Dopazo, Joaquin and Quesada Gomez, Jose Manuel} } @article {742, title = {Reporting guidelines for human microbiome research: the STORMS checklist.}, journal = {Nat Med}, volume = {27}, year = {2021}, month = {2021 11}, pages = {1885-1892}, abstract = {

The particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called {\textquoteright}Strengthening The Organization and Reporting of Microbiome Studies{\textquoteright} (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results.

}, keywords = {Computational Biology, Dysbiosis, Humans, Microbiota, Observational Studies as Topic, Research Design, Translational Science, Biomedical}, issn = {1546-170X}, doi = {10.1038/s41591-021-01552-x}, author = {Mirzayi, Chloe and Renson, Audrey and Zohra, Fatima and Elsafoury, Shaimaa and Geistlinger, Ludwig and Kasselman, Lora J and Eckenrode, Kelly and van de Wijgert, Janneke and Loughman, Amy and Marques, Francine Z and MacIntyre, David A and Arumugam, Manimozhiyan and Azhar, Rimsha and Beghini, Francesco and Bergstrom, Kirk and Bhatt, Ami and Bisanz, Jordan E and Braun, Jonathan and Bravo, Hector Corrada and Buck, Gregory A and Bushman, Frederic and Casero, David and Clarke, Gerard and Collado, Maria Carmen and Cotter, Paul D and Cryan, John F and Demmer, Ryan T and Devkota, Suzanne and Elinav, Eran and Escobar, Juan S and Fettweis, Jennifer and Finn, Robert D and Fodor, Anthony A and Forslund, Sofia and Franke, Andre and Furlanello, Cesare and Gilbert, Jack and Grice, Elizabeth and Haibe-Kains, Benjamin and Handley, Scott and Herd, Pamela and Holmes, Susan and Jacobs, Jonathan P and Karstens, Lisa and Knight, Rob and Knights, Dan and Koren, Omry and Kwon, Douglas S and Langille, Morgan and Lindsay, Brianna and McGovern, Dermot and McHardy, Alice C and McWeeney, Shannon and Mueller, Noel T and Nezi, Luigi and Olm, Matthew and Palm, Noah and Pasolli, Edoardo and Raes, Jeroen and Redinbo, Matthew R and R{\"u}hlemann, Malte and Balfour Sartor, R and Schloss, Patrick D and Schriml, Lynn and Segal, Eran and Shardell, Michelle and Sharpton, Thomas and Smirnova, Ekaterina and Sokol, Harry and Sonnenburg, Justin L and Srinivasan, Sujatha and Thingholm, Louise B and Turnbaugh, Peter J and Upadhyay, Vaibhav and Walls, Ramona L and Wilmes, Paul and Yamada, Takuji and Zeller, Georg and Zhang, Mingyu and Zhao, Ni and Zhao, Liping and Bao, Wenjun and Culhane, Aedin and Devanarayan, Viswanath and Dopazo, Joaquin and Fan, Xiaohui and Fischer, Matthias and Jones, Wendell and Kusko, Rebecca and Mason, Christopher E and Mercer, Tim R and Sansone, Susanna-Assunta and Scherer, Andreas and Shi, Leming and Thakkar, Shraddha and Tong, Weida and Wolfinger, Russ and Hunter, Christopher and Segata, Nicola and Huttenhower, Curtis and Dowd, Jennifer B and Jones, Heidi E and Waldron, Levi} } @article {719, title = {Taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.}, journal = {Mol Med}, volume = {27}, year = {2021}, month = {2021 05 24}, pages = {50}, abstract = {

OBJECTIVE: To evaluate the taxonomic composition of the gut microbiome in gout patients with and without tophi formation, and predict bacterial functions that might have an impact on urate metabolism.

METHODS: Hypervariable V3-V4 regions of the bacterial 16S rRNA gene from fecal samples of gout patients with and without tophi (n = 33 and n = 25, respectively) were sequenced and compared to fecal samples from 53 healthy controls. We explored predictive functional profiles using bioinformatics in order to identify differences in taxonomy and metabolic pathways.

RESULTS: We identified a microbiome characterized by the lowest richness and a higher abundance of Phascolarctobacterium, Bacteroides, Akkermansia, and Ruminococcus_gnavus_group genera in patients with gout without tophi when compared to controls. The Proteobacteria phylum and the Escherichia-Shigella genus were more abundant in patients with tophaceous gout than in controls. Fold change analysis detected nine genera enriched in healthy controls compared to gout groups (Bifidobacterium, Butyricicoccus, Oscillobacter, Ruminococcaceae_UCG_010, Lachnospiraceae_ND2007_group, Haemophilus, Ruminococcus_1, Clostridium_sensu_stricto_1, and Ruminococcaceae_UGC_013). We found that the core microbiota of both gout groups shared Bacteroides caccae, Bacteroides stercoris ATCC 43183, and Bacteroides coprocola DSM 17136. These bacteria might perform functions linked to one-carbon metabolism, nucleotide binding, amino acid biosynthesis, and purine biosynthesis. Finally, we observed differences in key bacterial enzymes involved in urate synthesis, degradation, and elimination.

CONCLUSION: Our findings revealed that taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.

}, keywords = {Biodiversity, Computational Biology, Dysbiosis, Gastrointestinal Microbiome, Gout, Humans, Metagenome, metagenomics, Protein Interaction Mapping, Protein Interaction Maps, Uric Acid}, issn = {1528-3658}, doi = {10.1186/s10020-021-00311-5}, author = {M{\'e}ndez-Salazar, Eder Orlando and V{\'a}zquez-Mellado, Janitzia and Casimiro-Soriguer, Carlos S and Dopazo, Joaquin and Cubuk, Cankut and Zamudio-Cuevas, Yessica and Francisco-Balderas, Adriana and Mart{\'\i}nez-Flores, Karina and Fern{\'a}ndez-Torres, Javier and Lozada-P{\'e}rez, Carlos and Pineda, Carlos and S{\'a}nchez-Gonz{\'a}lez, Austreberto and Silveira, Luis H and Burguete-Garc{\'\i}a, Ana I and Orbe-Orihuela, Citlalli and Lagunas-Mart{\'\i}nez, Alfredo and Vazquez-Gomez, Alonso and L{\'o}pez-Reyes, Alberto and Palacios-Gonz{\'a}lez, Berenice and Mart{\'\i}nez-Nava, Gabriela Ang{\'e}lica} } @article {712, title = {A versatile workflow to integrate RNA-seq genomic and transcriptomic data into mechanistic models of signaling pathways.}, journal = {PLoS Comput Biol}, volume = {17}, year = {2021}, month = {2021 02}, pages = {e1008748}, abstract = {

MIGNON is a workflow for the analysis of RNA-Seq experiments, which not only efficiently manages the estimation of gene expression levels from raw sequencing reads, but also calls genomic variants present in the transcripts analyzed. Moreover, this is the first workflow that provides a framework for the integration of transcriptomic and genomic data based on a mechanistic model of signaling pathway activities that allows a detailed biological interpretation of the results, including a comprehensive functional profiling of cell activity. MIGNON covers the whole process, from reads to signaling circuit activity estimations, using state-of-the-art tools, it is easy to use and it is deployable in different computational environments, allowing an optimized use of the resources available.

}, keywords = {Algorithms, Cell Line, Tumor, Computational Biology, Databases, Factual, Gene Expression Profiling, Genomics, High-Throughput Nucleotide Sequencing, Humans, Models, Theoretical, mutation, RNA-seq, Signal Transduction, Software, Transcriptome, whole exome sequencing, Workflow}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1008748}, author = {Garrido-Rodriguez, Mart{\'\i}n and L{\'o}pez-L{\'o}pez, Daniel and Ortuno, Francisco M and Pe{\~n}a-Chilet, Maria and Mu{\~n}oz, Eduardo and Calzado, Marco A and Dopazo, Joaquin} } @article {689, title = {COVID-19 Disease Map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms.}, journal = {Sci Data}, volume = {7}, year = {2020}, month = {2020 05 05}, pages = {136}, keywords = {Betacoronavirus, Computational Biology, Coronavirus Infections, COVID-19, Databases, Factual, Host Microbial Interactions, Host-Pathogen Interactions, Humans, International Cooperation, Models, Biological, Pandemics, Pneumonia, Viral, SARS-CoV-2}, issn = {2052-4463}, doi = {10.1038/s41597-020-0477-8}, author = {Ostaszewski, Marek and Mazein, Alexander and Gillespie, Marc E and Kuperstein, Inna and Niarakis, Anna and Hermjakob, Henning and Pico, Alexander R and Willighagen, Egon L and Evelo, Chris T and Hasenauer, Jan and Schreiber, Falk and Dr{\"a}ger, Andreas and Demir, Emek and Wolkenhauer, Olaf and Furlong, Laura I and Barillot, Emmanuel and Dopazo, Joaquin and Orta-Resendiz, Aurelio and Messina, Francesco and Valencia, Alfonso and Funahashi, Akira and Kitano, Hiroaki and Auffray, Charles and Balling, Rudi and Schneider, Reinhard} } @article {713, title = {Drug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection.}, journal = {Signal Transduct Target Ther}, volume = {5}, year = {2020}, month = {2020 12 11}, pages = {290}, keywords = {Computational Chemistry, COVID-19, drug repositioning, Humans, Machine Learning, Molecular Docking Simulation, Molecular Targeted Therapy, Proteins, SARS-CoV-2, Signal Transduction}, issn = {2059-3635}, doi = {10.1038/s41392-020-00417-y}, author = {Loucera, Carlos and Esteban-Medina, Marina and Rian, Kinza and Falco, Matias M and Dopazo, Joaquin and Pe{\~n}a-Chilet, Maria} } @article {729, title = {The ELIXIR Human Copy Number Variations Community: building bioinformatics infrastructure for research.}, journal = {F1000Res}, volume = {9}, year = {2020}, month = {2020}, chapter = {1229}, abstract = {

Copy number variations (CNVs) are major causative contributors both in the genesis of genetic diseases and human neoplasias. While "High-Throughput" sequencing technologies are increasingly becoming the primary choice for genomic screening analysis, their ability to efficiently detect CNVs is still heterogeneous and remains to be developed. The aim of this white paper is to provide a guiding framework for the future contributions of ELIXIR{\textquoteright}s recently established with implications beyond human disease diagnostics and population genomics. This white paper is the direct result of a strategy meeting that took place in September 2018 in Hinxton (UK) and involved representatives of 11 ELIXIR Nodes. The meeting led to the definition of priority objectives and tasks, to address a wide range of CNV-related challenges ranging from detection and interpretation to sharing and training. Here, we provide suggestions on how to align these tasks within the ELIXIR Platforms strategy, and on how to frame the activities of this new ELIXIR Community in the international context.

}, keywords = {Computational Biology, DNA Copy Number Variations, High-Throughput Nucleotide Sequencing, Humans}, issn = {2046-1402}, doi = {10.12688/f1000research.24887.1}, author = {Salgado, David and Armean, Irina M and Baudis, Michael and Beltran, Sergi and Capella-Gut{\'\i}errez, Salvador and Carvalho-Silva, Denise and Dominguez Del Angel, Victoria and Dopazo, Joaquin and Furlong, Laura I and Gao, Bo and Garcia, Leyla and Gerloff, Dietlind and Gut, Ivo and Gyenesei, Attila and Habermann, Nina and Hancock, John M and Hanauer, Marc and Hovig, Eivind and Johansson, Lennart F and Keane, Thomas and Korbel, Jan and Lauer, Katharina B and Laurie, Steve and Lesko{\v s}ek, Brane and Lloyd, David and Marqu{\'e}s-Bonet, Tom{\'a}s and Mei, Hailiang and Monostory, Katalin and Pi{\~n}ero, Janet and Poterlowicz, Krzysztof and Rath, Ana and Samarakoon, Pubudu and Sanz, Ferran and Saunders, Gary and Sie, Daoud and Swertz, Morris A and Tsukanov, Kirill and Valencia, Alfonso and Vidak, Marko and Yenyxe Gonz{\'a}lez, Cristina and Ylstra, Bauke and B{\'e}roud, Christophe} } @article {693, title = {Immune Cell Associations with Cancer Risk.}, journal = {iScience}, volume = {23}, year = {2020}, month = {2020 Jul 24}, pages = {101296}, abstract = {

Proper immune system function hinders cancer development, but little is known about whether genetic variants linked to cancer risk alter immune cells. Here, we report 57 cancer risk loci associated with differences in immune and/or stromal cell contents in the corresponding tissue. Predicted target genes show expression and regulatory associations with immune features. Polygenic risk scores also reveal associations with immune and/or stromal cell contents, and breast cancer scores show consistent results in normal and tumor tissue. SH2B3 links peripheral alterations of several immune cell types to the risk of this malignancy. Pleiotropic SH2B3 variants are associated with breast cancer risk in BRCA1/2 mutation carriers. A retrospective case-cohort study indicates a positive association between blood counts of basophils, leukocytes, and monocytes and age at breast cancer diagnosis. These findings broaden our knowledge of the role of the immune system in cancer and highlight promising prevention strategies for individuals at high risk.

}, issn = {2589-0042}, doi = {10.1016/j.isci.2020.101296}, author = {Palomero, Luis and Galv{\'a}n-Femen{\'\i}a, Ivan and de Cid, Rafael and Esp{\'\i}n, Roderic and Barnes, Daniel R and Blommaert, Eline and Gil-Gil, Miguel and Falo, Catalina and Stradella, Agostina and Ouchi, Dan and Roso-Llorach, Albert and Violan, Concepci{\'o} and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin and Extremera, Ana Isabel and Garc{\'\i}a-Valero, Mar and Herranz, Carmen and Mateo, Francesca and Mereu, Elisabetta and Beesley, Jonathan and Chenevix-Trench, Georgia and Roux, Cecilia and Mak, Tak and Brunet, Joan and Hakem, Razq and Gorrini, Chiara and Antoniou, Antonis C and L{\'a}zaro, Conxi and Pujana, Miquel Angel} } @article {652, title = {[Impact assessment on data protection in research projects].}, journal = {Gac Sanit}, volume = {34}, year = {2020}, month = {2020 Sep - Oct}, pages = {521-523}, abstract = {

Recent changes in European regulations for personal data protection still allow the use of health data for research purposes, but they have set the Impact Assessment on Data Protection as an instrument for reflection and risk analysis in the process of data processing. The publication of a guide for facilitates this impact assessment, although it is not directly applicable to research projects. Experience in a specific project is detailed, showing how the context of the treatment becomes relevant with respect to the data characteristics. Carrying out an impact assessment is an opportunity to ensure compliance with the principles of data protection in an increasingly complex environment with greater ethical challenges.

}, keywords = {Computer Security, Humans}, issn = {1578-1283}, doi = {10.1016/j.gaceta.2019.10.006}, author = {Garc{\'\i}a-Le{\'o}n, Francisco Javier and Villegas-Portero, Rom{\'a}n and Goicoechea-Salazar, Juan Antonio and Mu{\~n}oyerro-Mu{\~n}iz, Dolores and Dopazo, Joaquin} } @article {702, title = {Mechanistic models of signaling pathways deconvolute the glioblastoma single-cell functional landscapeAbstract}, journal = {NAR Cancer}, volume = {2}, year = {2020}, month = {Jan-06-2020}, doi = {10.1093/narcan/zcaa011}, url = {https://academic.oup.com/narcancer/article/doi/10.1093/narcan/zcaa011/5862620http://academic.oup.com/narcancer/article-pdf/2/2/zcaa011/33428092/zcaa011.pdfhttp://academic.oup.com/narcancer/article-pdf/2/2/zcaa011/33428092/zcaa011.pdf}, author = {Falco, Matias M and Pe{\~n}a-Chilet, Maria and Loucera, Carlos and Hidalgo, Marta R and Dopazo, Joaquin} } @article {695, title = {Mechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments.}, journal = {Cells}, volume = {9}, year = {2020}, month = {2020 06 29}, abstract = {

Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such differences over the disease mechanisms or the drug action mechanisms are completely unknown. Here we applied mechanistic mathematical models of signaling activity to reveal the ultimate functional consequences that gender-specific gene expression activities have over cell functionality and fate. Moreover, we also used the mechanistic modeling framework to simulate the drug interventions and unravel how drug action mechanisms are affected by gender-specific differential gene expression. Interestingly, some cancers have many biological processes significantly affected by these gender-specific differences (e.g., bladder or head and neck carcinomas), while others (e.g., glioblastoma or rectum cancer) are almost insensitive to them. We found that many of these gender-specific differences affect cancer-specific pathways or in physiological signaling pathways, also involved in cancer origin and development. Finally, mechanistic models have the potential to be used for finding alternative therapeutic interventions on the pathways targeted by the drug, which lead to similar results compensating the downstream consequences of gender-specific differences in gene expression.

}, keywords = {Female, Gene Expression Regulation, Neoplastic, Humans, Male, Neoplasms, Signal Transduction}, issn = {2073-4409}, doi = {10.3390/cells9071579}, author = {Cubuk, Cankut and Can, Fatma E and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {707, title = {Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial.}, journal = {J Immunother Cancer}, volume = {8}, year = {2020}, month = {2020 11}, abstract = {

BACKGROUND: Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).

METHODS: This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level -1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).

RESULTS: From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4-26), the 6-month progression-free survival rate was 48\% (95\% CI 41\% to 55\%). The most common grade 3-4 adverse events included transaminitis (17.3\%) and neutropenia (11.5\%).

CONCLUSIONS: Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months. NCT03277924.

}, keywords = {Adult, Aged, Antineoplastic Agents, Immunological, Female, Humans, Male, Middle Aged, Nivolumab, Sarcoma, Sunitinib, Young Adult}, issn = {2051-1426}, doi = {10.1136/jitc-2020-001561}, author = {Martin-Broto, Javier and Hindi, Nadia and Grignani, Giovanni and Martinez-Trufero, Javier and Redondo, Andres and Valverde, Claudia and Stacchiotti, Silvia and Lopez-Pousa, Antonio and D{\textquoteright}Ambrosio, Lorenzo and Gutierrez, Antonio and Perez-Vega, Herminia and Encinas-Tobajas, Victor and de Alava, Enrique and Collini, Paola and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin and Carrasco-Garcia, Irene and Lopez-Alvarez, Maria and Moura, David S and Lopez-Martin, Jose A} } @article {665, title = {Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies.}, journal = {J Med Genet}, volume = {57}, year = {2020}, month = {2020 04}, pages = {258-268}, abstract = {

PURPOSE: Patients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients{\textquoteright} characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies.

METHODS: 68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test missense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies.

RESULTS: We identified 93.3\% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two variants reported in mutations databases as {\textquoteright}affecting functions{\textquoteright} are SNPs. Deep analysis of sequencing data revealed patients{\textquoteright} true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations) CONCLUSION: WES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source.

}, keywords = {Cell Line, DNA Copy Number Variations, DNA Repair, DNA-Binding Proteins, Fanconi Anemia, Fanconi Anemia Complementation Group A Protein, Female, Gene Knockout Techniques, Genetic Predisposition to Disease, Humans, Male, Mutation, Missense, Polymorphism, Single Nucleotide, whole exome sequencing}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2019-106249}, author = {Bogliolo, Massimo and Pujol, Roser and Aza-Carmona, Miriam and Mu{\~n}oz-Subirana, N{\'u}ria and Rodriguez-Santiago, Benjamin and Casado, Jos{\'e} Antonio and Rio, Paula and Bauser, Christopher and Reina-Castill{\'o}n, Judith and Lopez-Sanchez, Marcos and Gonzalez-Quereda, Lidia and Gallano, Pia and Catal{\'a}, Albert and Ruiz-Llobet, Ana and Badell, Isabel and Diaz-Heredia, Cristina and Hladun, Raquel and Senent, Leonort and Argiles, Bienvenida and Bergua Burgues, Juan Miguel and Ba{\~n}ez, Fatima and Arrizabalaga, Beatriz and L{\'o}pez Almaraz, Ricardo and Lopez, Monica and Figuera, {\'A}ngela and Molin{\'e}s, Antonio and P{\'e}rez de Soto, Inmaculada and Hernando, In{\'e}s and Mu{\~n}oz, Juan Antonio and Del Rosario Marin, Maria and Balma{\~n}a, Judith and Stjepanovic, Neda and Carrasco, Estela and Cuesta, Isabel and Cosuelo, Jos{\'e} Miguel and Regueiro, Alexandra and Moraleda Jimenez, Jos{\'e} and Galera-Mi{\~n}arro, Ana Maria and Rosi{\~n}ol, Laura and Carri{\'o}, Anna and Bel{\'e}ndez-Bieler, Cristina and Escudero Soto, Antonio and Cela, Elena and de la Mata, Gregorio and Fern{\'a}ndez-Delgado, Rafael and Garcia-Pardos, Maria Carmen and S{\'a}ez-Villaverde, Raquel and Barraga{\~n}o, Marta and Portugal, Raquel and Lendinez, Francisco and Hernadez, Ines and Vagace, Jos{\'e} Manue and Tapia, Maria and Nieto, Jos{\'e} and Garcia, Marta and Gonzalez, Macarena and Vicho, Cristina and Galvez, Eva and Valiente, Alberto and Antelo, Maria Luisa and Ancliff, Phil and Garc{\'\i}a, Francisco and Dopazo, Joaquin and Sevilla, Julian and Paprotka, Tobias and P{\'e}rez-Jurado, Luis Alberto and Bueren, Juan and Surralles, Jordi} } @article {653, title = {Pazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial.}, journal = {Lancet Oncol}, volume = {21}, year = {2020}, month = {2020 03}, pages = {456-466}, abstract = {

BACKGROUND: Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here.

METHODS: In this single-arm, phase 2 trial, adult patients (aged >=18 years) diagnosed with confirmed metastatic or unresectable typical solitary fibrous tumour of any location, who had progressed in the previous 6 months (by Choi criteria or Response Evaluation Criteria in Solid Tumors [RECIST]) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were enrolled at 11 tertiary hospitals in Italy, France, and Spain. Patients received pazopanib 800 mg once daily, taken orally, until progression, unacceptable toxicity, withdrawal of consent, non-compliance, or a delay in pazopanib administration of longer than 3 weeks. The primary endpoint was proportion of patients achieving an overall response measured by Choi criteria in patients who received at least 1 month of treatment with at least one radiological assessment. All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered in ClinicalTrials.gov, NCT02066285, and with the European Clinical Trials Database, EudraCT 2013-005456-15.

FINDINGS: From June 26, 2014, to Dec 13, 2018, of 40 patients who were assessed, 34 patients were enrolled and 31 patients were included in the response analysis. Median follow-up was 18 months (IQR 14-34), and 18 (58\%) of 31 patients had a partial response, 12 (39\%) had stable disease, and one (3\%) showed progressive disease according to Choi criteria and central review. The proportion of overall response based on Choi criteria was 58\% (95\% CI 34-69). There were no deaths caused by toxicity, and the most frequent adverse events were diarrhoea (18 [53\%] of 34 patients), fatigue (17 [50\%]), and hypertension (17 [50\%]).

INTERPRETATION: To our knowledge, this is the first prospective trial of pazopanib for advanced typical solitary fibrous tumour. The manageable toxicity and activity shown by pazopanib in this cohort suggest that this drug could be considered as first-line treatment for advanced typical solitary fibrous tumour.

FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.

}, keywords = {Aged, Female, Follow-Up Studies, Humans, Indazoles, Male, Middle Aged, Neoplasm Metastasis, Prognosis, Prospective Studies, Protein Kinase Inhibitors, Pyrimidines, Response Evaluation Criteria in Solid Tumors, Solitary Fibrous Tumors, Sulfonamides, Survival Rate}, issn = {1474-5488}, doi = {10.1016/S1470-2045(19)30826-5}, author = {Martin-Broto, Javier and Cruz, Josefina and Penel, Nicolas and Le Cesne, Axel and Hindi, Nadia and Luna, Pablo and Moura, David S and Bernabeu, Daniel and de Alava, Enrique and Lopez-Guerrero, Jose Antonio and Dopazo, Joaquin and Pe{\~n}a-Chilet, Maria and Gutierrez, Antonio and Collini, Paola and Karanian, Marie and Redondo, Andres and Lopez-Pousa, Antonio and Grignani, Giovanni and Diaz-Martin, Juan and Marcilla, David and Fernandez-Serra, Antonio and Gonzalez-Aguilera, Cristina and Casali, Paolo G and Blay, Jean-Yves and Stacchiotti, Silvia} } @article {694, title = {Platform to study intracellular polystyrene nanoplastic pollution and clinical outcomes.}, journal = {Stem Cells}, volume = {38}, year = {2020}, month = {2020 10 01}, pages = {1321-1325}, abstract = {

Increased pollution by plastics has become a serious global environmental problem, but the concerns for human health have been raised after reported presence of microplastics (MPs) and nanoplastics (NPs) in food and beverages. Unfortunately, few studies have investigate the potentially harmful effects of MPs/NPs on early human development and human health. Therefore, we used a new platform to study possible effects of polystyrene NPs (PSNPs) on the transcription profile of preimplantation human embryos and human induced pluripotent stem cells (hiPSCs). Two pluripotency genes, LEFTY1 and LEFTY2, which encode secreted ligands of the transforming growth factor-beta, were downregulated, while CA4 and OCLM, which are related to eye development, were upregulated in both samples. The gene set enrichment analysis showed that the development of atrioventricular heart valves and the dysfunction of cellular components, including extracellular matrix, were significantly affected after exposure of hiPSCs to PSNPs. Finally, using the HiPathia method, which uncovers disease mechanisms and predicts clinical outcomes, we determined the APOC3 circuit, which is responsible for increased risk for ischemic cardiovascular disease. These results clearly demonstrate that better understanding of NPs bioactivities and its implications for human health is of extreme importance. Thus, the presented platform opens further aspects to study interactions between different environmental and intracellular pollutions with the aim to decipher the mechanism and origin of human diseases.

}, keywords = {Environmental Pollution, Humans, Induced Pluripotent Stem Cells, Intracellular Space, Nanoparticles, Plastics, Polystyrenes, Transcriptome, Treatment Outcome}, issn = {1549-4918}, doi = {10.1002/stem.3244}, author = {Bojic, Sanja and Falco, Matias M and Stojkovic, Petra and Ljujic, Biljana and Gazdic Jankovic, Marina and Armstrong, Lyle and Markovic, Nebojsa and Dopazo, Joaquin and Lako, Majlinda and Bauer, Roman and Stojkovic, Miodrag} } @article {705, title = {SMN1 copy-number and sequence variant analysis from next-generation sequencing data.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 12}, pages = {2073-2077}, abstract = {

Spinal muscular atrophy (SMA) is a severe neuromuscular autosomal recessive disorder affecting 1/10,000 live births. Most SMA patients present homozygous deletion of SMN1, while the vast majority of SMA carriers present only a single SMN1 copy. The sequence similarity between SMN1 and SMN2, and the complexity of the SMN locus makes the estimation of the SMN1 copy-number by next-generation sequencing (NGS) very difficult. Here, we present SMAca, the first python tool to detect SMA carriers and estimate the absolute SMN1 copy-number using NGS data. Moreover, SMAca takes advantage of the knowledge of certain variants specific to SMN1 duplication to also identify silent carriers. This tool has been validated with a cohort of 326 samples from the Navarra 1000 Genomes Project (NAGEN1000). SMAca was developed with a focus on execution speed and easy installation. This combination makes it especially suitable to be integrated into production NGS pipelines. Source code and documentation are available at https://www.github.com/babelomics/SMAca.

}, keywords = {Base Sequence, DNA Copy Number Variations, High-Throughput Nucleotide Sequencing, Humans, Reproducibility of Results, Software, Survival of Motor Neuron 1 Protein}, issn = {1098-1004}, doi = {10.1002/humu.24120}, author = {L{\'o}pez-L{\'o}pez, Daniel and Loucera, Carlos and Carmona, Rosario and Aquino, Virginia and Salgado, Josefa and Pasalodos, Sara and Miranda, Mar{\'\i}a and Alonso, {\'A}ngel and Dopazo, Joaquin} } @article {710, title = {Transcriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response.}, journal = {Genes (Basel)}, volume = {12}, year = {2020}, month = {2020 12 31}, abstract = {

Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients{\textquoteright} quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.

}, keywords = {Animals, Diabetes Mellitus, Experimental, Gene Expression Profiling, Gene Expression Regulation, Gene ontology, Humans, Metabolic Networks and Pathways, Mice, Mice, Nude, Microarray Analysis, Molecular Sequence Annotation, Principal Component Analysis, Signal Transduction, Skin, Skin Transplantation, Skin Ulcer, Streptozocin, Tissue Engineering, Transcriptome, Transplantation, Heterologous, Wound Healing}, issn = {2073-4425}, doi = {10.3390/genes12010047}, author = {Le{\'o}n, Carlos and Garcia-Garcia, Francisco and Llames, Sara and Garc{\'\i}a-P{\'e}rez, Eva and Carretero, Marta and Arriba, Mar{\'\i}a Del Carmen and Dopazo, Joaquin and Del Rio, Marcela and Escamez, Maria Jos{\'e} and Mart{\'\i}nez-Santamar{\'\i}a, Luc{\'\i}a} } @article {672, title = {Antibiotic resistance and metabolic profiles as functional biomarkers that accurately predict the geographic origin of city metagenomics samples.}, journal = {Biol Direct}, volume = {14}, year = {2019}, month = {2019 08 20}, pages = {15}, abstract = {

BACKGROUND: The availability of hundreds of city microbiome profiles allows the development of increasingly accurate predictors of the origin of a sample based on its microbiota composition. Typical microbiome studies involve the analysis of bacterial abundance profiles.

RESULTS: Here we use a transformation of the conventional bacterial strain or gene abundance profiles to functional profiles that account for bacterial metabolism and other cell functionalities. These profiles are used as features for city classification in a machine learning algorithm that allows the extraction of the most relevant features for the classification.

CONCLUSIONS: We demonstrate here that the use of functional profiles not only predict accurately the most likely origin of a sample but also to provide an interesting functional point of view of the biogeography of the microbiota. Interestingly, we show how cities can be classified based on the observed profile of antibiotic resistances.

REVIEWERS: Open peer review: Reviewed by Jin Zhuang Dou, Jing Zhou, Torsten Semmler and Eran Elhaik.

}, keywords = {biomarkers, Cities, Drug Resistance, Microbial, Machine Learning, Metabolome, Metagenome, metagenomics, Microbiota}, issn = {1745-6150}, doi = {10.1186/s13062-019-0246-9}, author = {Casimiro-Soriguer, Carlos S and Loucera, Carlos and Perez Florido, Javier and L{\'o}pez-L{\'o}pez, Daniel and Dopazo, Joaquin} } @article {403, title = {A comparison of mechanistic signaling pathway activity analysis methods.}, journal = {Brief Bioinform}, volume = {20}, year = {2019}, month = {2019 Sep 27}, pages = {1655-1668}, abstract = {

Understanding the aspects of cell functionality that account for disease mechanisms or drug modes of action is a main challenge for precision medicine. Classical gene-based approaches ignore the modular nature of most human traits, whereas conventional pathway enrichment approaches produce only illustrative results of limited practical utility. Recently, a family of new methods has emerged that change the focus from the whole pathways to the definition of elementary subpathways within them that have any mechanistic significance and to the study of their activities. Thus, mechanistic pathway activity (MPA) methods constitute a new paradigm that allows recoding poorly informative genomic measurements into cell activity quantitative values and relate them to phenotypes. Here we provide a review on the MPA methods available and explain their contribution to systems medicine approaches for addressing challenges in the diagnostic and treatment of complex diseases.

}, keywords = {Algorithms, Humans, Postmortem Changes, Signal Transduction, Systems biology, Transcriptome}, issn = {1477-4054}, doi = {10.1093/bib/bby040}, author = {Amadoz, Alicia and Hidalgo, Marta R and Cubuk, Cankut and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin} } @article {422, title = {Differential metabolic activity and discovery of therapeutic targets using summarized metabolic pathway models.}, journal = {NPJ Syst Biol Appl}, volume = {5}, year = {2019}, month = {2019}, pages = {7}, abstract = {

In spite of the increasing availability of genomic and transcriptomic data, there is still a gap between the detection of perturbations in gene expression and the understanding of their contribution to the molecular mechanisms that ultimately account for the phenotype studied. Alterations in the metabolism are behind the initiation and progression of many diseases, including cancer. The wealth of available knowledge on metabolic processes can therefore be used to derive mechanistic models that link gene expression perturbations to changes in metabolic activity that provide relevant clues on molecular mechanisms of disease and drug modes of action (MoA). In particular, pathway modules, which recapitulate the main aspects of metabolism, are especially suitable for this type of modeling. We present Metabolizer, a web-based application that offers an intuitive, easy-to-use interactive interface to analyze differences in pathway metabolic module activities that can also be used for class prediction and in silico prediction of knock-out (KO) effects. Moreover, Metabolizer can automatically predict the optimal KO intervention for restoring a diseased phenotype. We provide different types of validations of some of the predictions made by Metabolizer. Metabolizer is a web tool that allows understanding molecular mechanisms of disease or the MoA of drugs within the context of the metabolism by using gene expression measurements. In addition, this tool automatically suggests potential therapeutic targets for individualized therapeutic interventions.

}, keywords = {Computational Biology, Computer Simulation, Drug discovery, Gene Regulatory Networks, Humans, Internet, Metabolic Networks and Pathways, Models, Biological, Neoplasms, Phenotype, Software, Transcriptome}, issn = {2056-7189}, doi = {10.1038/s41540-019-0087-2}, author = {Cubuk, Cankut and Hidalgo, Marta R and Amadoz, Alicia and Rian, Kinza and Salavert, Francisco and Pujana, Miguel A and Mateo, Francesca and Herranz, Carmen and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin} } @article {610, title = {Exploring the druggable space around the Fanconi anemia pathway using machine learning and mechanistic models.}, journal = {BMC Bioinformatics}, volume = {20}, year = {2019}, month = {2019 Jul 02}, pages = {370}, abstract = {

BACKGROUND: In spite of the abundance of genomic data, predictive models that describe phenotypes as a function of gene expression or mutations are difficult to obtain because they are affected by the curse of dimensionality, given the disbalance between samples and candidate genes. And this is especially dramatic in scenarios in which the availability of samples is difficult, such as the case of rare diseases.

RESULTS: The application of multi-output regression machine learning methodologies to predict the potential effect of external proteins over the signaling circuits that trigger Fanconi anemia related cell functionalities, inferred with a mechanistic model, allowed us to detect over 20 potential therapeutic targets.

CONCLUSIONS: The use of artificial intelligence methods for the prediction of potentially causal relationships between proteins of interest and cell activities related with disease-related phenotypes opens promising avenues for the systematic search of new targets in rare diseases.

}, keywords = {Databases, Factual, Fanconi Anemia, Genomics, Humans, Machine Learning, Phenotype, Proteins, Signal Transduction}, issn = {1471-2105}, doi = {10.1186/s12859-019-2969-0}, author = {Esteban-Medina, Marina and Pe{\~n}a-Chilet, Maria and Loucera, Carlos and Dopazo, Joaquin} } @article {423, title = {Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial.}, journal = {Lancet Oncol}, volume = {20}, year = {2019}, month = {2019 Jan}, pages = {134-144}, abstract = {

BACKGROUND: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.

METHODS: In this single-arm, phase 2 trial, adult patients (aged >= 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.

FINDINGS: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51\%) of 35 evaluable patients had partial responses, nine (26\%) had stable disease, and eight (23\%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51\% (95\% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29\%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31\%] of 36 patients), neutropenia (four [11\%]), increased concentrations of alanine aminotransferase (four [11\%]), and increased concentrations of bilirubin (three [8\%]).

INTERPRETATION: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.

FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.

}, keywords = {Adult, Aged, Angiogenesis Inhibitors, Antineoplastic Agents, Female, Humans, Indazoles, Male, Middle Aged, Multivariate Analysis, Pyrimidines, Response Evaluation Criteria in Solid Tumors, Soft Tissue Neoplasms, Solitary Fibrous Tumors, Sulfonamides, Survival Analysis}, issn = {1474-5488}, doi = {10.1016/S1470-2045(18)30676-4}, author = {Martin-Broto, Javier and Stacchiotti, Silvia and Lopez-Pousa, Antonio and Redondo, Andres and Bernabeu, Daniel and de Alava, Enrique and Casali, Paolo G and Italiano, Antoine and Gutierrez, Antonio and Moura, David S and Pe{\~n}a-Chilet, Maria and Diaz-Martin, Juan and Biscuola, Michele and Taron, Miguel and Collini, Paola and Ranchere-Vince, Dominique and Garcia Del Muro, Xavier and Grignani, Giovanni and Dumont, Sarah and Martinez-Trufero, Javier and Palmerini, Emanuela and Hindi, Nadia and Sebio, Ana and Dopazo, Joaquin and Dei Tos, Angelo Paolo and LeCesne, Axel and Blay, Jean-Yves and Cruz, Josefina} } @article {389, title = {Precision medicine needs pioneering clinical bioinformaticians.}, journal = {Brief Bioinform}, volume = {20}, year = {2019}, month = {2019 May 21}, pages = {752-766}, abstract = {

Success in precision medicine depends on accessing high-quality genetic and molecular data from large, well-annotated patient cohorts that couple biological samples to comprehensive clinical data, which in conjunction can lead to effective therapies. From such a scenario emerges the need for a new professional profile, an expert bioinformatician with training in clinical areas who can make sense of multi-omics data to improve therapeutic interventions in patients, and the design of optimized basket trials. In this review, we first describe the main policies and international initiatives that focus on precision medicine. Secondly, we review the currently ongoing clinical trials in precision medicine, introducing the concept of {\textquoteright}precision bioinformatics{\textquoteright}, and we describe current pioneering bioinformatics efforts aimed at implementing tools and computational infrastructures for precision medicine in health institutions around the world. Thirdly, we discuss the challenges related to the clinical training of bioinformaticians, and the urgent need for computational specialists capable of assimilating medical terminologies and protocols to address real clinical questions. We also propose some skills required to carry out common tasks in clinical bioinformatics and some tips for emergent groups. Finally, we explore the future perspectives and the challenges faced by precision medicine bioinformatics.

}, keywords = {Cohort Studies, Computational Biology, Humans, Precision Medicine}, issn = {1477-4054}, doi = {10.1093/bib/bbx144}, author = {G{\'o}mez-L{\'o}pez, Gonzalo and Dopazo, Joaquin and Cigudosa, Juan C and Valencia, Alfonso and Al-Shahrour, F{\'a}tima} } @article {555, title = {PyCellBase, an efficient python package for easy retrieval of biological data from heterogeneous sources.}, journal = {BMC Bioinformatics}, volume = {20}, year = {2019}, month = {2019 Mar 28}, pages = {159}, abstract = {

BACKGROUND: Biological databases and repositories are incrementing in diversity and complexity over the years. This rapid expansion of current and new sources of biological knowledge raises serious problems of data accessibility and integration. To handle the growing necessity of unification, CellBase was created as an integrative solution. CellBase provides a centralized NoSQL database containing biological information from different and heterogeneous sources. Access to this information is done through a RESTful web service API, which provides an efficient interface to the data.

RESULTS: In this work we present PyCellBase, a Python package that provides programmatic access to the rich RESTful web service API offered by CellBase. This package offers a fast and user-friendly access to biological information without the need of installing any local database. In addition, a series of command-line tools are provided to perform common bioinformatic tasks, such as variant annotation. CellBase data is always available by a high-availability cluster and queries have been tuned to ensure a real-time performance.

CONCLUSION: PyCellBase is an open-source Python package that provides an efficient access to heterogeneous biological information. It allows to perform tasks that require a comprehensive set of knowledge resources, as for example variant annotation. Queries can be easily fine-tuned to retrieve the desired information of particular biological features. PyCellBase offers the convenience of an object-oriented scripting language and provides the ability to integrate the obtained results into other Python applications and pipelines.

}, keywords = {Computational Biology, Databases, Factual, Software, User-Computer Interface}, issn = {1471-2105}, doi = {10.1186/s12859-019-2726-4}, author = {Perez-Gil, Daniel and Lopez, Francisco J and Dopazo, Joaquin and Marin-Garcia, Pablo and Rendon, Augusto and Medina, Ignacio} } @article {664, title = {Using mechanistic models for the clinical interpretation of complex genomic variation}, journal = {Scientific Reports}, volume = {9}, year = {2019}, month = {Jan-12-2019}, doi = {10.1038/s41598-019-55454-7}, url = {http://www.nature.com/articles/s41598-019-55454-7http://www.nature.com/articles/s41598-019-55454-7.pdfhttp://www.nature.com/articles/s41598-019-55454-7.pdfhttp://www.nature.com/articles/s41598-019-55454-7}, author = {Pe{\~n}a-Chilet, Maria and Esteban-Medina, Marina and Falco, Matias M. and Rian, Kinza and Hidalgo, Marta R. and Loucera, Carlos and Dopazo, Joaquin} } @article {397, title = {The effects of death and post-mortem cold ischemia on human tissue transcriptomes.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Feb 13}, pages = {490}, abstract = {

Post-mortem tissues samples are a key resource for investigating patterns of gene expression. However, the processes triggered by death and the post-mortem interval (PMI) can significantly alter physiologically normal RNA levels. We investigate the impact of PMI on gene expression using data from multiple tissues of post-mortem donors obtained from the GTEx project. We find that many genes change expression over relatively short PMIs in a tissue-specific manner, but this potentially confounding effect in a biological analysis can be minimized by taking into account appropriate covariates. By comparing ante- and post-mortem blood samples, we identify the cascade of transcriptional events triggered by death of the organism. These events do not appear to simply reflect stochastic variation resulting from mRNA degradation, but active and ongoing regulation of transcription. Finally, we develop a model to predict the time since death from the analysis of the transcriptome of a few readily accessible tissues.

}, keywords = {Blood, Cold Ischemia, Death, Female, gene expression, Humans, Models, Biological, Postmortem Changes, RNA, Messenger, Stochastic Processes, Transcriptome}, issn = {2041-1723}, doi = {10.1038/s41467-017-02772-x}, author = {Ferreira, Pedro G and Mu{\~n}oz-Aguirre, Manuel and Reverter, Ferran and S{\'a} Godinho, Caio P and Sousa, Abel and Amadoz, Alicia and Sodaei, Reza and Hidalgo, Marta R and Pervouchine, Dmitri and Carbonell-Caballero, Jos{\'e} and Nurtdinov, Ramil and Breschi, Alessandra and Amador, Raziel and Oliveira, Patr{\'\i}cia and Cubuk, Cankut and Curado, Jo{\~a}o and Aguet, Fran{\c c}ois and Oliveira, Carla and Dopazo, Joaquin and Sammeth, Michael and Ardlie, Kristin G and Guig{\'o}, Roderic} } @article {406, title = {The first complete genomic structure of Butyrivibrio fibrisolvens and its chromid.}, journal = {Microb Genom}, volume = {4}, year = {2018}, month = {2018 Oct}, abstract = {

Butyrivibrio fibrisolvens forms part of the gastrointestinal microbiome of ruminants and other mammals, including humans. Indeed, it is one of the most common bacteria found in the rumen and plays an important role in ruminal fermentation of polysaccharides, yet, to date, there is no closed reference genome published for this species in any ruminant animal. We successfully assembled the nearly complete genome sequence of B. fibrisolvens strain INBov1 isolated from cow rumen using Illumina paired-end reads, 454 Roche single-end and mate pair sequencing technology. Additionally, we constructed an optical restriction map of this strain to aid in scaffold ordering and positioning, and completed the first genomic structure of this species. Moreover, we identified and assembled the first chromid of this species (pINBov266). The INBov1 genome encodes a large set of genes involved in the cellulolytic process but lacks key genes. This seems to indicate that B. fibrisolvens plays an important role in ruminal cellulolytic processes, but does not have autonomous cellulolytic capacity. When searching for genes involved in the biohydrogenation of unsaturated fatty acids, no linoleate isomerase gene was found in this strain. INBov1 does encode oleate hydratase genes known to participate in the hydrogenation of oleic acids. Furthermore, INBov1 contains an enolase gene, which has been recently determined to participate in the synthesis of conjugated linoleic acids. This work confirms the presence of a novel chromid in B. fibrisolvens and provides a new potential reference genome sequence for this species, providing new insight into its role in biohydrogenation and carbohydrate degradation.

}, keywords = {Animals, Butyrivibrio fibrisolvens, Cattle, Genome, Bacterial, Genomics, Humans, Milk, Rumen, Sequence Analysis, DNA}, issn = {2057-5858}, doi = {10.1099/mgen.0.000216}, author = {Rodr{\'\i}guez Hern{\'a}ez, Javier and Cer{\'o}n Cucchi, Maria Esperanza and Cravero, Silvio and Martinez, Maria Carolina and Gonzalez, Sergio and Puebla, Andrea and Dopazo, Joaquin and Farber, Marisa and Paniego, Norma and Rivarola, M{\'a}ximo} } @article {405, title = {Gene Expression Integration into Pathway Modules Reveals a Pan-Cancer Metabolic Landscape.}, journal = {Cancer Res}, volume = {78}, year = {2018}, month = {2018 Nov 01}, pages = {6059-6072}, abstract = {

Metabolic reprogramming plays an important role in cancer development and progression and is a well-established hallmark of cancer. Despite its inherent complexity, cellular metabolism can be decomposed into functional modules that represent fundamental metabolic processes. Here, we performed a pan-cancer study involving 9,428 samples from 25 cancer types to reveal metabolic modules whose individual or coordinated activity predict cancer type and outcome, in turn highlighting novel therapeutic opportunities. Integration of gene expression levels into metabolic modules suggests that the activity of specific modules differs between cancers and the corresponding tissues of origin. Some modules may cooperate, as indicated by the positive correlation of their activity across a range of tumors. The activity of many metabolic modules was significantly associated with prognosis at a stronger magnitude than any of their constituent genes. Thus, modules may be classified as tumor suppressors and oncomodules according to their potential impact on cancer progression. Using this modeling framework, we also propose novel potential therapeutic targets that constitute alternative ways of treating cancer by inhibiting their reprogrammed metabolism. Collectively, this study provides an extensive resource of predicted cancer metabolic profiles and dependencies. Combining gene expression with metabolic modules identifies molecular mechanisms of cancer undetected on an individual gene level and allows discovery of new potential therapeutic targets. .

}, keywords = {Cell Line, Tumor, Cluster Analysis, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Humans, Kaplan-Meier Estimate, Metabolome, mutation, Neoplasms, Oncogenes, Phenotype, Prognosis, RNA, Small Interfering, Sequence Analysis, RNA, Transcriptome, Treatment Outcome}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-17-2705}, author = {Cubuk, Cankut and Hidalgo, Marta R and Amadoz, Alicia and Pujana, Miguel A and Mateo, Francesca and Herranz, Carmen and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin} } @article {398, title = {Genomics of the origin and evolution of Citrus.}, journal = {Nature}, volume = {554}, year = {2018}, month = {2018 Feb 15}, pages = {311-316}, abstract = {

The genus Citrus, comprising some of the most widely cultivated fruit crops worldwide, includes an uncertain number of species. Here we describe ten natural citrus species, using genomic, phylogenetic and biogeographic analyses of 60 accessions representing diverse citrus germ plasms, and propose that citrus diversified during the late Miocene epoch through a rapid southeast Asian radiation that correlates with a marked weakening of the monsoons. A second radiation enabled by migration across the Wallace line gave rise to the Australian limes in the early Pliocene epoch. Further identification and analyses of hybrids and admixed genomes provides insights into the genealogy of major commercial cultivars of citrus. Among mandarins and sweet orange, we find an extensive network of relatedness that illuminates the domestication of these groups. Widespread pummelo admixture among these mandarins and its correlation with fruit size and acidity suggests a plausible role of pummelo introgression in the selection of palatable mandarins. This work provides a new evolutionary framework for the genus Citrus.

}, keywords = {Asia, Southeastern, Biodiversity, citrus, Crop Production, Evolution, Molecular, Genetic Speciation, Genome, Plant, Genomics, Haplotypes, Heterozygote, History, Ancient, Human Migration, Hybridization, Genetic, Phylogeny}, issn = {1476-4687}, doi = {10.1038/nature25447}, author = {Wu, Guohong Albert and Terol, Javier and Iba{\~n}ez, Victoria and L{\'o}pez-Garc{\'\i}a, Antonio and P{\'e}rez-Rom{\'a}n, Estela and Borred{\'a}, Carles and Domingo, Concha and Tadeo, Francisco R and Carbonell-Caballero, Jos{\'e} and Alonso, Roberto and Curk, Franck and Du, Dongliang and Ollitrault, Patrick and Roose, Mikeal L and Dopazo, Joaquin and Gmitter, Frederick G and Rokhsar, Daniel S and Talon, Manuel} } @article {404, title = {Models of cell signaling uncover molecular mechanisms of high-risk neuroblastoma and predict disease outcome.}, journal = {Biol Direct}, volume = {13}, year = {2018}, month = {2018 Aug 22}, pages = {16}, abstract = {

BACKGROUND: Despite the progress in neuroblastoma therapies the mortality of high-risk patients is still high (40-50\%) and the molecular basis of the disease remains poorly known. Recently, a mathematical model was used to demonstrate that the network regulating stress signaling by the c-Jun N-terminal kinase pathway played a crucial role in survival of patients with neuroblastoma irrespective of their MYCN amplification status. This demonstrates the enormous potential of computational models of biological modules for the discovery of underlying molecular mechanisms of diseases.

RESULTS: Since signaling is known to be highly relevant in cancer, we have used a computational model of the whole cell signaling network to understand the molecular determinants of bad prognostic in neuroblastoma. Our model produced a comprehensive view of the molecular mechanisms of neuroblastoma tumorigenesis and progression.

CONCLUSION: We have also shown how the activity of signaling circuits can be considered a reliable model-based prognostic biomarker.

REVIEWERS: This article was reviewed by Tim Beissbarth, Wenzhong Xiao and Joanna Polanska. For the full reviews, please go to the Reviewers{\textquoteright} comments section.

}, keywords = {Computational Biology, Gene Expression Regulation, Neoplastic, Humans, JNK Mitogen-Activated Protein Kinases, Models, Theoretical, Neuroblastoma, Signal Transduction}, issn = {1745-6150}, doi = {10.1186/s13062-018-0219-4}, author = {Hidalgo, Marta R and Amadoz, Alicia and Cubuk, Cankut and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin} } @article {407, title = {The modular network structure of the mutational landscape of Acute Myeloid Leukemia.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0202926}, abstract = {

Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50\% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways.

}, keywords = {Adult, Aged, Cytodiagnosis, Exome Sequencing, Female, Gene Regulatory Networks, Genetic Association Studies, Genetic Heterogeneity, Humans, Karyotype, Leukemia, Myeloid, Acute, Male, Middle Aged, mutation, Neoplasm Proteins, Nucleophosmin, Prognosis}, issn = {1932-6203}, doi = {10.1371/journal.pone.0202926}, author = {Ib{\'a}{\~n}ez, Mariam and Carbonell-Caballero, Jos{\'e} and Such, Esperanza and Garc{\'\i}a-Alonso, Luz and Liquori, Alessandro and L{\'o}pez-Pav{\'\i}a, Mar{\'\i}a and LLop, Marta and Alonso, Carmen and Barrag{\'a}n, Eva and G{\'o}mez-Segu{\'\i}, In{\'e}s and Neef, Alexander and Herv{\'a}s, David and Montesinos, Pau and Sanz, Guillermo and Sanz, Miguel Angel and Dopazo, Joaquin and Cervera, Jos{\'e}} } @article {432, title = {ATGC transcriptomics: a web-based application to integrate, explore and analyze de novo transcriptomic data.}, journal = {BMC Bioinformatics}, volume = {18}, year = {2017}, month = {2017 Feb 22}, pages = {121}, abstract = {

BACKGROUND: In the last years, applications based on massively parallelized RNA sequencing (RNA-seq) have become valuable approaches for studying non-model species, e.g., without a fully sequenced genome. RNA-seq is a useful tool for detecting novel transcripts and genetic variations and for evaluating differential gene expression by digital measurements. The large and complex datasets resulting from functional genomic experiments represent a challenge in data processing, management, and analysis. This problem is especially significant for small research groups working with non-model species.

RESULTS: We developed a web-based application, called ATGC transcriptomics, with a flexible and adaptable interface that allows users to work with new generation sequencing (NGS) transcriptomic analysis results using an ontology-driven database. This new application simplifies data exploration, visualization, and integration for a better comprehension of the results.

CONCLUSIONS: ATGC transcriptomics provides access to non-expert computer users and small research groups to a scalable storage option and simple data integration, including database administration and management. The software is freely available under the terms of GNU public license at http://atgcinta.sourceforge.net .

}, keywords = {Animals, Databases, Genetic, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Internet, Sequence Analysis, RNA, Transcriptome, User-Computer Interface}, issn = {1471-2105}, doi = {10.1186/s12859-017-1494-2}, author = {Gonzalez, Sergio and Clavijo, Bernardo and Rivarola, M{\'a}ximo and Moreno, Patricio and Fernandez, Paula and Dopazo, Joaquin and Paniego, Norma} } @article {384, title = {Genomic expression differences between cutaneous cells from red hair color individuals and black hair color individuals based on bioinformatic analysis.}, journal = {Oncotarget}, volume = {8}, year = {2017}, month = {2017 Feb 14}, pages = {11589-11599}, abstract = {

The MC1R gene plays a crucial role in pigmentation synthesis. Loss-of-function MC1R variants, which impair protein function, are associated with red hair color (RHC) phenotype and increased skin cancer risk. Cultured cutaneous cells bearing loss-of-function MC1R variants show a distinct gene expression profile compared to wild-type MC1R cultured cutaneous cells. We analysed the gene signature associated with RHC co-cultured melanocytes and keratinocytes by Protein-Protein interaction (PPI) network analysis to identify genes related with non-functional MC1R variants. From two detected networks, we selected 23 nodes as hub genes based on topological parameters. Differential expression of hub genes was then evaluated in healthy skin biopsies from RHC and black hair color (BHC) individuals. We also compared gene expression in melanoma tumors from individuals with RHC versus BHC. Gene expression in normal skin from RHC cutaneous cells showed dysregulation in 8 out of 23 hub genes (CLN3, ATG10, WIPI2, SNX2, GABARAPL2, YWHA, PCNA and GBAS). Hub genes did not differ between melanoma tumors in RHC versus BHC individuals. The study suggests that healthy skin cells from RHC individuals present a constitutive genomic deregulation associated with the red hair phenotype and identify novel genes involved in melanocyte biology.

}, keywords = {Adult, Coculture Techniques, Computational Biology, gene expression, Genetic Predisposition to Disease, Genomics, Hair Color, Humans, Keratinocytes, Melanocytes, Middle Aged, Phenotype, Receptor, Melanocortin, Type 1}, issn = {1949-2553}, doi = {10.18632/oncotarget.14140}, url = {http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget\&page=article\&op=view\&path\%5B\%5D=14140\&path\%5B\%5D=45094}, author = {Puig-Butille, Joan Anton and Gimenez-Xavier, Pol and Visconti, Alessia and Nsengimana, J{\'e}r{\'e}mie and Garcia-Garcia, Francisco and Tell-Marti, Gemma and Escamez, Maria Jos{\'e} and Newton-Bishop, Julia and Bataille, Veronique and Del Rio, Marcela and Dopazo, Joaquin and Falchi, Mario and Puig, Susana} } @article {386, title = {GGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates.}, journal = {N Engl J Med}, volume = {376}, year = {2017}, month = {2017 May 04}, pages = {1794-1795}, keywords = {Aged, Amino Acid Sequence, Bone Density Conservation Agents, Dimethylallyltranstransferase, Diphosphonates, Exome, Farnesyltranstransferase, Female, Femoral Fractures, Geranyltranstransferase, Humans, Middle Aged, mutation}, issn = {1533-4406}, doi = {10.1056/NEJMc1612804}, url = {http://www.nejm.org/doi/full/10.1056/NEJMc1612804}, author = {Roca-Ayats, Neus and Balcells, Susana and Garcia-Giralt, Nat{\`a}lia and Falc{\'o}-Mascar{\'o}, Maite and Mart{\'\i}nez-Gil, N{\'u}ria and Abril, Josep F and Urreizti, Roser and Dopazo, Joaquin and Quesada-G{\'o}mez, Jos{\'e} M and Nogu{\'e}s, Xavier and Mellibovsky, Leonardo and Prieto-Alhambra, Daniel and Dunford, James E and Javaid, Muhammad K and Russell, R Graham and Grinberg, Daniel and D{\'\i}ez-P{\'e}rez, Adolfo} } @article {457, title = {Global Transcriptome Analysis of Primary Cerebrocortical Cells: Identification of Genes Regulated by Triiodothyronine in Specific Cell Types.}, journal = {Cereb Cortex}, volume = {27}, year = {2017}, month = {2017 01 01}, pages = {706-717}, abstract = {

Thyroid hormones, thyroxine, and triiodothyronine (T3) are crucial for cerebral cortex development acting through regulation of gene expression. To define the transcriptional program under T3 regulation, we have performed RNA-Seq of T3-treated and untreated primary mouse cerebrocortical cells. The expression of 1145 genes or 7.7\% of expressed genes was changed upon T3 addition, of which 371 responded to T3 in the presence of cycloheximide indicating direct transcriptional regulation. The results were compared with available transcriptomic datasets of defined cellular types. In this way, we could identify targets of T3 within genes enriched in astrocytes and neurons, in specific layers including the subplate, and in specific neurons such as prepronociceptin, cholecystokinin, or cortistatin neurons. The subplate and the prepronociceptin neurons appear as potentially major targets of T3 action. T3 upregulates mostly genes related to cell membrane events, such as G-protein signaling, neurotransmission, and ion transport and downregulates genes involved in nuclear events associated with the M phase of cell cycle, such as chromosome organization and segregation. Remarkably, the transcriptomic changes induced by T3 sustain the transition from fetal to adult patterns of gene expression. The results allow defining in molecular terms the elusive role of thyroid hormones on neocortical development.

}, keywords = {Animals, Astrocytes, Cells, Cultured, Cerebral Cortex, Fluorescent Antibody Technique, Gene Expression Profiling, Mice, 129 Strain, Mice, Inbred BALB C, Mice, Inbred C57BL, Neurons, Piperazines, Transcriptome, Triiodothyronine}, issn = {1460-2199}, doi = {10.1093/cercor/bhv273}, author = {Gil-Iba{\~n}ez, Pilar and Garcia-Garcia, Francisco and Dopazo, Joaquin and Bernal, Juan and Morte, Beatriz} } @article {399, title = {Graph-theoretical comparison of normal and tumor networks in identifying BRCA genes.}, journal = {BMC Syst Biol}, volume = {11}, year = {2017}, month = {2017 Nov 22}, pages = {110}, abstract = {

BACKGROUND: Identification of driver genes related to certain types of cancer is an important research topic. Several systems biology approaches have been suggested, in particular for the identification of breast cancer (BRCA) related genes. Such approaches usually rely on differential gene expression and/or mutational landscape data. In some cases interaction network data is also integrated to identify cancer-related modules computationally.

RESULTS: We provide a framework for the comparative graph-theoretical analysis of networks integrating the relevant gene expression, mutations, and potein-protein interaction network data. The comparisons involve a graph-theoretical analysis of normal and tumor network pairs across all instances of a given set of breast cancer samples. The network measures under consideration are based on appropriate formulations of various centrality measures: betweenness, clustering coefficients, degree centrality, random walk distances, graph-theoretical distances, and Jaccard index centrality.

CONCLUSIONS: Among all the studied centrality-based graph-theoretical properties, we show that a betweenness-based measure differentiates BRCA genes across all normal versus tumor network pairs, than the rest of the popular centrality-based measures. The AUROC and AUPR values of the gene lists ordered with respect to the measures under study as compared to NCBI BioSystems pathway and the COSMIC database of cancer genes are the largest with the betweenness-based differentiation, followed by the measure based on degree centrality. In order to test the robustness of the suggested measures in prioritizing cancer genes, we further tested the two most promising measures, those based on betweenness and degree centralities, on randomly rewired networks. We show that both measures are quite resilient to noise in the input interaction network. We also compared the same measures against a state-of-the-art alternative disease gene prioritization method, MUFFFINN. We show that both our graph-theoretical measures outperform MUFFINN prioritizations in terms of ROC and precions/recall analysis. Finally, we filter the ordered list of the best measure, the betweenness-based differentiation, via a maximum-weight independent set formulation and investigate the top 50 genes in regards to literature verification. We show that almost all genes in the list are verified by the breast cancer literature and three genes are presented as novel genes that may potentialy be BRCA-related but missing in literature.

}, keywords = {Breast Neoplasms, Female, Gene Regulatory Networks, Genes, Tumor Suppressor, Humans, Models, Theoretical, mutation}, issn = {1752-0509}, doi = {10.1186/s12918-017-0495-0}, author = {Dopazo, Joaquin and Erten, Cesim} } @article {429, title = {Graph-theoretical comparison of normal and tumor networks in identifying BRCA genes}, journal = {BMC Systems Biology}, volume = {11}, year = {2017}, month = {Jan-12-2017}, doi = {10.1186/s12918-017-0495-0}, url = {https://bmcsystbiol.biomedcentral.com/articles/10.1186/s12918-017-0495-0http://link.springer.com/content/pdf/10.1186/s12918-017-0495-0.pdf}, author = {Dopazo, Joaquin and Erten, Cesim} } @article {387, title = {HGVA: the Human Genome Variation Archive.}, journal = {Nucleic Acids Res}, volume = {45}, year = {2017}, month = {2017 Jul 03}, pages = {W189-W194}, abstract = {

High-profile genomic variation projects like the 1000 Genomes project or the Exome Aggregation Consortium, are generating a wealth of human genomic variation knowledge which can be used as an essential reference for identifying disease-causing genotypes. However, accessing these data, contrasting the various studies and integrating those data in downstream analyses remains cumbersome. The Human Genome Variation Archive (HGVA) tackles these challenges and facilitates access to genomic data for key reference projects in a clean, fast and integrated fashion. HGVA provides an efficient and intuitive web-interface for easy data mining, a comprehensive RESTful API and client libraries in Python, Java and JavaScript for fast programmatic access to its knowledge base. HGVA calculates population frequencies for these projects and enriches their data with variant annotation provided by CellBase, a rich and fast annotation solution. HGVA serves as a proof-of-concept of the genome analysis developments being carried out by the University of Cambridge together with UK{\textquoteright}s 100 000 genomes project and the National Institute for Health Research BioResource Rare-Diseases, in particular, deploying open-source for Computational Biology (OpenCB) software platform for storing and analyzing massive genomic datasets.

}, keywords = {Genetic Variation, Genome, Human, Humans, Internet, Software, User-Computer Interface}, issn = {1362-4962}, doi = {10.1093/nar/gkx445}, url = {https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkx445}, author = {Lopez, Javier and Coll, Jacobo and Haimel, Matthias and Kandasamy, Swaathi and T{\'a}rraga, Joaqu{\'\i}n and Furio-Tari, Pedro and Bari, Wasim and Bleda, Marta and Rueda, Antonio and Gr{\"a}f, Stefan and Rendon, Augusto and Dopazo, Joaquin and Medina, Ignacio} } @article {434, title = {High throughput estimation of functional cell activities reveals disease mechanisms and predicts relevant clinical outcomes.}, journal = {Oncotarget}, volume = {8}, year = {2017}, month = {2017 Jan 17}, pages = {5160-5178}, abstract = {

Understanding the aspects of the cell functionality that account for disease or drug action mechanisms is a main challenge for precision medicine. Here we propose a new method that models cell signaling using biological knowledge on signal transduction. The method recodes individual gene expression values (and/or gene mutations) into accurate measurements of changes in the activity of signaling circuits, which ultimately constitute high-throughput estimations of cell functionalities caused by gene activity within the pathway. Moreover, such estimations can be obtained either at cohort-level, in case/control comparisons, or personalized for individual patients. The accuracy of the method is demonstrated in an extensive analysis involving 5640 patients from 12 different cancer types. Circuit activity measurements not only have a high diagnostic value but also can be related to relevant disease outcomes such as survival, and can be used to assess therapeutic interventions.

}, keywords = {Computational Biology, gene expression, Gene Regulatory Networks, Humans, mutation, Neoplasms, Precision Medicine, Sequence Analysis, RNA, Signal Transduction}, issn = {1949-2553}, doi = {10.18632/oncotarget.14107}, author = {Hidalgo, Marta R and Cubuk, Cankut and Amadoz, Alicia and Salavert, Francisco and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin} } @article {383, title = {Integration of transcriptomic and metabolic data reveals hub transcription factors involved in drought stress response in sunflower (Helianthus annuus L.).}, journal = {Plant Mol Biol}, volume = {94}, year = {2017}, month = {2017 Jul}, pages = {549-564}, abstract = {

By integration of transcriptional and metabolic profiles we identified pathways and hubs transcription factors regulated during drought conditions in sunflower, useful for applications in molecular and/or biotechnological breeding. Drought is one of the most important environmental stresses that effects crop productivity in many agricultural regions. Sunflower is tolerant to drought conditions but the mechanisms involved in this tolerance remain unclear at the molecular level. The aim of this study was to characterize and integrate transcriptional and metabolic pathways related to drought stress in sunflower plants, by using a system biology approach. Our results showed a delay in plant senescence with an increase in the expression level of photosynthesis related genes as well as higher levels of sugars, osmoprotectant amino acids and ionic nutrients under drought conditions. In addition, we identified transcription factors that were upregulated during drought conditions and that may act as hubs in the transcriptional network. Many of these transcription factors belong to families implicated in the drought response in model species. The integration of transcriptomic and metabolomic data in this study, together with physiological measurements, has improved our understanding of the biological responses during droughts and contributes to elucidate the molecular mechanisms involved under this environmental condition. These findings will provide useful biotechnological tools to improve stress tolerance while maintaining crop yield under restricted water availability.

}, keywords = {Chlorophyll, Gene Expression Regulation, Plant, Helianthus, Plant Leaves, Plant Proteins, Protein Array Analysis, RNA, Plant, Stress, Physiological, Transcription Factors, Water}, issn = {1573-5028}, doi = {10.1007/s11103-017-0625-5}, author = {Moschen, Sebasti{\'a}n and Di Rienzo, Julio A and Higgins, Janet and Tohge, Takayuki and Watanabe, Mutsumi and Gonzalez, Sergio and Rivarola, M{\'a}ximo and Garcia-Garcia, Francisco and Dopazo, Joaquin and Hopp, H Esteban and Hoefgen, Rainer and Fernie, Alisdair R and Paniego, Norma and Fernandez, Paula and Heinz, Ruth A} } @article {433, title = {Mutations in TRAPPC11 are associated with a congenital disorder of glycosylation.}, journal = {Hum Mutat}, volume = {38}, year = {2017}, month = {2017 Feb}, pages = {148-151}, abstract = {

Congenital disorders of glycosylation (CDG) are a heterogeneous and rapidly growing group of diseases caused by abnormal glycosylation of proteins and/or lipids. Mutations in genes involved in the homeostasis of the endoplasmic reticulum (ER), the Golgi apparatus (GA), and the vesicular trafficking from the ER to the ER-Golgi intermediate compartment (ERGIC) have been found to be associated with CDG. Here, we report a patient with defects in both N- and O-glycosylation combined with a delayed vesicular transport in the GA due to mutations in TRAPPC11, a subunit of the TRAPPIII complex. TRAPPIII is implicated in the anterograde transport from the ER to the ERGIC as well as in the vesicle export from the GA. This report expands the spectrum of genetic alterations associated with CDG, providing new insights for the diagnosis and the understanding of the physiopathological mechanisms underlying glycosylation disorders.

}, keywords = {Abnormalities, Multiple, Alleles, Amino Acid Substitution, Brain, Congenital Disorders of Glycosylation, Genotype, Humans, Magnetic Resonance Imaging, Male, mutation, Phenotype, Vesicular Transport Proteins, Whole Genome Sequencing}, issn = {1098-1004}, doi = {10.1002/humu.23145}, author = {Matalonga, Leslie and Bravo, Miren and Serra-Peinado, Carla and Garc{\'\i}a-Pelegr{\'\i}, Elisabeth and Ugarteburu, Olatz and Vidal, Silvia and Llambrich, Maria and Quintana, Ester and Fuster-Jorge, Pedro and Gonzalez-Bravo, Maria Nieves and Beltran, Sergi and Dopazo, Joaquin and Garcia-Garcia, Francisco and Foulquier, Fran{\c c}ois and Matthijs, Gert and Mills, Philippa and Ribes, Antonia and Egea, Gustavo and Briones, Paz and Tort, Frederic and Gir{\'o}s, Marisa} } @article {388, title = {Reference genome assessment from a population scale perspective: an accurate profile of variability and noise.}, journal = {Bioinformatics}, volume = {33}, year = {2017}, month = {2017 Nov 15}, pages = {3511-3517}, abstract = {

MOTIVATION: Current plant and animal genomic studies are often based on newly assembled genomes that have not been properly consolidated. In this scenario, misassembled regions can easily lead to false-positive findings. Despite quality control scores are included within genotyping protocols, they are usually employed to evaluate individual sample quality rather than reference sequence reliability. We propose a statistical model that combines quality control scores across samples in order to detect incongruent patterns at every genomic region. Our model is inherently robust since common artifact signals are expected to be shared between independent samples over misassembled regions of the genome.

RESULTS: The reliability of our protocol has been extensively tested through different experiments and organisms with accurate results, improving state-of-the-art methods. Our analysis demonstrates synergistic relations between quality control scores and allelic variability estimators, that improve the detection of misassembled regions, and is able to find strong artifact signals even within the human reference assembly. Furthermore, we demonstrated how our model can be trained to properly rank the confidence of a set of candidate variants obtained from new independent samples.

AVAILABILITY AND IMPLEMENTATION: This tool is freely available at http://gitlab.com/carbonell/ces.

CONTACT: jcarbonell.cipf@gmail.com or joaquin.dopazo@juntadeandalucia.es.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

}, keywords = {Animals, Genetic Variation, Genome, Genomics, Genotype, Humans, Models, Statistical, Quality Control, Reproducibility of Results, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btx482}, url = {https://academic.oup.com/bioinformatics/article-lookup/doi/10.1093/bioinformatics/btx482}, author = {Carbonell-Caballero, Jos{\'e} and Amadoz, Alicia and Alonso, Roberto and Hidalgo, Marta R and Cubuk, Cankut and Conesa, David and L{\'o}pez-Qu{\'\i}lez, Antonio and Dopazo, Joaquin} } @article {382, title = {VISMapper: ultra-fast exhaustive cartography of viral insertion sites for gene therapy.}, journal = {BMC Bioinformatics}, volume = {18}, year = {2017}, month = {2017 Sep 20}, pages = {421}, abstract = {

BACKGROUND: The possibility of integrating viral vectors to become a persistent part of the host genome makes them a crucial element of clinical gene therapy. However, viral integration has associated risks, such as the unintentional activation of oncogenes that can result in cancer. Therefore, the analysis of integration sites of retroviral vectors is a crucial step in developing safer vectors for therapeutic use.

RESULTS: Here we present VISMapper, a vector integration site analysis web server, to analyze next-generation sequencing data for retroviral vector integration sites. VISMapper can be found at: http://vismapper.babelomics.org .

CONCLUSIONS: Because it uses novel mapping algorithms VISMapper is remarkably faster than previous available programs. It also provides a useful graphical interface to analyze the integration sites found in the genomic context.

}, keywords = {Base Sequence, Genetic Therapy, Genetic Vectors, High-Throughput Nucleotide Sequencing, Humans, Internet, User-Computer Interface, Virus Integration}, issn = {1471-2105}, doi = {10.1186/s12859-017-1837-z}, author = {Juanes, Jos{\'e} M and Gallego, Asunci{\'o}n and T{\'a}rraga, Joaqu{\'\i}n and Chaves, Felipe J and Marin-Garcia, Pablo and Medina, Ignacio and Arnau, Vicente and Dopazo, Joaquin} } @article {1231, title = {Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes.}, journal = {Genome biology}, volume = {18}, year = {2017}, month = {2017 Mar 08}, pages = {48}, abstract = {BACKGROUND: Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human. RESULTS: We performed de novo mutation (DNM) screening on 24 HSCR trios. We identify 28 DNMs in 21 different genes. Eight of the DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not reported in the ENS. Knockdown of all 12 genes with missense or loss-of-function DNMs showed that the orthologs of four genes (DENND3, NCLN, NUP98, and TBATA) are indispensable for ENS development in zebrafish, and these results were confirmed by CRISPR knockout. These genes are also expressed in human and mouse gut and/or ENS progenitors. Importantly, the encoded proteins are linked to neuronal processes shared by the central nervous system and the ENS. CONCLUSIONS: Our data open new fields of investigation into HSCR pathology and provide novel insights into the development of the ENS. Moreover, the study demonstrates that functional analyses of genes carrying DNMs are warranted to delineate the full genetic architecture of rare complex diseases.}, keywords = {Hirschprung, Rare Disease, WES}, issn = {1474-760X}, doi = {10.1186/s13059-017-1174-6}, url = {http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-6}, author = {Gui, Hongsheng and Schriemer, Duco and Cheng, William W and Chauhan, Rajendra K and Anti{\v n}olo, Guillermo and Berrios, Courtney and Bleda, Marta and Brooks, Alice S and Brouwer, Rutger W W and Burns, Alan J and Cherny, Stacey S and Dopazo, Joaquin and Eggen, Bart J L and Griseri, Paola and Jalloh, Binta and Le, Thuy-Linh and Lui, Vincent C H and Luz{\'o}n-Toro, Berta and Matera, Ivana and Ngan, Elly S W and Pelet, Anna and Ruiz-Ferrer, Macarena and Sham, Pak C and Shepherd, Iain T and So, Man-Ting and Sribudiani, Yunia and Tang, Clara S M and van den Hout, Mirjam C G N and van der Linde, Herma C and van Ham, Tjakko J and van IJcken, Wilfred F J and Verheij, Joke B G M and Amiel, Jeanne and Borrego, Salud and Ceccherini, Isabella and Chakravarti, Aravinda and Lyonnet, Stanislas and Tam, Paul K H and Garcia-Barcel{\'o}, Maria-Merc{\`e} and Hofstra, Robert Mw} } @article {431, title = {Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes}, journal = {Genome Biology}, volume = {18}, year = {2017}, month = {Jan-12-2017}, doi = {10.1186/s13059-017-1174-6}, url = {http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-6http://link.springer.com/content/pdf/10.1186/s13059-017-1174-6.pdf}, author = {Gui, Hongsheng and Schriemer, Duco and Cheng, William W. and Chauhan, Rajendra K. and Anti{\v n}olo, Guillermo and Berrios, Courtney and Bleda, Marta and Brooks, Alice S. and Brouwer, Rutger W. W. and Burns, Alan J. and Cherny, Stacey S. and Dopazo, Joaquin and Eggen, Bart J. L. and Griseri, Paola and Jalloh, Binta and Le, Thuy-Linh and Lui, Vincent C. H. and Luz{\'o}n-Toro, Berta and Matera, Ivana and Ngan, Elly S. W. and Pelet, Anna and Ruiz-Ferrer, Macarena and Sham, Pak C. and Shepherd, Iain T. and So, Man-Ting and Sribudiani, Yunia and Tang, Clara S. M. and van den Hout, Mirjam C. G. N. and van der Linde, Herma C. and van Ham, Tjakko J. and van IJcken, Wilfred F. J. and Verheij, Joke B. G. M. and Amiel, Jeanne and Borrego, Salud and Ceccherini, Isabella and Chakravarti, Aravinda and Lyonnet, Stanislas and Tam, Paul K. H. and Garcia-Barcel{\'o}, Maria-Merc{\`e} and Hofstra, Robert M. W.} } @article {1198, title = {Chronic subordination stress selectively downregulates the insulin signaling pathway in liver and skeletal muscle but not in adipose tissue of male mice.}, journal = {Stress (Amsterdam, Netherlands)}, year = {2016}, month = {2016 Mar 7}, pages = {1-11}, abstract = {Chronic stress has been associated with obesity, glucose intolerance, and insulin resistance. We developed a model of chronic psychosocial stress (CPS) in which subordinate mice are vulnerable to obesity and the metabolic-like syndrome while dominant mice exhibit a healthy metabolic phenotype. Here we tested the hypothesis that the metabolic difference between subordinate and dominant mice is associated with changes in functional pathways relevant for insulin sensitivity, glucose and lipid homeostasis. Male mice were exposed to CPS for four weeks and fed either a standard diet or a high-fat diet (HFD). We first measured, by real-time PCR candidate genes, in the liver, skeletal muscle, and the perigonadal white adipose tissue (pWAT). Subsequently, we used a probabilistic analysis approach to analyze different ways in which signals can be transmitted across the pathways in each tissue. Results showed that subordinate mice displayed a drastic downregulation of the insulin pathway in liver and muscle, indicative of insulin resistance, already on standard diet. Conversely, pWAT showed molecular changes suggestive of facilitated fat deposition in an otherwise insulin-sensitive tissue. The molecular changes in subordinate mice fed a standard diet were greater compared to HFD-fed controls. Finally, dominant mice maintained a substantially normal metabolic and molecular phenotype even when fed a HFD. Overall, our data demonstrate that subordination stress is a potent stimulus for the downregulation of the insulin signaling pathway in liver and muscle and a major risk factor for the development of obesity, insulin resistance, and type 2 diabetes mellitus.}, keywords = {Adipose tissue, insulin, IRS1, IRS2, metabolic syndrome, obesity, pathway analysis}, issn = {1607-8888}, doi = {10.3109/10253890.2016.1151491}, url = {http://www.tandfonline.com/doi/abs/10.3109/10253890.2016.1151491?journalCode=ists20}, author = {Sanghez, Valentina and Cubuk, Cankut and Sebasti{\'a}n-Leon, Patricia and Carobbio, Stefania and Dopazo, Joaquin and Vidal-Puig, Antonio and Bartolomucci, Alessandro} } @article {436, title = {Dysfunctional mitochondrial fission impairs cell reprogramming.}, journal = {Cell Cycle}, volume = {15}, year = {2016}, month = {2016 Dec}, pages = {3240-3250}, abstract = {

We have recently shown that mitochondrial fission is induced early in reprogramming in a Drp1-dependent manner; however, the identity of the factors controlling Drp1 recruitment to mitochondria was unexplored. To investigate this, we used a panel of RNAi targeting factors involved in the regulation of mitochondrial dynamics and we observed that MiD51, Gdap1 and, to a lesser extent, Mff were found to play key roles in this process. Cells derived from Gdap1-null mice were used to further explore the role of this factor in cell reprogramming. Microarray data revealed a prominent down-regulation of cell cycle pathways in Gdap1-null cells early in reprogramming and cell cycle profiling uncovered a G2/M growth arrest in Gdap1-null cells undergoing reprogramming. High-Content analysis showed that this growth arrest was DNA damage-independent. We propose that lack of efficient mitochondrial fission impairs cell reprogramming by interfering with cell cycle progression in a DNA damage-independent manner.

}, keywords = {Animals, Cell Cycle Checkpoints, Cellular Reprogramming, DNA Damage, G2 Phase, Gene Knockdown Techniques, Mice, Mitochondrial Dynamics, Mitosis, Nerve Tissue Proteins, Pluripotent Stem Cells, Transcription Factors}, issn = {1551-4005}, doi = {10.1080/15384101.2016.1241930}, author = {Prieto, Javier and Le{\'o}n, Marian and Ponsoda, Xavier and Garcia-Garcia, Francisco and Bort, Roque and Serna, Eva and Barneo-Mu{\~n}oz, Manuela and Palau, Francesc and Dopazo, Joaquin and L{\'o}pez-Garc{\'\i}a, Carlos and Torres, Josema} } @article {559, title = {Extension of human lncRNA transcripts by RACE coupled with long-read high-throughput sequencing (RACE-Seq)}, journal = {Nature Communications}, volume = {7}, year = {2016}, month = {Jan-11-2016}, doi = {10.1038/ncomms12339}, url = {http://www.nature.com/articles/ncomms12339http://www.nature.com/articles/ncomms12339.pdfhttp://www.nature.com/articles/ncomms12339.pdfhttp://www.nature.com/articles/ncomms12339}, author = {Lagarde, Julien and Uszczynska-Ratajczak, Barbara and Santoyo-L{\'o}pez, Javier and Gonzalez, Jose Manuel and Tapanari, Electra and Mudge, Jonathan M. and Steward, Charles A. and Wilming, Laurens and Tanzer, Andrea and Howald, C{\'e}dric and Chrast, Jacqueline and Vela-Boza, Alicia and Rueda, Antonio and Lopez-Domingo, Francisco J. and Dopazo, Joaquin and Reymond, Alexandre and Guig{\'o}, Roderic and Harrow, Jennifer} } @article {1211, title = {Extension of human lncRNA transcripts by RACE coupled with long-read high-throughput sequencing (RACE-Seq).}, journal = {Nature communications}, volume = {7}, year = {2016}, month = {2016}, pages = {12339}, abstract = {Long non-coding RNAs (lncRNAs) constitute a large, yet mostly uncharacterized fraction of the mammalian transcriptome. Such characterization requires a comprehensive, high-quality annotation of their gene structure and boundaries, which is currently lacking. Here we describe RACE-Seq, an experimental workflow designed to address this based on RACE (rapid amplification of cDNA ends) and long-read RNA sequencing. We apply RACE-Seq to 398 human lncRNA genes in seven tissues, leading to the discovery of 2,556 on-target, novel transcripts. About 60\% of the targeted loci are extended in either 5{\textquoteright} or 3{\textquoteright}, often reaching genomic hallmarks of gene boundaries. Analysis of the novel transcripts suggests that lncRNAs are as long, have as many exons and undergo as much alternative splicing as protein-coding genes, contrary to current assumptions. Overall, we show that RACE-Seq is an effective tool to annotate an organism{\textquoteright}s deep transcriptome, and compares favourably to other targeted sequencing techniques.}, issn = {2041-1723}, doi = {10.1038/ncomms12339}, url = {http://www.nature.com/articles/ncomms12339}, author = {Lagarde, Julien and Uszczynska-Ratajczak, Barbara and Santoyo-L{\'o}pez, Javier and Gonzalez, Jose Manuel and Tapanari, Electra and Mudge, Jonathan M and Steward, Charles A and Wilming, Laurens and Tanzer, Andrea and Howald, C{\'e}dric and Chrast, Jacqueline and Vela-Boza, Alicia and Antonio Rueda and L{\'o}pez-Domingo, Francisco J and Dopazo, Joaquin and Reymond, Alexandre and Guig{\'o}, Roderic and Harrow, Jennifer} } @article {1195, title = {HPG pore: an efficient and scalable framework for nanopore sequencing data.}, journal = {BMC bioinformatics}, volume = {17}, year = {2016}, month = {2016}, pages = {107}, abstract = {BACKGROUND: The use of nanopore technologies is expected to spread in the future because they are portable and can sequence long fragments of DNA molecules without prior amplification. The first nanopore sequencer available, the MinION{\texttrademark} from Oxford Nanopore Technologies, is a USB-connected, portable device that allows real-time DNA analysis. In addition, other new instruments are expected to be released soon, which promise to outperform the current short-read technologies in terms of throughput. Despite the flood of data expected from this technology, the data analysis solutions currently available are only designed to manage small projects and are not scalable. RESULTS: Here we present HPG Pore, a toolkit for exploring and analysing nanopore sequencing data. HPG Pore can run on both individual computers and in the Hadoop distributed computing framework, which allows easy scale-up to manage the large amounts of data expected to result from extensive use of nanopore technologies in the future. CONCLUSIONS: HPG Pore allows for virtually unlimited sequencing data scalability, thus guaranteeing its continued management in near future scenarios. HPG Pore is available in GitHub at http://github.com/opencb/hpg-pore .}, keywords = {hadoop, HPC, nanopore, NGS}, issn = {1471-2105}, doi = {10.1186/s12859-016-0966-0}, url = {http://www.biomedcentral.com/1471-2105/17/107}, author = {T{\'a}rraga, Joaqu{\'\i}n and Gallego, Asunci{\'o}n and Arnau, Vicente and Medina, Ignacio and Dopazo, Joaquin} } @article {560, title = {HPG pore: an efficient and scalable framework for nanopore sequencing data}, journal = {BMC Bioinformatics}, volume = {17}, year = {2016}, month = {Jan-12-2016}, doi = {10.1186/s12859-016-0966-0}, url = {http://www.biomedcentral.com/1471-2105/17/107http://link.springer.com/content/pdf/10.1186/s12859-016-0966-0}, author = {T{\'a}rraga, Joaqu{\'\i}n and Gallego, Asunci{\'o}n and Arnau, Vicente and Medina, Ignacio and Dopazo, Joaquin} } @article {452, title = {Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel.}, journal = {Sci Rep}, volume = {6}, year = {2016}, month = {2016 Apr 01}, pages = {23910}, abstract = {

Next-generation sequencing (NGS) has overcome important limitations to the molecular diagnosis of Inherited Retinal Dystrophies (IRD) such as the high clinical and genetic heterogeneity and the overlapping phenotypes. The purpose of this study was the identification of the genetic defect in 32 Spanish families with different forms of IRD. With that aim, we implemented a custom NGS panel comprising 64 IRD-associated genes in our population, and three disease-associated intronic regions. A total of 37 pathogenic mutations (14 novels) were found in 73\% of IRD patients ranging from 50\% for autosomal dominant cases, 75\% for syndromic cases, 83\% for autosomal recessive cases, and 100\% for X-linked cases. Additionally, unexpected phenotype-genotype correlations were found in 6 probands, which led to the refinement of their clinical diagnoses. Furthermore, intra- and interfamilial phenotypic variability was observed in two cases. Moreover, two cases unsuccessfully analysed by exome sequencing were resolved by applying this panel. Our results demonstrate that this hypothesis-free approach based on frequently mutated, population-specific loci is highly cost-efficient for the routine diagnosis of this heterogeneous condition and allows the unbiased analysis of a miscellaneous cohort. The molecular information found here has aid clinical diagnosis and has improved genetic counselling and patient management.

}, keywords = {Alleles, Computer Simulation, DNA Copy Number Variations, DNA Mutational Analysis, Eye Proteins, Gene Library, Genetic Association Studies, Genetic Heterogeneity, Genetic Therapy, High-Throughput Nucleotide Sequencing, Humans, mutation, Phenotype, Retinal Dystrophies}, issn = {2045-2322}, doi = {10.1038/srep23910}, author = {Bravo-Gil, Nereida and M{\'e}ndez-Vidal, Cristina and Romero-P{\'e}rez, Laura and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Rodr{\'\i}guez-de la R{\'u}a, Enrique and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {439, title = {Integrated gene set analysis for microRNA studies.}, journal = {Bioinformatics}, volume = {32}, year = {2016}, month = {2016 Sep 15}, pages = {2809-16}, abstract = {

MOTIVATION: Functional interpretation of miRNA expression data is currently done in a three step procedure: select differentially expressed miRNAs, find their target genes, and carry out gene set overrepresentation analysis Nevertheless, major limitations of this approach have already been described at the gene level, while some newer arise in the miRNA scenario.Here, we propose an enhanced methodology that builds on the well-established gene set analysis paradigm. Evidence for differential expression at the miRNA level is transferred to a gene differential inhibition score which is easily interpretable in terms of gene sets or pathways. Such transferred indexes account for the additive effect of several miRNAs targeting the same gene, and also incorporate cancellation effects between cases and controls. Together, these two desirable characteristics allow for more accurate modeling of regulatory processes.

RESULTS: We analyze high-throughput sequencing data from 20 different cancer types and provide exhaustive reports of gene and Gene Ontology-term deregulation by miRNA action.

AVAILABILITY AND IMPLEMENTATION: The proposed methodology was implemented in the Bioconductor library mdgsa http://bioconductor.org/packages/mdgsa For the purpose of reproducibility all of the scripts are available at https://github.com/dmontaner-papers/gsa4mirna

CONTACT: : david.montaner@gmail.com

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

}, keywords = {Computational Biology, Gene Expression Profiling, Gene ontology, Gene Regulatory Networks, High-Throughput Nucleotide Sequencing, Humans, MicroRNAs, Neoplasms, Reproducibility of Results}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btw334}, author = {Garcia-Garcia, Francisco and Panadero, Joaquin and Dopazo, Joaquin and Montaner, David} } @article {446, title = {Integrating transcriptomic and metabolomic analysis to understand natural leaf senescence in sunflower.}, journal = {Plant Biotechnol J}, volume = {14}, year = {2016}, month = {2016 Feb}, pages = {719-34}, abstract = {

Leaf senescence is a complex process, which has dramatic consequences on crop yield. In sunflower, gap between potential and actual yields reveals the economic impact of senescence. Indeed, sunflower plants are incapable of maintaining their green leaf area over sustained periods. This study characterizes the leaf senescence process in sunflower through a systems biology approach integrating transcriptomic and metabolomic analyses: plants being grown under both glasshouse and field conditions. Our results revealed a correspondence between profile changes detected at the molecular, biochemical and physiological level throughout the progression of leaf senescence measured at different plant developmental stages. Early metabolic changes were detected prior to anthesis and before the onset of the first senescence symptoms, with more pronounced changes observed when physiological and molecular variables were assessed under field conditions. During leaf development, photosynthetic activity and cell growth processes decreased, whereas sucrose, fatty acid, nucleotide and amino acid metabolisms increased. Pathways related to nutrient recycling processes were also up-regulated. Members of the NAC, AP2-EREBP, HB, bZIP and MYB transcription factor families showed high expression levels, and their expression level was highly correlated, suggesting their involvement in sunflower senescence. The results of this study thus contribute to the elucidation of the molecular mechanisms involved in the onset and progression of leaf senescence in sunflower leaves as well as to the identification of candidate genes involved in this process.

}, keywords = {Gas Chromatography-Mass Spectrometry, Gene Expression Profiling, Gene Expression Regulation, Plant, Gene ontology, Genes, Plant, Helianthus, Ions, metabolomics, Oligonucleotide Array Sequence Analysis, Plant Leaves, Principal Component Analysis, RNA, Messenger, Transcription Factors}, issn = {1467-7652}, doi = {10.1111/pbi.12422}, author = {Moschen, Sebasti{\'a}n and Bengoa Luoni, Sof{\'\i}a and Di Rienzo, Julio A and Caro, Mar{\'\i}a Del Pilar and Tohge, Takayuki and Watanabe, Mutsumi and Hollmann, Julien and Gonzalez, Sergio and Rivarola, M{\'a}ximo and Garcia-Garcia, Francisco and Dopazo, Joaquin and Hopp, Horacio Esteban and Hoefgen, Rainer and Fernie, Alisdair R and Paniego, Norma and Fernandez, Paula and Heinz, Ruth A} } @article {453, title = {The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0148346}, abstract = {

Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations.

}, keywords = {Exome, Gene Regulatory Networks, Genome, Human, Humans, INDEL Mutation, Leukemia, Promyelocytic, Acute, mutation, Mutation Rate, Polymorphism, Single Nucleotide, Reproducibility of Results}, issn = {1932-6203}, doi = {10.1371/journal.pone.0148346}, author = {Ib{\'a}{\~n}ez, Mariam and Carbonell-Caballero, Jos{\'e} and Garc{\'\i}a-Alonso, Luz and Such, Esperanza and Jim{\'e}nez-Almaz{\'a}n, Jorge and Vidal, Enrique and Barrag{\'a}n, Eva and L{\'o}pez-Pav{\'\i}a, Mar{\'\i}a and LLop, Marta and Mart{\'\i}n, Iv{\'a}n and G{\'o}mez-Segu{\'\i}, In{\'e}s and Montesinos, Pau and Sanz, Miguel A and Dopazo, Joaquin and Cervera, Jos{\'e}} } @article {449, title = {Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.}, journal = {Brain}, volume = {139}, year = {2016}, month = {2016 Jan}, pages = {62-72}, abstract = {

Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.

}, keywords = {Adult, Aged, Animals, Axons, Charcot-Marie-Tooth Disease, Female, gene expression, Humans, Infant, Male, Mice, Middle Aged, mutation, Pedigree, Phenotype, Sciatic Nerve, Sural Nerve, Transcription Factors, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awv311}, author = {Sevilla, Teresa and Lupo, Vincenzo and Mart{\'\i}nez-Rubio, Dolores and Sancho, Paula and Sivera, Rafael and Chumillas, Mar{\'\i}a J and Garc{\'\i}a-Romero, Mar and Pascual-Pascual, Samuel I and Muelas, Nuria and Dopazo, Joaquin and V{\'\i}lchez, Juan J and Palau, Francesc and Espin{\'o}s, Carmen} } @article {435, title = {The pan-cancer pathological regulatory landscape}, journal = {Scientific Reports}, volume = {6}, year = {2016}, month = {Jan-12-2016}, doi = {10.1038/srep39709}, url = {http://www.nature.com/articles/srep39709http://www.nature.com/articles/srep39709.pdfhttp://www.nature.com/articles/srep39709.pdfhttp://www.nature.com/articles/srep39709}, author = {Falco, Matias M. and Bleda, Marta and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin} } @article {442, title = {Progress in pharmacogenetics: consortiums and new strategies.}, journal = {Drug Metab Pers Ther}, volume = {31}, year = {2016}, month = {2016 Mar}, pages = {17-23}, abstract = {

Pharmacogenetics (PGx), as a field dedicated to achieving the goal of personalized medicine (PM), is devoted to the study of genes involved in inter-individual response to drugs. Due to its nature, PGx requires access to large samples; therefore, in order to progress, the formation of collaborative consortia seems to be crucial. Some examples of this collective effort are the European Society of Pharmacogenomics and personalized Therapy and the Ibero-American network of Pharmacogenetics. As an emerging field, one of the major challenges that PGx faces is translating their discoveries from research bench to bedside. The development of genomic high-throughput technologies is generating a revolution and offers the possibility of producing vast amounts of genome-wide single nucleotide polymorphisms for each patient. Moreover, there is a need of identifying and replicating associations of new biomarkers, and, in addition, a greater effort must be invested in developing regulatory organizations to accomplish a correct standardization. In this review, we outline the current progress in PGx using examples to highlight both the importance of polymorphisms and the research strategies for their detection. These concepts need to be applied together with a proper dissemination of knowledge to improve clinician and patient understanding, in a multidisciplinary team-based approach.

}, keywords = {Cooperative Behavior, Genome-Wide Association Study, High-Throughput Screening Assays, Humans, Patient Care Team, pharmacogenetics, Polymorphism, Single Nucleotide, Precision Medicine}, issn = {2363-8915}, doi = {10.1515/dmpt-2015-0039}, author = {Maro{\~n}as, Olalla and Latorre, Ana and Dopazo, Joaquin and Pirmohamed, Munir and Rodr{\'\i}guez-Antona, Cristina and Siest, G{\'e}rard and Carracedo, {\'A}ngel and LLerena, Adri{\'a}n} } @article {450, title = {Screening of CD96 and ASXL1 in 11 patients with Opitz C or Bohring-Opitz syndromes.}, journal = {Am J Med Genet A}, volume = {170A}, year = {2016}, month = {2016 Jan}, pages = {24-31}, abstract = {

Opitz C trigonocephaly (or Opitz C syndrome, OTCS) and Bohring-Opitz syndrome (BOS or C-like syndrome) are two rare genetic disorders with phenotypic overlap. The genetic causes of these diseases are not understood. However, two genes have been associated with OTCS or BOS with dominantly inherited de novo mutations. Whereas CD96 has been related to OTCS (one case) and to BOS (one case), ASXL1 has been related to BOS only (several cases). In this study we analyze CD96 and ASXL1 in a group of 11 affected individuals, including 2 sibs, 10 of them were diagnosed with OTCS, and one had a BOS phenotype. Exome sequences were available on six patients with OTCS and three parent pairs. Thus, we could analyze the CD96 and ASXL1 sequences in these patients bioinformatically. Sanger sequencing of all exons of CD96 and ASXL1 was carried out in the remaining patients. Detailed scrutiny of the sequences and assessment of variants allowed us to exclude putative pathogenic and private mutations in all but one of the patients. In this patient (with BOS) we identified a de novo mutation in ASXL1 (c.2100dupT). By nature and location within the gene, this mutation resembles those previously described in other BOS patients and we conclude that it may be responsible for the condition. Our results indicate that in 10 of 11, the disease (OTCS or BOS) cannot be explained by small changes in CD96 or ASXL1. However, the cohort is too small to make generalizations about the genetic etiology of these diseases.

}, keywords = {Adolescent, Antigens, CD, Child, Child, Preschool, Craniosynostoses, Exome, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Intellectual Disability, Male, mutation, Pedigree, Phenotype, Prognosis, Repressor Proteins}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37418}, author = {Urreizti, Roser and Roca-Ayats, Neus and Trepat, Judith and Garcia-Garcia, Francisco and Alem{\'a}n, Alejandro and Orteschi, Daniela and Marangi, Giuseppe and Neri, Giovanni and Opitz, John M and Dopazo, Joaquin and Cormand, Bru and Vilageliu, Llu{\"\i}sa and Balcells, Susana and Grinberg, Daniel} } @article {445, title = {Serum metabolomic profiling facilitates the non-invasive identification of metabolic biomarkers associated with the onset and progression of non-small cell lung cancer.}, journal = {Oncotarget}, volume = {7}, year = {2016}, month = {2016 Mar 15}, pages = {12904-16}, abstract = {

Lung cancer (LC) is responsible for most cancer deaths. One of the main factors contributing to the lethality of this disease is the fact that a large proportion of patients are diagnosed at advanced stages when a clinical intervention is unlikely to succeed. In this study, we evaluated the potential of metabolomics by 1H-NMR to facilitate the identification of accurate and reliable biomarkers to support the early diagnosis and prognosis of non-small cell lung cancer (NSCLC).We found that the metabolic profile of NSCLC patients, compared with healthy individuals, is characterized by statistically significant changes in the concentration of 18 metabolites representing different amino acids, organic acids and alcohols, as well as different lipids and molecules involved in lipid metabolism. Furthermore, the analysis of the differences between the metabolic profiles of NSCLC patients at different stages of the disease revealed the existence of 17 metabolites involved in metabolic changes associated with disease progression.Our results underscore the potential of metabolomics profiling to uncover pathophysiological mechanisms that could be useful to objectively discriminate NSCLC patients from healthy individuals, as well as between different stages of the disease.

}, keywords = {Adult, Aged, Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung, Disease Progression, Female, Humans, Lung Neoplasms, Male, metabolomics, Middle Aged, Proton Magnetic Resonance Spectroscopy}, issn = {1949-2553}, doi = {10.18632/oncotarget.7354}, author = {Puchades-Carrasco, Leonor and Jantus-Lewintre, Eloisa and P{\'e}rez-Rambla, Clara and Garcia-Garcia, Francisco and Lucas, Rut and Calabuig, Silvia and Blasco, Ana and Dopazo, Joaquin and Camps, Carlos and Pineda-Lucena, Antonio} } @article {451, title = {Stress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis.}, journal = {Mol Metab}, volume = {5}, year = {2016}, month = {2016 Jan}, pages = {19-33}, abstract = {

BACKGROUND: Stress-associated conditions such as psychoemotional reactivity and depression have been paradoxically linked to either weight gain or weight loss. This bi-directional effect of stress is not understood at the functional level. Here we tested the hypothesis that pre-stress level of adaptive thermogenesis and brown adipose tissue (BAT) functions explain the vulnerability or resilience to stress-induced obesity.

METHODS: We used wt and triple Ī²1,Ī²2,Ī²3-Adrenergic Receptors knockout (Ī²-less) mice exposed to a model of chronic subordination stress (CSS) at either room temperature (22~{\textdegree}C) or murine thermoneutrality (30~{\textdegree}C). A combined behavioral, physiological, molecular, and immunohistochemical analysis was conducted to determine stress-induced modulation of energy balance and BAT structure and function. Immortalized brown adipocytes were used for in~vitro assays.

RESULTS: Departing from our initial observation that Ī²ARs are dispensable for cold-induced BAT browning, we demonstrated that under physiological conditions promoting low adaptive thermogenesis and BAT activity (e.g. thermoneutrality or genetic deletion of the Ī²ARs), exposure to CSS acted as a stimulus for BAT activation and thermogenesis, resulting in resistance to diet-induced obesity despite the presence of hyperphagia. Conversely, in wt mice acclimatized to room temperature, and therefore characterized by sustained BAT function, exposure to CSS increased vulnerability to obesity. Exposure to CSS enhanced the sympathetic innervation of BAT in wt acclimatized to thermoneutrality and in Ī²-less mice. Despite increased sympathetic innervation suggesting adrenergic-mediated browning, norepinephrine did not promote browning in Ī²ARs knockout brown adipocytes, which led us to identify an alternative sympathetic/brown adipocytes purinergic pathway in the BAT. This pathway is downregulated under conditions of low adaptive thermogenesis requirements, is induced by stress, and elicits activation of UCP1 in wt and Ī²-less brown adipocytes. Importantly, this purinergic pathway is conserved in human BAT.

CONCLUSION: Our findings demonstrate that thermogenesis and BAT function are determinant of the resilience or vulnerability to stress-induced obesity. Our data support a model in which adrenergic and purinergic pathways exert complementary/synergistic functions in BAT, thus suggesting an alternative to Ī²ARs agonists for the activation of human BAT.

}, issn = {2212-8778}, doi = {10.1016/j.molmet.2015.10.005}, author = {Razzoli, Maria and Frontini, Andrea and Gurney, Allison and Mondini, Eleonora and Cubuk, Cankut and Katz, Liora S and Cero, Cheryl and Bolan, Patrick J and Dopazo, Joaquin and Vidal-Puig, Antonio and Cinti, Saverio and Bartolomucci, Alessandro} } @article {454, title = {The transcriptomics of an experimentally evolved plant-virus interaction.}, journal = {Sci Rep}, volume = {6}, year = {2016}, month = {2016 04 26}, pages = {24901}, abstract = {

Models of plant-virus interaction assume that the ability of a virus to infect a host genotype depends on the matching between virulence and resistance genes. Recently, we evolved tobacco etch potyvirus (TEV) lineages on different ecotypes of Arabidopsis thaliana, and found that some ecotypes selected for specialist viruses whereas others selected for generalists. Here we sought to evaluate the transcriptomic basis of such relationships. We have characterized the transcriptomic responses of five ecotypes infected with the ancestral and evolved viruses. Genes and functional categories differentially expressed by plants infected with local TEV isolates were identified, showing heterogeneous responses among ecotypes, although significant parallelism existed among lineages evolved in the same ecotype. Although genes involved in immune responses were altered upon infection, other functional groups were also pervasively over-represented, suggesting that plant resistance genes were not the only drivers of viral adaptation. Finally, the transcriptomic consequences of infection with the generalist and specialist lineages were compared. Whilst the generalist induced very similar perturbations in the transcriptomes of the different ecotypes, the perturbations induced by the specialist were divergent. Plant defense mechanisms were activated when the infecting virus was specialist but they were down-regulated when infecting with generalist.

}, keywords = {Arabidopsis, Ecotype, Gene Expression Profiling, Host-Pathogen Interactions, Potyvirus}, issn = {2045-2322}, doi = {10.1038/srep24901}, author = {Hillung, Julia and Garcia-Garcia, Francisco and Dopazo, Joaquin and Cuevas, Jos{\'e} M and Elena, Santiago F} } @article {438, title = {Web-based network analysis and visualization using CellMaps.}, journal = {Bioinformatics}, volume = {32}, year = {2016}, month = {2016 Oct 01}, pages = {3041-3}, abstract = {

UNLABELLED: : CellMaps is an HTML5 open-source web tool that allows displaying, editing, exploring and analyzing biological networks as well as integrating metadata into them. Computations and analyses are remotely executed in high-end servers, and all the functionalities are available through RESTful web services. CellMaps can easily be integrated in any web page by using an available JavaScript API.

AVAILABILITY AND IMPLEMENTATION: The application is available at: http://cellmaps.babelomics.org/ and the code can be found in: https://github.com/opencb/cell-maps The client is implemented in JavaScript and the server in C and Java.

CONTACT: jdopazo@cipf.es

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

}, keywords = {Biochemical Phenomena, Internet, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btw332}, author = {Salavert, Francisco and Garc{\'\i}a-Alonso, Luz and S{\'a}nchez, Rub{\'e}n and Alonso, Roberto and Bleda, Marta and Medina, Ignacio and Dopazo, Joaquin} } @article {558, title = {Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 12}, pages = {1343-1354}, abstract = {

Classical Rett syndrome (RTT) is a neurodevelopmental disorder where most of cases carry MECP2 mutations. Atypical RTT variants involve mutations in CDKL5 and FOXG1. However, a subset of RTT patients remains that do not carry any mutation in the described genes. Whole exome sequencing was carried out in a cohort of 21 female probands with clinical features overlapping with those of RTT, but without mutations in the customarily studied genes. Candidates were functionally validated by assessing the appearance of a neurological phenotype in Caenorhabditis elegans upon disruption of the corresponding ortholog gene. We detected pathogenic variants that accounted for the RTT-like phenotype in 14 (66.6~\%) patients. Five patients were carriers of mutations in genes already known to be associated with other syndromic neurodevelopmental disorders. We determined that the other patients harbored mutations in genes that have not previously been linked to RTT or other neurodevelopmental syndromes, such as the ankyrin repeat containing protein ANKRD31 or the neuronal acetylcholine receptor subunit alpha-5 (CHRNA5). Furthermore, worm assays demonstrated that mutations in the studied candidate genes caused locomotion defects. Our findings indicate that mutations in a variety of genes contribute to the development of RTT-like phenotypes.

}, keywords = {Adolescent, Adult, Animals, Caenorhabditis elegans, Carrier Proteins, Cell Cycle Proteins, Child, Child, Preschool, DNA Mutational Analysis, Exome, Female, Forkhead Transcription Factors, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Methyl-CpG-Binding Protein 2, mutation, Nerve Tissue Proteins, Protein Serine-Threonine Kinases, Receptors, Nicotinic, Rett Syndrome}, issn = {1432-1203}, doi = {10.1007/s00439-016-1721-3}, author = {Lucariello, Mario and Vidal, Enrique and Vidal, Silvia and Saez, Mauricio and Roa, Laura and Huertas, Dori and Pineda, Merc{\`e} and Dalf{\'o}, Esther and Dopazo, Joaquin and Jurado, Paola and Armstrong, Judith and Esteller, Manel} } @article {1129, title = {Babelomics 5.0: functional interpretation for new generations of genomic data.}, journal = {Nucleic acids research}, volume = {43}, number = {W1}, year = {2015}, month = {2015 Apr 20}, pages = {W117-W121}, abstract = {Babelomics has been running for more than one decade offering a user-friendly interface for the functional analysis of gene expression and genomic data. Here we present its fifth release, which includes support for Next Generation Sequencing data including gene expression (RNA-seq), exome or genome resequencing. Babelomics has simplified its interface, being now more intuitive. Improved visualization options, such as a genome viewer as well as an interactive network viewer, have been implemented. New technical enhancements at both, client and server sides, makes the user experience faster and more dynamic. Babelomics offers user-friendly access to a full range of methods that cover: (i) primary data analysis, (ii) a variety of tests for different experimental designs and (iii) different enrichment and network analysis algorithms for the interpretation of the results of such tests in the proper functional context. In addition to the public server, local copies of Babelomics can be downloaded and installed. Babelomics is freely available at: http://www.babelomics.org.}, keywords = {babelomics, data integration, gene set analysis, interactome, network analysis, NGS, RNA-seq, Systems biology, transcriptomics}, issn = {1362-4962}, doi = {10.1093/nar/gkv384}, url = {http://nar.oxfordjournals.org/content/43/W1/W117}, author = {Alonso, Roberto and Salavert, Francisco and Garcia-Garcia, Francisco and Carbonell-Caballero, Jos{\'e} and Bleda, Marta and Garc{\'\i}a-Alonso, Luz and Sanchis-Juan, Alba and Perez-Gil, Daniel and Marin-Garcia, Pablo and S{\'a}nchez, Rub{\'e}n and Cubuk, Cankut and Hidalgo, Marta R and Amadoz, Alicia and Hernansaiz-Ballesteros, Rosa D and Alem{\'a}n, Alejandro and T{\'a}rraga, Joaqu{\'\i}n and Montaner, David and Medina, Ignacio and Dopazo, Joaquin} } @article {1162, title = {Concurrent and Accurate Short Read Mapping on Multicore Processors.}, journal = {IEEE/ACM transactions on computational biology and bioinformatics / IEEE, ACM}, volume = {12}, year = {2015}, month = {2015 Sep-Oct}, pages = {995-1007}, abstract = {We introduce a parallel aligner with a work-flow organization for fast and accurate mapping of RNA sequences on servers equipped with multicore processors. Our software, [Formula: see text] ([Formula: see text] is an open-source application. The software is available at http://www.opencb.org, exploits a suffix array to rapidly map a large fraction of the RNA fragments (reads), as well as leverages the accuracy of the Smith-Waterman algorithm to deal with conflictive reads. The aligner is enhanced with a careful strategy to detect splice junctions based on an adaptive division of RNA reads into small segments (or seeds), which are then mapped onto a number of candidate alignment locations, providing crucial information for the successful alignment of the complete reads. The experimental results on a platform with Intel multicore technology report the parallel performance of [Formula: see text], on RNA reads of 100-400 nucleotides, which excels in execution time/sensitivity to state-of-the-art aligners such as TopHat 2+Bowtie 2, MapSplice, and STAR.}, keywords = {HPC, NGS, short real mapping}, issn = {1557-9964}, doi = {10.1109/TCBB.2015.2392077}, url = {http://ieeexplore.ieee.org/xpl/articleDetails.jsp?tp=\&arnumber=7010005}, author = {Martinez, Hector and T{\'a}rraga, Joaqu{\'\i}n and Medina, Ignacio and Barrachina, Sergio and Castillo, Maribel and Dopazo, Joaquin and Quintana-Orti, Enrique S} } @article {471, title = {Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease}, journal = {Scientific Reports}, volume = {5}, year = {2015}, month = {Jan-12-2015}, doi = {10.1038/srep16473}, url = {http://www.nature.com/articles/srep16473http://www.nature.com/articles/srep16473.pdfhttp://www.nature.com/articles/srep16473.pdfhttp://www.nature.com/articles/srep16473}, author = {Luz{\'o}n-Toro, Berta and Gui, Hongsheng and Ruiz-Ferrer, Macarena and Sze-Man Tang, Clara and Fern{\'a}ndez, Raquel M. and Sham, Pak-Chung and Torroglosa, Ana and Kwong-Hang Tam, Paul and Espino-Pais{\'a}n, Laura and Cherny, Stacey S. and Bleda, Marta and Enguix-Riego, Mar{\'\i}a Del Valle and Dopazo, Joaquin and Anti{\v n}olo, Guillermo and Garcia-Barcel{\'o}, Maria-Merc{\`e} and Borrego, Salud} } @article {461, title = {Family-based genome-wide association study in Patagonia confirms the association of the DMD locus and cleft lip and palate.}, journal = {Eur J Oral Sci}, volume = {123}, year = {2015}, month = {2015 Oct}, pages = {381-384}, abstract = {

The etiology of cleft lip with or without cleft palate (CL{\textpm}P) is complex and heterogeneous, and multiple genetic and environmental factors are involved. Some candidate genes reported to be associated with oral clefts are located on the X chromosome. At least three genes causing X-linked syndromes [midline 1 (MID1), oral-facial-digital syndrome 1 (OFD1), and dystrophin (DMD)] were previously found to be associated with isolated CL{\textpm}P. We attempted to confirm the role of X-linked genes in the etiology of isolated CL{\textpm}P in a South American population through a family-based genome-wide scan. We studied 27 affected children and their mothers, from 26 families, in a Patagonian population with a high prevalence of CL{\textpm}P. We conducted an exploratory analysis of the X chromosome to identify candidate regions associated with CL{\textpm}P. Four genomic segments were identified, two of which showed a statistically significant association with CL{\textpm}P. One is an 11-kb region of Xp21.1 containing the DMD gene, and the other is an intergenic region (8.7~kb; Xp11.4). Our results are consistent with recent data on the involvement of the DMD gene in the etiology of CL{\textpm}P. The MID1 and OFD1 genes were not included in the four potential CL{\textpm}P-associated X-chromosome genomic segments.

}, issn = {1600-0722}, doi = {10.1111/eos.12212}, author = {Fonseca, Renata F and de Carvalho, Fl{\'a}via M and Poletta, Fernando A and Montaner, David and Dopazo, Joaquin and Mereb, Juan C and Moreira, Miguel A M and Seuanez, Hector N and Vieira, Alexandre R and Castilla, Eduardo E and Orioli, I{\^e}da M} } @article {472, title = {Fast inexact mapping using advanced tree exploration on backward search methods.}, journal = {BMC Bioinformatics}, volume = {16}, year = {2015}, month = {2015 Jan 28}, pages = {18}, abstract = {

BACKGROUND: Short sequence mapping methods for Next Generation Sequencing consist on a combination of seeding techniques followed by local alignment based on dynamic programming approaches. Most seeding algorithms are based on backward search alignment, using the Burrows Wheeler Transform, the Ferragina and Manzini Index or Suffix Arrays. All these backward search algorithms have excellent performance, but their computational cost highly increases when allowing errors. In this paper, we discuss an inexact mapping algorithm based on pruning strategies for search tree exploration over genomic data.

RESULTS: The proposed algorithm achieves a 13x speed-up over similar algorithms when allowing 6 base errors, including insertions, deletions and mismatches. This algorithm can deal with 400 bps reads with up to 9 errors in a high quality Illumina dataset. In this example, the algorithm works as a preprocessor that reduces by 55\% the number of reads to be aligned. Depending on the aligner the overall execution time is reduced between 20-40\%.

CONCLUSIONS: Although not intended as a complete sequence mapping tool, the proposed algorithm could be used as a preprocessing step to modern sequence mappers. This step significantly reduces the number reads to be aligned, accelerating overall alignment time. Furthermore, this algorithm could be used for accelerating the seeding step of already available sequence mappers. In addition, an out-of-core index has been implemented for working with large genomes on systems without expensive memory configurations.

}, keywords = {Algorithms, Genome, Human, Genomics, High-Throughput Nucleotide Sequencing, Humans, Sequence Alignment, Sequence Analysis, DNA, Software}, issn = {1471-2105}, doi = {10.1186/s12859-014-0438-3}, author = {Salavert, Jos{\'e} and Tom{\'a}s, Andr{\'e}s and T{\'a}rraga, Joaqu{\'\i}n and Medina, Ignacio and Dopazo, Joaquin and Blanquer, Ignacio} } @article {562, title = {Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas}, journal = {BMC Medical Genomics}, volume = {8}, year = {2015}, month = {Dec}, pages = {83}, abstract = {The molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk.}, issn = {1755-8794}, doi = {10.1186/s12920-015-0160-7}, url = {https://doi.org/10.1186/s12920-015-0160-7}, author = {Luz{\'o}n-Toro, Berta and Bleda, Marta and Navarro, Elena and Garc{\'\i}a-Alonso, Luz and Ruiz-Ferrer, Macarena and Medina, Ignacio and Mart{\'\i}n-S{\'a}nchez, Marta and Gonzalez, Cristina Y. and Fern{\'a}ndez, Raquel M. and Torroglosa, Ana and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {1179, title = {Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas.}, journal = {BMC medical genomics}, volume = {8}, year = {2015}, month = {2015}, pages = {83}, abstract = {BACKGROUND: The molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk. METHODS: We carried out the first screening for epistasis by Multifactor-Dimensionality Reduction (MDR) in genome-wide association study (GWAS) on sMTC and juvenile PTC, to identify the potential simultaneous involvement of pairs of variants in the disease. RESULTS: We have identified two significant epistatic gene interactions in sMTC (CHFR-AC016582.2 and C8orf37-RNU1-55P) and three in juvenile PTC (RP11-648k4.2-DIO1, RP11-648k4.2-DMGDH and RP11-648k4.2-LOXL1). Interestingly, each interacting gene pair included a non-coding RNA, providing thus support to the relevance that these elements are increasingly gaining to explain carcinoma development and progression. CONCLUSIONS: Overall, this study contributes to the understanding of the genetic basis of thyroid carcinoma susceptibility in two different case scenarios such as sMTC and juvenile PTC.}, keywords = {epistasis, GWAS, Thyroid cancer}, issn = {1755-8794}, doi = {10.1186/s12920-015-0160-7}, url = {http://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-015-0160-7}, author = {Luz{\'o}n-Toro, Berta and Bleda, Marta and Navarro, Elena and Garc{\'\i}a-Alonso, Luz and Ruiz-Ferrer, Macarena and Medina, Ignacio and Mart{\'\i}n-S{\'a}nchez, Marta and Gonzalez, Cristina Y and Fern{\'a}ndez, Raquel M and Torroglosa, Ana and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {563, title = {Involvement of a citrus meiotic recombination TTC-repeat motif in the formation of gross deletions generated by ionizing radiation and MULE activation}, journal = {BMC Genomics}, volume = {16}, year = {2015}, month = {Feb}, pages = {69}, abstract = {Transposable-element mediated chromosomal rearrangements require the involvement of two transposons and two double-strand breaks (DSB) located in close proximity. In radiobiology, DSB proximity is also a major factor contributing to rearrangements. However, the whole issue of DSB proximity remains virtually unexplored.}, issn = {1471-2164}, doi = {10.1186/s12864-015-1280-3}, url = {https://doi.org/10.1186/s12864-015-1280-3}, author = {Terol, Javier and Iba{\~n}ez, Victoria and Carbonell, Jos{\'e} and Alonso, Roberto and Estornell, Leandro H. and Licciardello, Concetta and Gut, Ivo G. and Dopazo, Joaquin and Talon, Manuel} } @article {460, title = {A Pan-Cancer Catalogue of Cancer Driver Protein Interaction Interfaces.}, journal = {PLoS Comput Biol}, volume = {11}, year = {2015}, month = {2015 Oct}, pages = {e1004518}, abstract = {

Despite their importance in maintaining the integrity of all cellular pathways, the role of mutations on protein-protein interaction (PPI) interfaces as cancer drivers has not been systematically studied. Here we analyzed the mutation patterns of the PPI interfaces from 10,028 proteins in a pan-cancer cohort of 5,989 tumors from 23 projects of The Cancer Genome Atlas (TCGA) to find interfaces enriched in somatic missense mutations. To that end we use e-Driver, an algorithm to analyze the mutation distribution of specific protein functional regions. We identified 103 PPI interfaces enriched in somatic cancer mutations. 32 of these interfaces are found in proteins coded by known cancer driver genes. The remaining 71 interfaces are found in proteins that have not been previously identified as cancer drivers even that, in most cases, there is an extensive literature suggesting they play an important role in cancer. Finally, we integrate these findings with clinical information to show how tumors apparently driven by the same gene have different behaviors, including patient outcomes, depending on which specific interfaces are mutated.

}, keywords = {Animals, Base Sequence, Biomarkers, Tumor, Catalogs as Topic, Chromosome Mapping, Computer Simulation, DNA Mutational Analysis, Genetic Predisposition to Disease, Humans, Models, Genetic, Molecular Sequence Data, mutation, Neoplasm Proteins, Neoplasms, Polymorphism, Single Nucleotide, Protein Interaction Mapping, Signal Transduction}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1004518}, author = {Porta-Pardo, Eduard and Garc{\'\i}a-Alonso, Luz and Hrabe, Thomas and Dopazo, Joaquin and Godzik, Adam} } @article {1121, title = {A phylogenetic analysis of 34 chloroplast genomes elucidates the relationships between wild and domestic species within the genus Citrus.}, journal = {Molecular biology and evolution}, volume = {32}, number = {8}, year = {2015}, month = {2015 Apr 14}, pages = {2015-2035}, abstract = {Citrus genus includes some of the most important cultivated fruit trees worldwide. Despite being extensively studied because of its commercial relevance, the origin of cultivated citrus species and the history of its domestication still remain an open question. Here we present a phylogenetic analysis of the chloroplast genomes of 34 citrus genotypes which constitutes the most comprehensive and detailed study to date on the evolution and variability of the genus Citrus. A statistical model was used to estimate divergence times between the major citrus groups. Additionally, a complete map of the variability across the genome of different citrus species was produced, including single nucleotide variants, heteroplasmic positions, indels and large structural variants. The distribution of all these variants provided further independent support to the phylogeny obtained. An unexpected finding was the high level of heteroplasmy found in several of the analysed genomes. The use of the complete chloroplast DNA not only paves the way for a better understanding of the phylogenetic relationships within the Citrus genus, but also provides original insights into other elusive evolutionary processes such as chloroplast inheritance, heteroplasmy and gene selection.}, keywords = {chloroplast, citrus, Phylogeny, WGS}, issn = {1537-1719}, doi = {10.1093/molbev/msv082}, url = {http://mbe.oxfordjournals.org/content/early/2015/04/27/molbev.msv082.full}, author = {Carbonell-Caballero, Jos{\'e} and Alonso, Roberto and Iba{\~n}ez, Victoria and Terol, Javier and Talon, Manuel and Dopazo, Joaquin} } @article {468, title = {PTMcode v2: a resource for functional associations of post-translational modifications within and between proteins.}, journal = {Nucleic Acids Res}, volume = {43}, year = {2015}, month = {2015 Jan}, pages = {D494-502}, abstract = {

The post-translational regulation of proteins is mainly driven by two molecular events, their modification by several types of moieties and their interaction with other proteins. These two processes are interdependent and together are responsible for the function of the protein in a particular cell state. Several databases focus on the prediction and compilation of protein-protein interactions (PPIs) and no less on the collection and analysis of protein post-translational modifications (PTMs), however, there are no resources that concentrate on describing the regulatory role of PTMs in PPIs. We developed several methods based on residue co-evolution and proximity to predict the functional associations of pairs of PTMs that we apply to modifications in the same protein and between two interacting proteins. In order to make data available for understudied organisms, PTMcode v2 (http://ptmcode.embl.de) includes a new strategy to propagate PTMs from validated modified sites through orthologous proteins. The second release of PTMcode covers 19 eukaryotic species from which we collected more than 300,000 experimentally verified PTMs (>1,300,000 propagated) of 69 types extracting the post-translational regulation of >100,000 proteins and >100,000 interactions. In total, we report 8 million associations of PTMs regulating single proteins and over 9.4 million interplays tuning PPIs.

}, keywords = {Databases, Protein, Internet, Protein Interaction Mapping, Protein Processing, Post-Translational}, issn = {1362-4962}, doi = {10.1093/nar/gku1081}, author = {Minguez, Pablo and Letunic, Ivica and Parca, Luca and Garc{\'\i}a-Alonso, Luz and Dopazo, Joaquin and Huerta-Cepas, Jaime and Bork, Peer} } @article {467, title = {Re-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F.}, journal = {Am J Med Genet A}, volume = {167}, year = {2015}, month = {2015 Jul}, pages = {1597-600}, abstract = {

Mutations in USH2A are a common cause of Retinitis Pigmentosa (RP). Among the most frequently reported USH2A variants, c.2276G>T (p.C759F) has been found in both affected and healthy individuals. The pathogenicity of this variant remains controversial since it was detected in homozygosity in two healthy siblings of a Spanish family (S23), eleven years ago. The fact that these individuals remain asymptomatic today, prompted us to study the presence of other pathogenic variants in this family using targeted resequencing of 26 retinal genes in one of the affected individuals. This approach allowed us to identify one novel pathogenic homozygous mutation in exon 13 of PDE6B (c.1678C>T; p.R560C). This variant cosegregated with the disease and was absent in 200 control individuals. Remarkably, the identified variant in PDE6B corresponds to the mutation responsible of the retinal degeneration in the naturally occurring rd10 mutant mice. To our knowledge, this is the first report of the identification of the rd10 mice mutation in a RP family. These findings, together with a review of the literature, support the hypothesis that homozygous p.C759F mutations are not pathogenic and led us to exclude the implication of p.C759F in the RP of family S23. Our results indicate the need of re-evaluating all families genetically diagnosed with this mutation.

}, keywords = {Base Sequence, Cyclic Nucleotide Phosphodiesterases, Type 6, Extracellular Matrix Proteins, Gene Library, Humans, Molecular Sequence Data, Mutation, Missense, Pedigree, Retinitis pigmentosa, Sequence Analysis, DNA, Spain}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37003}, author = {Pozo, Mar{\'\i}a Gonz{\'a}lez-Del and Bravo-Gil, Nereida and M{\'e}ndez-Vidal, Cristina and Montero-de-Espinosa, Ignacio and Mill{\'a}n, Jos{\'e} M and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {474, title = {Using activation status of signaling pathways as mechanism-based biomarkers to predict drug sensitivity.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015 Dec 18}, pages = {18494}, abstract = {

Many complex traits, as drug response, are associated with changes in biological pathways rather than being caused by single gene alterations. Here, a predictive framework is presented in which gene expression data are recoded into activity statuses of signal transduction circuits (sub-pathways within signaling pathways that connect receptor proteins to final effector proteins that trigger cell actions). Such activity values are used as features by a prediction algorithm which can efficiently predict a continuous variable such as the IC50 value. The main advantage of this prediction method is that the features selected by the predictor, the signaling circuits, are themselves rich-informative, mechanism-based biomarkers which provide insight into or drug molecular mechanisms of action (MoA).

}, keywords = {Algorithms, Antineoplastic Agents, biomarkers, Cell Line, Tumor, Cell Survival, gene expression, Humans, Lethal Dose 50, Neoplasms, Phosphorylation, Proteins, Signal Transduction}, issn = {2045-2322}, doi = {10.1038/srep18494}, author = {Amadoz, Alicia and Sebasti{\'a}n-Leon, Patricia and Vidal, Enrique and Salavert, Francisco and Dopazo, Joaquin} } @article {1127, title = {Whole Exome Sequencing Reveals ZNF408 as a New Gene Associated With Autosomal Recessive Retinitis Pigmentosa with Vitreal Alterations.}, journal = {Human molecular genetics}, volume = {24}, number = {14}, year = {2015}, month = {2015 Apr 16}, pages = {4037-4048}, abstract = {Retinitis Pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors ten predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.}, issn = {1460-2083}, doi = {10.1093/hmg/ddv140}, url = {http://hmg.oxfordjournals.org/content/early/2015/04/16/hmg.ddv140.abstract}, author = {Avila-Fernandez, Almudena and Perez-Carro, Raquel and Corton, Marta and Lopez-Molina, Maria Isabel and Campello, Laura and Garanto, Alex and Fernadez-Sanchez, Laura and Duijkers, Lonneke and Lopez-Martinez, Miguel Angel and Riveiro-Alvarez, Rosa and da Silva, Luciana Rodrigues Jacy and Sanchez-Alcudia, Roc{\'\i}o and Martin-Garrido, Esther and Reyes, Noelia and Garcia-Garcia, Francisco and Dopazo, Joaquin and Garcia-Sandoval, Blanca and Collin, Rob W and Cuenca, Nicolas and Ayuso, Carmen} } @article {463, title = {Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Jul 15}, pages = {4037-48}, abstract = {

Retinitis pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole-exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors 10 predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.

}, keywords = {Amino Acid Sequence, Animals, Chlorocebus aethiops, Chromosome Mapping, COS Cells, DNA-Binding Proteins, Exome, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Molecular Sequence Data, Mutant Proteins, Pedigree, Retina, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Retinitis pigmentosa, Transcription Factors}, issn = {1460-2083}, doi = {10.1093/hmg/ddv140}, author = {Avila-Fernandez, Almudena and Perez-Carro, Raquel and Corton, Marta and Lopez-Molina, Maria Isabel and Campello, Laura and Garanto, Alejandro and Fernandez-Sanchez, Laura and Duijkers, Lonneke and Lopez-Martinez, Miguel Angel and Riveiro-Alvarez, Rosa and da Silva, Luciana Rodrigues Jacy and Sanchez-Alcudia, Roc{\'\i}o and Martin-Garrido, Esther and Reyes, Noelia and Garcia-Garcia, Francisco and Dopazo, Joaquin and Garcia-Sandoval, Blanca and Collin, Rob W J and Cuenca, Nicolas and Ayuso, Carmen} } @article {493, title = {The Activation of the Sox2 RR2 Pluripotency Transcriptional Reporter in Human Breast Cancer Cell Lines is Dynamic and Labels Cells with Higher Tumorigenic Potential.}, journal = {Front Oncol}, volume = {4}, year = {2014}, month = {2014}, pages = {308}, abstract = {

The striking similarity displayed at the mechanistic level between tumorigenesis and the generation of induced pluripotent stem cells and the fact that genes and pathways relevant for embryonic development are reactivated during tumor progression highlights the link between pluripotency and cancer. Based on these observations, we tested whether it is possible to use a pluripotency-associated transcriptional reporter, whose activation is driven by the SRR2 enhancer from the Sox2 gene promoter (named S4+ reporter), to isolate cancer stem cells (CSCs) from breast cancer cell lines. The S4+ pluripotency transcriptional reporter allows the isolation of cells with enhanced tumorigenic potential and its activation was switched on and off in the cell lines studied, reflecting a plastic cellular process. Microarray analysis comparing the populations in which the reporter construct is active versus inactive showed that positive cells expressed higher mRNA levels of cytokines (IL-8, IL-6, TNF) and genes (such as ATF3, SNAI2, and KLF6) previously related with the CSC phenotype in breast cancer.

}, issn = {2234-943X}, doi = {10.3389/fonc.2014.00308}, author = {Iglesias, Juan Manuel and Leis, Olatz and P{\'e}rez Ruiz, Est{\'\i}baliz and Gumuzio Barrie, Juan and Garcia-Garcia, Francisco and Aduriz, Ariane and Beloqui, Izaskun and Hernandez-Garcia, Susana and Lopez-Mato, Maria Paz and Dopazo, Joaquin and Pandiella, Atanasio and Menendez, Javier A and Martin, Angel Garcia} } @article {1087, title = {Assessing technical performance in differential gene expression experiments with external spike-in RNA control ratio mixtures.}, journal = {Nature communications}, volume = {5}, year = {2014}, month = {2014}, pages = {5125}, abstract = {There is a critical need for standard approaches to assess, report and compare the technical performance of genome-scale differential gene expression experiments. Here we assess technical performance with a proposed standard {\textquoteright}dashboard{\textquoteright} of metrics derived from analysis of external spike-in RNA control ratio mixtures. These control ratio mixtures with defined abundance ratios enable assessment of diagnostic performance of differentially expressed transcript lists, limit of detection of ratio (LODR) estimates and expression ratio variability and measurement bias. The performance metrics suite is applicable to analysis of a typical experiment, and here we also apply these metrics to evaluate technical performance among laboratories. An interlaboratory study using identical samples shared among 12 laboratories with three different measurement processes demonstrates generally consistent diagnostic power across 11 laboratories. Ratio measurement variability and bias are also comparable among laboratories for the same measurement process. We observe different biases for measurement processes using different mRNA-enrichment protocols.}, keywords = {RNA-seq}, issn = {2041-1723}, doi = {10.1038/ncomms6125}, url = {http://www.nature.com/ncomms/2014/140925/ncomms6125/full/ncomms6125.html}, author = {Munro, Sarah A and Lund, Steven P and Pine, P Scott and Binder, Hans and Clevert, Djork-Arn{\'e} and Ana Conesa and Dopazo, Joaquin and Fasold, Mario and Hochreiter, Sepp and Hong, Huixiao and Jafari, Nadereh and Kreil, David P and Labaj, Pawe{\l} P and Li, Sheng and Liao, Yang and Lin, Simon M and Meehan, Joseph and Mason, Christopher E and Santoyo-L{\'o}pez, Javier and Setterquist, Robert A and Shi, Leming and Shi, Wei and Smyth, Gordon K and Stralis-Pavese, Nancy and Su, Zhenqiang and Tong, Weida and Wang, Charles and Wang, Jian and Xu, Joshua and Ye, Zhan and Yang, Yong and Yu, Ying and Salit, Marc} } @article {1074, title = {A Comprehensive DNA Methylation Profile of Epithelial-to-Mesenchymal Transition.}, journal = {Cancer research}, volume = {74}, number = {19}, year = {2014}, month = {2014 Aug 8}, pages = {5608{\textendash}19}, abstract = {Epithelial-to-mesenchymal transition (EMT) is a plastic process in which fully differentiated epithelial cells are converted into poorly differentiated, migratory and invasive mesenchymal cells and it has been related to the metastasis potential of tumors. This is a reversible process and cells can also eventually undergo mesenchymal-to-epithelial transition (MET). The existence of a dynamic EMT process suggests the involvement of epigenetic shifts in the phenotype. Herein, we obtained the DNA methylomes at single-base resolution of MDCK cells undergoing epithelial-to-mesenchymal transition (EMT) and translated the identified differentially methylated regions (DMRs) to human breast cancer cells undergoing a gain of migratory and invasive capabilities associated with the EMT phenotype. We noticed dynamic and reversible changes of DNA methylation, both on promoter sequences and gene-bodies in association with transcription regulation of EMT-related genes. Most importantly, the identified DNA methylation markers of EMT were present in primary mammary tumors in association with the epithelial or the mesenchymal phenotype of the studied breast cancer samples.}, keywords = {Methyl-Seq, Methylomics, Next Generation Sequencing}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-13-3659}, url = {http://www.ncbi.nlm.nih.gov/pubmed/25106427}, author = {Carmona, F Javier and Davalos, Veronica and Vidal, Enrique and Gomez, Antonio and Heyn, Holger and Hashimoto, Yutaka and Vizoso, Miguel and Martinez-Cardus, Anna and Sayols, Sergi and Ferreira, Humberto and Sanchez-Mut, Jose and Moran, Sebastian and Margeli, Mireia and Castella, Eva and Berdasco, Maria and Stefansson, Olafur Andri and Eyfjord, Jorunn E and Gonzalez-Suarez, Eva and Dopazo, Joaquin and Orozco, Modesto and Gut, Ivo and Esteller, Manel} } @article {486, title = {Deciphering intrafamilial phenotypic variability by exome sequencing in a Bardet-Biedl family.}, journal = {Mol Genet Genomic Med}, volume = {2}, year = {2014}, month = {2014 Mar}, pages = {124-33}, abstract = {

Bardet-Biedl syndrome (BBS) is a model ciliopathy characterized by a wide range of clinical variability. The heterogeneity of this condition is reflected in the number of underlying gene defects and the epistatic interactions between the proteins encoded. BBS is generally inherited in an autosomal recessive trait. However, in some families, mutations across different loci interact to modulate the expressivity of the phenotype. In order to investigate the magnitude of epistasis in one BBS family with remarkable intrafamilial phenotypic variability, we designed an exome sequencing-based approach using SOLID 5500xl platform. This strategy allowed the reliable detection of the primary causal mutations in our family consisting of two novel compound heterozygous mutations in McKusick-Kaufman syndrome (MKKS) gene (p.D90G and p.V396F). Additionally, exome sequencing enabled the detection of one novel heterozygous NPHP4 variant which is predicted to activate a cryptic acceptor splice site and is only present in the most severely affected patient. Here, we provide an exome sequencing analysis of a BBS family and show the potential utility of this tool, in combination with network analysis, to detect disease-causing mutations and second-site modifiers. Our data demonstrate how next-generation sequencing (NGS) can facilitate the dissection of epistatic phenomena, and shed light on the genetic basis of phenotypic variability.

}, issn = {2324-9269}, doi = {10.1002/mgg3.50}, author = {Gonz{\'a}lez-del Pozo, Mar{\'\i}a and M{\'e}ndez-Vidal, Cristina and Santoyo-L{\'o}pez, Javier and Vela-Boza, Alicia and Bravo-Gil, Nereida and Rueda, Antonio and Garc{\'\i}a-Alonso, Luz and V{\'a}zquez-Marouschek, Carmen and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {489, title = {Exome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e116176}, abstract = {

This study aimed to identify the underlying molecular genetic cause in four Spanish families clinically diagnosed of Retinitis Pigmentosa (RP), comprising one autosomal dominant RP (adRP), two autosomal recessive RP (arRP) and one with two possible modes of inheritance: arRP or X-Linked RP (XLRP). We performed whole exome sequencing (WES) using NimbleGen SeqCap EZ Exome V3 sample preparation kit and SOLID 5500xl platform. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation and the absence in local control population. This strategy allowed the detection of: (i) one novel heterozygous splice-site deletion in RHO, c.937-2_944del, (ii) one rare homozygous mutation in C2orf71, c.1795T>C; p.Cys599Arg, not previously associated with the disease, (iii) two heterozygous null mutations in ABCA4, c.2041C>T; p.R681* and c.6088C>T; p.R2030*, and (iv) one mutation, c.2405-2406delAG; p.Glu802Glyfs*31 in the ORF15 of RPGR. The molecular findings for RHO and C2orf71 confirmed the initial diagnosis of adRP and arRP, respectively, while patients with the two ABCA4 mutations, both previously associated with Stargardt disease, presented symptoms of RP with early macular involvement. Finally, the X-Linked inheritance was confirmed for the family with the RPGR mutation. This latter finding allowed the inclusion of carrier sisters in our preimplantational genetic diagnosis program.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Base Sequence, Child, Chromosome Segregation, DNA Mutational Analysis, Exome, Family, Female, Humans, Inheritance Patterns, Male, Middle Aged, Molecular Sequence Data, mutation, Pedigree, Retinal Dystrophies, Rhodopsin}, issn = {1932-6203}, doi = {10.1371/journal.pone.0116176}, author = {Gonz{\'a}lez-del Pozo, Mar{\'\i}a and M{\'e}ndez-Vidal, Cristina and Bravo-Gil, Nereida and Vela-Boza, Alicia and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {1005, title = {Genomics and transcriptomics in drug discovery.}, journal = {Drug discovery today}, volume = {19}, number = {2}, year = {2014}, month = {2013 Jun 14}, pages = {126-32}, abstract = {The popularization of genomic high-throughput technologies is causing a revolution in biomedical research and, particularly, is transforming the field of drug discovery. Systems biology offers a framework to understand the extensive human genetic heterogeneity revealed by genomic sequencing in the context of the network of functional, regulatory and physical protein-drug interactions. Thus, approaches to find biomarkers and therapeutic targets will have to take into account the complex system nature of the relationships of the proteins with the disease. Pharmaceutical companies will have to reorient their drug discovery strategies considering the human genetic heterogeneity. Consequently, modeling and computational data analysis will have an increasingly important role in drug discovery.}, keywords = {adverse effects, Drug discovery, drug repositioning, metagenomics, modeling, network analysis, pathway analysis}, issn = {1878-5832}, doi = {10.1016/j.drudis.2013.06.003}, url = {http://www.ncbi.nlm.nih.gov/pubmed/23773860}, author = {Dopazo, Joaquin} } @article {482, title = {ngsCAT: a tool to assess the efficiency of targeted enrichment sequencing.}, journal = {Bioinformatics}, volume = {30}, year = {2014}, month = {2014 Jun 15}, pages = {1767-8}, abstract = {

MOTIVATION: Targeted enrichment sequencing by next-generation sequencing is a common approach to interrogate specific loci or the whole exome in the human genome. The efficiency and the lack of bias in the enrichment process need to be assessed as a quality control step before performing downstream analysis of the sequence data. Tools that can report on the sensitivity, specificity, uniformity and other enrichment-specific features are needed.

RESULTS: We have implemented the next-generation sequencing data Capture Assessment Tool (ngsCAT), a tool that takes the information of the mapped reads and the coordinates of the targeted regions as input files, and generates a report with metrics and figures that allows the evaluation of the efficiency of the enrichment process. The tool can also take as input the information of two samples allowing the comparison of two different experiments.

AVAILABILITY AND IMPLEMENTATION: Documentation and downloads for ngsCAT can be found at http://www.bioinfomgp.org/ngscat.

}, keywords = {Exome, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Sequence Analysis, DNA, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btu108}, author = {L{\'o}pez-Domingo, Francisco J and Florido, Javier P and Rueda, Antonio and Dopazo, Joaquin and Santoyo-L{\'o}pez, Javier} } @article {490, title = {Novel RP1 mutations and a recurrent BBS1 variant explain the co-existence of two distinct retinal phenotypes in the same pedigree.}, journal = {BMC Genet}, volume = {15}, year = {2014}, month = {2014 Dec 14}, pages = {143}, abstract = {

BACKGROUND: Molecular diagnosis of Inherited Retinal Dystrophies (IRD) has long been challenging due to the extensive clinical and genetic heterogeneity present in this group of disorders. Here, we describe the clinical application of an integrated next-generation sequencing approach to determine the underlying genetic defects in a Spanish family with a provisional clinical diagnosis of autosomal recessive Retinitis Pigmentosa (arRP).

RESULTS: Exome sequencing of the index patient resulted in the identification of the homozygous BBS1 p.M390R mutation. Sanger sequencing of additional members of the family showed lack of co-segregation of the p.M390R variant in some individuals. Clinical reanalysis indicated co-ocurrence of two different phenotypes in the same family: Bardet-Biedl syndrome in the individual harboring the BBS1 mutation and non-syndromic arRP in extended family members. To identify possible causative mutations underlying arRP, we conducted disease-targeted gene sequencing using a panel of 26 IRD genes. The in-house custom panel was validated using 18 DNA samples known to harbor mutations in relevant genes. All variants were redetected, indicating a high mutation detection rate. This approach allowed the identification of two novel heterozygous null mutations in RP1 (c.4582_4585delATCA; p.I1528Vfs*10 and c.5962dupA; p.I1988Nfs*3) which co-segregated with the disease in arRP patients. Additionally, a mutational screening in 96 patients of our cohort with genetically unresolved IRD revealed the presence of the c.5962dupA mutation in one unrelated family.

CONCLUSIONS: The combination of molecular findings for RP1 and BBS1 genes through exome and gene panel sequencing enabled us to explain the co-existence of two different retinal phenotypes in a family. The identification of two novel variants in RP1 suggests that the use of panels containing the prevalent genes of a particular population, together with an optimized data analysis pipeline, is an efficient and cost-effective approach that can be reliably implemented into the routine diagnostic process of diverse inherited retinal disorders. Moreover, the identification of these novel variants in two unrelated families supports the relatively high prevalence of RP1 mutations in Spanish population and the role of private mutations for commonly mutated genes, while extending the mutational spectrum of RP1.

}, keywords = {Bardet-Biedl Syndrome, Base Sequence, Case-Control Studies, DNA Mutational Analysis, Eye Proteins, Genes, Recessive, Genetic Association Studies, Humans, Microsatellite Repeats, Microtubule-Associated Proteins, Mutation, Missense, Pedigree, Phenotype, Retina, Retinitis pigmentosa}, issn = {1471-2156}, doi = {10.1186/s12863-014-0143-2}, author = {M{\'e}ndez-Vidal, Cristina and Bravo-Gil, Nereida and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Vela-Boza, Alicia and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {491, title = {Pathway network inference from gene expression data.}, journal = {BMC Syst Biol}, volume = {8 Suppl 2}, year = {2014}, month = {2014}, pages = {S7}, abstract = {

BACKGROUND: The development of high-throughput omics technologies enabled genome-wide measurements of the activity of cellular elements and provides the analytical resources for the progress of the Systems Biology discipline. Analysis and interpretation of gene expression data has evolved from the gene to the pathway and interaction level, i.e. from the detection of differentially expressed genes, to the establishment of gene interaction networks and the identification of enriched functional categories. Still, the understanding of biological systems requires a further level of analysis that addresses the characterization of the interaction between functional modules.

RESULTS: We present a novel computational methodology to study the functional interconnections among the molecular elements of a biological system. The PANA approach uses high-throughput genomics measurements and a functional annotation scheme to extract an activity profile from each functional block -or pathway- followed by machine-learning methods to infer the relationships between these functional profiles. The result is a global, interconnected network of pathways that represents the functional cross-talk within the molecular system. We have applied this approach to describe the functional transcriptional connections during the yeast cell cycle and to identify pathways that change their connectivity in a disease condition using an Alzheimer example.

CONCLUSIONS: PANA is a useful tool to deepen in our understanding of the functional interdependences that operate within complex biological systems. We show the approach is algorithmically consistent and the inferred network is well supported by the available functional data. The method allows the dissection of the molecular basis of the functional connections and we describe the different regulatory mechanisms that explain the network{\textquoteright}s topology obtained for the yeast cell cycle data.

}, keywords = {Alzheimer Disease, Cell Cycle, DNA Replication, Gene Expression Profiling, Gene Regulatory Networks, Gluconeogenesis, Glycolysis, Oxidative Phosphorylation, Proteolysis, Purines, Saccharomyces cerevisiae, Systems biology, Ubiquitin}, issn = {1752-0509}, doi = {10.1186/1752-0509-8-S2-S7}, author = {Ponzoni, Ignacio and Nueda, Mar{\'\i}a and Tarazona, Sonia and G{\"o}tz, Stefan and Montaner, David and Dussaut, Julieta and Dopazo, Joaquin and Conesa, Ana} } @article {492, title = {Permanent cardiac sarcomere changes in a rabbit model of intrauterine growth restriction.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e113067}, abstract = {

BACKGROUND: Intrauterine growth restriction (IUGR) induces fetal cardiac remodelling and dysfunction, which persists postnatally and may explain the link between low birth weight and increased cardiovascular mortality in adulthood. However, the cellular and molecular bases for these changes are still not well understood. We tested the hypothesis that IUGR is associated with structural and functional gene expression changes in the fetal sarcomere cytoarchitecture, which remain present in adulthood.

METHODS AND RESULTS: IUGR was induced in New Zealand pregnant rabbits by selective ligation of the utero-placental vessels. Fetal echocardiography demonstrated more globular hearts and signs of cardiac dysfunction in IUGR. Second harmonic generation microscopy (SHGM) showed shorter sarcomere length and shorter A-band and thick-thin filament interaction lengths, that were already present in utero and persisted at 70 postnatal days (adulthood). Sarcomeric M-band (GO: 0031430) functional term was over-represented in IUGR fetal hearts.

CONCLUSION: The results suggest that IUGR induces cardiac dysfunction and permanent changes on the sarcomere.

}, keywords = {Animals, biomarkers, Blood Pressure, Body Weight, Disease Models, Animal, Echocardiography, Female, Fetal Growth Retardation, Fetal Heart, Fetus, Gene Expression Profiling, Organ Size, Placenta, Pregnancy, Rabbits, Sarcomeres}, issn = {1932-6203}, doi = {10.1371/journal.pone.0113067}, author = {Torre, Iratxe and Gonz{\'a}lez-Tendero, Anna and Garc{\'\i}a-Ca{\~n}adilla, Patricia and Crispi, F{\'a}tima and Garcia-Garcia, Francisco and Bijnens, Bart and Iruretagoyena, Igor and Dopazo, Joaquin and Amat-Rold{\'a}n, Ivan and Gratac{\'o}s, Eduard} } @article {494, title = {The role of the interactome in the maintenance of deleterious variability in human populations.}, journal = {Mol Syst Biol}, volume = {10}, year = {2014}, month = {2014 Sep 26}, pages = {752}, abstract = {

Recent genomic projects have revealed the existence of an unexpectedly large amount of deleterious variability in the human genome. Several hypotheses have been proposed to explain such an apparently high mutational load. However, the mechanisms by which deleterious mutations in some genes cause a pathological effect but are apparently innocuous in other genes remain largely unknown. This study searched for deleterious variants in the 1,000 genomes populations, as well as in a newly sequenced population of 252 healthy Spanish individuals. In addition, variants causative of monogenic diseases and somatic variants from 41 chronic lymphocytic leukaemia patients were analysed. The deleterious variants found were analysed in the context of the interactome to understand the role of network topology in the maintenance of the observed mutational load. Our results suggest that one of the mechanisms whereby the effect of these deleterious variants on the phenotype is suppressed could be related to the configuration of the protein interaction network. Most of the deleterious variants observed in healthy individuals are concentrated in peripheral regions of the interactome, in combinations that preserve their connectivity, and have a marginal effect on interactome integrity. On the contrary, likely pathogenic cancer somatic deleterious variants tend to occur in internal regions of the interactome, often with associated structural consequences. Finally, variants causative of monogenic diseases seem to occupy an intermediate position. Our observations suggest that the real pathological potential of a variant might be more a systems property rather than an intrinsic property of individual proteins.

}, keywords = {Alleles, Exome, Gene Library, Genetic Variation, Genetics, Population, Genome, Human, Genomics, Humans, Models, Genetic, mutation, Phenotype, Protein Conformation, Protein Interaction Maps, Sequence Analysis, DNA, Whites}, issn = {1744-4292}, doi = {10.15252/msb.20145222}, author = {Garc{\'\i}a-Alonso, Luz and Jim{\'e}nez-Almaz{\'a}n, Jorge and Carbonell-Caballero, Jos{\'e} and Vela-Boza, Alicia and Santoyo-L{\'o}pez, Javier and Anti{\v n}olo, Guillermo and Dopazo, Joaquin} } @article {483, title = {Sequencing and functional analysis of the genome of a nematode egg-parasitic fungus, Pochonia chlamydosporia.}, journal = {Fungal Genet Biol}, volume = {65}, year = {2014}, month = {2014 Apr}, pages = {69-80}, abstract = {

Pochonia chlamydosporia is a worldwide-distributed soil fungus with a great capacity to infect and destroy the eggs and kill females of plant-parasitic nematodes. Additionally, it has the ability to colonize endophytically roots of economically-important crop plants, thereby promoting their growth and eliciting plant defenses. This multitrophic behavior makes P. chlamydosporia a potentially useful tool for sustainable agriculture approaches. We sequenced and assembled \~{}41 Mb of P. chlamydosporia genomic DNA and predicted 12,122 gene models, of which many were homologous to genes of fungal pathogens of invertebrates and fungal plant pathogens. Predicted genes (65\%) were functionally annotated according to Gene Ontology, and 16\% of them found to share homology with genes in the Pathogen Host Interactions (PHI) database. The genome of this fungus is highly enriched in genes encoding hydrolytic enzymes, such as proteases, glycoside hydrolases and carbohydrate esterases. We used RNA-Seq technology in order to identify the genes expressed during endophytic behavior of P. chlamydosporia when colonizing barley roots. Functional annotation of these genes showed that hydrolytic enzymes and transporters are expressed during endophytism. This structural and functional analysis of the P. chlamydosporia genome provides a starting point for understanding the molecular mechanisms involved in the multitrophic lifestyle of this fungus. The genomic information provided here should also prove useful for enhancing the capabilities of this fungus as a biocontrol agent of plant-parasitic nematodes and as a plant growth-promoting organism.

}, keywords = {Animals, Ascomycota, Female, Gene Expression Regulation, Fungal, Gene ontology, Genome, Fungal, Hordeum, Host-Pathogen Interactions, Nematoda, Ovum, Phylogeny, Plant Roots, Sequence Analysis, DNA, Signal Transduction, Transcriptome}, issn = {1096-0937}, doi = {10.1016/j.fgb.2014.02.002}, author = {Larriba, Eduardo and Jaime, Mar{\'\i}a D L A and Carbonell-Caballero, Jos{\'e} and Conesa, Ana and Dopazo, Joaquin and Nislow, Corey and Mart{\'\i}n-Nieto, Jos{\'e} and Lopez-Llorca, Luis Vicente} } @article {484, title = {Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Apr}, pages = {470-7}, abstract = {

Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain Ī±-keto acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly, and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1Ī±), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients{\textquoteright} clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention.

}, keywords = {Amino Acids, Branched-Chain, Developmental Disabilities, Fibroblasts, Humans, Male, Mutation, Missense, Nervous System Diseases, Pediatrics, Protein Kinases}, issn = {1098-1004}, doi = {10.1002/humu.22513}, author = {Garc{\'\i}a-Cazorla, Angels and Oyarzabal, Alfonso and Fort, Joana and Robles, Concepci{\'o}n and Castej{\'o}n, Esperanza and Ruiz-Sala, Pedro and Bodoy, Susanna and Merinero, Bego{\~n}a and Lopez-Sala, Anna and Dopazo, Joaquin and Nunes, Virginia and Ugarte, Magdalena and Artuch, Rafael and Palac{\'\i}n, Manuel and Rodr{\'\i}guez-Pombo, Pilar and Alcaide, Patricia and Navarrete, Rosa and Sanz, Paloma and Font-Llitj{\'o}s, Mariona and Vilaseca, Ma Antonia and Ormaizabal, Aida and Pristoupilova, Anna and Agull{\'o}, Sergi Beltran} } @article {565, title = {Understanding disease mechanisms with models of signaling pathway activities}, journal = {BMC systems biology}, volume = {8}, year = {2014}, month = {10}, pages = {121}, doi = {10.1186/s12918-014-0121-3}, author = {Sebasti{\'a}n-Leon, Patricia and Vidal, Enrique and Minguez, Pablo and Conesa, Ana and Tarazona, Sonia and Amadoz, Alicia and Armero, Carmen and Salavert Torres, Francisco and Vidal-Puig, Antonio and Montaner, David and Dopazo, Joaquin} } @article {503, title = {Defining the genomic signature of totipotency and pluripotency during early human development.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e62135}, abstract = {

The genetic mechanisms governing human pre-implantation embryo development and the in vitro counterparts, human embryonic stem cells (hESCs), still remain incomplete. Previous global genome studies demonstrated that totipotent blastomeres from day-3 human embryos and pluripotent inner cell masses (ICMs) from blastocysts, display unique and differing transcriptomes. Nevertheless, comparative gene expression analysis has revealed that no significant differences exist between hESCs derived from blastomeres versus those obtained from ICMs, suggesting that pluripotent hESCs involve a new developmental progression. To understand early human stages evolution, we developed an undifferentiation network signature (UNS) and applied it to a differential gene expression profile between single blastomeres from day-3 embryos, ICMs and hESCs. This allowed us to establish a unique signature composed of highly interconnected genes characteristic of totipotency (61 genes), in vivo pluripotency (20 genes), and in vitro pluripotency (107 genes), and which are also proprietary according to functional analysis. This systems biology approach has led to an improved understanding of the molecular and signaling processes governing human pre-implantation embryo development, as well as enabling us to comprehend how hESCs might adapt to in vitro culture conditions.

}, keywords = {Blastocyst Inner Cell Mass, Blastomeres, Cell Differentiation, Embryonic Development, Embryonic Stem Cells, Gene Expression Profiling, Gene Regulatory Networks, Genome, Human, Humans, Molecular Sequence Annotation, Pluripotent Stem Cells, Totipotent Stem Cells}, issn = {1932-6203}, doi = {10.1371/journal.pone.0062135}, author = {Galan, Amparo and Diaz-Gimeno, Patricia and Poo, Maria Eugenia and Valbuena, Diana and Sanchez, Eva and Ruiz, Veronica and Dopazo, Joaquin and Montaner, David and Conesa, Ana and Simon, Carlos} } @article {566, title = {Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria.}, journal = {Mol Genet Metab}, volume = {110}, year = {2013}, month = {2013 Sep-Oct}, pages = {73-7}, abstract = {

3-Methylglutaconic aciduria (3-MGA-uria) is a heterogeneous group of syndromes characterized by an increased excretion of 3-methylglutaconic and 3-methylglutaric acids. Five types of 3-MGA-uria (I to V) with different clinical presentations have been described. Causative mutations in TAZ, OPA3, DNAJC19, ATP12, ATP5E, and TMEM70 have been identified. After excluding the known genetic causes of 3-MGA-uria we used exome sequencing to investigate a patient with Leigh syndrome and 3-MGA-uria. We identified a homozygous variant in SERAC1 (c.202C>T; p.Arg68*), that generates a premature stop codon at position 68 of SERAC1 protein. Western blot analysis in patient{\textquoteright}s fibroblasts showed a complete absence of SERAC1 that was consistent with the prediction of a truncated protein and supports the pathogenic role of the mutation. During the course of this project a parallel study identified mutations in SERAC1 as the genetic cause of the disease in 15 patients with MEGDEL syndrome, which was compatible with the clinical and biochemical phenotypes of the patient described here. In addition, our patient developed microcephaly and optic atrophy, two features not previously reported in MEGDEL syndrome. We highlight the usefulness of exome sequencing to reveal the genetic bases of human rare diseases even if only one affected individual is available.

}, keywords = {Adolescent, Adult, Carboxylic Ester Hydrolases, Child, Exome, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Metabolism, Inborn Errors, mutation}, issn = {1096-7206}, doi = {10.1016/j.ymgme.2013.04.021}, author = {Tort, Frederic and Garc{\'\i}a-Silva, Mar{\'\i}a Teresa and Ferrer-Cort{\`e}s, X{\`e}nia and Navarro-Sastre, Aleix and Garcia-Villoria, Judith and Coll, Maria Josep and Vidal, Enrique and Jim{\'e}nez-Almaz{\'a}n, Jorge and Dopazo, Joaquin and Briones, Paz and Elpeleg, Orly and Ribes, Antonia} } @article {497, title = {Grape antioxidant dietary fiber inhibits intestinal polyposis in ApcMin/+ mice: relation to cell cycle and immune response.}, journal = {Carcinogenesis}, volume = {34}, year = {2013}, month = {2013 Aug}, pages = {1881-8}, abstract = {

Epidemiological and experimental studies suggest that fiber and phenolic compounds might have a protective effect on the development of colon cancer in humans. Accordingly, we assessed the chemopreventive efficacy and associated mechanisms of action of a lyophilized red grape pomace containing proanthocyanidin (PA)-rich dietary fiber [grape antioxidant dietary fiber (GADF)] on spontaneous intestinal tumorigenesis in the Apc(Min/+) mouse model. Mice were fed a standard diet (control group) or a 1\% (w/w) GADF-supplemented diet (GADF group) for 6 weeks. GADF supplementation greatly reduced intestinal tumorigenesis, significantly decreasing the total number of polyps by 76\%. Moreover, size distribution analysis showed a considerable reduction in all polyp size categories [diameter <1mm (65\%), 1-2mm (67\%) and >2mm (87\%)]. In terms of polyp formation in the proximal, middle and distal portions of the small intestine, a decrease of 76, 81 and 73\% was observed, respectively. Putative molecular mechanisms underlying the inhibition of intestinal tumorigenesis were investigated by comparison of microarray expression profiles of GADF-treated and non-treated mice. We observed that the effects of GADF are mainly associated with the induction of a G1 cell cycle arrest and the downregulation of genes related to the immune response and inflammation. Our findings show for the first time the efficacy and associated mechanisms of action of GADF against intestinal tumorigenesis in Apc(Min/+) mice, suggesting its potential for the prevention of colorectal cancer.

}, keywords = {Animals, Antioxidants, Body Weight, Carcinogenesis, Cell Cycle, Cell Cycle Checkpoints, Colorectal Neoplasms, Dietary Fiber, Dietary Supplements, Down-Regulation, G1 Phase, Inflammation, Intestinal Polyposis, Intestinal Polyps, Intestine, Small, Male, Mice, Transcriptome, Vitis}, issn = {1460-2180}, doi = {10.1093/carcin/bgt140}, author = {S{\'a}nchez-Tena, Susana and Lizarraga, Daneida and Miranda, Anibal and Vinardell, Maria P and Garcia-Garcia, Francisco and Dopazo, Joaquin and Torres, Josep L and Saura-Calixto, Fulgencio and Capell{\`a}, Gabriel and Cascante, Marta} } @article {500, title = {Inferring the functional effect of gene expression changes in signaling pathways.}, journal = {Nucleic Acids Res}, volume = {41}, year = {2013}, month = {2013 Jul}, pages = {W213-7}, abstract = {

Signaling pathways constitute a valuable source of information that allows interpreting the way in which alterations in gene activities affect to particular cell functionalities. There are web tools available that allow viewing and editing pathways, as well as representing experimental data on them. However, few methods aimed to identify the signaling circuits, within a pathway, associated to the biological problem studied exist and none of them provide a convenient graphical web interface. We present PATHiWAYS, a web-based signaling pathway visualization system that infers changes in signaling that affect cell functionality from the measurements of gene expression values in typical expression microarray case-control experiments. A simple probabilistic model of the pathway is used to estimate the probabilities for signal transmission from any receptor to any final effector molecule (taking into account the pathway topology) using for this the individual probabilities of gene product presence/absence inferred from gene expression values. Significant changes in these probabilities allow linking different cell functionalities triggered by the pathway to the biological problem studied. PATHiWAYS is available at: http://pathiways.babelomics.org/.

}, keywords = {Animals, Humans, Internet, Mice, Models, Statistical, Receptors, Cell Surface, Signal Transduction, Software, Transcriptome}, issn = {1362-4962}, doi = {10.1093/nar/gkt451}, author = {Sebasti{\'a}n-Leon, Patricia and Carbonell, Jos{\'e} and Salavert, Francisco and S{\'a}nchez, Rub{\'e}n and Medina, Ignacio and Dopazo, Joaquin} } @article {496, title = {Intrauterine growth restriction is associated with cardiac ultrastructural and gene expression changes related to the energetic metabolism in a rabbit model.}, journal = {Am J Physiol Heart Circ Physiol}, volume = {305}, year = {2013}, month = {2013 Dec}, pages = {H1752-60}, abstract = {

Intrauterine growth restriction (IUGR) affects 7-10\% of pregnancies and is associated with cardiovascular remodeling and dysfunction, which persists into adulthood. The underlying subcellular remodeling and cardiovascular programming events are still poorly documented. Cardiac muscle is central in the fetal adaptive mechanism to IUGR given its high energetic demands. The energetic homeostasis depends on the correct interaction of several molecular pathways and the adequate arrangement of intracellular energetic units (ICEUs), where mitochondria interact with the contractile machinery and the main cardiac ATPases to enable a quick and efficient energy transfer. We studied subcellular cardiac adaptations to IUGR in an experimental rabbit model. We evaluated the ultrastructure of ICEUs with transmission electron microscopy and observed an altered spatial arrangement in IUGR, with significant increases in cytosolic space between mitochondria and myofilaments. A global decrease of mitochondrial density was also observed. In addition, we conducted a global gene expression profile by advanced bioinformatics tools to assess the expression of genes involved in the cardiomyocyte energetic metabolism and identified four gene modules with a coordinated over-representation in IUGR: oxygen homeostasis (GO: 0032364), mitochondrial respiratory chain complex I (GO:0005747), oxidative phosphorylation (GO: 0006119), and NADH dehydrogenase activity (GO:0003954). These findings might contribute to changes in energetic homeostasis in IUGR. The potential persistence and role of these changes in long-term cardiovascular programming deserves further investigation.

}, keywords = {Animals, Disease Models, Animal, Energy Metabolism, Female, Fetal Growth Retardation, gene expression, Mitochondria, Myocardium, Oxidative Phosphorylation, Placenta, Pregnancy, Rabbits}, issn = {1522-1539}, doi = {10.1152/ajpheart.00514.2013}, author = {Gonz{\'a}lez-Tendero, Anna and Torre, Iratxe and Garc{\'\i}a-Ca{\~n}adilla, Patricia and Crispi, F{\'a}tima and Garcia-Garcia, Francisco and Dopazo, Joaquin and Bijnens, Bart and Gratac{\'o}s, Eduard} } @article {1022, title = {Mammosphere Formation in Breast Carcinoma Cell Lines Depends upon Expression of E-cadherin}, journal = {PLoS ONE}, volume = {8}, year = {2013}, month = {2013/10/04}, pages = {e77281 -}, publisher = {Public Library of Science}, abstract = {

Tumors are heterogeneous at the cellular level where the ability to maintain tumor growth resides in discrete cell populations. Floating sphere-forming assays are broadly used to test stem cell activity in tissues, tumors and cell lines. Spheroids are originated from a small population of cells with stem cell features able to grow in suspension culture and behaving as tumorigenic in mice. We tested the ability of eleven common breast cancer cell lines representing the major breast cancer subtypes to grow as mammospheres, measuring the ability to maintain cell viability upon serial non-adherent passage. Only MCF7, T47D, BT474, MDA-MB-436 and JIMT1 were successfully propagated as long-term mammosphere cultures, measured as the increase in the number of viable cells upon serial non-adherent passages. Other cell lines tested (SKBR3, MDA-MB-231, MDA-MB-468 and MDA-MB-435) formed cell clumps that can be disaggregated mechanically, but cell viability drops dramatically on their second passage. HCC1937 and HCC1569 cells formed typical mammospheres, although they could not be propagated as long-term mammosphere cultures. All the sphere forming lines but MDA-MB-436 express E-cadherin on their surface. Knock down of E-cadherin expression in MCF-7 cells abrogated its ability to grow as mammospheres, while re-expression of E-cadherin in SKBR3 cells allow them to form mammospheres. Therefore, the mammosphere assay is suitable to reveal stem like features in breast cancer cell lines that express E-cadherin.

}, url = {http://dx.doi.org/10.1371\%2Fjournal.pone.0077281}, author = {Manuel Iglesias, Juan and Beloqui, Izaskun and Garcia-Garcia, Francisco and Leis, Olatz and Vazquez-Martin, Alejandro and Eguiara, Arrate and Cufi, Silvia and Pavon, Andres and Menendez, Javier A. and Dopazo, Joaquin and Martin, Angel G.} } @article {505, title = {Mammosphere formation in breast carcinoma cell lines depends upon expression of E-cadherin.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e77281}, abstract = {

Tumors are heterogeneous at the cellular level where the ability to maintain tumor growth resides in discrete cell populations. Floating sphere-forming assays are broadly used to test stem cell activity in tissues, tumors and cell lines. Spheroids are originated from a small population of cells with stem cell features able to grow in suspension culture and behaving as tumorigenic in mice. We tested the ability of eleven common breast cancer cell lines representing the major breast cancer subtypes to grow as mammospheres, measuring the ability to maintain cell viability upon serial non-adherent passage. Only MCF7, T47D, BT474, MDA-MB-436 and JIMT1 were successfully propagated as long-term mammosphere cultures, measured as the increase in the number of viable cells upon serial non-adherent passages. Other cell lines tested (SKBR3, MDA-MB-231, MDA-MB-468 and MDA-MB-435) formed cell clumps that can be disaggregated mechanically, but cell viability drops dramatically on their second passage. HCC1937 and HCC1569 cells formed typical mammospheres, although they could not be propagated as long-term mammosphere cultures. All the sphere forming lines but MDA-MB-436 express E-cadherin on their surface. Knock down of E-cadherin expression in MCF-7 cells abrogated its ability to grow as mammospheres, while re-expression of E-cadherin in SKBR3 cells allow them to form mammospheres. Therefore, the mammosphere assay is suitable to reveal stem like features in breast cancer cell lines that express E-cadherin.

}, keywords = {Breast Neoplasms, Cadherins, Cell Line, Tumor, Cell Proliferation, Cluster Analysis, Female, gene expression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, MCF-7 Cells, Neoplastic Stem Cells, Spheroids, Cellular, Tumor Cells, Cultured}, issn = {1932-6203}, doi = {10.1371/journal.pone.0077281}, author = {Manuel Iglesias, Juan and Beloqui, Izaskun and Garcia-Garcia, Francisco and Leis, Olatz and Vazquez-Martin, Alejandro and Eguiara, Arrate and Cufi, Silvia and Pavon, Andres and Menendez, Javier A and Dopazo, Joaquin and Martin, Angel G} } @conference {567, title = {Multicore and Cloud-based Solutions for Genomic Variant Analysis}, booktitle = {Proceedings of the 18th International Conference on Parallel Processing Workshops}, year = {2013}, publisher = {Springer-Verlag}, organization = {Springer-Verlag}, address = {Berlin, Heidelberg}, keywords = {genomic variant analysis, multicore, mutation, OpenMP, web service}, isbn = {978-3-642-36948-3}, doi = {10.1007/978-3-642-36949-0_30}, url = {http://dx.doi.org/10.1007/978-3-642-36949-0_30}, author = {Gonzalez, Cristina Y. and Bleda, Marta and Salavert, Francisco and S{\'a}nchez, Rub{\'e}n and Dopazo, Joaquin and Medina, Ignacio} } @article {507, title = {Novel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome.}, journal = {Clin Chim Acta}, volume = {421}, year = {2013}, month = {2013 Jun 05}, pages = {184-90}, abstract = {

BACKGROUND: Genome-wide expression analysis using microarrays has been used as a research strategy to discovery new biomarkers and candidate genes for a number of diseases. We aim to find new biomarkers for the prediction of acute coronary syndrome (ACS) with a differentially expressed mRNA profiling approach using whole genomic expression analysis in a peripheral blood cell model from patients with early ACS.

METHODS AND RESULTS: This study was carried out in two phases. On phase 1 a restricted clinical criteria (ACS-Ph1, n=9 and CG-Ph1, n=6) was used in order to select potential mRNA biomarkers candidates. A subsequent phase 2 study was performed using selected phase 1 markers analyzed by RT-qPCR using a larger and independent casuistic (ACS-Ph2, n=74 and CG-Ph2, n=41). A total of 549 genes were found to be differentially expressed in the first 48 h after the ACS-Ph1. Technical and biological validation further confirmed that ALOX15, AREG, BCL2A1, BCL2L1, CA1, COX7B, ECHDC3, IL18R1, IRS2, KCNE1, MMP9, MYL4 and TREML4, are differentially expressed in both phases of this study.

CONCLUSIONS: Transcriptomic analysis by microarray technology demonstrated differential expression during a 48 h time course suggesting a potential use of some of these genes as biomarkers for very early stages of ACS, as well as for monitoring early cardiac ischemic recovery.

}, keywords = {Acute Coronary Syndrome, Acute-Phase Proteins, Adult, biomarkers, Blood Cells, Early Diagnosis, gene expression, Gene Expression Profiling, Humans, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, RNA, Messenger, Transcriptome}, issn = {1873-3492}, doi = {10.1016/j.cca.2013.03.011}, author = {Silbiger, Vivian N and Luchessi, Andr{\'e} D and Hirata, Ros{\'a}rio D C and Lima-Neto, L{\'\i}dio G and Cavichioli, D{\'e}bora and Carracedo, {\'A}ngel and Bri{\'o}n, Maria and Dopazo, Joaquin and Garcia-Garcia, Francisco and Dos Santos, Elizabete S and Ramos, Rui F and Sampaio, Marcelo F and Armaganijan, Dikran and Sousa, Amanda G M R and Hirata, Mario H} } @article {495, title = {Pathways systematically associated to Hirschsprung{\textquoteright}s disease.}, journal = {Orphanet J Rare Dis}, volume = {8}, year = {2013}, month = {2013 Dec 02}, pages = {187}, abstract = {

Despite it has been reported that several loci are involved in Hirschsprung{\textquoteright}s disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung{\textquoteright}s disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations.

}, keywords = {Female, Genetic Predisposition to Disease, Genotype, Hirschsprung Disease, Humans, Male, Polymorphism, Single Nucleotide}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-187}, author = {Fern{\'a}ndez, Raquel M and Bleda, Marta and Luz{\'o}n-Toro, Berta and Garc{\'\i}a-Alonso, Luz and Arnold, Stacey and Sribudiani, Yunia and Besmond, Claude and Lantieri, Francesca and Doan, Betty and Ceccherini, Isabella and Lyonnet, Stanislas and Hofstra, Robert Mw and Chakravarti, Aravinda and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {501, title = {Role of CPI-17 in restoring skin homoeostasis in cutaneous field of cancerization: effects of topical application of a film-forming medical device containing photolyase and UV filters.}, journal = {Exp Dermatol}, volume = {22}, year = {2013}, month = {2013 Jul}, pages = {494-6}, abstract = {

Cutaneous field of cancerization (CFC) is caused in part by the carcinogenic effect of the cyclobutane pyrimidine dimers CPD and 6-4 photoproducts (6-4PPs). Photoreactivation is carried out by photolyases which specifically recognize and repair both photoproducts. The study evaluates the molecular effects of topical application of a film-forming medical device containing photolyase and UV filters on the precancerous field in AK from seven patients. Skin improvement after treatment was confirmed in all patients by histopathological and molecular assessment. A gene set analysis showed that skin recovery was associated with biological processes involved in tissue homoeostasis and cell maintenance. The CFC response was associated with over-expression of the CPI-17 gene, and a dependence on the initial expression level was observed (P~=~0.001). Low CPI-17 levels were directly associated with pro-inflammatory genes such as TNF (P~=~0.012) and IL-1B (P~=~0.07). Our results suggest a role for CPI-17 in restoring skin homoeostasis in CFC lesions.

}, keywords = {Administration, Topical, Adult, Aged, Aged, 80 and over, Biopsy, Deoxyribodipyrimidine Photo-Lyase, Female, Gene Expression Profiling, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Homeostasis, Humans, Inflammation, Intracellular Signaling Peptides and Proteins, Liposomes, Male, Middle Aged, Muscle Proteins, Phenotype, Phosphoprotein Phosphatases, Reactive Oxygen Species, Skin, Skin Neoplasms, Ultraviolet Rays}, issn = {1600-0625}, doi = {10.1111/exd.12177}, author = {Puig-Butille, Joan Anton and Malvehy, Josep and Potrony, Miriam and Trullas, Carles and Garcia-Garcia, Francisco and Dopazo, Joaquin and Puig, Susana} } @article {1032, title = {Whole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa.}, journal = {Molecular vision}, volume = {19}, year = {2013}, month = {2013}, pages = {2187-95}, abstract = {PURPOSE: Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by extreme genetic and clinical heterogeneity. Thus, the diagnosis is not always easily performed due to phenotypic and genetic overlap. Current clinical practices have focused on the systematic evaluation of a set of known genes for each phenotype, but this approach may fail in patients with inaccurate diagnosis or infrequent genetic cause. In the present study, we investigated the genetic cause of autosomal recessive RP (arRP) in a Spanish family in which the causal mutation has not yet been identified with primer extension technology and resequencing. METHODS: We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the SOLiD 5500{\texttimes}l next-generation sequencing platform. We sequenced the exomes of both unaffected parents and two affected siblings. Exome analysis resulted in the identification of 43,204 variants in the index patient. All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. In silico prediction tools were used to determine mutational impact on protein function and the structure of the identified variants. RESULTS: Novel Usher syndrome type 2A (USH2A) compound heterozygous mutations, c.4325T>C (p.F1442S) and c.15188T>G (p.L5063R), located in exons 20 and 70, respectively, were identified as probable causative mutations for RP in this family. Family segregation of the variants showed the presence of both mutations in all affected members and in two siblings who were apparently asymptomatic at the time of family ascertainment. Clinical reassessment confirmed the diagnosis of RP in these patients. CONCLUSIONS: Using WES, we identified two heterozygous novel mutations in USH2A as the most likely disease-causing variants in a Spanish family diagnosed with arRP in which the cause of the disease had not yet been identified with commonly used techniques. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases where conventional genetic approaches have previously failed in achieving a proper diagnosis.}, issn = {1090-0535}, url = {http://www.molvis.org/molvis/v19/2187/}, author = {M{\'e}ndez-Vidal, Cristina and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Vela-Boza, Alicia and Santoyo-L{\'o}pez, Javier and L{\'o}pez-Domingo, Francisco J and V{\'a}zquez-Marouschek, Carmen and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {916, title = {CellBase, a comprehensive collection of RESTful web services for retrieving relevant biological information from heterogeneous sources.}, journal = {Nucleic acids research}, volume = {40}, year = {2012}, month = {2012 Jul}, pages = {W609-14}, abstract = {During the past years, the advances in high-throughput technologies have produced an unprecedented growth in the number and size of repositories and databases storing relevant biological data. Today, there is more biological information than ever but, unfortunately, the current status of many of these repositories is far from being optimal. Some of the most common problems are that the information is spread out in many small databases; frequently there are different standards among repositories and some databases are no longer supported or they contain too specific and unconnected information. In addition, data size is increasingly becoming an obstacle when accessing or storing biological data. All these issues make very difficult to extract and integrate information from different sources, to analyze experiments or to access and query this information in a programmatic way. CellBase provides a solution to the growing necessity of integration by easing the access to biological data. CellBase implements a set of RESTful web services that query a centralized database containing the most relevant biological data sources. The database is hosted in our servers and is regularly updated. CellBase documentation can be found at http://docs.bioinfo.cipf.es/projects/cellbase.}, issn = {1362-4962}, doi = {10.1093/nar/gks575}, url = {http://nar.oxfordjournals.org/content/40/W1/W609.long}, author = {Bleda, Marta and T{\'a}rraga, Joaqu{\'\i}n and De Maria, Alejandro and Salavert, Francisco and Garc{\'\i}a-Alonso, Luz and Celma, Matilde and Martin, Ainoha and Dopazo, Joaquin and Medina, Ignacio} } @article {512, title = {Discovering the hidden sub-network component in a ranked list of genes or proteins derived from genomic experiments.}, journal = {Nucleic Acids Res}, volume = {40}, year = {2012}, month = {2012 Nov 01}, pages = {e158}, abstract = {

Genomic experiments (e.g. differential gene expression, single-nucleotide polymorphism association) typically produce ranked list of genes. We present a simple but powerful approach which uses protein-protein interaction data to detect sub-networks within such ranked lists of genes or proteins. We performed an exhaustive study of network parameters that allowed us concluding that the average number of components and the average number of nodes per component are the parameters that best discriminate between real and random networks. A novel aspect that increases the efficiency of this strategy in finding sub-networks is that, in addition to direct connections, also connections mediated by intermediate nodes are considered to build up the sub-networks. The possibility of using of such intermediate nodes makes this approach more robust to noise. It also overcomes some limitations intrinsic to experimental designs based on differential expression, in which some nodes are invariant across conditions. The proposed approach can also be used for candidate disease-gene prioritization. Here, we demonstrate the usefulness of the approach by means of several case examples that include a differential expression analysis in Fanconi Anemia, a genome-wide association study of bipolar disorder and a genome-scale study of essentiality in cancer genes. An efficient and easy-to-use web interface (available at http://www.babelomics.org) based on HTML5 technologies is also provided to run the algorithm and represent the network.

}, keywords = {Bipolar Disorder, Fanconi Anemia, Gene Regulatory Networks, Genes, Neoplasm, Genome-Wide Association Study, Genomics, Humans, Protein Interaction Mapping}, issn = {1362-4962}, doi = {10.1093/nar/gks699}, author = {Garc{\'\i}a-Alonso, Luz and Alonso, Roberto and Vidal, Enrique and Amadoz, Alicia and De Maria, Alejandro and Minguez, Pablo and Medina, Ignacio and Dopazo, Joaquin} } @article {513, title = {Diversification of the expanded teleost-specific toll-like receptor family in Atlantic cod, Gadus morhua.}, journal = {BMC Evol Biol}, volume = {12}, year = {2012}, month = {2012 Dec 29}, pages = {256}, abstract = {

BACKGROUND: Toll-like receptors (Tlrs) are major molecular pattern recognition receptors of the innate immune system. Atlantic cod (Gadus morhua) is the first vertebrate known to have lost most of the mammalian Tlr orthologues, particularly all bacterial recognising and other cell surface Tlrs. On the other hand, its genome encodes a unique repertoire of teleost-specific Tlrs. The aim of this study was to investigate if these duplicate Tlrs have been retained through adaptive evolution to compensate for the lack of other cell surface Tlrs in the cod genome.

RESULTS: In this study, one tlr21, 12 tlr22 and two tlr23 genes representing the teleost-specific Tlr family have been cloned and characterised in cod. Phylogenetic analysis grouped all tlr22 genes under a single clade, indicating that the multiple cod paralogues have arisen through lineage-specific duplications. All tlrs examined were transcribed in immune-related tissues as well as in stomach, gut and gonads of adult cod and were differentially expressed during early development. These tlrs were also differentially regulated following immune challenge by immersion with Vibrio anguillarum, indicating their role in the immune response. An increase in water temperature from 4 to 12{\textdegree}C was associated with a 5.5-fold down-regulation of tlr22d transcript levels in spleen. Maximum likelihood analysis with different evolution models revealed that tlr22 genes are under positive selection. A total of 24 codons were found to be positively selected, of which 19 are in the ligand binding region of ectodomain.

CONCLUSION: Positive selection pressure coupled with experimental evidence of differential expression strongly support the hypothesis that teleost-specific tlr paralogues in cod are undergoing neofunctionalisation and can recognise bacterial pathogen-associated molecular patterns to compensate for the lack of other cell surface Tlrs.

}, keywords = {Amino Acid Sequence, Animals, Binding Sites, Evolution, Molecular, Fish Diseases, Fish Proteins, Gadus morhua, Gene Expression Profiling, Genetic Variation, Gills, Head Kidney, Host-Pathogen Interactions, Models, Molecular, Molecular Sequence Data, Multigene Family, Phylogeny, Protein Structure, Tertiary, Reverse Transcriptase Polymerase Chain Reaction, Selection, Genetic, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Temperature, Toll-Like Receptors, Vibrio}, issn = {1471-2148}, doi = {10.1186/1471-2148-12-256}, author = {Sundaram, Arvind Y M and Kiron, Viswanath and Dopazo, Joaquin and Fernandes, Jorge M O} } @article {514, title = {Extensive translatome remodeling during ER stress response in mammalian cells.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e35915}, abstract = {

In this work we have described the translatome of two mammalian cell lines, NIH3T3 and Jurkat, by scoring the relative polysome association of \~{}10,000 mRNA under normal and ER stress conditions. We have found that translation efficiencies of mRNA correlated poorly with transcript abundance, although a general tendency was observed so that the highest translation efficiencies were found in abundant mRNA. Despite the differences found between mouse (NIH3T3) and human (Jurkat) cells, both cell types share a common translatome composed by \~{}800-900 mRNA that encode proteins involved in basic cellular functions. Upon stress, an extensive remodeling in translatomes was observed so that translation of \~{}50\% of mRNA was inhibited in both cell types, this effect being more dramatic for those mRNA that accounted for most of the cell translation. Interestingly, we found two subsets comprising 1000-1500 mRNA whose translation resisted or was induced by stress. Translation arrest resistant class includes many mRNA encoding aminoacyl tRNA synthetases, ATPases and enzymes involved in DNA replication and stress response such as BiP. This class of mRNA is characterized by high translation rates in both control and stress conditions. Translation inducible class includes mRNA whose translation was relieved after stress, showing a high enrichment in early response transcription factors of bZIP and zinc finger C2H2 classes. Unlike yeast, a general coordination between changes in translation and transcription upon stress (potentiation) was not observed in mammalian cells. Among the different features of mRNA analyzed, we found a relevant association of translation efficiency with the presence of upstream ATG in the 5{\textquoteright}UTR and with the length of coding sequence of mRNA, and a looser association with other parameters such as the length and the G+C content of 5{\textquoteright}UTR. A model for translatome remodeling during the acute phase of stress response in mammalian cells is proposed.

}, keywords = {Animals, Endoplasmic Reticulum Stress, Humans, Jurkat Cells, Mice, NIH 3T3 Cells, Oligonucleotide Array Sequence Analysis, Protein Biosynthesis, RNA, Messenger, Transcription, Genetic}, issn = {1932-6203}, doi = {10.1371/journal.pone.0035915}, author = {Ventoso, Iv{\'a}n and Kochetov, Alex and Montaner, David and Dopazo, Joaquin and Santoyo, Javier} } @article {515, title = {Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung{\textquoteright}s disease.}, journal = {Orphanet J Rare Dis}, volume = {7}, year = {2012}, month = {2012 Dec 28}, pages = {103}, abstract = {

Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung{\textquoteright}s disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.

}, keywords = {Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Hirschsprung Disease, Humans, Male}, issn = {1750-1172}, doi = {10.1186/1750-1172-7-103}, author = {Fern{\'a}ndez, Raquel Ma and Bleda, Marta and N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Medina, Ignacio and Luz{\'o}n-Toro, Berta and Garc{\'\i}a-Alonso, Luz and Torroglosa, Ana and Marb{\`a}, Martina and Enguix-Riego, Ma Valle and Montaner, David and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {516, title = {IL1Ī² induces mesenchymal stem cells migration and leucocyte chemotaxis through NF-ĪŗB.}, journal = {Stem Cell Rev Rep}, volume = {8}, year = {2012}, month = {2012 Sep}, pages = {905-16}, abstract = {

Mesenchymal stem cells are often transplanted into inflammatory environments where they are able to survive and modulate host immune responses through a poorly understood mechanism. In this paper we analyzed the responses of MSC to IL-1Ī²: a representative inflammatory mediator. Microarray analysis of MSC treated with IL-1Ī² revealed that this cytokine activateds a set of genes related to biological processes such as cell survival, cell migration, cell adhesion, chemokine production, induction of angiogenesis and modulation of the immune response. Further more detailed analysis by real-time PCR and functional assays revealed that IL-1Ī² mainly increaseds the production of chemokines such as CCL5, CCL20, CXCL1, CXCL3, CXCL5, CXCL6, CXCL10, CXCL11 and CX(3)CL1, interleukins IL-6, IL-8, IL23A, IL32, Toll-like receptors TLR2, TLR4, CLDN1, metalloproteins MMP1 and MMP3, growth factors CSF2 and TNF-Ī±, together with adhesion molecules ICAM1 and ICAM4. Functional analysis of MSC proliferation, migration and adhesion to extracellular matrix components revealed that IL-1Ī² did not affect proliferation but also served to induce the secretion of trophic factors and adhesion to ECM components such as collagen and laminin. IL-1Ī² treatment enhanced the ability of MSC to recruit monocytes and granulocytes in vitro. Blockade of NF-ĪŗĪ² transcription factor activation with IĪŗB kinase beta (IKKĪ²) shRNA impaired MSC migration, adhesion and leucocyte recruitment, induced by IL-1Ī² demonstrating that NF-ĪŗB pathway is an important downstream regulator of these responses. These findings are relevant to understanding the biological responses of MSC to inflammatory environments.

}, keywords = {Cell Adhesion, Cell Movement, Cell Proliferation, Chemokines, Chemotaxis, Leukocyte, Collagen, Fibronectins, Gene Expression Profiling, Gene Knockdown Techniques, HEK293 Cells, Humans, I-kappa B Kinase, Inflammation Mediators, Intercellular Signaling Peptides and Proteins, Interleukin-1beta, Laminin, Leukocytes, Mesenchymal Stem Cells, NF-kappa B, Oligonucleotide Array Sequence Analysis, RNA Interference, Signal Transduction}, issn = {2629-3277}, doi = {10.1007/s12015-012-9364-9}, author = {Carrero, Rub{\'e}n and Cerrada, Inmaculada and Lled{\'o}, Elisa and Dopazo, Joaquin and Garcia-Garcia, Francisco and Rubio, Mari-Paz and Trigueros, C{\'e}sar and Dorronsoro, Akaitz and Ruiz-Sauri, Amparo and Montero, Jos{\'e} Anastasio and Sep{\'u}lveda, Pilar} } @article {517, title = {Inferring the regulatory network behind a gene expression experiment.}, journal = {Nucleic Acids Res}, volume = {40}, year = {2012}, month = {2012 Jul}, pages = {W168-72}, abstract = {

Transcription factors (TFs) and miRNAs are the most important dynamic regulators in the control of gene expression in multicellular organisms. These regulatory elements play crucial roles in development, cell cycling and cell signaling, and they have also been associated with many diseases. The Regulatory Network Analysis Tool (RENATO) web server makes the exploration of regulatory networks easy, enabling a better understanding of functional modularity and network integrity under specific perturbations. RENATO is suitable for the analysis of the result of expression profiling experiments. The program analyses lists of genes and search for the regulators compatible with its activation or deactivation. Tests of single enrichment or gene set enrichment allow the selection of the subset of TFs or miRNAs significantly involved in the regulation of the query genes. RENATO also offers an interactive advanced graphical interface that allows exploring the regulatory network found.RENATO is available at: http://renato.bioinfo.cipf.es/.

}, keywords = {Binding Sites, Databases, Genetic, Fanconi Anemia, Gene Regulatory Networks, Internet, MicroRNAs, Software, Transcription Factors, Transcriptome}, issn = {1362-4962}, doi = {10.1093/nar/gks573}, author = {Bleda, Marta and Medina, Ignacio and Alonso, Roberto and De Maria, Alejandro and Salavert, Francisco and Dopazo, Joaquin} } @article {920, title = {A map of human microRNA variation uncovers unexpectedly high levels of variability.}, journal = {Genome medicine}, volume = {4}, year = {2012}, month = {2012 Aug 20}, pages = {62}, abstract = {ABSTRACT: BACKGROUND: MicroRNAs (miRNAs) are key components of the gene regulatory network in many species. During the past few years, these regulatory elements have been shown to be involved in an increasing number and range of diseases. Consequently, the compilation of a comprehensive map of natural variability in healthy population seems an obvious requirement for future research on miRNA-related pathologies. METHODS: Data on 14 populations from the 1000 Genomes Project were analysed, along with new data extracted from 60 exomes of healthy individuals from a southern Spain population, sequenced in the context of the Medical Genome Project, to derive an accurate map of miRNA variability. RESULTS: Despite the common belief that miRNAs are highly conserved elements, analysis of the sequences of the 1,152 individuals indicated that the observed level of variability is double what was expected. A total of 527 variants were found. Among these, 45 variants affected the recognition region of the corresponding miRNA and were found in 43 different miRNAs, 26 of which are known to be involved in 57 diseases. Different parts of the mature structure of the miRNA were affected to different degrees by variants, which suggests the existence of a selective pressure related to the relative functional impact of the change. Moreover, 41 variants showed a significant deviation from the Hardy-Weinberg equilibrium, which supports the existence of a selective process against some alleles. The average number of variants per individual in miRNAs was 28. CONCLUSIONS: Despite an expectation that miRNAs would be highly conserved genomic elements, our study reports a level of variability comparable to that observed for coding genes.}, keywords = {NGS}, issn = {1756-994X}, doi = {10.1186/gm363}, url = {http://genomemedicine.com/content/4/8/62/abstract}, author = {Carbonell, Jos{\'e} and Alloza, Eva and Arce, Pablo and Borrego, Salud and Santoyo, Javier and Ruiz-Ferrer, Macarena and Medina, Ignacio and Jim{\'e}nez-Almaz{\'a}n, Jorge and M{\'e}ndez-Vidal, Cristina and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Vela, Alicia and Bhattacharya, Shomi S and Anti{\v n}olo, Guillermo and Dopazo, Joaquin} } @article {521, title = {The protease MT1-MMP drives a combinatorial proteolytic program in activated endothelial cells.}, journal = {FASEB J}, volume = {26}, year = {2012}, month = {2012 Nov}, pages = {4481-94}, abstract = {

The mechanism by which proteolytic events translate into biological responses is not well understood. To explore the link of pericellular proteolysis to events relevant to capillary sprouting within the inflammatory context, we aimed at the identification of the collection of substrates of the protease MT1-MMP in endothelial tip cells induced by inflammatory stimuli. We applied quantitative proteomics to endothelial cells (ECs) derived from wild-type and MT1-MMP-null mice to identify the substrate repertoire of this protease in TNF-Ī±-activated ECs. Bioinformatics analysis revealed a combinatorial MT1-MMP proteolytic program, in which combined rather than single substrate processing would determine biological decisions by activated ECs, including chemotaxis, cell motility and adhesion, and vasculature development. MT1-MMP-deficient ECs inefficiently processed several of these substrates (TSP1, CYR61, NID1, and SEM3C), validating the model. This novel concept of MT1-MMP-driven combinatorial proteolysis in angiogenesis might be extendable to proteolytic actions in other cellular contexts.

}, keywords = {Animals, Blotting, Western, Combinatorial Chemistry Techniques, Computational Biology, Endothelial Cells, Gene Expression Regulation, Enzymologic, Inflammation, Matrix Metalloproteinase 14, Mice, Protein Array Analysis, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, RNA, Small Interfering, Transcriptome, Tumor Necrosis Factor-alpha}, issn = {1530-6860}, doi = {10.1096/fj.12-205906}, author = {Koziol, Agnieszka and Gonzalo, Pilar and Mota, Alba and Poll{\'a}n, Angela and Lorenzo, Cristina and Colom{\'e}, Nuria and Montaner, David and Dopazo, Joaquin and Arribas, Joaqu{\'\i}n and Canals, Francesc and Arroyo, Alicia G} } @article {519, title = {SNPeffect 4.0: on-line prediction of molecular and structural effects of protein-coding variants.}, journal = {Nucleic Acids Res}, volume = {40}, year = {2012}, month = {2012 Jan}, pages = {D935-9}, abstract = {

Single nucleotide variants (SNVs) are, together with copy number variation, the primary source of variation in the human genome and are associated with phenotypic variation such as altered response to drug treatment and susceptibility to disease. Linking structural effects of non-synonymous SNVs to functional outcomes is a major issue in structural bioinformatics. The SNPeffect database (http://snpeffect.switchlab.org) uses sequence- and structure-based bioinformatics tools to predict the effect of protein-coding SNVs on the structural phenotype of proteins. It integrates aggregation prediction (TANGO), amyloid prediction (WALTZ), chaperone-binding prediction (LIMBO) and protein stability analysis (FoldX) for structural phenotyping. Additionally, SNPeffect holds information on affected catalytic sites and a number of post-translational modifications. The database contains all known human protein variants from UniProt, but users can now also submit custom protein variants for a SNPeffect analysis, including automated structure modeling. The new meta-analysis application allows plotting correlations between phenotypic features for a user-selected set of variants.

}, keywords = {Databases, Protein, Humans, Internet, Meta-Analysis as Topic, Phenotype, Polymorphism, Single Nucleotide, Protein Conformation, Proteins}, issn = {1362-4962}, doi = {10.1093/nar/gkr996}, author = {De Baets, Greet and Van Durme, Joost and Reumers, Joke and Maurer-Stroh, Sebastian and Vanhee, Peter and Dopazo, Joaquin and Schymkowitz, Joost and Rousseau, Frederic} } @article {1028, title = {Transdifferentiation of MALME-3M and MCF-7 Cells toward Adipocyte-like Cells is Dependent on Clathrin-mediated Endocytosis.}, journal = {SpringerPlus}, volume = {1}, year = {2012}, month = {2012}, pages = {44}, abstract = {ABSTRACT: Enforced cell transdifferentiation of human cancer cells is a promising alternative to conventional chemotherapy. We previously identified albumin-associated lipid- and, more specifically, saturated fatty acid-induced transdifferentiation programs in human cancer cells (HCCLs). In this study, we further characterized the adipocyte-like cells, resulting from the transdifferentiation of human cancer cell lines MCF-7 and MALME-3M, and proposed a common mechanistic approach for these transdifferentiating programs. We showed the loss of pigmentation in MALME-3M cells treated with albumin-associated lipids, based on electron microscopic analysis, and the overexpression of perilipin 2 (PLIN2) by western blotting in MALME-3M and MCF-7 cells treated with unsaturated fatty acids. Comparing the gene expression profiles of naive melanoma MALME-3M cells and albumin-associated lipid-treated cells, based on RNA sequencing, we confirmed the transcriptional upregulation of some key adipogenic gene markers and also an alternative splicing of the adipogenic master regulator PPARG, that is probably related to the reported up regulated expression of the protein. Most importantly, these results also showed the upregulation of genes responsible for Clathrin (CLTC) and other adaptor-related proteins. An increase in CLTC expression in the transdifferentiated cells was confirmed by western blotting. Inactivation of CLTC by chlorpromazine (CHP), an inhibitor of CTLC mediated endocytosis (CME), and gene silencing by siRNAs, partially reversed the accumulation of neutral lipids observed in the transdifferentiated cells. These findings give a deeper insight into the phenotypic changes observed in HCCL to adipocyte-like transdifferentiation and point towards CME as a key pathway in distinct transdifferentiation programs. DISCLOSURES: Simon C and Aguilar-Gallardo C are co-inventors of the International Patent Application No. PCT/EP2011/004941 entitled "Methods for tumor treatment and adipogenesis differentiation".}, issn = {2193-1801}, doi = {10.1186/2193-1801-1-44}, url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725915/}, author = {Carcel-Trullols, Jaime and Aguilar-Gallardo, Crist{\'o}bal and Garc{\'\i}a-Alcalde, Fernando and Pardo-Cea, Miguel Angel and Dopazo, Joaquin and Ana Conesa and Simon, Carlos} } @article {900, title = {Using GPUs for the Exact Alignment of Short-read Genetic Sequences by Means of the Burrows{\textendash}Wheeler Transform.}, journal = {IEEE/ACM transactions on computational biology and bioinformatics / IEEE, ACM}, volume = {9}, number = {4}, year = {2012}, month = {2012 Mar 20}, pages = {1245-1256}, abstract = {General Purpose Graphic Processing Units (GPGPUs) constitute an inexpensive resource for computing-intensive applications that could exploit an intrinsic fine-grain parallelism. This paper presents the design and implementation in GPGPUs of an exact alignment tool for nucleotide sequences based on the Burrows-Wheeler Transform. We compare this algorithm with state-of-the-art implementations of the same algorithm over standard CPUs, and considering the same conditions in terms of I/O. Excluding disk transfers, the implementation of the algorithm in GPUs shows a speedup larger than 12x, when compared to CPU execution. This implementation exploits the parallelism by concurrently searching different sequences on the same reference search tree, maximising memory locality and ensuring a symmetric access to the data. The article describes the behaviour of the algorithm in GPU, showing a good scalability in the performance, only limited by the size of the GPU inner memory.}, keywords = {Burrows-Wheeler transform, CPU execution, GPGPU, NGS}, issn = {1557-9964}, doi = {10.1109/TCBB.2012.49}, url = {http://ieeexplore.ieee.org.sire.ub.edu/xpl/articleDetails.jsp?reload=true\&arnumber=6175888}, author = {Salavert Torres, Jose and Blanquer Espert, Ignacio and Tomas Dominguez, Andres and Hernendez, Vicente and Medina, Ignacio and Terraga, Joaquin and Dopazo, Joaquin} } @article {523, title = {VARIANT: Command Line, Web service and Web interface for fast and accurate functional characterization of variants found by Next-Generation Sequencing.}, journal = {Nucleic Acids Res}, volume = {40}, year = {2012}, month = {2012 Jul}, pages = {W54-8}, abstract = {

The massive use of Next-Generation Sequencing (NGS) technologies is uncovering an unexpected amount of variability. The functional characterization of such variability, particularly in the most common form of variation found, the Single Nucleotide Variants (SNVs), has become a priority that needs to be addressed in a systematic way. VARIANT (VARIant ANalyis Tool) reports information on the variants found that include consequence type and annotations taken from different databases and repositories (SNPs and variants from dbSNP and 1000 genomes, and disease-related variants from the Genome-Wide Association Study (GWAS) catalog, Online Mendelian Inheritance in Man (OMIM), Catalog of Somatic Mutations in Cancer (COSMIC) mutations, etc). VARIANT also produces a rich variety of annotations that include information on the regulatory (transcription factor or miRNA-binding sites, etc.) or structural roles, or on the selective pressures on the sites affected by the variation. This information allows extending the conventional reports beyond the coding regions and expands the knowledge on the contribution of non-coding or synonymous variants to the phenotype studied. Contrarily to other tools, VARIANT uses a remote database and operates through efficient RESTful Web Services that optimize search and transaction operations. In this way, local problems of installation, update or disk size limitations are overcome without the need of sacrifice speed (thousands of variants are processed per minute). VARIANT is available at: http://variant.bioinfo.cipf.es.

}, keywords = {Databases, Nucleic Acid, Genetic Variation, High-Throughput Nucleotide Sequencing, Internet, Molecular Sequence Annotation, mutation, Polymorphism, Single Nucleotide, Software, User-Computer Interface}, issn = {1362-4962}, doi = {10.1093/nar/gks572}, author = {Medina, Ignacio and De Maria, Alejandro and Bleda, Marta and Salavert, Francisco and Alonso, Roberto and Gonzalez, Cristina Y and Dopazo, Joaquin} } @article {524, title = {Whole-genome bisulfite DNA sequencing of a DNMT3B mutant patient.}, journal = {Epigenetics}, volume = {7}, year = {2012}, month = {2012 Jun 01}, pages = {542-50}, abstract = {

The immunodeficiency, centromere instability and facial anomalies (ICF) syndrome is associated to mutations of the DNA methyl-transferase DNMT3B, resulting in a reduction of enzyme activity. Aberrant expression of immune system genes and hypomethylation of pericentromeric regions accompanied by chromosomal instability were determined as alterations driving the disease phenotype. However, so far only technologies capable to analyze single loci were applied to determine epigenetic alterations in ICF patients. In the current study, we performed whole-genome bisulphite sequencing to assess alteration in DNA methylation at base pair resolution. Genome-wide we detected a decrease of methylation level of 42\%, with the most profound changes occurring in inactive heterochromatic regions, satellite repeats and transposons. Interestingly, transcriptional active loci and ribosomal RNA repeats escaped global hypomethylation. Despite a genome-wide loss of DNA methylation the epigenetic landscape and crucial regulatory structures were conserved. Remarkably, we revealed a mislocated activity of mutant DNMT3B to H3K4me1 loci resulting in hypermethylation of active promoters. Functionally, we could associate alterations in promoter methylation with the ICF syndrome immunodeficient phenotype by detecting changes in genes related to the B-cell receptor mediated maturation pathway.

}, keywords = {B-Lymphocytes, Cell Line, Transformed, Child, Preschool, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, Epigenesis, Genetic, Face, Female, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Immunologic Deficiency Syndromes, mutation, Primary Immunodeficiency Diseases, Sequence Analysis, DNA, Sulfites}, issn = {1559-2308}, doi = {10.4161/epi.20523}, author = {Heyn, Holger and Vidal, Enrique and Sayols, Sergi and Sanchez-Mut, Jose V and Moran, Sebastian and Medina, Ignacio and Sandoval, Juan and Sim{\'o}-Riudalbas, Laia and Szczesna, Karolina and Huertas, Dori and Gatto, Sole and Matarazzo, Maria R and Dopazo, Joaquin and Esteller, Manel} } @article {21479216, title = {Analysis of normal-tumour tissue interaction in tumours: prediction of prostate cancer features from the molecular profile of adjacent normal cells.}, journal = {PloS one}, volume = {6}, year = {2011}, month = {2011}, pages = {e16492}, abstract = {

Statistical modelling, in combination with genome-wide expression profiling techniques, has demonstrated that the molecular state of the tumour is sufficient to infer its pathological state. These studies have been extremely important in diagnostics and have contributed to improving our understanding of tumour biology. However, their importance in in-depth understanding of cancer patho-physiology may be limited since they do not explicitly take into consideration the fundamental role of the tissue microenvironment in specifying tumour physiology. Because of the importance of normal cells in shaping the tissue microenvironment we formulate the hypothesis that molecular components of the profile of normal epithelial cells adjacent the tumour are predictive of tumour physiology. We addressed this hypothesis by developing statistical models that link gene expression profiles representing the molecular state of adjacent normal epithelial cells to tumour features in prostate cancer. Furthermore, network analysis showed that predictive genes are linked to the activity of important secreted factors, which have the potential to influence tumor biology, such as IL1, IGF1, PDGF BB, AGT, and TGF\β.

}, author = {Trevino, Victor and Tadesse, Mahlet G and Vannucci, Marina and Fatima Al-Shahrour and Antczak, Philipp and Durant, Sarah and Bikfalvi, Andreas and Dopazo, Joaquin and Campbell, Moray J and Falciani, Francesco} } @article {21408226, title = {Assessing the biological significance of gene expression signatures and co-expression modules by studying their network properties.}, journal = {PloS one}, volume = {6}, year = {2011}, month = {2011}, pages = {e17474}, abstract = {

Microarray experiments have been extensively used to define signatures, which are sets of genes that can be considered markers of experimental conditions (typically diseases). Paradoxically, in spite of the apparent functional role that might be attributed to such gene sets, signatures do not seem to be reproducible across experiments. Given the close relationship between function and protein interaction, network properties can be used to study to what extent signatures are composed of genes whose resulting proteins show a considerable level of interaction (and consequently a putative common functional role).We have analysed 618 signatures and 507 modules of co-expression in cancer looking for significant values of four main protein-protein interaction (PPI) network parameters: connection degree, cluster coefficient, betweenness and number of components. A total of 3904 gene ontology (GO) modules, 146 KEGG pathways, and 263 Biocarta pathways have been used as functional modules of reference.Co-expression modules found in microarray experiments display a high level of connectivity, similar to the one shown by conventional modules based on functional definitions (GO, KEGG and Biocarta). A general observation for all the classes studied is that the networks formed by the modules improve their topological parameters when an external protein is allowed to be introduced within the paths (up to the 70\% of GO modules show network parameters beyond the random expectation). This fact suggests that functional definitions are incomplete and some genes might still be missing. Conversely, signatures are clearly not capturing the altered functions in the corresponding studies. This is probably because the way in which the genes have been selected in the signatures is too conservative. These results suggest that gene selection methods which take into account relationships among genes should be superior to methods that assume independence among genes outside their functional contexts.

}, doi = {doi:10.1371/journal.pone.0017474}, url = {http://www.plosone.org/article/info\%3Adoi\%2F10.1371\%2Fjournal.pone.0017474}, author = {Minguez, Pablo and Dopazo, Joaquin} } @article {529, title = {Differential expression in RNA-seq: a matter of depth.}, journal = {Genome Res}, volume = {21}, year = {2011}, month = {2011 Dec}, pages = {2213-23}, abstract = {

Next-generation sequencing (NGS) technologies are revolutionizing genome research, and in particular, their application to transcriptomics (RNA-seq) is increasingly being used for gene expression profiling as a replacement for microarrays. However, the properties of RNA-seq data have not been yet fully established, and additional research is needed for understanding how these data respond to differential expression analysis. In this work, we set out to gain insights into the characteristics of RNA-seq data analysis by studying an important parameter of this technology: the sequencing depth. We have analyzed how sequencing depth affects the detection of transcripts and their identification as differentially expressed, looking at aspects such as transcript biotype, length, expression level, and fold-change. We have evaluated different algorithms available for the analysis of RNA-seq and proposed a novel approach--NOISeq--that differs from existing methods in that it is data-adaptive and nonparametric. Our results reveal that most existing methodologies suffer from a strong dependency on sequencing depth for their differential expression calls and that this results in a considerable number of false positives that increases as the number of reads grows. In contrast, our proposed method models the noise distribution from the actual data, can therefore better adapt to the size of the data set, and is more effective in controlling the rate of false discoveries. This work discusses the true potential of RNA-seq for studying regulation at low expression ranges, the noise within RNA-seq data, and the issue of replication.

}, keywords = {Algorithms, Expressed Sequence Tags, Gene Expression Profiling, Gene Expression Regulation, Humans, Models, Genetic, Oligonucleotide Array Sequence Analysis}, issn = {1549-5469}, doi = {10.1101/gr.124321.111}, author = {Tarazona, Sonia and Garc{\'\i}a-Alcalde, Fernando and Dopazo, Joaquin and Ferrer, Alberto and Conesa, Ana} } @article {21266330, title = {Differential Lipid Partitioning Between Adipocytes and Tissue Macrophages Modulates Macrophage Lipotoxicity and M2/M1 Polarization in Obese Mice.}, journal = {Diabetes}, volume = {60}, number = {3}, year = {2011}, month = {2011 Jan 24}, pages = {797-809}, abstract = {

OBJECTIVE Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response. RESEARCH DESIGN AND METHODS We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment. RESULTS We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization. CONCLUSIONS Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.

}, author = {Prieur, Xavier and Mok, Crystal Y L and Velagapudi, Vidya R and N{\'u}{\~n}ez, Vanessa and Fuentes, Luc{\'\i}a and Montaner, David and Ishikawa, Ko and Camacho, Alberto and Barbarroja, Nuria and O{\textquoteright}Rahilly, Stephen and Sethi, Jaswinder and Dopazo, Joaquin and Oresic, Matej and Ricote, Mercedes and Vidal-Puig, Antonio} } @article {531, title = {Early peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass.}, journal = {BMC Med Genomics}, volume = {4}, year = {2011}, month = {2011 Dec 30}, pages = {86}, abstract = {

BACKGROUND: The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARĪ³2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARĪ³ dependent transcriptional responses involved in the process of beta cell mass expansion

RESULTS: Here we have investigated PPARĪ³ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARĪ³2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARĪ³ in maintenance/activation of mechanisms essential for the continued function of the beta cell.

CONCLUSIONS: Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARĪ³ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-Ī² signaling and decreased oxidative phosphorylation.

}, keywords = {Animals, Cell Proliferation, Cell Survival, Cholesterol, Down-Regulation, Female, Gene Expression Regulation, Gene Knockout Techniques, Insulin Resistance, Insulin-Secreting Cells, Mice, obesity, Oxidation-Reduction, Phosphorylation, PPAR gamma, Signal Transduction, Transcription, Genetic, Transforming Growth Factor beta}, issn = {1755-8794}, doi = {10.1186/1755-8794-4-86}, author = {Vivas, Yurena and Martinez-Garcia, Cristina and Izquierdo, Adriana and Garcia-Garcia, Francisco and Callejas, Sergio and Velasco, Ismael and Campbell, Mark and Ros, Manuel and Dopazo, Ana and Dopazo, Joaquin and Vidal-Puig, Antonio and Medina-Gomez, Gema} } @article {532, title = {Early transcriptional defense responses in Arabidopsis cell suspension culture under high-light conditions.}, journal = {Plant Physiol}, volume = {156}, year = {2011}, month = {2011 Jul}, pages = {1439-56}, abstract = {

The early transcriptional defense responses and reactive oxygen species (ROS) production in Arabidopsis (Arabidopsis thaliana) cell suspension culture (ACSC), containing functional chloroplasts, were examined at high light (HL). The transcriptional analysis revealed that most of the ROS markers identified among the 449 transcripts with significant differential expression were transcripts specifically up-regulated by singlet oxygen ((1)O(2)). On the contrary, minimal correlation was established with transcripts specifically up-regulated by superoxide radical or hydrogen peroxide. The transcriptional analysis was supported by fluorescence microscopy experiments. The incubation of ACSC with the (1)O(2) sensor green reagent and 2{\textquoteright},7{\textquoteright}-dichlorofluorescein diacetate showed that the 30-min-HL-treated cultures emitted fluorescence that corresponded with the production of (1)O(2) but not of hydrogen peroxide. Furthermore, the in vivo photodamage of the D1 protein of photosystem II indicated that the photogeneration of (1)O(2) took place within the photosystem II reaction center. Functional enrichment analyses identified transcripts that are key components of the ROS signaling transduction pathway in plants as well as others encoding transcription factors that regulate both ROS scavenging and water deficit stress. A meta-analysis examining the transcriptional profiles of mutants and hormone treatments in Arabidopsis showed a high correlation between ACSC at HL and the fluorescent mutant family of Arabidopsis, a producer of (1)O(2) in plastids. Intriguingly, a high correlation was also observed with ABA deficient1 and more axillary growth4, two mutants with defects in the biosynthesis pathways of two key (apo)carotenoid-derived plant hormones (i.e. abscisic acid and strigolactones, respectively). ACSC has proven to be a valuable system for studying early transcriptional responses to HL stress.

}, keywords = {Arabidopsis, Blotting, Western, Cell Culture Techniques, Cells, Cultured, Chloroplasts, Cluster Analysis, Gene Expression Profiling, Gene Expression Regulation, Plant, Hydrogen Peroxide, Light, mutation, Oligonucleotide Array Sequence Analysis, Photosystem II Protein Complex, Plant Growth Regulators, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Signal Transduction, Stress, Physiological, Transcription, Genetic}, issn = {1532-2548}, doi = {10.1104/pp.111.177766}, author = {Gonz{\'a}lez-P{\'e}rez, Sergio and Guti{\'e}rrez, Jorge and Garcia-Garcia, Francisco and Osuna, Daniel and Dopazo, Joaquin and Lorenzo, Oscar and Revuelta, Jos{\'e} L and Arellano, Juan B} } @article {533, title = {Evidence for short-time divergence and long-time conservation of tissue-specific expression after gene duplication.}, journal = {Brief Bioinform}, volume = {12}, year = {2011}, month = {2011 Sep}, pages = {442-8}, abstract = {

Gene duplication is one of the main mechanisms by which genomes can acquire novel functions. It has been proposed that the retention of gene duplicates can be associated to processes of tissue expression divergence. These models predict that acquisition of divergent expression patterns should be acquired shortly after the duplication, and that larger divergence in tissue expression would be expected for paralogs, as compared to orthologs of a similar age. Many studies have shown that gene duplicates tend to have divergent expression patterns and that gene family expansions are associated with high levels of tissue specificity. However, the timeframe in which these processes occur have rarely been investigated in detail, particularly in vertebrates, and most analyses do not include direct comparisons of orthologs as a baseline for the expected levels of tissue specificity in absence of duplications. To assess the specific contribution of duplications to expression divergence, we combine here phylogenetic analyses and expression data from human and mouse. In particular, we study differences in spatial expression among human-mouse paralogs, specifically duplicated after the radiation of mammals, and compare them to pairs of orthologs in the same species. Our results show that gene duplication leads to increased levels of tissue specificity and that this tends to occur promptly after the duplication event.

}, keywords = {Animals, Conserved Sequence, Evolution, Molecular, Gene Duplication, gene expression, Genome, Humans, Mice, Organ Specificity}, issn = {1477-4054}, doi = {10.1093/bib/bbr022}, author = {Huerta-Cepas, Jaime and Dopazo, Joaquin and Huynen, Martijn A and Gabald{\'o}n, Toni} } @article {21731483, title = {An evolutionary trade-off between protein turnover rate and protein aggregation favors a higher aggregation propensity in fast degrading proteins.}, journal = {PLoS computational biology}, volume = {7}, year = {2011}, month = {2011 Jun}, pages = {e1002090}, abstract = {

We previously showed the existence of selective pressure against protein aggregation by the enrichment of aggregation-opposing {\textquoteright}gatekeeper{\textquoteright} residues at strategic places along the sequence of proteins. Here we analyzed the relationship between protein lifetime and protein aggregation by combining experimentally determined turnover rates, expression data, structural data and chaperone interaction data on a set of more than 500 proteins. We find that selective pressure on protein sequences against aggregation is not homogeneous but that short-living proteins on average have a higher aggregation propensity and fewer chaperone interactions than long-living proteins. We also find that short-living proteins are more often associated to deposition diseases. These findings suggest that the efficient degradation of high-turnover proteins is sufficient to preclude aggregation, but also that factors that inhibit proteasomal activity, such as physiological ageing, will primarily affect the aggregation of short-living proteins.

}, doi = {10.1371/journal.pcbi.1002090}, author = {De Baets, Greet and Reumers, Joke and Delgado Blanco, Javier and Dopazo, Joaquin and Schymkowitz, Joost and Rousseau, Frederic} } @article {879, title = {Fortunella margarita Transcriptional Reprogramming Triggered by Xanthomonas citri subsp. citri.}, journal = {BMC plant biology}, volume = {11}, year = {2011}, month = {2011}, pages = {159}, abstract = {ABSTRACT:}, issn = {1471-2229}, author = {Khalaf, Abeer A and Gmitter, Frederick G and Ana Conesa and Dopazo, Joaquin and Moore, Gloria A} } @article {535, title = {Large-scale transcriptional profiling and functional assays reveal important roles for Rho-GTPase signalling and SCL during haematopoietic differentiation of human embryonic stem cells.}, journal = {Hum Mol Genet}, volume = {20}, year = {2011}, month = {2011 Dec 15}, pages = {4932-46}, abstract = {

Understanding the transcriptional cues that direct differentiation of human embryonic stem cells (hESCs) and human-induced pluripotent stem cells to defined and functional cell types is essential for future clinical applications. In this study, we have compared transcriptional profiles of haematopoietic progenitors derived from hESCs at various developmental stages of a feeder- and serum-free differentiation method and show that the largest transcriptional changes occur during the first 4 days of differentiation. Data mining on the basis of molecular function revealed Rho-GTPase signalling as a key regulator of differentiation. Inhibition of this pathway resulted in a significant reduction in the numbers of emerging haematopoietic progenitors throughout the differentiation window, thereby uncovering a previously unappreciated role for Rho-GTPase signalling during human haematopoietic development. Our analysis indicated that SCL was the 11th most upregulated transcript during the first 4 days of the hESC differentiation process. Overexpression of SCL in hESCs promoted differentiation to meso-endodermal lineages, the emergence of haematopoietic and erythro-megakaryocytic progenitors and accelerated erythroid differentiation. Importantly, intrasplenic transplantation of SCL-overexpressing hESC-derived haematopoietic cells enhanced recovery from induced acute anaemia without significant cell engraftment, suggesting a paracrine-mediated effect.

}, keywords = {Acute Disease, Anemia, Hemolytic, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Line, Cell Lineage, Cluster Analysis, Embryonic Stem Cells, Erythroid Cells, Flow Cytometry, Gene Expression Profiling, Hematopoietic Stem Cells, Humans, Mice, Myeloid Cells, Paracrine Communication, Proto-Oncogene Proteins, Reverse Transcriptase Polymerase Chain Reaction, rho GTP-Binding Proteins, Signal Transduction, Stem Cell Transplantation, T-Cell Acute Lymphocytic Leukemia Protein 1, Transcriptome}, issn = {1460-2083}, doi = {10.1093/hmg/ddr431}, author = {Yung, Sun and Ledran, Maria and Moreno-Gimeno, Inmaculada and Conesa, Ana and Montaner, David and Dopazo, Joaquin and Dimmick, Ian and Slater, Nicholas J and Marenah, Lamin and Real, Pedro J and Paraskevopoulou, Iliana and Bisbal, Viviana and Burks, Deborah and Santibanez-Koref, Mauro and Moreno, Ruben and Mountford, Joanne and Menendez, Pablo and Armstrong, Lyle and Lako, Majlinda} } @article {536, title = {Mutation screening of multiple genes in Spanish patients with autosomal recessive retinitis pigmentosa by targeted resequencing.}, journal = {PLoS One}, volume = {6}, year = {2011}, month = {2011}, pages = {e27894}, abstract = {

Retinitis Pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. RP is the leading cause of visual loss in individuals younger than 60 years, with a prevalence of about 1 in 4000. The molecular genetic diagnosis of autosomal recessive RP (arRP) is challenging due to the large genetic and clinical heterogeneity. Traditional methods for sequencing arRP genes are often laborious and not easily available and a screening technique that enables the rapid detection of the genetic cause would be very helpful in the clinical practice. The goal of this study was to develop and apply microarray-based resequencing technology capable of detecting both known and novel mutations on a single high-throughput platform. Hence, the coding regions and exon/intron boundaries of 16 arRP genes were resequenced using microarrays in 102 Spanish patients with clinical diagnosis of arRP. All the detected variations were confirmed by direct sequencing and potential pathogenicity was assessed by functional predictions and frequency in controls. For validation purposes 4 positive controls for variants consisting of previously identified changes were hybridized on the array. As a result of the screening, we detected 44 variants, of which 15 are very likely pathogenic detected in 14 arRP families (14\%). Finally, the design of this array can easily be transformed in an equivalent diagnostic system based on targeted enrichment followed by next generation sequencing.

}, keywords = {Alleles, DNA Mutational Analysis, Exons, Genetic Variation, Genome, Hispanic or Latino, Humans, Introns, Language, mutation, Mutation, Missense, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, Reproducibility of Results, Retinitis pigmentosa, United States}, issn = {1932-6203}, doi = {10.1371/journal.pone.0027894}, author = {Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Borrego, Salud and Barrag{\'a}n, Isabel and Pieras, Juan I and Santoyo, Javier and Matamala, Nerea and Naranjo, Bel{\'e}n and Dopazo, Joaquin and Anti{\v n}olo, Guillermo} } @article {541, title = {myKaryoView: a light-weight client for visualization of genomic data.}, journal = {PLoS One}, volume = {6}, year = {2011}, month = {2011}, pages = {e26345}, abstract = {

The Distributed Annotation System (DAS) is a protocol for easy sharing and integration of biological annotations. In order to visualize feature annotations in a genomic context a client is required. Here we present myKaryoView, a simple light-weight DAS tool for visualization of genomic annotation. myKaryoView has been specifically configured to help analyse data derived from personal genomics, although it can also be used as a generic genome browser visualization. Several well-known data sources are provided to facilitate comparison of known genes and normal variation regions. The navigation experience is enhanced by simultaneous rendering of different levels of detail across chromosomes. A simple interface is provided to allow searches for any SNP, gene or chromosomal region. User-defined DAS data sources may also be added when querying the system. We demonstrate myKaryoView capabilities for adding user-defined sources with a set of genetic profiles of family-related individuals downloaded directly from 23andMe. myKaryoView is a web tool for visualization of genomic data specifically designed for direct-to-consumer genomic data that uses publicly available data distributed throughout the Internet. It does not require data to be held locally and it is capable of rendering any feature as long as it conforms to DAS specifications. Configuration and addition of sources to myKaryoView can be done through the interface. Here we show a proof of principle of myKaryoView{\textquoteright}s ability to display personal genomics data with 23andMe genome data sources. The tool is available at: http://mykaryoview.com.

}, keywords = {Computer Graphics, Databases, Genetic, Genomics, Internet, Molecular Sequence Annotation, User-Computer Interface}, issn = {1932-6203}, doi = {10.1371/journal.pone.0026345}, author = {Jimenez, Rafael C and Salazar, Gustavo A and Gel, Bernat and Dopazo, Joaquin and Mulder, Nicola and Corpas, Manuel} } @article {537, title = {Natural selection on functional modules, a genome-wide analysis.}, journal = {PLoS Comput Biol}, volume = {7}, year = {2011}, month = {2011 Mar}, pages = {e1001093}, abstract = {

Classically, the functional consequences of natural selection over genomes have been analyzed as the compound effects of individual genes. The current paradigm for large-scale analysis of adaptation is based on the observed significant deviations of rates of individual genes from neutral evolutionary expectation. This approach, which assumed independence among genes, has not been able to identify biological functions significantly enriched in positively selected genes in individual species. Alternatively, pooling related species has enhanced the search for signatures of selection. However, grouping signatures does not allow testing for adaptive differences between species. Here we introduce the Gene-Set Selection Analysis (GSSA), a new genome-wide approach to test for evidences of natural selection on functional modules. GSSA is able to detect lineage specific evolutionary rate changes in a notable number of functional modules. For example, in nine mammal and Drosophilae genomes GSSA identifies hundreds of functional modules with significant associations to high and low rates of evolution. Many of the detected functional modules with high evolutionary rates have been previously identified as biological functions under positive selection. Notably, GSSA identifies conserved functional modules with many positively selected genes, which questions whether they are exclusively selected for fitting genomes to environmental changes. Our results agree with previous studies suggesting that adaptation requires positive selection, but not every mutation under positive selection contributes to the adaptive dynamical process of the evolution of species.

}, keywords = {Animals, Databases, Genetic, Drosophila, Genome, Insect, Genome-Wide Association Study, Genomics, Mammals, Phylogeny, Selection, Genetic, Sequence Analysis, DNA}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1001093}, author = {Serra, Fran{\c c}ois and Arbiza, Leonardo and Dopazo, Joaquin and Dopazo, Hern{\'a}n} } @article {539, title = {Phylemon 2.0: a suite of web-tools for molecular evolution, phylogenetics, phylogenomics and hypotheses testing.}, journal = {Nucleic Acids Res}, volume = {39}, year = {2011}, month = {2011 Jul}, pages = {W470-4}, abstract = {

Phylemon 2.0 is a new release of the suite of web tools for molecular evolution, phylogenetics, phylogenomics and hypotheses testing. It has been designed as a response to the increasing demand of molecular sequence analyses for experts and non-expert users. Phylemon 2.0 has several unique features that differentiates it from other similar web resources: (i) it offers an integrated environment that enables evolutionary analyses, format conversion, file storage and edition of results; (ii) it suggests further analyses, thereby guiding the users through the web server; and (iii) it allows users to design and save phylogenetic pipelines to be used over multiple genes (phylogenomics). Altogether, Phylemon 2.0 integrates a suite of 30 tools covering sequence alignment reconstruction and trimming; tree reconstruction, visualization and manipulation; and evolutionary hypotheses testing.

}, keywords = {Evolution, Molecular, Genomics, Internet, Phylogeny, Sequence Alignment, Software}, issn = {1362-4962}, doi = {10.1093/nar/gkr408}, author = {S{\'a}nchez, Rub{\'e}n and Serra, Fran{\c c}ois and T{\'a}rraga, Joaqu{\'\i}n and Medina, Ignacio and Carbonell, Jos{\'e} and Pulido, Luis and De Maria, Alejandro and Capella-Gut{\'\i}errez, Salvador and Huerta-Cepas, Jaime and Gabald{\'o}n, Toni and Dopazo, Joaquin and Dopazo, Hern{\'a}n} } @article {20028698, title = {Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus.}, journal = {Genome research}, volume = {20}, year = {2010}, month = {2010 Feb}, pages = {170-9}, abstract = {

Monozygotic (MZ) twins are partially concordant for most complex diseases, including autoimmune disorders. Whereas phenotypic concordance can be used to study heritability, discordance suggests the role of non-genetic factors. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. Here we report the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis, and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.

}, author = {Javierre, Biola M and Fernandez, Agustin F and Richter, Julia and Fatima Al-Shahrour and Martin-Subero, J Ignacio and Rodriguez-Ubreva, Javier and Berdasco, Maria and Fraga, Mario F and O{\textquoteright}Hanlon, Terrance P and Rider, Lisa G and Jacinto, Filipe V and Lopez-Longo, F Javier and Dopazo, Joaquin and Forn, Marta and Peinado, Miguel A and Carre{\~n}o, Luis and Sawalha, Amr H and Harley, John B and Siebert, Reiner and Esteller, Manel and Miller, Frederick W and Ballestar, Esteban} } @article {547, title = {DNA methylation epigenotypes in breast cancer molecular subtypes.}, journal = {Breast Cancer Res}, volume = {12}, year = {2010}, month = {2010}, pages = {R77}, abstract = {

INTRODUCTION: Identification of gene expression based breast cancer subtypes is considered as a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene expression changes occurring in breast cancer. So far, these epigenetic contributions to sporadic breast cancer subtypes have not been well characterized, and there is only a limited understanding of the epigenetic mechanisms affected in those particular breast cancer subtypes. The present study was undertaken to dissect the breast cancer methylome and deliver specific epigenotypes associated with particular breast cancer subtypes.

METHODS: Using a microarray approach we analyzed DNA methylation in regulatory regions of 806 cancer related genes in 28 breast cancer paired samples. We subsequently performed substantial technical and biological validation by Pyrosequencing, investigating the top qualifying 19 CpG regions in independent cohorts encompassing 47 basal-like, 44 ERBB2+ overexpressing, 48 luminal A and 48 luminal B paired breast cancer/adjacent tissues. Using all-subset selection method, we identified the most subtype predictive methylation profiles in multivariable logistic regression analysis.

RESULTS: The approach efficiently recognized 15 individual CpG loci differentially methylated in breast cancer tumor subtypes. We further identify novel subtype specific epigenotypes which clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors.

CONCLUSIONS: Our results provide evidence that well defined DNA methylation profiles enables breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.

}, keywords = {Aged, Breast Neoplasms, CpG Islands, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Profiling, Genes, p53, Genotype, Humans, Ki-67 Antigen, Middle Aged, mutation, Neoplasm Grading, Oligonucleotide Array Sequence Analysis, Receptor, ErbB-2, Tumor Suppressor Protein p53}, issn = {1465-542X}, doi = {10.1186/bcr2721}, author = {Bediaga, Naiara G and Acha-Sagredo, Amelia and Guerra, Isabel and Viguri, Amparo and Albaina, Carmen and Ruiz Diaz, Irune and Rezola, Ricardo and Alberdi, Maria Jesus and Dopazo, Joaquin and Montaner, David and Renobales, Mertxe and Fernandez, Agustin F and Field, John K and Fraga, Mario F and Liloglou, Triantafillos and de Pancorbo, Marian M} } @article {548, title = {ETE: a python Environment for Tree Exploration.}, journal = {BMC Bioinformatics}, volume = {11}, year = {2010}, month = {2010 Jan 13}, pages = {24}, abstract = {

BACKGROUND: Many bioinformatics analyses, ranging from gene clustering to phylogenetics, produce hierarchical trees as their main result. These are used to represent the relationships among different biological entities, thus facilitating their analysis and interpretation. A number of standalone programs are available that focus on tree visualization or that perform specific analyses on them. However, such applications are rarely suitable for large-scale surveys, in which a higher level of automation is required. Currently, many genome-wide analyses rely on tree-like data representation and hence there is a growing need for scalable tools to handle tree structures at large scale.

RESULTS: Here we present the Environment for Tree Exploration (ETE), a python programming toolkit that assists in the automated manipulation, analysis and visualization of hierarchical trees. ETE libraries provide a broad set of tree handling options as well as specific methods to analyze phylogenetic and clustering trees. Among other features, ETE allows for the independent analysis of tree partitions, has support for the extended newick format, provides an integrated node annotation system and permits to link trees to external data such as multiple sequence alignments or numerical arrays. In addition, ETE implements a number of built-in analytical tools, including phylogeny-based orthology prediction and cluster validation techniques. Finally, ETE{\textquoteright}s programmable tree drawing engine can be used to automate the graphical rendering of trees with customized node-specific visualizations.

CONCLUSIONS: ETE provides a complete set of methods to manipulate tree data structures that extends current functionality in other bioinformatic toolkits of a more general purpose. ETE is free software and can be downloaded from http://ete.cgenomics.org.

}, keywords = {Computational Biology, Databases, Genetic, Phylogeny, Software}, issn = {1471-2105}, doi = {10.1186/1471-2105-11-24}, author = {Huerta-Cepas, Jaime and Dopazo, Joaquin and Gabald{\'o}n, Toni} } @article {549, title = {Exploring the link between germline and somatic genetic alterations in breast carcinogenesis.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010 Nov 22}, pages = {e14078}, abstract = {

Recent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germline-somatic link in carcinogenesis, we evaluated the distribution of somatic gene labels within the ordered results of a breast cancer risk GWAS. This analysis suggested frequent influence on risk of genetic variation in loci encoding for "driver kinases" (i.e., kinases encoded by genes that showed higher somatic mutation rates than expected by chance and, therefore, whose deregulation may contribute to cancer development and/or progression). Assessment of these predictions using a population-based case-control study in Poland replicated the association for rs3732568 in EPHB1 (odds ratio (OR)ā€Š=ā€Š0.79; 95\% confidence interval (CI): 0.63-0.98; P(trend)ā€Š=ā€Š0.031). Analyses by early age at diagnosis and by estrogen receptor Ī± (ERĪ±) tumor status indicated potential associations for rs6852678 in CDKL2 (ORā€Š=ā€Š0.32, 95\% CI: 0.10-1.00; P(recessive)ā€Š=ā€Š0.044) and rs10878640 in DYRK2 (ORā€Š=ā€Š2.39, 95\% CI: 1.32-4.30; P(dominant)ā€Š=ā€Š0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERĪ± tumor status P(interaction)<0.05). The identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. Together, these data may lay the foundations for replication in additional populations and could potentially increase our knowledge of the underlying molecular mechanisms of breast carcinogenesis.

}, keywords = {Adult, Bone Morphogenetic Protein Receptors, Type I, Breast, Breast Neoplasms, Calcium-Calmodulin-Dependent Protein Kinases, Case-Control Studies, Cyclin-Dependent Kinases, Disease Progression, Estrogen Receptor alpha, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Germ-Line Mutation, Humans, Odds Ratio, Poland, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases, Protein-Tyrosine Kinases, Receptor Protein-Tyrosine Kinases, Receptor, EphA3, Receptor, EphA7, Receptor, EphB1, Risk Factors}, issn = {1932-6203}, doi = {10.1371/journal.pone.0014078}, author = {Bonifaci, N{\'u}ria and G{\'o}rski, Bohdan and Masoj{\'c}, Bartlomiej and Woko{\l}orczyk, Dominika and Jakubowska, Anna and D{\k e}bniak, Tadeusz and Berenguer, Antoni and Serra Musach, Jordi and Brunet, Joan and Dopazo, Joaquin and Narod, Steven A and Lubi{\'n}ski, Jan and L{\'a}zaro, Conxi and Cybulski, Cezary and Pujana, Miguel Angel} } @article {19897487, title = {FM19G11, a new hypoxia-inducible factor (HIF) modulator, affects stem cell differentiation status.}, journal = {The Journal of biological chemistry}, volume = {285}, year = {2010}, month = {2010 Jan 8}, pages = {1333-42}, abstract = {

The biology of the alpha subunits of hypoxia-inducible factors (HIFalpha) has expanded from their role in angiogenesis to their current position in the self-renewal and differentiation of stem cells. The results reported in this article show the discovery of FM19G11, a novel chemical entity that inhibits HIFalpha proteins that repress target genes of the two alpha subunits, in various tumor cell lines as well as in adult and embryonic stem cell models from rodents and humans, respectively. FM19G11 inhibits at nanomolar range the transcriptional and protein expression of Oct4, Sox2, Nanog, and Tgf-alpha undifferentiating factors, in adult rat and human embryonic stem cells, FM19G11 activity occurs in ependymal progenitor stem cells from rats (epSPC), a cell model reported for spinal cord regeneration, which allows the progression of oligodendrocyte cell differentiation in a hypoxic environment, has created interest in its characterization for pharmacological research. Experiments using small interfering RNA showed a significant depletion in Sox2 protein only in the case of HIF2alpha silencing, but not in HIF1alpha-mediated ablation. Moreover, chromatin immunoprecipitation data, together with the significant presence of functional hypoxia response element consensus sequences in the promoter region of Sox2, strongly validated that this factor behaves as a target gene of HIF2alpha in epSPCs. FM19G11 causes a reduction of overall histone acetylation with significant repression of p300, a histone acetyltransferase required as a co-factor for HIF-transcription activation. Arrays carried out in the presence and absence of the inhibitor showed the predominant involvement of epigenetic-associated events mediated by the drug.

}, author = {Moreno-Manzano, Victoria and Rodr{\'\i}guez-Jim{\'e}nez, Francisco J and Ace{\~n}a-Bonilla, Jose L and Fustero-Lard{\'\i}es, Santos and Erceg, Slaven and Dopazo, Joaquin and Montaner, David and Stojkovic, Miodrag and S{\'a}nchez-Puelles, Jose M} } @article {552, title = {Functional genomics and networks: new approaches in the extraction of complex gene modules.}, journal = {Expert Rev Proteomics}, volume = {7}, year = {2010}, month = {2010 Feb}, pages = {55-63}, abstract = {

The engine that makes the cell work is made of an intricate network of molecular interactions. Nowadays, the elements and relationships of this complex network can be studied with several types of high-throughput techniques. The dream of having a global picture of the cell from different perspectives that can jointly explain cell behavior is, at least technically, feasible. However, this task can only be accomplished by filling the gap between data and information. The availability of methods capable of accurately managing, integrating and analyzing the results from these experiments is crucial for this purpose. Here, we review the new challenges raised by the availability of different genomic data, as well as the new proposals presented to cope with the increasing data complexity. Special emphasis is given to approaches that explore the transcriptome trying to describe the modules of genes that account for the traits studied.

}, keywords = {Gene Expression Regulation, Gene Regulatory Networks, Genomics, Protein Binding, Proteins, Systems biology}, issn = {1744-8387}, doi = {10.1586/epr.09.103}, author = {Minguez, Pablo and Dopazo, Joaquin} } @article {553, title = {Functional genomics of 5- to 8-cell stage human embryos by blastomere single-cell cDNA analysis.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010 Oct 26}, pages = {e13615}, abstract = {

Blastomere fate and embryonic genome activation (EGA) during human embryonic development are unsolved areas of high scientific and clinical interest. Forty-nine blastomeres from 5- to 8-cell human embryos have been investigated following an efficient single-cell cDNA amplification protocol to provide a template for high-density microarray analysis. The previously described markers, characteristic of Inner Cell Mass (ICM) (n = 120), stemness (n = 190) and Trophectoderm (TE) (n = 45), were analyzed, and a housekeeping pattern of 46 genes was established. All the human blastomeres from the 5- to 8-cell stage embryo displayed a common gene expression pattern corresponding to ICM markers (e.g., DDX3, FOXD3, LEFTY1, MYC, NANOG, POU5F1), stemness (e.g., POU5F1, DNMT3B, GABRB3, SOX2, ZFP42, TERT), and TE markers (e.g., GATA6, EOMES, CDX2, LHCGR). The EGA profile was also investigated between the 5-6- and 8-cell stage embryos, and compared to the blastocyst stage. Known genes (n = 92) such as depleted maternal transcripts (e.g., CCNA1, CCNB1, DPPA2) and embryo-specific activation (e.g., POU5F1, CDH1, DPPA4), as well as novel genes, were confirmed. In summary, the global single-cell cDNA amplification microarray analysis of the 5- to 8-cell stage human embryos reveals that blastomere fate is not committed to ICM or TE. Finally, new EGA features in human embryogenesis are presented.

}, keywords = {Blastomeres, DNA, Complementary, Gene Expression Profiling, Genomics, Humans, Oligonucleotide Array Sequence Analysis}, issn = {1932-6203}, doi = {10.1371/journal.pone.0013615}, author = {Galan, Amparo and Montaner, David and P{\'o}o, M Eugenia and Valbuena, Diana and Ruiz, Veronica and Aguilar, Crist{\'o}bal and Dopazo, Joaquin and Simon, Carlos} } @article {572, title = {Hypoxia promotes efficient differentiation of human embryonic stem cells to functional endothelium.}, journal = {Stem Cells}, volume = {28}, year = {2010}, month = {2010 Mar 31}, pages = {407-18}, abstract = {

Early development of mammalian embryos occurs in an environment of relative hypoxia. Nevertheless, human embryonic stem cells (hESC), which are derived from the inner cell mass of blastocyst, are routinely cultured under the same atmospheric conditions (21\% O(2)) as somatic cells. We hypothesized that O(2) levels modulate gene expression and differentiation potential of hESC, and thus, we performed gene profiling of hESC maintained under normoxic or hypoxic (1\% or 5\% O(2)) conditions. Our analysis revealed that hypoxia downregulates expression of pluripotency markers in hESC but increases significantly the expression of genes associated with angio- and vasculogenesis including vascular endothelial growth factor and angiopoitein-like proteins. Consequently, we were able to efficiently differentiate hESC to functional endothelial cells (EC) by varying O(2) levels; after 24 hours at 5\% O(2), more than 50\% of cells were CD34+. Transplantation of resulting endothelial-like cells improved both systolic function and fractional shortening in a rodent model of myocardial infarction. Moreover, analysis of the infarcted zone revealed that transplanted EC reduced the area of fibrous scar tissue by 50\%. Thus, use of hypoxic conditions to specify the endothelial lineage suggests a novel strategy for cellular therapies aimed at repair of damaged vasculature in pathologies such as cerebral ischemia and myocardial infarction.

}, keywords = {Angiopoietin-1, Animals, biomarkers, Cell Culture Techniques, Cell Differentiation, Cell Hypoxia, Cell Transplantation, Cells, Cultured, Down-Regulation, Embryonic Stem Cells, Endothelial Cells, Gene Expression Profiling, Gene Expression Regulation, Humans, Male, Myocardial Infarction, Neovascularization, Physiologic, Oxygen, Pluripotent Stem Cells, Rats, Rats, Nude, Vascular Endothelial Growth Factor A}, issn = {1549-4918}, doi = {10.1002/stem.295}, author = {Prado-Lopez, Sonia and Conesa, Ana and Armi{\~n}{\'a}n, Ana and Mart{\'\i}nez-Losa, Magdalena and Escobedo-Lucea, Carmen and Gandia, Carolina and Tarazona, Sonia and Melguizo, Dario and Blesa, David and Montaner, David and Sanz-Gonz{\'a}lez, Silvia and Sep{\'u}lveda, Pilar and G{\"o}tz, Stefan and O{\textquoteright}Connor, Jos{\'e} Enrique and Moreno, Ruben and Dopazo, Joaquin and Burks, Deborah J and Stojkovic, Miodrag} } @article {20361057, title = {Initial genomics of the human nucleolus.}, journal = {PLoS genetics}, volume = {6}, year = {2010}, month = {2010}, pages = {e1000889}, abstract = {

We report for the first time the genomics of a nuclear compartment of the eukaryotic cell. 454 sequencing and microarray analysis revealed the pattern of nucleolus-associated chromatin domains (NADs) in the linear human genome and identified different gene families and certain satellite repeats as the major building blocks of NADs, which constitute about 4\% of the genome. Bioinformatic evaluation showed that NAD-localized genes take part in specific biological processes, like the response to other organisms, odor perception, and tissue development. 3D FISH and immunofluorescence experiments illustrated the spatial distribution of NAD-specific chromatin within interphase nuclei and its alteration upon transcriptional changes. Altogether, our findings describe the nature of DNA sequences associated with the human nucleolus and provide insights into the function of the nucleolus in genome organization and establishment of nuclear architecture.

}, keywords = {NGS, nucleolus}, doi = {10.1371/journal.pgen.1000889}, url = {http://www.plosgenetics.org/article/info\%3Adoi\%2F10.1371\%2Fjournal.pgen.1000889}, author = {N{\'e}meth, Attila and Ana Conesa and Santoyo-L{\'o}pez, Javier and Medina, Ignacio and Montaner, David and P{\'e}terfia, B{\'a}lint and Solovei, Irina and Cremer, Thomas and Dopazo, Joaquin and L{\"a}ngst, Gernot} } @article {20676074, title = {The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.}, journal = {Nature biotechnology}, volume = {28}, year = {2010}, month = {2010 Aug}, pages = {827-38}, abstract = {

Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, \>30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.

}, url = {http://www.nature.com/nbt/journal/v28/n8/full/nbt.1665.html}, author = {Shi, Leming and Campbell, Gregory and Jones, Wendell D and Campagne, Fabien and Wen, Zhining and Walker, Stephen J and Su, Zhenqiang and Chu, Tzu-Ming and Goodsaid, Federico M and Pusztai, Lajos and Shaughnessy, John D and Oberthuer, Andr{\'e} and Thomas, Russell S and Paules, Richard S and Fielden, Mark and Barlogie, Bart and Chen, Weijie and Du, Pan and Fischer, Matthias and Furlanello, Cesare and Gallas, Brandon D and Ge, Xijin and Megherbi, Dalila B and Symmans, W Fraser and Wang, May D and Zhang, John and Bitter, Hans and Brors, Benedikt and Bushel, Pierre R and Bylesjo, Max and Chen, Minjun and Cheng, Jie and Cheng, Jing and Chou, Jeff and Davison, Timothy S and Delorenzi, Mauro and Deng, Youping and Devanarayan, Viswanath and Dix, David J and Dopazo, Joaquin and Dorff, Kevin C and Elloumi, Fathi and Fan, Jianqing and Fan, Shicai and Fan, Xiaohui and Fang, Hong and Gonzaludo, Nina and Hess, Kenneth R and Hong, Huixiao and Huan, Jun and Irizarry, Rafael A and Judson, Richard and Juraeva, Dilafruz and Lababidi, Samir and Lambert, Christophe G and Li, Li and Li, Yanen and Li, Zhen and Lin, Simon M and Liu, Guozhen and Lobenhofer, Edward K and Luo, Jun and Luo, Wen and McCall, Matthew N and Nikolsky, Yuri and Pennello, Gene A and Perkins, Roger G and Philip, Reena and Popovici, Vlad and Price, Nathan D and Qian, Feng and Scherer, Andreas and Shi, Tieliu and Shi, Weiwei and Sung, Jaeyun and Thierry-Mieg, Danielle and Thierry-Mieg, Jean and Thodima, Venkata and Trygg, Johan and Vishnuvajjala, Lakshmi and Wang, Sue Jane and Wu, Jianping and Wu, Yichao and Xie, Qian and Yousef, Waleed A and Zhang, Liang and Zhang, Xuegong and Zhong, Sheng and Zhou, Yiming and Zhu, Sheng and Arasappan, Dhivya and Bao, Wenjun and Lucas, Anne Bergstrom and Berthold, Frank and Brennan, Richard J and Buness, Andreas and Catalano, Jennifer G and Chang, Chang and Chen, Rong and Cheng, Yiyu and Cui, Jian and Czika, Wendy and Demichelis, Francesca and Deng, Xutao and Dosymbekov, Damir and Eils, Roland and Feng, Yang and Fostel, Jennifer and Fulmer-Smentek, Stephanie and Fuscoe, James C and Gatto, Laurent and Ge, Weigong and Goldstein, Darlene R and Guo, Li and Halbert, Donald N and Han, Jing and Harris, Stephen C and Hatzis, Christos and Herman, Damir and Huang, Jianping and Jensen, Roderick V and Jiang, Rui and Johnson, Charles D and Jurman, Giuseppe and Kahlert, Yvonne and Khuder, Sadik A and Kohl, Matthias and Li, Jianying and Li, Li and Li, Menglong and Li, Quan-Zhen and Li, Shao and Li, Zhiguang and Liu, Jie and Liu, Ying and Liu, Zhichao and Meng, Lu and Madera, Manuel and Martinez-Murillo, Francisco and Medina, Ignacio and Meehan, Joseph and Miclaus, Kelci and Moffitt, Richard A and Montaner, David and Mukherjee, Piali and Mulligan, George J and Neville, Padraic and Nikolskaya, Tatiana and Ning, Baitang and Page, Grier P and Parker, Joel and Parry, R Mitchell and Peng, Xuejun and Peterson, Ron L and Phan, John H and Quanz, Brian and Ren, Yi and Riccadonna, Samantha and Roter, Alan H and Samuelson, Frank W and Schumacher, Martin M and Shambaugh, Joseph D and Shi, Qiang and Shippy, Richard and Si, Shengzhu and Smalter, Aaron and Sotiriou, Christos and Soukup, Mat and Staedtler, Frank and Steiner, Guido and Stokes, Todd H and Sun, Qinglan and Tan, Pei-Yi and Tang, Rong and Tezak, Zivana and Thorn, Brett and Tsyganova, Marina and Turpaz, Yaron and Vega, Silvia C and Visintainer, Roberto and von Frese, Juergen and Wang, Charles and Wang, Eric and Wang, Junwei and Wang, Wei and Westermann, Frank and Willey, James C and Woods, Matthew and Wu, Shujian and Xiao, Nianqing and Xu, Joshua and Xu, Lei and Yang, Lun and Zeng, Xiao and Zhang, Jialu and Zhang, Li and Zhang, Min and Zhao, Chen and Puri, Raj K and Scherf, Uwe and Tong, Weida and Wolfinger, Russell D} } @article {574, title = {Multidimensional gene set analysis of genomic data.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010 Apr 27}, pages = {e10348}, abstract = {

Understanding the functional implications of changes in gene expression, mutations, etc., is the aim of most genomic experiments. To achieve this, several functional profiling methods have been proposed. Such methods study the behaviour of different gene modules (e.g. gene ontology terms) in response to one particular variable (e.g. differential gene expression). In spite to the wealth of information provided by functional profiling methods, a common limitation to all of them is their inherent unidimensional nature. In order to overcome this restriction we present a multidimensional logistic model that allows studying the relationship of gene modules with different genome-scale measurements (e.g. differential expression, genotyping association, methylation, copy number alterations, heterozygosity, etc.) simultaneously. Moreover, the relationship of such functional modules with the interactions among the variables can also be studied, which produces novel results impossible to be derived from the conventional unidimensional functional profiling methods. We report sound results of gene sets associations that remained undetected by the conventional one-dimensional gene set analysis in several examples. Our findings demonstrate the potential of the proposed approach for the discovery of new cell functionalities with complex dependences on more than one variable.

}, keywords = {Databases, Genetic, Gene Expression Profiling, Gene Regulatory Networks, Genome, Human, Genomics, Humans, Models, Statistical}, issn = {1932-6203}, doi = {10.1371/journal.pone.0010348}, author = {Montaner, David and Dopazo, Joaquin} } @article {575, title = {Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa.}, journal = {Hum Mutat}, volume = {31}, year = {2010}, month = {2010 Nov}, pages = {E1772-800}, abstract = {

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene(EYS) encoding an ortholog of Drosophila space maker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9\% (12/28) are very likely pathogenic, 17.9\% (5/28)are possibly pathogenic, whereas 39.3\% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain.Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9\% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study.

}, keywords = {Amino Acid Sequence, Animals, Case-Control Studies, DNA Mutational Analysis, Drosophila Proteins, Evolution, Molecular, Eye Proteins, Female, Genes, Recessive, Genetic Variation, Humans, Male, Molecular Sequence Data, mutation, Pedigree, Polymorphism, Single Nucleotide, Protein Structure, Tertiary, Retinitis pigmentosa, Spain, Structural Homology, Protein}, issn = {1098-1004}, doi = {10.1002/humu.21334}, author = {Barrag{\'a}n, Isabel and Borrego, Salud and Pieras, Juan Ignacio and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Santoyo, Javier and Ayuso, Carmen and Baiget, Montserrat and Mill{\'a}n, Jos{\'e} M and Mena, Marcela and Abd El-Aziz, Mai M and Audo, Isabelle and Zeitz, Christina and Littink, Karin W and Dopazo, Joaquin and Bhattacharya, Shomi S and Anti{\v n}olo, Guillermo} } @article {808, title = {Selection upon Genome Architecture: Conservation of Functional Neighborhoods with Changing Genes}, journal = {PLoS Comput. Biol.}, volume = {6}, number = {10}, year = {2010}, pages = {e1000953}, doi = {doi:10.1371/journal.pcbi.1000953}, url = {http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000953}, author = {Al-Shahrour, F{\'a}tima and Minguez, Pablo and Marqu{\'e}s-Bonet, Tom{\'a}s and Gazave, Elodie and Navarro, Arcadi and Dopazo, Joaquin} } @article {576, title = {Serial Expression Analysis: a web tool for the analysis of serial gene expression data.}, journal = {Nucleic Acids Res}, volume = {38}, year = {2010}, month = {2010 Jul}, pages = {W239-45}, abstract = {

Serial transcriptomics experiments investigate the dynamics of gene expression changes associated with a quantitative variable such as time or dosage. The statistical analysis of these data implies the study of global and gene-specific expression trends, the identification of significant serial changes, the comparison of expression profiles and the assessment of transcriptional changes in terms of cellular processes. We have created the SEA (Serial Expression Analysis) suite to provide a complete web-based resource for the analysis of serial transcriptomics data. SEA offers five different algorithms based on univariate, multivariate and functional profiling strategies framed within a user-friendly interface and a project-oriented architecture to facilitate the analysis of serial gene expression data sets from different perspectives. SEA is available at sea.bioinfo.cipf.es.

}, keywords = {Algorithms, Gene Expression Profiling, Internet, Kinetics, Linear Models, Oligonucleotide Array Sequence Analysis, Software}, issn = {1362-4962}, doi = {10.1093/nar/gkq488}, author = {Nueda, Maria Jos{\'e} and Carbonell, Jos{\'e} and Medina, Ignacio and Dopazo, Joaquin and Conesa, Ana} } @article {578, title = {Exploring the antimicrobial action of a carbon monoxide-releasing compound through whole-genome transcription profiling of Escherichia coli.}, journal = {Microbiology (Reading)}, volume = {155}, year = {2009}, month = {2009 Mar}, pages = {813-824}, abstract = {

We recently reported that carbon monoxide (CO) has bactericidal activity. To understand its mode of action we analysed the gene expression changes occurring when Escherichia coli, grown aerobically and anaerobically, is treated with the CO-releasing molecule CORM-2 (tricarbonyldichlororuthenium(II) dimer). Microarray analysis shows that the E. coli CORM-2 response is multifaceted, with a high number of differentially regulated genes spread through several functional categories, namely genes involved in inorganic ion transport and metabolism, regulators, and genes implicated in post-translational modification, such as chaperones. CORM-2 has a higher impact in E. coli cells grown anaerobically, as judged by the repression of genes belonging to eight functional classes which are not seen in the response of aerobically CORM-2-treated cells. The biological relevance of the variations caused by CORM-2 was substantiated by studying the CORM-2 sensitivity of selected E. coli mutants. The results show that the deletion of redox-sensing regulators SoxS and OxyR increased the sensitivity to CORM-2 and suggest that while SoxS plays an important role in protection against CORM-2 under both growth conditions, OxyR seems to participate only in the aerobic CORM-2 response. Under anaerobic conditions, we found that the heat-shock proteins IbpA and IbpB contribute to CORM-2 defence since the deletion of these genes increases the sensitivity of the strain. The induction of several met genes and the hypersensitivity to CORM-2 of the DeltametR, DeltametI and DeltametN mutant strains suggest that CO has effects on the methionine metabolism of E. coli. CORM-2 also affects the transcription of several E. coli biofilm-related genes and increases biofilm formation in E. coli. In particular, the absence of tqsA or bhsA increases the resistance of E. coli to CORM-2, and deletion of tsqA leads to a strain that has lost its capacity to form biofilm upon treatment with CORM-2. In spite of the relatively stable nature of the CO molecule, our results show that CO is able to trigger a significant alteration in the transcriptome of E. coli which necessarily has effects in several key metabolic pathways.

}, keywords = {Biofilms, Carbon Monoxide, Escherichia coli, Escherichia coli Proteins, Gene Expression Profiling, Gene Expression Regulation, Bacterial, Genes, Bacterial, Genes, Regulator, Genetic Complementation Test, Methionine, Microbial Viability, mutation, Oligonucleotide Array Sequence Analysis, Organometallic Compounds, Phenotype, RNA, Bacterial}, issn = {1350-0872}, doi = {10.1099/mic.0.023911-0}, author = {Nobre, L{\'\i}gia S and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin and Saraiva, L{\'\i}gia M} } @article {579, title = {Formulating and testing hypotheses in functional genomics.}, journal = {Artif Intell Med}, volume = {45}, year = {2009}, month = {2009 Feb-Mar}, pages = {97-107}, abstract = {

OBJECTIVE: The ultimate goal of any genome-scale experiment is to provide a functional interpretation of the results, relating the available genomic information to the hypotheses that originated the experiment.

METHODS AND RESULTS: Initially, this interpretation has been made on a pre-selection of relevant genes, based on the experimental values, followed by the study of the enrichment in some functional properties. Nevertheless, functional enrichment methods, demonstrated to have a flaw: the first step of gene selection was too stringent given that the cooperation among genes was ignored. The assumption that modules of genes related by relevant biological properties (functionality, co-regulation, chromosomal location, etc.) are the real actors of the cell biology lead to the development of new procedures, inspired in systems biology criteria, generically known as gene-set methods. These methods have been successfully used to analyze transcriptomic and large-scale genotyping experiments as well as to test other different genome-scale hypothesis in other fields such as phylogenomics.

}, keywords = {Biological Evolution, Computational Biology, Genomics, Genotype, Models, Theoretical}, issn = {1873-2860}, doi = {10.1016/j.artmed.2008.08.003}, author = {Dopazo, Joaquin} } @article {580, title = {Functional assessment of time course microarray data.}, journal = {BMC Bioinformatics}, volume = {10 Suppl 6}, year = {2009}, month = {2009 Jun 16}, pages = {S9}, abstract = {

MOTIVATION: Time-course microarray experiments study the progress of gene expression along time across one or several experimental conditions. Most developed analysis methods focus on the clustering or the differential expression analysis of genes and do not integrate functional information. The assessment of the functional aspects of time-course transcriptomics data requires the use of approaches that exploit the activation dynamics of the functional categories to where genes are annotated.

METHODS: We present three novel methodologies for the functional assessment of time-course microarray data. i) maSigFun derives from the maSigPro method, a regression-based strategy to model time-dependent expression patterns and identify genes with differences across series. maSigFun fits a regression model for groups of genes labeled by a functional class and selects those categories which have a significant model. ii) PCA-maSigFun fits a PCA model of each functional class-defined expression matrix to extract orthogonal patterns of expression change, which are then assessed for their fit to a time-dependent regression model. iii) ASCA-functional uses the ASCA model to rank genes according to their correlation to principal time expression patterns and assess functional enrichment on a GSA fashion. We used simulated and experimental datasets to study these novel approaches. Results were compared to alternative methodologies.

RESULTS: Synthetic and experimental data showed that the different methods are able to capture different aspects of the relationship between genes, functions and co-expression that are biologically meaningful. The methods should not be considered as competitive but they provide different insights into the molecular and functional dynamic events taking place within the biological system under study.

}, keywords = {Computer Simulation, Gene Expression Profiling, Oligonucleotide Array Sequence Analysis, Time Factors}, issn = {1471-2105}, doi = {10.1186/1471-2105-10-S6-S9}, author = {Nueda, Maria Jos{\'e} and Sebasti{\'a}n, Patricia and Tarazona, Sonia and Garcia-Garcia, Francisco and Dopazo, Joaquin and Ferrer, Alberto and Conesa, Ana} } @article {581, title = {Functional signatures identified in B-cell non-Hodgkin lymphoma profiles.}, journal = {Leuk Lymphoma}, volume = {50}, year = {2009}, month = {2009 Oct}, pages = {1699-708}, abstract = {

Gene-expression profiling in B-cell lymphomas has provided crucial data on specific lymphoma types, which can contribute to the identification of essential lymphoma survival genes and pathways. In this study, the gene-expression profiling data of all major B-cell lymphoma types were analyzed by unsupervised clustering. The transcriptome classification so obtained, was explored using gene set enrichment analysis generating a heatmap for B-cell lymphoma that identifies common lymphoma survival mechanisms and potential therapeutic targets, recognizing sets of coregulated genes and functional pathways expressed in different lymphoma types. Some of the most relevant signatures (stroma, cell cycle, B-cell receptor (BCR)) are shared by multiple lymphoma types or subclasses. A specific attention was paid to the analysis of BCR and coregulated pathways, defining molecular heterogeneity within multiple B-cell lymphoma types.

}, keywords = {Adult, Cluster Analysis, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Genetic Heterogeneity, Humans, Lymphoma, B-Cell, Neoplasm Proteins, Oligonucleotide Array Sequence Analysis, RNA, Messenger, RNA, Neoplasm, Transcription, Genetic}, issn = {1029-2403}, doi = {10.1080/10428190903189035}, author = {Aggarwal, Mohit and S{\'a}nchez-Beato, Margarita and G{\'o}mez-L{\'o}pez, Gonzalo and Al-Shahrour, F{\'a}tima and Mart{\'\i}nez, Nerea and Rodr{\'\i}guez, Antonia and Ruiz-Ballesteros, Elena and Camacho, Francisca I and P{\'e}rez-Rosado, Alberto and de la Cueva, Paloma and Artiga, Mar{\'\i}a J and Pisano, David G and Kimby, Eva and Dopazo, Joaquin and Villuendas, Raquel and Piris, Miguel A} } @article {582, title = {Gene set internal coherence in the context of functional profiling.}, journal = {BMC Genomics}, volume = {10}, year = {2009}, month = {2009 Apr 27}, pages = {197}, abstract = {

BACKGROUND: Functional profiling methods have been extensively used in the context of high-throughput experiments and, in particular, in microarray data analysis. Such methods use available biological information to define different types of functional gene modules (e.g. gene ontology -GO-, KEGG pathways, etc.) whose representation in a pre-defined list of genes is further studied. In the most popular type of microarray experimental designs (e.g. up- or down-regulated genes, clusters of co-expressing genes, etc.) or in other genomic experiments (e.g. Chip-on-chip, epigenomics, etc.) these lists are composed by genes with a high degree of co-expression. Therefore, an implicit assumption in the application of functional profiling methods within this context is that the genes corresponding to the modules tested are effectively defining sets of co-expressing genes. Nevertheless not all the functional modules are biologically coherent entities in terms of co-expression, which will eventually hinder its detection with conventional methods of functional enrichment.

RESULTS: Using a large collection of microarray data we have carried out a detailed survey of internal correlation in GO terms and KEGG pathways, providing a coherence index to be used for measuring functional module co-regulation. An unexpected low level of internal correlation was found among the modules studied. Only around 30\% of the modules defined by GO terms and 57\% of the modules defined by KEGG pathways display an internal correlation higher than the expected by chance.This information on the internal correlation of the genes within the functional modules can be used in the context of a logistic regression model in a simple way to improve their detection in gene expression experiments.

CONCLUSION: For the first time, an exhaustive study on the internal co-expression of the most popular functional categories has been carried out. Interestingly, the real level of coexpression within many of them is lower than expected (or even inexistent), which will preclude its detection by means of most conventional functional profiling methods. If the gene-to-function correlation information is used in functional profiling methods, the results obtained improve the ones obtained by conventional enrichment methods.

}, keywords = {Algorithms, Breast Neoplasms, Carcinoma, Intraductal, Noninfiltrating, Computational Biology, Databases, Nucleic Acid, Female, Gene Expression Profiling, Genomics, Humans, Oligonucleotide Array Sequence Analysis, Papillomavirus Infections, Reproducibility of Results}, issn = {1471-2164}, doi = {10.1186/1471-2164-10-197}, author = {Montaner, David and Minguez, Pablo and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin} } @article {IgnacioMedina07012009, title = {Gene set-based analysis of polymorphisms: finding pathways or biological processes associated to traits in genome-wide association studies}, journal = {Nucl. Acids Res.}, volume = {37}, number = {suppl_2}, year = {2009}, pages = {W340-344}, abstract = {

Genome-wide association studies have become a popular strategy to find associations of genes to traits of interest. Despite the high-resolution available today to carry out genotyping studies, the success of its application in real studies has been limited by the testing strategy used. As an alternative to brute force solutions involving the use of very large cohorts, we propose the use of the Gene Set Analysis (GSA), a different analysis strategy based on testing the association of modules of functionally related genes. We show here how the Gene Set-based Analysis of Polymorphisms (GeSBAP), which is a simple implementation of the GSA strategy for the analysis of genome-wide association studies, provides a significant increase in the power testing for this type of studies. GeSBAP is freely available at http://bioinfo.cipf.es/gesbap/

}, keywords = {babelomics, gene set, GESBAP, pathway-based analysis, SNP}, doi = {10.1093/nar/gkp481}, url = {http://nar.oxfordjournals.org/cgi/content/abstract/37/suppl_2/W340}, author = {Medina, Ignacio and Montaner, David and Bonifaci, N{\'u}ria and Pujana, Miguel Angel and Carbonell, Jos{\'e} and T{\'a}rraga, Joaqu{\'\i}n and Fatima Al-Shahrour and Dopazo, Joaquin} } @article {583, title = {Gene set-based analysis of polymorphisms: finding pathways or biological processes associated to traits in genome-wide association studies.}, journal = {Nucleic Acids Res}, volume = {37}, year = {2009}, month = {2009 Jul}, pages = {W340-4}, abstract = {

Genome-wide association studies have become a popular strategy to find associations of genes to traits of interest. Despite the high-resolution available today to carry out genotyping studies, the success of its application in real studies has been limited by the testing strategy used. As an alternative to brute force solutions involving the use of very large cohorts, we propose the use of the Gene Set Analysis (GSA), a different analysis strategy based on testing the association of modules of functionally related genes. We show here how the Gene Set-based Analysis of Polymorphisms (GeSBAP), which is a simple implementation of the GSA strategy for the analysis of genome-wide association studies, provides a significant increase in the power testing for this type of studies. GeSBAP is freely available at http://bioinfo.cipf.es/gesbap/.

}, keywords = {Biological Phenomena, Breast Neoplasms, Female, Genes, Genetic Variation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Software, User-Computer Interface}, issn = {1362-4962}, doi = {10.1093/nar/gkp481}, author = {Medina, Ignacio and Montaner, David and Bonifaci, N{\'u}ria and Pujana, Miguel Angel and Carbonell, Jos{\'e} and T{\'a}rraga, Joaqu{\'\i}n and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin} } @conference {585, title = {Peripheral blood cells transcriptome to study new biomarkers for myocardial infarction follow up}, year = {2009}, month = {06}, author = {Silbiger, Vivian and Luchessi, Andr{\'e} and Hirata, Rosario and Carracedo, {\'A}ngel and Bri{\'o}n, Maria and Lima Neto, Lidio and P. Pastorelli, C and Dopazo, Joaquin and Montaner, David and Garcia, F and P. Sampaio, M and P. Pereira, M and S. Santos, E and Armaganijan, Dikran and Hirata, Mario} } @article {PabloMinguez05192009, title = {SNOW, a web-based tool for the statistical analysis of protein-protein interaction networks}, journal = {Nucl. Acids Res.}, volume = {37}, year = {2009}, pages = {W109-114}, abstract = {

Understanding the structure and the dynamics of the complex intercellular network of interactions that contributes to the structure and function of a living cell is one of the main challenges of today{\textquoteright}s biology. SNOW inputs a collection of protein (or gene) identifiers and, by using the interactome as scaffold, draws the connections among them, calculates several relevant network parameters and, as a novelty among the rest of tools of its class, it estimates their statistical significance. The parameters calculated for each node are: connectivity, betweenness and clustering coefficient. It also calculates the number of components, number of bicomponents and articulation points. An interactive network viewer is also available to explore the resulting network. SNOW is available at http://snow.bioinfo.cipf.es.

}, keywords = {interactome, network, snow}, doi = {10.1093/nar/gkp402}, url = {http://nar.oxfordjournals.org/content/early/2009/05/19/nar.gkp402.full}, author = {Minguez, Pablo and Gotz, S. and Montaner, David and Fatima Al-Shahrour and Dopazo, Joaquin} } @article {586, title = {SNOW, a web-based tool for the statistical analysis of protein-protein interaction networks.}, journal = {Nucleic Acids Res}, volume = {37}, year = {2009}, month = {2009 Jul}, pages = {W109-14}, abstract = {

Understanding the structure and the dynamics of the complex intercellular network of interactions that contributes to the structure and function of a living cell is one of the main challenges of today{\textquoteright}s biology. SNOW inputs a collection of protein (or gene) identifiers and, by using the interactome as scaffold, draws the connections among them, calculates several relevant network parameters and, as a novelty among the rest of tools of its class, it estimates their statistical significance. The parameters calculated for each node are: connectivity, betweenness and clustering coefficient. It also calculates the number of components, number of bicomponents and articulation points. An interactive network viewer is also available to explore the resulting network. SNOW is available at http://snow.bioinfo.cipf.es.

}, keywords = {Computer Graphics, Data Interpretation, Statistical, Databases, Protein, Humans, Internet, Protein Interaction Mapping, Software}, issn = {1362-4962}, doi = {10.1093/nar/gkp402}, author = {Minguez, Pablo and G{\"o}tz, Stefan and Montaner, David and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin} } @article {584, title = {On the Use of Functional Module Definitions in the Analysis of Genomic Experiments}, journal = {Molecular and Cellular Toxicology}, volume = {5}, year = {2009}, month = {09}, pages = {47-47}, author = {Dopazo, Joaquin} } @article {590, title = {Direct functional assessment of the composite phenotype through multivariate projection strategies.}, journal = {Genomics}, volume = {92}, year = {2008}, month = {2008 Dec}, pages = {373-83}, abstract = {

We present a novel approach for the analysis of transcriptomics data that integrates functional annotation of gene sets with expression values in a multivariate fashion, and directly assesses the relation of functional features to a multivariate space of response phenotypical variables. Multivariate projection methods are used to obtain new correlated variables for a set of genes that share a given function. These new functional variables are then related to the response variables of interest. The analysis of the principal directions of the multivariate regression allows for the identification of gene function features correlated with the phenotype. Two different transcriptomics studies are used to illustrate the statistical and interpretative aspects of the methodology. We demonstrate the superiority of the proposed method over equivalent approaches.

}, keywords = {Breast Neoplasms, Computational Biology, Databases, Genetic, Female, Gene Expression Profiling, Humans, Mathematical Computing, Multivariate Analysis, Phenotype}, issn = {1089-8646}, doi = {10.1016/j.ygeno.2008.05.015}, author = {Conesa, Ana and Bro, Rasmus and Garcia-Garcia, Francisco and Prats, Jos{\'e} Manuel and G{\"o}tz, Stefan and Kjeldahl, Karin and Montaner, David and Dopazo, Joaquin} } @article {591, title = {Expression and microarrays.}, journal = {Methods Mol Biol}, volume = {453}, year = {2008}, month = {2008}, pages = {245-55}, abstract = {

High throughput methodologies have increased by several orders of magnitude the amount of experimental microarray data available. Nevertheless, translating these data into useful biological knowledge remains a challenge. There is a risk of perceiving these methodologies as mere factories that produce never-ending quantities of data if a proper biological interpretation is not provided. Methods of interpreting these data are continuously evolving. Typically, a simple two-step approach has been used, in which genes of interest are first selected based on thresholds for the experimental values, and then enrichment in biologically relevant terms in the annotations of these genes is analyzed in a second step. For various reasons, such methods are quite poor in terms of performance and new procedures inspired by systems biology that directly address sets of functionally related genes are currently under development.

}, keywords = {Animals, Computational Biology, gene expression, Gene Expression Profiling, Humans, Oligonucleotide Array Sequence Analysis}, issn = {1064-3745}, doi = {10.1007/978-1-60327-429-6_12}, author = {Dopazo, Joaquin and Al-Shahrour, F{\'a}tima} } @article {593, title = {GEPAS, a web-based tool for microarray data analysis and interpretation.}, journal = {Nucleic Acids Res}, volume = {36}, year = {2008}, month = {2008 Jul 01}, pages = {W308-14}, abstract = {

Gene Expression Profile Analysis Suite (GEPAS) is one of the most complete and extensively used web-based packages for microarray data analysis. During its more than 5 years of activity it has continuously been updated to keep pace with the state-of-the-art in the changing microarray data analysis arena. GEPAS offers diverse analysis options that include well established as well as novel algorithms for normalization, gene selection, class prediction, clustering and functional profiling of the experiment. New options for time-course (or dose-response) experiments, microarray-based class prediction, new clustering methods and new tests for differential expression have been included. The new pipeliner module allows automating the execution of sequential analysis steps by means of a simple but powerful graphic interface. An extensive re-engineering of GEPAS has been carried out which includes the use of web services and Web 2.0 technology features, a new user interface with persistent sessions and a new extended database of gene identifiers. GEPAS is nowadays the most quoted web tool in its field and it is extensively used by researchers of many countries and its records indicate an average usage rate of 500 experiments per day. GEPAS, is available at http://www.gepas.org.

}, keywords = {Computer Graphics, Dose-Response Relationship, Drug, Gene Expression Profiling, Internet, Kinetics, Oligonucleotide Array Sequence Analysis, Software}, issn = {1362-4962}, doi = {10.1093/nar/gkn303}, author = {T{\'a}rraga, Joaqu{\'\i}n and Medina, Ignacio and Carbonell, Jos{\'e} and Huerta-Cepas, Jaime and Minguez, Pablo and Alloza, Eva and Al-Shahrour, F{\'a}tima and Vegas-Azc{\'a}rate, Susana and Goetz, Stefan and Escobar, Pablo and Garcia-Garcia, Francisco and Conesa, Ana and Montaner, David and Dopazo, Joaquin} } @article {594, title = {High-throughput functional annotation and data mining with the Blast2GO suite.}, journal = {Nucleic Acids Res}, volume = {36}, year = {2008}, month = {2008 Jun}, pages = {3420-35}, abstract = {

Functional genomics technologies have been widely adopted in the biological research of both model and non-model species. An efficient functional annotation of DNA or protein sequences is a major requirement for the successful application of these approaches as functional information on gene products is often the key to the interpretation of experimental results. Therefore, there is an increasing need for bioinformatics resources which are able to cope with large amount of sequence data, produce valuable annotation results and are easily accessible to laboratories where functional genomics projects are being undertaken. We present the Blast2GO suite as an integrated and biologist-oriented solution for the high-throughput and automatic functional annotation of DNA or protein sequences based on the Gene Ontology vocabulary. The most outstanding Blast2GO features are: (i) the combination of various annotation strategies and tools controlling type and intensity of annotation, (ii) the numerous graphical features such as the interactive GO-graph visualization for gene-set function profiling or descriptive charts, (iii) the general sequence management features and (iv) high-throughput capabilities. We used the Blast2GO framework to carry out a detailed analysis of annotation behaviour through homology transfer and its impact in functional genomics research. Our aim is to offer biologists useful information to take into account when addressing the task of functionally characterizing their sequence data.

}, keywords = {Animals, Computational Biology, Computer Graphics, Databases, Genetic, Expressed Sequence Tags, Genes, Genomics, Sequence Analysis, DNA, Sequence Analysis, Protein, Software, Vocabulary, Controlled}, issn = {1362-4962}, doi = {10.1093/nar/gkn176}, author = {G{\"o}tz, Stefan and Garc{\'\i}a-G{\'o}mez, Juan Miguel and Terol, Javier and Williams, Tim D and Nagaraj, Shivashankar H and Nueda, Maria Jos{\'e} and Robles, Montserrat and Talon, Manuel and Dopazo, Joaquin and Conesa, Ana} } @article {595, title = {Interoperability with Moby 1.0--it{\textquoteright}s better than sharing your toothbrush!}, journal = {Brief Bioinform}, volume = {9}, year = {2008}, month = {2008 May}, pages = {220-31}, abstract = {

The BioMoby project was initiated in 2001 from within the model organism database community. It aimed to standardize methodologies to facilitate information exchange and access to analytical resources, using a consensus driven approach. Six years later, the BioMoby development community is pleased to announce the release of the 1.0 version of the interoperability framework, registry Application Programming Interface and supporting Perl and Java code-bases. Together, these provide interoperable access to over 1400 bioinformatics resources worldwide through the BioMoby platform, and this number continues to grow. Here we highlight and discuss the features of BioMoby that make it distinct from other Semantic Web Service and interoperability initiatives, and that have been instrumental to its deployment and use by a wide community of bioinformatics service providers. The standard, client software, and supporting code libraries are all freely available at http://www.biomoby.org/.

}, keywords = {Computational Biology, Database Management Systems, Databases, Factual, Information Storage and Retrieval, Internet, Programming Languages, Systems Integration}, issn = {1477-4054}, doi = {10.1093/bib/bbn003}, author = {Wilkinson, Mark D and Senger, Martin and Kawas, Edward and Bruskiewich, Richard and Gouzy, Jerome and Noirot, Celine and Bardou, Philippe and Ng, Ambrose and Haase, Dirk and Saiz, Enrique de Andres and Wang, Dennis and Gibbons, Frank and Gordon, Paul M K and Sensen, Christoph W and Carrasco, Jose Manuel Rodriguez and Fern{\'a}ndez, Jos{\'e} M and Shen, Lixin and Links, Matthew and Ng, Michael and Opushneva, Nina and Neerincx, Pieter B T and Leunissen, Jack A M and Ernst, Rebecca and Twigger, Simon and Usadel, Bjorn and Good, Benjamin and Wong, Yan and Stein, Lincoln and Crosby, William and Karlsson, Johan and Royo, Romina and P{\'a}rraga, Iv{\'a}n and Ram{\'\i}rez, Sergio and Gelpi, Josep Lluis and Trelles, Oswaldo and Pisano, David G and Jimenez, Natalia and Kerhornou, Arnaud and Rosset, Roman and Zamacola, Leire and T{\'a}rraga, Joaqu{\'\i}n and Huerta-Cepas, Jaime and Carazo, Jose Mar{\'\i}a and Dopazo, Joaquin and Guig{\'o}, Roderic and Navarro, Arcadi and Orozco, Modesto and Valencia, Alfonso and Claros, M Gonzalo and P{\'e}rez, Antonio J and Aldana, Jose and Rojano, M Mar and Fernandez-Santa Cruz, Raul and Navas, Ismael and Schiltz, Gary and Farmer, Andrew and Gessler, Damian and Schoof, Heiko and Groscurth, Andreas} } @article {596, title = {Joint annotation of coding and non-coding single nucleotide polymorphisms and mutations in the SNPeffect and PupaSuite databases.}, journal = {Nucleic Acids Res}, volume = {36}, year = {2008}, month = {2008 Jan}, pages = {D825-9}, abstract = {

Single nucleotide polymorphisms (SNPs) are, together with copy number variation, the primary source of variation in the human genome. SNPs are associated with altered response to drug treatment, susceptibility to disease and other phenotypic variation. Furthermore, during genetic screens for disease-associated mutations in groups of patients and control individuals, the distinction between disease causing mutation and polymorphism is often unclear. Annotation of the functional and structural implications of single nucleotide changes thus provides valuable information to interpret and guide experiments. The SNPeffect and PupaSuite databases are now synchronized to deliver annotations for both non-coding and coding SNP, as well as annotations for the SwissProt set of human disease mutations. In addition, SNPeffect now contains predictions of Tango2: an improved aggregation detector, and Waltz: a novel predictor of amyloid-forming sequences, as well as improved predictors for regions that are recognized by the Hsp70 family of chaperones. The new PupaSuite version incorporates predictions for SNPs in silencers and miRNAs including their targets, as well as additional methods for predicting SNPs in TFBSs and splice sites. Also predictions for mouse and rat genomes have been added. In addition, a PupaSuite web service has been developed to enable data access, programmatically. The combined database holds annotations for 4,965,073 regulatory as well as 133,505 coding human SNPs and 14,935 disease mutations, and phenotypic descriptions of 43,797 human proteins and is accessible via http://snpeffect.vib.be and http://pupasuite.bioinfo.cipf.es/.

}, keywords = {Amino Acid Substitution, Animals, Databases, Genetic, Genetic Diseases, Inborn, HSP70 Heat-Shock Proteins, Humans, Internet, Mice, MicroRNAs, mutation, Polymorphism, Single Nucleotide, Proteins, Rats, RNA Splice Sites, Transcription Factors}, issn = {1362-4962}, doi = {10.1093/nar/gkm979}, author = {Reumers, Joke and Conde, Lucia and Medina, Ignacio and Maurer-Stroh, Sebastian and Van Durme, Joost and Dopazo, Joaquin and Rousseau, Frederic and Schymkowitz, Joost} } @article {598, title = {PhylomeDB: a database for genome-wide collections of gene phylogenies.}, journal = {Nucleic Acids Res}, volume = {36}, year = {2008}, month = {2008 Jan}, pages = {D491-6}, abstract = {

The complete collection of evolutionary histories of all genes in a genome, also known as phylome, constitutes a valuable source of information. The reconstruction of phylomes has been previously prevented by large demands of time and computer power, but is now feasible thanks to recent developments in computers and algorithms. To provide a publicly available repository of complete phylomes that allows researchers to access and store large-scale phylogenomic analyses, we have developed PhylomeDB. PhylomeDB is a database of complete phylomes derived for different genomes within a specific taxonomic range. All phylomes in the database are built using a high-quality phylogenetic pipeline that includes evolutionary model testing and alignment trimming phases. For each genome, PhylomeDB provides the alignments, phylogentic trees and tree-based orthology predictions for every single encoded protein. The current version of PhylomeDB includes the phylomes of Human, the yeast Saccharomyces cerevisiae and the bacterium Escherichia coli, comprising a total of 32 289 seed sequences with their corresponding alignments and 172 324 phylogenetic trees. PhylomeDB can be publicly accessed at http://phylomedb.bioinfo.cipf.es.

}, keywords = {Base Sequence, Escherichia coli, Genes, Genomics, History, Ancient, Humans, Phylogeny, Proteins, Saccharomyces cerevisiae, Sequence Alignment}, issn = {1362-4962}, doi = {10.1093/nar/gkm899}, author = {Huerta-Cepas, Jaime and Bueno, Anibal and Dopazo, Joaquin and Gabald{\'o}n, Toni} } @article {599, title = {SNP and haplotype mapping for genetic analysis in the rat.}, journal = {Nat Genet}, volume = {40}, year = {2008}, month = {2008 May}, pages = {560-6}, abstract = {

The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81\% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies.

}, keywords = {Animals, Chromosome Mapping, Databases, Genetic, Genome, Haplotypes, Linkage Disequilibrium, Phylogeny, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Rats, Rats, Inbred Strains, Recombination, Genetic}, issn = {1546-1718}, doi = {10.1038/ng.124}, author = {Saar, Kathrin and Beck, Alfred and Bihoreau, Marie-Th{\'e}r{\`e}se and Birney, Ewan and Brocklebank, Denise and Chen, Yuan and Cuppen, Edwin and Demonchy, Stephanie and Dopazo, Joaquin and Flicek, Paul and Foglio, Mario and Fujiyama, Asao and Gut, Ivo G and Gauguier, Dominique and Guig{\'o}, Roderic and Guryev, Victor and Heinig, Matthias and Hummel, Oliver and Jahn, Niels and Klages, Sven and Kren, Vladimir and Kube, Michael and Kuhl, Heiner and Kuramoto, Takashi and Kuroki, Yoko and Lechner, Doris and Lee, Young-Ae and Lopez-Bigas, Nuria and Lathrop, G Mark and Mashimo, Tomoji and Medina, Ignacio and Mott, Richard and Patone, Giannino and Perrier-Cornet, Jeanne-Antide and Platzer, Matthias and Pravenec, Michal and Reinhardt, Richard and Sakaki, Yoshiyuki and Schilhabel, Markus and Schulz, Herbert and Serikawa, Tadao and Shikhagaie, Medya and Tatsumoto, Shouji and Taudien, Stefan and Toyoda, Atsushi and Voigt, Birger and Zelenika, Diana and Zimdahl, Heike and Hubner, Norbert} } @article {600, title = {Use of estimated evolutionary strength at the codon level improves the prediction of disease-related protein mutations in humans.}, journal = {Hum Mutat}, volume = {29}, year = {2008}, month = {2008 Jan}, pages = {198-204}, abstract = {

Predicting the functional impact of protein variation is one of the most challenging problems in bioinformatics. A rapidly growing number of genome-scale studies provide large amounts of experimental data, allowing the application of rigorous statistical approaches for predicting whether a given single point mutation has an impact on human health. Up until now, existing methods have limited their source data to either protein or gene information. Novel in this work, we take advantage of both and focus on protein evolutionary information by using estimated selective pressures at the codon level. Here we introduce a new method (SeqProfCod) to predict the likelihood that a given protein variant is associated with human disease or not. Our method relies on a support vector machine (SVM) classifier trained using three sources of information: protein sequence, multiple protein sequence alignments, and the estimation of selective pressure at the codon level. SeqProfCod has been benchmarked with a large dataset of 8,987 single point mutations from 1,434 human proteins from SWISS-PROT. It achieves 82\% overall accuracy and a correlation coefficient of 0.59, indicating that the estimation of the selective pressure helps in predicting the functional impact of single-point mutations. Moreover, this study demonstrates the synergic effect of combining two sources of information for predicting the functional effects of protein variants: protein sequence/profile-based information and the evolutionary estimation of the selective pressures at the codon level. The results of large-scale application of SeqProfCod over all annotated point mutations in SWISS-PROT (available for download at http://sgu.bioinfo.cipf.es/services/Omidios/; last accessed: 24 August 2007), could be used to support clinical studies.

}, keywords = {Algorithms, Codon, Computational Biology, Databases, Protein, DNA Mutational Analysis, Evolution, Molecular, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, Iduronic Acid, Point Mutation, Polymorphism, Single Nucleotide, Proteins, Tumor Suppressor Protein p53}, issn = {1098-1004}, doi = {10.1002/humu.20628}, author = {Capriotti, Emidio and Arbiza, Leonardo and Casadio, Rita and Dopazo, Joaquin and Dopazo, Hern{\'a}n and Marti-Renom, Marc A} } @article {603, title = {DBAli tools: mining the protein structure space.}, journal = {Nucleic Acids Res}, volume = {35}, year = {2007}, month = {2007 Jul}, pages = {W393-7}, abstract = {

The DBAli tools use a comprehensive set of structural alignments in the DBAli database to leverage the structural information deposited in the Protein Data Bank (PDB). These tools include (i) the DBAlit program that allows users to input the 3D coordinates of a protein structure for comparison by MAMMOTH against all chains in the PDB; (ii) the AnnoLite and AnnoLyze programs that annotate a target structure based on its stored relationships to other structures; (iii) the ModClus program that clusters structures by sequence and structure similarities; (iv) the ModDom program that identifies domains as recurrent structural fragments and (v) an implementation of the COMPARER method in the SALIGN command in MODELLER that creates a multiple structure alignment for a set of related protein structures. Thus, the DBAli tools, which are freely accessible via the World Wide Web at http://salilab.org/DBAli/, allow users to mine the protein structure space by establishing relationships between protein structures and their functions.

}, keywords = {Algorithms, Amino Acid Sequence, Computational Biology, Data Interpretation, Statistical, Databases, Protein, Internet, Molecular Sequence Data, Protein Conformation, Proteins, Pseudomonas aeruginosa, Sequence Alignment, Sequence Analysis, Protein, Sequence Homology, Amino Acid, Software, Structure-Activity Relationship}, issn = {1362-4962}, doi = {10.1093/nar/gkm236}, author = {Marti-Renom, Marc A and Pieper, Ursula and Madhusudhan, M S and Rossi, Andrea and Eswar, Narayanan and Davis, Fred P and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin and Sali, Andrej} } @article {604, title = {Evidence for systems-level molecular mechanisms of tumorigenesis.}, journal = {BMC Genomics}, volume = {8}, year = {2007}, month = {2007 Jun 20}, pages = {185}, abstract = {

BACKGROUND: Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth.

RESULTS: Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs") defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree) and global (betweenness and closeness) measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis.

CONCLUSION: Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.

}, keywords = {Cell Transformation, Neoplastic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, Models, Biological, Models, Genetic, Models, Statistical, Neoplasm Proteins, Neoplasms, Prostatic Neoplasms, Protein Interaction Mapping, RNA, Messenger, Signal Transduction, Systems biology}, issn = {1471-2164}, doi = {10.1186/1471-2164-8-185}, author = {Hern{\'a}ndez, Pilar and Huerta-Cepas, Jaime and Montaner, David and Al-Shahrour, F{\'a}tima and Valls, Joan and G{\'o}mez, Laia and Capell{\`a}, Gabriel and Dopazo, Joaquin and Pujana, Miguel Angel} } @article {605, title = {FatiGO +: a functional profiling tool for genomic data. Integration of functional annotation, regulatory motifs and interaction data with microarray experiments.}, journal = {Nucleic Acids Res}, volume = {35}, year = {2007}, month = {2007 Jul}, pages = {W91-6}, abstract = {

The ultimate goal of any genome-scale experiment is to provide a functional interpretation of the data, relating the available information with the hypotheses that originated the experiment. Thus, functional profiling methods have become essential in diverse scenarios such as microarray experiments, proteomics, etc. We present the FatiGO+, a web-based tool for the functional profiling of genome-scale experiments, specially oriented to the interpretation of microarray experiments. In addition to different functional annotations (gene ontology, KEGG pathways, Interpro motifs, Swissprot keywords and text-mining based bioentities related to diseases and chemical compounds) FatiGO+ includes, as a novelty, regulatory and structural information. The regulatory information used includes predictions of targets for distinct regulatory elements (obtained from the Transfac and CisRed databases). Additionally FatiGO+ uses predictions of target motifs of miRNA to infer which of these can be activated or deactivated in the sample of genes studied. Finally, properties of gene products related to their relative location and connections in the interactome have also been used. Also, enrichment of any of these functional terms can be directly analysed on chromosomal coordinates. FatiGO+ can be found at: http://www.fatigoplus.org and within the Babelomics environment http://www.babelomics.org.

}, keywords = {Amino Acid Motifs, Animals, Binding Sites, Computational Biology, Gene Expression Profiling, Genes, Genomics, Humans, Internet, Oligonucleotide Array Sequence Analysis, Programming Languages, Software, Systems Integration, Transcription Factors}, issn = {1362-4962}, doi = {10.1093/nar/gkm260}, author = {Al-Shahrour, F{\'a}tima and Minguez, Pablo and T{\'a}rraga, Joaqu{\'\i}n and Medina, Ignacio and Alloza, Eva and Montaner, David and Dopazo, Joaquin} } @article {606, title = {From genes to functional classes in the study of biological systems.}, journal = {BMC Bioinformatics}, volume = {8}, year = {2007}, month = {2007 Apr 03}, pages = {114}, abstract = {

BACKGROUND: With the popularization of high-throughput techniques, the need for procedures that help in the biological interpretation of results has increased enormously. Recently, new procedures inspired in systems biology criteria have started to be developed.

RESULTS: Here we present FatiScan, a web-based program which implements a threshold-independent test for the functional interpretation of large-scale experiments that does not depend on the pre-selection of genes based on the multiple application of independent tests to each gene. The test implemented aims to directly test the behaviour of blocks of functionally related genes, instead of focusing on single genes. In addition, the test does not depend on the type of the data used for obtaining significance values, and consequently different types of biologically informative terms (gene ontology, pathways, functional motifs, transcription factor binding sites or regulatory sites from CisRed) can be applied to different classes of genome-scale studies. We exemplify its application in microarray gene expression, evolution and interactomics.

CONCLUSION: Methods for gene set enrichment which, in addition, are independent from the original data and experimental design constitute a promising alternative for the functional profiling of genome-scale experiments. A web server that performs the test described and other similar ones can be found at: http://www.babelomics.org.

}, keywords = {Algorithms, Chromosome Mapping, Computer Simulation, Gene Expression Profiling, Models, Biological, Multigene Family, Signal Transduction, Software, Systems biology, User-Computer Interface}, issn = {1471-2105}, doi = {10.1186/1471-2105-8-114}, author = {Al-Shahrour, F{\'a}tima and Arbiza, Leonardo and Dopazo, Hern{\'a}n and Huerta-Cepas, Jaime and Minguez, Pablo and Montaner, David and Dopazo, Joaquin} } @article {607, title = {Functional profiling and gene expression analysis of chromosomal copy number alterations.}, journal = {Bioinformation}, volume = {1}, year = {2007}, month = {2007 Apr 10}, pages = {432-5}, abstract = {

Contrarily to the traditional view in which only one or a few key genes were supposed to be the causative factors of diseases, we discuss the importance of considering groups of functionally related genes in the study of pathologies characterised by chromosomal copy number alterations. Recent observations have reported the existence of regions in higher eukaryotic chromosomes (including humans) containing genes of related function that show a high degree of coregulation. Copy number alterations will consequently affect to clusters of functionally related genes, which will be the final causative agents of the diseased phenotype, in many cases. Therefore, we propose that the functional profiling of the regions affected by copy number alterations must be an important aspect to take into account in the understanding of this type of pathologies. To illustrate this, we present an integrated study of DNA copy number variations, gene expression along with the functional profiling of chromosomal regions in a case of multiple myeloma.

}, issn = {0973-2063}, doi = {10.6026/97320630001432}, author = {Conde, Lucia and Montaner, David and Burguet-Castell, Jordi and T{\'a}rraga, Joaqu{\'\i}n and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin} } @article {592, title = {Functional profiling of microarray experiments using text-mining derived bioentities.}, journal = {Bioinformatics}, volume = {23}, year = {2007}, month = {2007 Nov 15}, pages = {3098-9}, abstract = {

MOTIVATION: The increasing use of microarray technologies brought about a parallel demand in methods for the functional interpretation of the results. Beyond the conventional functional annotations for genes, such as gene ontology, pathways, etc. other sources of information are still to be exploited. Text-mining methods allow extracting informative terms (bioentities) with different functional, chemical, clinical, etc. meanings, that can be associated to genes. We show how to use these associations within an appropriate statistical framework and how to apply them through easy-to-use, web-based environments to the functional interpretation of microarray experiments. Functional enrichment and gene set enrichment tests using bioentities are presented.

}, keywords = {Artificial Intelligence, Databases, Protein, Gene Expression Profiling, Information Storage and Retrieval, Natural Language Processing, Proteins, Research Design, Systems Integration}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btm445}, author = {Minguez, Pablo and Al-Shahrour, F{\'a}tima and Montaner, David and Dopazo, Joaquin} } @article {608, title = {ISACGH: a web-based environment for the analysis of Array CGH and gene expression which includes functional profiling.}, journal = {Nucleic Acids Res}, volume = {35}, year = {2007}, month = {2007 Jul}, pages = {W81-5}, abstract = {

We present the ISACGH, a web-based system that allows for the combination of genomic data with gene expression values and provides different options for functional profiling of the regions found. Several visualization options offer a convenient representation of the results. Different efficient methods for accurate estimation of genomic copy number from array-CGH hybridization data have been included in the program. Moreover, the connection to the gene expression analysis package GEPAS allows the use of different facilities for data pre-processing and analysis. A DAS server allows exporting the results to the Ensembl viewer where contextual genomic information can be obtained. The program is freely available at: http://isacgh.bioinfo.cipf.es or within http://www.gepas.org.

}, keywords = {Animals, Cluster Analysis, Computational Biology, Computer Graphics, Gene Expression Profiling, Humans, Internet, Models, Genetic, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Programming Languages, Software, Systems Integration, User-Computer Interface}, issn = {1362-4962}, doi = {10.1093/nar/gkm257}, author = {Conde, Lucia and Montaner, David and Burguet-Castell, Jordi and T{\'a}rraga, Joaqu{\'\i}n and Medina, Ignacio and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin} } @book {557, title = {Methods of Microarray Data Analysis IISupervised Neural Networks for Clustering Conditions in DNA Array Data After Reducing Noise by Clustering Gene Expression Profiles}, year = {2002}, pages = {91 - 103}, publisher = {Kluwer Academic Publishers}, organization = {Kluwer Academic Publishers}, address = {Boston}, doi = {10.1007/b11298210.1007/0-306-47598-7_7}, url = {http://www.springerlink.com/index/10.1007/b112982http://link.springer.com/10.1007/0-306-47598-7_7http://www.springerlink.com/index/pdf/10.1007/0-306-47598-7_7}, author = {Mateos, Alvaro and Herrero, Javier and Tamames, Javier and Dopazo, Joaquin}, editor = {Lin, Simon M. and Johnson, Kimberly F.} }