TY - JOUR T1 - Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches. JF - Front Immunol Y1 - 2024 A1 - Niarakis, Anna A1 - Ostaszewski, Marek A1 - Mazein, Alexander A1 - Kuperstein, Inna A1 - Kutmon, Martina A1 - Gillespie, Marc E A1 - Funahashi, Akira A1 - Acencio, Marcio Luis A1 - Hemedan, Ahmed A1 - Aichem, Michael A1 - Klein, Karsten A1 - Czauderna, Tobias A1 - Burtscher, Felicia A1 - Yamada, Takahiro G A1 - Hiki, Yusuke A1 - Hiroi, Noriko F A1 - Hu, Finterly A1 - Pham, Nhung A1 - Ehrhart, Friederike A1 - Willighagen, Egon L A1 - Valdeolivas, Alberto A1 - Dugourd, Aurélien A1 - Messina, Francesco A1 - Esteban-Medina, Marina A1 - Peña-Chilet, Maria A1 - Rian, Kinza A1 - Soliman, Sylvain A1 - Aghamiri, Sara Sadat A1 - Puniya, Bhanwar Lal A1 - Naldi, Aurélien A1 - Helikar, Tomáš A1 - Singh, Vidisha A1 - Fernández, Marco Fariñas A1 - Bermudez, Viviam A1 - Tsirvouli, Eirini A1 - Montagud, Arnau A1 - Noël, Vincent A1 - Ponce-de-Leon, Miguel A1 - Maier, Dieter A1 - Bauch, Angela A1 - Gyori, Benjamin M A1 - Bachman, John A A1 - Luna, Augustin A1 - Piñero, Janet A1 - Furlong, Laura I A1 - Balaur, Irina A1 - Rougny, Adrien A1 - Jarosz, Yohan A1 - Overall, Rupert W A1 - Phair, Robert A1 - Perfetto, Livia A1 - Matthews, Lisa A1 - Rex, Devasahayam Arokia Balaya A1 - Orlic-Milacic, Marija A1 - Gomez, Luis Cristobal Monraz A1 - De Meulder, Bertrand A1 - Ravel, Jean Marie A1 - Jassal, Bijay A1 - Satagopam, Venkata A1 - Wu, Guanming A1 - Golebiewski, Martin A1 - Gawron, Piotr A1 - Calzone, Laurence A1 - Beckmann, Jacques S A1 - Evelo, Chris T A1 - D'Eustachio, Peter A1 - Schreiber, Falk A1 - Saez-Rodriguez, Julio A1 - Dopazo, Joaquin A1 - Kuiper, Martin A1 - Valencia, Alfonso A1 - Wolkenhauer, Olaf A1 - Kitano, Hiroaki A1 - Barillot, Emmanuel A1 - Auffray, Charles A1 - Balling, Rudi A1 - Schneider, Reinhard KW - Computer Simulation KW - COVID-19 KW - drug repositioning KW - Humans KW - SARS-CoV-2 KW - Systems biology AB -

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.

VL - 14 ER - TY - JOUR T1 - Case report: Analysis of phage therapy failure in a patient with a Pseudomonas aeruginosa prosthetic vascular graft infection JF - Front Med (Lausanne) Y1 - 2023 A1 - Blasco, Lucia A1 - López-Hernández, Inmaculada A1 - Rodríguez-Fernández, Miguel A1 - Perez-Florido, Javier A1 - Casimiro-Soriguer, Carlos S AB -

Clinical case of a patient with a multidrug-resistant prosthetic vascular graft infection which was treated with a cocktail of phages (PT07, 14/01, and PNM) in combination with ceftazidime-avibactam (CZA). After the application of the phage treatment and in absence of antimicrobial therapy, a new bloodstream infection (BSI) with a septic residual limb metastasis occurred, now involving a wild-type strain being susceptible to ß-lactams and quinolones. Clinical strains were analyzed by microbiology and whole genome sequencing techniques. In relation with phage administration, the clinical isolates of before phage therapy (HE2011471) and post phage therapy (HE2105886) showed a clonal relationship but with important genomic changes which could be involved in the resistance to this therapy. Finally, phenotypic studies showed a decrease in Minimum Inhibitory Concentration (MIC) to ß-lactams and quinolones as well as an increase of the biofilm production and phage resistant mutants in the clinical isolate of post phage therapy.

VL - 10 UR - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10235614/ ER - TY - JOUR T1 - A crowdsourcing database for the copy-number variation of the Spanish population. JF - Hum Genomics Y1 - 2023 A1 - López-López, Daniel A1 - Roldán, Gema A1 - Fernandez-Rueda, Jose L A1 - Bostelmann, Gerrit A1 - Carmona, Rosario A1 - Aquino, Virginia A1 - Perez-Florido, Javier A1 - Ortuno, Francisco A1 - Pita, Guillermo A1 - Núñez-Torres, Rocío A1 - González-Neira, Anna A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin AB -

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.

VL - 17 IS - 1 ER - TY - JOUR T1 - 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). JF - Med Clin (Barc) Y1 - 2023 A1 - Loucera, Carlos A1 - Carmona, Rosario A1 - Bostelmann, Gerrit A1 - Muñoyerro-Muñiz, Dolores A1 - Villegas, Román A1 - Gonzalez-Manzanares, Rafael A1 - Dopazo, Joaquin A1 - Anguita, Manuel AB -

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±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.

ER - TY - JOUR T1 - microRNAs-mediated regulation of insulin signaling in white adipose tissue during aging: Role of caloric restriction. JF - Aging Cell Y1 - 2023 A1 - Corrales, Patricia A1 - Martin-Taboada, Marina A1 - Vivas-García, Yurena A1 - Torres, Lucia A1 - Ramirez-Jimenez, Laura A1 - Lopez, Yamila A1 - Horrillo, Daniel A1 - Vila-Bedmar, Rocio A1 - Barber-Cano, Eloisa A1 - Izquierdo-Lahuerta, Adriana A1 - Peña-Chilet, Maria A1 - Martínez, Carmen A1 - Dopazo, Joaquin A1 - Ros, Manuel A1 - Medina-Gomez, Gema AB -

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.

ER - TY - JOUR T1 - Rapid degeneration of iPSC-derived motor neurons lacking Gdap1 engages a mitochondrial-sustained innate immune response. JF - Cell Death Discov Y1 - 2023 A1 - León, Marian A1 - Prieto, Javier A1 - Molina-Navarro, María Micaela A1 - Garcia-Garcia, Francisco A1 - Barneo-Muñoz, Manuela A1 - Ponsoda, Xavier A1 - Sáez, Rosana A1 - Palau, Francesc A1 - Dopazo, Joaquin A1 - Izpisua Belmonte, Juan Carlos A1 - Torres, Josema AB -

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.

VL - 9 IS - 1 ER - TY - JOUR T1 - Real-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments. JF - Virol J Y1 - 2023 A1 - Loucera, Carlos A1 - Carmona, Rosario A1 - Esteban-Medina, Marina A1 - Bostelmann, Gerrit A1 - Muñoyerro-Muñiz, Dolores A1 - Villegas, Román A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin AB -

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.

VL - 20 IS - 1 ER - TY - JOUR T1 - Assessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival. JF - Viruses Y1 - 2022 A1 - Loucera, Carlos A1 - Perez-Florido, Javier A1 - Casimiro-Soriguer, Carlos S A1 - Ortuno, Francisco M A1 - Carmona, Rosario A1 - Bostelmann, Gerrit A1 - Martínez-González, L Javier A1 - Muñoyerro-Muñiz, Dolores A1 - Villegas, Román A1 - Rodríguez-Baño, Jesús A1 - Romero-Gómez, Manuel A1 - Lorusso, Nicola A1 - Garcia-León, Javier A1 - Navarro-Marí, Jose M A1 - Camacho-Martinez, Pedro A1 - Merino-Diaz, Laura A1 - Salazar, Adolfo de A1 - Viñuela, Laura A1 - Lepe, Jose A A1 - García, Federico A1 - Dopazo, Joaquin KW - COVID-19 KW - Genome, Viral KW - Humans KW - mutation KW - Pandemics KW - Phylogeny KW - SARS-CoV-2 AB -

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.

VL - 14 IS - 9 ER - TY - JOUR T1 - CIBERER: Spanish National Network for Research on Rare Diseases: a highly productive collaborative initiative. JF - Clin Genet Y1 - 2022 A1 - Luque, Juan A1 - Mendes, Ingrid A1 - Gómez, Beatriz A1 - Morte, Beatriz A1 - de Heredia, Miguel López A1 - Herreras, Enrique A1 - Corrochano, Virginia A1 - Bueren, Juan A1 - Gallano, Pia A1 - Artuch, Rafael A1 - Fillat, Cristina A1 - Pérez-Jurado, Luis A A1 - Montoliu, Lluis A1 - Carracedo, Ángel A1 - Millán, José M A1 - Webb, Susan M A1 - Palau, Francesc A1 - Lapunzina, Pablo AB -

CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on Rare Diseases currently consists of 75 research groups belonging to universities, research centers and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical and cellular research of rare diseases. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this paper, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions towards the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to rare disease research. This article is protected by copyright. All rights reserved.

ER - TY - JOUR T1 - Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions. JF - Int J Mol Sci Y1 - 2022 A1 - Puerto-Camacho, Pilar A1 - Diaz-Martin, Juan A1 - Olmedo-Pelayo, Joaquín A1 - Bolado-Carrancio, Alfonso A1 - Salguero-Aranda, Carmen A1 - Jordán-Pérez, Carmen A1 - Esteban-Medina, Marina A1 - Alamo-Alvarez, Inmaculada A1 - Delgado-Bellido, Daniel A1 - Lobo-Selma, Laura A1 - Dopazo, Joaquin A1 - Sastre, Ana A1 - Alonso, Javier A1 - Grünewald, Thomas G P A1 - Bernabeu, Carmelo A1 - Byron, Adam A1 - Brunton, Valerie G A1 - Amaral, Ana Teresa A1 - de Alava, Enrique KW - Bone Neoplasms KW - Endoglin KW - Humans KW - Matrix Metalloproteinase 14 KW - Proteomics KW - Receptors, Growth Factor KW - Sarcoma, Ewing KW - Signal Transduction AB -

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.

VL - 23 IS - 15 ER - TY - JOUR T1 - Incidence and Prevalence of Children's Diffuse Lung Disease in Spain. JF - Arch Bronconeumol Y1 - 2022 A1 - Torrent-Vernetta, Alba A1 - Gaboli, Mirella A1 - Castillo-Corullón, Silvia A1 - Mondéjar-López, Pedro A1 - Sanz Santiago, Verónica A1 - Costa-Colomer, Jordi A1 - Osona, Borja A1 - Torres-Borrego, Javier A1 - de la Serna-Blázquez, Olga A1 - Bellón Alonso, Sara A1 - Caro Aguilera, Pilar A1 - Gimeno-Díaz de Atauri, Álvaro A1 - Valenzuela Soria, Alfredo A1 - Ayats, Roser A1 - Martin de Vicente, Carlos A1 - Velasco González, Valle A1 - Moure González, José Domingo A1 - Canino Calderín, Elisa María A1 - Pastor-Vivero, María Dolores A1 - Villar Álvarez, María Ángeles A1 - Rovira-Amigo, Sandra A1 - Iglesias Serrano, Ignacio A1 - Díez Izquierdo, Ana A1 - de Mir Messa, Inés A1 - Gartner, Silvia A1 - Navarro, Alexandra A1 - Baz-Redón, Noelia A1 - Carmona, Rosario A1 - Camats-Tarruella, Núria A1 - Fernández-Cancio, Mónica A1 - Rapp, Christina A1 - Dopazo, Joaquin A1 - Griese, Matthias A1 - Moreno-Galdó, Antonio AB -

BACKGROUND: Children's diffuse lung disease, also known as children'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.

VL - 58 IS - 1 ER - TY - JOUR T1 - Novel genes and sex differences in COVID-19 severity. JF - Hum Mol Genet Y1 - 2022 A1 - Cruz, Raquel A1 - Almeida, Silvia Diz-de A1 - Heredia, Miguel López A1 - Quintela, Inés A1 - Ceballos, Francisco C A1 - Pita, Guillermo A1 - Lorenzo-Salazar, José M A1 - González-Montelongo, Rafaela A1 - Gago-Domínguez, Manuela A1 - Porras, Marta Sevilla A1 - Castaño, Jair Antonio Tenorio A1 - Nevado, Julián A1 - Aguado, Jose María A1 - Aguilar, Carlos A1 - Aguilera-Albesa, Sergio A1 - Almadana, Virginia A1 - Almoguera, Berta A1 - Alvarez, Nuria A1 - Andreu-Bernabeu, Álvaro A1 - Arana-Arri, Eunate A1 - Arango, Celso A1 - Arranz, María J A1 - Artiga, Maria-Jesus A1 - Baptista-Rosas, Raúl C A1 - Barreda-Sánchez, María A1 - Belhassen-Garcia, Moncef A1 - Bezerra, Joao F A1 - Bezerra, Marcos A C A1 - Boix-Palop, Lucía A1 - Brión, Maria A1 - Brugada, Ramón A1 - Bustos, Matilde A1 - Calderón, Enrique J A1 - Carbonell, Cristina A1 - Castano, Luis A1 - Castelao, Jose E A1 - Conde-Vicente, Rosa A1 - Cordero-Lorenzana, M Lourdes A1 - Cortes-Sanchez, Jose L A1 - Corton, Marta A1 - Darnaude, M Teresa A1 - De Martino-Rodríguez, Alba A1 - Campo-Pérez, Victor A1 - Bustamante, Aranzazu Diaz A1 - Domínguez-Garrido, Elena A1 - Luchessi, André D A1 - Eirós, Rocío A1 - Sanabria, Gladys Mercedes Estigarribia A1 - Fariñas, María Carmen A1 - Fernández-Robelo, Uxía A1 - Fernández-Rodríguez, Amanda A1 - Fernández-Villa, Tania A1 - Gil-Fournier, Belén A1 - Gómez-Arrue, Javier A1 - Álvarez, Beatriz González A1 - Quirós, Fernan Gonzalez Bernaldo A1 - González-Peñas, Javier A1 - Gutiérrez-Bautista, Juan F A1 - Herrero, María José A1 - Herrero-Gonzalez, Antonio A1 - Jimenez-Sousa, María A A1 - Lattig, María Claudia A1 - Borja, Anabel Liger A1 - Lopez-Rodriguez, Rosario A1 - Mancebo, Esther A1 - Martín-López, Caridad A1 - Martín, Vicente A1 - Martinez-Nieto, Oscar A1 - Martinez-Lopez, Iciar A1 - Martinez-Resendez, Michel F A1 - Martinez-Perez, Ángel A1 - Mazzeu, Juliana A A1 - Macías, Eleuterio Merayo A1 - Minguez, Pablo A1 - Cuerda, Victor Moreno A1 - Silbiger, Vivian N A1 - Oliveira, Silviene F A1 - Ortega-Paino, Eva A1 - Parellada, Mara A1 - Paz-Artal, Estela A1 - Santos, Ney P C A1 - Pérez-Matute, Patricia A1 - Perez, Patricia A1 - Pérez-Tomás, M Elena A1 - Perucho, Teresa A1 - Pinsach-Abuin, Mel Lina A1 - Pompa-Mera, Ericka N A1 - Porras-Hurtado, Gloria L A1 - Pujol, Aurora A1 - León, Soraya Ramiro A1 - Resino, Salvador A1 - Fernandes, Marianne R A1 - Rodríguez-Ruiz, Emilio A1 - Rodriguez-Artalejo, Fernando A1 - Rodriguez-Garcia, José A A1 - Ruiz-Cabello, Francisco A1 - Ruiz-Hornillos, Javier A1 - Ryan, Pablo A1 - Soria, José Manuel A1 - Souto, Juan Carlos A1 - Tamayo, Eduardo A1 - Tamayo-Velasco, Alvaro A1 - Taracido-Fernandez, Juan Carlos A1 - Teper, Alejandro A1 - Torres-Tobar, Lilian A1 - Urioste, Miguel A1 - Valencia-Ramos, Juan A1 - Yáñez, Zuleima A1 - Zarate, Ruth A1 - Nakanishi, Tomoko A1 - Pigazzini, Sara A1 - Degenhardt, Frauke A1 - Butler-Laporte, Guillaume A1 - Maya-Miles, Douglas A1 - Bujanda, Luis A1 - Bouysran, Youssef A1 - Palom, Adriana A1 - Ellinghaus, David A1 - Martínez-Bueno, Manuel A1 - Rolker, Selina A1 - Amitrano, Sara A1 - Roade, Luisa A1 - Fava, Francesca A1 - Spinner, Christoph D A1 - Prati, Daniele A1 - Bernardo, David A1 - García, Federico A1 - Darcis, Gilles A1 - Fernández-Cadenas, Israel A1 - Holter, Jan Cato A1 - Banales, Jesus M A1 - Frithiof, Robert A1 - Duga, Stefano A1 - Asselta, Rosanna A1 - Pereira, Alexandre C A1 - Romero-Gómez, Manuel A1 - Nafría-Jiménez, Beatriz A1 - Hov, Johannes R A1 - Migeotte, Isabelle A1 - Renieri, Alessandra A1 - Planas, Anna M A1 - Ludwig, Kerstin U A1 - Buti, Maria A1 - Rahmouni, Souad A1 - Alarcón-Riquelme, Marta E A1 - Schulte, Eva C A1 - Franke, Andre A1 - Karlsen, Tom H A1 - Valenti, Luca A1 - Zeberg, Hugo A1 - Richards, Brent A1 - Ganna, Andrea A1 - Boada, Mercè A1 - Rojas, Itziar A1 - Ruiz, Agustín A1 - Sánchez, Pascual A1 - Real, Luis Miguel A1 - Guillén-Navarro, Encarna A1 - Ayuso, Carmen A1 - González-Neira, Anna A1 - Riancho, José A A1 - Rojas-Martinez, Augusto A1 - Flores, Carlos A1 - Lapunzina, Pablo A1 - Carracedo, Ángel AB -

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

ER - TY - JOUR T1 - A comprehensive database for integrated analysis of omics data in autoimmune diseases. JF - BMC Bioinformatics Y1 - 2021 A1 - Martorell-Marugán, Jordi A1 - López-Domínguez, Raúl A1 - García-Moreno, Adrián A1 - Toro-Domínguez, Daniel A1 - Villatoro-García, Juan Antonio A1 - Barturen, Guillermo A1 - Martín-Gómez, Adoración A1 - Troule, Kevin A1 - Gómez-López, Gonzalo A1 - Al-Shahrour, Fátima A1 - González-Rumayor, Víctor A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin A1 - Saez-Rodriguez, Julio A1 - Alarcón-Riquelme, Marta E A1 - Carmona-Sáez, Pedro KW - Autoimmune Diseases KW - Computational Biology KW - Databases, Factual KW - Humans AB -

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.

VL - 22 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/34167460?dopt=Abstract ER - TY - JOUR T1 - COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms. JF - Mol Syst Biol Y1 - 2021 A1 - Ostaszewski, Marek A1 - Niarakis, Anna A1 - Mazein, Alexander A1 - Kuperstein, Inna A1 - Phair, Robert A1 - Orta-Resendiz, Aurelio A1 - Singh, Vidisha A1 - Aghamiri, Sara Sadat A1 - Acencio, Marcio Luis A1 - Glaab, Enrico A1 - Ruepp, Andreas A1 - Fobo, Gisela A1 - Montrone, Corinna A1 - Brauner, Barbara A1 - Frishman, Goar A1 - Monraz Gómez, Luis Cristóbal A1 - Somers, Julia A1 - Hoch, Matti A1 - Kumar Gupta, Shailendra A1 - Scheel, Julia A1 - Borlinghaus, Hanna A1 - Czauderna, Tobias A1 - Schreiber, Falk A1 - Montagud, Arnau A1 - Ponce de Leon, Miguel A1 - Funahashi, Akira A1 - Hiki, Yusuke A1 - Hiroi, Noriko A1 - Yamada, Takahiro G A1 - Dräger, Andreas A1 - Renz, Alina A1 - Naveez, Muhammad A1 - Bocskei, Zsolt A1 - Messina, Francesco A1 - Börnigen, Daniela A1 - Fergusson, Liam A1 - Conti, Marta A1 - Rameil, Marius A1 - Nakonecnij, Vanessa A1 - Vanhoefer, Jakob A1 - Schmiester, Leonard A1 - Wang, Muying A1 - Ackerman, Emily E A1 - Shoemaker, Jason E A1 - Zucker, Jeremy A1 - Oxford, Kristie A1 - Teuton, Jeremy A1 - Kocakaya, Ebru A1 - Summak, Gökçe Yağmur A1 - Hanspers, Kristina A1 - Kutmon, Martina A1 - Coort, Susan A1 - Eijssen, Lars A1 - Ehrhart, Friederike A1 - Rex, Devasahayam Arokia Balaya A1 - Slenter, Denise A1 - Martens, Marvin A1 - Pham, Nhung A1 - Haw, Robin A1 - Jassal, Bijay A1 - Matthews, Lisa A1 - Orlic-Milacic, Marija A1 - Senff Ribeiro, Andrea A1 - Rothfels, Karen A1 - Shamovsky, Veronica A1 - Stephan, Ralf A1 - Sevilla, Cristoffer A1 - Varusai, Thawfeek A1 - Ravel, Jean-Marie A1 - Fraser, Rupsha A1 - Ortseifen, Vera A1 - Marchesi, Silvia A1 - Gawron, Piotr A1 - Smula, Ewa A1 - Heirendt, Laurent A1 - Satagopam, Venkata A1 - Wu, Guanming A1 - Riutta, Anders A1 - Golebiewski, Martin A1 - Owen, Stuart A1 - Goble, Carole A1 - Hu, Xiaoming A1 - Overall, Rupert W A1 - Maier, Dieter A1 - Bauch, Angela A1 - Gyori, Benjamin M A1 - Bachman, John A A1 - Vega, Carlos A1 - Grouès, Valentin A1 - Vazquez, Miguel A1 - Porras, Pablo A1 - Licata, Luana A1 - Iannuccelli, Marta A1 - Sacco, Francesca A1 - Nesterova, Anastasia A1 - Yuryev, Anton A1 - de Waard, Anita A1 - Turei, Denes A1 - Luna, Augustin A1 - Babur, Ozgun A1 - Soliman, Sylvain A1 - Valdeolivas, Alberto A1 - Esteban-Medina, Marina A1 - Peña-Chilet, Maria A1 - Rian, Kinza A1 - Helikar, Tomáš A1 - Puniya, Bhanwar Lal A1 - Modos, Dezso A1 - Treveil, Agatha A1 - Olbei, Marton A1 - De Meulder, Bertrand A1 - Ballereau, Stephane A1 - Dugourd, Aurélien A1 - Naldi, Aurélien A1 - Noël, Vincent A1 - Calzone, Laurence A1 - Sander, Chris A1 - Demir, Emek A1 - Korcsmaros, Tamas A1 - Freeman, Tom C A1 - Augé, Franck A1 - Beckmann, Jacques S A1 - Hasenauer, Jan A1 - Wolkenhauer, Olaf A1 - Wilighagen, Egon L A1 - Pico, Alexander R A1 - Evelo, Chris T A1 - Gillespie, Marc E A1 - Stein, Lincoln D A1 - Hermjakob, Henning A1 - D'Eustachio, Peter A1 - Saez-Rodriguez, Julio A1 - Dopazo, Joaquin A1 - Valencia, Alfonso A1 - Kitano, Hiroaki A1 - Barillot, Emmanuel A1 - Auffray, Charles A1 - Balling, Rudi A1 - Schneider, Reinhard KW - Antiviral Agents KW - Computational Biology KW - Computer Graphics KW - COVID-19 KW - Cytokines KW - Data Mining KW - Databases, Factual KW - Gene Expression Regulation KW - Host Microbial Interactions KW - Humans KW - Immunity, Cellular KW - Immunity, Humoral KW - Immunity, Innate KW - Lymphocytes KW - Metabolic Networks and Pathways KW - Myeloid Cells KW - Protein Interaction Mapping KW - SARS-CoV-2 KW - Signal Transduction KW - Software KW - Transcription Factors KW - Viral Proteins AB -

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.

VL - 17 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/34664389?dopt=Abstract ER - TY - JOUR T1 - CSVS, a crowdsourcing database of the Spanish population genetic variability. JF - Nucleic Acids Res Y1 - 2021 A1 - Peña-Chilet, Maria A1 - Roldán, Gema A1 - Perez-Florido, Javier A1 - Ortuno, Francisco M A1 - Carmona, Rosario A1 - Aquino, Virginia A1 - López-López, Daniel A1 - Loucera, Carlos A1 - Fernandez-Rueda, Jose L A1 - Gallego, Asunción A1 - Garcia-Garcia, Francisco A1 - González-Neira, Anna A1 - Pita, Guillermo A1 - Núñez-Torres, Rocío A1 - Santoyo-López, Javier A1 - Ayuso, Carmen A1 - Minguez, Pablo A1 - Avila-Fernandez, Almudena A1 - Corton, Marta A1 - Moreno-Pelayo, Miguel Ángel A1 - Morin, Matías A1 - Gallego-Martinez, Alvaro A1 - Lopez-Escamez, Jose A A1 - Borrego, Salud A1 - Antiňolo, Guillermo A1 - Amigo, Jorge A1 - Salgado-Garrido, Josefa A1 - Pasalodos-Sanchez, Sara A1 - Morte, Beatriz A1 - Carracedo, Ángel A1 - Alonso, Ángel A1 - Dopazo, Joaquin KW - Alleles KW - Chromosome Mapping KW - Crowdsourcing KW - Databases, Genetic KW - Exome KW - Gene Frequency KW - Genetic Variation KW - Genetics, Population KW - Genome, Human KW - Genomics KW - Humans KW - Internet KW - Precision Medicine KW - Software KW - Spain AB -

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/.

VL - 49 IS - D1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/32990755?dopt=Abstract ER - TY - JOUR T1 - De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects. JF - Am J Med Genet A Y1 - 2021 A1 - Martinez-Delgado, Beatriz A1 - Lopez-Martin, Estrella A1 - Lara-Herguedas, Julián A1 - Monzon, Sara A1 - Cuesta, Isabel A1 - Juliá, Miguel A1 - Aquino, Virginia A1 - Rodriguez-Martin, Carlos A1 - Damian, Alejandra A1 - Gonzalo, Irene A1 - Gomez-Mariano, Gema A1 - Baladron, Beatriz A1 - Cazorla, Rosario A1 - Iglesias, Gema A1 - Roman, Enriqueta A1 - Ros, Purificacion A1 - Tutor, Pablo A1 - Mellor, Susana A1 - Jimenez, Carlos A1 - Cabrejas, Maria Jose A1 - Gonzalez-Vioque, Emiliano A1 - Alonso, Javier A1 - Bermejo-Sánchez, Eva A1 - Posada, Manuel KW - Child, Preschool KW - Cytoskeletal Proteins KW - Dwarfism KW - Exons KW - Gene Expression Regulation KW - Genetic Association Studies KW - Humans KW - Male KW - Neurodevelopmental Disorders KW - Protein Isoforms KW - RNA, Messenger KW - Sequence Deletion KW - Syndrome KW - Transcription Factors KW - Transcription Initiation Site KW - Transcription, Genetic AB -

Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full-length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.

VL - 185 IS - 3 ER - TY - JOUR T1 - A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin. JF - Mol Oncol Y1 - 2021 A1 - Moura, David S A1 - Peña-Chilet, Maria A1 - Cordero Varela, Juan Antonio A1 - Alvarez-Alegret, Ramiro A1 - Agra-Pujol, Carolina A1 - Izquierdo, Francisco A1 - Ramos, Rafael A1 - Ortega-Medina, Luis A1 - Martin-Davila, Francisco A1 - Castilla-Ramirez, Carolina A1 - Hernandez-Leon, Carmen Nieves A1 - Romagosa, Cleofe A1 - Vaz Salgado, Maria Angeles A1 - Lavernia, Javier A1 - Bagué, Silvia A1 - Mayodormo-Aranda, Empar A1 - Vicioso, Luis A1 - Hernández Barceló, Jose Emilio A1 - Rubio-Casadevall, Jordi A1 - de Juan, Ana A1 - Fiaño-Valverde, Maria Concepcion A1 - Hindi, Nadia A1 - Lopez-Alvarez, Maria A1 - Lacerenza, Serena A1 - Dopazo, Joaquin A1 - Gutierrez, Antonio A1 - Alvarez, Rosa A1 - Valverde, Claudia A1 - Martinez-Trufero, Javier A1 - Martin-Broto, Javier AB -

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.

VL - 15 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/33983674?dopt=Abstract ER - TY - JOUR T1 - Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system developmentAbstractBackgroundResultsConclusionsGraphic abstract JF - Clinical Epigenetics Y1 - 2021 A1 - Villalba-Benito, Leticia A1 - López-López, Daniel A1 - Torroglosa, Ana A1 - Casimiro-Soriguer, Carlos S. A1 - Luzón-Toro, Berta A1 - Fernández, Raquel María A1 - Moya-Jiménez, María José A1 - Antiňolo, Guillermo A1 - Dopazo, Joaquin A1 - Borrego, Salud VL - 13 UR - http://link.springer.com/article/10.1186/s13148-021-01040-6/fulltext.html IS - 1 JO - Clin Epigenet ER - TY - JOUR T1 - Immunotherapy in nonsmall-cell lung cancer: current status and future prospects for liquid biopsy. JF - Cancer Immunol Immunother Y1 - 2021 A1 - Brozos-Vázquez, Elena María A1 - Díaz-Peña, Roberto A1 - García-González, Jorge A1 - León-Mateos, Luis A1 - Mondelo-Macía, Patricia A1 - Peña-Chilet, Maria A1 - López-López, Rafael KW - Animals KW - Biomarkers, Tumor KW - Carcinoma, Non-Small-Cell Lung KW - Cell-Free Nucleic Acids KW - Exosomes KW - Humans KW - Immunotherapy KW - Liquid Biopsy KW - Lung Neoplasms AB -

Immunotherapy has been one of the great advances in the recent years for the treatment of advanced tumors, with nonsmall-cell lung cancer (NSCLC) being one of the cancers that has benefited most from this approach. Currently, the only validated companion diagnostic test for first-line immunotherapy in metastatic NSCLC patients is testing for programmed death ligand 1 (PD-L1) expression in tumor tissues. However, not all patients experience an effective response with the established selection criteria and immune checkpoint inhibitors (ICIs). Liquid biopsy offers a noninvasive opportunity to monitor disease in patients with cancer and identify those who would benefit the most from immunotherapy. This review focuses on the use of liquid biopsy in immunotherapy treatment of NSCLC patients. Circulating tumor cells (CTCs), cell-free DNA (cfDNA) and exosomes are promising tools for developing new biomarkers. We discuss the current application and future implementation of these parameters to improve therapeutic decision-making and identify the patients who will benefit most from immunotherapy.

VL - 70 IS - 5 ER - TY - JOUR T1 - Mutational Characterization of Cutaneous Melanoma Supports Divergent Pathways Model for Melanoma Development. JF - Cancers (Basel) Y1 - 2021 A1 - Millán-Esteban, David A1 - Peña-Chilet, Maria A1 - García-Casado, Zaida A1 - Manrique-Silva, Esperanza A1 - Requena, Celia A1 - Bañuls, José A1 - Lopez-Guerrero, Jose Antonio A1 - Rodríguez-Hernández, Aranzazu A1 - Traves, Víctor A1 - Dopazo, Joaquin A1 - Virós, Amaya A1 - Kumar, Rajiv A1 - Nagore, Eduardo AB -

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.

VL - 13 IS - 20 ER - TY - JOUR T1 - The NCI Genomic Data Commons JF - Nature Genetics Y1 - 2021 A1 - Heath, Allison P. A1 - Ferretti, Vincent A1 - Agrawal, Stuti A1 - An, Maksim A1 - Angelakos, James C. A1 - Arya, Renuka A1 - Bajari, Rosita A1 - Baqar, Bilal A1 - Barnowski, Justin H. B. A1 - Burt, Jeffrey A1 - Catton, Ann A1 - Chan, Brandon F. A1 - Chu, Fay A1 - Cullion, Kim A1 - Davidsen, Tanja A1 - Do, Phuong-My A1 - Dompierre, Christian A1 - Ferguson, Martin L. A1 - Fitzsimons, Michael S. A1 - Ford, Michael A1 - Fukuma, Miyuki A1 - Gaheen, Sharon A1 - Ganji, Gajanan L. A1 - Garcia, Tzintzuni I. A1 - George, Sameera S. A1 - Gerhard, Daniela S. A1 - Gerthoffert, Francois A1 - Gomez, Fauzi A1 - Han, Kang A1 - Hernandez, Kyle M. A1 - Issac, Biju A1 - Jackson, Richard A1 - Jensen, Mark A. A1 - Joshi, Sid A1 - Kadam, Ajinkya A1 - Khurana, Aishmit A1 - Kim, Kyle M. J. A1 - Kraft, Victoria E. A1 - Li, Shenglai A1 - Lichtenberg, Tara M. A1 - Lodato, Janice A1 - Lolla, Laxmi A1 - Martinov, Plamen A1 - Mazzone, Jeffrey A. A1 - Miller, Daniel P. A1 - Miller, Ian A1 - Miller, Joshua S. A1 - Miyauchi, Koji A1 - Murphy, Mark W. A1 - Nullet, Thomas A1 - Ogwara, Rowland O. A1 - Ortuño, Francisco M. A1 - Pedrosa, Jesús A1 - Pham, Phuong L. A1 - Popov, Maxim Y. A1 - Porter, James J. A1 - Powell, Raymond A1 - Rademacher, Karl A1 - Reid, Colin P. A1 - Rich, Samantha A1 - Rogel, Bessie A1 - Sahni, Himanso A1 - Savage, Jeremiah H. A1 - Schmitt, Kyle A. A1 - Simmons, Trevar J. A1 - Sislow, Joseph A1 - Spring, Jonathan A1 - Stein, Lincoln A1 - Sullivan, Sean A1 - Tang, Yajing A1 - Thiagarajan, Mathangi A1 - Troyer, Heather D. A1 - Wang, Chang A1 - Wang, Zhining A1 - West, Bedford L. A1 - Wilmer, Alex A1 - Wilson, Shane A1 - Wu, Kaman A1 - Wysocki, William P. A1 - Xiang, Linda A1 - Yamada, Joseph T. A1 - Yang, Liming A1 - Yu, Christine A1 - Yung, Christina K. A1 - Zenklusen, Jean Claude A1 - Zhang, Junjun A1 - Zhang, Zhenyu A1 - Zhao, Yuanheng A1 - Zubair, Ariz A1 - Staudt, Louis M. A1 - Grossman, Robert L. UR - http://www.nature.com/articles/s41588-021-00791-5 JO - Nat Genet ER - TY - JOUR T1 - Orchestrating and sharing large multimodal data for transparent and reproducible research. JF - Nat Commun Y1 - 2021 A1 - Mammoliti, Anthony A1 - Smirnov, Petr A1 - Nakano, Minoru A1 - Safikhani, Zhaleh A1 - Eeles, Christopher A1 - Seo, Heewon A1 - Nair, Sisira Kadambat A1 - Mer, Arvind S A1 - Smith, Ian A1 - Ho, Chantal A1 - Beri, Gangesh A1 - Kusko, Rebecca A1 - Lin, Eva A1 - Yu, Yihong A1 - Martin, Scott A1 - Hafner, Marc A1 - Haibe-Kains, Benjamin AB -

Reproducibility is essential to open science, as there is limited relevance for findings that can not be reproduced by independent research groups, regardless of its validity. It is therefore crucial for scientists to describe their experiments in sufficient detail so they can be reproduced, scrutinized, challenged, and built upon. However, the intrinsic complexity and continuous growth of biomedical data makes it increasingly difficult to process, analyze, and share with the community in a FAIR (findable, accessible, interoperable, and reusable) manner. To overcome these issues, we created a cloud-based platform called ORCESTRA ( orcestra.ca ), which provides a flexible framework for the reproducible processing of multimodal biomedical data. It enables processing of clinical, genomic and perturbation profiles of cancer samples through automated processing pipelines that are user-customizable. ORCESTRA creates integrated and fully documented data objects with persistent identifiers (DOI) and manages multiple dataset versions, which can be shared for future studies.

VL - 12 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/34608132?dopt=Abstract ER - TY - JOUR T1 - Real world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients. JF - Sci Rep Y1 - 2021 A1 - Loucera, Carlos A1 - Peña-Chilet, Maria A1 - Esteban-Medina, Marina A1 - Muñoyerro-Muñiz, Dolores A1 - Villegas, Román A1 - López-Miranda, José A1 - Rodríguez-Baño, Jesús A1 - Túnez, Isaac A1 - Bouillon, Roger A1 - Dopazo, Joaquin A1 - Quesada Gomez, Jose Manuel KW - Calcifediol KW - COVID-19 KW - Female KW - Humans KW - Kaplan-Meier Estimate KW - Male KW - Retrospective Studies KW - Spain KW - Survival Analysis KW - Vitamin D AB -

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.

VL - 11 IS - 1 ER - TY - JOUR T1 - Reporting guidelines for human microbiome research: the STORMS checklist. JF - Nat Med Y1 - 2021 A1 - Mirzayi, Chloe A1 - Renson, Audrey A1 - Zohra, Fatima A1 - Elsafoury, Shaimaa A1 - Geistlinger, Ludwig A1 - Kasselman, Lora J A1 - Eckenrode, Kelly A1 - van de Wijgert, Janneke A1 - Loughman, Amy A1 - Marques, Francine Z A1 - MacIntyre, David A A1 - Arumugam, Manimozhiyan A1 - Azhar, Rimsha A1 - Beghini, Francesco A1 - Bergstrom, Kirk A1 - Bhatt, Ami A1 - Bisanz, Jordan E A1 - Braun, Jonathan A1 - Bravo, Hector Corrada A1 - Buck, Gregory A A1 - Bushman, Frederic A1 - Casero, David A1 - Clarke, Gerard A1 - Collado, Maria Carmen A1 - Cotter, Paul D A1 - Cryan, John F A1 - Demmer, Ryan T A1 - Devkota, Suzanne A1 - Elinav, Eran A1 - Escobar, Juan S A1 - Fettweis, Jennifer A1 - Finn, Robert D A1 - Fodor, Anthony A A1 - Forslund, Sofia A1 - Franke, Andre A1 - Furlanello, Cesare A1 - Gilbert, Jack A1 - Grice, Elizabeth A1 - Haibe-Kains, Benjamin A1 - Handley, Scott A1 - Herd, Pamela A1 - Holmes, Susan A1 - Jacobs, Jonathan P A1 - Karstens, Lisa A1 - Knight, Rob A1 - Knights, Dan A1 - Koren, Omry A1 - Kwon, Douglas S A1 - Langille, Morgan A1 - Lindsay, Brianna A1 - McGovern, Dermot A1 - McHardy, Alice C A1 - McWeeney, Shannon A1 - Mueller, Noel T A1 - Nezi, Luigi A1 - Olm, Matthew A1 - Palm, Noah A1 - Pasolli, Edoardo A1 - Raes, Jeroen A1 - Redinbo, Matthew R A1 - Rühlemann, Malte A1 - Balfour Sartor, R A1 - Schloss, Patrick D A1 - Schriml, Lynn A1 - Segal, Eran A1 - Shardell, Michelle A1 - Sharpton, Thomas A1 - Smirnova, Ekaterina A1 - Sokol, Harry A1 - Sonnenburg, Justin L A1 - Srinivasan, Sujatha A1 - Thingholm, Louise B A1 - Turnbaugh, Peter J A1 - Upadhyay, Vaibhav A1 - Walls, Ramona L A1 - Wilmes, Paul A1 - Yamada, Takuji A1 - Zeller, Georg A1 - Zhang, Mingyu A1 - Zhao, Ni A1 - Zhao, Liping A1 - Bao, Wenjun A1 - Culhane, Aedin A1 - Devanarayan, Viswanath A1 - Dopazo, Joaquin A1 - Fan, Xiaohui A1 - Fischer, Matthias A1 - Jones, Wendell A1 - Kusko, Rebecca A1 - Mason, Christopher E A1 - Mercer, Tim R A1 - Sansone, Susanna-Assunta A1 - Scherer, Andreas A1 - Shi, Leming A1 - Thakkar, Shraddha A1 - Tong, Weida A1 - Wolfinger, Russ A1 - Hunter, Christopher A1 - Segata, Nicola A1 - Huttenhower, Curtis A1 - Dowd, Jennifer B A1 - Jones, Heidi E A1 - Waldron, Levi KW - Computational Biology KW - Dysbiosis KW - Humans KW - Microbiota KW - Observational Studies as Topic KW - Research Design KW - Translational Science, Biomedical AB -

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 'Strengthening The Organization and Reporting of Microbiome Studies' (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.

VL - 27 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/34789871?dopt=Abstract ER - TY - JOUR T1 - Schuurs–Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review JF - Genes Y1 - 2021 A1 - Tenorio-Castaño, Jair A1 - Morte, Beatriz A1 - Nevado, Julián A1 - Martínez-Glez, Víctor A1 - Santos-Simarro, Fernando A1 - García-Miñaur, Sixto A1 - Palomares-Bralo, María A1 - Pacio-Míguez, Marta A1 - Gómez, Beatriz A1 - Arias, Pedro A1 - Alcochea, Alba A1 - Carrión, Juan A1 - Arias, Patricia A1 - Almoguera, Berta A1 - López-Grondona, Fermina A1 - Lorda-Sanchez, Isabel A1 - Galán-Gómez, Enrique A1 - Valenzuela, Irene A1 - Méndez Perez, María A1 - Cuscó, Ivón A1 - Barros, Francisco A1 - Pié, Juan A1 - Ramos, Sergio A1 - Ramos, Feliciano A1 - Kuechler, Alma A1 - Tizzano, Eduardo A1 - Ayuso, Carmen A1 - Kaiser, Frank A1 - Pérez-Jurado, Luis A1 - Carracedo, Ángel A1 - Lapunzina, Pablo VL - 12 UR - https://www.mdpi.com/2073-4425/12/5/738https://www.mdpi.com/2073-4425/12/5/738/pdf IS - 5 JO - Genes ER - TY - JOUR T1 - Taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism. JF - Mol Med Y1 - 2021 A1 - Méndez-Salazar, Eder Orlando A1 - Vázquez-Mellado, Janitzia A1 - Casimiro-Soriguer, Carlos S A1 - Dopazo, Joaquin A1 - Cubuk, Cankut A1 - Zamudio-Cuevas, Yessica A1 - Francisco-Balderas, Adriana A1 - Martínez-Flores, Karina A1 - Fernández-Torres, Javier A1 - Lozada-Pérez, Carlos A1 - Pineda, Carlos A1 - Sánchez-González, Austreberto A1 - Silveira, Luis H A1 - Burguete-García, Ana I A1 - Orbe-Orihuela, Citlalli A1 - Lagunas-Martínez, Alfredo A1 - Vazquez-Gomez, Alonso A1 - López-Reyes, Alberto A1 - Palacios-González, Berenice A1 - Martínez-Nava, Gabriela Angélica KW - Biodiversity KW - Computational Biology KW - Dysbiosis KW - Gastrointestinal Microbiome KW - Gout KW - Humans KW - Metagenome KW - metagenomics KW - Protein Interaction Mapping KW - Protein Interaction Maps KW - Uric Acid AB -

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.

VL - 27 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/34030623?dopt=Abstract ER - TY - JOUR T1 - Association of a single nucleotide polymorphism in the ubxn6 gene with long-term non-progression phenotype in HIV-positive individuals. JF - Clin Microbiol Infect Y1 - 2020 A1 - Díez-Fuertes, F A1 - De La Torre-Tarazona, H E A1 - Calonge, E A1 - Pernas, M A1 - Bermejo, M A1 - García-Pérez, J A1 - Álvarez, A A1 - Capa, L A1 - García-García, F A1 - Saumoy, M A1 - Riera, M A1 - Boland-Auge, A A1 - López-Galíndez, C A1 - Lathrop, M A1 - Dopazo, J A1 - Sakuntabhai, A A1 - Alcamí, J KW - Adaptor Proteins, Vesicular Transport KW - Autophagy-Related Proteins KW - Caveolin 1 KW - Cohort Studies KW - Dendritic Cells KW - Disease Progression KW - Gene Frequency KW - Gene Knockdown Techniques KW - Genetic Association Studies KW - HeLa Cells KW - HIV Infections KW - HIV Long-Term Survivors KW - HIV-1 KW - Humans KW - Macrophages KW - Oligonucleotide Array Sequence Analysis KW - Phenotype KW - Polymorphism, Single Nucleotide KW - whole exome sequencing AB -

OBJECTIVES: The long-term non-progressors (LTNPs) are a heterogeneous group of HIV-positive individuals characterized by their ability to maintain high CD4 T-cell counts and partially control viral replication for years in the absence of antiretroviral therapy. The present study aims to identify host single nucleotide polymorphisms (SNPs) associated with non-progression in a cohort of 352 individuals.

METHODS: DNA microarrays and exome sequencing were used for genotyping about 240 000 functional polymorphisms throughout more than 20 000 human genes. The allele frequencies of 85 LTNPs were compared with a control population. SNPs associated with LTNPs were confirmed in a population of typical progressors. Functional analyses in the affected gene were carried out through knockdown experiments in HeLa-P4, macrophages and dendritic cells.

RESULTS: Several SNPs located within the major histocompatibility complex region previously related to LTNPs were confirmed in this new cohort. The SNP rs1127888 (UBXN6) surpassed the statistical significance of these markers after Bonferroni correction (q = 2.11 × 10). An uncommon allelic frequency of rs1127888 among LTNPs was confirmed by comparison with typical progressors and other publicly available populations. UBXN6 knockdown experiments caused an increase in CAV1 expression and its accumulation in the plasma membrane. In vitro infection of different cell types with HIV-1 replication-competent recombinant viruses caused a reduction of the viral replication capacity compared with their corresponding wild-type cells expressing UBXN6.

CONCLUSIONS: A higher prevalence of Ala31Thr in UBXN6 was found among LTNPs within its N-terminal region, which is crucial for UBXN6/VCP protein complex formation. UBXN6 knockdown affected CAV1 turnover and HIV-1 replication capacity.

VL - 26 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/31158522?dopt=Abstract ER - TY - JOUR T1 - Community Assessment of the Predictability of Cancer Protein and Phosphoprotein Levels from Genomics and Transcriptomics. JF - Cell Syst Y1 - 2020 A1 - Yang, Mi A1 - Petralia, Francesca A1 - Li, Zhi A1 - Li, Hongyang A1 - Ma, Weiping A1 - Song, Xiaoyu A1 - Kim, Sunkyu A1 - Lee, Heewon A1 - Yu, Han A1 - Lee, Bora A1 - Bae, Seohui A1 - Heo, Eunji A1 - Kaczmarczyk, Jan A1 - Stępniak, Piotr A1 - Warchoł, Michał A1 - Yu, Thomas A1 - Calinawan, Anna P A1 - Boutros, Paul C A1 - Payne, Samuel H A1 - Reva, Boris A1 - Boja, Emily A1 - Rodriguez, Henry A1 - Stolovitzky, Gustavo A1 - Guan, Yuanfang A1 - Kang, Jaewoo A1 - Wang, Pei A1 - Fenyö, David A1 - Saez-Rodriguez, Julio KW - Crowdsourcing KW - Female KW - Genomics KW - Humans KW - Machine Learning KW - Male KW - Neoplasms KW - Phosphoproteins KW - Proteins KW - Proteomics KW - Transcriptome AB -

Cancer is driven by genomic alterations, but the processes causing this disease are largely performed by proteins. However, proteins are harder and more expensive to measure than genes and transcripts. To catalyze developments of methods to infer protein levels from other omics measurements, we leveraged crowdsourcing via the NCI-CPTAC DREAM proteogenomic challenge. We asked for methods to predict protein and phosphorylation levels from genomic and transcriptomic data in cancer patients. The best performance was achieved by an ensemble of models, including as predictors transcript level of the corresponding genes, interaction between genes, conservation across tumor types, and phosphosite proximity for phosphorylation prediction. Proteins from metabolic pathways and complexes were the best and worst predicted, respectively. The performance of even the best-performing model was modest, suggesting that many proteins are strongly regulated through translational control and degradation. Our results set a reference for the limitations of computational inference in proteogenomics. A record of this paper's transparent peer review process is included in the Supplemental Information.

VL - 11 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/32710834?dopt=Abstract ER - TY - JOUR T1 - COVID-19 Disease Map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms. JF - Sci Data Y1 - 2020 A1 - Ostaszewski, Marek A1 - Mazein, Alexander A1 - Gillespie, Marc E A1 - Kuperstein, Inna A1 - Niarakis, Anna A1 - Hermjakob, Henning A1 - Pico, Alexander R A1 - Willighagen, Egon L A1 - Evelo, Chris T A1 - Hasenauer, Jan A1 - Schreiber, Falk A1 - Dräger, Andreas A1 - Demir, Emek A1 - Wolkenhauer, Olaf A1 - Furlong, Laura I A1 - Barillot, Emmanuel A1 - Dopazo, Joaquin A1 - Orta-Resendiz, Aurelio A1 - Messina, Francesco A1 - Valencia, Alfonso A1 - Funahashi, Akira A1 - Kitano, Hiroaki A1 - Auffray, Charles A1 - Balling, Rudi A1 - Schneider, Reinhard KW - Betacoronavirus KW - Computational Biology KW - Coronavirus Infections KW - COVID-19 KW - Databases, Factual KW - Host Microbial Interactions KW - Host-Pathogen Interactions KW - Humans KW - International Cooperation KW - Models, Biological KW - Pandemics KW - Pneumonia, Viral KW - SARS-CoV-2 VL - 7 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/32371892?dopt=Abstract ER - TY - JOUR T1 - The ELIXIR Human Copy Number Variations Community: building bioinformatics infrastructure for research. JF - F1000Res Y1 - 2020 A1 - Salgado, David A1 - Armean, Irina M A1 - Baudis, Michael A1 - Beltran, Sergi A1 - Capella-Gutíerrez, Salvador A1 - Carvalho-Silva, Denise A1 - Dominguez Del Angel, Victoria A1 - Dopazo, Joaquin A1 - Furlong, Laura I A1 - Gao, Bo A1 - Garcia, Leyla A1 - Gerloff, Dietlind A1 - Gut, Ivo A1 - Gyenesei, Attila A1 - Habermann, Nina A1 - Hancock, John M A1 - Hanauer, Marc A1 - Hovig, Eivind A1 - Johansson, Lennart F A1 - Keane, Thomas A1 - Korbel, Jan A1 - Lauer, Katharina B A1 - Laurie, Steve A1 - Leskošek, Brane A1 - Lloyd, David A1 - Marqués-Bonet, Tomás A1 - Mei, Hailiang A1 - Monostory, Katalin A1 - Piñero, Janet A1 - Poterlowicz, Krzysztof A1 - Rath, Ana A1 - Samarakoon, Pubudu A1 - Sanz, Ferran A1 - Saunders, Gary A1 - Sie, Daoud A1 - Swertz, Morris A A1 - Tsukanov, Kirill A1 - Valencia, Alfonso A1 - Vidak, Marko A1 - Yenyxe González, Cristina A1 - Ylstra, Bauke A1 - Béroud, Christophe KW - Computational Biology KW - DNA Copy Number Variations KW - High-Throughput Nucleotide Sequencing KW - Humans AB -

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'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.

VL - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/34367618?dopt=Abstract ER - TY - JOUR T1 - Immune Cell Associations with Cancer Risk. JF - iScience Y1 - 2020 A1 - Palomero, Luis A1 - Galván-Femenía, Ivan A1 - de Cid, Rafael A1 - Espín, Roderic A1 - Barnes, Daniel R A1 - Blommaert, Eline A1 - Gil-Gil, Miguel A1 - Falo, Catalina A1 - Stradella, Agostina A1 - Ouchi, Dan A1 - Roso-Llorach, Albert A1 - Violan, Concepció A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin A1 - Extremera, Ana Isabel A1 - García-Valero, Mar A1 - Herranz, Carmen A1 - Mateo, Francesca A1 - Mereu, Elisabetta A1 - Beesley, Jonathan A1 - Chenevix-Trench, Georgia A1 - Roux, Cecilia A1 - Mak, Tak A1 - Brunet, Joan A1 - Hakem, Razq A1 - Gorrini, Chiara A1 - Antoniou, Antonis C A1 - Lázaro, Conxi A1 - Pujana, Miquel Angel AB -

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.

VL - 23 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/32622267?dopt=Abstract ER - TY - JOUR T1 - Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies. JF - J Med Genet Y1 - 2020 A1 - Bogliolo, Massimo A1 - Pujol, Roser A1 - Aza-Carmona, Miriam A1 - Muñoz-Subirana, Núria A1 - Rodriguez-Santiago, Benjamin A1 - Casado, José Antonio A1 - Rio, Paula A1 - Bauser, Christopher A1 - Reina-Castillón, Judith A1 - Lopez-Sanchez, Marcos A1 - Gonzalez-Quereda, Lidia A1 - Gallano, Pia A1 - Catalá, Albert A1 - Ruiz-Llobet, Ana A1 - Badell, Isabel A1 - Diaz-Heredia, Cristina A1 - Hladun, Raquel A1 - Senent, Leonort A1 - Argiles, Bienvenida A1 - Bergua Burgues, Juan Miguel A1 - Bañez, Fatima A1 - Arrizabalaga, Beatriz A1 - López Almaraz, Ricardo A1 - Lopez, Monica A1 - Figuera, Ángela A1 - Molinés, Antonio A1 - Pérez de Soto, Inmaculada A1 - Hernando, Inés A1 - Muñoz, Juan Antonio A1 - Del Rosario Marin, Maria A1 - Balmaña, Judith A1 - Stjepanovic, Neda A1 - Carrasco, Estela A1 - Cuesta, Isabel A1 - Cosuelo, José Miguel A1 - Regueiro, Alexandra A1 - Moraleda Jimenez, José A1 - Galera-Miñarro, Ana Maria A1 - Rosiñol, Laura A1 - Carrió, Anna A1 - Beléndez-Bieler, Cristina A1 - Escudero Soto, Antonio A1 - Cela, Elena A1 - de la Mata, Gregorio A1 - Fernández-Delgado, Rafael A1 - Garcia-Pardos, Maria Carmen A1 - Sáez-Villaverde, Raquel A1 - Barragaño, Marta A1 - Portugal, Raquel A1 - Lendinez, Francisco A1 - Hernadez, Ines A1 - Vagace, José Manue A1 - Tapia, Maria A1 - Nieto, José A1 - Garcia, Marta A1 - Gonzalez, Macarena A1 - Vicho, Cristina A1 - Galvez, Eva A1 - Valiente, Alberto A1 - Antelo, Maria Luisa A1 - Ancliff, Phil A1 - García, Francisco A1 - Dopazo, Joaquin A1 - Sevilla, Julian A1 - Paprotka, Tobias A1 - Pérez-Jurado, Luis Alberto A1 - Bueren, Juan A1 - Surralles, Jordi KW - Cell Line KW - DNA Copy Number Variations KW - DNA Repair KW - DNA-Binding Proteins KW - Fanconi Anemia KW - Fanconi Anemia Complementation Group A Protein KW - Female KW - Gene Knockout Techniques KW - Genetic Predisposition to Disease KW - Humans KW - Male KW - Mutation, Missense KW - Polymorphism, Single Nucleotide KW - whole exome sequencing AB -

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' 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 'affecting functions' are SNPs. Deep analysis of sequencing data revealed patients' 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.

VL - 57 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/31586946?dopt=Abstract ER - TY - JOUR T1 - Pazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial. JF - Lancet Oncol Y1 - 2020 A1 - Martin-Broto, Javier A1 - Cruz, Josefina A1 - Penel, Nicolas A1 - Le Cesne, Axel A1 - Hindi, Nadia A1 - Luna, Pablo A1 - Moura, David S A1 - Bernabeu, Daniel A1 - de Alava, Enrique A1 - Lopez-Guerrero, Jose Antonio A1 - Dopazo, Joaquin A1 - Peña-Chilet, Maria A1 - Gutierrez, Antonio A1 - Collini, Paola A1 - Karanian, Marie A1 - Redondo, Andres A1 - Lopez-Pousa, Antonio A1 - Grignani, Giovanni A1 - Diaz-Martin, Juan A1 - Marcilla, David A1 - Fernandez-Serra, Antonio A1 - Gonzalez-Aguilera, Cristina A1 - Casali, Paolo G A1 - Blay, Jean-Yves A1 - Stacchiotti, Silvia KW - Aged KW - Female KW - Follow-Up Studies KW - Humans KW - Indazoles KW - Male KW - Middle Aged KW - Neoplasm Metastasis KW - Prognosis KW - Prospective Studies KW - Protein Kinase Inhibitors KW - Pyrimidines KW - Response Evaluation Criteria in Solid Tumors KW - Solitary Fibrous Tumors KW - Sulfonamides KW - Survival Rate AB -

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.

VL - 21 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/32066540?dopt=Abstract ER - TY - JOUR T1 - Platform to study intracellular polystyrene nanoplastic pollution and clinical outcomes. JF - Stem Cells Y1 - 2020 A1 - Bojic, Sanja A1 - Falco, Matias M A1 - Stojkovic, Petra A1 - Ljujic, Biljana A1 - Gazdic Jankovic, Marina A1 - Armstrong, Lyle A1 - Markovic, Nebojsa A1 - Dopazo, Joaquin A1 - Lako, Majlinda A1 - Bauer, Roman A1 - Stojkovic, Miodrag KW - Environmental Pollution KW - Humans KW - Induced Pluripotent Stem Cells KW - Intracellular Space KW - Nanoparticles KW - Plastics KW - Polystyrenes KW - Transcriptome KW - Treatment Outcome AB -

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.

VL - 38 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/32614127?dopt=Abstract ER - TY - JOUR T1 - Transparency and reproducibility in artificial intelligence. JF - Nature Y1 - 2020 A1 - Haibe-Kains, Benjamin A1 - Adam, George Alexandru A1 - Hosny, Ahmed A1 - Khodakarami, Farnoosh A1 - Waldron, Levi A1 - Wang, Bo A1 - McIntosh, Chris A1 - Goldenberg, Anna A1 - Kundaje, Anshul A1 - Greene, Casey S A1 - Broderick, Tamara A1 - Hoffman, Michael M A1 - Leek, Jeffrey T A1 - Korthauer, Keegan A1 - Huber, Wolfgang A1 - Brazma, Alvis A1 - Pineau, Joelle A1 - Tibshirani, Robert A1 - Hastie, Trevor A1 - Ioannidis, John P A A1 - Quackenbush, John A1 - Aerts, Hugo J W L KW - Algorithms KW - Artificial Intelligence KW - Reproducibility of Results VL - 586 IS - 7829 U1 - https://www.ncbi.nlm.nih.gov/pubmed/33057217?dopt=Abstract ER - TY - JOUR T1 - Using AnABlast for intergenic sORF prediction in the Caenorhabditis elegans genome. JF - Bioinformatics Y1 - 2020 A1 - Casimiro-Soriguer, C S A1 - Rigual, M M A1 - Brokate-Llanos, A M A1 - Muñoz, M J A1 - Garzón, A A1 - Pérez-Pulido, A J A1 - Jimenez, J KW - Animals KW - Caenorhabditis elegans KW - Computational Biology KW - Genome KW - Open Reading Frames KW - Software AB -

MOTIVATION: Short bioactive peptides encoded by small open reading frames (sORFs) play important roles in eukaryotes. Bioinformatics prediction of ORFs is an early step in a genome sequence analysis, but sORFs encoding short peptides, often using non-AUG initiation codons, are not easily discriminated from false ORFs occurring by chance.

RESULTS: AnABlast is a computational tool designed to highlight putative protein-coding regions in genomic DNA sequences. This protein-coding finder is independent of ORF length and reading frame shifts, thus making of AnABlast a potentially useful tool to predict sORFs. Using this algorithm, here, we report the identification of 82 putative new intergenic sORFs in the Caenorhabditis elegans genome. Sequence similarity, motif presence, expression data and RNA interference experiments support that the underlined sORFs likely encode functional peptides, encouraging the use of AnABlast as a new approach for the accurate prediction of intergenic sORFs in annotated eukaryotic genomes.

AVAILABILITY AND IMPLEMENTATION: AnABlast is freely available at http://www.bioinfocabd.upo.es/ab/. The C.elegans genome browser with AnABlast results, annotated genes and all data used in this study is available at http://www.bioinfocabd.upo.es/celegans.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

VL - 36 IS - 19 U1 - https://www.ncbi.nlm.nih.gov/pubmed/32614398?dopt=Abstract ER - TY - JOUR T1 - Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen. JF - Nat Commun Y1 - 2019 A1 - Menden, Michael P A1 - Wang, Dennis A1 - Mason, Mike J A1 - Szalai, Bence A1 - Bulusu, Krishna C A1 - Guan, Yuanfang A1 - Yu, Thomas A1 - Kang, Jaewoo A1 - Jeon, Minji A1 - Wolfinger, Russ A1 - Nguyen, Tin A1 - Zaslavskiy, Mikhail A1 - Jang, In Sock A1 - Ghazoui, Zara A1 - Ahsen, Mehmet Eren A1 - Vogel, Robert A1 - Neto, Elias Chaibub A1 - Norman, Thea A1 - Tang, Eric K Y A1 - Garnett, Mathew J A1 - Veroli, Giovanni Y Di A1 - Fawell, Stephen A1 - Stolovitzky, Gustavo A1 - Guinney, Justin A1 - Dry, Jonathan R A1 - Saez-Rodriguez, Julio KW - ADAM17 Protein KW - Antineoplastic Combined Chemotherapy Protocols KW - Benchmarking KW - Biomarkers, Tumor KW - Cell Line, Tumor KW - Computational Biology KW - Datasets as Topic KW - Drug Antagonism KW - Drug Resistance, Neoplasm KW - Drug Synergism KW - Genomics KW - Humans KW - Molecular Targeted Therapy KW - mutation KW - Neoplasms KW - pharmacogenetics KW - Phosphatidylinositol 3-Kinases KW - Phosphoinositide-3 Kinase Inhibitors KW - Treatment Outcome AB -

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.

VL - 10 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/31209238?dopt=Abstract ER - TY - JOUR T1 - Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses. JF - Br J Dermatol Y1 - 2019 A1 - Chacón-Solano, E A1 - León, C A1 - Díaz, F A1 - García-García, F A1 - García, M A1 - Escámez, M J A1 - Guerrero-Aspizua, S A1 - Conti, C J A1 - Mencía, Á A1 - Martínez-Santamaría, L A1 - Llames, S A1 - Pévida, M A1 - Carbonell-Caballero, J A1 - Puig-Butillé, J A A1 - Maseda, R A1 - Puig, S A1 - de Lucas, R A1 - Baselga, E A1 - Larcher, F A1 - Dopazo, J A1 - Del Rio, M KW - Adolescent KW - Adult KW - Biopsy KW - Blister KW - Case-Control Studies KW - Cells, Cultured KW - Child KW - Child, Preschool KW - Epidermolysis Bullosa KW - Epidermolysis Bullosa Dystrophica KW - Extracellular Matrix KW - Extracellular Matrix Proteins KW - Female KW - Fibroblasts KW - Fibrosis KW - Gene Expression Regulation KW - Healthy Volunteers KW - Humans KW - Infant KW - Infant, Newborn KW - Male KW - Middle Aged KW - mutation KW - Periodontal Diseases KW - Photosensitivity Disorders KW - Primary Cell Culture KW - RNA-seq KW - Skin KW - Xeroderma Pigmentosum KW - Young Adult AB -

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.

OBJECTIVES: To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.

METHODS: We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies.

RESULTS: Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB.

CONCLUSIONS: Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What's already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development. Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix-synthetic capacity. This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor-β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention. It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.

VL - 181 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/30693469?dopt=Abstract ER - TY - JOUR T1 - Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial. JF - Lancet Oncol Y1 - 2019 A1 - Martin-Broto, Javier A1 - Stacchiotti, Silvia A1 - Lopez-Pousa, Antonio A1 - Redondo, Andres A1 - Bernabeu, Daniel A1 - de Alava, Enrique A1 - Casali, Paolo G A1 - Italiano, Antoine A1 - Gutierrez, Antonio A1 - Moura, David S A1 - Peña-Chilet, Maria A1 - Diaz-Martin, Juan A1 - Biscuola, Michele A1 - Taron, Miguel A1 - Collini, Paola A1 - Ranchere-Vince, Dominique A1 - Garcia Del Muro, Xavier A1 - Grignani, Giovanni A1 - Dumont, Sarah A1 - Martinez-Trufero, Javier A1 - Palmerini, Emanuela A1 - Hindi, Nadia A1 - Sebio, Ana A1 - Dopazo, Joaquin A1 - Dei Tos, Angelo Paolo A1 - LeCesne, Axel A1 - Blay, Jean-Yves A1 - Cruz, Josefina KW - Adult KW - Aged KW - Angiogenesis Inhibitors KW - Antineoplastic Agents KW - Female KW - Humans KW - Indazoles KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Pyrimidines KW - Response Evaluation Criteria in Solid Tumors KW - Soft Tissue Neoplasms KW - Solitary Fibrous Tumors KW - Sulfonamides KW - Survival Analysis AB -

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.

VL - 20 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/30578023?dopt=Abstract ER - TY - JOUR T1 - A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection JF - Nature Communications Y1 - 2018 A1 - Fourati, Slim A1 - Talla, Aarthi A1 - Mahmoudian, Mehrad A1 - Burkhart, Joshua G. A1 - Klén, Riku A1 - Henao, Ricardo A1 - Yu, Thomas A1 - Aydın, Zafer A1 - Yeung, Ka Yee A1 - Ahsen, Mehmet Eren A1 - Almugbel, Reem A1 - Jahandideh, Samad A1 - Liang, Xiao A1 - Nordling, Torbjörn E. M. A1 - Shiga, Motoki A1 - Stanescu, Ana A1 - Vogel, Robert A1 - Pandey, Gaurav A1 - Chiu, Christopher A1 - McClain, Micah T. A1 - Woods, Christopher W. A1 - Ginsburg, Geoffrey S. A1 - Elo, Laura L. A1 - Tsalik, Ephraim L. A1 - Mangravite, Lara M. A1 - Sieberts, Solveig K. VL - 9 UR - http://www.nature.com/articles/s41467-018-06735-8http://www.nature.com/articles/s41467-018-06735-8.pdfhttp://www.nature.com/articles/s41467-018-06735-8.pdfhttp://www.nature.com/articles/s41467-018-06735-8 IS - 1 JO - Nat Commun ER - TY - JOUR T1 - The effects of death and post-mortem cold ischemia on human tissue transcriptomes. JF - Nat Commun Y1 - 2018 A1 - Ferreira, Pedro G A1 - Muñoz-Aguirre, Manuel A1 - Reverter, Ferran A1 - Sá Godinho, Caio P A1 - Sousa, Abel A1 - Amadoz, Alicia A1 - Sodaei, Reza A1 - Hidalgo, Marta R A1 - Pervouchine, Dmitri A1 - Carbonell-Caballero, José A1 - Nurtdinov, Ramil A1 - Breschi, Alessandra A1 - Amador, Raziel A1 - Oliveira, Patrícia A1 - Cubuk, Cankut A1 - Curado, João A1 - Aguet, François A1 - Oliveira, Carla A1 - Dopazo, Joaquin A1 - Sammeth, Michael A1 - Ardlie, Kristin G A1 - Guigó, Roderic KW - Blood KW - Cold Ischemia KW - Death KW - Female KW - gene expression KW - Humans KW - Models, Biological KW - Postmortem Changes KW - RNA, Messenger KW - Stochastic Processes KW - Transcriptome AB -

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.

VL - 9 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/29440659?dopt=Abstract ER - TY - JOUR T1 - Evolution of the Quorum network and the mobilome (plasmids and bacteriophages) in clinical strains of Acinetobacter baumannii during a decade. JF - Sci Rep Y1 - 2018 A1 - López, M A1 - Rueda, A A1 - Florido, J P A1 - Blasco, L A1 - Fernández-García, L A1 - Trastoy, R A1 - Fernández-Cuenca, F A1 - Martínez-Martínez, L A1 - Vila, J A1 - Pascual, A A1 - Bou, G A1 - Tomas, M KW - Acinetobacter baumannii KW - Acinetobacter Infections KW - Bacteriophages KW - Cross Infection KW - Humans KW - Plasmids KW - Quorum Sensing KW - Retrospective Studies AB -

In this study, we compared eighteen clinical strains of A. baumannii belonging to the ST-2 clone and isolated from patients in the same intensive care unit (ICU) in 2000 (9 strains referred to collectively as Ab_GEIH-2000) and 2010 (9 strains referred to collectively as Ab_GEIH-2010), during the GEIH-REIPI project (Umbrella BioProject PRJNA422585). We observed two main molecular differences between the Ab_GEIH-2010 and the Ab_GEIH-2000 collections, acquired over the course of the decade long sampling interval and involving the mobilome: i) a plasmid harbouring genes for bla ß-lactamase and abKA/abkB proteins of a toxin-antitoxin system; and ii) two temperate bacteriophages, Ab105-1ϕ (63 proteins) and Ab105-2ϕ (93 proteins), containing important viral defence proteins. Moreover, all Ab_GEIH-2010 strains contained a Quorum functional network of Quorum Sensing (QS) and Quorum Quenching (QQ) mechanisms, including a new QQ enzyme, AidA, which acts as a bacterial defence mechanism against the exogenous 3-oxo-C12-HSL. Interestingly, the infective capacity of the bacteriophages isolated in this study (Ab105-1ϕ and Ab105-2ϕ) was higher in the Ab_GEIH-2010 strains (carrying a functional Quorum network) than in the Ab_GEIH-2000 strains (carrying a deficient Quorum network), in which the bacteriophages showed little or no infectivity. This is the first study about the evolution of the Quorum network and the mobilome in clinical strains of Acinetobacter baumannii during a decade.

VL - 8 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/29410443?dopt=Abstract ER - TY - JOUR T1 - Genomics of the origin and evolution of Citrus. JF - Nature Y1 - 2018 A1 - Wu, Guohong Albert A1 - Terol, Javier A1 - Ibañez, Victoria A1 - López-García, Antonio A1 - Pérez-Román, Estela A1 - Borredá, Carles A1 - Domingo, Concha A1 - Tadeo, Francisco R A1 - Carbonell-Caballero, José A1 - Alonso, Roberto A1 - Curk, Franck A1 - Du, Dongliang A1 - Ollitrault, Patrick A1 - Roose, Mikeal L A1 - Dopazo, Joaquin A1 - Gmitter, Frederick G A1 - Rokhsar, Daniel S A1 - Talon, Manuel KW - Asia, Southeastern KW - Biodiversity KW - citrus KW - Crop Production KW - Evolution, Molecular KW - Genetic Speciation KW - Genome, Plant KW - Genomics KW - Haplotypes KW - Heterozygote KW - History, Ancient KW - Human Migration KW - Hybridization, Genetic KW - Phylogeny AB -

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.

VL - 554 IS - 7692 U1 - https://www.ncbi.nlm.nih.gov/pubmed/29414943?dopt=Abstract ER - TY - JOUR T1 - LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus. JF - Nat Commun Y1 - 2018 A1 - Cobo-Vuilleumier, Nadia A1 - Lorenzo, Petra I A1 - Rodríguez, Noelia García A1 - Herrera Gómez, Irene de Gracia A1 - Fuente-Martin, Esther A1 - López-Noriega, Livia A1 - Mellado-Gil, José Manuel A1 - Romero-Zerbo, Silvana-Yanina A1 - Baquié, Mathurin A1 - Lachaud, Christian Claude A1 - Stifter, Katja A1 - Perdomo, German A1 - Bugliani, Marco A1 - De Tata, Vincenzo A1 - Bosco, Domenico A1 - Parnaud, Geraldine A1 - Pozo, David A1 - Hmadcha, Abdelkrim A1 - Florido, Javier P A1 - Toscano, Miguel G A1 - de Haan, Peter A1 - Schoonjans, Kristina A1 - Sánchez Palazón, Luis A1 - Marchetti, Piero A1 - Schirmbeck, Reinhold A1 - Martín-Montalvo, Alejandro A1 - Meda, Paolo A1 - Soria, Bernat A1 - Bermúdez-Silva, Francisco-Javier A1 - St-Onge, Luc A1 - Gauthier, Benoit R KW - Animals KW - Apoptosis KW - Cell Communication KW - Cell Survival KW - Diabetes Mellitus, Experimental KW - Diabetes Mellitus, Type 2 KW - Female KW - Gene Expression Regulation KW - Humans KW - Hypoglycemic Agents KW - Immunity, Innate KW - insulin KW - Insulin-Secreting Cells KW - Islets of Langerhans KW - Islets of Langerhans Transplantation KW - Macrophages KW - Male KW - Mice KW - Mice, Inbred C57BL KW - Phenalenes KW - Receptors, Cytoplasmic and Nuclear KW - Streptozocin KW - T-Lymphocytes, Regulatory KW - Transplantation, Heterologous AB -

Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus.

VL - 9 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/29662071?dopt=Abstract ER - TY - JOUR T1 - The modular network structure of the mutational landscape of Acute Myeloid Leukemia. JF - PLoS One Y1 - 2018 A1 - Ibáñez, Mariam A1 - Carbonell-Caballero, José A1 - Such, Esperanza A1 - García-Alonso, Luz A1 - Liquori, Alessandro A1 - López-Pavía, María A1 - LLop, Marta A1 - Alonso, Carmen A1 - Barragán, Eva A1 - Gómez-Seguí, Inés A1 - Neef, Alexander A1 - Hervás, David A1 - Montesinos, Pau A1 - Sanz, Guillermo A1 - Sanz, Miguel Angel A1 - Dopazo, Joaquin A1 - Cervera, José KW - Adult KW - Aged KW - Cytodiagnosis KW - Female KW - Gene Regulatory Networks KW - Genetic Association Studies KW - Genetic Heterogeneity KW - Humans KW - Karyotype KW - Leukemia, Myeloid, Acute KW - Male KW - Middle Aged KW - mutation KW - Neoplasm Proteins KW - Nucleophosmin KW - Prognosis KW - whole exome sequencing AB -

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.

VL - 13 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/30303964?dopt=Abstract ER - TY - JOUR T1 - Genomic expression differences between cutaneous cells from red hair color individuals and black hair color individuals based on bioinformatic analysis. JF - Oncotarget Y1 - 2017 A1 - Puig-Butille, Joan Anton A1 - Gimenez-Xavier, Pol A1 - Visconti, Alessia A1 - Nsengimana, Jérémie A1 - Garcia-Garcia, Francisco A1 - Tell-Marti, Gemma A1 - Escamez, Maria José A1 - Newton-Bishop, Julia A1 - Bataille, Veronique A1 - Del Rio, Marcela A1 - Dopazo, Joaquin A1 - Falchi, Mario A1 - Puig, Susana KW - Adult KW - Coculture Techniques KW - Computational Biology KW - gene expression KW - Genetic Predisposition to Disease KW - Genomics KW - Hair Color KW - Humans KW - Keratinocytes KW - Melanocytes KW - Middle Aged KW - Phenotype KW - Receptor, Melanocortin, Type 1 AB -

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.

VL - 8 UR - http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=14140&path%5B%5D=45094 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/28030792?dopt=Abstract ER - TY - JOUR T1 - GGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates. JF - N Engl J Med Y1 - 2017 A1 - Roca-Ayats, Neus A1 - Balcells, Susana A1 - Garcia-Giralt, Natàlia A1 - Falcó-Mascaró, Maite A1 - Martínez-Gil, Núria A1 - Abril, Josep F A1 - Urreizti, Roser A1 - Dopazo, Joaquin A1 - Quesada-Gómez, José M A1 - Nogués, Xavier A1 - Mellibovsky, Leonardo A1 - Prieto-Alhambra, Daniel A1 - Dunford, James E A1 - Javaid, Muhammad K A1 - Russell, R Graham A1 - Grinberg, Daniel A1 - Díez-Pérez, Adolfo KW - Aged KW - Amino Acid Sequence KW - Bone Density Conservation Agents KW - Dimethylallyltranstransferase KW - Diphosphonates KW - Exome KW - Farnesyltranstransferase KW - Female KW - Femoral Fractures KW - Geranyltranstransferase KW - Humans KW - Middle Aged KW - mutation VL - 376 UR - http://www.nejm.org/doi/full/10.1056/NEJMc1612804 IS - 18 U1 - https://www.ncbi.nlm.nih.gov/pubmed/28467865?dopt=Abstract ER - TY - JOUR T1 - Global Transcriptome Analysis of Primary Cerebrocortical Cells: Identification of Genes Regulated by Triiodothyronine in Specific Cell Types. JF - Cereb Cortex Y1 - 2017 A1 - Gil-Ibañez, Pilar A1 - Garcia-Garcia, Francisco A1 - Dopazo, Joaquin A1 - Bernal, Juan A1 - Morte, Beatriz KW - Animals KW - Astrocytes KW - Cells, Cultured KW - Cerebral Cortex KW - Fluorescent Antibody Technique KW - Gene Expression Profiling KW - Mice, 129 Strain KW - Mice, Inbred BALB C KW - Mice, Inbred C57BL KW - Neurons KW - Piperazines KW - Transcriptome KW - Triiodothyronine AB -

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.

VL - 27 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/26534908?dopt=Abstract ER - TY - JOUR T1 - HGVA: the Human Genome Variation Archive. JF - Nucleic Acids Res Y1 - 2017 A1 - Lopez, Javier A1 - Coll, Jacobo A1 - Haimel, Matthias A1 - Kandasamy, Swaathi A1 - Tárraga, Joaquín A1 - Furio-Tari, Pedro A1 - Bari, Wasim A1 - Bleda, Marta A1 - Rueda, Antonio A1 - Gräf, Stefan A1 - Rendon, Augusto A1 - Dopazo, Joaquin A1 - Medina, Ignacio KW - Genetic Variation KW - Genome, Human KW - Humans KW - Internet KW - Software KW - User-Computer Interface AB -

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'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.

VL - 45 UR - https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkx445 IS - W1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/28535294?dopt=Abstract ER - TY - JOUR T1 - Mutations in TRAPPC11 are associated with a congenital disorder of glycosylation. JF - Hum Mutat Y1 - 2017 A1 - Matalonga, Leslie A1 - Bravo, Miren A1 - Serra-Peinado, Carla A1 - García-Pelegrí, Elisabeth A1 - Ugarteburu, Olatz A1 - Vidal, Silvia A1 - Llambrich, Maria A1 - Quintana, Ester A1 - Fuster-Jorge, Pedro A1 - Gonzalez-Bravo, Maria Nieves A1 - Beltran, Sergi A1 - Dopazo, Joaquin A1 - Garcia-Garcia, Francisco A1 - Foulquier, François A1 - Matthijs, Gert A1 - Mills, Philippa A1 - Ribes, Antonia A1 - Egea, Gustavo A1 - Briones, Paz A1 - Tort, Frederic A1 - Girós, Marisa KW - Abnormalities, Multiple KW - Alleles KW - Amino Acid Substitution KW - Brain KW - Congenital Disorders of Glycosylation KW - Genotype KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - mutation KW - Phenotype KW - Vesicular Transport Proteins KW - Whole Genome Sequencing AB -

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.

VL - 38 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/27862579?dopt=Abstract ER - TY - JOUR T1 - Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes JF - Genome Biology Y1 - 2017 A1 - Gui, Hongsheng A1 - Schriemer, Duco A1 - Cheng, William W. A1 - Chauhan, Rajendra K. A1 - Antiňolo, Guillermo A1 - Berrios, Courtney A1 - Bleda, Marta A1 - Brooks, Alice S. A1 - Brouwer, Rutger W. W. A1 - Burns, Alan J. A1 - Cherny, Stacey S. A1 - Dopazo, Joaquin A1 - Eggen, Bart J. L. A1 - Griseri, Paola A1 - Jalloh, Binta A1 - Le, Thuy-Linh A1 - Lui, Vincent C. H. A1 - Luzón-Toro, Berta A1 - Matera, Ivana A1 - Ngan, Elly S. W. A1 - Pelet, Anna A1 - Ruiz-Ferrer, Macarena A1 - Sham, Pak C. A1 - Shepherd, Iain T. A1 - So, Man-Ting A1 - Sribudiani, Yunia A1 - Tang, Clara S. M. A1 - van den Hout, Mirjam C. G. N. A1 - van der Linde, Herma C. A1 - van Ham, Tjakko J. A1 - van IJcken, Wilfred F. J. A1 - Verheij, Joke B. G. M. A1 - Amiel, Jeanne A1 - Borrego, Salud A1 - Ceccherini, Isabella A1 - Chakravarti, Aravinda A1 - Lyonnet, Stanislas A1 - Tam, Paul K. H. A1 - Garcia-Barceló, Maria-Mercè A1 - Hofstra, Robert M. W. VL - 18 UR - http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-6http://link.springer.com/content/pdf/10.1186/s13059-017-1174-6.pdf IS - 1 JO - Genome Biol ER - TY - JOUR T1 - Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes. JF - Genome biology Y1 - 2017 A1 - Gui, Hongsheng A1 - Schriemer, Duco A1 - Cheng, William W A1 - Chauhan, Rajendra K A1 - Antiňolo, Guillermo A1 - Berrios, Courtney A1 - Bleda, Marta A1 - Brooks, Alice S A1 - Brouwer, Rutger W W A1 - Burns, Alan J A1 - Cherny, Stacey S A1 - Dopazo, Joaquin A1 - Eggen, Bart J L A1 - Griseri, Paola A1 - Jalloh, Binta A1 - Le, Thuy-Linh A1 - Lui, Vincent C H A1 - Luzón-Toro, Berta A1 - Matera, Ivana A1 - Ngan, Elly S W A1 - Pelet, Anna A1 - Ruiz-Ferrer, Macarena A1 - Sham, Pak C A1 - Shepherd, Iain T A1 - So, Man-Ting A1 - Sribudiani, Yunia A1 - Tang, Clara S M A1 - van den Hout, Mirjam C G N A1 - van der Linde, Herma C A1 - van Ham, Tjakko J A1 - van IJcken, Wilfred F J A1 - Verheij, Joke B G M A1 - Amiel, Jeanne A1 - Borrego, Salud A1 - Ceccherini, Isabella A1 - Chakravarti, Aravinda A1 - Lyonnet, Stanislas A1 - Tam, Paul K H A1 - Garcia-Barceló, Maria-Mercè A1 - Hofstra, Robert Mw KW - Hirschprung KW - Rare Disease KW - WES AB - 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. VL - 18 UR - http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-6 ER - TY - JOUR T1 - 267 Spanish exomes reveal population-specific differences in disease-related genetic variation. JF - Molecular biology and evolution Y1 - 2016 A1 - Joaquín Dopazo A1 - Amadoz, Alicia A1 - Bleda, Marta A1 - García-Alonso, Luz A1 - Alemán, Alejandro A1 - Garcia-Garcia, Francisco A1 - Rodriguez, Juan A A1 - Daub, Josephine T A1 - Muntané, Gerard A1 - Antonio Rueda A1 - Vela-Boza, Alicia A1 - López-Domingo, Francisco J A1 - Florido, Javier P A1 - Arce, Pablo A1 - Ruiz-Ferrer, Macarena A1 - Méndez-Vidal, Cristina A1 - Arnold, Todd E A1 - Spleiss, Olivia A1 - Alvarez-Tejado, Miguel A1 - Navarro, Arcadi A1 - Bhattacharya, Shomi S A1 - Borrego, Salud A1 - Santoyo-López, Javier A1 - Antiňolo, Guillermo KW - disease KW - NGS KW - polymorphisms KW - Population genomics KW - prioritization KW - SNP AB - Recent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalogue of local variability motivated the whole exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including about 10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies in order to distinguish real disease associations from population-specific polymorphisms. UR - https://mbe.oxfordjournals.org/content/early/2016/02/17/molbev.msw005.full ER - TY - JOUR T1 - Chronic subordination stress selectively downregulates the insulin signaling pathway in liver and skeletal muscle but not in adipose tissue of male mice. JF - Stress (Amsterdam, Netherlands) Y1 - 2016 A1 - Sanghez, Valentina A1 - Cubuk, Cankut A1 - Sebastián-Leon, Patricia A1 - Carobbio, Stefania A1 - Dopazo, Joaquin A1 - Vidal-Puig, Antonio A1 - Bartolomucci, Alessandro KW - Adipose tissue KW - insulin KW - IRS1 KW - IRS2 KW - metabolic syndrome KW - obesity KW - pathway analysis AB - 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. UR - http://www.tandfonline.com/doi/abs/10.3109/10253890.2016.1151491?journalCode=ists20 ER - TY - JOUR T1 - Dysfunctional mitochondrial fission impairs cell reprogramming. JF - Cell Cycle Y1 - 2016 A1 - Prieto, Javier A1 - León, Marian A1 - Ponsoda, Xavier A1 - Garcia-Garcia, Francisco A1 - Bort, Roque A1 - Serna, Eva A1 - Barneo-Muñoz, Manuela A1 - Palau, Francesc A1 - Dopazo, Joaquin A1 - López-García, Carlos A1 - Torres, Josema KW - Animals KW - Cell Cycle Checkpoints KW - Cellular Reprogramming KW - DNA Damage KW - G2 Phase KW - Gene Knockdown Techniques KW - Mice KW - Mitochondrial Dynamics KW - Mitosis KW - Nerve Tissue Proteins KW - Pluripotent Stem Cells KW - Transcription Factors AB -

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.

VL - 15 IS - 23 U1 - https://www.ncbi.nlm.nih.gov/pubmed/27753531?dopt=Abstract ER - TY - JOUR T1 - Highly sensitive and ultrafast read mapping for RNA-seq analysis. JF - DNA Res Y1 - 2016 A1 - Medina, I A1 - Tárraga, J A1 - Martínez, H A1 - Barrachina, S A1 - Castillo, M I A1 - Paschall, J A1 - Salavert-Torres, J A1 - Blanquer-Espert, I A1 - Hernández-García, V A1 - Quintana-Ortí, E S A1 - Dopazo, J KW - Genomics KW - High-Throughput Nucleotide Sequencing KW - Humans KW - Sensitivity and Specificity KW - Sequence Analysis, RNA KW - Transcriptome AB -

As sequencing technologies progress, the amount of data produced grows exponentially, shifting the bottleneck of discovery towards the data analysis phase. In particular, currently available mapping solutions for RNA-seq leave room for improvement in terms of sensitivity and performance, hindering an efficient analysis of transcriptomes by massive sequencing. Here, we present an innovative approach that combines re-engineering, optimization and parallelization. This solution results in a significant increase of mapping sensitivity over a wide range of read lengths and substantial shorter runtimes when compared with current RNA-seq mapping methods available.

VL - 23 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/26740642?dopt=Abstract ER - TY - JOUR T1 - Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa. JF - Sci Rep Y1 - 2016 A1 - Corton, M A1 - Avila-Fernández, A A1 - Campello, L A1 - Sánchez, M A1 - Benavides, B A1 - López-Molina, M I A1 - Fernández-Sánchez, L A1 - Sánchez-Alcudia, R A1 - da Silva, L R J A1 - Reyes, N A1 - Martín-Garrido, E A1 - Zurita, O A1 - Fernández-San José, P A1 - Pérez-Carro, R A1 - García-García, F A1 - Dopazo, J A1 - García-Sandoval, B A1 - Cuenca, N A1 - Ayuso, C KW - Aged KW - Animals KW - Co-Repressor Proteins KW - Codon, Nonsense KW - Cohort Studies KW - Comparative Genomic Hybridization KW - Consanguinity KW - DNA Mutational Analysis KW - Exome KW - Eye Proteins KW - Female KW - Gene Expression Regulation KW - Genes, Recessive KW - Homeodomain Proteins KW - Homozygote KW - Humans KW - Male KW - Mice KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Protein Interaction Mapping KW - Retina KW - Retinal Dystrophies KW - Retinal Rod Photoreceptor Cells KW - Retinitis pigmentosa KW - Spain KW - Trans-Activators KW - Transcription Factors AB -

Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.

VL - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/27734943?dopt=Abstract ER - TY - JOUR T1 - Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel. JF - Sci Rep Y1 - 2016 A1 - Bravo-Gil, Nereida A1 - Méndez-Vidal, Cristina A1 - Romero-Pérez, Laura A1 - González-del Pozo, María A1 - Rodríguez-de la Rúa, Enrique A1 - Dopazo, Joaquin A1 - Borrego, Salud A1 - Antiňolo, Guillermo KW - Alleles KW - Computer Simulation KW - DNA Copy Number Variations KW - DNA Mutational Analysis KW - Eye Proteins KW - Gene Library KW - Genetic Association Studies KW - Genetic Heterogeneity KW - Genetic Therapy KW - High-Throughput Nucleotide Sequencing KW - Humans KW - mutation KW - Phenotype KW - Retinal Dystrophies AB -

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.

VL - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/27032803?dopt=Abstract ER - TY - JOUR T1 - The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations. JF - PLoS One Y1 - 2016 A1 - Ibáñez, Mariam A1 - Carbonell-Caballero, José A1 - García-Alonso, Luz A1 - Such, Esperanza A1 - Jiménez-Almazán, Jorge A1 - Vidal, Enrique A1 - Barragán, Eva A1 - López-Pavía, María A1 - LLop, Marta A1 - Martín, Iván A1 - Gómez-Seguí, Inés A1 - Montesinos, Pau A1 - Sanz, Miguel A A1 - Dopazo, Joaquin A1 - Cervera, José KW - Exome KW - Gene Regulatory Networks KW - Genome, Human KW - Humans KW - INDEL Mutation KW - Leukemia, Promyelocytic, Acute KW - mutation KW - Mutation Rate KW - Polymorphism, Single Nucleotide KW - Reproducibility of Results AB -

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.

VL - 11 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/26886259?dopt=Abstract ER - TY - JOUR T1 - The pan-cancer pathological regulatory landscape JF - Scientific Reports Y1 - 2016 A1 - Falco, Matias M. A1 - Bleda, Marta A1 - Carbonell-Caballero, José A1 - Dopazo, Joaquin VL - 6 UR - http://www.nature.com/articles/srep39709http://www.nature.com/articles/srep39709.pdfhttp://www.nature.com/articles/srep39709.pdfhttp://www.nature.com/articles/srep39709 IS - 1 JO - Sci Rep ER - TY - JOUR T1 - The pan-cancer pathological regulatory landscape. JF - Scientific reports Y1 - 2016 A1 - Falco, Matias M A1 - Bleda, Marta A1 - Carbonell-Caballero, José A1 - Joaquín Dopazo AB - Dysregulation of the normal gene expression program is the cause of a broad range of diseases, including cancer. Detecting the specific perturbed regulators that have an effect on the generation and the development of the disease is crucial for understanding the disease mechanism and for taking decisions on efficient preventive and curative therapies. Moreover, detecting such perturbations at the patient level is even more important from the perspective of personalized medicine. We applied the Transcription Factor Target Enrichment Analysis, a method that detects the activity of transcription factors based on the quantification of the collective transcriptional activation of their targets, to a large collection of 5607 cancer samples covering eleven cancer types. We produced for the first time a comprehensive catalogue of altered transcription factor activities in cancer, a considerable number of them significantly associated to patient’s survival. Moreover, we described several interesting TFs whose activity do not change substantially in the cancer with respect to the normal tissue but ultimately play an important role in patient prognostic determination, which suggest they might be promising therapeutic targets. An additional advantage of this method is that it allows obtaining personalized TF activity estimations for individual patients. VL - 6 UR - http://www.nature.com/articles/srep39709 ER - TY - JOUR T1 - Screening of CD96 and ASXL1 in 11 patients with Opitz C or Bohring-Opitz syndromes. JF - Am J Med Genet A Y1 - 2016 A1 - Urreizti, Roser A1 - Roca-Ayats, Neus A1 - Trepat, Judith A1 - Garcia-Garcia, Francisco A1 - Alemán, Alejandro A1 - Orteschi, Daniela A1 - Marangi, Giuseppe A1 - Neri, Giovanni A1 - Opitz, John M A1 - Dopazo, Joaquin A1 - Cormand, Bru A1 - Vilageliu, Lluïsa A1 - Balcells, Susana A1 - Grinberg, Daniel KW - Adolescent KW - Antigens, CD KW - Child KW - Child, Preschool KW - Craniosynostoses KW - Exome KW - Female KW - High-Throughput Nucleotide Sequencing KW - Humans KW - Infant KW - Intellectual Disability KW - Male KW - mutation KW - Pedigree KW - Phenotype KW - Prognosis KW - Repressor Proteins AB -

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.

VL - 170A IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/26768331?dopt=Abstract ER - TY - JOUR T1 - Serum metabolomic profiling facilitates the non-invasive identification of metabolic biomarkers associated with the onset and progression of non-small cell lung cancer. JF - Oncotarget Y1 - 2016 A1 - Puchades-Carrasco, Leonor A1 - Jantus-Lewintre, Eloisa A1 - Pérez-Rambla, Clara A1 - Garcia-Garcia, Francisco A1 - Lucas, Rut A1 - Calabuig, Silvia A1 - Blasco, Ana A1 - Dopazo, Joaquin A1 - Camps, Carlos A1 - Pineda-Lucena, Antonio KW - Adult KW - Aged KW - Biomarkers, Tumor KW - Carcinoma, Non-Small-Cell Lung KW - Disease Progression KW - Female KW - Humans KW - Lung Neoplasms KW - Male KW - metabolomics KW - Middle Aged KW - Proton Magnetic Resonance Spectroscopy AB -

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.

VL - 7 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/26883203?dopt=Abstract ER - TY - JOUR T1 - Stress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis. JF - Mol Metab Y1 - 2016 A1 - Razzoli, Maria A1 - Frontini, Andrea A1 - Gurney, Allison A1 - Mondini, Eleonora A1 - Cubuk, Cankut A1 - Katz, Liora S A1 - Cero, Cheryl A1 - Bolan, Patrick J A1 - Dopazo, Joaquin A1 - Vidal-Puig, Antonio A1 - Cinti, Saverio A1 - Bartolomucci, Alessandro AB -

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 β1,β2,β3-Adrenergic Receptors knockout (β-less) mice exposed to a model of chronic subordination stress (CSS) at either room temperature (22 °C) or murine thermoneutrality (30 °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 βARs 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 βARs), 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 β-less mice. Despite increased sympathetic innervation suggesting adrenergic-mediated browning, norepinephrine did not promote browning in βARs 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 β-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 βARs agonists for the activation of human BAT.

VL - 5 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/26844204?dopt=Abstract ER - TY - JOUR T1 - Web-based network analysis and visualization using CellMaps. JF - Bioinformatics Y1 - 2016 A1 - Salavert, Francisco A1 - García-Alonso, Luz A1 - Sánchez, Rubén A1 - Alonso, Roberto A1 - Bleda, Marta A1 - Medina, Ignacio A1 - Dopazo, Joaquin KW - Biochemical Phenomena KW - Internet KW - Software AB -

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.

VL - 32 IS - 19 U1 - https://www.ncbi.nlm.nih.gov/pubmed/27296979?dopt=Abstract ER - TY - JOUR T1 - Babelomics 5.0: functional interpretation for new generations of genomic data. JF - Nucleic acids research Y1 - 2015 A1 - Alonso, Roberto A1 - Salavert, Francisco A1 - Garcia-Garcia, Francisco A1 - Carbonell-Caballero, José A1 - Bleda, Marta A1 - García-Alonso, Luz A1 - Sanchis-Juan, Alba A1 - Perez-Gil, Daniel A1 - Marin-Garcia, Pablo A1 - Sánchez, Rubén A1 - Cubuk, Cankut A1 - Hidalgo, Marta R A1 - Amadoz, Alicia A1 - Hernansaiz-Ballesteros, Rosa D A1 - Alemán, Alejandro A1 - Tárraga, Joaquín A1 - Montaner, David A1 - Medina, Ignacio A1 - Dopazo, Joaquin KW - babelomics KW - data integration KW - gene set analysis KW - interactome KW - network analysis KW - NGS KW - RNA-seq KW - Systems biology KW - transcriptomics AB - 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. VL - 43 UR - http://nar.oxfordjournals.org/content/43/W1/W117 ER - TY - JOUR T1 - BRCA1 Alternative splicing landscape in breast tissue samples. JF - BMC cancer Y1 - 2015 A1 - Romero, Atocha A1 - Garcia-Garcia, Francisco A1 - López-Perolio, Irene A1 - Ruiz de Garibay, Gorka A1 - García-Sáenz, José A A1 - Garre, Pilar A1 - Ayllón, Patricia A1 - Benito, Esperanza A1 - Joaquín Dopazo A1 - Díaz-Rubio, Eduardo A1 - Caldés, Trinidad A1 - de la Hoya, Miguel AB - BACKGROUND: BRCA1 is a key protein in cell network, involved in DNA repair pathways and cell cycle. Recently, the ENIGMA consortium has reported a high number of alternative splicing (AS) events at this locus in blood-derived samples. However, BRCA1 splicing pattern in breast tissue samples is unknown. Here, we provide an accurate description of BRCA1 splicing events distribution in breast tissue samples. METHODS: BRCA1 splicing events were scanned in 70 breast tumor samples, 4 breast samples from healthy individuals and in 72 blood-derived samples by capillary electrophoresis (capillary EP). Molecular subtype was identified in all tumor samples. Splicing events were considered predominant if their relative expression level was at least the 10% of the full-length reference signal. RESULTS: 54 BRCA1 AS events were identified, 27 of them were annotated as predominant in at least one sample. Δ5q, Δ13, Δ9, Δ5 and ▼1aA were significantly more frequently annotated as predominant in breast tumor samples than in blood-derived samples. Predominant splicing events were, on average, more frequent in tumor samples than in normal breast tissue samples (P = 0.010). Similarly, likely inactivating splicing events (PTC-NMDs, Non-Coding, Δ5 and Δ18) were more frequently annotated as predominant in tumor than in normal breast samples (P = 0.020), whereas there were no significant differences for other splicing events (No-Fs) frequency distribution between tumor and normal breast samples (P = 0.689). CONCLUSIONS: Our results complement recent findings by the ENIGMA consortium, demonstrating that BRCA1 AS, despite its tremendous complexity, is similar in breast and blood samples, with no evidences for tissue specific AS events. Further on, we conclude that somatic inactivation of BRCA1 through spliciogenic mutations is, at best, a rare mechanism in breast carcinogenesis, albeit our data detects an excess of likely inactivating AS events in breast tumor samples. VL - 15 UR - http://www.biomedcentral.com/1471-2407/15/219 ER - TY - JOUR T1 - Combining tumor genome simulation with crowdsourcing to benchmark somatic single-nucleotide-variant detection. JF - Nature methods Y1 - 2015 A1 - Ewing, Adam D A1 - Houlahan, Kathleen E A1 - Hu, Yin A1 - Ellrott, Kyle A1 - Caloian, Cristian A1 - Yamaguchi, Takafumi N A1 - Bare, J Christopher A1 - P’ng, Christine A1 - Waggott, Daryl A1 - Sabelnykova, Veronica Y A1 - Kellen, Michael R A1 - Norman, Thea C A1 - Haussler, David A1 - Friend, Stephen H A1 - Stolovitzky, Gustavo A1 - Margolin, Adam A A1 - Stuart, Joshua M A1 - Boutros, Paul C ED - ICGC-TCGA DREAM Somatic Mutation Calling Challenge participants ED - Liu Xi ED - Ninad Dewal ED - Yu Fan ED - Wenyi Wang ED - David Wheeler ED - Andreas Wilm ED - Grace Hui Ting ED - Chenhao Li ED - Denis Bertrand ED - Niranjan Nagarajan ED - Qing-Rong Chen ED - Chih-Hao Hsu ED - Ying Hu ED - Chunhua Yan ED - Warren Kibbe ED - Daoud Meerzaman ED - Kristian Cibulskis ED - Mara Rosenberg ED - Louis Bergelson ED - Adam Kiezun ED - Amie Radenbaugh ED - Anne-Sophie Sertier ED - Anthony Ferrari ED - Laurie Tonton ED - Kunal Bhutani ED - Nancy F Hansen ED - Difei Wang ED - Lei Song ED - Zhongwu Lai ED - Liao, Yang ED - Shi, Wei ED - Carbonell-Caballero, José ED - Joaquín Dopazo ED - Cheryl C K Lau ED - Justin Guinney KW - cancer KW - NGS KW - variant calling AB - The detection of somatic mutations from cancer genome sequences is key to understanding the genetic basis of disease progression, patient survival and response to therapy. Benchmarking is needed for tool assessment and improvement but is complicated by a lack of gold standards, by extensive resource requirements and by difficulties in sharing personal genomic information. To resolve these issues, we launched the ICGC-TCGA DREAM Somatic Mutation Calling Challenge, a crowdsourced benchmark of somatic mutation detection algorithms. Here we report the BAMSurgeon tool for simulating cancer genomes and the results of 248 analyses of three in silico tumors created with it. Different algorithms exhibit characteristic error profiles, and, intriguingly, false positives show a trinucleotide profile very similar to one found in human tumors. Although the three simulated tumors differ in sequence contamination (deviation from normal cell sequence) and in subclonality, an ensemble of pipelines outperforms the best individual pipeline in all cases. BAMSurgeon is available at https://github.com/adamewing/bamsurgeon/. UR - http://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.3407.html ER - TY - JOUR T1 - Concurrent and Accurate Short Read Mapping on Multicore Processors. JF - IEEE/ACM transactions on computational biology and bioinformatics / IEEE, ACM Y1 - 2015 A1 - Martinez, Hector A1 - Tárraga, Joaquín A1 - Medina, Ignacio A1 - Barrachina, Sergio A1 - Castillo, Maribel A1 - Dopazo, Joaquin A1 - Quintana-Orti, Enrique S KW - HPC KW - NGS KW - short real mapping AB - 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. VL - 12 UR - http://ieeexplore.ieee.org/xpl/articleDetails.jsp?tp=&arnumber=7010005 ER - TY - JOUR T1 - Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease. JF - Scientific reports Y1 - 2015 A1 - Luzón-Toro, Berta A1 - Gui, Hongsheng A1 - Ruiz-Ferrer, Macarena A1 - Sze-Man Tang, Clara A1 - Fernández, Raquel M A1 - Sham, Pak-Chung A1 - Torroglosa, Ana A1 - Kwong-Hang Tam, Paul A1 - Espino-Paisán, Laura A1 - Cherny, Stacey S A1 - Bleda, Marta A1 - Enguix-Riego, María Del Valle A1 - Joaquín Dopazo A1 - Antiňolo, Guillermo A1 - Garcia-Barceló, Maria-Mercè A1 - Borrego, Salud KW - babelomics KW - Hirschprung KW - NGS KW - prioritization AB - Hirschsprung disease (HSCR; OMIM 142623) is a developmental disorder characterized by aganglionosis along variable lengths of the distal gastrointestinal tract, which results in intestinal obstruction. Interactions among known HSCR genes and/or unknown disease susceptibility loci lead to variable severity of phenotype. Neither linkage nor genome-wide association studies have efficiently contributed to completely dissect the genetic pathways underlying this complex genetic disorder. We have performed whole exome sequencing of 16 HSCR patients from 8 unrelated families with SOLID platform. Variants shared by affected relatives were validated by Sanger sequencing. We searched for genes recurrently mutated across families. Only variations in the FAT3 gene were significantly enriched in five families. Within-family analysis identified compound heterozygotes for AHNAK and several genes (N = 23) with heterozygous variants that co-segregated with the phenotype. Network and pathway analyses facilitated the discovery of polygenic inheritance involving FAT3, HSCR known genes and their gene partners. Altogether, our approach has facilitated the detection of more than one damaging variant in biologically plausible genes that could jointly contribute to the phenotype. Our data may contribute to the understanding of the complex interactions that occur during enteric nervous system development and the etiopathology of familial HSCR. VL - 5 UR - http://www.nature.com/articles/srep16473 ER - TY - JOUR T1 - Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease JF - Scientific Reports Y1 - 2015 A1 - Luzón-Toro, Berta A1 - Gui, Hongsheng A1 - Ruiz-Ferrer, Macarena A1 - Sze-Man Tang, Clara A1 - Fernández, Raquel M. A1 - Sham, Pak-Chung A1 - Torroglosa, Ana A1 - Kwong-Hang Tam, Paul A1 - Espino-Paisán, Laura A1 - Cherny, Stacey S. A1 - Bleda, Marta A1 - Enguix-Riego, María Del Valle A1 - Dopazo, Joaquin A1 - Antiňolo, Guillermo A1 - Garcia-Barceló, Maria-Mercè A1 - Borrego, Salud VL - 5 UR - http://www.nature.com/articles/srep16473http://www.nature.com/articles/srep16473.pdfhttp://www.nature.com/articles/srep16473.pdfhttp://www.nature.com/articles/srep16473 IS - 1 JO - Sci Rep ER - TY - JOUR T1 - Fast inexact mapping using advanced tree exploration on backward search methods. JF - BMC Bioinformatics Y1 - 2015 A1 - Salavert, José A1 - Tomás, Andrés A1 - Tárraga, Joaquín A1 - Medina, Ignacio A1 - Dopazo, Joaquin A1 - Blanquer, Ignacio KW - Algorithms KW - Genome, Human KW - Genomics KW - High-Throughput Nucleotide Sequencing KW - Humans KW - Sequence Alignment KW - Sequence Analysis, DNA KW - Software AB -

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.

VL - 16 U1 - https://www.ncbi.nlm.nih.gov/pubmed/25626517?dopt=Abstract ER - TY - JOUR T1 - Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas JF - BMC Medical Genomics Y1 - 2015 A1 - Luzón-Toro, Berta A1 - Bleda, Marta A1 - Navarro, Elena A1 - García-Alonso, Luz A1 - Ruiz-Ferrer, Macarena A1 - Medina, Ignacio A1 - Martín-Sánchez, Marta A1 - Gonzalez, Cristina Y. A1 - Fernández, Raquel M. A1 - Torroglosa, Ana A1 - Antiňolo, Guillermo A1 - Dopazo, Joaquin A1 - Borrego, Salud AB - 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. VL - 8 UR - https://doi.org/10.1186/s12920-015-0160-7 ER - TY - JOUR T1 - Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas. JF - BMC medical genomics Y1 - 2015 A1 - Luzón-Toro, Berta A1 - Bleda, Marta A1 - Navarro, Elena A1 - García-Alonso, Luz A1 - Ruiz-Ferrer, Macarena A1 - Medina, Ignacio A1 - Martín-Sánchez, Marta A1 - Gonzalez, Cristina Y A1 - Fernández, Raquel M A1 - Torroglosa, Ana A1 - Antiňolo, Guillermo A1 - Dopazo, Joaquin A1 - Borrego, Salud KW - epistasis KW - GWAS KW - Thyroid cancer AB - 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. VL - 8 UR - http://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-015-0160-7 ER - TY - JOUR T1 - Prediction of human population responses to toxic compounds by a collaborative competition. JF - Nature biotechnology Y1 - 2015 A1 - Eduati, Federica A1 - Mangravite, Lara M A1 - Wang, Tao A1 - Tang, Hao A1 - Bare, J Christopher A1 - Huang, Ruili A1 - Norman, Thea A1 - Kellen, Mike A1 - Menden, Michael P A1 - Yang, Jichen A1 - Zhan, Xiaowei A1 - Zhong, Rui A1 - Xiao, Guanghua A1 - Xia, Menghang A1 - Abdo, Nour A1 - Kosyk, Oksana AB - The ability to computationally predict the effects of toxic compounds on humans could help address the deficiencies of current chemical safety testing. Here, we report the results from a community-based DREAM challenge to predict toxicities of environmental compounds with potential adverse health effects for human populations. We measured the cytotoxicity of 156 compounds in 884 lymphoblastoid cell lines for which genotype and transcriptional data are available as part of the Tox21 1000 Genomes Project. The challenge participants developed algorithms to predict interindividual variability of toxic response from genomic profiles and population-level cytotoxicity data from structural attributes of the compounds. 179 submitted predictions were evaluated against an experimental data set to which participants were blinded. Individual cytotoxicity predictions were better than random, with modest correlations (Pearson’s r < 0.28), consistent with complex trait genomic prediction. In contrast, predictions of population-level response to different compounds were higher (r < 0.66). The results highlight the possibility of predicting health risks associated with unknown compounds, although risk estimation accuracy remains suboptimal. UR - http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.3299.html ER - TY - JOUR T1 - PTMcode v2: a resource for functional associations of post-translational modifications within and between proteins. JF - Nucleic Acids Res Y1 - 2015 A1 - Minguez, Pablo A1 - Letunic, Ivica A1 - Parca, Luca A1 - García-Alonso, Luz A1 - Dopazo, Joaquin A1 - Huerta-Cepas, Jaime A1 - Bork, Peer KW - Databases, Protein KW - Internet KW - Protein Interaction Mapping KW - Protein Processing, Post-Translational AB -

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.

VL - 43 IS - Database issue U1 - https://www.ncbi.nlm.nih.gov/pubmed/25361965?dopt=Abstract ER - TY - JOUR T1 - Re-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F. JF - Am J Med Genet A Y1 - 2015 A1 - Pozo, María González-Del A1 - Bravo-Gil, Nereida A1 - Méndez-Vidal, Cristina A1 - Montero-de-Espinosa, Ignacio A1 - Millán, José M A1 - Dopazo, Joaquin A1 - Borrego, Salud A1 - Antiňolo, Guillermo KW - Base Sequence KW - Cyclic Nucleotide Phosphodiesterases, Type 6 KW - Extracellular Matrix Proteins KW - Gene Library KW - Humans KW - Molecular Sequence Data KW - Mutation, Missense KW - Pedigree KW - Retinitis pigmentosa KW - Sequence Analysis, DNA KW - Spain AB -

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.

VL - 167 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/25823529?dopt=Abstract ER - TY - JOUR T1 - Therapeutic targets for olive pollen allergy defined by gene markers modulated by Ole e 1-derived peptides. JF - Molecular immunology Y1 - 2015 A1 - Calzada, David A1 - Aguerri, Miriam A1 - Baos, Selene A1 - Montaner, David A1 - Mata, Manuel A1 - Joaquín Dopazo A1 - Quiralte, Joaquín A1 - Florido, Fernando A1 - Lahoz, Carlos A1 - Cárdaba, Blanca AB - Two regions of Ole e 1, the major olive-pollen allergen, have been characterized as T-cell epitopes, one as immunodominant region (aa91-130) and the other, as mainly recognized by non-allergic subjects (aa10-31). This report tries to characterize the specific relevance of these epitopes in the allergic response to olive pollen by analyzing the secreted cytokines and the gene expression profiles induced after specific stimulation of peripheral blood mononuclear cells (PBMCs). PBMCs from olive pollen-allergic and non-allergic control subjects were stimulated with olive-pollen extract and Ole e 1 dodecapeptides containing relevant T-cell epitopes. Levels of cytokines were measured in cellular supernatants and gene expression was determined by microarrays, on the RNAs extracted from PBMCs. One hundred eighty-nine differential genes (fold change >2 or <-2, P<0.05) were validated by qRT-PCR in a large population. It was not possible to define a pattern of response according the overall cytokine results but interesting differences were observed, mainly in the regulatory cytokines. Principal component (PCA) gene-expression analysis defined clusters that correlated with the experimental conditions in the group of allergic subjects. Gene expression and functional analyses revealed differential genes and pathways among the experimental conditions. A set of 51 genes (many essential to T-cell tolerance and homeostasis) correlated with the response to aa10-31 of Ole e 1. In conclusion, two peptides derived from Ole e 1 could regulate the immune response in allergic patients, by gene-expression modification of several regulation-related genes. These results open new research ways to the regulation of allergy by Oleaceae family members. VL - 64 UR - http://www.sciencedirect.com/science/article/pii/S0161589014003356 ER - TY - JOUR T1 - Acceleration of short and long DNA read mapping without loss of accuracy using suffix array. JF - Bioinformatics (Oxford, England) Y1 - 2014 A1 - Tárraga, Joaquín A1 - Arnau, Vicente A1 - Martinez, Hector A1 - Moreno, Raul A1 - Cazorla, Diego A1 - Salavert-Torres, José A1 - Blanquer-Espert, Ignacio A1 - Joaquín Dopazo A1 - Medina, Ignacio KW - NGS KW - short read mapping. HPC. suffix arrays AB - HPG Aligner applies suffix arrays for DNA read mapping. This implementation produces a highly sensitive and extremely fast mapping of DNA reads that scales up almost linearly with read length. The approach presented here is faster (over 20x for long reads) and more sensitive (over 98% in a wide range of read lengths) than the current, state-of-the-art mappers. HPG Aligner is not only an optimal alternative for current sequencers but also the only solution available to cope with longer reads and growing throughputs produced by forthcoming sequencing technologies. VL - 30 UR - http://bioinformatics.oxfordjournals.org/content/early/2014/08/19/bioinformatics.btu553.long ER - TY - JOUR T1 - The Activation of the Sox2 RR2 Pluripotency Transcriptional Reporter in Human Breast Cancer Cell Lines is Dynamic and Labels Cells with Higher Tumorigenic Potential. JF - Front Oncol Y1 - 2014 A1 - Iglesias, Juan Manuel A1 - Leis, Olatz A1 - Pérez Ruiz, Estíbaliz A1 - Gumuzio Barrie, Juan A1 - Garcia-Garcia, Francisco A1 - Aduriz, Ariane A1 - Beloqui, Izaskun A1 - Hernandez-Garcia, Susana A1 - Lopez-Mato, Maria Paz A1 - Dopazo, Joaquin A1 - Pandiella, Atanasio A1 - Menendez, Javier A A1 - Martin, Angel Garcia AB -

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.

VL - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/25414831?dopt=Abstract ER - TY - JOUR T1 - Assessing technical performance in differential gene expression experiments with external spike-in RNA control ratio mixtures. JF - Nature communications Y1 - 2014 A1 - Munro, Sarah A A1 - Lund, Steven P A1 - Pine, P Scott A1 - Binder, Hans A1 - Clevert, Djork-Arné A1 - Ana Conesa A1 - Dopazo, Joaquin A1 - Fasold, Mario A1 - Hochreiter, Sepp A1 - Hong, Huixiao A1 - Jafari, Nadereh A1 - Kreil, David P A1 - Labaj, Paweł P A1 - Li, Sheng A1 - Liao, Yang A1 - Lin, Simon M A1 - Meehan, Joseph A1 - Mason, Christopher E A1 - Santoyo-López, Javier A1 - Setterquist, Robert A A1 - Shi, Leming A1 - Shi, Wei A1 - Smyth, Gordon K A1 - Stralis-Pavese, Nancy A1 - Su, Zhenqiang A1 - Tong, Weida A1 - Wang, Charles A1 - Wang, Jian A1 - Xu, Joshua A1 - Ye, Zhan A1 - Yang, Yong A1 - Yu, Ying A1 - Salit, Marc KW - RNA-seq AB - 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 ’dashboard’ 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. VL - 5 UR - http://www.nature.com/ncomms/2014/140925/ncomms6125/full/ncomms6125.html ER - TY - JOUR T1 - A Comprehensive DNA Methylation Profile of Epithelial-to-Mesenchymal Transition. JF - Cancer research Y1 - 2014 A1 - Carmona, F Javier A1 - Davalos, Veronica A1 - Vidal, Enrique A1 - Gomez, Antonio A1 - Heyn, Holger A1 - Hashimoto, Yutaka A1 - Vizoso, Miguel A1 - Martinez-Cardus, Anna A1 - Sayols, Sergi A1 - Ferreira, Humberto A1 - Sanchez-Mut, Jose A1 - Moran, Sebastian A1 - Margeli, Mireia A1 - Castella, Eva A1 - Berdasco, Maria A1 - Stefansson, Olafur Andri A1 - Eyfjord, Jorunn E A1 - Gonzalez-Suarez, Eva A1 - Dopazo, Joaquin A1 - Orozco, Modesto A1 - Gut, Ivo A1 - Esteller, Manel KW - Methyl-Seq KW - Methylomics KW - Next Generation Sequencing AB - 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. VL - 74 UR - http://www.ncbi.nlm.nih.gov/pubmed/25106427 ER - TY - JOUR T1 - Deciphering intrafamilial phenotypic variability by exome sequencing in a Bardet-Biedl family. JF - Mol Genet Genomic Med Y1 - 2014 A1 - González-del Pozo, María A1 - Méndez-Vidal, Cristina A1 - Santoyo-López, Javier A1 - Vela-Boza, Alicia A1 - Bravo-Gil, Nereida A1 - Rueda, Antonio A1 - García-Alonso, Luz A1 - Vázquez-Marouschek, Carmen A1 - Dopazo, Joaquin A1 - Borrego, Salud A1 - Antiňolo, Guillermo AB -

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.

VL - 2 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/24689075?dopt=Abstract ER - TY - JOUR T1 - Deciphering intrafamilial phenotypic variability by exome sequencing in a Bardet–Biedl family JF - Molecular Genetics & Genomic Medicine Y1 - 2014 A1 - González-del Pozo, María A1 - Méndez-Vidal, Cristina A1 - Santoyo-López, Javier A1 - Vela-Boza, Alicia A1 - Nereida Bravo-Gil A1 - Antonio Rueda A1 - García-Alonso, Luz A1 - Vázquez-Marouschek, Carmen A1 - Joaquín Dopazo A1 - Borrego, Salud A1 - Antiňolo, Guillermo AB - 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. VL - 2 UR - http://onlinelibrary.wiley.com/doi/10.1002/mgg3.50/full ER - TY - JOUR T1 - Exome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies. JF - PLoS One Y1 - 2014 A1 - González-del Pozo, María A1 - Méndez-Vidal, Cristina A1 - Bravo-Gil, Nereida A1 - Vela-Boza, Alicia A1 - Dopazo, Joaquin A1 - Borrego, Salud A1 - Antiňolo, Guillermo KW - Adolescent KW - Adult KW - Amino Acid Sequence KW - Base Sequence KW - Child KW - Chromosome Segregation KW - DNA Mutational Analysis KW - Exome KW - Family KW - Female KW - Humans KW - Inheritance Patterns KW - Male KW - Middle Aged KW - Molecular Sequence Data KW - mutation KW - Pedigree KW - Retinal Dystrophies KW - Rhodopsin AB -

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.

VL - 9 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/25544989?dopt=Abstract ER - TY - JOUR T1 - A New Overgrowth Syndrome is Due to Mutations in RNF125. JF - Human mutation Y1 - 2014 A1 - Tenorio, Jair A1 - Mansilla, Alicia A1 - Valencia, María A1 - Martínez-Glez, Víctor A1 - Romanelli, Valeria A1 - Arias, Pedro A1 - Castrejón, Nerea A1 - Poletta, Fernando A1 - Guillén-Navarro, Encarna A1 - Gordo, Gema A1 - Mansilla, Elena A1 - García-Santiago, Fé A1 - González-Casado, Isabel A1 - Vallespín, Elena A1 - Palomares, María A1 - Mori, María A A1 - Santos-Simarro, Fernando A1 - García-Miñaur, Sixto A1 - Fernández, Luis A1 - Mena, Rocío A1 - Benito-Sanz, Sara A1 - Del Pozo, Angela A1 - Silla, Juan Carlos A1 - Ibañez, Kristina A1 - López-Granados, Eduardo A1 - Martín-Trujillo, Alex A1 - Montaner, David A1 - Heath, Karen E A1 - Campos-Barros, Angel A1 - Joaquín Dopazo A1 - Nevado, Julián A1 - Monk, David A1 - Ruiz-Pérez, Víctor L A1 - Lapunzina, Pablo KW - NGS KW - prioritization KW - Rare Disease AB - Overgrowth syndromes (OGS) are a group of disorders in which all parameters of growth and physical development are above the mean for age and sex. We evaluated a series of 270 families from the Spanish Overgrowth Syndrome Registry with no known overgrowth syndrome. We identified one de novo deletion and three missense mutations in RNF125 in six patients from 4 families with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycaemia and inflammatory diseases resembling Sjögren syndrome. RNF125 encodes an E3 ubiquitin ligase and is a novel gene of OGS. Our studies of the RNF125 pathway point to upregulation of RIG-I-IPS1-MDA5 and/or disruption of the PI3K-AKT and interferon signaling pathways as the putative final effectors. This article is protected by copyright. All rights reserved. VL - 35 UR - http://onlinelibrary.wiley.com/doi/10.1002/humu.22689/abstract ER - TY - JOUR T1 - Novel RP1 mutations and a recurrent BBS1 variant explain the co-existence of two distinct retinal phenotypes in the same pedigree. JF - BMC Genet Y1 - 2014 A1 - Méndez-Vidal, Cristina A1 - Bravo-Gil, Nereida A1 - González-del Pozo, María A1 - Vela-Boza, Alicia A1 - Dopazo, Joaquin A1 - Borrego, Salud A1 - Antiňolo, Guillermo KW - Bardet-Biedl Syndrome KW - Base Sequence KW - Case-Control Studies KW - DNA Mutational Analysis KW - Eye Proteins KW - Genes, Recessive KW - Genetic Association Studies KW - Humans KW - Microsatellite Repeats KW - Microtubule-Associated Proteins KW - Mutation, Missense KW - Pedigree KW - Phenotype KW - Retina KW - Retinitis pigmentosa AB -

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.

VL - 15 U1 - https://www.ncbi.nlm.nih.gov/pubmed/25494902?dopt=Abstract ER - TY - JOUR T1 - Permanent cardiac sarcomere changes in a rabbit model of intrauterine growth restriction. JF - PLoS One Y1 - 2014 A1 - Torre, Iratxe A1 - González-Tendero, Anna A1 - García-Cañadilla, Patricia A1 - Crispi, Fátima A1 - Garcia-Garcia, Francisco A1 - Bijnens, Bart A1 - Iruretagoyena, Igor A1 - Dopazo, Joaquin A1 - Amat-Roldán, Ivan A1 - Gratacós, Eduard KW - Animals KW - biomarkers KW - Blood Pressure KW - Body Weight KW - Disease Models, Animal KW - Echocardiography KW - Female KW - Fetal Growth Retardation KW - Fetal Heart KW - Fetus KW - Gene Expression Profiling KW - Organ Size KW - Placenta KW - Pregnancy KW - Rabbits KW - Sarcomeres AB -

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.

VL - 9 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/25402351?dopt=Abstract ER - TY - JOUR T1 - Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients. JF - Hum Mutat Y1 - 2014 A1 - García-Cazorla, Angels A1 - Oyarzabal, Alfonso A1 - Fort, Joana A1 - Robles, Concepción A1 - Castejón, Esperanza A1 - Ruiz-Sala, Pedro A1 - Bodoy, Susanna A1 - Merinero, Begoña A1 - Lopez-Sala, Anna A1 - Dopazo, Joaquin A1 - Nunes, Virginia A1 - Ugarte, Magdalena A1 - Artuch, Rafael A1 - Palacín, Manuel A1 - Rodríguez-Pombo, Pilar A1 - Alcaide, Patricia A1 - Navarrete, Rosa A1 - Sanz, Paloma A1 - Font-Llitjós, Mariona A1 - Vilaseca, Ma Antonia A1 - Ormaizabal, Aida A1 - Pristoupilova, Anna A1 - Agulló, Sergi Beltran KW - Amino Acids, Branched-Chain KW - Developmental Disabilities KW - Fibroblasts KW - Humans KW - Male KW - Mutation, Missense KW - Nervous System Diseases KW - Pediatrics KW - Protein Kinases AB -

Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain α-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-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients' 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.

VL - 35 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/24449431?dopt=Abstract ER - TY - JOUR T1 - Two Novel Mutations in the BCKDK Gene (Branched-Chain Keto-Acid Dehydrogenase Kinase) are Responsible of a Neurobehavioral Deficit in two Pediatric Unrelated Patients. JF - Human mutation Y1 - 2014 A1 - García-Cazorla, Angels A1 - Oyarzabal, Alfonso A1 - Fort, Joana A1 - Robles, Concepción A1 - Castejón, Esperanza A1 - Ruiz-Sala, Pedro A1 - Bodoy, Susanna A1 - Merinero, Begoña A1 - Lopez-Sala, Anna A1 - Joaquín Dopazo A1 - Nunes, Virginia A1 - Ugarte, Magdalena A1 - Artuch, Rafael A1 - Palacín, Manuel A1 - Rodríguez-Pombo, Pilar AB - Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain 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-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients’ 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. This article is protected by copyright. All rights reserved. VL - 35 UR - http://onlinelibrary.wiley.com/doi/10.1002/humu.22513/abstract ER - TY - JOUR T1 - Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer. JF - Oncotarget Y1 - 2013 A1 - Puig-Butille, Joan Anton A1 - Escamez, Maria José A1 - Garcia-Garcia, Francisco A1 - Tell-Marti, Gemma A1 - Fabra, Angels A1 - Martínez-Santamaría, Lucía A1 - Badenas, Celia A1 - Aguilera, Paula A1 - Pevida, Marta A1 - Joaquín Dopazo A1 - Del Rio, Marcela A1 - Puig, Susana AB - Germline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer. We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach. As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson’s, Alzheimer and Huntington. Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development. UR - http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=1444&path%5B%5D=1824 ER - TY - JOUR T1 - Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria. JF - Mol Genet Metab Y1 - 2013 A1 - Tort, Frederic A1 - García-Silva, María Teresa A1 - Ferrer-Cortès, Xènia A1 - Navarro-Sastre, Aleix A1 - Garcia-Villoria, Judith A1 - Coll, Maria Josep A1 - Vidal, Enrique A1 - Jiménez-Almazán, Jorge A1 - Dopazo, Joaquin A1 - Briones, Paz A1 - Elpeleg, Orly A1 - Ribes, Antonia KW - Adolescent KW - Adult KW - Carboxylic Ester Hydrolases KW - Child KW - Exome KW - Female KW - High-Throughput Nucleotide Sequencing KW - Humans KW - Infant KW - Male KW - Metabolism, Inborn Errors KW - mutation AB -

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'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.

VL - 110 IS - 1-2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/23707711?dopt=Abstract ER - TY - JOUR T1 - Genome Maps, a new generation genome browser. JF - Nucleic acids research Y1 - 2013 A1 - Medina, Ignacio A1 - Salavert, Francisco A1 - Sánchez, Rubén A1 - De Maria, Alejandro A1 - Alonso, Roberto A1 - Escobar, Pablo A1 - Bleda, Marta A1 - Joaquín Dopazo KW - BAM KW - genome viewer KW - HTML5 KW - javascript KW - Next Generation Sequencing KW - NGS KW - SVG KW - VCF AB - Genome browsers have gained importance as more genomes and related genomic information become available. However, the increase of information brought about by new generation sequencing technologies is, at the same time, causing a subtle but continuous decrease in the efficiency of conventional genome browsers. Here, we present Genome Maps, a genome browser that implements an innovative model of data transfer and management. The program uses highly efficient technologies from the new HTML5 standard, such as scalable vector graphics, that optimize workloads at both server and client sides and ensure future scalability. Thus, data management and representation are entirely carried out by the browser, without the need of any Java Applet, Flash or other plug-in technology installation. Relevant biological data on genes, transcripts, exons, regulatory features, single-nucleotide polymorphisms, karyotype and so forth, are imported from web services and are available as tracks. In addition, several DAS servers are already included in Genome Maps. As a novelty, this web-based genome browser allows the local upload of huge genomic data files (e.g. VCF or BAM) that can be dynamically visualized in real time at the client side, thus facilitating the management of medical data affected by privacy restrictions. Finally, Genome Maps can easily be integrated in any web application by including only a few lines of code. Genome Maps is an open source collaborative initiative available in the GitHub repository (https://github.com/compbio-bigdata-viz/genome-maps). Genome Maps is available at: http://www.genomemaps.org. VL - 41 UR - http://nar.oxfordjournals.org/content/41/W1/W41 ER - TY - JOUR T1 - Intrauterine growth restriction is associated with cardiac ultrastructural and gene expression changes related to the energetic metabolism in a rabbit model. JF - Am J Physiol Heart Circ Physiol Y1 - 2013 A1 - González-Tendero, Anna A1 - Torre, Iratxe A1 - García-Cañadilla, Patricia A1 - Crispi, Fátima A1 - Garcia-Garcia, Francisco A1 - Dopazo, Joaquin A1 - Bijnens, Bart A1 - Gratacós, Eduard KW - Animals KW - Disease Models, Animal KW - Energy Metabolism KW - Female KW - Fetal Growth Retardation KW - gene expression KW - Mitochondria KW - Myocardium KW - Oxidative Phosphorylation KW - Placenta KW - Pregnancy KW - Rabbits AB -

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.

VL - 305 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/24097427?dopt=Abstract ER - TY - JOUR T1 - Mammosphere formation in breast carcinoma cell lines depends upon expression of E-cadherin. JF - PLoS One Y1 - 2013 A1 - Manuel Iglesias, Juan A1 - Beloqui, Izaskun A1 - Garcia-Garcia, Francisco A1 - Leis, Olatz A1 - Vazquez-Martin, Alejandro A1 - Eguiara, Arrate A1 - Cufi, Silvia A1 - Pavon, Andres A1 - Menendez, Javier A A1 - Dopazo, Joaquin A1 - Martin, Angel G KW - Breast Neoplasms KW - Cadherins KW - Cell Line, Tumor KW - Cell Proliferation KW - Cluster Analysis KW - Female KW - gene expression KW - Gene Expression Profiling KW - Gene Expression Regulation, Neoplastic KW - Gene Knockdown Techniques KW - Humans KW - MCF-7 Cells KW - Neoplastic Stem Cells KW - Spheroids, Cellular KW - Tumor Cells, Cultured AB -

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.

VL - 8 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/24124614?dopt=Abstract ER - TY - JOUR T1 - Mammosphere Formation in Breast Carcinoma Cell Lines Depends upon Expression of E-cadherin JF - PLoS ONE Y1 - 2013 A1 - Manuel Iglesias, Juan A1 - Beloqui, Izaskun A1 - Garcia-Garcia, Francisco A1 - Leis, Olatz A1 - Vazquez-Martin, Alejandro A1 - Eguiara, Arrate A1 - Cufi, Silvia A1 - Pavon, Andres A1 - Menendez, Javier A. A1 - Dopazo, Joaquin A1 - Martin, Angel G. AB -

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.

PB - Public Library of Science VL - 8 UR - http://dx.doi.org/10.1371%2Fjournal.pone.0077281 ER - TY - CONF T1 - Multicore and Cloud-based Solutions for Genomic Variant Analysis T2 - Proceedings of the 18th International Conference on Parallel Processing Workshops Y1 - 2013 A1 - Gonzalez, Cristina Y. A1 - Bleda, Marta A1 - Salavert, Francisco A1 - Sánchez, Rubén A1 - Dopazo, Joaquin A1 - Medina, Ignacio KW - genomic variant analysis KW - multicore KW - mutation KW - OpenMP KW - web service JF - Proceedings of the 18th International Conference on Parallel Processing Workshops PB - Springer-Verlag CY - Berlin, Heidelberg SN - 978-3-642-36948-3 UR - http://dx.doi.org/10.1007/978-3-642-36949-0_30 ER - TY - JOUR T1 - Novel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome. JF - Clin Chim Acta Y1 - 2013 A1 - Silbiger, Vivian N A1 - Luchessi, André D A1 - Hirata, Rosário D C A1 - Lima-Neto, Lídio G A1 - Cavichioli, Débora A1 - Carracedo, Ángel A1 - Brión, Maria A1 - Dopazo, Joaquin A1 - Garcia-Garcia, Francisco A1 - Dos Santos, Elizabete S A1 - Ramos, Rui F A1 - Sampaio, Marcelo F A1 - Armaganijan, Dikran A1 - Sousa, Amanda G M R A1 - Hirata, Mario H KW - Acute Coronary Syndrome KW - Acute-Phase Proteins KW - Adult KW - biomarkers KW - Blood Cells KW - Early Diagnosis KW - gene expression KW - Gene Expression Profiling KW - Humans KW - Male KW - Middle Aged KW - Oligonucleotide Array Sequence Analysis KW - RNA, Messenger KW - Transcriptome AB -

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.

VL - 421 U1 - https://www.ncbi.nlm.nih.gov/pubmed/23535507?dopt=Abstract ER - TY - JOUR T1 - Novel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome: Transcriptional profiling of acute coronary syndrome. JF - Clinica chimica acta; international journal of clinical chemistry Y1 - 2013 A1 - Silbiger, Vivian N A1 - Luchessi, André D A1 - Hirata, Rosário D C A1 - Lima-Neto, Lídio G A1 - Cavichioli, Débora A1 - Carracedo, Ángel A1 - Brión, Maria A1 - Joaquín Dopazo A1 - Garcia-Garcia, Francisco A1 - Dos Santos, Elizabete S A1 - Ramos, Rui F A1 - Sampaio, Marcelo F A1 - Armaganijan, Dikran A1 - Sousa, Amanda G M R A1 - Hirata, Mario H AB - {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 ER - TY - JOUR T1 - Pathways systematically associated to Hirschsprung’s disease. JF - Orphanet journal of rare diseases Y1 - 2013 A1 - Fernández, Raquel M A1 - Bleda, Marta A1 - Luzón-Toro, Berta A1 - García-Alonso, Luz A1 - Arnold, Stacey A1 - Sribudiani, Yunia A1 - Besmond, Claude A1 - Lantieri, Francesca A1 - Doan, Betty A1 - Ceccherini, Isabella A1 - Lyonnet, Stanislas A1 - Hofstra, Robert Mw A1 - Chakravarti, Aravinda A1 - Antiňolo, Guillermo A1 - Joaquín Dopazo A1 - Borrego, Salud KW - GWAS KW - Hirschprung KW - network analysis KW - Pathway Based Analysis AB - Despite it has been reported that several loci are involved in Hirschsprung’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’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. VL - 8 UR - http://www.ojrd.com/content/8/1/187/abstract ER - TY - JOUR T1 - Pathways systematically associated to Hirschsprung's disease. JF - Orphanet J Rare Dis Y1 - 2013 A1 - Fernández, Raquel M A1 - Bleda, Marta A1 - Luzón-Toro, Berta A1 - García-Alonso, Luz A1 - Arnold, Stacey A1 - Sribudiani, Yunia A1 - Besmond, Claude A1 - Lantieri, Francesca A1 - Doan, Betty A1 - Ceccherini, Isabella A1 - Lyonnet, Stanislas A1 - Hofstra, Robert Mw A1 - Chakravarti, Aravinda A1 - Antiňolo, Guillermo A1 - Dopazo, Joaquin A1 - Borrego, Salud KW - Female KW - Genetic Predisposition to Disease KW - Genotype KW - Hirschsprung Disease KW - Humans KW - Male KW - Polymorphism, Single Nucleotide AB -

Despite it has been reported that several loci are involved in Hirschsprung'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'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.

VL - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/24289864?dopt=Abstract ER - TY - JOUR T1 - Whole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa. JF - Molecular vision Y1 - 2013 A1 - Méndez-Vidal, Cristina A1 - González-del Pozo, María A1 - Vela-Boza, Alicia A1 - Santoyo-López, Javier A1 - López-Domingo, Francisco J A1 - Vázquez-Marouschek, Carmen A1 - Dopazo, Joaquin A1 - Borrego, Salud A1 - Antiňolo, Guillermo AB - 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×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. VL - 19 UR - http://www.molvis.org/molvis/v19/2187/ ER - TY - JOUR T1 - CellBase, a comprehensive collection of RESTful web services for retrieving relevant biological information from heterogeneous sources. JF - Nucleic acids research Y1 - 2012 A1 - Bleda, Marta A1 - Tárraga, Joaquín A1 - De Maria, Alejandro A1 - Salavert, Francisco A1 - García-Alonso, Luz A1 - Celma, Matilde A1 - Martin, Ainoha A1 - Dopazo, Joaquin A1 - Medina, Ignacio AB - 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. VL - 40 UR - http://nar.oxfordjournals.org/content/40/W1/W609.long ER - TY - JOUR T1 - Development, Characterization and Experimental Validation of a Cultivated Sunflower (Helianthus annuus L.) Gene Expression Oligonucleotide Microarray. JF - PloS one Y1 - 2012 A1 - Fernandez, Paula A1 - Soria, Marcelo A1 - Blesa, David A1 - Dirienzo, Julio A1 - Moschen, Sebastián A1 - Rivarola, Máximo A1 - Clavijo, Bernardo Jose A1 - Gonzalez, Sergio A1 - Peluffo, Lucila A1 - Príncipi, Dario A1 - Dosio, Guillermo A1 - Aguirrezabal, Luis A1 - Garcia-Garcia, Francisco A1 - Ana Conesa A1 - Hopp, Esteban A1 - Joaquín Dopazo A1 - Heinz, Ruth Amelia A1 - Paniego, Norma AB - Oligonucleotide-based microarrays with accurate gene coverage represent a key strategy for transcriptional studies in orphan species such as sunflower, H. annuus L., which lacks full genome sequences. The goal of this study was the development and functional annotation of a comprehensive sunflower unigene collection and the design and validation of a custom sunflower oligonucleotide-based microarray. A large scale EST (>130,000 ESTs) curation, assembly and sequence annotation was performed using Blast2GO (www.blast2go.de). The EST assembly comprises 41,013 putative transcripts (12,924 contigs and 28,089 singletons). The resulting Sunflower Unigen Resource (SUR version 1.0) was used to design an oligonucleotide-based Agilent microarray for cultivated sunflower. This microarray includes a total of 42,326 features: 1,417 Agilent controls, 74 control probes for sunflower replicated 10 times (740 controls) and 40,169 different non-control probes. Microarray performance was validated using a model experiment examining the induction of senescence by water deficit. Pre-processing and differential expression analysis of Agilent microarrays was performed using the Bioconductor limma package. The analyses based on p-values calculated by eBayes (p<0.01) allowed the detection of 558 differentially expressed genes between water stress and control conditions; from these, ten genes were further validated by qPCR. Over-represented ontologies were identified using FatiScan in the Babelomics suite. This work generated a curated and trustable sunflower unigene collection, and a custom, validated sunflower oligonucleotide-based microarray using Agilent technology. Both the curated unigene collection and the validated oligonucleotide microarray provide key resources for sunflower genome analysis, transcriptional studies, and molecular breeding for crop improvement. VL - 7 UR - http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045899 ER - TY - JOUR T1 - Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung’s disease. JF - Orphanet journal of rare diseases Y1 - 2012 A1 - Fernández, Raquel Ma A1 - Bleda, Marta A1 - Núñez-Torres, Rocío A1 - Medina, Ignacio A1 - Luzón-Toro, Berta A1 - García-Alonso, Luz A1 - Torroglosa, Ana A1 - Marbà, Martina A1 - Enguix-Riego, Ma Valle A1 - Montaner, David A1 - Antiňolo, Guillermo A1 - Joaquín Dopazo A1 - Borrego, Salud AB - 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’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. VL - 7 UR - http://www.ojrd.com/content/7/1/103/abstract ER - TY - JOUR T1 - Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung's disease. JF - Orphanet J Rare Dis Y1 - 2012 A1 - Fernández, Raquel Ma A1 - Bleda, Marta A1 - Núñez-Torres, Rocío A1 - Medina, Ignacio A1 - Luzón-Toro, Berta A1 - García-Alonso, Luz A1 - Torroglosa, Ana A1 - Marbà, Martina A1 - Enguix-Riego, Ma Valle A1 - Montaner, David A1 - Antiňolo, Guillermo A1 - Dopazo, Joaquin A1 - Borrego, Salud KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Hirschsprung Disease KW - Humans KW - Male AB -

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'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.

VL - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/23270508?dopt=Abstract ER - TY - JOUR T1 - Inferring the regulatory network behind a gene expression experiment. JF - Nucleic Acids Res Y1 - 2012 A1 - Bleda, Marta A1 - Medina, Ignacio A1 - Alonso, Roberto A1 - De Maria, Alejandro A1 - Salavert, Francisco A1 - Dopazo, Joaquin KW - Binding Sites KW - Databases, Genetic KW - Fanconi Anemia KW - Gene Regulatory Networks KW - Internet KW - MicroRNAs KW - Software KW - Transcription Factors KW - Transcriptome AB -

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/.

VL - 40 IS - Web Server issue U1 - https://www.ncbi.nlm.nih.gov/pubmed/22693210?dopt=Abstract ER - TY - JOUR T1 - A map of human microRNA variation uncovers unexpectedly high levels of variability. JF - Genome medicine Y1 - 2012 A1 - Carbonell, José A1 - Alloza, Eva A1 - Arce, Pablo A1 - Borrego, Salud A1 - Santoyo, Javier A1 - Ruiz-Ferrer, Macarena A1 - Medina, Ignacio A1 - Jiménez-Almazán, Jorge A1 - Méndez-Vidal, Cristina A1 - González-del Pozo, María A1 - Vela, Alicia A1 - Bhattacharya, Shomi S A1 - Antiňolo, Guillermo A1 - Dopazo, Joaquin KW - NGS AB - 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. VL - 4 UR - http://genomemedicine.com/content/4/8/62/abstract ER - TY - JOUR T1 - Transcriptome profiling of the intoxication response of Tenebrio molitor larvae to Bacillus thuringiensis Cry3Aa protoxin. JF - PloS one Y1 - 2012 A1 - Oppert, Brenda A1 - Dowd, Scot E A1 - Bouffard, Pascal A1 - Li, Lewyn A1 - Ana Conesa A1 - Lorenzen, Marcé D A1 - Toutges, Michelle A1 - Marshall, Jeremy A1 - Huestis, Diana L A1 - Fabrick, Jeff A1 - Oppert, Cris A1 - Jurat-Fuentes, Juan Luis KW - Administration KW - Animals KW - Bacterial Proteins KW - Base Sequence KW - Biosynthetic Pathways KW - Complementary KW - DNA KW - Endotoxins KW - Energy Metabolism KW - Gene Expression Profiling KW - Hemolysin Proteins KW - Larva KW - Microarray Analysis KW - Molecular Sequence Data KW - Oral KW - Sequence Analysis KW - Tenebrio KW - Time Factors KW - Transcriptome AB - Bacillus thuringiensis (Bt) crystal (Cry) proteins are effective against a select number of insect pests, but improvements are needed to increase efficacy and decrease time to mortality for coleopteran pests. To gain insight into the Bt intoxication process in Coleoptera, we performed RNA-Seq on cDNA generated from the guts of Tenebrio molitor larvae that consumed either a control diet or a diet containing Cry3Aa protoxin. Approximately 134,090 and 124,287 sequence reads from the control and Cry3Aa-treated groups were assembled into 1,318 and 1,140 contigs, respectively. Enrichment analyses indicated that functions associated with mitochondrial respiration, signalling, maintenance of cell structure, membrane integrity, protein recycling/synthesis, and glycosyl hydrolases were significantly increased in Cry3Aa-treated larvae, whereas functions associated with many metabolic processes were reduced, especially glycolysis, tricarboxylic acid cycle, and fatty acid synthesis. Microarray analysis was used to evaluate temporal changes in gene expression after 6, 12 or 24 h of Cry3Aa exposure. Overall, microarray analysis indicated that transcripts related to allergens, chitin-binding proteins, glycosyl hydrolases, and tubulins were induced, and those related to immunity and metabolism were repressed in Cry3Aa-intoxicated larvae. The 24 h microarray data validated most of the RNA-Seq data. Of the three intoxication intervals, larvae demonstrated more differential expression of transcripts after 12 h exposure to Cry3Aa. Gene expression examined by three different methods in control vs. Cry3Aa-treated larvae at the 24 h time point indicated that transcripts encoding proteins with chitin-binding domain 3 were the most differentially expressed in Cry3Aa-intoxicated larvae. Overall, the data suggest that T. molitor larvae mount a complex response to Cry3Aa during the initial 24 h of intoxication. Data from this study represent the largest genetic sequence dataset for T. molitor to date. Furthermore, the methods in this study are useful for comparative analyses in organisms lacking a sequenced genome. VL - 7 ER - TY - JOUR T1 - Using GPUs for the Exact Alignment of Short-Read Genetic Sequences by Means of the Burrows-Wheeler Transform JF - IEEE/ACM Transactions on Computational Biology and Bioinformatics Y1 - 2012 A1 - Torres, J. S. A1 - Espert, I. B. A1 - Dominguez, A. T. A1 - Garcia, V. Hernendez A1 - Castello, I. Medina A1 - Gimenez, J. Terraga A1 - Blazquez, J. Dopazo VL - 9 UR - http://ieeexplore.ieee.org/document/6175888/http://xplorestaging.ieee.org/ielx5/8857/6202798/06175888.pdf?arnumber=6175888 IS - 4 JO - IEEE/ACM Trans. Comput. Biol. and Bioinf. ER - TY - JOUR T1 - Using GPUs for the exact alignment of short-read genetic sequences by means of the Burrows-Wheeler transform. JF - IEEE/ACM Trans Comput Biol Bioinform Y1 - 2012 A1 - Salavert Torres, Jose A1 - Blanquer Espert, Ignacio A1 - Domínguez, Andrés Tomás A1 - Hernández García, Vicente A1 - Medina Castelló, Ignacio A1 - Tárraga Giménez, Joaquín A1 - Dopazo Blázquez, Joaquín KW - Algorithms KW - Animals KW - Computational Biology KW - Computer Graphics KW - Data Compression KW - Drosophila melanogaster KW - Genes, Insect KW - Image Processing, Computer-Assisted KW - Models, Genetic KW - Sequence Alignment KW - Sequence Analysis, DNA AB -

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 12, when compared to CPU execution. This implementation exploits the parallelism by concurrently searching different sequences on the same reference search tree, maximizing memory locality and ensuring a symmetric access to the data. The paper describes the behavior of the algorithm in GPU, showing a good scalability in the performance, only limited by the size of the GPU inner memory.

VL - 9 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/22450827?dopt=Abstract ER - TY - JOUR T1 - VARIANT: Command Line, Web service and Web interface for fast and accurate functional characterization of variants found by Next-Generation Sequencing. JF - Nucleic Acids Res Y1 - 2012 A1 - Medina, Ignacio A1 - De Maria, Alejandro A1 - Bleda, Marta A1 - Salavert, Francisco A1 - Alonso, Roberto A1 - Gonzalez, Cristina Y A1 - Dopazo, Joaquin KW - Databases, Nucleic Acid KW - Genetic Variation KW - High-Throughput Nucleotide Sequencing KW - Internet KW - Molecular Sequence Annotation KW - mutation KW - Polymorphism, Single Nucleotide KW - Software KW - User-Computer Interface AB -

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.

VL - 40 IS - Web Server issue U1 - https://www.ncbi.nlm.nih.gov/pubmed/22693211?dopt=Abstract ER - TY - JOUR T1 - Analysis of normal-tumour tissue interaction in tumours: prediction of prostate cancer features from the molecular profile of adjacent normal cells. JF - PloS one Y1 - 2011 A1 - Trevino, Victor A1 - Tadesse, Mahlet G A1 - Vannucci, Marina A1 - Fatima Al-Shahrour A1 - Antczak, Philipp A1 - Durant, Sarah A1 - Bikfalvi, Andreas A1 - Dopazo, Joaquin A1 - Campbell, Moray J A1 - Falciani, Francesco AB -

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 TGFβ.

VL - 6 ER - TY - JOUR T1 - Differential Lipid Partitioning Between Adipocytes and Tissue Macrophages Modulates Macrophage Lipotoxicity and M2/M1 Polarization in Obese Mice. JF - Diabetes Y1 - 2011 A1 - Prieur, Xavier A1 - Mok, Crystal Y L A1 - Velagapudi, Vidya R A1 - Núñez, Vanessa A1 - Fuentes, Lucía A1 - Montaner, David A1 - Ishikawa, Ko A1 - Camacho, Alberto A1 - Barbarroja, Nuria A1 - O’Rahilly, Stephen A1 - Sethi, Jaswinder A1 - Dopazo, Joaquin A1 - Oresic, Matej A1 - Ricote, Mercedes A1 - Vidal-Puig, Antonio AB -

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.

VL - 60 ER - TY - JOUR T1 - Evolution of the biosynthesis of di-myo-inositol phosphate, a marker of adaptation to hot marine environments. JF - Environmental microbiology Y1 - 2011 A1 - Gonçalves, Luís G A1 - Borges, Nuno A1 - Serra, François A1 - Fernandes, Pedro L A1 - Dopazo, Hernán A1 - Santos, Helena AB -

The synthesis of di-myo-inositol phosphate (DIP), a common compatible solute in hyperthermophiles, involves the consecutive actions of inositol-1-phosphate cytidylyltransferase (IPCT) and di-myo-inositol phosphate phosphate synthase (DIPPS). In most cases, both activities are present in a single gene product, but separate genes are also found in a few organisms. Genes for IPCT and DIPPS were found in the genomes of 33 organisms, all with thermophilic/hyperthermophilic lifestyles. Phylogeny of IPCT/DIPPS revealed an incongruent topology with 16S RNA phylogeny, thus suggesting horizontal gene transfer. The phylogenetic tree of the DIPPS domain was rooted by using phosphatidylinositol phosphate synthase sequences as out-group. The root locates at the separation of genomes with fused and split genes. We propose that the gene encoding DIPPS was recruited from the biosynthesis of phosphatidylinositol. The last DIP-synthesizing ancestor harboured separated genes for IPCT and DIPPS and this architecture was maintained in a crenarchaeal lineage, and transferred by horizontal gene transfer to hyperthermophilic marine Thermotoga species. It is plausible that the driving force for the assembly of those two genes in the early ancestor is related to the acquired advantage of DIP producers to cope with high temperature. This work corroborates the view that Archaea were the first hyperthermophilic organisms.

ER - TY - JOUR T1 - An evolutionary trade-off between protein turnover rate and protein aggregation favors a higher aggregation propensity in fast degrading proteins. JF - PLoS computational biology Y1 - 2011 A1 - De Baets, Greet A1 - Reumers, Joke A1 - Delgado Blanco, Javier A1 - Dopazo, Joaquin A1 - Schymkowitz, Joost A1 - Rousseau, Frederic AB -

We previously showed the existence of selective pressure against protein aggregation by the enrichment of aggregation-opposing ’gatekeeper’ 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.

VL - 7 ER - TY - JOUR T1 - Histone modifications and expression of DAM6 gene in peach are modulated during bud dormancy release in a cultivar-dependent manner. JF - The New phytologist Y1 - 2011 A1 - Leida, Carmen A1 - Ana Conesa A1 - Llácer, Gerardo A1 - Badenes, María Luisa A1 - Ríos, Gabino AB -

• Bud dormancy release in many woody perennial plants responds to the seasonal accumulation of chilling stimulus. MADS-box transcription factors encoded by DORMANCY ASSOCIATED MADS-box (DAM) genes in peach (Prunus persica) are implicated in this pathway, but other regulatory factors remain to be identified. In addition, the regulation of DAM gene expression is not well known at the molecular level. • A microarray hybridization approach was performed to identify genes whose expression correlates with the bud dormancy-related behaviour in 10 different peach cultivars. Histone modifications in DAM6 gene were investigated by chromatin immunoprecipitation in two different cultivars. • The expression of DAM4-DAM6 and several genes related to abscisic acid and drought stress response correlated with the dormancy behaviour of peach cultivars. The trimethylation of histone H3 at K27 in the DAM6 promoter, coding region and the second large intron was preceded by a decrease in acetylated H3 and trimethylated H3K4 in the region of translation start, coinciding with repression of DAM6 during dormancy release. • Analysis of chromatin modifications reinforced the role of epigenetic mechanisms in DAM6 regulation and bud dormancy release, and highlighted common features with the vernalization process in Arabidopsis thaliana and cereals.

ER - TY - JOUR T1 - Large-scale transcriptional profiling and functional assays reveal important roles for Rho-GTPase signalling and SCL during haematopoietic differentiation of human embryonic stem cells. JF - Hum Mol Genet Y1 - 2011 A1 - Yung, Sun A1 - Ledran, Maria A1 - Moreno-Gimeno, Inmaculada A1 - Conesa, Ana A1 - Montaner, David A1 - Dopazo, Joaquin A1 - Dimmick, Ian A1 - Slater, Nicholas J A1 - Marenah, Lamin A1 - Real, Pedro J A1 - Paraskevopoulou, Iliana A1 - Bisbal, Viviana A1 - Burks, Deborah A1 - Santibanez-Koref, Mauro A1 - Moreno, Ruben A1 - Mountford, Joanne A1 - Menendez, Pablo A1 - Armstrong, Lyle A1 - Lako, Majlinda KW - Acute Disease KW - Anemia, Hemolytic KW - Animals KW - Basic Helix-Loop-Helix Transcription Factors KW - Cell Differentiation KW - Cell Line KW - Cell Lineage KW - Cluster Analysis KW - Embryonic Stem Cells KW - Erythroid Cells KW - Flow Cytometry KW - Gene Expression Profiling KW - Hematopoietic Stem Cells KW - Humans KW - Mice KW - Myeloid Cells KW - Paracrine Communication KW - Proto-Oncogene Proteins KW - Reverse Transcriptase Polymerase Chain Reaction KW - rho GTP-Binding Proteins KW - Signal Transduction KW - Stem Cell Transplantation KW - T-Cell Acute Lymphocytic Leukemia Protein 1 KW - Transcriptome AB -

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.

VL - 20 IS - 24 U1 - https://www.ncbi.nlm.nih.gov/pubmed/21937587?dopt=Abstract ER - TY - JOUR T1 - Mutation screening of multiple genes in Spanish patients with autosomal recessive retinitis pigmentosa by targeted resequencing. JF - PLoS One Y1 - 2011 A1 - González-del Pozo, María A1 - Borrego, Salud A1 - Barragán, Isabel A1 - Pieras, Juan I A1 - Santoyo, Javier A1 - Matamala, Nerea A1 - Naranjo, Belén A1 - Dopazo, Joaquin A1 - Antiňolo, Guillermo KW - Alleles KW - DNA Mutational Analysis KW - Exons KW - Genetic Variation KW - Genome KW - Hispanic or Latino KW - Humans KW - Introns KW - Language KW - mutation KW - Mutation, Missense KW - Oligonucleotide Array Sequence Analysis KW - Polymerase Chain Reaction KW - Reproducibility of Results KW - Retinitis pigmentosa KW - United States AB -

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.

VL - 6 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/22164218?dopt=Abstract ER - TY - JOUR T1 - N-glycosylation efficiency is determined by the distance to the C-terminus and the amino acid preceding an Asn-Ser-Thr sequon. JF - Protein science : a publication of the Protein Society Y1 - 2011 A1 - Bañó-Polo, Manuel A1 - Baldin, Francesca A1 - Tamborero, Silvia A1 - Marti-Renom, Marc A A1 - Mingarro, Ismael AB -

N-glycosylation is the most common and versatile protein modification. In eukaryotic cells, this modification is catalyzed cotranslationally by the enzyme oligosaccharyltransferase, which targets the β-amide of the asparagine in an Asn-Xaa-Ser/Thr consensus sequon (where Xaa is any amino acid but proline) in nascent proteins as they enter the endoplasmic reticulum. Because modification of the glycosylation acceptor site on membrane proteins occurs in a compartment-specific manner, the presence of glycosylation is used to indicate membrane protein topology. Moreover, glycosylation sites can be added to gain topological information. In this study, we explored the determinants of N-glycosylation with the in vitro transcription/translation of a truncated model protein in the presence of microsomes and surveyed 25,488 glycoproteins, of which 2,533 glycosylation sites had been experimentally validated. We found that glycosylation efficiency was dependent on both the distance to the C-terminus and the nature of the amino acid that preceded the consensus sequon. These findings establish a broadly applicable method for membrane protein tagging in topological studies.

VL - 20 ER - TY - JOUR T1 - Recent human evolution has shaped geographical differences in susceptibility to disease. JF - BMC genomics Y1 - 2011 A1 - Marigorta, Urko M A1 - Lao, Oscar A1 - Casals, Ferran A1 - Calafell, Francesc A1 - Morcillo-Suarez, Carlos A1 - Faria, Rui A1 - Bosch, Elena A1 - Serra, François A1 - Bertranpetit, Jaume A1 - Dopazo, Hernán A1 - Navarro, Arcadi AB -

Searching for associations between genetic variants and complex diseases has been a very active area of research for over two decades. More than 51,000 potential associations have been studied and published, a figure that keeps increasing, especially with the recent explosion of array-based Genome-Wide Association Studies. Even if the number of true associations described so far is high, many of the putative risk variants detected so far have failed to be consistently replicated and are widely considered false positives. Here, we focus on the world-wide patterns of replicability of published association studies.

VL - 12 ER - TY - JOUR T1 - Role of tomato BRANCHED1-like genes in the control of shoot branching. JF - The Plant journal : for cell and molecular biology Y1 - 2011 A1 - Martín-Trillo, Mar A1 - Grandío, Eduardo González A1 - Serra, François A1 - Marcel, Fabien A1 - Rodríguez-Buey, María Luisa A1 - Schmitz, Gregor A1 - Theres, Klaus A1 - Bendahmane, Abdelhafid A1 - Dopazo, Hernán A1 - Cubas, Pilar AB -

In angiosperms, shoot branching greatly determines overall plant architecture and affects fundamental aspects of plant life. Branching patterns are determined by genetic pathways conserved widely across angiosperms. In Arabidopsis thaliana (Brassicaceae, Rosidae) BRANCHED1 (BRC1) plays a central role in this process, acting locally to arrest axillary bud growth. In tomato (Solanum lycopersicum, Solanaceae, Asteridae) we have identified two BRC1-like paralogues, SlBRC1a and SlBRC1b. These genes are expressed in arrested axillary buds and both are down-regulated upon bud activation, although SlBRC1a is transcribed at much lower levels than SlBRC1b. Alternative splicing of SlBRC1a renders two transcripts that encode two BRC1-like proteins with different C-t domains due to a 3’-terminal frameshift. The phenotype of loss-of-function lines suggests that SlBRC1b has retained the ancestral role of BRC1 in shoot branch suppression. We have isolated the BRC1a and BRC1b genes of other Solanum species and have studied their evolution rates across the lineages. These studies indicate that, after duplication of an ancestral BRC1-like gene, BRC1b genes continued to evolve under a strong purifying selection that was consistent with the conserved function of SlBRC1b in shoot branching control. In contrast, the coding sequences of Solanum BRC1a genes have evolved at a higher evolution rate. Branch-site tests indicate that this difference does not reflect relaxation but rather positive selective pressure for adaptation.

VL - 67 ER - TY - JOUR T1 - Structure determination of genomic domains by satisfaction of spatial restraints. JF - Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology Y1 - 2011 A1 - Baù, Davide A1 - Marti-Renom, Marc A AB -

The three-dimensional (3D) architecture of a genome is non-random and known to facilitate the spatial colocalization of regulatory elements with the genes they regulate. Determining the 3D structure of a genome may therefore probe an essential step in characterizing how genes are regulated. Currently, there are several experimental and theoretical approaches that aim at determining the 3D structure of genomes and genomic domains; however, approaches integrating experiments and computation to identify the most likely 3D folding of a genome at medium to high resolutions have not been widely explored. Here, we review existing methodologies and propose that the integrative modeling platform ( http://www.integrativemodeling.org ), a computational package developed for structurally characterizing protein assemblies, could be used for integrating diverse experimental data towards the determination of the 3D architecture of genomic domains and entire genomes at unprecedented resolution. Our approach, through the visualization of looping interactions between distal regulatory elements, will allow for the characterization of global chromatin features and their relation to gene expression. We illustrate our work by outlining the recent determination of the 3D architecture of the α-globin domain in the human genome.

VL - 19 ER - TY - JOUR T1 - The three-dimensional folding of the α-globin gene domain reveals formation of chromatin globules. JF - Nature structural & molecular biology Y1 - 2011 A1 - Baù, Davide A1 - Sanyal, Amartya A1 - Lajoie, Bryan R A1 - Capriotti, Emidio A1 - Byron, Meg A1 - Lawrence, Jeanne B A1 - Dekker, Job A1 - Marti-Renom, Marc A AB -

We developed a general approach that combines chromosome conformation capture carbon copy (5C) with the Integrated Modeling Platform (IMP) to generate high-resolution three-dimensional models of chromatin at the megabase scale. We applied this approach to the ENm008 domain on human chromosome 16, containing the α-globin locus, which is expressed in K562 cells and silenced in lymphoblastoid cells (GM12878). The models accurately reproduce the known looping interactions between the α-globin genes and their distal regulatory elements. Further, we find using our approach that the domain folds into a single globular conformation in GM12878 cells, whereas two globules are formed in K562 cells. The central cores of these globules are enriched for transcribed genes, whereas nontranscribed chromatin is more peripheral. We propose that globule formation represents a higher-order folding state related to clustering of transcribed genes around shared transcription machineries, as previously observed by microscopy.

VL - 18 ER - TY - JOUR T1 - Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. JF - Genome research Y1 - 2010 A1 - Javierre, Biola M A1 - Fernandez, Agustin F A1 - Richter, Julia A1 - Fatima Al-Shahrour A1 - Martin-Subero, J Ignacio A1 - Rodriguez-Ubreva, Javier A1 - Berdasco, Maria A1 - Fraga, Mario F A1 - O’Hanlon, Terrance P A1 - Rider, Lisa G A1 - Jacinto, Filipe V A1 - Lopez-Longo, F Javier A1 - Dopazo, Joaquin A1 - Forn, Marta A1 - Peinado, Miguel A A1 - Carreño, Luis A1 - Sawalha, Amr H A1 - Harley, John B A1 - Siebert, Reiner A1 - Esteller, Manel A1 - Miller, Frederick W A1 - Ballestar, Esteban AB -

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.

VL - 20 ER - TY - JOUR T1 - DNA methylation epigenotypes in breast cancer molecular subtypes. JF - Breast Cancer Res Y1 - 2010 A1 - Bediaga, Naiara G A1 - Acha-Sagredo, Amelia A1 - Guerra, Isabel A1 - Viguri, Amparo A1 - Albaina, Carmen A1 - Ruiz Diaz, Irune A1 - Rezola, Ricardo A1 - Alberdi, Maria Jesus A1 - Dopazo, Joaquin A1 - Montaner, David A1 - Renobales, Mertxe A1 - Fernandez, Agustin F A1 - Field, John K A1 - Fraga, Mario F A1 - Liloglou, Triantafillos A1 - de Pancorbo, Marian M KW - Aged KW - Breast Neoplasms KW - CpG Islands KW - DNA Methylation KW - Epigenesis, Genetic KW - Female KW - Gene Expression Profiling KW - Genes, p53 KW - Genotype KW - Humans KW - Ki-67 Antigen KW - Middle Aged KW - mutation KW - Neoplasm Grading KW - Oligonucleotide Array Sequence Analysis KW - Receptor, ErbB-2 KW - Tumor Suppressor Protein p53 AB -

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.

VL - 12 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/20920229?dopt=Abstract ER - TY - JOUR T1 - Exploring the link between germline and somatic genetic alterations in breast carcinogenesis. JF - PLoS One Y1 - 2010 A1 - Bonifaci, Núria A1 - Górski, Bohdan A1 - Masojć, Bartlomiej A1 - Wokołorczyk, Dominika A1 - Jakubowska, Anna A1 - Dębniak, Tadeusz A1 - Berenguer, Antoni A1 - Serra Musach, Jordi A1 - Brunet, Joan A1 - Dopazo, Joaquin A1 - Narod, Steven A A1 - Lubiński, Jan A1 - Lázaro, Conxi A1 - Cybulski, Cezary A1 - Pujana, Miguel Angel KW - Adult KW - Bone Morphogenetic Protein Receptors, Type I KW - Breast KW - Breast Neoplasms KW - Calcium-Calmodulin-Dependent Protein Kinases KW - Case-Control Studies KW - Cyclin-Dependent Kinases KW - Disease Progression KW - Estrogen Receptor alpha KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Germ-Line Mutation KW - Humans KW - Odds Ratio KW - Poland KW - Polymorphism, Single Nucleotide KW - Protein Serine-Threonine Kinases KW - Protein-Tyrosine Kinases KW - Receptor Protein-Tyrosine Kinases KW - Receptor, EphA3 KW - Receptor, EphA7 KW - Receptor, EphB1 KW - Risk Factors AB -

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) = 0.79; 95% confidence interval (CI): 0.63-0.98; P(trend) = 0.031). Analyses by early age at diagnosis and by estrogen receptor α (ERα) tumor status indicated potential associations for rs6852678 in CDKL2 (OR = 0.32, 95% CI: 0.10-1.00; P(recessive) = 0.044) and rs10878640 in DYRK2 (OR = 2.39, 95% CI: 1.32-4.30; P(dominant) = 0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERα 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.

VL - 5 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/21124932?dopt=Abstract ER - TY - JOUR T1 - Fine-scale evolution: genomic, phenotypic and ecological differentiation in two coexisting Salinibacter ruber strains. JF - The ISME journal Y1 - 2010 A1 - Peña, Arantxa A1 - Teeling, Hanno A1 - Huerta-Cepas, Jaime A1 - Santos, Fernando A1 - Yarza, Pablo A1 - Brito-Echeverría, Jocelyn A1 - Lucio, Marianna A1 - Schmitt-Kopplin, Philippe A1 - Meseguer, Inmaculada A1 - Schenowitz, Chantal A1 - Dossat, Carole A1 - Barbe, Valerie A1 - Joaquín Dopazo A1 - Rosselló-Mora, Ramon A1 - Schüler, Margarete A1 - Glöckner, Frank Oliver A1 - Amann, Rudolf A1 - Gabaldón, Toni A1 - Antón, Josefa AB -

Genomic and metagenomic data indicate a high degree of genomic variation within microbial populations, although the ecological and evolutive meaning of this microdiversity remains unknown. Microevolution analyses, including genomic and experimental approaches, are so far very scarce for non-pathogenic bacteria. In this study, we compare the genomes, metabolomes and selected ecological traits of the strains M8 and M31 of the hyperhalophilic bacterium Salinibacter ruber that contain ribosomal RNA (rRNA) gene and intergenic regions that are identical in sequence and were simultaneously isolated from a Mediterranean solar saltern. Comparative analyses indicate that S. ruber genomes present a mosaic structure with conserved and hypervariable regions (HVRs). The HVRs or genomic islands, are enriched in transposases, genes related to surface properties, strain-specific genes and highly divergent orthologous. However, the many indels outside the HVRs indicate that genome plasticity extends beyond them. Overall, 10% of the genes encoded in the M8 genome are absent from M31 and could stem from recent acquisitions. S. ruber genomes also harbor 34 genes located outside HVRs that are transcribed during standard growth and probably derive from lateral gene transfers with Archaea preceding the M8/M31 divergence. Metabolomic analyses, phage susceptibility and competition experiments indicate that these genomic differences cannot be considered neutral from an ecological perspective. The results point to the avoidance of competition by micro-niche adaptation and response to viral predation as putative major forces that drive microevolution within these Salinibacter strains. In addition, this work highlights the extent of bacterial functional diversity and environmental adaptation, beyond the resolution of the 16S rRNA and internal transcribed spacers regions.The ISME Journal advance online publication, 18 February 2010; doi:10.1038/ismej.2010.6.

ER - TY - JOUR T1 - Functional analysis of multiple genomic signatures demonstrates that classification algorithms choose phenotype-related genes. JF - Pharmacogenomics J Y1 - 2010 A1 - Shi, W A1 - Bessarabova, M A1 - Dosymbekov, D A1 - Dezso, Z A1 - Nikolskaya, T A1 - Dudoladova, M A1 - Serebryiskaya, T A1 - Bugrim, A A1 - Guryanov, A A1 - Brennan, R J A1 - Shah, R A1 - Dopazo, J A1 - Chen, M A1 - Deng, Y A1 - Shi, T A1 - Jurman, G A1 - Furlanello, C A1 - Thomas, R S A1 - Corton, J C A1 - Tong, W A1 - Shi, L A1 - Nikolsky, Y KW - Algorithms KW - Databases, Genetic KW - Endpoint Determination KW - Gene Expression Profiling KW - Genomics KW - Humans KW - Neural Networks, Computer KW - Oligonucleotide Array Sequence Analysis KW - Phenotype KW - Predictive Value of Tests KW - Proteins KW - Quality Control AB -

Gene expression signatures of toxicity and clinical response benefit both safety assessment and clinical practice; however, difficulties in connecting signature genes with the predicted end points have limited their application. The Microarray Quality Control Consortium II (MAQCII) project generated 262 signatures for ten clinical and three toxicological end points from six gene expression data sets, an unprecedented collection of diverse signatures that has permitted a wide-ranging analysis on the nature of such predictive models. A comprehensive analysis of the genes of these signatures and their nonredundant unions using ontology enrichment, biological network building and interactome connectivity analyses demonstrated the link between gene signatures and the biological basis of their predictive power. Different signatures for a given end point were more similar at the level of biological properties and transcriptional control than at the gene level. Signatures tended to be enriched in function and pathway in an end point and model-specific manner, and showed a topological bias for incoming interactions. Importantly, the level of biological similarity between different signatures for a given end point correlated positively with the accuracy of the signature predictions. These findings will aid the understanding, and application of predictive genomic signatures, and support their broader application in predictive medicine.

VL - 10 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/20676069?dopt=Abstract ER - TY - JOUR T1 - Hypoxia promotes efficient differentiation of human embryonic stem cells to functional endothelium. JF - Stem Cells Y1 - 2010 A1 - Prado-Lopez, Sonia A1 - Conesa, Ana A1 - Armiñán, Ana A1 - Martínez-Losa, Magdalena A1 - Escobedo-Lucea, Carmen A1 - Gandia, Carolina A1 - Tarazona, Sonia A1 - Melguizo, Dario A1 - Blesa, David A1 - Montaner, David A1 - Sanz-González, Silvia A1 - Sepúlveda, Pilar A1 - Götz, Stefan A1 - O'Connor, José Enrique A1 - Moreno, Ruben A1 - Dopazo, Joaquin A1 - Burks, Deborah J A1 - Stojkovic, Miodrag KW - Angiopoietin-1 KW - Animals KW - biomarkers KW - Cell Culture Techniques KW - Cell Differentiation KW - Cell Hypoxia KW - Cell Transplantation KW - Cells, Cultured KW - Down-Regulation KW - Embryonic Stem Cells KW - Endothelial Cells KW - Gene Expression Profiling KW - Gene Expression Regulation KW - Humans KW - Male KW - Myocardial Infarction KW - Neovascularization, Physiologic KW - Oxygen KW - Pluripotent Stem Cells KW - Rats KW - Rats, Nude KW - Vascular Endothelial Growth Factor A AB -

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.

VL - 28 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/20049902?dopt=Abstract ER - TY - JOUR T1 - The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models. JF - Nature biotechnology Y1 - 2010 A1 - Shi, Leming A1 - Campbell, Gregory A1 - Jones, Wendell D A1 - Campagne, Fabien A1 - Wen, Zhining A1 - Walker, Stephen J A1 - Su, Zhenqiang A1 - Chu, Tzu-Ming A1 - Goodsaid, Federico M A1 - Pusztai, Lajos A1 - Shaughnessy, John D A1 - Oberthuer, André A1 - Thomas, Russell S A1 - Paules, Richard S A1 - Fielden, Mark A1 - Barlogie, Bart A1 - Chen, Weijie A1 - Du, Pan A1 - Fischer, Matthias A1 - Furlanello, Cesare A1 - Gallas, Brandon D A1 - Ge, Xijin A1 - Megherbi, Dalila B A1 - Symmans, W Fraser A1 - Wang, May D A1 - Zhang, John A1 - Bitter, Hans A1 - Brors, Benedikt A1 - Bushel, Pierre R A1 - Bylesjo, Max A1 - Chen, Minjun A1 - Cheng, Jie A1 - Cheng, Jing A1 - Chou, Jeff A1 - Davison, Timothy S A1 - Delorenzi, Mauro A1 - Deng, Youping A1 - Devanarayan, Viswanath A1 - Dix, David J A1 - Dopazo, Joaquin A1 - Dorff, Kevin C A1 - Elloumi, Fathi A1 - Fan, Jianqing A1 - Fan, Shicai A1 - Fan, Xiaohui A1 - Fang, Hong A1 - Gonzaludo, Nina A1 - Hess, Kenneth R A1 - Hong, Huixiao A1 - Huan, Jun A1 - Irizarry, Rafael A A1 - Judson, Richard A1 - Juraeva, Dilafruz A1 - Lababidi, Samir A1 - Lambert, Christophe G A1 - Li, Li A1 - Li, Yanen A1 - Li, Zhen A1 - Lin, Simon M A1 - Liu, Guozhen A1 - Lobenhofer, Edward K A1 - Luo, Jun A1 - Luo, Wen A1 - McCall, Matthew N A1 - Nikolsky, Yuri A1 - Pennello, Gene A A1 - Perkins, Roger G A1 - Philip, Reena A1 - Popovici, Vlad A1 - Price, Nathan D A1 - Qian, Feng A1 - Scherer, Andreas A1 - Shi, Tieliu A1 - Shi, Weiwei A1 - Sung, Jaeyun A1 - Thierry-Mieg, Danielle A1 - Thierry-Mieg, Jean A1 - Thodima, Venkata A1 - Trygg, Johan A1 - Vishnuvajjala, Lakshmi A1 - Wang, Sue Jane A1 - Wu, Jianping A1 - Wu, Yichao A1 - Xie, Qian A1 - Yousef, Waleed A A1 - Zhang, Liang A1 - Zhang, Xuegong A1 - Zhong, Sheng A1 - Zhou, Yiming A1 - Zhu, Sheng A1 - Arasappan, Dhivya A1 - Bao, Wenjun A1 - Lucas, Anne Bergstrom A1 - Berthold, Frank A1 - Brennan, Richard J A1 - Buness, Andreas A1 - Catalano, Jennifer G A1 - Chang, Chang A1 - Chen, Rong A1 - Cheng, Yiyu A1 - Cui, Jian A1 - Czika, Wendy A1 - Demichelis, Francesca A1 - Deng, Xutao A1 - Dosymbekov, Damir A1 - Eils, Roland A1 - Feng, Yang A1 - Fostel, Jennifer A1 - Fulmer-Smentek, Stephanie A1 - Fuscoe, James C A1 - Gatto, Laurent A1 - Ge, Weigong A1 - Goldstein, Darlene R A1 - Guo, Li A1 - Halbert, Donald N A1 - Han, Jing A1 - Harris, Stephen C A1 - Hatzis, Christos A1 - Herman, Damir A1 - Huang, Jianping A1 - Jensen, Roderick V A1 - Jiang, Rui A1 - Johnson, Charles D A1 - Jurman, Giuseppe A1 - Kahlert, Yvonne A1 - Khuder, Sadik A A1 - Kohl, Matthias A1 - Li, Jianying A1 - Li, Li A1 - Li, Menglong A1 - Li, Quan-Zhen A1 - Li, Shao A1 - Li, Zhiguang A1 - Liu, Jie A1 - Liu, Ying A1 - Liu, Zhichao A1 - Meng, Lu A1 - Madera, Manuel A1 - Martinez-Murillo, Francisco A1 - Medina, Ignacio A1 - Meehan, Joseph A1 - Miclaus, Kelci A1 - Moffitt, Richard A A1 - Montaner, David A1 - Mukherjee, Piali A1 - Mulligan, George J A1 - Neville, Padraic A1 - Nikolskaya, Tatiana A1 - Ning, Baitang A1 - Page, Grier P A1 - Parker, Joel A1 - Parry, R Mitchell A1 - Peng, Xuejun A1 - Peterson, Ron L A1 - Phan, John H A1 - Quanz, Brian A1 - Ren, Yi A1 - Riccadonna, Samantha A1 - Roter, Alan H A1 - Samuelson, Frank W A1 - Schumacher, Martin M A1 - Shambaugh, Joseph D A1 - Shi, Qiang A1 - Shippy, Richard A1 - Si, Shengzhu A1 - Smalter, Aaron A1 - Sotiriou, Christos A1 - Soukup, Mat A1 - Staedtler, Frank A1 - Steiner, Guido A1 - Stokes, Todd H A1 - Sun, Qinglan A1 - Tan, Pei-Yi A1 - Tang, Rong A1 - Tezak, Zivana A1 - Thorn, Brett A1 - Tsyganova, Marina A1 - Turpaz, Yaron A1 - Vega, Silvia C A1 - Visintainer, Roberto A1 - von Frese, Juergen A1 - Wang, Charles A1 - Wang, Eric A1 - Wang, Junwei A1 - Wang, Wei A1 - Westermann, Frank A1 - Willey, James C A1 - Woods, Matthew A1 - Wu, Shujian A1 - Xiao, Nianqing A1 - Xu, Joshua A1 - Xu, Lei A1 - Yang, Lun A1 - Zeng, Xiao A1 - Zhang, Jialu A1 - Zhang, Li A1 - Zhang, Min A1 - Zhao, Chen A1 - Puri, Raj K A1 - Scherf, Uwe A1 - Tong, Weida A1 - Wolfinger, Russell D AB -

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.

VL - 28 UR - http://www.nature.com/nbt/journal/v28/n8/full/nbt.1665.html ER - TY - JOUR T1 - Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa. JF - Hum Mutat Y1 - 2010 A1 - Barragán, Isabel A1 - Borrego, Salud A1 - Pieras, Juan Ignacio A1 - González-del Pozo, María A1 - Santoyo, Javier A1 - Ayuso, Carmen A1 - Baiget, Montserrat A1 - Millán, José M A1 - Mena, Marcela A1 - Abd El-Aziz, Mai M A1 - Audo, Isabelle A1 - Zeitz, Christina A1 - Littink, Karin W A1 - Dopazo, Joaquin A1 - Bhattacharya, Shomi S A1 - Antiňolo, Guillermo KW - Amino Acid Sequence KW - Animals KW - Case-Control Studies KW - DNA Mutational Analysis KW - Drosophila Proteins KW - Evolution, Molecular KW - Eye Proteins KW - Female KW - Genes, Recessive KW - Genetic Variation KW - Humans KW - Male KW - Molecular Sequence Data KW - mutation KW - Pedigree KW - Polymorphism, Single Nucleotide KW - Protein Structure, Tertiary KW - Retinitis pigmentosa KW - Spain KW - Structural Homology, Protein AB -

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.

VL - 31 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/21069908?dopt=Abstract ER - TY - JOUR T1 - Analysis of chronic lymphotic leukemia transcriptomic profile: differences between molecular subgroups JF - Leuk Lymphoma Y1 - 2009 A1 - Jantus Lewintre, E. A1 - Reinoso Martin, C. A1 - Montaner, D. A1 - Marin, M. A1 - Jose Terol, M. A1 - Farras, R. A1 - Benet, I. A1 - Calvete, J. J. A1 - Dopazo, J. A1 - Garcia-Conde, J. KW - cancer KW - microarray data analysis AB -

B cell chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder with a variable clinical course. Patients with unmutated IgV(H) gene show a shorter progression-free and overall survival than patients with immunoglobulin heavy chain variable regions (IgV(H)) gene mutated. In addition, BCL6 mutations identify a subgroup of patients with high risk of progression. Gene expression was analysed in 36 early-stage patients using high-density microarrays. Around 150 genes differentially expressed were found according to IgV(H) mutations, whereas no difference was found according to BCL6 mutations. Functional profiling methods allowed us to distinguish KEGG and gene ontology terms showing coordinated gene expression changes across subgroups of CLL. We validated a set of differentially expressed genes according to IgV(H) status, scoring them as putative prognostic markers in CLL. Among them, CRY1, LPL, CD82 and DUSP22 are the ones with at least equal or superior performance to ZAP70 which is actually the most used surrogate marker of IgV(H) status.

VL - 50 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19127482 N1 -

Jantus Lewintre, Eloisa Reinoso Martin, Cristina Montaner, David Marin, Miguel Jose Terol, Maria Farras, Rosa Benet, Isabel Calvete, Juan J Dopazo, Joaquin Garcia-Conde, Javier Research Support, Non-U.S. Gov’t England Leukemia & lymphoma Leuk Lymphoma. 2009 Jan;50(1):68-79.

ER - TY - JOUR T1 - Gene set-based analysis of polymorphisms: finding pathways or biological processes associated to traits in genome-wide association studies JF - Nucl. Acids Res. Y1 - 2009 A1 - Medina, Ignacio A1 - Montaner, David A1 - Bonifaci, Núria A1 - Pujana, Miguel Angel A1 - Carbonell, José A1 - Tárraga, Joaquín A1 - Fatima Al-Shahrour A1 - Dopazo, Joaquin KW - babelomics KW - gene set KW - GESBAP KW - pathway-based analysis KW - SNP AB -

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/

VL - 37 UR - http://nar.oxfordjournals.org/cgi/content/abstract/37/suppl_2/W340 ER - TY - JOUR T1 - Gene set-based analysis of polymorphisms: finding pathways or biological processes associated to traits in genome-wide association studies. JF - Nucleic Acids Res Y1 - 2009 A1 - Medina, Ignacio A1 - Montaner, David A1 - Bonifaci, Núria A1 - Pujana, Miguel Angel A1 - Carbonell, José A1 - Tárraga, Joaquín A1 - Al-Shahrour, Fátima A1 - Dopazo, Joaquin KW - Biological Phenomena KW - Breast Neoplasms KW - Female KW - Genes KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Software KW - User-Computer Interface AB -

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/.

VL - 37 IS - Web Server issue U1 - https://www.ncbi.nlm.nih.gov/pubmed/19502494?dopt=Abstract ER - TY - JOUR T1 - Membrane transporters and carbon metabolism implicated in chloride homeostasis differentiate salt stress responses in tolerant and sensitive Citrus rootstocks JF - Funct Integr Genomics Y1 - 2009 A1 - Brumos, J. A1 - Colmenero-Flores, J. M. A1 - A. Conesa A1 - Izquierdo, P. A1 - Sanchez, G. A1 - Iglesias, D. J. A1 - Lopez-Climent, M. F. A1 - Gomez-Cadenas, A. A1 - Talon, M. AB -

Salinity tolerance in Citrus is strongly related to leaf chloride accumulation. Both chloride homeostasis and specific genetic responses to Cl(-) toxicity are issues scarcely investigated in plants. To discriminate the transcriptomic network related to Cl(-) toxicity and salinity tolerance, we have used two Cl(-) salt treatments (NaCl and KCl) to perform a comparative microarray approach on two Citrus genotypes, the salt-sensitive Carrizo citrange, a poor Cl(-) excluder, and the tolerant Cleopatra mandarin, an efficient Cl(-) excluder. The data indicated that Cl(-) toxicity, rather than Na(+) toxicity and/or the concomitant osmotic perturbation, is the primary factor involved in the molecular responses of citrus plant leaves to salinity. A number of uncharacterized membrane transporter genes, like NRT1-2, were differentially regulated in the tolerant and the sensitive genotypes, suggesting its potential implication in Cl(-) homeostasis. Analyses of enriched functional categories showed that the tolerant rootstock induced wider stress responses in gene expression while repressing central metabolic processes such as photosynthesis and carbon utilization. These features were in agreement with phenotypic changes in the patterns of photosynthesis, transpiration, and stomatal conductance and support the concept that regulation of transpiration and its associated metabolic adjustments configure an adaptive response to salinity that reduces Cl(-) accumulation in the tolerant genotype.

UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19190944 N1 -

Journal article Functional & integrative genomics Funct Integr Genomics. 2009 Feb 4.

ER - TY - JOUR T1 - MODBASE, a database of annotated comparative protein structure models and associated resources JF - Nucleic Acids Res Y1 - 2009 A1 - Pieper, U. A1 - Eswar, N. A1 - Webb, B. M. A1 - Eramian, D. A1 - Kelly, L. A1 - Barkan, D. T. A1 - Carter, H. A1 - Mankoo, P. A1 - Karchin, R. A1 - M. A. Marti-Renom A1 - Davis, F. P. A1 - Sali, A. KW - *Databases KW - Molecular Mutation Polymorphism KW - Protein Genomics Humans Ligands *Models KW - Protein User-Computer Interface KW - Single Nucleotide Protein Folding Protein Interaction Domains and Motifs *Protein Structure KW - Tertiary Proteins/genetics *Structural Homology AB - MODBASE (http://salilab.org/modbase) is a database of annotated comparative protein structure models. The models are calculated by MODPIPE, an automated modeling pipeline that relies primarily on MODELLER for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE currently contains 5,152,695 reliable models for domains in 1,593,209 unique protein sequences; only models based on statistically significant alignments and/or models assessed to have the correct fold are included. MODBASE also allows users to calculate comparative models on demand, through an interface to the MODWEB modeling server (http://salilab.org/modweb). Other resources integrated with MODBASE include databases of multiple protein structure alignments (DBAli), structurally defined ligand binding sites (LIGBASE), predicted ligand binding sites (AnnoLyze), structurally defined binary domain interfaces (PIBASE) and annotated single nucleotide polymorphisms and somatic mutations found in human proteins (LS-SNP, LS-Mut). MODBASE models are also available through the Protein Model Portal (http://www.proteinmodelportal.org/). VL - 37 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18948282 N1 - Pieper, Ursula Eswar, Narayanan Webb, Ben M Eramian, David Kelly, Libusha Barkan, David T Carter, Hannah Mankoo, Parminder Karchin, Rachel Marti-Renom, Marc A Davis, Fred P Sali, Andrej GM08284/GM/NIGMS NIH HHS/United States P01 GM71790/GM/NIGMS NIH HHS/United States R01 GM54762/GM/NIGMS NIH HHS/United States U01 GM61390/GM/NIGMS NIH HHS/United States U54 GM074929/GM/NIGMS NIH HHS/United States U54 GM074945/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S. England Nucleic acids research Nucleic Acids Res. 2009 Jan;37(Database issue):D347-54. Epub 2008 Oct 23. ER - TY - JOUR T1 - Modeling and managing experimental data using FuGE. JF - OMICS Y1 - 2009 A1 - Andrew R Jones A1 - Allyson L Lister A1 - Leandro Hermida A1 - Peter Wilkinson A1 - Martin Eisenacher A1 - Khalid Belhajjame A1 - Frank Gibson A1 - Phil Lord A1 - Matthew Pocock A1 - Heiko Rosenfelder A1 - Santoyo-López, Javier A1 - Anil Wipat A1 - Norman W Paton VL - 13 ER - TY - JOUR T1 - Pere Alberch: Originator of EvoDevo JF - Biological Theory Y1 - 2009 A1 - Reiss, JO A1 - Burke, A C A1 - Archer, C A1 - De Renzi, M A1 - H. Dopazo A1 - Etxeberria, A A1 - Gale, E A A1 - Hinchliffe, J R A1 - Nuño de la Rosa, L A1 - Rose, C S A1 - Rasskin-Gutman, D A1 - Müller, G VL - 3 ER - TY - CONF T1 - Peripheral blood cells transcriptome to study new biomarkers for myocardial infarction follow up Y1 - 2009 A1 - Silbiger, Vivian A1 - Luchessi, André A1 - Hirata, Rosario A1 - Carracedo, Ángel A1 - Brión, Maria A1 - Lima Neto, Lidio A1 - P. Pastorelli, C A1 - Dopazo, Joaquin A1 - Montaner, David A1 - Garcia, F A1 - P. Sampaio, M A1 - P. Pereira, M A1 - S. Santos, E A1 - Armaganijan, Dikran A1 - Hirata, Mario ER - TY - JOUR T1 - Statistical methods for analysis of high-throughput RNA interference screens JF - Nature Methods Y1 - 2009 A1 - Birmingham, Amanda A1 - Selfors, Laura M A1 - Forster, Thorsten A1 - Wrobel, David A1 - Kennedy, Caleb J A1 - Shanks, Emma A1 - Santoyo-López, Javier A1 - Dunican, Dara J A1 - Long, Aideen A1 - Kelleher, Dermot A1 - Smith, Queta A1 - Beijersbergen, Roderick L A1 - Ghazal, Peter A1 - Shamu, Caroline E KW - gene silencing KW - regulation KW - siRNA PB - Nature Publishing Group VL - 6 SN - 1548-7091 UR - http://dx.doi.org/10.1038/nmeth.1351 N1 -

10.1038/nmeth.1351

ER - TY - CHAP T1 - Structural Comparison and Alignment T2 - Structural Bioinformatics Y1 - 2009 A1 - M. A. Marti-Renom A1 - E. Capriotti A1 - Shindyalov, I. A1 - Bourne, P. KW - Structural Bioinformatics JF - Structural Bioinformatics PB - Wiley-Blackwell CY - New Jersey. USA UR - http://www.amazon.com/gp/product/0470181052/ ER - TY - JOUR T1 - Biological processes, properties and molecular wiring diagrams of candidate low-penetrance breast cancer susceptibility genes JF - BMC Med Genomics Y1 - 2008 A1 - Bonifaci, N. A1 - Berenguer, A. A1 - Diez, J. A1 - Reina, O. A1 - Medina, Ignacio A1 - Dopazo, J. A1 - Moreno, V. A1 - Pujana, M. A. KW - gene set KW - GWAS KW - SNP AB -

ABSTRACT: BACKGROUND: Recent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined. METHODS: We applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence. RESULTS: First, examination of the distribution of Gene Ontology terms in ordered WGAS results identified asymmetrical distribution of Cell Communication and Cell Death processes linked to risk. Second, analysis of 11 different types of molecular or functional relationships in genomic and proteomic data sets defined the "omic" properties of candidate genes: i/ differential expression in tumors relative to normal tissue; ii/ somatic genomic copy number changes correlating with gene expression levels; iii/ differentially expressed across age at diagnosis; and iv/ expression changes after BRCA1 perturbation. Finally, network modeling of the effects of variants on germline gene expression showed higher connectivity than expected by chance between novel candidates and with known susceptibility genes, which supports functional relationships and provides mechanistic hypotheses of risk. CONCLUSION: This study proposes that cell communication and cell death are major biological processes perturbed in risk of breast cancer conferred by low-penetrance variants, and defines the common omic properties, molecular interactions and possible functional effects of candidate genes and proteins.

VL - 1 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19094230 N1 -

Bonifaci, Nuria Berenguer, Antoni Diez, Javier Reina, Oscar Medina, Ignacio Dopazo, Joaquin Moreno, Victor Pujana, Miguel Angel England BMC medical genomics BMC Med Genomics. 2008 Dec 18;1:62.

ER - TY - JOUR T1 - Direct functional assessment of the composite phenotype through multivariate projection strategies. JF - Genomics Y1 - 2008 A1 - Conesa, Ana A1 - Bro, Rasmus A1 - Garcia-Garcia, Francisco A1 - Prats, José Manuel A1 - Götz, Stefan A1 - Kjeldahl, Karin A1 - Montaner, David A1 - Dopazo, Joaquin KW - Breast Neoplasms KW - Computational Biology KW - Databases, Genetic KW - Female KW - Gene Expression Profiling KW - Humans KW - Mathematical Computing KW - Multivariate Analysis KW - Phenotype AB -

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.

VL - 92 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18652888?dopt=Abstract ER - TY - JOUR T1 - Direct functional assessment of the composite phenotype through multivariate projection strategies JF - Genomics Y1 - 2008 A1 - A. Conesa A1 - Bro, R. A1 - Garcia-Garcia, F. A1 - Prats, J. M. A1 - Gotz, S. A1 - Kjeldahl, K. A1 - Montaner, D. A1 - Dopazo, J. KW - Breast Neoplasms/genetics Computational Biology/*methods Databases KW - Genetic Female Gene Expression Profiling/*statistics & numerical data Humans Mathematical Computing Multivariate Analysis Phenotype AB -

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.

VL - 92 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18652888 N1 -

Conesa, Ana Bro, Rasmus Garcia-Garcia, Francisco Prats, Jose Manuel Gotz, Stefan Kjeldahl, Karin Montaner, David Dopazo, Joaquin Evaluation Studies Research Support, Non-U.S. Gov’t United States Genomics Genomics. 2008 Dec;92(6):373-83. Epub 2008 Sep 13.

ER - TY - JOUR T1 - Interoperability with Moby 1.0--it's better than sharing your toothbrush! JF - Brief Bioinform Y1 - 2008 A1 - Wilkinson, Mark D A1 - Senger, Martin A1 - Kawas, Edward A1 - Bruskiewich, Richard A1 - Gouzy, Jerome A1 - Noirot, Celine A1 - Bardou, Philippe A1 - Ng, Ambrose A1 - Haase, Dirk A1 - Saiz, Enrique de Andres A1 - Wang, Dennis A1 - Gibbons, Frank A1 - Gordon, Paul M K A1 - Sensen, Christoph W A1 - Carrasco, Jose Manuel Rodriguez A1 - Fernández, José M A1 - Shen, Lixin A1 - Links, Matthew A1 - Ng, Michael A1 - Opushneva, Nina A1 - Neerincx, Pieter B T A1 - Leunissen, Jack A M A1 - Ernst, Rebecca A1 - Twigger, Simon A1 - Usadel, Bjorn A1 - Good, Benjamin A1 - Wong, Yan A1 - Stein, Lincoln A1 - Crosby, William A1 - Karlsson, Johan A1 - Royo, Romina A1 - Párraga, Iván A1 - Ramírez, Sergio A1 - Gelpi, Josep Lluis A1 - Trelles, Oswaldo A1 - Pisano, David G A1 - Jimenez, Natalia A1 - Kerhornou, Arnaud A1 - Rosset, Roman A1 - Zamacola, Leire A1 - Tárraga, Joaquín A1 - Huerta-Cepas, Jaime A1 - Carazo, Jose María A1 - Dopazo, Joaquin A1 - Guigó, Roderic A1 - Navarro, Arcadi A1 - Orozco, Modesto A1 - Valencia, Alfonso A1 - Claros, M Gonzalo A1 - Pérez, Antonio J A1 - Aldana, Jose A1 - Rojano, M Mar A1 - Fernandez-Santa Cruz, Raul A1 - Navas, Ismael A1 - Schiltz, Gary A1 - Farmer, Andrew A1 - Gessler, Damian A1 - Schoof, Heiko A1 - Groscurth, Andreas KW - Computational Biology KW - Database Management Systems KW - Databases, Factual KW - Information Storage and Retrieval KW - Internet KW - Programming Languages KW - Systems Integration AB -

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/.

VL - 9 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18238804?dopt=Abstract ER - TY - JOUR T1 - Interoperability with Moby 1.0–it’s better than sharing your toothbrush! JF - Brief Bioinform Y1 - 2008 A1 - Wilkinson, M. D. A1 - Senger, M. A1 - Kawas, E. A1 - Bruskiewich, R. A1 - Gouzy, J. A1 - Noirot, C. A1 - Bardou, P. A1 - Ng, A. A1 - Haase, D. A1 - Saiz Ede, A. A1 - Wang, D. A1 - Gibbons, F. A1 - Gordon, P. M. A1 - Sensen, C. W. A1 - Carrasco, J. M. A1 - Fernandez, J. M. A1 - Shen, L. A1 - Links, M. A1 - Ng, M. A1 - Opushneva, N. A1 - Neerincx, P. B. A1 - Leunissen, J. A. A1 - Ernst, R. A1 - Twigger, S. A1 - Usadel, B. A1 - Good, B. A1 - Wong, Y. A1 - Stein, L. A1 - Crosby, W. A1 - Karlsson, J. A1 - Royo, R. A1 - Parraga, I. A1 - Ramirez, S. A1 - Gelpi, J. L. A1 - Trelles, O. A1 - Pisano, D. G. A1 - Jimenez, N. A1 - Kerhornou, A. A1 - Rosset, R. A1 - Zamacola, L. A1 - Tarraga, J. A1 - Huerta-Cepas, J. A1 - Carazo, J. M. A1 - Dopazo, J. A1 - R. Guigo A1 - Navarro, A. A1 - Orozco, M. A1 - Valencia, A. A1 - Claros, M. G. A1 - Perez, A. J. A1 - Aldana, J. A1 - Rojano, M. M. A1 - Fernandez-Santa Cruz, R. A1 - Navas, I. A1 - Schiltz, G. A1 - Farmer, A. A1 - Gessler, D. A1 - Schoof, H. A1 - Groscurth, A. KW - Computational Biology/*methods *Database Management Systems *Databases KW - Factual Information Storage and Retrieval/*methods *Internet *Programming Languages Systems Integration AB -

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/.

VL - 9 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18238804 N1 -

BioMoby Consortium Wilkinson, Mark D Senger, Martin Kawas, Edward Bruskiewich, Richard Gouzy, Jerome Noirot, Celine Bardou, Philippe Ng, Ambrose Haase, Dirk Saiz, Enrique de Andres Wang, Dennis Gibbons, Frank Gordon, Paul M K Sensen, Christoph W Carrasco, Jose Manuel Rodriguez Fernandez, Jose M Shen, Lixin Links, Matthew Ng, Michael Opushneva, Nina Neerincx, Pieter B T Leunissen, Jack A M Ernst, Rebecca Twigger, Simon Usadel, Bjorn Good, Benjamin Wong, Yan Stein, Lincoln Crosby, William Karlsson, Johan Royo, Romina Parraga, Ivan Ramirez, Sergio Gelpi, Josep Lluis Trelles, Oswaldo Pisano, David G Jimenez, Natalia Kerhornou, Arnaud Rosset, Roman Zamacola, Leire Tarraga, Joaquin Huerta-Cepas, Jaime Carazo, Jose Maria Dopazo, Joaquin Guigo, Roderic Navarro, Arcadi Orozco, Modesto Valencia, Alfonso Claros, M Gonzalo Perez, Antonio J Aldana, Jose Rojano, M Mar Fernandez-Santa Cruz, Raul Navas, Ismael Schiltz, Gary Farmer, Andrew Gessler, Damian Schoof, Heiko Groscurth, Andreas Research Support, Non-U.S. Gov’t Review England Briefings in bioinformatics Brief Bioinform. 2008 May;9(3):220-31. Epub 2008 Jan 31.

ER - TY - JOUR T1 - Large-scale Gene Ontology analysis of plant transcriptome-derived sequences retrieved by AFLP technology JF - BMC Genomics Y1 - 2008 A1 - Botton, A. A1 - Galla, G. A1 - A. Conesa A1 - Bachem, C. A1 - Ramina, A. A1 - Barcaccia, G. AB -

BACKGROUND: After 10-year-use of AFLP (Amplified Fragment Length Polymorphism) technology for DNA fingerprinting and mRNA profiling, large repertories of genome- and transcriptome-derived sequences are available in public databases for model, crop and tree species. AFLP marker systems have been and are being extensively exploited for genome scanning and gene mapping, as well as cDNA-AFLP for transcriptome profiling and differentially expressed gene cloning. The evaluation, annotation and classification of genomic markers and expressed transcripts would be of great utility for both functional genomics and systems biology research in plants. This may be achieved by means of the Gene Ontology (GO), consisting in three structured vocabularies (i.e. ontologies) describing genes, transcripts and proteins of any organism in terms of their associated cellular component, biological process and molecular function in a species-independent manner. In this paper, the functional annotation of about 8,000 AFLP-derived ESTs retrieved in the NCBI databases was carried out by using GO terminology. RESULTS: Descriptive statistics on the type, size and nature of gene sequences obtained by means of AFLP technology were calculated. The gene products associated with mRNA transcripts were then classified according to the three main GO vocabularies. A comparison of the functional content of cDNA-AFLP records was also performed by splitting the sequence dataset into monocots and dicots and by comparing them to all annotated ESTs of Arabidopsis and rice, respectively. On the whole, the statistical parameters adopted for the in silico AFLP-derived transcriptome-anchored sequence analysis proved to be critical for obtaining reliable GO results. Such an exhaustive annotation may offer a suitable platform for functional genomics, particularly useful in non-model species. CONCLUSION: Reliable GO annotations of AFLP-derived sequences can be gathered through the optimization of the experimental steps and the statistical parameters adopted. The Blast2GO software was shown to represent a comprehensive bioinformatics solution for an annotation-based functional analysis. According to the whole set of GO annotations, the AFLP technology generates thorough information for angiosperm gene products and shares common features across angiosperm species and families. The utility of this technology for structural and functional genomics in plants can be implemented by serial annotation analyses of genome-anchored fragments and organ/tissue-specific repertories of transcriptome-derived fragments.

VL - 9 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18652646 N1 -

Botton, Alessandro Galla, Giulio Conesa, Ana Bachem, Christian Ramina, Angelo Barcaccia, Gianni England BMC genomics BMC Genomics. 2008 Jul 24;9:347.

ER - TY - JOUR T1 - PhylomeDB: a database for genome-wide collections of gene phylogenies. JF - Nucleic Acids Res Y1 - 2008 A1 - Huerta-Cepas, Jaime A1 - Bueno, Anibal A1 - Dopazo, Joaquin A1 - Gabaldón, Toni KW - Base Sequence KW - Escherichia coli KW - Genes KW - Genomics KW - History, Ancient KW - Humans KW - Phylogeny KW - Proteins KW - Saccharomyces cerevisiae KW - Sequence Alignment AB -

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.

VL - 36 IS - Database issue U1 - https://www.ncbi.nlm.nih.gov/pubmed/17962297?dopt=Abstract ER - TY - JOUR T1 - PhylomeDB: a database for genome-wide collections of gene phylogenies JF - Nucleic Acids Res Y1 - 2008 A1 - Huerta-Cepas, J. A1 - Bueno, A. A1 - Dopazo, J. A1 - Gabaldón, T. KW - Ancient Humans *Phylogeny Proteins/classification/genetics Saccharomyces cerevisiae/classification/genetics Sequence Alignment KW - Base Sequence Escherichia coli/classification/genetics Genes *Genomics History AB - 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. VL - 36 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17962297 N1 - Huerta-Cepas, Jaime Bueno, Anibal Dopazo, Joaquin Gabaldon, Toni Historical Article Research Support, Non-U.S. Gov’t England Nucleic acids research Nucleic Acids Res. 2008 Jan;36(Database issue):D491-6. Epub 2007 Oct 25. ER - TY - JOUR T1 - SNP and haplotype mapping for genetic analysis in the rat JF - Nat Genet Y1 - 2008 A1 - K. Saar A1 - A. Beck A1 - M. T. Bihoreau A1 - E. Birney A1 - D. Brocklebank A1 - Y. Chen A1 - E. Cuppen A1 - S. Demonchy A1 - Dopazo, J. A1 - P. Flicek A1 - M. Foglio A1 - A. Fujiyama A1 - I. G. Gut A1 - D. Gauguier A1 - R. Guigo A1 - V. Guryev A1 - M. Heinig A1 - O. Hummel A1 - N. Jahn A1 - S. Klages A1 - V. Kren A1 - M. Kube A1 - H. Kuhl A1 - Kuramoto, T. A1 - Kuroki, Y. A1 - Lechner, D. A1 - Lee, Y. A. A1 - Lopez-Bigas, N. A1 - Lathrop, G. M. A1 - Mashimo, T. A1 - Medina, Ignacio A1 - Mott, R. A1 - Patone, G. A1 - Perrier-Cornet, J. A. A1 - Platzer, M. A1 - Pravenec, M. A1 - Reinhardt, R. A1 - Sakaki, Y. A1 - Schilhabel, M. A1 - Schulz, H. A1 - Serikawa, T. A1 - Shikhagaie, M. A1 - Tatsumoto, S. A1 - Taudien, S. A1 - Toyoda, A. A1 - Voigt, B. A1 - Zelenika, D. A1 - Zimdahl, H. A1 - Hubner, N. KW - Animals Chromosome Mapping *Databases KW - Genetic KW - Genetic Genome *Haplotypes Linkage Disequilibrium Phylogeny *Polymorphism KW - Inbred Strains/*genetics Recombination KW - Single Nucleotide *Quantitative Trait Loci Rats/*genetics Rats AB -

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.

VL - 40 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18443594 N1 -

STAR Consortium Saar, Kathrin Beck, Alfred Bihoreau, Marie-Therese Birney, Ewan Brocklebank, Denise Chen, Yuan Cuppen, Edwin Demonchy, Stephanie Dopazo, Joaquin Flicek, Paul Foglio, Mario Fujiyama, Asao Gut, Ivo G Gauguier, Dominique Guigo, Roderic Guryev, Victor Heinig, Matthias Hummel, Oliver Jahn, Niels Klages, Sven Kren, Vladimir Kube, Michael Kuhl, Heiner Kuramoto, Takashi Kuroki, Yoko Lechner, Doris Lee, Young-Ae Lopez-Bigas, Nuria Lathrop, G Mark Mashimo, Tomoji Medina, Ignacio Mott, Richard Patone, Giannino Perrier-Cornet, Jeanne-Antide Platzer, Matthias Pravenec, Michal Reinhardt, Richard Sakaki, Yoshiyuki Schilhabel, Markus Schulz, Herbert Serikawa, Tadao Shikhagaie, Medya Tatsumoto, Shouji Taudien, Stefan Toyoda, Atsushi Voigt, Birger Zelenika, Diana Zimdahl, Heike Hubner, Norbert 057733/Z/99/A/Wellcome Trust/United Kingdom 066780/Z/01/Z/Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov’t Technical Report United States Nature genetics Nat Genet. 2008 May;40(5):560-6.

ER - TY - JOUR T1 - SNP and haplotype mapping for genetic analysis in the rat. JF - Nat Genet Y1 - 2008 A1 - Saar, Kathrin A1 - Beck, Alfred A1 - Bihoreau, Marie-Thérèse A1 - Birney, Ewan A1 - Brocklebank, Denise A1 - Chen, Yuan A1 - Cuppen, Edwin A1 - Demonchy, Stephanie A1 - Dopazo, Joaquin A1 - Flicek, Paul A1 - Foglio, Mario A1 - Fujiyama, Asao A1 - Gut, Ivo G A1 - Gauguier, Dominique A1 - Guigó, Roderic A1 - Guryev, Victor A1 - Heinig, Matthias A1 - Hummel, Oliver A1 - Jahn, Niels A1 - Klages, Sven A1 - Kren, Vladimir A1 - Kube, Michael A1 - Kuhl, Heiner A1 - Kuramoto, Takashi A1 - Kuroki, Yoko A1 - Lechner, Doris A1 - Lee, Young-Ae A1 - Lopez-Bigas, Nuria A1 - Lathrop, G Mark A1 - Mashimo, Tomoji A1 - Medina, Ignacio A1 - Mott, Richard A1 - Patone, Giannino A1 - Perrier-Cornet, Jeanne-Antide A1 - Platzer, Matthias A1 - Pravenec, Michal A1 - Reinhardt, Richard A1 - Sakaki, Yoshiyuki A1 - Schilhabel, Markus A1 - Schulz, Herbert A1 - Serikawa, Tadao A1 - Shikhagaie, Medya A1 - Tatsumoto, Shouji A1 - Taudien, Stefan A1 - Toyoda, Atsushi A1 - Voigt, Birger A1 - Zelenika, Diana A1 - Zimdahl, Heike A1 - Hubner, Norbert KW - Animals KW - Chromosome Mapping KW - Databases, Genetic KW - Genome KW - Haplotypes KW - Linkage Disequilibrium KW - Phylogeny KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Rats KW - Rats, Inbred Strains KW - Recombination, Genetic AB -

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.

VL - 40 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18443594?dopt=Abstract ER - TY - JOUR T1 - Transcriptional profiling of mRNA expression in the mouse distal colon JF - Gastroenterology Y1 - 2008 A1 - Hoogerwerf, W. A. A1 - Sinha, M. A1 - A. Conesa A1 - Luxon, B. A. A1 - Shahinian, V. B. A1 - Cornelissen, G. A1 - Halberg, F. A1 - Bostwick, J. A1 - Timm, J. A1 - Cassone, V. M. KW - Animals Blotting KW - Genetic KW - Inbred C57BL Microarray Analysis Proteins/*genetics/metabolism RNA KW - Messenger/biosynthesis/*genetics Reverse Transcriptase Polymerase Chain Reaction *Transcription KW - Western Cell Proliferation Circadian Rhythm/*genetics Colon/cytology/*metabolism Male Mice Mice AB - BACKGROUND & AIMS: Intestinal epithelial cells and the myenteric plexus of the mouse gastrointestinal tract contain a circadian clock-based intrinsic time-keeping system. Because disruption of the biological clock has been associated with increased susceptibility to colon cancer and gastrointestinal symptoms, we aimed to identify rhythmically expressed genes in the mouse distal colon. METHODS: Microarray analysis was used to identify genes that were rhythmically expressed over a 24-hour light/dark cycle. The transcripts were then classified according to expression pattern, function, and association with physiologic and pathophysiologic processes of the colon. RESULTS: A circadian gene expression pattern was detected in approximately 3.7% of distal colonic genes. A large percentage of these genes were involved in cell signaling, differentiation, and proliferation and cell death. Of all the rhythmically expressed genes in the mouse colon, approximately 7% (64/906) have been associated with colorectal cancer formation (eg, B-cell leukemia/lymphoma-2 [Bcl2]) and 1.8% (18/906) with various colonic functions such as motility and secretion (eg, vasoactive intestinal polypeptide, cystic fibrosis transmembrane conductance regulator). CONCLUSIONS: A subset of genes in the murine colon follows a rhythmic expression pattern. These findings may have significant implications for colonic physiology and pathophysiology. VL - 135 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18848557 N1 - Hoogerwerf, Willemijntje A Sinha, Mala Conesa, Ana Luxon, Bruce A Shahinian, Vahakn B Cornelissen, Germaine Halberg, Franz Bostwick, Jonathon Timm, John Cassone, Vincent M R21 DK074477-01A1/DK/NIDDK NIH HHS/United States Comparative Study Research Support, N.I.H., Extramural United States Gastroenterology Gastroenterology. 2008 Dec;135(6):2019-29. Epub 2008 Sep 3. ER - TY - JOUR T1 - Analysis of 13000 unique Citrus clusters associated with fruit quality, production and salinity tolerance JF - BMC Genomics Y1 - 2007 A1 - Terol, J. A1 - A. Conesa A1 - Colmenero, J. M. A1 - Cercos, M. A1 - Tadeo, F. A1 - Agusti, J. A1 - Alos, E. A1 - Andres, F. A1 - Soler, G. A1 - Brumos, J. A1 - Iglesias, D. J. A1 - Gotz, S. A1 - Legaz, F. A1 - Argout, X. A1 - Courtois, B. A1 - Ollitrault, P. A1 - Dossat, C. A1 - Wincker, P. A1 - Morillon, R. A1 - Talon, M. KW - Acclimatization/*genetics Amino Acid Motifs Citrus/*genetics Cluster Analysis Expressed Sequence Tags Fruit/genetics Gene Duplication *Gene Expression Regulation KW - Plant Gene Library Genes KW - Plant Genomics Molecular Sequence Data Multigene Family Phylogeny *Salts/adverse effects AB - BACKGROUND: Improvement of Citrus, the most economically important fruit crop in the world, is extremely slow and inherently costly because of the long-term nature of tree breeding and an unusual combination of reproductive characteristics. Aside from disease resistance, major commercial traits in Citrus are improved fruit quality, higher yield and tolerance to environmental stresses, especially salinity. RESULTS: A normalized full length and 9 standard cDNA libraries were generated, representing particular treatments and tissues from selected varieties (Citrus clementina and C. sinensis) and rootstocks (C. reshni, and C. sinenis x Poncirus trifoliata) differing in fruit quality, resistance to abscission, and tolerance to salinity. The goal of this work was to provide a large expressed sequence tag (EST) collection enriched with transcripts related to these well appreciated agronomical traits. Towards this end, more than 54000 ESTs derived from these libraries were analyzed and annotated. Assembly of 52626 useful sequences generated 15664 putative transcription units distributed in 7120 contigs, and 8544 singletons. BLAST annotation produced significant hits for more than 80% of the hypothetical transcription units and suggested that 647 of these might be Citrus specific unigenes. The unigene set, composed of 13000 putative different transcripts, including more than 5000 novel Citrus genes, was assigned with putative functions based on similarity, GO annotations and protein domains CONCLUSION: Comparative genomics with Arabidopsis revealed the presence of putative conserved orthologs and single copy genes in Citrus and also the occurrence of both gene duplication events and increased number of genes for specific pathways. In addition, phylogenetic analysis performed on the ammonium transporter family and glycosyl transferase family 20 suggested the existence of Citrus paralogs. Analysis of the Citrus gene space showed that the most important metabolic pathways known to affect fruit quality were represented in the unigene set. Overall, the similarity analyses indicated that the sequences of the genes belonging to these varieties and rootstocks were essentially identical, suggesting that the differential behaviour of these species cannot be attributed to major sequence divergences. This Citrus EST assembly contributes both crucial information to discover genes of agronomical interest and tools for genetic and genomic analyses, such as the development of new markers and microarrays. VL - 8 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17254327 N1 - Terol, Javier Conesa, Ana Colmenero, Jose M Cercos, Manuel Tadeo, Francisco Agusti, Javier Alos, Enriqueta Andres, Fernando Soler, Guillermo Brumos, Javier Iglesias, Domingo J Gotz, Stefan Legaz, Francisco Argout, Xavier Courtois, Brigitte Ollitrault, Patrick Dossat, Carole Wincker, Patrick Morillon, Raphael Talon, Manuel Comparative Study Research Support, Non-U.S. Gov’t England BMC genomics BMC Genomics. 2007 Jan 25;8:31. ER - TY - JOUR T1 - Association study of 69 genes in the ret pathway identifies low-penetrance loci in sporadic medullary thyroid carcinoma JF - Cancer Res Y1 - 2007 A1 - Ruiz-Llorente, S. A1 - Montero-Conde, C. A1 - Milne, R. L. A1 - Moya, C. M. A1 - Cebrian, A. A1 - Leton, R. A1 - Cascon, A. A1 - Mercadillo, F. A1 - Landa, I. A1 - Borrego, S. A1 - Perez de Nanclares, G. A1 - Alvarez-Escola, C. A1 - Diaz-Perez, J. A. A1 - Carracedo, A. A1 - Urioste, M. A1 - Gonzalez-Neira, A. A1 - Benitez, J. A1 - Santisteban, P. A1 - Dopazo, J. A1 - Ponder, B. A. A1 - M. Robledo KW - 80 and over Carcinoma KW - Adolescent Adult Aged Aged KW - Genetic KW - Genetic Proto-Oncogene Proteins c-ret/*genetics/metabolism Signal Transduction Thyroid Neoplasms/*genetics/metabolism Transcription KW - Medullary/*genetics/metabolism Case-Control Studies Cyclin-Dependent Kinase Inhibitor p15/biosynthesis/genetics Female Genetic Predisposition to Disease Germ-Line Mutation Haplotypes Humans Male Middle Aged Penetrance Polymorphism KW - Single Nucleotide Promoter Regions AB - To date, few association studies have been done to better understand the genetic basis for the development of sporadic medullary thyroid carcinoma (sMTC). To identify additional low-penetrance genes, we have done a two-stage case-control study in two European populations using high-throughput genotyping. We selected 417 single nucleotide polymorphisms (SNP) belonging to 69 genes either related to RET signaling pathway/functions or involved in key processes for cancer development. TagSNPs and functional variants were included where possible. These SNPs were initially studied in the largest known series of sMTC cases (n = 266) and controls (n = 422), all of Spanish origin. In stage II, an independent British series of 155 sMTC patients and 531 controls was included to validate the previous results. Associations were assessed by an exhaustive analysis of individual SNPs but also considering gene- and linkage disequilibrium-based haplotypes. This strategy allowed us to identify seven low-penetrance genes, six of them (STAT1, AURKA, BCL2, CDKN2B, CDK6, and COMT) consistently associated with sMTC risk in the two case-control series and a seventh (HRAS) with individual SNPs and haplotypes associated with sMTC in the Spanish data set. The potential role of CDKN2B was confirmed by a functional assay showing a role of a SNP (rs7044859) in the promoter region in altering the binding of the transcription factor HNF1. These results highlight the utility of association studies using homogeneous series of cases for better understanding complex diseases. VL - 67 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17909067 N1 - Ruiz-Llorente, Sergio Montero-Conde, Cristina Milne, Roger L Moya, Christian M Cebrian, Arancha Leton, Rocio Cascon, Alberto Mercadillo, Fatima Landa, Inigo Borrego, Salud Perez de Nanclares, Guiomar Alvarez-Escola, Cristina Diaz-Perez, Jose Angel Carracedo, Angel Urioste, Miguel Gonzalez-Neira, Anna Benitez, Javier Santisteban, Pilar Dopazo, Joaquin Ponder, Bruce A Robledo, Mercedes Medullary Thyroid Carcinoma Clinical Group Research Support, Non-U.S. Gov’t United States Cancer research Cancer Res. 2007 Oct 1;67(19):9561-7. ER - TY - JOUR T1 - Characterization of protein hubs by inferring interacting motifs from protein interactions JF - PLoS Comput Biol Y1 - 2007 A1 - Aragues, R. A1 - Sali, A. A1 - Bonet, J. A1 - M. A. Marti-Renom A1 - Oliva, B. KW - Amino Acid Motifs Amino Acid Sequence Binding Sites Computer Simulation *Models KW - Chemical *Models KW - Molecular Molecular Sequence Data Protein Binding Protein Interaction Mapping/*methods Proteins/*chemistry Sequence Analysis KW - Protein/*methods AB - The characterization of protein interactions is essential for understanding biological systems. While genome-scale methods are available for identifying interacting proteins, they do not pinpoint the interacting motifs (e.g., a domain, sequence segments, a binding site, or a set of residues). Here, we develop and apply a method for delineating the interacting motifs of hub proteins (i.e., highly connected proteins). The method relies on the observation that proteins with common interaction partners tend to interact with these partners through a common interacting motif. The sole input for the method are binary protein interactions; neither sequence nor structure information is needed. The approach is evaluated by comparing the inferred interacting motifs with domain families defined for 368 proteins in the Structural Classification of Proteins (SCOP). The positive predictive value of the method for detecting proteins with common SCOP families is 75% at sensitivity of 10%. Most of the inferred interacting motifs were significantly associated with sequence patterns, which could be responsible for the common interactions. We find that yeast hubs with multiple interacting motifs are more likely to be essential than hubs with one or two interacting motifs, thus rationalizing the previously observed correlation between essentiality and the number of interacting partners of a protein. We also find that yeast hubs with multiple interacting motifs evolve slower than the average protein, contrary to the hubs with one or two interacting motifs. The proposed method will help us discover unknown interacting motifs and provide biological insights about protein hubs and their roles in interaction networks. VL - 3 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17941705 N1 - Aragues, Ramon Sali, Andrej Bonet, Jaume Marti-Renom, Marc A Oliva, Baldo PN2 EY016525,/EY/NEI NIH HHS/United States U54 RR022220/RR/NCRR NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t United States PLoS computational biology PLoS Comput Biol. 2007 Sep;3(9):1761-71. Epub 2007 Jul 30. ER - TY - JOUR T1 - Functional profiling and gene expression analysis of chromosomal copy number alterations. JF - Bioinformation Y1 - 2007 A1 - Conde, Lucia A1 - Montaner, David A1 - Burguet-Castell, Jordi A1 - Tárraga, Joaquín A1 - Al-Shahrour, Fátima A1 - Dopazo, Joaquin AB -

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.

VL - 1 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17597935?dopt=Abstract ER - TY - JOUR T1 - Functional profiling and gene expression analysis of chromosomal copy number alterations JF - Bioinformation Y1 - 2007 A1 - L. Conde A1 - Montaner, D. A1 - Burguet-Castell, J. A1 - Tarraga, J. A1 - Fatima Al-Shahrour A1 - Dopazo, J. KW - babelomics AB -

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.

VL - 1 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17597935 N1 -

Conde, Lucia Montaner, David Burguet-Castell, Jordi Tarraga, Joaquin Al-Shahrour, Fatima Dopazo, Joaquin Singapore Bioinformation Bioinformation. 2007 Apr 10;1(10):432-5.

ER - TY - JOUR T1 - Identification of conserved domains in the promoter regions of nitric oxide synthase 2: implications for the species-specific transcription and evolutionary differences JF - BMC Genomics Y1 - 2007 A1 - Rico, D. A1 - Vaquerizas, J. M. A1 - H. Dopazo A1 - Bosca, L. KW - Animals Base Sequence Conserved Sequence Enhancer Elements KW - Genetic *Evolution KW - Genetic Response Elements Species Specificity KW - Molecular Humans Inflammation/metabolism Interferon-gamma/metabolism Mice NF-kappa B/metabolism Nitric Oxide Synthase Type II/*genetics *Promoter Regions AB - BACKGROUND: The majority of the genes involved in the inflammatory response are highly conserved in mammals. These genes are not significantly expressed under normal conditions and are mainly regulated at the transcription and prost-transcriptional level. Transcription from the promoters of these genes is very dependent on NF-kappaB activation, which integrates the response to diverse extracellular stresses. However, in spite of the high conservation of the pattern of promoter regulation in kappaB-regulated genes, there is inter-species diversity in some genes. One example is nitric oxide synthase 2 (NOS-2), which exhibits a species-specific pattern of expression in response to infection or pro-inflammatory challenge. RESULTS: We have conducted a comparative genomic analysis of NOS-2 with different bioinformatic approaches. This analysis shows that in the NOS-2 gene promoter the position and the evolutionary divergence of some conserved regions are different in rodents and non-rodent mammals, and in particular in primates. Two not previously described distal regions in rodents that are similar to the unique upstream region responsible of the NF-kappaB activation of NOS-2 in humans are fragmented and translocated to different locations in the rodent promoters. The rodent sequences moreover lack the functional kappaB sites and IFN-gamma response sites present in the homologous human, rhesus monkey and chimpanzee regions. The absence of kappaB binding in these regions was confirmed by electrophoretic mobility shift assays. CONCLUSION: The data presented reveal divergence between rodents and other mammals in the location and functionality of conserved regions of the NOS-2 promoter containing NF-kappaB and IFN-gamma response elements. VL - 8 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17686182 N1 - Rico, Daniel Vaquerizas, Juan M Dopazo, Hernan Bosca, Lisardo Research Support, Non-U.S. Gov’t England BMC genomics BMC Genomics. 2007 Aug 8;8:271. ER - TY - JOUR T1 - ISACGH: a web-based environment for the analysis of Array CGH and gene expression which includes functional profiling. JF - Nucleic Acids Res Y1 - 2007 A1 - Conde, Lucia A1 - Montaner, David A1 - Burguet-Castell, Jordi A1 - Tárraga, Joaquín A1 - Medina, Ignacio A1 - Al-Shahrour, Fátima A1 - Dopazo, Joaquin KW - Animals KW - Cluster Analysis KW - Computational Biology KW - Computer Graphics KW - Gene Expression Profiling KW - Humans KW - Internet KW - Models, Genetic KW - Nucleic Acid Hybridization KW - Oligonucleotide Array Sequence Analysis KW - Programming Languages KW - Software KW - Systems Integration KW - User-Computer Interface AB -

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.

VL - 35 IS - Web Server issue U1 - https://www.ncbi.nlm.nih.gov/pubmed/17468499?dopt=Abstract ER - TY - JOUR T1 - ISACGH: a web-based environment for the analysis of Array CGH and gene expression which includes functional profiling JF - Nucleic Acids Res Y1 - 2007 A1 - L. Conde A1 - Montaner, D. A1 - Burguet-Castell, J. A1 - Tarraga, J. A1 - Medina, Ignacio A1 - Fatima Al-Shahrour A1 - Dopazo, J. KW - Animals Cluster Analysis Computational Biology/*methods Computer Graphics Gene Expression Profiling/*methods Humans Internet Models KW - Genetic *Nucleic Acid Hybridization Oligonucleotide Array Sequence Analysis/*methods Programming Languages *Software Systems Integration User-Computer Interface AB - 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. VL - 35 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17468499 N1 - Conde, Lucia Montaner, David Burguet-Castell, Jordi Tarraga, Joaquin Medina, Ignacio Al-Shahrour, Fatima Dopazo, Joaquin Research Support, Non-U.S. Gov’t England Nucleic acids research Nucleic Acids Res. 2007 Jul;35(Web Server issue):W81-5. Epub 2007 Apr 27. ER - TY - JOUR T1 - PeroxisomeDB: a database for the peroxisomal proteome, functional genomics and disease JF - Nucleic Acids Res Y1 - 2007 A1 - Schluter, A. A1 - Fourcade, S. A1 - Domenech-Estevez, E. A1 - Gabaldón, T. A1 - Huerta-Cepas, J. A1 - Berthommier, G. A1 - Ripp, R. A1 - Wanders, R. J. A1 - Poch, O. A1 - Pujol, A. KW - Animals *Databases KW - Protein Genomics Humans Internet Mice Peroxisomal Disorders/*genetics Peroxisomes/*metabolism Protein Sorting Signals Proteome/chemistry/*genetics/*physiology Rats Saccharomyces cerevisiae Proteins/genetics/physiology Software User-Computer Interface AB - Peroxisomes are essential organelles of eukaryotic origin, ubiquitously distributed in cells and organisms, playing key roles in lipid and antioxidant metabolism. Loss or malfunction of peroxisomes causes more than 20 fatal inherited conditions. We have created a peroxisomal database (http://www.peroxisomeDB.org) that includes the complete peroxisomal proteome of Homo sapiens and Saccharomyces cerevisiae, by gathering, updating and integrating the available genetic and functional information on peroxisomal genes. PeroxisomeDB is structured in interrelated sections ’Genes’, ’Functions’, ’Metabolic pathways’ and ’Diseases’, that include hyperlinks to selected features of NCBI, ENSEMBL and UCSC databases. We have designed graphical depictions of the main peroxisomal metabolic routes and have included updated flow charts for diagnosis. Precomputed BLAST, PSI-BLAST, multiple sequence alignment (MUSCLE) and phylogenetic trees are provided to assist in direct multispecies comparison to study evolutionary conserved functions and pathways. Highlights of the PeroxisomeDB include new tools developed for facilitating (i) identification of novel peroxisomal proteins, by means of identifying proteins carrying peroxisome targeting signal (PTS) motifs, (ii) detection of peroxisomes in silico, particularly useful for screening the deluge of newly sequenced genomes. PeroxisomeDB should contribute to the systematic characterization of the peroxisomal proteome and facilitate system biology approaches on the organelle. VL - 35 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17135190 N1 - Schluter, Agatha Fourcade, Stephane Domenech-Estevez, Enric Gabaldon, Toni Huerta-Cepas, Jaime Berthommier, Guillaume Ripp, Raymond Wanders, Ronald J A Poch, Olivier Pujol, Aurora Research Support, Non-U.S. Gov’t England Nucleic acids research Nucleic Acids Res. 2007 Jan;35(Database issue):D815-22. Epub 2006 Nov 28. ER - TY - JOUR T1 - BABELOMICS: a systems biology perspective in the functional annotation of genome-scale experiments JF - Nucleic Acids Res Y1 - 2006 A1 - Fatima Al-Shahrour A1 - Minguez, P. A1 - Tarraga, J. A1 - Montaner, D. A1 - Alloza, E. A1 - Vaquerizas, J. M. A1 - L. Conde A1 - Blaschke, C. A1 - Vera, J. A1 - Dopazo, J. KW - babelomics KW - functional profiling AB -

We present a new version of Babelomics, a complete suite of web tools for functional analysis of genome-scale experiments, with new and improved tools. New functionally relevant terms have been included such as CisRed motifs or bioentities obtained by text-mining procedures. An improved indexing has considerably speeded up several of the modules. An improved version of the FatiScan method for studying the coordinate behaviour of groups of functionally related genes is presented, along with a similar tool, the Gene Set Enrichment Analysis. Babelomics is now more oriented to test systems biology inspired hypotheses. Babelomics can be found at http://www.babelomics.org.

VL - 34 UR - http://nar.oxfordjournals.org/content/34/suppl_2/W472.long N1 -

Al-Shahrour, Fatima Minguez, Pablo Tarraga, Joaquin Montaner, David Alloza, Eva Vaquerizas, Juan M Conde, Lucia Blaschke, Christian Vera, Javier Dopazo, Joaquin Research Support, Non-U.S. Gov’t England Nucleic acids research Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W472-6.

ER - TY - JOUR T1 - Blast2GO goes grid: developing a grid-enabled prototype for functional genomics analysis JF - Stud Health Technol Inform Y1 - 2006 A1 - Aparicio, G. A1 - Gotz, S. A1 - A. Conesa A1 - Segrelles, D. A1 - Blanquer, I. A1 - Garcia, J. M. A1 - Hernandez, V. A1 - Robles, M. A1 - Talon, M. KW - babelomics AB -

The vast amount in complexity of data generated in Genomic Research implies that new dedicated and powerful computational tools need to be developed to meet their analysis requirements. Blast2GO (B2G) is a bioinformatics tool for Gene Ontology-based DNA or protein sequence annotation and function-based data mining. The application has been developed with the aim of affering an easy-to-use tool for functional genomics research. Typical B2G users are middle size genomics labs carrying out sequencing, ETS and microarray projects, handling datasets up to several thousand sequences. In the current version of B2G. The power and analytical potential of both annotation and function data-mining is somehow restricted to the computational power behind each particular installation. In order to be able to offer the possibility of an enhanced computational capacity within this bioinformatics application, a Grid component is being developed. A prototype has been conceived for the particular problem of speeding up the Blast searches to obtain fast results for large datasets. Many efforts have been done in the literature concerning the speeding up of Blast searches, but few of them deal with the use of large heterogeneous production Grid Infrastructures. These are the infrastructures that could reach the largest number of resources and the best load balancing for data access. The Grid Service under development will analyse requests based on the number of sequences, splitting them accordingly to the available resources. Lower-level computation will be performed through MPIBLAST. The software architecture is based on the WSRF standard.

VL - 120 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16823138 N1 -

Aparicio, G Gotz, S Conesa, A Segrelles, D Blanquer, I Garcia, J M Hernandez, V Robles, M Talon, M Netherlands Studies in health technology and informatics Stud Health Technol Inform. 2006;120:194-204.

ER - TY - JOUR T1 - ERCC4 associated with breast cancer risk: a two-stage case-control study using high-throughput genotyping JF - Cancer Res Y1 - 2006 A1 - Milne, R. L. A1 - Ribas, G. A1 - Gonzalez-Neira, A. A1 - Fagerholm, R. A1 - Salas, A. A1 - Gonzalez, E. A1 - Dopazo, J. A1 - Nevanlinna, H. A1 - M. Robledo A1 - Benitez, J. KW - 80 and over Breast Neoplasms/epidemiology/*genetics/pathology Case-Control Studies DNA-Binding Proteins/genetics/*physiology Female Finland/epidemiology Genes KW - Adult Aged Aged KW - Recessive Genetic Predisposition to Disease Genotype Humans Introns/genetics Linkage Disequilibrium Middle Aged Neoplasm Proteins/genetics/*physiology Neoplasm Staging *Polymorphism KW - Single Nucleotide Risk Spain/epidemiology AB - The failure of linkage studies to identify further high-penetrance susceptibility genes for breast cancer points to a polygenic model, with more common variants having modest effects on risk, as the most likely candidate. We have carried out a two-stage case-control study in two European populations to identify low-penetrance genes for breast cancer using high-throughput genotyping. Single-nucleotide polymorphisms (SNPs) were selected across preselected cancer-related genes, choosing tagSNPs and functional variants where possible. In stage 1, genotype frequencies for 640 SNPs in 111 genes were compared between 864 breast cancer cases and 845 controls from the Spanish population. In stage 2, candidate SNPs identified in stage 1 (nominal P < 0.01) were tested in a Finnish series of 884 cases and 1,104 controls. Of the 10 candidate SNPs in seven genes identified in stage 1, one (rs744154) on intron 1 of ERCC4, a gene belonging to the nucleotide excision repair pathway, was associated with recessive protection from breast cancer after adjustment for multiple testing in stage 2 (odds ratio, 0.57; Bonferroni-adjusted P = 0.04). After considering potential functional SNPs in the region of high linkage disequilibrium that extends across the entire gene and upstream into the promoter region, we concluded that rs744154 itself could be causal. Although intronic, it is located on the first intron, in a region that is highly conserved across species, and could therefore be functionally important. This study suggests that common intronic variation in ERCC4 is associated with protection from breast cancer. VL - 66 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17018596 N1 - Milne, Roger Laughlin Ribas, Gloria Gonzalez-Neira, Anna Fagerholm, Rainer Salas, Antonio Gonzalez, Emilio Dopazo, Joaquin Nevanlinna, Heli Robledo, Mercedes Benitez, Javier Comparative Study Multicenter Study Research Support, Non-U.S. Gov’t United States Cancer research Cancer Res. 2006 Oct 1;66(19):9420-7. ER - TY - JOUR T1 - Identification of overexpressed genes in frequently gained/amplified chromosome regions in multiple myeloma JF - Haematologica Y1 - 2006 A1 - Largo, C. A1 - Alvarez, S. A1 - Saez, B. A1 - Blesa, D. A1 - Martin-Subero, J. I. A1 - Gonzalez-Garcia, I. A1 - Brieva, J. A. A1 - Dopazo, J. A1 - Siebert, R. A1 - Calasanz, M. J. A1 - Cigudosa, J. C. KW - B-Cell KW - Caspases Cell Line KW - Human *Gene Amplification Gene Dosage Gene Expression Profiling *Gene Expression Regulation KW - Marginal Zone/genetics Multiple Myeloma/*genetics Neoplasm Proteins/genetics Proto-Oncogene Proteins c-bcl-2/genetics KW - Neoplasm Humans Immunoglobulin Heavy Chains/genetics Lymphoma KW - Neoplastic Gene Rearrangement *Genes KW - Tumor *Chromosomes AB - BACKGROUND AND OBJECTIVES: Multiple myeloma (MM) is a malignancy characterized by clonal expansion of plasma cells. In 50% of the cases, the neoplastic transformation begins with a chromosomal translocation that juxtaposes the IGH gene locus to an oncogene. Gene copy number changes are also frequent in MM but less characterized than in other neoplasias. We aimed to characterize genes that are amplified and overexpressed in human myeloma cell lines (HMCL) to provide putative molecular targets for MM therapy. DESIGN AND METHODS: Nine HMCL were characterized by fluorescent in situ hybridization, comparative genomic hybridization (CGH) and cDNA microarrays for gene expression profiling and copy number changes. RESULTS: After defining the IGH-translocations present in the cell lines, we conducted expression-profiling analysis. Supervised analysis identified 166 genes with significantly different expression among the cell lines harboring MMSET/FGFR3 (4p16), MAF (16q) and CCND1 (11q13) rearrangements. Array-CGH was then performed. Five chromosomes recurrently affected by gains/amplifications in primary samples and cell lines were analyzed in detail. Sixty amplified and overexpressed genes were found and 25 (42%) of them were only overexpressed when amplified; moreover, six showed a significant association between overexpression and gain/amplification. We also found co-amplification and overexpression for genes located within the same amplicons, such as MALT1 and BCL2. INTERPRETATION AND CONCLUSIONS: Parallel analysis of gene copy numbers and expression levels by cDNA microarray in MM allowed efficient identification of genes whose expression levels are elevated because of increased copy number. This is the first time that MALT1 and BCL2 have been shown to be overexpressed and amplified in MM. VL - 91 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16461302 N1 - Largo, Cristina Alvarez, Sara Saez, Borja Blesa, David Martin-Subero, Jose I Gonzalez-Garcia, Ines Brieva, Jose A Dopazo, Joaquin Siebert, Reiner Calasanz, Maria J Cigudosa, Juan C Research Support, Non-U.S. Gov’t Italy Haematologica Haematologica. 2006 Feb;91(2):184-91. ER - TY - JOUR T1 - MODBASE: a database of annotated comparative protein structure models and associated resources JF - Nucleic Acids Res Y1 - 2006 A1 - Pieper, U. A1 - Eswar, N. A1 - Davis, F. P. A1 - Braberg, H. A1 - Madhusudhan, M. S. A1 - Rossi, A. A1 - M. A. Marti-Renom A1 - Karchin, R. A1 - Webb, B. M. A1 - Eramian, D. A1 - Shen, M. Y. A1 - Kelly, L. A1 - Melo, F. A1 - Sali, A. KW - Binding Sites *Databases KW - Molecular Polymorphism KW - Protein Humans Internet Ligands *Models KW - Protein Systems Integration User-Computer Interface KW - Single Nucleotide Protein Structure KW - Tertiary Proteins/*chemistry/genetics/metabolism Software *Structural Homology AB - MODBASE (http://salilab.org/modbase) is a database of annotated comparative protein structure models for all available protein sequences that can be matched to at least one known protein structure. The models are calculated by MODPIPE, an automated modeling pipeline that relies on MODELLER for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE is updated regularly to reflect the growth in protein sequence and structure databases, and improvements in the software for calculating the models. MODBASE currently contains 3 094 524 reliable models for domains in 1 094 750 out of 1 817 889 unique protein sequences in the UniProt database (July 5, 2005); only models based on statistically significant alignments and models assessed to have the correct fold despite insignificant alignments are included. MODBASE also allows users to generate comparative models for proteins of interest with the automated modeling server MODWEB (http://salilab.org/modweb). Our other resources integrated with MODBASE include comprehensive databases of multiple protein structure alignments (DBAli, http://salilab.org/dbali), structurally defined ligand binding sites and structurally defined binary domain interfaces (PIBASE, http://salilab.org/pibase) as well as predictions of ligand binding sites, interactions between yeast proteins, and functional consequences of human nsSNPs (LS-SNP, http://salilab.org/LS-SNP). VL - 34 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16381869 N1 - Pieper, Ursula Eswar, Narayanan Davis, Fred P Braberg, Hannes Madhusudhan, M S Rossi, Andrea Marti-Renom, Marc Karchin, Rachel Webb, Ben M Eramian, David Shen, Min-Yi Kelly, Libusha Melo, Francisco Sali, Andrej GM 08284/GM/NIGMS NIH HHS/United States P50 GM62529/GM/NIGMS NIH HHS/United States R01 GM 54762/GM/NIGMS NIH HHS/United States R33 CA84699/CA/NCI NIH HHS/United States U54 GM074945/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t England Nucleic acids research Nucleic Acids Res. 2006 Jan 1;34(Database issue):D291-5. ER - TY - JOUR T1 - Next station in microarray data analysis: GEPAS JF - Nucleic Acids Res Y1 - 2006 A1 - Montaner, D. A1 - Tarraga, J. A1 - Huerta-Cepas, J. A1 - Burguet, J. A1 - Vaquerizas, J. M. A1 - L. Conde A1 - Minguez, P. A1 - Vera, J. A1 - Mukherjee, S. A1 - Valls, J. A1 - Pujana, M. A. A1 - Alloza, E. A1 - Herrero, J. A1 - Fatima Al-Shahrour A1 - Dopazo, J. KW - gepas KW - microarray data analysis AB -

The Gene Expression Profile Analysis Suite (GEPAS) has been running for more than four years. During this time it has evolved to keep pace with the new interests and trends in the still changing world of microarray data analysis. GEPAS has been designed to provide an intuitive although powerful web-based interface that offers diverse analysis options from the early step of preprocessing (normalization of Affymetrix and two-colour microarray experiments and other preprocessing options), to the final step of the functional annotation of the experiment (using Gene Ontology, pathways, PubMed abstracts etc.), and include different possibilities for clustering, gene selection, class prediction and array-comparative genomic hybridization management. GEPAS is extensively used by researchers of many countries and its records indicate an average usage rate of 400 experiments per day. The web-based pipeline for microarray gene expression data, GEPAS, is available at http://www.gepas.org.

VL - 34 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16845056 N1 -

Montaner, David Tarraga, Joaquin Huerta-Cepas, Jaime Burguet, Jordi Vaquerizas, Juan M Conde, Lucia Minguez, Pablo Vera, Javier Mukherjee, Sach Valls, Joan Pujana, Miguel A G Alloza, Eva Herrero, Javier Al-Shahrour, Fatima Dopazo, Joaquin Research Support, Non-U.S. Gov’t England Nucleic acids research Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W486-91.

ER - TY - JOUR T1 - Refinement of protein structures by iterative comparative modeling and CryoEM density fitting JF - J Mol Biol Y1 - 2006 A1 - Topf, M. A1 - Baker, M. L. A1 - M. A. Marti-Renom A1 - Chiu, W. A1 - Sali, A. KW - Amino Acid Sequence Cryoelectron Microscopy *Models KW - Molecular Molecular Sequence Data Plant Viruses/chemistry *Protein Conformation Software Viral Proteins/*chemistry/genetics AB - We developed a method for structure characterization of assembly components by iterative comparative protein structure modeling and fitting into cryo-electron microscopy (cryoEM) density maps. Specifically, we calculate a comparative model of a given component by considering many alternative alignments between the target sequence and a related template structure while optimizing the fit of a model into the corresponding density map. The method relies on the previously developed Moulder protocol that iterates over alignment, model building, and model assessment. The protocol was benchmarked using 20 varied target-template pairs of known structures with less than 30% sequence identity and corresponding simulated density maps at resolutions from 5A to 25A. Relative to the models based on the best existing sequence profile alignment methods, the percentage of C(alpha) atoms that are within 5A of the corresponding C(alpha) atoms in the superposed native structure increases on average from 52% to 66%, which is half-way between the starting models and the models from the best possible alignments (82%). The test also reveals that despite the improvements in the accuracy of the fitness function, this function is still the bottleneck in reducing the remaining errors. To demonstrate the usefulness of the protocol, we applied it to the upper domain of the P8 capsid protein of rice dwarf virus that has been studied by cryoEM at 6.8A. The C(alpha) root-mean-square deviation of the model based on the remotely related template, bluetongue virus VP7, improved from 8.7A to 6.0A, while the best possible model has a C(alpha) RMSD value of 5.3A. Moreover, the resulting model fits better into the cryoEM density map than the initial template structure. The method is being implemented in our program MODELLER for protein structure modeling by satisfaction of spatial restraints and will be applicable to the rapidly increasing number of cryoEM density maps of macromolecular assemblies. VL - 357 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16490207 N1 - Topf, Maya Baker, Matthew L Marti-Renom, Marc A Chiu, Wah Sali, Andrej 2 PN2 EY016525-02/EY/NEI NIH HHS/United States P20RR020647/RR/NCRR NIH HHS/United States P41RR02250/RR/NCRR NIH HHS/United States R01 GM54762/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S. England Journal of molecular biology J Mol Biol. 2006 Apr 14;357(5):1655-68. Epub 2006 Feb 2. ER - TY - JOUR T1 - Selective pressures at a codon-level predict deleterious mutations in human disease genes JF - J Mol Biol Y1 - 2006 A1 - Arbiza, L. A1 - Duchi, S. A1 - Montaner, D. A1 - Burguet, J. A1 - Pantoja-Uceda, D. A1 - Pineda-Lucena, A. A1 - Dopazo, J. A1 - H. Dopazo KW - Amino Acid Sequence Amino Acid Substitution Codon/*genetics Databases KW - Genetic Evolution KW - Genetic Models KW - Human Humans Models KW - Inborn/*genetics Genome KW - Molecular Genes KW - Molecular Molecular Sequence Data *Mutation Neoplasms/genetics Proteins/genetics *Selection (Genetics) Tumor Suppressor Protein p53/chemistry/genetics KW - p53 Genetic Diseases AB - Deleterious mutations affecting biological function of proteins are constantly being rejected by purifying selection from the gene pool. The non-synonymous/synonymous substitution rate ratio (omega) is a measure of selective pressure on amino acid replacement mutations for protein-coding genes. Different methods have been developed in order to predict non-synonymous changes affecting gene function. However, none has considered the estimation of selective constraints acting on protein residues. Here, we have used codon-based maximum likelihood models in order to estimate the selective pressures on the individual amino acid residues of a well-known model protein: p53. We demonstrate that the number of residues under strong purifying selection in p53 is much higher than those that are strictly conserved during the evolution of the species. In agreement with theoretical expectations, residues that have been noted to be of structural relevance, or in direct association with DNA, were among those showing the highest signals of purifying selection. Conversely, those changing according to a neutral, or nearly neutral mode of evolution, were observed to be irrelevant for protein function. Finally, using more than 40 human disease genes, we demonstrate that residues evolving under strong selective pressures (omega<0.1) are significantly associated (p<0.01) with human disease. We hypothesize that non-synonymous change on amino acids showing omega<0.1 will most likely affect protein function. The application of this evolutionary prediction at a genomic scale will provide an a priori hypothesis of the phenotypic effect of non-synonymous coding single nucleotide polymorphisms (SNPs) in the human genome. VL - 358 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16584746 N1 - Arbiza, Leonardo Duchi, Serena Montaner, David Burguet, Jordi Pantoja-Uceda, David Pineda-Lucena, Antonio Dopazo, Joaquin Dopazo, Hernan Research Support, Non-U.S. Gov’t England Journal of molecular biology J Mol Biol. 2006 May 19;358(5):1390-404. Epub 2006 Mar 15. ER - TY - JOUR T1 - An anaerobic mitochondrion that produces hydrogen JF - Nature Y1 - 2005 A1 - Boxma, B. A1 - de Graaf, R. M. A1 - van der Staay, G. W. A1 - van Alen, T. A. A1 - Ricard, G. A1 - Gabaldón, T. A1 - van Hoek, A. H. A1 - Moon-van der Staay, S. Y. A1 - Koopman, W. J. A1 - van Hellemond, J. J. A1 - Tielens, A. G. A1 - Friedrich, T. A1 - Veenhuis, M. A1 - M. A. Huynen A1 - Hackstein, J. H. KW - *Anaerobiosis Animals Ciliophora/*cytology/genetics/*metabolism/ultrastructure Cockroaches/parasitology DNA KW - Mitochondrial/genetics Electron Transport Electron Transport Complex I/antagonists & inhibitors/metabolism Genome Glucose/metabolism Hydrogen/*metabolism Mitochondria/enzymology/genetics/*metabolism/ultrastructure Molecular Sequence Data Open Reading Fra AB - Hydrogenosomes are organelles that produce ATP and hydrogen, and are found in various unrelated eukaryotes, such as anaerobic flagellates, chytridiomycete fungi and ciliates. Although all of these organelles generate hydrogen, the hydrogenosomes from these organisms are structurally and metabolically quite different, just like mitochondria where large differences also exist. These differences have led to a continuing debate about the evolutionary origin of hydrogenosomes. Here we show that the hydrogenosomes of the anaerobic ciliate Nyctotherus ovalis, which thrives in the hindgut of cockroaches, have retained a rudimentary genome encoding components of a mitochondrial electron transport chain. Phylogenetic analyses reveal that those proteins cluster with their homologues from aerobic ciliates. In addition, several nucleus-encoded components of the mitochondrial proteome, such as pyruvate dehydrogenase and complex II, were identified. The N. ovalis hydrogenosome is sensitive to inhibitors of mitochondrial complex I and produces succinate as a major metabolic end product–biochemical traits typical of anaerobic mitochondria. The production of hydrogen, together with the presence of a genome encoding respiratory chain components, and biochemical features characteristic of anaerobic mitochondria, identify the N. ovalis organelle as a missing link between mitochondria and hydrogenosomes. VL - 434 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15744302 N1 - Boxma, Brigitte de Graaf, Rob M van der Staay, Georg W M van Alen, Theo A Ricard, Guenola Gabaldon, Toni van Hoek, Angela H A M Moon-van der Staay, Seung Yeo Koopman, Werner J H van Hellemond, Jaap J Tielens, Aloysius G M Friedrich, Thorsten Veenhuis, Marten Huynen, Martijn A Hackstein, Johannes H P Research Support, Non-U.S. Gov’t England Nature Nature. 2005 Mar 3;434(7029):74-9. ER - TY - JOUR T1 - Development of a citrus genome-wide EST collection and cDNA microarray as resources for genomic studies JF - Plant Mol Biol Y1 - 2005 A1 - J. Forment A1 - J. Gadea A1 - Huerta, L. A1 - Abizanda, L. A1 - Agusti, J. A1 - Alamar, S. A1 - Alos, E. A1 - Andres, F. A1 - Arribas, R. A1 - Beltran, J. P. A1 - Berbel, A. A1 - Blazquez, M. A. A1 - Brumos, J. A1 - Canas, L. A. A1 - Cercos, M. A1 - Colmenero-Flores, J. M. A1 - A. Conesa A1 - Estables, B. A1 - Gandia, M. A1 - Garcia-Martinez, J. L. A1 - Gimeno, J. A1 - Gisbert, A. A1 - Gomez, G. A1 - Gonzalez-Candelas, L. A1 - Granell, A. A1 - Guerri, J. A1 - Lafuente, M. T. A1 - Madueno, F. A1 - Marcos, J. F. A1 - Marques, M. C. A1 - Martinez, F. A1 - Martinez-Godoy, M. A. A1 - Miralles, S. A1 - Moreno, P. A1 - Navarro, L. A1 - Pallas, V. A1 - Perez-Amador, M. A. A1 - Perez-Valle, J. A1 - Pons, C. A1 - Rodrigo, I. A1 - Rodriguez, P. L. A1 - Royo, C. A1 - Serrano, R. A1 - Soler, G. A1 - Tadeo, F. A1 - Talon, M. A1 - Terol, J. A1 - Trenor, M. A1 - Vaello, L. A1 - Vicente, O. A1 - Vidal, Ch A1 - Zacarias, L. A1 - Conejero, V. KW - Citrus/*genetics DNA KW - Complementary/chemistry/genetics *Expressed Sequence Tags Gene Expression Profiling Gene Library *Genome KW - DNA KW - Plant Genomics/*methods Molecular Sequence Data Oligonucleotide Array Sequence Analysis/*methods RNA KW - Plant/genetics/metabolism Reproducibility of Results Sequence Analysis AB - A functional genomics project has been initiated to approach the molecular characterization of the main biological and agronomical traits of citrus. As a key part of this project, a citrus EST collection has been generated from 25 cDNA libraries covering different tissues, developmental stages and stress conditions. The collection includes a total of 22,635 high-quality ESTs, grouped in 11,836 putative unigenes, which represent at least one third of the estimated number of genes in the citrus genome. Functional annotation of unigenes which have Arabidopsis orthologues (68% of all unigenes) revealed gene representation in every major functional category, suggesting that a genome-wide EST collection was obtained. A Citrus clementina Hort. ex Tan. cv. Clemenules genomic library, that will contribute to further characterization of relevant genes, has also been constructed. To initiate the analysis of citrus transcriptome, we have developed a cDNA microarray containing 12,672 probes corresponding to 6875 putative unigenes of the collection. Technical characterization of the microarray showed high intra- and inter-array reproducibility, as well as a good range of sensitivity. We have also validated gene expression data achieved with this microarray through an independent technique such as RNA gel blot analysis. VL - 57 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15830128 N1 - Forment, J Gadea, J Huerta, L Abizanda, L Agusti, J Alamar, S Alos, E Andres, F Arribas, R Beltran, J P Berbel, A Blazquez, M A Brumos, J Canas, L A Cercos, M Colmenero-Flores, J M Conesa, A Estables, B Gandia, M Garcia-Martinez, J L Gimeno, J Gisbert, A Gomez, G Gonzalez-Candelas, L Granell, A Guerri, J Lafuente, M T Madueno, F Marcos, J F Marques, M C Martinez, F Martinez-Godoy, M A Miralles, S Moreno, P Navarro, L Pallas, V Perez-Amador, M A Perez-Valle, J Pons, C Rodrigo, I Rodriguez, P L Royo, C Serrano, R Soler, G Tadeo, F Talon, M Terol, J Trenor, M Vaello, L Vicente, O Vidal, Ch Zacarias, L Conejero, V Comparative Study Research Support, U.S. Gov’t, Non-P.H.S. Netherlands Plant molecular biology Plant Mol Biol. 2005 Feb;57(3):375-91. ER - TY - JOUR T1 - A novel candidate region linked to development of both pheochromocytoma and head/neck paraganglioma JF - Genes Chromosomes Cancer Y1 - 2005 A1 - Cascon, A. A1 - Ruiz-Llorente, S. A1 - Rodriguez-Perales, S. A1 - Honrado, E. A1 - Martinez-Ramirez, A. A1 - Leton, R. A1 - Montero-Conde, C. A1 - Benitez, J. A1 - Dopazo, J. A1 - Cigudosa, J. C. A1 - M. Robledo KW - 80 and over Child Chromosomes KW - Adolescent Adrenal Gland Neoplasms/*genetics Adult Aged Aged KW - Biological/*genetics KW - Human KW - Pair 1/genetics Chromosomes KW - Pair 11/genetics Chromosomes KW - Pair 3/genetics Chromosomes KW - Pair 8/genetics Female Gene Deletion Head and Neck Neoplasms/*genetics Humans Male Middle Aged Nucleic Acid Hybridization Paraganglioma/*genetics Pheochromocytoma/*genetics Tumor Markers AB - Although the histologic distinction between pheochromocytomas and head and neck paragangliomas is clear, little is known about the genetic differences between them. To date, various sets of genes have been found to be involved in inherited susceptibility to developing both tumor types, but the genes involved in sporadic pathogenesis are still unknown. To define new candidate regions, we performed CGH analysis on 29 pheochromocytomas and on 24 paragangliomas mainly of head and neck origin (20 of 24), which allowed us to differentiate between the two tumor types. Loss of 3q was significantly more frequent in pheochromocytomas, and loss of 1q appeared only in paragangliomas. We also found gain of 11q13 to be a significantly frequent alteration in malignant cases of both types. In addition, recurrent loss of 8p22-23 was found in 62% of pheochromocytomas (including all malignant cases) versus in 33% of paragangliomas, suggesting that this region contains candidate genes involved in the pathogenesis of this abnormality. Using FISH analysis on tissue microarrays, we confirmed genomic deletion of this region in 55% of pheochromocytomas compared to 12% of paragangliomas. Loss of 8p22-23 appears to be an important event in the sporadic development of these tumors, and additional molecular studies are necessary to identify candidate genes in this chromosomal region. VL - 42 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15609347 N1 - Cascon, Alberto Ruiz-Llorente, Sergio Rodriguez-Perales, Sandra Honrado, Emiliano Martinez-Ramirez, Angel Leton, Rocio Montero-Conde, Cristina Benitez, Javier Dopazo, Joaquin Cigudosa, Juan C Robledo, Mercedes Research Support, Non-U.S. Gov’t United States Genes, chromosomes & cancer Genes Chromosomes Cancer. 2005 Mar;42(3):260-8. ER - TY - JOUR T1 - Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers JF - Breast Cancer Res Treat Y1 - 2005 A1 - Palacios, J. A1 - Honrado, E. A1 - Osorio, A. A1 - Cazorla, A. A1 - Sarrio, D. A1 - Barroso, A. A1 - Rodriguez, S. A1 - Cigudosa, J. C. A1 - Diez, O. A1 - Alonso, C. A1 - Lerma, E. A1 - Dopazo, J. A1 - Rivas, C. A1 - Benitez, J. KW - Adult Apoptosis Breast Neoplasms/*genetics/*pathology Cell Cycle Proteins Cluster Analysis Female *Genes KW - Biological/genetics/metabolism KW - BRCA1 *Genes KW - BRCA2 Humans Immunohistochemistry In Situ Hybridization KW - Fluorescence Phenotype Spain *Tissue Array Analysis *Tumor Markers AB - Familial breast cancers that are associated with BRCA1 or BRCA2 germline mutations differ in both their morphological and immunohistochemical characteristics. To further characterize the molecular difference between genotypes, the authors evaluated the expression of 37 immunohistochemical markers in a tissue microarray (TMA) containing cores from 20 BRCA1, 14 BRCA2, and 59 sporadic age-matched breast carcinomas. Markers analyzed included, amog others, common markers in breast cancer, such as hormone receptors, p53 and HER2, along with 15 molecules involved in cell cycle regulation, such as cyclins, cyclin dependent kinases (CDK) and CDK inhibitors (CDKI), apoptosis markers, such as BCL2 and active caspase 3, and two basal/myoepithelial markers (CK 5/6 and P-cadherin). In addition, we analyzed the amplification of CCND1, CCNE, HER2 and MYC by FISH.Unsupervised cluster data analysis of both hereditary and sporadic cases using the complete set of immunohistochemical markers demonstrated that most BRCA1-associated carcinomas grouped in a branch of ER-, HER2-negative tumors that expressed basal cell markers and/or p53 and had higher expression of activated caspase 3. The cell cycle proteins associated with these tumors were E2F6, cyclins A, B1 and E, SKP2 and Topo IIalpha. In contrast, most BRCA2-associated carcinomas grouped in a branch composed by ER/PR/BCL2-positive tumors with a higher expression of the cell cycle proteins cyclin D1, cyclin D3, p27, p16, p21, CDK4, CDK2 and CDK1. In conclusion, our study in hereditary breast cancer tumors analyzing 37 immunohistochemical markers, define the molecular differences between BRCA1 and BRCA2 tumors with respect to hormonal receptors, cell cycle, apoptosis and basal cell markers. VL - 90 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15770521 N1 - Palacios, Jose Honrado, Emiliano Osorio, Ana Cazorla, Alicia Sarrio, David Barroso, Alicia Rodriguez, Sandra Cigudosa, Juan C Diez, Orland Alonso, Carmen Lerma, Enrique Dopazo, Joaquin Rivas, Carmen Benitez, Javier Research Support, Non-U.S. Gov’t Netherlands Breast cancer research and treatment Breast Cancer Res Treat. 2005 Mar;90(1):5-14. ER - TY - JOUR T1 - A predictor based on the somatic genomic changes of the BRCA1/BRCA2 breast cancer tumors identifies the non-BRCA1/BRCA2 tumors with BRCA1 promoter hypermethylation JF - Clin Cancer Res Y1 - 2005 A1 - Alvarez, S. A1 - Diaz-Uriarte, R. A1 - Osorio, A. A1 - Barroso, A. A1 - Melchor, L. A1 - Paz, M. F. A1 - Honrado, E. A1 - Rodriguez, R. A1 - Urioste, M. A1 - Valle, L. A1 - Diez, O. A1 - Cigudosa, J. C. A1 - Dopazo, J. A1 - Esteller, M. A1 - Benitez, J. KW - BRCA1 Protein/*genetics BRCA2 Protein/*genetics Breast Neoplasms/*genetics/pathology Chromosomes KW - Genetic/*genetics KW - Human KW - Human Humans Male Mutation Nucleic Acid Hybridization/methods Promoter Regions KW - Pair 12/genetics Chromosomes KW - Pair 15/genetics Chromosomes KW - Pair 18/genetics Chromosomes KW - Pair 2/genetics Chromosomes KW - Pair 8/genetics *DNA Methylation Female Genome AB - The genetic changes underlying in the development and progression of familial breast cancer are poorly understood. To identify a somatic genetic signature of tumor progression for each familial group, BRCA1, BRCA2, and non-BRCA1/BRCA2 (BRCAX) tumors, by high-resolution comparative genomic hybridization, we have analyzed 77 tumors previously characterized for BRCA1 and BRCA2 germ line mutations. Based on a combination of the somatic genetic changes observed at the six most different chromosomal regions and the status of the estrogen receptor, we developed using random forests a molecular classifier, which assigns to a given tumor a probability to belong either to the BRCA1 or to the BRCA2 class. Because 76.5% (26 of 34) of the BRCAX cases were classified with our predictor to the BRCA1 class with a probability of >50%, we analyzed the BRCA1 promoter region for aberrant methylation in all the BRCAX cases. We found that 15 of the 34 BRCAX analyzed tumors had hypermethylation of the BRCA1 gene. When we considered the predictor, we observed that all the cases with this epigenetic event were assigned to the BRCA1 class with a probability of >50%. Interestingly, 84.6% of the cases (11 of 13) assigned to the BRCA1 class with a probability >80% had an aberrant methylation of the BRCA1 promoter. This fact suggests that somatic BRCA1 inactivation could modify the profile of tumor progression in most of the BRCAX cases. VL - 11 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15709182 N1 - Alvarez, Sara Diaz-Uriarte, Ramon Osorio, Ana Barroso, Alicia Melchor, Lorenzo Paz, Maria Fe Honrado, Emiliano Rodriguez, Raquel Urioste, Miguel Valle, Laura Diez, Orland Cigudosa, Juan Cruz Dopazo, Joaquin Esteller, Manel Benitez, Javier Comparative Study Research Support, Non-U.S. Gov’t United States Clinical cancer research : an official journal of the American Association for Cancer Research Clin Cancer Res. 2005 Feb 1;11(3):1146-53. ER - TY - CHAP T1 - Salinibacter ruber: genomics and biogeography T2 - Adaptation to life in high salt concentrations in Archaea, Bacteria and Eukarya Y1 - 2005 A1 - Antón, J A1 - Peña, A A1 - Valens, M A1 - Santos, F A1 - Glöckner, F.O A1 - Bauer, M A1 - Dopazo, J. A1 - Herrero, J. A1 - Rosselló-Mora, R A1 - Amann, R JF - Adaptation to life in high salt concentrations in Archaea, Bacteria and Eukarya PB - Nina Gunde-Cimerman, Ana Plemenitas, and Aharon Oren. Kluwer Academic Publishers CY - Dordrecht, Netherlands VL - 9 ER - TY - JOUR T1 - Expression profiling of T-cell lymphomas differentiates peripheral and lymphoblastic lymphomas and defines survival related genes. JF - Clinical cancer research : an official journal of the American Association for Cancer Research Y1 - 2004 A1 - Martinez-Delgado, Beatriz A1 - Meléndez, Barbara A1 - Cuadros, Marta A1 - Alvarez, Javier A1 - Castrillo, Jose Maria A1 - Ruiz De La Parte, Ana A1 - Mollejo, Manuela A1 - Bellas, Carmen A1 - Diaz, Ramon A1 - Lombardía, Luis A1 - Fatima Al-Shahrour A1 - Domínguez, Orlando A1 - Cascon, Alberto A1 - Robledo, Mercedes A1 - Rivas, Carmen A1 - Benitez, Javier AB -

PURPOSE: T-Cell lymphomas constitute heterogeneous and aggressive tumors in which pathogenic alterations remain largely unknown. Expression profiling has demonstrated to be a useful tool for molecular classification of tumors. EXPERIMENTAL DESIGN: Using DNA microarrays (CNIO-OncoChip) containing 6386 cancer-related genes, we established the expression profiling of T-cell lymphomas and compared them to normal lymphocytes and lymph nodes. RESULTS: We found significant differences between the peripheral and lymphoblastic T-cell lymphomas, which include a deregulation of nuclear factor-kappaB signaling pathway. We also identify differentially expressed genes between peripheral T-cell lymphoma tumors and normal T lymphocytes or reactive lymph nodes, which could represent candidate tumor markers of these lymphomas. Additionally, a close relationship between genes associated to survival and those that differentiate among the stages of disease and responses to therapy was found. CONCLUSIONS: Our results reflect the value of gene expression profiling to gain insight about the molecular alterations involved in the pathogenesis of T-cell lymphomas.

VL - 10 UR - http://clincancerres.aacrjournals.org/content/10/15/4971.long ER - TY - JOUR T1 - Gene expression analysis of chromosomal regions with gain or loss of genetic material detected by comparative genomic hybridization JF - Genes Chromosomes Cancer Y1 - 2004 A1 - Melendez, B. A1 - Diaz-Uriarte, R. A1 - Cuadros, M. A1 - Martinez-Ramirez, A. A1 - Fernandez-Piqueras, J. A1 - Dopazo, A. A1 - Cigudosa, J. C. A1 - Rivas, C. A1 - Dopazo, J. A1 - Martinez-Delgado, B. A1 - Benitez, J. KW - Chromosomes KW - Fluorescence Lymphoma KW - Human KW - Pair 13/*genetics Chromosomes KW - Pair 19/*genetics Chromosomes KW - Pair 6/*genetics Expressed Sequence Tags *Gene Dosage Gene Expression Profiling Humans In Situ Hybridization KW - T-Cell/*genetics Nucleic Acid Hybridization Oligonucleotide Array Sequence Analysis AB - Comparative genomic hybridization (CGH) has been widely used to detect copy number alterations in cancer and to identify regions containing candidate tumor-responsible genes; however, gene expression changes have been described only in highly amplified regions (amplicons). To study the overall impact of slight copy number changes on gene expression, we analyzed 16 T-cell lymphomas by using CGH and a custom-designed cDNA microarray containing 7,657 genes and expressed sequence tags related to tumorigenesis. We evaluated mean gene expression and variability within CGH-altered regions and explored the relationship between the effects of the gene and its position within these regions. Minimally overlapping CGH candidate areas (6q25, 13q21-q22, and 19q13.1) revealed a weak relationship between altered genomic content and gene expression. However, some candidate genes showed modified expression within these regions in the majority of tumors; these candidate genes were evaluated and confirmed in another independent series of 23 T-cell lymphomas by use of the same cDNA microarray and by FISH on a tissue microarray. When all the CGH regions detected for each tumor were considered, we found a significant increase or decrease in the mean expression of the genes contained in gained or lost regions, respectively. In addition, we found that the expression of a gene was dependent not only on its position within an altered region but also on its own mechanism of regulation: genes in the same altered region responded very differently to the gain or loss of genetic material. Supplementary material for this article can be found on the Genes, Chromosomes, and Cancer website at http://www.interscience.wiley.com/jpages/1045-2257/suppmat/index.html. VL - 41 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15382261 N1 - Melendez, Barbara Diaz-Uriarte, Ramon Cuadros, Marta Martinez-Ramirez, Angel Fernandez-Piqueras, Jose Dopazo, Ana Cigudosa, Juan-Cruz Rivas, Carmen Dopazo, Joaquin Martinez-Delgado, Beatriz Benitez, Javier Research Support, Non-U.S. Gov’t United States Genes, chromosomes & cancer Genes Chromosomes Cancer. 2004 Dec;41(4):353-65. ER - TY - CHAP T1 - Gene expression Correlation and Gene Ontology-Based Similarity: An Assessment of Quantitative Relationship T2 - IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology Y1 - 2004 A1 - Wang, H A1 - F. Azuaje A1 - Bodenreider, O A1 - Dopazo, J. JF - IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology ER - TY - JOUR T1 - MODBASE, a database of annotated comparative protein structure models, and associated resources JF - Nucleic Acids Res Y1 - 2004 A1 - Pieper, U. A1 - Eswar, N. A1 - Braberg, H. A1 - Madhusudhan, M. S. A1 - Davis, F. P. A1 - Stuart, A. C. A1 - Mirkovic, N. A1 - Rossi, A. A1 - M. A. Marti-Renom A1 - Fiser, A. A1 - Webb, B. A1 - Greenblatt, D. A1 - Huang, C. C. A1 - Ferrin, T. E. A1 - Sali, A. KW - Amino Acid Sequence Animals Binding Sites *Computational Biology *Databases KW - Molecular Molecular Sequence Data Polymorphism KW - Protein Genomics Humans Internet Ligands Models KW - Single Nucleotide Protein Binding Protein Conformation Proteins/*chemistry/genetics Sequence Alignment Software User-Computer Interface AB - MODBASE (http://salilab.org/modbase) is a relational database of annotated comparative protein structure models for all available protein sequences matched to at least one known protein structure. The models are calculated by MODPIPE, an automated modeling pipeline that relies on the MODELLER package for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE uses the MySQL relational database management system for flexible querying and CHIMERA for viewing the sequences and structures (http://www.cgl.ucsf.edu/chimera/). MODBASE is updated regularly to reflect the growth in protein sequence and structure databases, as well as improvements in the software for calculating the models. For ease of access, MODBASE is organized into different data sets. The largest data set contains 1,26,629 models for domains in 659,495 out of 1,182,126 unique protein sequences in the complete Swiss-Prot/TrEMBL database (August 25, 2003); only models based on alignments with significant similarity scores and models assessed to have the correct fold despite insignificant alignments are included. Another model data set supports target selection and structure-based annotation by the New York Structural Genomics Research Consortium; e.g. the 53 new structures produced by the consortium allowed us to characterize structurally 24,113 sequences. MODBASE also contains binding site predictions for small ligands and a set of predicted interactions between pairs of modeled sequences from the same genome. Our other resources associated with MODBASE include a comprehensive database of multiple protein structure alignments (DBALI, http://salilab.org/dbali) as well as web servers for automated comparative modeling with MODPIPE (MODWEB, http://salilab. org/modweb), modeling of loops in protein structures (MODLOOP, http://salilab.org/modloop) and predicting functional consequences of single nucleotide polymorphisms (SNPWEB, http://salilab. org/snpweb). VL - 32 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14681398 N1 - Pieper, Ursula Eswar, Narayanan Braberg, Hannes Madhusudhan, M S Davis, Fred P Stuart, Ashley C Mirkovic, Nebojsa Rossi, Andrea Marti-Renom, Marc A Fiser, Andras Webb, Ben Greenblatt, Daniel Huang, Conrad C Ferrin, Thomas E Sali, Andrej P41 RR01081/RR/NCRR NIH HHS/United States P50 GM62529/GM/NIGMS NIH HHS/United States R01 GM 54762/GM/NIGMS NIH HHS/United States R33 CA84699/CA/NCI NIH HHS/United States Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S. England Nucleic acids research Nucleic Acids Res. 2004 Jan 1;32(Database issue):D217-22. ER - TY - JOUR T1 - Bioinformatics methods for the analysis of expression arrays: data clustering and information extraction JF - J Biotechnol Y1 - 2002 A1 - J. Tamames A1 - Clark, D. A1 - Herrero, J. A1 - Dopazo, J. A1 - Blaschke, C. A1 - Fernandez, J. M. A1 - Oliveros, J. C. A1 - Valencia, A. KW - Abstracting and Indexing as Topic/methods *Cluster Analysis *Database Management Systems Databases KW - Computer-Assisted/methods Information Storage and Retrieval/*methods Internet Medline National Library of Medicine (U.S.) Oligonucleotide Array Sequence Analysis/*methods United States KW - Genetic Gene Expression Gene Expression Profiling/*methods Image Processing AB - Expression arrays facilitate the monitoring of changes in the expression patterns of large collections of genes. The analysis of expression array data has become a computationally-intensive task that requires the development of bioinformatics technology for a number of key stages in the process, such as image analysis, database storage, gene clustering and information extraction. Here, we review the current trends in each of these areas, with particular emphasis on the development of the related technology being carried out within our groups. VL - 98 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12141992 N1 - Tamames, Javier Clark, Dominic Herrero, Javier Dopazo, Joaquin Blaschke, Christian Fernandez, Jose M Oliveros, Juan C Valencia, Alfonso Review Netherlands Journal of biotechnology J Biotechnol. 2002 Sep 25;98(2-3):269-83. ER - TY - JOUR T1 - Annotated draft genomic sequence from a Streptococcus pneumoniae type 19F clinical isolate JF - Microb Drug Resist Y1 - 2001 A1 - Dopazo, J. A1 - Mendoza, A. A1 - Herrero, J. A1 - Caldara, F. A1 - Humbert, Y. A1 - Friedli, L. A1 - Guerrier, M. A1 - Grand-Schenk, E. A1 - Gandin, C. A1 - de Francesco, M. A1 - Polissi, A. A1 - Buell, G. A1 - Feger, G. A1 - Garcia, E. A1 - Peitsch, M. A1 - Garcia-Bustos, J. F. KW - Bacterial Molecular Sequence Data Pneumococcal Infections/*microbiology Prokaryotic Cells RNA KW - Bacterial/chemistry/genetics Genes KW - Bacterial/genetics *Genome KW - DNA KW - Transfer/metabolism Streptococcus pneumoniae/*genetics AB - The public availability of numerous microbial genomes is enabling the analysis of bacterial biology in great detail and with an unprecedented, organism-wide and taxon-wide, broad scope. Streptococcus pneumoniae is one of the most important bacterial pathogens throughout the world. We present here sequences and functional annotations for 2.1-Mbp of pneumococcal DNA, covering more than 90% of the total estimated size of the genome. The sequenced strain is a clinical isolate resistant to macrolides and tetracycline. It carries a type 19F capsular locus, but multilocus sequence typing for several conserved genetic loci suggests that the strain sequenced belongs to a pneumococcal lineage that most often expresses a serotype 15 capsular polysaccharide. A total of 2,046 putative open reading frames (ORFs) longer than 100 amino acids were identified (average of 1,009 bp per ORF), including all described two-component systems and aminoacyl tRNA synthetases. Comparisons to other complete, or nearly complete, bacterial genomes were made and are presented in a graphical form for all the predicted proteins. VL - 7 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11442348 N1 - Dopazo, J Mendoza, A Herrero, J Caldara, F Humbert, Y Friedli, L Guerrier, M Grand-Schenk, E Gandin, C de Francesco, M Polissi, A Buell, G Feger, G Garcia, E Peitsch, M Garcia-Bustos, J F United States Microbial drug resistance (Larchmont, N.Y.) Microb Drug Resist. 2001 Summer;7(2):99-125. ER -