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 - 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 - Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis. JF - Cell Rep Y1 - 2023 A1 - Pellegrinelli, Vanessa A1 - Figueroa-Juárez, Elizabeth A1 - Samuelson, Isabella A1 - U-Din, Mueez A1 - Rodriguez-Fdez, Sonia A1 - Virtue, Samuel A1 - Leggat, Jennifer A1 - Cubuk, Cankut A1 - Peirce, Vivian J A1 - Niemi, Tarja A1 - Campbell, Mark A1 - Rodriguez-Cuenca, Sergio A1 - Dopazo, Joaquin A1 - Carobbio, Stefania A1 - Virtanen, Kirsi A A1 - Vidal-Puig, Antonio AB -

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

VL - 42 IS - 6 ER - TY - JOUR T1 - Detection of High Level of Co-Infection and the Emergence of Novel SARS CoV-2 Delta-Omicron and Omicron-Omicron Recombinants in the Epidemiological Surveillance of Andalusia. JF - Int J Mol Sci Y1 - 2023 A1 - Perez-Florido, Javier A1 - Casimiro-Soriguer, Carlos S A1 - Ortuno, Francisco A1 - Fernandez-Rueda, Jose L A1 - Aguado, Andrea A1 - Lara, María A1 - Riazzo, Cristina A1 - Rodriguez-Iglesias, Manuel A A1 - Camacho-Martinez, Pedro A1 - Merino-Diaz, Laura A1 - Pupo-Ledo, Inmaculada A1 - de Salazar, Adolfo A1 - Viñuela, Laura A1 - Fuentes, Ana A1 - Chueca, Natalia A1 - García, Federico A1 - Dopazo, Joaquin A1 - Lepe, Jose A AB -

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

VL - 24 IS - 3 ER - TY - JOUR T1 - Evaluation of a combined detection of SARS-CoV-2 and its variants using real-time allele-specific PCR strategy: an advantage for clinical practice. JF - Epidemiol Infect Y1 - 2023 A1 - Chaves-Blanco, Lucía A1 - de Salazar, Adolfo A1 - Fuentes, Ana A1 - Viñuela, Laura A1 - Perez-Florido, Javier A1 - Dopazo, Joaquin A1 - García, Federico KW - Alleles KW - COVID-19 KW - COVID-19 Testing KW - Humans KW - Real-Time Polymerase Chain Reaction KW - SARS-CoV-2 KW - Sensitivity and Specificity AB -

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

VL - 151 ER - TY - JOUR T1 - Visualization of automatically combined disease maps and pathway diagrams for rare diseases. JF - Front Bioinform Y1 - 2023 A1 - Gawron, Piotr A1 - Hoksza, David A1 - Piñero, Janet A1 - Peña-Chilet, Maria A1 - Esteban-Medina, Marina A1 - Fernandez-Rueda, Jose Luis A1 - Colonna, Vincenza A1 - Smula, Ewa A1 - Heirendt, Laurent A1 - Ancien, François A1 - Grouès, Valentin A1 - Satagopam, Venkata P A1 - Schneider, Reinhard A1 - Dopazo, Joaquin A1 - Furlong, Laura I A1 - Ostaszewski, Marek AB -

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

VL - 3 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 - 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 - 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 - 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 - DOME: recommendations for supervised machine learning validation in biology. JF - Nat Methods Y1 - 2021 A1 - Walsh, Ian A1 - Fishman, Dmytro A1 - Garcia-Gasulla, Dario A1 - Titma, Tiina A1 - Pollastri, Gianluca A1 - Harrow, Jennifer A1 - Psomopoulos, Fotis E A1 - Tosatto, Silvio C E KW - Algorithms KW - Computational Biology KW - Guidelines as Topic KW - Humans KW - Models, Biological KW - Research Design KW - Supervised Machine Learning VL - 18 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/34316068?dopt=Abstract ER - TY - JOUR T1 - Genome-scale mechanistic modeling of signaling pathways made easy: A bioconductor/cytoscape/web server framework for the analysis of omic data JF - Computational and Structural Biotechnology Journal Y1 - 2021 A1 - Rian, Kinza A1 - Hidalgo, Marta R. A1 - Cubuk, Cankut A1 - Falco, Matias M. A1 - Loucera, Carlos A1 - Esteban-Medina, Marina A1 - Alamo-Alvarez, Inmaculada A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin VL - 19 UR - https://linkinghub.elsevier.com/retrieve/pii/S2001037021002038 JO - Computational and Structural Biotechnology Journal 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 - Mechanistic modeling of the SARS-CoV-2 disease map. JF - BioData Min Y1 - 2021 A1 - Rian, Kinza A1 - Esteban-Medina, Marina A1 - Hidalgo, Marta R A1 - Cubuk, Cankut A1 - Falco, Matias M A1 - Loucera, Carlos A1 - Gunyel, Devrim A1 - Ostaszewski, Marek A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin AB -

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

VL - 14 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/33478554?dopt=Abstract 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 - Phylogenetic Analysis of the 2020 West Nile Virus (WNV) Outbreak in Andalusia (Spain) JF - Viruses Y1 - 2021 A1 - Casimiro-Soriguer, Carlos S. A1 - Perez-Florido, Javier A1 - Fernandez-Rueda, Jose L. A1 - Pedrosa-Corral, Irene A1 - Guillot-Sulay, Vicente A1 - Lorusso, Nicola A1 - Martinez-Gonzalez, Luis Javier A1 - Navarro-Marí, Jose M. A1 - Dopazo, Joaquin A1 - Sanbonmatsu-Gámez, Sara VL - 13 UR - https://www.mdpi.com/1999-4915/13/5/836 IS - 5 JO - Viruses 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 - 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 - 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 - Drug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection. JF - Signal Transduct Target Ther Y1 - 2020 A1 - Loucera, Carlos A1 - Esteban-Medina, Marina A1 - Rian, Kinza A1 - Falco, Matias M A1 - Dopazo, Joaquin A1 - Peña-Chilet, Maria KW - Computational Chemistry KW - COVID-19 KW - drug repositioning KW - Humans KW - Machine Learning KW - Molecular Docking Simulation KW - Molecular Targeted Therapy KW - Proteins KW - SARS-CoV-2 KW - Signal Transduction VL - 5 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/33311438?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 - Mechanistic models of signaling pathways deconvolute the glioblastoma single-cell functional landscapeAbstract JF - NAR Cancer Y1 - 2020 A1 - Falco, Matias M A1 - Peña-Chilet, Maria A1 - Loucera, Carlos A1 - Hidalgo, Marta R A1 - Dopazo, Joaquin VL - 2 UR - https://academic.oup.com/narcancer/article/doi/10.1093/narcan/zcaa011/5862620http://academic.oup.com/narcancer/article-pdf/2/2/zcaa011/33428092/zcaa011.pdfhttp://academic.oup.com/narcancer/article-pdf/2/2/zcaa011/33428092/zcaa011.pdf IS - 2 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 - Antibiotic resistance and metabolic profiles as functional biomarkers that accurately predict the geographic origin of city metagenomics samples. JF - Biol Direct Y1 - 2019 A1 - Casimiro-Soriguer, Carlos S A1 - Loucera, Carlos A1 - Perez Florido, Javier A1 - López-López, Daniel A1 - Dopazo, Joaquin KW - biomarkers KW - Cities KW - Drug Resistance, Microbial KW - Machine Learning KW - Metabolome KW - Metagenome KW - metagenomics KW - Microbiota AB -

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

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

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

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

VL - 14 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/31429791?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 - Using mechanistic models for the clinical interpretation of complex genomic variation JF - Scientific Reports Y1 - 2019 A1 - Peña-Chilet, Maria A1 - Esteban-Medina, Marina A1 - Falco, Matias M. A1 - Rian, Kinza A1 - Hidalgo, Marta R. A1 - Loucera, Carlos A1 - Dopazo, Joaquin VL - 9 UR - http://www.nature.com/articles/s41598-019-55454-7http://www.nature.com/articles/s41598-019-55454-7.pdfhttp://www.nature.com/articles/s41598-019-55454-7.pdfhttp://www.nature.com/articles/s41598-019-55454-7 IS - 1 JO - Sci Rep 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 - The first complete genomic structure of Butyrivibrio fibrisolvens and its chromid. JF - Microb Genom Y1 - 2018 A1 - Rodríguez Hernáez, Javier A1 - Cerón Cucchi, Maria Esperanza A1 - Cravero, Silvio A1 - Martinez, Maria Carolina A1 - Gonzalez, Sergio A1 - Puebla, Andrea A1 - Dopazo, Joaquin A1 - Farber, Marisa A1 - Paniego, Norma A1 - Rivarola, Máximo KW - Animals KW - Butyrivibrio fibrisolvens KW - Cattle KW - Genome, Bacterial KW - Genomics KW - Humans KW - Milk KW - Rumen KW - Sequence Analysis, DNA AB -

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

VL - 4 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/30216146?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 - ATGC transcriptomics: a web-based application to integrate, explore and analyze de novo transcriptomic data. JF - BMC Bioinformatics Y1 - 2017 A1 - Gonzalez, Sergio A1 - Clavijo, Bernardo A1 - Rivarola, Máximo A1 - Moreno, Patricio A1 - Fernandez, Paula A1 - Dopazo, Joaquin A1 - Paniego, Norma KW - Animals KW - Databases, Genetic KW - Gene Expression Profiling KW - High-Throughput Nucleotide Sequencing KW - Internet KW - Sequence Analysis, RNA KW - Transcriptome KW - User-Computer Interface AB -

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

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

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

VL - 18 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/28222698?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 - 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 - Integration of transcriptomic and metabolic data reveals hub transcription factors involved in drought stress response in sunflower (Helianthus annuus L.). JF - Plant Mol Biol Y1 - 2017 A1 - Moschen, Sebastián A1 - Di Rienzo, Julio A A1 - Higgins, Janet A1 - Tohge, Takayuki A1 - Watanabe, Mutsumi A1 - Gonzalez, Sergio A1 - Rivarola, Máximo A1 - Garcia-Garcia, Francisco A1 - Dopazo, Joaquin A1 - Hopp, H Esteban A1 - Hoefgen, Rainer A1 - Fernie, Alisdair R A1 - Paniego, Norma A1 - Fernandez, Paula A1 - Heinz, Ruth A KW - Chlorophyll KW - Gene Expression Regulation, Plant KW - Helianthus KW - Plant Leaves KW - Plant Proteins KW - Protein Array Analysis KW - RNA, Plant KW - Stress, Physiological KW - Transcription Factors KW - Water AB -

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

VL - 94 IS - 4-5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/28639116?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 - 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 - Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns. JF - Transl Psychiatry Y1 - 2016 A1 - Sanchez-Mut, J V A1 - Heyn, H A1 - Vidal, E A1 - Moran, S A1 - Sayols, S A1 - Delgado-Morales, R A1 - Schultz, M D A1 - Ansoleaga, B A1 - Garcia-Esparcia, P A1 - Pons-Espinal, M A1 - de Lagran, M M A1 - Dopazo, J A1 - Rabano, A A1 - Avila, J A1 - Dierssen, M A1 - Lott, I A1 - Ferrer, I A1 - Ecker, J R A1 - Esteller, M KW - Adult KW - Aged KW - Aged, 80 and over KW - DNA Methylation KW - Epigenomics KW - Female KW - Humans KW - Male KW - Middle Aged KW - neurodegenerative diseases KW - Prefrontal Cortex KW - Tissue Array Analysis AB -

Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and Alzheimer-like neurodegenerative profile associated with Down's syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation changes can be used as biomarkers of the disorders and as potential new targets for the development of new therapies.

VL - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/26784972?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 - Integrating transcriptomic and metabolomic analysis to understand natural leaf senescence in sunflower. JF - Plant Biotechnol J Y1 - 2016 A1 - Moschen, Sebastián A1 - Bengoa Luoni, Sofía A1 - Di Rienzo, Julio A A1 - Caro, María Del Pilar A1 - Tohge, Takayuki A1 - Watanabe, Mutsumi A1 - Hollmann, Julien A1 - Gonzalez, Sergio A1 - Rivarola, Máximo A1 - Garcia-Garcia, Francisco A1 - Dopazo, Joaquin A1 - Hopp, Horacio Esteban A1 - Hoefgen, Rainer A1 - Fernie, Alisdair R A1 - Paniego, Norma A1 - Fernandez, Paula A1 - Heinz, Ruth A KW - Gas Chromatography-Mass Spectrometry KW - Gene Expression Profiling KW - Gene Expression Regulation, Plant KW - Gene ontology KW - Genes, Plant KW - Helianthus KW - Ions KW - metabolomics KW - Oligonucleotide Array Sequence Analysis KW - Plant Leaves KW - Principal Component Analysis KW - RNA, Messenger KW - Transcription Factors AB -

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

VL - 14 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/26132509?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 - 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 - 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 - 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 - 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 - Comparative gene expression study of the vestibular organ of the Igf1 deficient mouse using whole-transcript arrays. JF - Hearing research Y1 - 2015 A1 - Rodríguez-de la Rosa, Lourdes A1 - Sánchez-Calderón, Hortensia A1 - Contreras, Julio A1 - Murillo-Cuesta, Silvia A1 - Falagan, Sandra A1 - Avendaño, Carlos A1 - Joaquín Dopazo A1 - Varela-Nieto, Isabel A1 - Milo, Marta AB - The auditory and vestibular organs form the inner ear and have a common developmental origin. Insulin like growth factor 1 (IGF-1) has a central role in the development of the cochlea and maintenance of hearing. Its deficiency causes sensorineural hearing loss in man and mice. During chicken early development, IGF-1 modulates neurogenesis of the cochleovestibular ganglion but no further studies have been conducted to explore the potential role of IGF-1 in the vestibular system. In this study we have compared the whole transcriptome of the vestibular organ from wild type and Igf1(-/-) mice at different developmental and postnatal times. RNA was prepared from E18.5, P15 and P90 vestibular organs of Igf1(-/-) and Igf1(+/+) mice and the transcriptome analysed in triplicates using Affymetrix® Mouse Gene 1.1 ST Array Plates. These plates are whole-transcript arrays that include probes to measure both messenger (mRNA) and long intergenic non-coding RNA transcripts (lincRNA), with a coverage of over 28 thousand coding transcripts and over 7 thousands non-coding transcripts. Given the complexity of the data we used two different methods VSN-RMA and mmBGX to analyse and compare the data. This is to better evaluate the number of false positives and to quantify uncertainty of low signals. We identified a number of differentially expressed genes that we described using functional analysis and validated using RT-qPCR. The morphology of the vestibular organ did not show differences between genotypes and no evident alterations were observed in the vestibular sensory areas of the null mice. However, well-defined cellular alterations were found in the vestibular neurons with respect their number and size. Although these mice did not show a dramatic vestibular phenotype, we conducted a functional analysis on differentially expressed genes between genotypes and across time. This was with the aim to identify new pathways that are involved in the development of the vestibular organ as well as pathways that maybe affected by the lack of IGF-1 and be associated to the morphological changes of the vestibular neurons that we observed in the Igf1(-/-) mice. UR - http://www.sciencedirect.com/science/article/pii/S0378595515001835 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 - 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 - Family-based genome-wide association study in Patagonia confirms the association of the DMD locus and cleft lip and palate. JF - Eur J Oral Sci Y1 - 2015 A1 - Fonseca, Renata F A1 - de Carvalho, Flávia M A1 - Poletta, Fernando A A1 - Montaner, David A1 - Dopazo, Joaquin A1 - Mereb, Juan C A1 - Moreira, Miguel A M A1 - Seuanez, Hector N A1 - Vieira, Alexandre R A1 - Castilla, Eduardo E A1 - Orioli, Iêda M AB -

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

VL - 123 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/26331285?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 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 - 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 - 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 - Whole Exome Sequencing Reveals ZNF408 as a New Gene Associated With Autosomal Recessive Retinitis Pigmentosa with Vitreal Alterations. JF - Human molecular genetics Y1 - 2015 A1 - Avila-Fernandez, Almudena A1 - Perez-Carro, Raquel A1 - Corton, Marta A1 - Lopez-Molina, Maria Isabel A1 - Campello, Laura A1 - Garanto, Alex A1 - Fernadez-Sanchez, Laura A1 - Duijkers, Lonneke A1 - Lopez-Martinez, Miguel Angel A1 - Riveiro-Alvarez, Rosa A1 - da Silva, Luciana Rodrigues Jacy A1 - Sanchez-Alcudia, Rocío A1 - Martin-Garrido, Esther A1 - Reyes, Noelia A1 - Garcia-Garcia, Francisco A1 - Dopazo, Joaquin A1 - Garcia-Sandoval, Blanca A1 - Collin, Rob W A1 - Cuenca, Nicolas A1 - Ayuso, Carmen AB - Retinitis Pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors ten predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina. VL - 24 UR - http://hmg.oxfordjournals.org/content/early/2015/04/16/hmg.ddv140.abstract ER - TY - JOUR T1 - Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations. JF - Hum Mol Genet Y1 - 2015 A1 - Avila-Fernandez, Almudena A1 - Perez-Carro, Raquel A1 - Corton, Marta A1 - Lopez-Molina, Maria Isabel A1 - Campello, Laura A1 - Garanto, Alejandro A1 - Fernandez-Sanchez, Laura A1 - Duijkers, Lonneke A1 - Lopez-Martinez, Miguel Angel A1 - Riveiro-Alvarez, Rosa A1 - da Silva, Luciana Rodrigues Jacy A1 - Sanchez-Alcudia, Rocío A1 - Martin-Garrido, Esther A1 - Reyes, Noelia A1 - Garcia-Garcia, Francisco A1 - Dopazo, Joaquin A1 - Garcia-Sandoval, Blanca A1 - Collin, Rob W J A1 - Cuenca, Nicolas A1 - Ayuso, Carmen KW - Amino Acid Sequence KW - Animals KW - Chlorocebus aethiops KW - Chromosome Mapping KW - COS Cells KW - DNA-Binding Proteins KW - Exome KW - Genome-Wide Association Study KW - High-Throughput Nucleotide Sequencing KW - Homozygote KW - Humans KW - Molecular Sequence Data KW - Mutant Proteins KW - Pedigree KW - Retina KW - Retinal Cone Photoreceptor Cells KW - Retinal Rod Photoreceptor Cells KW - Retinitis pigmentosa KW - Transcription Factors AB -

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

VL - 24 IS - 14 U1 - https://www.ncbi.nlm.nih.gov/pubmed/25882705?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 - 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 - ngsCAT: a tool to assess the efficiency of targeted enrichment sequencing. JF - Bioinformatics Y1 - 2014 A1 - López-Domingo, Francisco J A1 - Florido, Javier P A1 - Rueda, Antonio A1 - Dopazo, Joaquin A1 - Santoyo-López, Javier KW - Exome KW - Genome, Human KW - High-Throughput Nucleotide Sequencing KW - Humans KW - Sequence Analysis, DNA KW - Software AB -

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

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

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

VL - 30 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/24578402?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 - Differential gene-expression analysis defines a molecular pattern related to olive pollen allergy. JF - J Biol Regul Homeost Agents Y1 - 2013 A1 - Aguerri, M A1 - Calzada, D A1 - Montaner, D A1 - Mata, M A1 - Florido, F A1 - Quiralte, J A1 - Dopazo, J A1 - Lahoz, C A1 - Cardaba, B KW - Adult KW - Female KW - Gene Expression Profiling KW - Humans KW - Male KW - Middle Aged KW - Olea KW - Principal Component Analysis KW - Rhinitis, Allergic, Seasonal AB -

Analysis of gene-expression profiles by microarrays is useful for characterization of candidate genes, key regulatory networks, and to define phenotypes or molecular signatures which improve the diagnosis and/or classification of the allergic processes. We have used this approach in the study of olive pollen response in order to find differential molecular markers among responders and non-responders to this allergenic source. Five clinical groups, non-allergic, asymptomatic, allergic but not to olive pollen, untreated-olive-pollen allergic patients and olive-pollen allergic patients (under specific-immunotherapy), were assessed during and outside pollen seasons. Whole-genome gene expression analysis was performed in RNAs extracted from PBMCs. After assessment of data quality and principal components analysis (PCA), differential gene-expression, by multiple testing and, functional analyses by KEGG, for pathways and Gene-Ontology for biological processes were performed. Relevance was defined by fold change and corrected P values (less than 0.05). The most differential genes were validated by qRT-PCR in a larger set of individuals. Interestingly, gene-expression profiling obtained by PCA clearly showed five clusters of samples that correlated with the five clinical groups. Furthermore, differential gene expression and functional analyses revealed differential genes and pathways in the five clinical groups. The 93 most significant genes found were validated, and one set of 35 genes was able to discriminate profiles of olive pollen response. Our results, in addition to providing new information on allergic response, define a possible molecular signature for olive pollen allergy which could be useful for the diagnosis and treatment of this and other sensitizations.

VL - 27 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/23830385?dopt=Abstract 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 - 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 - 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 - Diversification of the expanded teleost-specific toll-like receptor family in Atlantic cod, Gadus morhua. JF - BMC Evol Biol Y1 - 2012 A1 - Sundaram, Arvind Y M A1 - Kiron, Viswanath A1 - Dopazo, Joaquin A1 - Fernandes, Jorge M O KW - Amino Acid Sequence KW - Animals KW - Binding Sites KW - Evolution, Molecular KW - Fish Diseases KW - Fish Proteins KW - Gadus morhua KW - Gene Expression Profiling KW - Genetic Variation KW - Gills KW - Head Kidney KW - Host-Pathogen Interactions KW - Models, Molecular KW - Molecular Sequence Data KW - Multigene Family KW - Phylogeny KW - Protein Structure, Tertiary KW - Reverse Transcriptase Polymerase Chain Reaction KW - Selection, Genetic KW - Sequence Analysis, DNA KW - Sequence Homology, Amino Acid KW - Temperature KW - Toll-Like Receptors KW - Vibrio AB -

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

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

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

VL - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/23273344?dopt=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 - 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 - 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 - 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 - ARSyN: a method for the identification and removal of systematic noise in multifactorial time course microarray experiments. JF - Biostatistics (Oxford, England) Y1 - 2011 A1 - Nueda, Maria J A1 - Alberto Ferrer A1 - Ana Conesa AB - Transcriptomic profiling experiments that aim to the identification of responsive genes in specific biological conditions are commonly set up under defined experimental designs that try to assess the effects of factors and their interactions on gene expression. Data from these controlled experiments, however, may also contain sources of unwanted noise that can distort the signal under study, affect the residuals of applied statistical models, and hamper data analysis. Commonly, normalization methods are applied to transcriptomics data to remove technical artifacts, but these are normally based on general assumptions of transcript distribution and greatly ignore both the characteristics of the experiment under consideration and the coordinative nature of gene expression. In this paper, we propose a novel methodology, ARSyN, for the preprocessing of microarray data that takes into account these 2 last aspects. By combining analysis of variance (ANOVA) modeling of gene expression values and multivariate analysis of estimated effects, the method identifies the nonstructured part of the signal associated to the experimental factors (the noise within the signal) and the structured variation of the ANOVA errors (the signal of the noise). By removing these noise fractions from the original data, we create a filtered data set that is rich in the information of interest and includes only the random noise required for inferential analysis. In this work, we focus on multifactorial time course microarray (MTCM) experiments with 2 factors: one quantitative such as time or dosage and the other qualitative, as tissue, strain, or treatment. However, the method can be used in other situations such as experiments with only one factor or more complex designs with more than 2 factors. The filtered data obtained after applying ARSyN can be further analyzed with the appropriate statistical technique to obtain the biological information required. To evaluate the performance of the filtering strategy, we have applied different statistical approaches for MTCM analysis to several real and simulated data sets, studying also the efficiency of these techniques. By comparing the results obtained with the original and ARSyN filtered data and also with other filtering techniques, we can conclude that the proposed method increases the statistical power to detect biological signals, especially in cases where there are high levels of structural noise. Software for ARSyN is freely available at http://www.ua.es/personal/mj.nueda. ER - TY - JOUR T1 - Differential expression in RNA-seq: a matter of depth. JF - Genome Res Y1 - 2011 A1 - Tarazona, Sonia A1 - García-Alcalde, Fernando A1 - Dopazo, Joaquin A1 - Ferrer, Alberto A1 - Conesa, Ana KW - Algorithms KW - Expressed Sequence Tags KW - Gene Expression Profiling KW - Gene Expression Regulation KW - Humans KW - Models, Genetic KW - Oligonucleotide Array Sequence Analysis AB -

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

VL - 21 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/21903743?dopt=Abstract 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 - Profiling the venom gland transcriptomes of Costa Rican snakes by 454 pyrosequencing. JF - BMC genomics Y1 - 2011 A1 - Durban, Jordi A1 - Juárez, Paula A1 - Angulo, Yamileth A1 - Lomonte, Bruno A1 - Flores-Diaz, Marietta A1 - Alape-Girón, Alberto A1 - Sasa, Mahmood A1 - Sanz, Libia A1 - Gutiérrez, José M A1 - Joaquín Dopazo A1 - Ana Conesa A1 - Calvete, Juan J AB -

A long term research goal of venomics, of applied importance for improving current antivenom therapy, but also for drug discovery, is to understand the pharmacological potential of venoms. Individually or combined, proteomic and transcriptomic studies have demonstrated their feasibility to explore in depth the molecular diversity of venoms. In the absence of genome sequence, transcriptomes represent also valuable searchable databases for proteomic projects.

VL - 12 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 - 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 - FM19G11, a new hypoxia-inducible factor (HIF) modulator, affects stem cell differentiation status. JF - The Journal of biological chemistry Y1 - 2010 A1 - Moreno-Manzano, Victoria A1 - Rodríguez-Jiménez, Francisco J A1 - Aceña-Bonilla, Jose L A1 - Fustero-Lardíes, Santos A1 - Erceg, Slaven A1 - Dopazo, Joaquin A1 - Montaner, David A1 - Stojkovic, Miodrag A1 - Sánchez-Puelles, Jose M AB -

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

VL - 285 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 - 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 - 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 - Functional assessment of time course microarray data. JF - BMC Bioinformatics Y1 - 2009 A1 - Nueda, Maria José A1 - Sebastián, Patricia A1 - Tarazona, Sonia A1 - Garcia-Garcia, Francisco A1 - Dopazo, Joaquin A1 - Ferrer, Alberto A1 - Conesa, Ana KW - Computer Simulation KW - Gene Expression Profiling KW - Oligonucleotide Array Sequence Analysis KW - Time Factors AB -

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

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

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

VL - 10 Suppl 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19534758?dopt=Abstract ER - TY - JOUR T1 - ModLink+: Improving fold recognition by using protein-protein interactions JF - Bioinformatics Y1 - 2009 A1 - Fornes, O. A1 - Aragues, R. A1 - Espadaler, J. A1 - M. A. Marti-Renom A1 - Sali, A. A1 - Oliva, B. KW - protein folding AB -

MOTIVATION: Several strategies have been developed to predict the fold of a target protein sequence, most of which are based on aligning the target sequence to other sequences of known structure. Previously, we demonstrated that the consideration of protein-protein interactions significantly increases the accuracy of fold assignment compared to PSI-BLAST sequence comparisons. A drawback of our method was the low number of proteins to which a fold could be assigned. Here, we present an improved version of the method that addresses this limitation. We also compare our method to other state-of-the-art fold assignment methodologies. RESULTS: Our approach (ModLink+) has been tested on 3,716 proteins with domain folds classified in the Structural Classification Of Proteins (SCOP) as well as known interacting partners in the Database of Interacting Proteins (DIP). For this test set, the ratio of success (PPV) on fold assignment increases from 75% for PSI-BLAST, 83% for HHSearch and 81% for PRC to more than 90% for ModLink+ at the e-value cutoff of 10(-3). Under this e-value, ModLink+ can assign a fold to 30-45% of the proteins in the test set, while our previous method could cover less than 25%. When applied to 6,384 proteins with unknown fold in the yeast proteome, ModLink+ combined with PSI-BLAST assigns a fold for domains in 3,738 proteins, while PSI-BLAST alone only covers 2,122 proteins, HHSearch 2,969 and PRC 2,826 proteins, using a threshold e-value that would represent a PPV higher than 82% for each method in the test set. AVAILABILITY: The ModLink+ server is freely accessible in the World Wide Web at http://sbi.imim.es/modlink/. CONTACT: boliva@imim.es.

UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19357100 N1 -

Journal article Bioinformatics (Oxford, England) Bioinformatics. 2009 Apr 8.

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 - 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 - 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 - Discovering gene expression patterns in time course microarray experiments by ANOVA-SCA JF - Bioinformatics Y1 - 2007 A1 - Nueda, M. J. A1 - A. Conesa A1 - Westerhuis, J. A. A1 - Hoefsloot, H. C. A1 - Smilde, A. K. A1 - Talon, M. A1 - Ferrer, A. KW - Algorithms *Analysis of Variance Computational Biology/*methods Computer Simulation Data Interpretation KW - Genetic KW - Genetic Models KW - Statistical Gene Expression Profiling/*methods Models KW - Statistical Oligonucleotide Array Sequence Analysis/*methods Principal Component Analysis Time Factors Transcription AB - MOTIVATION: Designed microarray experiments are used to investigate the effects that controlled experimental factors have on gene expression and learn about the transcriptional responses associated with external variables. In these datasets, signals of interest coexist with varying sources of unwanted noise in a framework of (co)relation among the measured variables and with the different levels of the studied factors. Discovering experimentally relevant transcriptional changes require methodologies that take all these elements into account. RESULTS: In this work, we develop the application of the Analysis of variance-simultaneous component analysis (ANOVA-SCA) Smilde et al. Bioinformatics, (2005) to the analysis of multiple series time course microarray data as an example of multifactorial gene expression profiling experiments. We denoted this implementation as ASCA-genes. We show how the combination of ANOVA-modeling and a dimension reduction technique is effective in extracting targeted signals from data by-passing structural noise. The methodology is valuable for identifying main and secondary responses associated with the experimental factors and spotting relevant experimental conditions. We additionally propose a novel approach for gene selection in the context of the relation of individual transcriptional patterns to global gene expression signals. We demonstrate the methodology on both real and synthetic datasets. AVAILABILITY: ASCA-genes has been implemented in the statistical language R and is available at http://www.ivia.es/centrodegenomica/bioinformatics.htm. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. VL - 23 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17519250 N1 - Nueda, Maria Jose Conesa, Ana Westerhuis, Johan A Hoefsloot, Huub C J Smilde, Age K Talon, Manuel Ferrer, Alberto Research Support, Non-U.S. Gov’t England Bioinformatics (Oxford, England) Bioinformatics. 2007 Jul 15;23(14):1792-800. Epub 2007 May 22. ER - TY - CHAP T1 - Microarray Technology in Agricultural Research T2 - Microarray Technology Through Applications Y1 - 2007 A1 - A. Conesa A1 - J. Forment A1 - J. Gadea A1 - van Dijk, J. KW - babelomics JF - Microarray Technology Through Applications PB - F. Falciani. Publisher: Taylor and Francis Group 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 - Protein translocation into peroxisomes by ring-shaped import receptors JF - FEBS Lett Y1 - 2007 A1 - Stanley, W. A. A1 - Fodor, K. A1 - M. A. Marti-Renom A1 - Schliebs, W. A1 - Wilmanns, M. KW - Amino Acid Sequence Binding Sites Humans Molecular Sequence Data Peroxisomes/*metabolism Protein Structure KW - Cytoplasmic and Nuclear/*chemistry KW - Tertiary Protein Transport Receptors AB - Folded and functional proteins destined for translocation from the cytosol into the peroxisomal matrix are recognized by two different peroxisomal import receptors, Pex5p and Pex7p. Both cargo-loaded receptors dock on the same translocon components, followed by cargo release and receptor recycling, as part of the complete translocation process. Recent structural and functional evidence on the Pex5p receptor has provided insight on the molecular requirements of specific cargo recognition, while the remaining processes still remain largely elusive. Comparison of experimental structures of Pex5p and a structural model of Pex7p reveal that both receptors are built by ring-like arrangements with cargo binding sites, central to the respective structures. Although, molecular insight into the complete peroxisomal translocon still remains to be determined, emerging data allow to deduce common molecular principles that may hold for other translocation systems as well. VL - 581 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17884042 N1 - Stanley, Will A Fodor, Krisztian Marti-Renom, Marc A Schliebs, Wolfgang Wilmanns, Matthias Review Netherlands FEBS letters FEBS Lett. 2007 Oct 16;581(25):4795-802. Epub 2007 Sep 11. ER - TY - JOUR T1 - Transcriptional response of Citrus aurantifolia to infection by Citrus tristeza virus JF - Virology Y1 - 2007 A1 - Gandia, M. A1 - A. Conesa A1 - Ancillo, G. A1 - J. Gadea A1 - J. Forment A1 - Pallas, V. A1 - Flores, R. A1 - Duran-Vila, N. A1 - Moreno, P. A1 - Guerri, J. KW - Citrus/*genetics/physiology/virology Closterovirus/genetics/*physiology Genes KW - Genetic KW - Plant Oligonucleotide Array Sequence Analysis Reverse Transcriptase Polymerase Chain Reaction *Transcription AB - Changes in gene expression of Mexican lime plants in response to infection with a severe (T305) or a mild (T385) isolate of Citrus tristeza virus (CTV) were analyzed using a cDNA microarray containing 12,672 probes to 6875 different citrus genes. Statistically significant (P<0.01) expression changes of 334 genes were detected in response to infection with isolate T305, whereas infection with T385 induced no significant change. Induced genes included 145 without significant similarity with known sequences and 189 that were classified in seven functional categories. Genes related with response to stress and defense were the main category and included 28% of the genes induced. Selected transcription changes detected by microarray analysis were confirmed by quantitative real-time RT-PCR. Changes detected in the transcriptome upon infecting lime with T305 may be associated either with symptom expression, with a strain-specific defense mechanism, or with a general response to stress. VL - 367 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17617431 N1 - Gandia, Monica Conesa, Ana Ancillo, Gema Gadea, Jose Forment, Javier Pallas, Vicente Flores, Ricardo Duran-Vila, Nuria Moreno, Pedro Guerri, Jose Research Support, Non-U.S. Gov’t United States Virology Virology. 2007 Oct 25;367(2):298-306. Epub 2007 Jul 9. 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 - maSigPro: a method to identify significantly differential expression profiles in time-course microarray experiments JF - Bioinformatics Y1 - 2006 A1 - A. Conesa A1 - Nueda, M. J. A1 - Ferrer, A. A1 - Talon, M. KW - *Algorithms Computer Simulation Gene Expression/*physiology Gene Expression Profiling/*methods *Models KW - Genetic Models KW - Statistical Oligonucleotide Array Sequence Analysis/*methods *Software Time Factors AB - MOTIVATION: Multi-series time-course microarray experiments are useful approaches for exploring biological processes. In this type of experiments, the researcher is frequently interested in studying gene expression changes along time and in evaluating trend differences between the various experimental groups. The large amount of data, multiplicity of experimental conditions and the dynamic nature of the experiments poses great challenges to data analysis. RESULTS: In this work, we propose a statistical procedure to identify genes that show different gene expression profiles across analytical groups in time-course experiments. The method is a two-regression step approach where the experimental groups are identified by dummy variables. The procedure first adjusts a global regression model with all the defined variables to identify differentially expressed genes, and in second a variable selection strategy is applied to study differences between groups and to find statistically significant different profiles. The methodology is illustrated on both a real and a simulated microarray dataset. VL - 22 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16481333 N1 - Conesa, Ana Nueda, Maria Jose Ferrer, Alberto Talon, Manuel England Bioinformatics (Oxford, England) Bioinformatics. 2006 May 1;22(9):1096-102. Epub 2006 Feb 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 - PupasView: a visual tool for selecting suitable SNPs, with putative pathological effect in genes, for genotyping purposes JF - Nucleic Acids Res Y1 - 2005 A1 - L. Conde A1 - Vaquerizas, J. M. A1 - Ferrer-Costa, C. A1 - de la Cruz, X. A1 - Orozco, M. A1 - Dopazo, J. KW - Computer Graphics Genes *Genetic Predisposition to Disease Genotype Internet Phenotype *Polymorphism KW - Single Nucleotide *Software User-Computer Interface AB - We have developed a web tool, PupasView, for the selection of single nucleotide polymorphisms (SNPs) with potential phenotypic effect. PupasView constitutes an interactive environment in which functional information and population frequency data can be used as sequential filters over linkage disequilibrium parameters to obtain a final list of SNPs optimal for genotyping purposes. PupasView is the first resource that integrates phenotypic effects caused by SNPs at both the translational and the transcriptional level. PupasView retrieves SNPs that could affect conserved regions that the cellular machinery uses for the correct processing of genes (intron/exon boundaries or exonic splicing enhancers), predicted transcription factor binding sites and changes in amino acids in the proteins for which a putative pathological effect is calculated. The program uses the mapping of SNPs in the genome provided by Ensembl. PupasView will be of much help in studies of multifactorial disorders, where the use of functional SNPs will increase the sensitivity of the identification of the genes responsible for the disease. The PupasView web interface is accessible through http://pupasview.ochoa.fib.es and through http://www.pupasnp.org. VL - 33 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15980522 N1 - Conde, Lucia Vaquerizas, Juan M Ferrer-Costa, Carles de la Cruz, Xavier Orozco, Modesto Dopazo, Joaquin Research Support, Non-U.S. Gov’t England Nucleic acids research Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W501-5. 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 - 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 - Tools for comparative protein structure modeling and analysis JF - Nucleic Acids Res Y1 - 2003 A1 - Eswar, N. A1 - John, B. A1 - Mirkovic, N. A1 - Fiser, A. A1 - Ilyin, V. A. A1 - Pieper, U. A1 - Stuart, A. C. A1 - M. A. Marti-Renom A1 - Madhusudhan, M. S. A1 - Yerkovich, B. A1 - Sali, A. KW - Amino Acid *Software *Structural Homology KW - Internet Models KW - Molecular Protein Folding Proteins/chemistry Reproducibility of Results Sequence Alignment Sequence Homology KW - Protein Systems Integration AB - The following resources for comparative protein structure modeling and analysis are described (http://salilab.org): MODELLER, a program for comparative modeling by satisfaction of spatial restraints; MODWEB, a web server for automated comparative modeling that relies on PSI-BLAST, IMPALA and MODELLER; MODLOOP, a web server for automated loop modeling that relies on MODELLER; MOULDER, a CPU intensive protocol of MODWEB for building comparative models based on distant known structures; MODBASE, a comprehensive database of annotated comparative models for all sequences detectably related to a known structure; MODVIEW, a Netscape plugin for Linux that integrates viewing of multiple sequences and structures; and SNPWEB, a web server for structure-based prediction of the functional impact of a single amino acid substitution. VL - 31 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12824331 N1 - Eswar, Narayanan John, Bino Mirkovic, Nebojsa Fiser, Andras Ilyin, Valentin A Pieper, Ursula Stuart, Ashley C Marti-Renom, Marc A Madhusudhan, M S Yerkovich, Bozidar Sali, Andrej 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. 2003 Jul 1;31(13):3375-80. 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 - Identification of genes involved in resistance to interferon-alpha in cutaneous T-cell lymphoma JF - Am J Pathol Y1 - 2002 A1 - Tracey, L. A1 - Villuendas, R. A1 - Ortiz, P. A1 - Dopazo, A. A1 - Spiteri, I. A1 - Lombardia, L. A1 - Rodriguez-Peralto, J. L. A1 - Fernandez-Herrera, J. A1 - Hernandez, A. A1 - Fraga, J. A1 - Dominguez, O. A1 - Herrero, J. A1 - Alonso, M. A. A1 - Dopazo, J. A1 - Piris, M. A. KW - Antineoplastic Agents/*pharmacology/therapeutic use Carrier Proteins/biosynthesis/genetics DNA-Binding Proteins/biosynthesis/genetics Drug Resistance KW - Biological Oligonucleotide Array Sequence Analysis RNA KW - Cultured KW - Cutaneous/diagnosis/drug therapy/*genetics/metabolism *Membrane Glycoproteins Models KW - Interleukin-1 Reproducibility of Results STAT1 Transcription Factor STAT3 Transcription Factor Trans-Activators/biosynthesis/genetics Tumor Cells KW - Neoplasm Gene Expression Profiling *Gene Expression Regulation KW - Neoplasm/biosynthesis *Receptors KW - Neoplastic Humans Interferon-alpha/*pharmacology/therapeutic use Kinetics Lymphoma KW - T-Cell AB - Interferon-alpha therapy has been shown to be active in the treatment of mycosis fungoides although the individual response to this therapy is unpredictable and dependent on essentially unknown factors. In an effort to better understand the molecular mechanisms of interferon-alpha resistance we have developed an interferon-alpha resistant variant from a sensitive cutaneous T-cell lymphoma cell line. We have performed expression analysis to detect genes differentially expressed between both variants using a cDNA microarray including 6386 cancer-implicated genes. The experiments showed that resistance to interferon-alpha is consistently associated with changes in the expression of a set of 39 genes, involved in signal transduction, apoptosis, transcription regulation, and cell growth. Additional studies performed confirm that STAT1 and STAT3 expression and interferon-alpha induction and activation are not altered between both variants. The gene MAL, highly overexpressed by resistant cells, was also found to be expressed by tumoral cells in a series of cutaneous T-cell lymphoma patients treated with interferon-alpha and/or photochemotherapy. MAL expression was associated with longer time to complete remission. Time-course experiments of the sensitive and resistant cells showed a differential expression of a subset of genes involved in interferon-response (1 to 4 hours), cell growth and apoptosis (24 to 48 hours.), and signal transduction. VL - 161 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12414529 N1 - Tracey, Lorraine Villuendas, Raquel Ortiz, Pablo Dopazo, Ana Spiteri, Inmaculada Lombardia, Luis Rodriguez-Peralto, Jose L Fernandez-Herrera, Jesus Hernandez, Almudena Fraga, Javier Dominguez, Orlando Herrero, Javier Alonso, Miguel A Dopazo, Joaquin Piris, Miguel A Research Support, Non-U.S. Gov’t United States The American journal of pathology Am J Pathol. 2002 Nov;161(5):1825-37. ER - TY - JOUR T1 - Reliability of assessment of protein structure prediction methods JF - Structure Y1 - 2002 A1 - M. A. Marti-Renom A1 - Madhusudhan, M. S. A1 - Fiser, A. A1 - Rost, B. A1 - Sali, A. KW - *Computer Simulation Humans *Models KW - Molecular *Protein Conformation Proteins/*chemistry Reproducibility of Results AB -

The reliability of ranking of protein structure modeling methods is assessed. The assessment is based on the parametric Student’s t test and the nonparametric Wilcox signed rank test of statistical significance of the difference between paired samples. The approach is applied to the ranking of the comparative modeling methods tested at the fourth meeting on Critical Assessment of Techniques for Protein Structure Prediction (CASP). It is shown that the 14 CASP4 test sequences may not be sufficient to reliably distinguish between the top eight methods, given the model quality differences and their standard deviations. We suggest that CASP needs to be supplemented by an assessment of protein structure prediction methods that is automated, continuous in time, based on several criteria applied to a large number of models, and with quantitative statistical reliability assigned to each characterization.

VL - 10 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12005441 N1 -

Marti-Renom, Marc A Madhusudhan, M S Fiser, Andras Rost, Burkhard Sali, Andrej GM 54762/GM/NIGMS NIH HHS/United States GM62413/GM/NIGMS NIH HHS/United States Comparative Study Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S. United States Structure (London, England : 1993) Structure. 2002 Mar;10(3):435-40.

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 - TY - JOUR T1 - EVA: continuous automatic evaluation of protein structure prediction servers JF - Bioinformatics Y1 - 2001 A1 - Eyrich, V. A. A1 - M. A. Marti-Renom A1 - Przybylski, D. A1 - Madhusudhan, M. S. A1 - Fiser, A. A1 - Pazos, F. A1 - Valencia, A. A1 - Sali, A. A1 - Rost, B. KW - Automation Internet *Protein Conformation Proteins/*analysis *Software AB - Evaluation of protein structure prediction methods is difficult and time-consuming. Here, we describe EVA, a web server for assessing protein structure prediction methods, in an automated, continuous and large-scale fashion. Currently, EVA evaluates the performance of a variety of prediction methods available through the internet. Every week, the sequences of the latest experimentally determined protein structures are sent to prediction servers, results are collected, performance is evaluated, and a summary is published on the web. EVA has so far collected data for more than 3000 protein chains. These results may provide valuable insight to both developers and users of prediction methods. AVAILABILITY: http://cubic.bioc.columbia.edu/eva. CONTACT: eva@cubic.bioc.columbia.edu VL - 17 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11751240 N1 - Eyrich, V A Marti-Renom, M A Przybylski, D Madhusudhan, M S Fiser, A Pazos, F Valencia, A Sali, A Rost, B England Bioinformatics (Oxford, England) Bioinformatics. 2001 Dec;17(12):1242-3. ER - TY - JOUR T1 - Methods and approaches in the analysis of gene expression data JF - J Immunol Methods Y1 - 2001 A1 - Dopazo, J. A1 - Zanders, E. A1 - Dragoni, I. A1 - Amphlett, G. A1 - Falciani, F. AB -

The application of high-density DNA array technology to monitor gene transcription has been responsible for a real paradigm shift in biology. The majority of research groups now have the ability to measure the expression of a significant proportion of the human genome in a single experiment, resulting in an unprecedented volume of data being made available to the scientific community. As a consequence of this, the storage, analysis and interpretation of this information present a major challenge. In the field of immunology the analysis of gene expression profiles has opened new areas of investigation. The study of cellular responses has revealed that cells respond to an activation signal with waves of co-ordinated gene expression profiles and that the components of these responses are the key to understanding the specific mechanisms which lead to phenotypic differentiation. The discovery of ’cell type specific’ gene expression signatures have also helped the interpretation of the mechanisms leading to disease progression. Here we review the principles behind the most commonly used data analysis methods and discuss the approaches that have been employed in immunological research.

VL - 250 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11251224 N1 -

Dopazo, J Zanders, E Dragoni, I Amphlett, G Falciani, F Comparative Study Review Netherlands Journal of immunological methods J Immunol Methods. 2001 Apr;250(1-2):93-112.

ER - TY - JOUR T1 - Phylogenetic analysis of viroid and viroid-like satellite RNAs from plants: a reassessment JF - J Mol Evol Y1 - 2001 A1 - Elena, S. F. A1 - Dopazo, J. A1 - de la Pena, M. A1 - Flores, R. A1 - Diener, T. O. A1 - Moya, A. KW - Evolution KW - Molecular *Phylogeny Plant Viruses/*genetics RNA KW - Satellite/*genetics RNA KW - Viral/genetics Viroids/*genetics AB - The proposed monophyletic origin of a group of subviral plant pathogens (viroids and viroid-like satellite RNAs), as well as the phylogenetic relationships and the resulting taxonomy of these entities, has been recently questioned. The criticism comes from the (apparent) lack of sequence similarity among these RNAs necessary to reliably infer a phylogeny. Here we show that, despite their low overall sequence similarity, a sequence alignment manually adjusted to take into account all the local similarities and the insertions/deletions and duplications/rearrangements described in the literature for viroids and viroid-like satellite RNA, along with the use of an appropriate estimator of genetic distances, constitutes a data set suitable for a phylogenetic reconstruction. When the likelihood-mapping method was applied to this data set, the tree-likeness obtained was higher than that corresponding to a sequence alignment that does not take into consideration the local similarities. In addition, bootstrap analysis also supports the major groups previously proposed and the reconstruction is consistent with the biological properties of this RNAs. VL - 53 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11479686 N1 - Elena, S F Dopazo, J de la Pena, M Flores, R Diener, T O Moya, A Letter Research Support, Non-U.S. Gov’t United States Journal of molecular evolution J Mol Evol. 2001 Aug;53(2):155-9. ER -