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

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.

%B Front Immunol %V 14 %P 1282859 %8 2023 %G eng %R 10.3389/fimmu.2023.1282859 %0 Journal Article %J Int J Mol Sci %D 2022 %T Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions. %A Puerto-Camacho, Pilar %A Diaz-Martin, Juan %A Olmedo-Pelayo, Joaquín %A Bolado-Carrancio, Alfonso %A Salguero-Aranda, Carmen %A Jordán-Pérez, Carmen %A Esteban-Medina, Marina %A Alamo-Alvarez, Inmaculada %A Delgado-Bellido, Daniel %A Lobo-Selma, Laura %A Dopazo, Joaquin %A Sastre, Ana %A Alonso, Javier %A Grünewald, Thomas G P %A Bernabeu, Carmelo %A Byron, Adam %A Brunton, Valerie G %A Amaral, Ana Teresa %A de Alava, Enrique %K Bone Neoplasms %K Endoglin %K Humans %K Matrix Metalloproteinase 14 %K Proteomics %K Receptors, Growth Factor %K Sarcoma, Ewing %K Signal Transduction %X

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

%B Int J Mol Sci %V 23 %8 2022 Aug 04 %G eng %N 15 %R 10.3390/ijms23158657 %0 Journal Article %J Hum Mol Genet %D 2022 %T Novel genes and sex differences in COVID-19 severity. %A Cruz, Raquel %A Almeida, Silvia Diz-de %A Heredia, Miguel López %A Quintela, Inés %A Ceballos, Francisco C %A Pita, Guillermo %A Lorenzo-Salazar, José M %A González-Montelongo, Rafaela %A Gago-Domínguez, Manuela %A Porras, Marta Sevilla %A Castaño, Jair Antonio Tenorio %A Nevado, Julián %A Aguado, Jose María %A Aguilar, Carlos %A Aguilera-Albesa, Sergio %A Almadana, Virginia %A Almoguera, Berta %A Alvarez, Nuria %A Andreu-Bernabeu, Álvaro %A Arana-Arri, Eunate %A Arango, Celso %A Arranz, María J %A Artiga, Maria-Jesus %A Baptista-Rosas, Raúl C %A Barreda-Sánchez, María %A Belhassen-Garcia, Moncef %A Bezerra, Joao F %A Bezerra, Marcos A C %A Boix-Palop, Lucía %A Brión, Maria %A Brugada, Ramón %A Bustos, Matilde %A Calderón, Enrique J %A Carbonell, Cristina %A Castano, Luis %A Castelao, Jose E %A Conde-Vicente, Rosa %A Cordero-Lorenzana, M Lourdes %A Cortes-Sanchez, Jose L %A Corton, Marta %A Darnaude, M Teresa %A De Martino-Rodríguez, Alba %A Campo-Pérez, Victor %A Bustamante, Aranzazu Diaz %A Domínguez-Garrido, Elena %A Luchessi, André D %A Eirós, Rocío %A Sanabria, Gladys Mercedes Estigarribia %A Fariñas, María Carmen %A Fernández-Robelo, Uxía %A Fernández-Rodríguez, Amanda %A Fernández-Villa, Tania %A Gil-Fournier, Belén %A Gómez-Arrue, Javier %A Álvarez, Beatriz González %A Quirós, Fernan Gonzalez Bernaldo %A González-Peñas, Javier %A Gutiérrez-Bautista, Juan F %A Herrero, María José %A Herrero-Gonzalez, Antonio %A Jimenez-Sousa, María A %A Lattig, María Claudia %A Borja, Anabel Liger %A Lopez-Rodriguez, Rosario %A Mancebo, Esther %A Martín-López, Caridad %A Martín, Vicente %A Martinez-Nieto, Oscar %A Martinez-Lopez, Iciar %A Martinez-Resendez, Michel F %A Martinez-Perez, Ángel %A Mazzeu, Juliana A %A Macías, Eleuterio Merayo %A Minguez, Pablo %A Cuerda, Victor Moreno %A Silbiger, Vivian N %A Oliveira, Silviene F %A Ortega-Paino, Eva %A Parellada, Mara %A Paz-Artal, Estela %A Santos, Ney P C %A Pérez-Matute, Patricia %A Perez, Patricia %A Pérez-Tomás, M Elena %A Perucho, Teresa %A Pinsach-Abuin, Mel Lina %A Pompa-Mera, Ericka N %A Porras-Hurtado, Gloria L %A Pujol, Aurora %A León, Soraya Ramiro %A Resino, Salvador %A Fernandes, Marianne R %A Rodríguez-Ruiz, Emilio %A Rodriguez-Artalejo, Fernando %A Rodriguez-Garcia, José A %A Ruiz-Cabello, Francisco %A Ruiz-Hornillos, Javier %A Ryan, Pablo %A Soria, José Manuel %A Souto, Juan Carlos %A Tamayo, Eduardo %A Tamayo-Velasco, Alvaro %A Taracido-Fernandez, Juan Carlos %A Teper, Alejandro %A Torres-Tobar, Lilian %A Urioste, Miguel %A Valencia-Ramos, Juan %A Yáñez, Zuleima %A Zarate, Ruth %A Nakanishi, Tomoko %A Pigazzini, Sara %A Degenhardt, Frauke %A Butler-Laporte, Guillaume %A Maya-Miles, Douglas %A Bujanda, Luis %A Bouysran, Youssef %A Palom, Adriana %A Ellinghaus, David %A Martínez-Bueno, Manuel %A Rolker, Selina %A Amitrano, Sara %A Roade, Luisa %A Fava, Francesca %A Spinner, Christoph D %A Prati, Daniele %A Bernardo, David %A García, Federico %A Darcis, Gilles %A Fernández-Cadenas, Israel %A Holter, Jan Cato %A Banales, Jesus M %A Frithiof, Robert %A Duga, Stefano %A Asselta, Rosanna %A Pereira, Alexandre C %A Romero-Gómez, Manuel %A Nafría-Jiménez, Beatriz %A Hov, Johannes R %A Migeotte, Isabelle %A Renieri, Alessandra %A Planas, Anna M %A Ludwig, Kerstin U %A Buti, Maria %A Rahmouni, Souad %A Alarcón-Riquelme, Marta E %A Schulte, Eva C %A Franke, Andre %A Karlsen, Tom H %A Valenti, Luca %A Zeberg, Hugo %A Richards, Brent %A Ganna, Andrea %A Boada, Mercè %A Rojas, Itziar %A Ruiz, Agustín %A Sánchez, Pascual %A Real, Luis Miguel %A Guillén-Navarro, Encarna %A Ayuso, Carmen %A González-Neira, Anna %A Riancho, José A %A Rojas-Martinez, Augusto %A Flores, Carlos %A Lapunzina, Pablo %A Carracedo, Ángel %X

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.

%B Hum Mol Genet %8 2022 Jun 16 %G eng %R 10.1093/hmg/ddac132 %0 Journal Article %J Mol Syst Biol %D 2021 %T COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms. %A Ostaszewski, Marek %A Niarakis, Anna %A Mazein, Alexander %A Kuperstein, Inna %A Phair, Robert %A Orta-Resendiz, Aurelio %A Singh, Vidisha %A Aghamiri, Sara Sadat %A Acencio, Marcio Luis %A Glaab, Enrico %A Ruepp, Andreas %A Fobo, Gisela %A Montrone, Corinna %A Brauner, Barbara %A Frishman, Goar %A Monraz Gómez, Luis Cristóbal %A Somers, Julia %A Hoch, Matti %A Kumar Gupta, Shailendra %A Scheel, Julia %A Borlinghaus, Hanna %A Czauderna, Tobias %A Schreiber, Falk %A Montagud, Arnau %A Ponce de Leon, Miguel %A Funahashi, Akira %A Hiki, Yusuke %A Hiroi, Noriko %A Yamada, Takahiro G %A Dräger, Andreas %A Renz, Alina %A Naveez, Muhammad %A Bocskei, Zsolt %A Messina, Francesco %A Börnigen, Daniela %A Fergusson, Liam %A Conti, Marta %A Rameil, Marius %A Nakonecnij, Vanessa %A Vanhoefer, Jakob %A Schmiester, Leonard %A Wang, Muying %A Ackerman, Emily E %A Shoemaker, Jason E %A Zucker, Jeremy %A Oxford, Kristie %A Teuton, Jeremy %A Kocakaya, Ebru %A Summak, Gökçe Yağmur %A Hanspers, Kristina %A Kutmon, Martina %A Coort, Susan %A Eijssen, Lars %A Ehrhart, Friederike %A Rex, Devasahayam Arokia Balaya %A Slenter, Denise %A Martens, Marvin %A Pham, Nhung %A Haw, Robin %A Jassal, Bijay %A Matthews, Lisa %A Orlic-Milacic, Marija %A Senff Ribeiro, Andrea %A Rothfels, Karen %A Shamovsky, Veronica %A Stephan, Ralf %A Sevilla, Cristoffer %A Varusai, Thawfeek %A Ravel, Jean-Marie %A Fraser, Rupsha %A Ortseifen, Vera %A Marchesi, Silvia %A Gawron, Piotr %A Smula, Ewa %A Heirendt, Laurent %A Satagopam, Venkata %A Wu, Guanming %A Riutta, Anders %A Golebiewski, Martin %A Owen, Stuart %A Goble, Carole %A Hu, Xiaoming %A Overall, Rupert W %A Maier, Dieter %A Bauch, Angela %A Gyori, Benjamin M %A Bachman, John A %A Vega, Carlos %A Grouès, Valentin %A Vazquez, Miguel %A Porras, Pablo %A Licata, Luana %A Iannuccelli, Marta %A Sacco, Francesca %A Nesterova, Anastasia %A Yuryev, Anton %A de Waard, Anita %A Turei, Denes %A Luna, Augustin %A Babur, Ozgun %A Soliman, Sylvain %A Valdeolivas, Alberto %A Esteban-Medina, Marina %A Peña-Chilet, Maria %A Rian, Kinza %A Helikar, Tomáš %A Puniya, Bhanwar Lal %A Modos, Dezso %A Treveil, Agatha %A Olbei, Marton %A De Meulder, Bertrand %A Ballereau, Stephane %A Dugourd, Aurélien %A Naldi, Aurélien %A Noël, Vincent %A Calzone, Laurence %A Sander, Chris %A Demir, Emek %A Korcsmaros, Tamas %A Freeman, Tom C %A Augé, Franck %A Beckmann, Jacques S %A Hasenauer, Jan %A Wolkenhauer, Olaf %A Wilighagen, Egon L %A Pico, Alexander R %A Evelo, Chris T %A Gillespie, Marc E %A Stein, Lincoln D %A Hermjakob, Henning %A D'Eustachio, Peter %A Saez-Rodriguez, Julio %A Dopazo, Joaquin %A Valencia, Alfonso %A Kitano, Hiroaki %A Barillot, Emmanuel %A Auffray, Charles %A Balling, Rudi %A Schneider, Reinhard %K Antiviral Agents %K Computational Biology %K Computer Graphics %K COVID-19 %K Cytokines %K Data Mining %K Databases, Factual %K Gene Expression Regulation %K Host Microbial Interactions %K Humans %K Immunity, Cellular %K Immunity, Humoral %K Immunity, Innate %K Lymphocytes %K Metabolic Networks and Pathways %K Myeloid Cells %K Protein Interaction Mapping %K SARS-CoV-2 %K Signal Transduction %K Software %K Transcription Factors %K Viral Proteins %X

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.

%B Mol Syst Biol %V 17 %P e10387 %8 2021 10 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/34664389?dopt=Abstract %R 10.15252/msb.202110387 %0 Journal Article %J Am J Med Genet A %D 2021 %T De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects. %A Martinez-Delgado, Beatriz %A Lopez-Martin, Estrella %A Lara-Herguedas, Julián %A Monzon, Sara %A Cuesta, Isabel %A Juliá, Miguel %A Aquino, Virginia %A Rodriguez-Martin, Carlos %A Damian, Alejandra %A Gonzalo, Irene %A Gomez-Mariano, Gema %A Baladron, Beatriz %A Cazorla, Rosario %A Iglesias, Gema %A Roman, Enriqueta %A Ros, Purificacion %A Tutor, Pablo %A Mellor, Susana %A Jimenez, Carlos %A Cabrejas, Maria Jose %A Gonzalez-Vioque, Emiliano %A Alonso, Javier %A Bermejo-Sánchez, Eva %A Posada, Manuel %K Child, Preschool %K Cytoskeletal Proteins %K Dwarfism %K Exons %K Gene Expression Regulation %K Genetic Association Studies %K Humans %K Male %K Neurodevelopmental Disorders %K Protein Isoforms %K RNA, Messenger %K Sequence Deletion %K Syndrome %K Transcription Factors %K Transcription Initiation Site %K Transcription, Genetic %X

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

%B Am J Med Genet A %V 185 %P 877-883 %8 2021 03 %G eng %N 3 %R 10.1002/ajmg.a.62017 %0 Journal Article %J Nature Genetics %D 2021 %T The NCI Genomic Data Commons %A Heath, Allison P. %A Ferretti, Vincent %A Agrawal, Stuti %A An, Maksim %A Angelakos, James C. %A Arya, Renuka %A Bajari, Rosita %A Baqar, Bilal %A Barnowski, Justin H. B. %A Burt, Jeffrey %A Catton, Ann %A Chan, Brandon F. %A Chu, Fay %A Cullion, Kim %A Davidsen, Tanja %A Do, Phuong-My %A Dompierre, Christian %A Ferguson, Martin L. %A Fitzsimons, Michael S. %A Ford, Michael %A Fukuma, Miyuki %A Gaheen, Sharon %A Ganji, Gajanan L. %A Garcia, Tzintzuni I. %A George, Sameera S. %A Gerhard, Daniela S. %A Gerthoffert, Francois %A Gomez, Fauzi %A Han, Kang %A Hernandez, Kyle M. %A Issac, Biju %A Jackson, Richard %A Jensen, Mark A. %A Joshi, Sid %A Kadam, Ajinkya %A Khurana, Aishmit %A Kim, Kyle M. J. %A Kraft, Victoria E. %A Li, Shenglai %A Lichtenberg, Tara M. %A Lodato, Janice %A Lolla, Laxmi %A Martinov, Plamen %A Mazzone, Jeffrey A. %A Miller, Daniel P. %A Miller, Ian %A Miller, Joshua S. %A Miyauchi, Koji %A Murphy, Mark W. %A Nullet, Thomas %A Ogwara, Rowland O. %A Ortuño, Francisco M. %A Pedrosa, Jesús %A Pham, Phuong L. %A Popov, Maxim Y. %A Porter, James J. %A Powell, Raymond %A Rademacher, Karl %A Reid, Colin P. %A Rich, Samantha %A Rogel, Bessie %A Sahni, Himanso %A Savage, Jeremiah H. %A Schmitt, Kyle A. %A Simmons, Trevar J. %A Sislow, Joseph %A Spring, Jonathan %A Stein, Lincoln %A Sullivan, Sean %A Tang, Yajing %A Thiagarajan, Mathangi %A Troyer, Heather D. %A Wang, Chang %A Wang, Zhining %A West, Bedford L. %A Wilmer, Alex %A Wilson, Shane %A Wu, Kaman %A Wysocki, William P. %A Xiang, Linda %A Yamada, Joseph T. %A Yang, Liming %A Yu, Christine %A Yung, Christina K. %A Zenklusen, Jean Claude %A Zhang, Junjun %A Zhang, Zhenyu %A Zhao, Yuanheng %A Zubair, Ariz %A Staudt, Louis M. %A Grossman, Robert L. %B Nature Genetics %8 Oct-02-2022 %G eng %U http://www.nature.com/articles/s41588-021-00791-5 %! Nat Genet %R 10.1038/s41588-021-00791-5 %0 Journal Article %J Front Mol Neurosci %D 2021 %T Presenilin-1 Mutations Are a Cause of Primary Lateral Sclerosis-Like Syndrome. %A Vázquez-Costa, Juan Francisco %A Payá-Montes, María %A Martínez-Molina, Marina %A Jaijo, Teresa %A Szymanski, Jazek %A Mazón, Miguel %A Sopena-Novales, Pablo %A Pérez-Tur, Jordi %A Sevilla, Teresa %X

Background and Purpose: Primary lateral sclerosis (PLS) is a progressive upper motor neuron (UMN) disorder. It is debated whether PLS is part of the amyotrophic lateral sclerosis (ALS) spectrum, or a syndrome encompassing different neurodegenerative diseases. Recently, new diagnostic criteria for PLS have been proposed. We describe four patients of two pedigrees, meeting definite PLS criteria and harboring two different mutations in presenilin 1 ().

Methods: Patients underwent neurological and neuropsychological examination, MRI, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid-related biomarkers, and next-generation sequencing (NGS) testing.

Results: Four patients, aged 25-45 years old, presented with a progressive UMN syndrome meeting clinical criteria of definite PLS. Cognitive symptoms and signs were mild or absent during the first year of the disease but appeared or progressed later in the disease course. Brain MRI showed microbleeds in two siblings, but iron-related hypointensities in the motor cortex were absent. Brain FDG-PET showed variable areas of hypometabolism, including the motor cortex and frontotemporal lobes. Amyloid deposition was confirmed with either cerebrospinal fluid (CSF) or imaging biomarkers. Two heterozygous likely pathogenic mutations in (p.Pro88Leu and p.Leu166Pro) were found in the NGS testing.

Conclusion: Clinically defined PLS is a syndrome encompassing different neurodegenerative diseases. The NGS testing should be part of the diagnostic workup in patients with PLS, at least in those with red flags, such as early-onset, cognitive impairment, and/or family history of neurodegenerative diseases.

%B Front Mol Neurosci %V 14 %P 721047 %8 2021 %G eng %R 10.3389/fnmol.2021.721047 %0 Journal Article %J Nat Med %D 2021 %T Reporting guidelines for human microbiome research: the STORMS checklist. %A Mirzayi, Chloe %A Renson, Audrey %A Zohra, Fatima %A Elsafoury, Shaimaa %A Geistlinger, Ludwig %A Kasselman, Lora J %A Eckenrode, Kelly %A van de Wijgert, Janneke %A Loughman, Amy %A Marques, Francine Z %A MacIntyre, David A %A Arumugam, Manimozhiyan %A Azhar, Rimsha %A Beghini, Francesco %A Bergstrom, Kirk %A Bhatt, Ami %A Bisanz, Jordan E %A Braun, Jonathan %A Bravo, Hector Corrada %A Buck, Gregory A %A Bushman, Frederic %A Casero, David %A Clarke, Gerard %A Collado, Maria Carmen %A Cotter, Paul D %A Cryan, John F %A Demmer, Ryan T %A Devkota, Suzanne %A Elinav, Eran %A Escobar, Juan S %A Fettweis, Jennifer %A Finn, Robert D %A Fodor, Anthony A %A Forslund, Sofia %A Franke, Andre %A Furlanello, Cesare %A Gilbert, Jack %A Grice, Elizabeth %A Haibe-Kains, Benjamin %A Handley, Scott %A Herd, Pamela %A Holmes, Susan %A Jacobs, Jonathan P %A Karstens, Lisa %A Knight, Rob %A Knights, Dan %A Koren, Omry %A Kwon, Douglas S %A Langille, Morgan %A Lindsay, Brianna %A McGovern, Dermot %A McHardy, Alice C %A McWeeney, Shannon %A Mueller, Noel T %A Nezi, Luigi %A Olm, Matthew %A Palm, Noah %A Pasolli, Edoardo %A Raes, Jeroen %A Redinbo, Matthew R %A Rühlemann, Malte %A Balfour Sartor, R %A Schloss, Patrick D %A Schriml, Lynn %A Segal, Eran %A Shardell, Michelle %A Sharpton, Thomas %A Smirnova, Ekaterina %A Sokol, Harry %A Sonnenburg, Justin L %A Srinivasan, Sujatha %A Thingholm, Louise B %A Turnbaugh, Peter J %A Upadhyay, Vaibhav %A Walls, Ramona L %A Wilmes, Paul %A Yamada, Takuji %A Zeller, Georg %A Zhang, Mingyu %A Zhao, Ni %A Zhao, Liping %A Bao, Wenjun %A Culhane, Aedin %A Devanarayan, Viswanath %A Dopazo, Joaquin %A Fan, Xiaohui %A Fischer, Matthias %A Jones, Wendell %A Kusko, Rebecca %A Mason, Christopher E %A Mercer, Tim R %A Sansone, Susanna-Assunta %A Scherer, Andreas %A Shi, Leming %A Thakkar, Shraddha %A Tong, Weida %A Wolfinger, Russ %A Hunter, Christopher %A Segata, Nicola %A Huttenhower, Curtis %A Dowd, Jennifer B %A Jones, Heidi E %A Waldron, Levi %K Computational Biology %K Dysbiosis %K Humans %K Microbiota %K Observational Studies as Topic %K Research Design %K Translational Science, Biomedical %X

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.

%B Nat Med %V 27 %P 1885-1892 %8 2021 11 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/34789871?dopt=Abstract %R 10.1038/s41591-021-01552-x %0 Journal Article %J F1000Res %D 2020 %T The ELIXIR Human Copy Number Variations Community: building bioinformatics infrastructure for research. %A Salgado, David %A Armean, Irina M %A Baudis, Michael %A Beltran, Sergi %A Capella-Gutíerrez, Salvador %A Carvalho-Silva, Denise %A Dominguez Del Angel, Victoria %A Dopazo, Joaquin %A Furlong, Laura I %A Gao, Bo %A Garcia, Leyla %A Gerloff, Dietlind %A Gut, Ivo %A Gyenesei, Attila %A Habermann, Nina %A Hancock, John M %A Hanauer, Marc %A Hovig, Eivind %A Johansson, Lennart F %A Keane, Thomas %A Korbel, Jan %A Lauer, Katharina B %A Laurie, Steve %A Leskošek, Brane %A Lloyd, David %A Marqués-Bonet, Tomás %A Mei, Hailiang %A Monostory, Katalin %A Piñero, Janet %A Poterlowicz, Krzysztof %A Rath, Ana %A Samarakoon, Pubudu %A Sanz, Ferran %A Saunders, Gary %A Sie, Daoud %A Swertz, Morris A %A Tsukanov, Kirill %A Valencia, Alfonso %A Vidak, Marko %A Yenyxe González, Cristina %A Ylstra, Bauke %A Béroud, Christophe %K Computational Biology %K DNA Copy Number Variations %K High-Throughput Nucleotide Sequencing %K Humans %X

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.

%B F1000Res %V 9 %8 2020 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/34367618?dopt=Abstract %& 1229 %R 10.12688/f1000research.24887.1 %0 Journal Article %J J Med Genet %D 2020 %T Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies. %A Bogliolo, Massimo %A Pujol, Roser %A Aza-Carmona, Miriam %A Muñoz-Subirana, Núria %A Rodriguez-Santiago, Benjamin %A Casado, José Antonio %A Rio, Paula %A Bauser, Christopher %A Reina-Castillón, Judith %A Lopez-Sanchez, Marcos %A Gonzalez-Quereda, Lidia %A Gallano, Pia %A Catalá, Albert %A Ruiz-Llobet, Ana %A Badell, Isabel %A Diaz-Heredia, Cristina %A Hladun, Raquel %A Senent, Leonort %A Argiles, Bienvenida %A Bergua Burgues, Juan Miguel %A Bañez, Fatima %A Arrizabalaga, Beatriz %A López Almaraz, Ricardo %A Lopez, Monica %A Figuera, Ángela %A Molinés, Antonio %A Pérez de Soto, Inmaculada %A Hernando, Inés %A Muñoz, Juan Antonio %A Del Rosario Marin, Maria %A Balmaña, Judith %A Stjepanovic, Neda %A Carrasco, Estela %A Cuesta, Isabel %A Cosuelo, José Miguel %A Regueiro, Alexandra %A Moraleda Jimenez, José %A Galera-Miñarro, Ana Maria %A Rosiñol, Laura %A Carrió, Anna %A Beléndez-Bieler, Cristina %A Escudero Soto, Antonio %A Cela, Elena %A de la Mata, Gregorio %A Fernández-Delgado, Rafael %A Garcia-Pardos, Maria Carmen %A Sáez-Villaverde, Raquel %A Barragaño, Marta %A Portugal, Raquel %A Lendinez, Francisco %A Hernadez, Ines %A Vagace, José Manue %A Tapia, Maria %A Nieto, José %A Garcia, Marta %A Gonzalez, Macarena %A Vicho, Cristina %A Galvez, Eva %A Valiente, Alberto %A Antelo, Maria Luisa %A Ancliff, Phil %A García, Francisco %A Dopazo, Joaquin %A Sevilla, Julian %A Paprotka, Tobias %A Pérez-Jurado, Luis Alberto %A Bueren, Juan %A Surralles, Jordi %K Cell Line %K DNA Copy Number Variations %K DNA Repair %K DNA-Binding Proteins %K Fanconi Anemia %K Fanconi Anemia Complementation Group A Protein %K Female %K Gene Knockout Techniques %K Genetic Predisposition to Disease %K Humans %K Male %K Mutation, Missense %K Polymorphism, Single Nucleotide %K whole exome sequencing %X

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.

%B J Med Genet %V 57 %P 258-268 %8 2020 04 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/31586946?dopt=Abstract %R 10.1136/jmedgenet-2019-106249 %0 Journal Article %J Stem Cells %D 2020 %T Platform to study intracellular polystyrene nanoplastic pollution and clinical outcomes. %A Bojic, Sanja %A Falco, Matias M %A Stojkovic, Petra %A Ljujic, Biljana %A Gazdic Jankovic, Marina %A Armstrong, Lyle %A Markovic, Nebojsa %A Dopazo, Joaquin %A Lako, Majlinda %A Bauer, Roman %A Stojkovic, Miodrag %K Environmental Pollution %K Humans %K Induced Pluripotent Stem Cells %K Intracellular Space %K Nanoparticles %K Plastics %K Polystyrenes %K Transcriptome %K Treatment Outcome %X

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.

%B Stem Cells %V 38 %P 1321-1325 %8 2020 10 01 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/32614127?dopt=Abstract %R 10.1002/stem.3244 %0 Journal Article %J Bioinformatics %D 2020 %T Using AnABlast for intergenic sORF prediction in the Caenorhabditis elegans genome. %A Casimiro-Soriguer, C S %A Rigual, M M %A Brokate-Llanos, A M %A Muñoz, M J %A Garzón, A %A Pérez-Pulido, A J %A Jimenez, J %K Animals %K Caenorhabditis elegans %K Computational Biology %K Genome %K Open Reading Frames %K Software %X

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

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

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

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

%B Bioinformatics %V 36 %P 4827-4832 %8 2020 12 08 %G eng %N 19 %1 https://www.ncbi.nlm.nih.gov/pubmed/32614398?dopt=Abstract %R 10.1093/bioinformatics/btaa608 %0 Journal Article %J Nat Commun %D 2019 %T Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen. %A Menden, Michael P %A Wang, Dennis %A Mason, Mike J %A Szalai, Bence %A Bulusu, Krishna C %A Guan, Yuanfang %A Yu, Thomas %A Kang, Jaewoo %A Jeon, Minji %A Wolfinger, Russ %A Nguyen, Tin %A Zaslavskiy, Mikhail %A Jang, In Sock %A Ghazoui, Zara %A Ahsen, Mehmet Eren %A Vogel, Robert %A Neto, Elias Chaibub %A Norman, Thea %A Tang, Eric K Y %A Garnett, Mathew J %A Veroli, Giovanni Y Di %A Fawell, Stephen %A Stolovitzky, Gustavo %A Guinney, Justin %A Dry, Jonathan R %A Saez-Rodriguez, Julio %K ADAM17 Protein %K Antineoplastic Combined Chemotherapy Protocols %K Benchmarking %K Biomarkers, Tumor %K Cell Line, Tumor %K Computational Biology %K Datasets as Topic %K Drug Antagonism %K Drug Resistance, Neoplasm %K Drug Synergism %K Genomics %K Humans %K Molecular Targeted Therapy %K mutation %K Neoplasms %K pharmacogenetics %K Phosphatidylinositol 3-Kinases %K Phosphoinositide-3 Kinase Inhibitors %K Treatment Outcome %X

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.

%B Nat Commun %V 10 %P 2674 %8 2019 06 17 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31209238?dopt=Abstract %R 10.1038/s41467-019-09799-2 %0 Journal Article %J Nature Communications %D 2018 %T A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection %A Fourati, Slim %A Talla, Aarthi %A Mahmoudian, Mehrad %A Burkhart, Joshua G. %A Klén, Riku %A Henao, Ricardo %A Yu, Thomas %A Aydın, Zafer %A Yeung, Ka Yee %A Ahsen, Mehmet Eren %A Almugbel, Reem %A Jahandideh, Samad %A Liang, Xiao %A Nordling, Torbjörn E. M. %A Shiga, Motoki %A Stanescu, Ana %A Vogel, Robert %A Pandey, Gaurav %A Chiu, Christopher %A McClain, Micah T. %A Woods, Christopher W. %A Ginsburg, Geoffrey S. %A Elo, Laura L. %A Tsalik, Ephraim L. %A Mangravite, Lara M. %A Sieberts, Solveig K. %B Nature Communications %V 9 %8 Jan-12-2018 %G eng %U 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 %N 1 %! Nat Commun %R 10.1038/s41467-018-06735-8 %0 Journal Article %J N Engl J Med %D 2017 %T GGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates. %A Roca-Ayats, Neus %A Balcells, Susana %A Garcia-Giralt, Natàlia %A Falcó-Mascaró, Maite %A Martínez-Gil, Núria %A Abril, Josep F %A Urreizti, Roser %A Dopazo, Joaquin %A Quesada-Gómez, José M %A Nogués, Xavier %A Mellibovsky, Leonardo %A Prieto-Alhambra, Daniel %A Dunford, James E %A Javaid, Muhammad K %A Russell, R Graham %A Grinberg, Daniel %A Díez-Pérez, Adolfo %K Aged %K Amino Acid Sequence %K Bone Density Conservation Agents %K Dimethylallyltranstransferase %K Diphosphonates %K Exome %K Farnesyltranstransferase %K Female %K Femoral Fractures %K Geranyltranstransferase %K Humans %K Middle Aged %K mutation %B N Engl J Med %V 376 %P 1794-1795 %8 2017 05 04 %G eng %U http://www.nejm.org/doi/full/10.1056/NEJMc1612804 %N 18 %1 https://www.ncbi.nlm.nih.gov/pubmed/28467865?dopt=Abstract %R 10.1056/NEJMc1612804 %0 Journal Article %J BMC Bioinformatics %D 2017 %T VISMapper: ultra-fast exhaustive cartography of viral insertion sites for gene therapy. %A Juanes, José M %A Gallego, Asunción %A Tárraga, Joaquín %A Chaves, Felipe J %A Marin-Garcia, Pablo %A Medina, Ignacio %A Arnau, Vicente %A Dopazo, Joaquin %K Base Sequence %K Genetic Therapy %K Genetic Vectors %K High-Throughput Nucleotide Sequencing %K Humans %K Internet %K User-Computer Interface %K Virus Integration %X

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

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

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

%B BMC Bioinformatics %V 18 %P 421 %8 2017 Sep 20 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/28931371?dopt=Abstract %R 10.1186/s12859-017-1837-z %0 Journal Article %J Genome biology %D 2017 %T Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes. %A Gui, Hongsheng %A Schriemer, Duco %A Cheng, William W %A Chauhan, Rajendra K %A Antiňolo, Guillermo %A Berrios, Courtney %A Bleda, Marta %A Brooks, Alice S %A Brouwer, Rutger W W %A Burns, Alan J %A Cherny, Stacey S %A Dopazo, Joaquin %A Eggen, Bart J L %A Griseri, Paola %A Jalloh, Binta %A Le, Thuy-Linh %A Lui, Vincent C H %A Luzón-Toro, Berta %A Matera, Ivana %A Ngan, Elly S W %A Pelet, Anna %A Ruiz-Ferrer, Macarena %A Sham, Pak C %A Shepherd, Iain T %A So, Man-Ting %A Sribudiani, Yunia %A Tang, Clara S M %A van den Hout, Mirjam C G N %A van der Linde, Herma C %A van Ham, Tjakko J %A van IJcken, Wilfred F J %A Verheij, Joke B G M %A Amiel, Jeanne %A Borrego, Salud %A Ceccherini, Isabella %A Chakravarti, Aravinda %A Lyonnet, Stanislas %A Tam, Paul K H %A Garcia-Barceló, Maria-Mercè %A Hofstra, Robert Mw %K Hirschprung %K Rare Disease %K WES %X BACKGROUND: Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human. RESULTS: We performed de novo mutation (DNM) screening on 24 HSCR trios. We identify 28 DNMs in 21 different genes. Eight of the DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not reported in the ENS. Knockdown of all 12 genes with missense or loss-of-function DNMs showed that the orthologs of four genes (DENND3, NCLN, NUP98, and TBATA) are indispensable for ENS development in zebrafish, and these results were confirmed by CRISPR knockout. These genes are also expressed in human and mouse gut and/or ENS progenitors. Importantly, the encoded proteins are linked to neuronal processes shared by the central nervous system and the ENS. CONCLUSIONS: Our data open new fields of investigation into HSCR pathology and provide novel insights into the development of the ENS. Moreover, the study demonstrates that functional analyses of genes carrying DNMs are warranted to delineate the full genetic architecture of rare complex diseases. %B Genome biology %V 18 %P 48 %8 2017 Mar 08 %G eng %U http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-6 %R 10.1186/s13059-017-1174-6 %0 Journal Article %J Genome Biology %D 2017 %T Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes %A Gui, Hongsheng %A Schriemer, Duco %A Cheng, William W. %A Chauhan, Rajendra K. %A Antiňolo, Guillermo %A Berrios, Courtney %A Bleda, Marta %A Brooks, Alice S. %A Brouwer, Rutger W. W. %A Burns, Alan J. %A Cherny, Stacey S. %A Dopazo, Joaquin %A Eggen, Bart J. L. %A Griseri, Paola %A Jalloh, Binta %A Le, Thuy-Linh %A Lui, Vincent C. H. %A Luzón-Toro, Berta %A Matera, Ivana %A Ngan, Elly S. W. %A Pelet, Anna %A Ruiz-Ferrer, Macarena %A Sham, Pak C. %A Shepherd, Iain T. %A So, Man-Ting %A Sribudiani, Yunia %A Tang, Clara S. M. %A van den Hout, Mirjam C. G. N. %A van der Linde, Herma C. %A van Ham, Tjakko J. %A van IJcken, Wilfred F. J. %A Verheij, Joke B. G. M. %A Amiel, Jeanne %A Borrego, Salud %A Ceccherini, Isabella %A Chakravarti, Aravinda %A Lyonnet, Stanislas %A Tam, Paul K. H. %A Garcia-Barceló, Maria-Mercè %A Hofstra, Robert M. W. %B Genome Biology %V 18 %8 Jan-12-2017 %G eng %U http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-6http://link.springer.com/content/pdf/10.1186/s13059-017-1174-6.pdf %N 1 %! Genome Biol %R 10.1186/s13059-017-1174-6 %0 Journal Article %J PLoS One %D 2016 %T The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations. %A Ibáñez, Mariam %A Carbonell-Caballero, José %A García-Alonso, Luz %A Such, Esperanza %A Jiménez-Almazán, Jorge %A Vidal, Enrique %A Barragán, Eva %A López-Pavía, María %A LLop, Marta %A Martín, Iván %A Gómez-Seguí, Inés %A Montesinos, Pau %A Sanz, Miguel A %A Dopazo, Joaquin %A Cervera, José %K Exome %K Gene Regulatory Networks %K Genome, Human %K Humans %K INDEL Mutation %K Leukemia, Promyelocytic, Acute %K mutation %K Mutation Rate %K Polymorphism, Single Nucleotide %K Reproducibility of Results %X

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

%B PLoS One %V 11 %P e0148346 %8 2016 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/26886259?dopt=Abstract %R 10.1371/journal.pone.0148346 %0 Journal Article %J Oncotarget %D 2016 %T Serum metabolomic profiling facilitates the non-invasive identification of metabolic biomarkers associated with the onset and progression of non-small cell lung cancer. %A Puchades-Carrasco, Leonor %A Jantus-Lewintre, Eloisa %A Pérez-Rambla, Clara %A Garcia-Garcia, Francisco %A Lucas, Rut %A Calabuig, Silvia %A Blasco, Ana %A Dopazo, Joaquin %A Camps, Carlos %A Pineda-Lucena, Antonio %K Adult %K Aged %K Biomarkers, Tumor %K Carcinoma, Non-Small-Cell Lung %K Disease Progression %K Female %K Humans %K Lung Neoplasms %K Male %K metabolomics %K Middle Aged %K Proton Magnetic Resonance Spectroscopy %X

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

%B Oncotarget %V 7 %P 12904-16 %8 2016 Mar 15 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/26883203?dopt=Abstract %R 10.18632/oncotarget.7354 %0 Journal Article %J Hum Genet %D 2016 %T Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype. %A Lucariello, Mario %A Vidal, Enrique %A Vidal, Silvia %A Saez, Mauricio %A Roa, Laura %A Huertas, Dori %A Pineda, Mercè %A Dalfó, Esther %A Dopazo, Joaquin %A Jurado, Paola %A Armstrong, Judith %A Esteller, Manel %K Adolescent %K Adult %K Animals %K Caenorhabditis elegans %K Carrier Proteins %K Cell Cycle Proteins %K Child %K Child, Preschool %K DNA Mutational Analysis %K Exome %K Female %K Forkhead Transcription Factors %K Genetic Variation %K High-Throughput Nucleotide Sequencing %K Humans %K Methyl-CpG-Binding Protein 2 %K mutation %K Nerve Tissue Proteins %K Protein Serine-Threonine Kinases %K Receptors, Nicotinic %K Rett Syndrome %X

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

%B Hum Genet %V 135 %P 1343-1354 %8 2016 12 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/27541642?dopt=Abstract %R 10.1007/s00439-016-1721-3 %0 Journal Article %J J Invest Dermatol %D 2015 %T Differential Features Between Chronic Skin Inflammatory Diseases Revealed in Skin-Humanized Psoriasis and Atopic Dermatitis Mouse Models. %A Carretero, M %A Guerrero-Aspizua, S %A Illera, N %A Galvez, V %A Navarro, M %A García-García, F %A Dopazo, J %A Jorcano, J L %A Larcher, F %A Del Rio, M %X

Psoriasis (PS) and atopic dermatitis (AD) are chronic and relapsing inflammatory diseases of the skin affecting a large number of patients worldwide. Psoriasis is characterized by a Th1/Th17 immunological response whereas acute AD lesions exhibit Th2-dominant inflammation. Current single gene and signaling pathways-based models of inflammatory skin diseases are incomplete. Previous work allowed us to model psoriasis in skin-humanized mice through proper combinations of inflammatory cell components and disruption of barrier function. Herein we describe and characterize an animal model for AD using similar bioengineered-based approaches, by intradermal injection of human Th2 lymphocytes in regenerated human skin after partial removal of stratum corneum. In the present work we have extensively compared this model with the previous and an improved version of the PS model, in which Th17/Th1 lymphocytes replace exogenous cytokines. Comparative expression analyses revealed marked differences in specific epidermal proliferation and differentiation markers and immune-related molecules including antimicrobial peptides. Likewise, the composition of the dermal inflammatory infiltrate presented important differences. Availability of accurate and reliable animal models for these diseases will contribute to the understanding of the pathogenesis and provide valuable tools for drug development and testing.Journal of Investigative Dermatology accepted article preview online, 23 September 2015. doi:10.1038/jid.2015.362.

%B J Invest Dermatol %8 2015 Sep 23 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/26398345?dopt=Abstract %R 10.1038/jid.2015.362 %0 Journal Article %J Nature communications %D 2014 %T Assessing technical performance in differential gene expression experiments with external spike-in RNA control ratio mixtures. %A Munro, Sarah A %A Lund, Steven P %A Pine, P Scott %A Binder, Hans %A Clevert, Djork-Arné %A Ana Conesa %A Dopazo, Joaquin %A Fasold, Mario %A Hochreiter, Sepp %A Hong, Huixiao %A Jafari, Nadereh %A Kreil, David P %A Labaj, Paweł P %A Li, Sheng %A Liao, Yang %A Lin, Simon M %A Meehan, Joseph %A Mason, Christopher E %A Santoyo-López, Javier %A Setterquist, Robert A %A Shi, Leming %A Shi, Wei %A Smyth, Gordon K %A Stralis-Pavese, Nancy %A Su, Zhenqiang %A Tong, Weida %A Wang, Charles %A Wang, Jian %A Xu, Joshua %A Ye, Zhan %A Yang, Yong %A Yu, Ying %A Salit, Marc %K RNA-seq %X 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. %B Nature communications %V 5 %P 5125 %8 2014 %G eng %U http://www.nature.com/ncomms/2014/140925/ncomms6125/full/ncomms6125.html %R 10.1038/ncomms6125 %0 Journal Article %J Mol Syst Biol %D 2014 %T The role of the interactome in the maintenance of deleterious variability in human populations. %A García-Alonso, Luz %A Jiménez-Almazán, Jorge %A Carbonell-Caballero, José %A Vela-Boza, Alicia %A Santoyo-López, Javier %A Antiňolo, Guillermo %A Dopazo, Joaquin %K Alleles %K Exome %K Gene Library %K Genetic Variation %K Genetics, Population %K Genome, Human %K Genomics %K Humans %K Models, Genetic %K mutation %K Phenotype %K Protein Conformation %K Protein Interaction Maps %K Sequence Analysis, DNA %K Whites %X

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

%B Mol Syst Biol %V 10 %P 752 %8 2014 Sep 26 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/25261458?dopt=Abstract %R 10.15252/msb.20145222 %0 Journal Article %J Fungal Genet Biol %D 2014 %T Sequencing and functional analysis of the genome of a nematode egg-parasitic fungus, Pochonia chlamydosporia. %A Larriba, Eduardo %A Jaime, María D L A %A Carbonell-Caballero, José %A Conesa, Ana %A Dopazo, Joaquin %A Nislow, Corey %A Martín-Nieto, José %A Lopez-Llorca, Luis Vicente %K Animals %K Ascomycota %K Female %K Gene Expression Regulation, Fungal %K Gene ontology %K Genome, Fungal %K Hordeum %K Host-Pathogen Interactions %K Nematoda %K Ovum %K Phylogeny %K Plant Roots %K Sequence Analysis, DNA %K Signal Transduction %K Transcriptome %X

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

%B Fungal Genet Biol %V 65 %P 69-80 %8 2014 Apr %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/24530791?dopt=Abstract %R 10.1016/j.fgb.2014.02.002 %0 Journal Article %J Mol Genet Metab %D 2013 %T Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria. %A Tort, Frederic %A García-Silva, María Teresa %A Ferrer-Cortès, Xènia %A Navarro-Sastre, Aleix %A Garcia-Villoria, Judith %A Coll, Maria Josep %A Vidal, Enrique %A Jiménez-Almazán, Jorge %A Dopazo, Joaquin %A Briones, Paz %A Elpeleg, Orly %A Ribes, Antonia %K Adolescent %K Adult %K Carboxylic Ester Hydrolases %K Child %K Exome %K Female %K High-Throughput Nucleotide Sequencing %K Humans %K Infant %K Male %K Metabolism, Inborn Errors %K mutation %X

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.

%B Mol Genet Metab %V 110 %P 73-7 %8 2013 Sep-Oct %G eng %N 1-2 %1 https://www.ncbi.nlm.nih.gov/pubmed/23707711?dopt=Abstract %R 10.1016/j.ymgme.2013.04.021 %0 Journal Article %J BMC genomics %D 2012 %T Identification of yeast genes that confer resistance to chitosan oligosaccharide (COS) using chemogenomics. %A Jaime, María D L A %A Lopez-Llorca, Luis Vicente %A Ana Conesa %A Lee, Anna Y %A Proctor, Michael %A Heisler, Lawrence E %A Gebbia, Marinella %A Giaever, Guri %A Westwood, J Timothy %A Nislow, Corey %X BACKGROUND: Chitosan oligosaccharide (COS), a deacetylated derivative of chitin, is an abundant, and renewable natural polymer. COS has higher antimicrobial properties than chitosan and is presumed to act by disrupting/permeabilizing the cell membranes of bacteria, yeast and fungi. COS is relatively non-toxic to mammals. By identifying the molecular and genetic targets of COS, we hope to gain a better understanding of the antifungal mode of action of COS. RESULTS: Three different chemogenomic fitness assays, haploinsufficiency (HIP), homozygous deletion (HOP), and multicopy suppression (MSP) profiling were combined with a transcriptomic analysis to gain insight in to the mode of action and mechanisms of resistance to chitosan oligosaccharides. The fitness assays identified 39 yeast deletion strains sensitive to COS and 21 suppressors of COS sensitivity. The genes identified are involved in processes such as RNA biology (transcription, translation and regulatory mechanisms), membrane functions (e.g. signalling, transport and targeting), membrane structural components, cell division, and proteasome processes. The transcriptomes of control wild type and 5 suppressor strains overexpressing ARL1, BCK2, ERG24, MSG5, or RBA50, were analyzed in the presence and absence of COS. Some of the up-regulated transcripts in the suppressor overexpressing strains exposed to COS included genes involved in transcription, cell cycle, stress response and the Ras signal transduction pathway. Down-regulated transcripts included those encoding protein folding components and respiratory chain proteins. The COS-induced transcriptional response is distinct from previously described environmental stress responses (i.e. thermal, salt, osmotic and oxidative stress) and pre-treatment with these well characterized environmental stressors provided little or any resistance to COS. CONCLUSIONS: Overexpression of the ARL1 gene, a member of the Ras superfamily that regulates membrane trafficking, provides protection against COS-induced cell membrane permeability and damage. We found that the ARL1 COS-resistant over-expression strain was as sensitive to Amphotericin B, Fluconazole and Terbinafine as the wild type cells and that when COS and Fluconazole are used in combination they act in a synergistic fashion. The gene targets of COS identified in this study indicate that COS’s mechanism of action is different from other commonly studied fungicides that target membranes, suggesting that COS may be an effective fungicide for drug-resistant fungal pathogens. %B BMC genomics %V 13 %P 267 %8 2012 %G eng %R 10.1186/1471-2164-13-267 %0 Journal Article %J Genome medicine %D 2012 %T A map of human microRNA variation uncovers unexpectedly high levels of variability. %A Carbonell, José %A Alloza, Eva %A Arce, Pablo %A Borrego, Salud %A Santoyo, Javier %A Ruiz-Ferrer, Macarena %A Medina, Ignacio %A Jiménez-Almazán, Jorge %A Méndez-Vidal, Cristina %A González-del Pozo, María %A Vela, Alicia %A Bhattacharya, Shomi S %A Antiňolo, Guillermo %A Dopazo, Joaquin %K NGS %X ABSTRACT: BACKGROUND: MicroRNAs (miRNAs) are key components of the gene regulatory network in many species. During the past few years, these regulatory elements have been shown to be involved in an increasing number and range of diseases. Consequently, the compilation of a comprehensive map of natural variability in healthy population seems an obvious requirement for future research on miRNA-related pathologies. METHODS: Data on 14 populations from the 1000 Genomes Project were analysed, along with new data extracted from 60 exomes of healthy individuals from a southern Spain population, sequenced in the context of the Medical Genome Project, to derive an accurate map of miRNA variability. RESULTS: Despite the common belief that miRNAs are highly conserved elements, analysis of the sequences of the 1,152 individuals indicated that the observed level of variability is double what was expected. A total of 527 variants were found. Among these, 45 variants affected the recognition region of the corresponding miRNA and were found in 43 different miRNAs, 26 of which are known to be involved in 57 diseases. Different parts of the mature structure of the miRNA were affected to different degrees by variants, which suggests the existence of a selective pressure related to the relative functional impact of the change. Moreover, 41 variants showed a significant deviation from the Hardy-Weinberg equilibrium, which supports the existence of a selective process against some alleles. The average number of variants per individual in miRNAs was 28. CONCLUSIONS: Despite an expectation that miRNAs would be highly conserved genomic elements, our study reports a level of variability comparable to that observed for coding genes. %B Genome medicine %V 4 %P 62 %8 2012 Aug 20 %G eng %U http://genomemedicine.com/content/4/8/62/abstract %R 10.1186/gm363 %0 Journal Article %J Molecular plant pathology %D 2012 %T Microarray analysis of Etrog citron (Citrus medica L.) reveals changes in chloroplast, cell wall, peroxidase and symporter activities in response to viroid infection. %A Rizza, Serena %A Ana Conesa %A Juarez, José %A Catara, Antonino %A Navarro, Luis %A Duran-Vila, Nuria %A Ancillo, Gema %X Viroids are small (246-401 nucleotides), single-stranded, circular RNA molecules that infect several crop plants and can cause diseases of economic importance. Citrus are the hosts in which the largest number of viroids have been identified. Citrus exocortis viroid (CEVd), the causal agent of citrus exocortis disease, induces considerable losses in citrus crops. Changes in the gene expression profile during the early (pre-symptomatic) and late (post-symptomatic) stages of Etrog citron infected with CEVd were investigated using a citrus cDNA microarray. MaSigPro analysis was performed and, on the basis of gene expression profiles as a function of the time after infection, the differentially expressed genes were classified into five clusters. FatiScan analysis revealed significant enrichment of functional categories for each cluster, indicating that viroid infection triggers important changes in chloroplast, cell wall, peroxidase and symporter activities. %B Molecular plant pathology %8 2012 Mar 15 %G eng %R 10.1111/j.1364-3703.2012.00794.x %0 Journal Article %J PloS one %D 2012 %T Transcriptome profiling of the intoxication response of Tenebrio molitor larvae to Bacillus thuringiensis Cry3Aa protoxin. %A Oppert, Brenda %A Dowd, Scot E %A Bouffard, Pascal %A Li, Lewyn %A Ana Conesa %A Lorenzen, Marcé D %A Toutges, Michelle %A Marshall, Jeremy %A Huestis, Diana L %A Fabrick, Jeff %A Oppert, Cris %A Jurat-Fuentes, Juan Luis %K Administration %K Animals %K Bacterial Proteins %K Base Sequence %K Biosynthetic Pathways %K Complementary %K DNA %K Endotoxins %K Energy Metabolism %K Gene Expression Profiling %K Hemolysin Proteins %K Larva %K Microarray Analysis %K Molecular Sequence Data %K Oral %K Sequence Analysis %K Tenebrio %K Time Factors %K Transcriptome %X 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. %B PloS one %V 7 %P e34624 %8 2012 %G eng %R 10.1371/journal.pone.0034624 %0 Journal Article %J Bioinformatics (Oxford, England) %D 2011 %T B2G-FAR, a species centered GO annotation repository. %A Götz, Stefan %A Arnold, Roland %A Sebastián-Leon, Patricia %A Martín-Rodríguez, Samuel %A Tischler, Patrick %A Jehl, Marc-André %A Joaquín Dopazo %A Rattei, Thomas %A Ana Conesa %X

MOTIVATION: Functional genomics research has expanded enormously in the last decade thanks to the cost-reduction in high-throughput technologies and the development of computational tools that generate, standardize and share information on gene and protein function such as the Gene Ontology (GO). Nevertheless many biologists, especially working with non-model organisms, still suffer from non-existing or low coverage functional annotation, or simply struggle retrieving, summarizing and querying these data. RESULTS: The Blast2GO Functional Annotation Repository (B2G-FAR) is a bioinformatics resource envisaged to provide functional information for otherwise uncharacterized sequence-data and offers data-mining tools to analyze a larger repertoire of species than currently available. This new annotation resource has been created by applying the Blast2GO functional annotation engine in a strongly high-throughput manner to the entire space of public available sequences. The resulting repository contains GO term predictions for over 13.2 million non-redundant protein sequences based on BLAST search alignments from the SIMAP database. We generated GO annotation for approximately 150.000 different taxa making available the 2000 species with the highest coverage through B2G-FAR. A second section within B2G-FAR holds functional annotations for 17 non-model organism Affymetrix GeneChips. Conclusions: B2G-FAR provides easy access to exhaustive functional annotation for 2000 species offering a good balance between quality and quantity, thereby supporting functional genomics research especially in the case of non-model organisms. AVAILABILITY: The annotation resource is available at http://b2gfar.bioinfo.cipf.es. CONTACT: aconesa@cipf.es, sgoetz@cipf.es.

%B Bioinformatics (Oxford, England) %V 27 %P 919-924 %8 2011 Feb 18 %G eng %0 Journal Article %J PLoS pathogens %D 2011 %T Discovery of an ebolavirus-like filovirus in europe. %A Negredo, Ana %A Palacios, Gustavo %A Vázquez-Morón, Sonia %A González, Félix %A Dopazo, Hernán %A Molero, Francisca %A Juste, Javier %A Quetglas, Juan %A Savji, Nazir %A de la Cruz Martínez, Maria %A Herrera, Jesus Enrique %A Pizarro, Manuel %A Hutchison, Stephen K %A Echevarría, Juan E %A Lipkin, W Ian %A Tenorio, Antonio %X

Filoviruses, amongst the most lethal of primate pathogens, have only been reported as natural infections in sub-Saharan Africa and the Philippines. Infections of bats with the ebolaviruses and marburgviruses do not appear to be associated with disease. Here we report identification in dead insectivorous bats of a genetically distinct filovirus, provisionally named Lloviu virus, after the site of detection, Cueva del Lloviu, in Spain.

%B PLoS pathogens %V 7 %P e1002304 %8 2011 Oct %G eng %0 Journal Article %J PLoS One %D 2011 %T myKaryoView: a light-weight client for visualization of genomic data. %A Jimenez, Rafael C %A Salazar, Gustavo A %A Gel, Bernat %A Dopazo, Joaquin %A Mulder, Nicola %A Corpas, Manuel %K Computer Graphics %K Databases, Genetic %K Genomics %K Internet %K Molecular Sequence Annotation %K User-Computer Interface %X

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

%B PLoS One %V 6 %P e26345 %8 2011 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/22046276?dopt=Abstract %R 10.1371/journal.pone.0026345 %0 Journal Article %J BMC genomics %D 2011 %T Profiling the venom gland transcriptomes of Costa Rican snakes by 454 pyrosequencing. %A Durban, Jordi %A Juárez, Paula %A Angulo, Yamileth %A Lomonte, Bruno %A Flores-Diaz, Marietta %A Alape-Girón, Alberto %A Sasa, Mahmood %A Sanz, Libia %A Gutiérrez, José M %A Joaquín Dopazo %A Ana Conesa %A Calvete, Juan J %X

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.

%B BMC genomics %V 12 %P 259 %8 2011 %G eng %0 Journal Article %J Genome research %D 2010 %T Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. %A Javierre, Biola M %A Fernandez, Agustin F %A Richter, Julia %A Fatima Al-Shahrour %A Martin-Subero, J Ignacio %A Rodriguez-Ubreva, Javier %A Berdasco, Maria %A Fraga, Mario F %A O’Hanlon, Terrance P %A Rider, Lisa G %A Jacinto, Filipe V %A Lopez-Longo, F Javier %A Dopazo, Joaquin %A Forn, Marta %A Peinado, Miguel A %A Carreño, Luis %A Sawalha, Amr H %A Harley, John B %A Siebert, Reiner %A Esteller, Manel %A Miller, Frederick W %A Ballestar, Esteban %X

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.

%B Genome research %V 20 %P 170-9 %8 2010 Feb %G eng %0 Journal Article %J PLoS One %D 2010 %T Exploring the link between germline and somatic genetic alterations in breast carcinogenesis. %A Bonifaci, Núria %A Górski, Bohdan %A Masojć, Bartlomiej %A Wokołorczyk, Dominika %A Jakubowska, Anna %A Dębniak, Tadeusz %A Berenguer, Antoni %A Serra Musach, Jordi %A Brunet, Joan %A Dopazo, Joaquin %A Narod, Steven A %A Lubiński, Jan %A Lázaro, Conxi %A Cybulski, Cezary %A Pujana, Miguel Angel %K Adult %K Bone Morphogenetic Protein Receptors, Type I %K Breast %K Breast Neoplasms %K Calcium-Calmodulin-Dependent Protein Kinases %K Case-Control Studies %K Cyclin-Dependent Kinases %K Disease Progression %K Estrogen Receptor alpha %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Germ-Line Mutation %K Humans %K Odds Ratio %K Poland %K Polymorphism, Single Nucleotide %K Protein Serine-Threonine Kinases %K Protein-Tyrosine Kinases %K Receptor Protein-Tyrosine Kinases %K Receptor, EphA3 %K Receptor, EphA7 %K Receptor, EphB1 %K Risk Factors %X

Recent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germline-somatic link in carcinogenesis, we evaluated the distribution of somatic gene labels within the ordered results of a breast cancer risk GWAS. This analysis suggested frequent influence on risk of genetic variation in loci encoding for "driver kinases" (i.e., kinases encoded by genes that showed higher somatic mutation rates than expected by chance and, therefore, whose deregulation may contribute to cancer development and/or progression). Assessment of these predictions using a population-based case-control study in Poland replicated the association for rs3732568 in EPHB1 (odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.63-0.98; P(trend) = 0.031). Analyses by early age at diagnosis and by estrogen receptor α (ERα) tumor status indicated potential associations for rs6852678 in CDKL2 (OR = 0.32, 95% CI: 0.10-1.00; P(recessive) = 0.044) and rs10878640 in DYRK2 (OR = 2.39, 95% CI: 1.32-4.30; P(dominant) = 0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERα tumor status P(interaction)<0.05). The identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. Together, these data may lay the foundations for replication in additional populations and could potentially increase our knowledge of the underlying molecular mechanisms of breast carcinogenesis.

%B PLoS One %V 5 %P e14078 %8 2010 Nov 22 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/21124932?dopt=Abstract %R 10.1371/journal.pone.0014078 %0 Journal Article %J Pharmacogenomics J %D 2010 %T Functional analysis of multiple genomic signatures demonstrates that classification algorithms choose phenotype-related genes. %A Shi, W %A Bessarabova, M %A Dosymbekov, D %A Dezso, Z %A Nikolskaya, T %A Dudoladova, M %A Serebryiskaya, T %A Bugrim, A %A Guryanov, A %A Brennan, R J %A Shah, R %A Dopazo, J %A Chen, M %A Deng, Y %A Shi, T %A Jurman, G %A Furlanello, C %A Thomas, R S %A Corton, J C %A Tong, W %A Shi, L %A Nikolsky, Y %K Algorithms %K Databases, Genetic %K Endpoint Determination %K Gene Expression Profiling %K Genomics %K Humans %K Neural Networks, Computer %K Oligonucleotide Array Sequence Analysis %K Phenotype %K Predictive Value of Tests %K Proteins %K Quality Control %X

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.

%B Pharmacogenomics J %V 10 %P 310-23 %8 2010 Aug %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/20676069?dopt=Abstract %R 10.1038/tpj.2010.35 %0 Journal Article %J Nature biotechnology %D 2010 %T The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models. %A Shi, Leming %A Campbell, Gregory %A Jones, Wendell D %A Campagne, Fabien %A Wen, Zhining %A Walker, Stephen J %A Su, Zhenqiang %A Chu, Tzu-Ming %A Goodsaid, Federico M %A Pusztai, Lajos %A Shaughnessy, John D %A Oberthuer, André %A Thomas, Russell S %A Paules, Richard S %A Fielden, Mark %A Barlogie, Bart %A Chen, Weijie %A Du, Pan %A Fischer, Matthias %A Furlanello, Cesare %A Gallas, Brandon D %A Ge, Xijin %A Megherbi, Dalila B %A Symmans, W Fraser %A Wang, May D %A Zhang, John %A Bitter, Hans %A Brors, Benedikt %A Bushel, Pierre R %A Bylesjo, Max %A Chen, Minjun %A Cheng, Jie %A Cheng, Jing %A Chou, Jeff %A Davison, Timothy S %A Delorenzi, Mauro %A Deng, Youping %A Devanarayan, Viswanath %A Dix, David J %A Dopazo, Joaquin %A Dorff, Kevin C %A Elloumi, Fathi %A Fan, Jianqing %A Fan, Shicai %A Fan, Xiaohui %A Fang, Hong %A Gonzaludo, Nina %A Hess, Kenneth R %A Hong, Huixiao %A Huan, Jun %A Irizarry, Rafael A %A Judson, Richard %A Juraeva, Dilafruz %A Lababidi, Samir %A Lambert, Christophe G %A Li, Li %A Li, Yanen %A Li, Zhen %A Lin, Simon M %A Liu, Guozhen %A Lobenhofer, Edward K %A Luo, Jun %A Luo, Wen %A McCall, Matthew N %A Nikolsky, Yuri %A Pennello, Gene A %A Perkins, Roger G %A Philip, Reena %A Popovici, Vlad %A Price, Nathan D %A Qian, Feng %A Scherer, Andreas %A Shi, Tieliu %A Shi, Weiwei %A Sung, Jaeyun %A Thierry-Mieg, Danielle %A Thierry-Mieg, Jean %A Thodima, Venkata %A Trygg, Johan %A Vishnuvajjala, Lakshmi %A Wang, Sue Jane %A Wu, Jianping %A Wu, Yichao %A Xie, Qian %A Yousef, Waleed A %A Zhang, Liang %A Zhang, Xuegong %A Zhong, Sheng %A Zhou, Yiming %A Zhu, Sheng %A Arasappan, Dhivya %A Bao, Wenjun %A Lucas, Anne Bergstrom %A Berthold, Frank %A Brennan, Richard J %A Buness, Andreas %A Catalano, Jennifer G %A Chang, Chang %A Chen, Rong %A Cheng, Yiyu %A Cui, Jian %A Czika, Wendy %A Demichelis, Francesca %A Deng, Xutao %A Dosymbekov, Damir %A Eils, Roland %A Feng, Yang %A Fostel, Jennifer %A Fulmer-Smentek, Stephanie %A Fuscoe, James C %A Gatto, Laurent %A Ge, Weigong %A Goldstein, Darlene R %A Guo, Li %A Halbert, Donald N %A Han, Jing %A Harris, Stephen C %A Hatzis, Christos %A Herman, Damir %A Huang, Jianping %A Jensen, Roderick V %A Jiang, Rui %A Johnson, Charles D %A Jurman, Giuseppe %A Kahlert, Yvonne %A Khuder, Sadik A %A Kohl, Matthias %A Li, Jianying %A Li, Li %A Li, Menglong %A Li, Quan-Zhen %A Li, Shao %A Li, Zhiguang %A Liu, Jie %A Liu, Ying %A Liu, Zhichao %A Meng, Lu %A Madera, Manuel %A Martinez-Murillo, Francisco %A Medina, Ignacio %A Meehan, Joseph %A Miclaus, Kelci %A Moffitt, Richard A %A Montaner, David %A Mukherjee, Piali %A Mulligan, George J %A Neville, Padraic %A Nikolskaya, Tatiana %A Ning, Baitang %A Page, Grier P %A Parker, Joel %A Parry, R Mitchell %A Peng, Xuejun %A Peterson, Ron L %A Phan, John H %A Quanz, Brian %A Ren, Yi %A Riccadonna, Samantha %A Roter, Alan H %A Samuelson, Frank W %A Schumacher, Martin M %A Shambaugh, Joseph D %A Shi, Qiang %A Shippy, Richard %A Si, Shengzhu %A Smalter, Aaron %A Sotiriou, Christos %A Soukup, Mat %A Staedtler, Frank %A Steiner, Guido %A Stokes, Todd H %A Sun, Qinglan %A Tan, Pei-Yi %A Tang, Rong %A Tezak, Zivana %A Thorn, Brett %A Tsyganova, Marina %A Turpaz, Yaron %A Vega, Silvia C %A Visintainer, Roberto %A von Frese, Juergen %A Wang, Charles %A Wang, Eric %A Wang, Junwei %A Wang, Wei %A Westermann, Frank %A Willey, James C %A Woods, Matthew %A Wu, Shujian %A Xiao, Nianqing %A Xu, Joshua %A Xu, Lei %A Yang, Lun %A Zeng, Xiao %A Zhang, Jialu %A Zhang, Li %A Zhang, Min %A Zhao, Chen %A Puri, Raj K %A Scherf, Uwe %A Tong, Weida %A Wolfinger, Russell D %X

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.

%B Nature biotechnology %V 28 %P 827-38 %8 2010 Aug %G eng %U http://www.nature.com/nbt/journal/v28/n8/full/nbt.1665.html %0 Journal Article %J Nucleic acids research %D 2010 %T SIMAP–a comprehensive database of pre-calculated protein sequence similarities, domains, annotations and clusters. %A Rattei, Thomas %A Tischler, Patrick %A Götz, Stefan %A Jehl, Marc-André %A Hoser, Jonathan %A Arnold, Roland %A Ana Conesa %A Mewes, Hans-Werner %X

The prediction of protein function as well as the reconstruction of evolutionary genesis employing sequence comparison at large is still the most powerful tool in sequence analysis. Due to the exponential growth of the number of known protein sequences and the subsequent quadratic growth of the similarity matrix, the computation of the Similarity Matrix of Proteins (SIMAP) becomes a computational intensive task. The SIMAP database provides a comprehensive and up-to-date pre-calculation of the protein sequence similarity matrix, sequence-based features and sequence clusters. As of September 2009, SIMAP covers 48 million proteins and more than 23 million non-redundant sequences. Novel features of SIMAP include the expansion of the sequence space by including databases such as ENSEMBL as well as the integration of metagenomes based on their consistent processing and annotation. Furthermore, protein function predictions by Blast2GO are pre-calculated for all sequences in SIMAP and the data access and query functions have been improved. SIMAP assists biologists to query the up-to-date sequence space systematically and facilitates large-scale downstream projects in computational biology. Access to SIMAP is freely provided through the web portal for individuals (http://mips.gsf.de/simap/) and for programmatic access through DAS (http://webclu.bio.wzw.tum.de/das/) and Web-Service (http://mips.gsf.de/webservices/services/SimapService2.0?wsdl).

%B Nucleic acids research %V 38 %P D223-6 %8 2010 Jan %G eng %0 Journal Article %J OMICS %D 2009 %T Modeling and managing experimental data using FuGE. %A Andrew R Jones %A Allyson L Lister %A Leandro Hermida %A Peter Wilkinson %A Martin Eisenacher %A Khalid Belhajjame %A Frank Gibson %A Phil Lord %A Matthew Pocock %A Heiko Rosenfelder %A Santoyo-López, Javier %A Anil Wipat %A Norman W Paton %B OMICS %V 13 %P 239-51 %G eng %0 Journal Article %J Brief Bioinform %D 2008 %T Interoperability with Moby 1.0--it's better than sharing your toothbrush! %A Wilkinson, Mark D %A Senger, Martin %A Kawas, Edward %A Bruskiewich, Richard %A Gouzy, Jerome %A Noirot, Celine %A Bardou, Philippe %A Ng, Ambrose %A Haase, Dirk %A Saiz, Enrique de Andres %A Wang, Dennis %A Gibbons, Frank %A Gordon, Paul M K %A Sensen, Christoph W %A Carrasco, Jose Manuel Rodriguez %A Fernández, José M %A Shen, Lixin %A Links, Matthew %A Ng, Michael %A Opushneva, Nina %A Neerincx, Pieter B T %A Leunissen, Jack A M %A Ernst, Rebecca %A Twigger, Simon %A Usadel, Bjorn %A Good, Benjamin %A Wong, Yan %A Stein, Lincoln %A Crosby, William %A Karlsson, Johan %A Royo, Romina %A Párraga, Iván %A Ramírez, Sergio %A Gelpi, Josep Lluis %A Trelles, Oswaldo %A Pisano, David G %A Jimenez, Natalia %A Kerhornou, Arnaud %A Rosset, Roman %A Zamacola, Leire %A Tárraga, Joaquín %A Huerta-Cepas, Jaime %A Carazo, Jose María %A Dopazo, Joaquin %A Guigó, Roderic %A Navarro, Arcadi %A Orozco, Modesto %A Valencia, Alfonso %A Claros, M Gonzalo %A Pérez, Antonio J %A Aldana, Jose %A Rojano, M Mar %A Fernandez-Santa Cruz, Raul %A Navas, Ismael %A Schiltz, Gary %A Farmer, Andrew %A Gessler, Damian %A Schoof, Heiko %A Groscurth, Andreas %K Computational Biology %K Database Management Systems %K Databases, Factual %K Information Storage and Retrieval %K Internet %K Programming Languages %K Systems Integration %X

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/.

%B Brief Bioinform %V 9 %P 220-31 %8 2008 May %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/18238804?dopt=Abstract %R 10.1093/bib/bbn003 %0 Journal Article %J Brief Bioinform %D 2008 %T Interoperability with Moby 1.0–it’s better than sharing your toothbrush! %A Wilkinson, M. D. %A Senger, M. %A Kawas, E. %A Bruskiewich, R. %A Gouzy, J. %A Noirot, C. %A Bardou, P. %A Ng, A. %A Haase, D. %A Saiz Ede, A. %A Wang, D. %A Gibbons, F. %A Gordon, P. M. %A Sensen, C. W. %A Carrasco, J. M. %A Fernandez, J. M. %A Shen, L. %A Links, M. %A Ng, M. %A Opushneva, N. %A Neerincx, P. B. %A Leunissen, J. A. %A Ernst, R. %A Twigger, S. %A Usadel, B. %A Good, B. %A Wong, Y. %A Stein, L. %A Crosby, W. %A Karlsson, J. %A Royo, R. %A Parraga, I. %A Ramirez, S. %A Gelpi, J. L. %A Trelles, O. %A Pisano, D. G. %A Jimenez, N. %A Kerhornou, A. %A Rosset, R. %A Zamacola, L. %A Tarraga, J. %A Huerta-Cepas, J. %A Carazo, J. M. %A Dopazo, J. %A R. Guigo %A Navarro, A. %A Orozco, M. %A Valencia, A. %A Claros, M. G. %A Perez, A. J. %A Aldana, J. %A Rojano, M. M. %A Fernandez-Santa Cruz, R. %A Navas, I. %A Schiltz, G. %A Farmer, A. %A Gessler, D. %A Schoof, H. %A Groscurth, A. %K Computational Biology/*methods *Database Management Systems *Databases %K Factual Information Storage and Retrieval/*methods *Internet *Programming Languages Systems Integration %X

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/.

%B Brief Bioinform %V 9 %P 220-31 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18238804 %0 Journal Article %J Nat Genet %D 2008 %T SNP and haplotype mapping for genetic analysis in the rat. %A Saar, Kathrin %A Beck, Alfred %A Bihoreau, Marie-Thérèse %A Birney, Ewan %A Brocklebank, Denise %A Chen, Yuan %A Cuppen, Edwin %A Demonchy, Stephanie %A Dopazo, Joaquin %A Flicek, Paul %A Foglio, Mario %A Fujiyama, Asao %A Gut, Ivo G %A Gauguier, Dominique %A Guigó, Roderic %A Guryev, Victor %A Heinig, Matthias %A Hummel, Oliver %A Jahn, Niels %A Klages, Sven %A Kren, Vladimir %A Kube, Michael %A Kuhl, Heiner %A Kuramoto, Takashi %A Kuroki, Yoko %A Lechner, Doris %A Lee, Young-Ae %A Lopez-Bigas, Nuria %A Lathrop, G Mark %A Mashimo, Tomoji %A Medina, Ignacio %A Mott, Richard %A Patone, Giannino %A Perrier-Cornet, Jeanne-Antide %A Platzer, Matthias %A Pravenec, Michal %A Reinhardt, Richard %A Sakaki, Yoshiyuki %A Schilhabel, Markus %A Schulz, Herbert %A Serikawa, Tadao %A Shikhagaie, Medya %A Tatsumoto, Shouji %A Taudien, Stefan %A Toyoda, Atsushi %A Voigt, Birger %A Zelenika, Diana %A Zimdahl, Heike %A Hubner, Norbert %K Animals %K Chromosome Mapping %K Databases, Genetic %K Genome %K Haplotypes %K Linkage Disequilibrium %K Phylogeny %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Rats %K Rats, Inbred Strains %K Recombination, Genetic %X

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.

%B Nat Genet %V 40 %P 560-6 %8 2008 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/18443594?dopt=Abstract %R 10.1038/ng.124 %0 Journal Article %J Nat Genet %D 2008 %T SNP and haplotype mapping for genetic analysis in the rat %A K. Saar %A A. Beck %A M. T. Bihoreau %A E. Birney %A D. Brocklebank %A Y. Chen %A E. Cuppen %A S. Demonchy %A Dopazo, J. %A P. Flicek %A M. Foglio %A A. Fujiyama %A I. G. Gut %A D. Gauguier %A R. Guigo %A V. Guryev %A M. Heinig %A O. Hummel %A N. Jahn %A S. Klages %A V. Kren %A M. Kube %A H. Kuhl %A Kuramoto, T. %A Kuroki, Y. %A Lechner, D. %A Lee, Y. A. %A Lopez-Bigas, N. %A Lathrop, G. M. %A Mashimo, T. %A Medina, Ignacio %A Mott, R. %A Patone, G. %A Perrier-Cornet, J. A. %A Platzer, M. %A Pravenec, M. %A Reinhardt, R. %A Sakaki, Y. %A Schilhabel, M. %A Schulz, H. %A Serikawa, T. %A Shikhagaie, M. %A Tatsumoto, S. %A Taudien, S. %A Toyoda, A. %A Voigt, B. %A Zelenika, D. %A Zimdahl, H. %A Hubner, N. %K Animals Chromosome Mapping *Databases %K Genetic %K Genetic Genome *Haplotypes Linkage Disequilibrium Phylogeny *Polymorphism %K Inbred Strains/*genetics Recombination %K Single Nucleotide *Quantitative Trait Loci Rats/*genetics Rats %X

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.

%B Nat Genet %V 40 %P 560-6 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18443594 %0 Journal Article %J Food Chem Toxicol %D 2008 %T Transcriptome analysis provides new insights into liver changes induced in the rat upon dietary administration of the food additives butylated hydroxytoluene, curcumin, propyl gallate and thiabendazole %A Stierum, R. %A A. Conesa %A Heijne, W. %A Ommen, B. %A Junker, K. %A Scott, M. P. %A Price, R. J. %A Meredith, C. %A Lake, B. G. %A Groten, J. %K Animals Aryl Hydrocarbon Hydroxylases/metabolism Body Weight/drug effects Butylated Hydroxytoluene/toxicity Curcumin/toxicity Cytochrome P-450 CYP1A2/metabolism Cytochrome P-450 CYP2B1/metabolism DNA %K Complementary/biosynthesis/genetics Data Interpretation %K Sprague-Dawley Reverse Transcriptase Polymerase Chain Reaction Steroid Hydroxylases/metabolism Thiabendazole/toxicity %K Statistical *Diet Food Additives/*toxicity Gene Expression/drug effects *Gene Expression Profiling Glutathione Transferase/metabolism Liver/*drug effects Male Organ Size/drug effects Oxidation-Reduction Palmitoyl Coenzyme A/metabolism Propyl Gallate/toxi %X Transcriptomics was performed to gain insight into mechanisms of food additives butylated hydroxytoluene (BHT), curcumin (CC), propyl gallate (PG), and thiabendazole (TB), additives for which interactions in the liver can not be excluded. Additives were administered in diets for 28 days to Sprague-Dawley rats and cDNA microarray experiments were performed on hepatic RNA. BHT induced changes in the expression of 10 genes, including phase I (CYP2B1/2; CYP3A9; CYP2C6) and phase II metabolism (GST mu2). The CYP2B1/2 and GST expression findings were confirmed by real time RT-PCR, western blotting, and increased GST activity towards DCNB. CC altered the expression of 12 genes. Three out of these were related to peroxisomes (phytanoyl-CoA dioxygenase, enoyl-CoA hydratase; CYP4A3). Increased cyanide insensitive palmitoyl-CoA oxidation was observed, suggesting that CC is a weak peroxisome proliferator. TB changed the expression of 12 genes, including CYP1A2. In line, CYP1A2 protein expression was increased. The expression level of five genes, associated with p53 was found to change upon TB treatment, including p53 itself, GADD45alpha, DN-7, protein kinase C beta and serum albumin. These array experiments led to the novel finding that TB is capable of inducing p53 at the protein level, at least at the highest dose levels employed above the current NOAEL. The expression of eight genes changed upon PG administration. This study shows the value of gene expression profiling in food toxicology in terms of generating novel hypotheses on the mechanisms of action of food additives in relation to pathology. %B Food Chem Toxicol %V 46 %P 2616-28 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18539377 %0 Journal Article %J Nucleic Acids Res %D 2003 %T Tools for comparative protein structure modeling and analysis %A Eswar, N. %A John, B. %A Mirkovic, N. %A Fiser, A. %A Ilyin, V. A. %A Pieper, U. %A Stuart, A. C. %A M. A. Marti-Renom %A Madhusudhan, M. S. %A Yerkovich, B. %A Sali, A. %K Amino Acid *Software *Structural Homology %K Internet Models %K Molecular Protein Folding Proteins/chemistry Reproducibility of Results Sequence Alignment Sequence Homology %K Protein Systems Integration %X 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. %B Nucleic Acids Res %V 31 %P 3375-80 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12824331 %0 Journal Article %J Appl Environ Microbiol %D 2002 %T Calnexin overexpression increases manganese peroxidase production in Aspergillus niger %A A. Conesa %A Jeenes, D. %A Archer, D. B. %A van den Hondel, C. A. %A Punt, P. J. %K Aspergillus niger/*enzymology/genetics Calcium-Binding Proteins/*metabolism Calnexin Culture Media *Fungal Proteins HSP70 Heat-Shock Proteins/metabolism Heme/metabolism Peroxidases/*biosynthesis/genetics Phanerochaete/enzymology/genetics Transformation %K Genetic %X Heme-containing peroxidases from white rot basidiomycetes, in contrast to most proteins of fungal origin, are poorly produced in industrial filamentous fungal strains. Factors limiting peroxidase production are believed to operate at the posttranslational level. In particular, insufficient availability of the prosthetic group which is required for peroxidase biosynthesis has been proposed to be an important bottleneck. In this work, we analyzed the role of two components of the secretion pathway, the chaperones calnexin and binding protein (BiP), in the production of a fungal peroxidase. Expression of the Phanerochaete chrysosporium manganese peroxidase (MnP) in Aspergillus niger resulted in an increase in the expression level of the clxA and bipA genes. In a heme-supplemented medium, where MnP was shown to be overproduced to higher levels, induction of clxA and bipA was also higher. Overexpression of these two chaperones in an MnP-producing strain was analyzed for its effect on MnP production. Whereas bipA overexpression seriously reduced MnP production, overexpression of calnexin resulted in a four- to fivefold increase in the extracellular MnP levels. However, when additional heme was provided in the culture medium, calnexin overexpression had no synergistic effect on MnP production. The possible function of these two chaperones in MnP maturation and production is discussed. %B Appl Environ Microbiol %V 68 %P 846-51 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11823227 %0 Book %D 2002 %T Methods of Microarray Data Analysis IISupervised Neural Networks for Clustering Conditions in DNA Array Data After Reducing Noise by Clustering Gene Expression Profiles %A Mateos, Alvaro %A Herrero, Javier %A Tamames, Javier %A Dopazo, Joaquin %E Lin, Simon M. %E Johnson, Kimberly F. %I Kluwer Academic Publishers %C Boston %P 91 - 103 %G eng %U http://www.springerlink.com/index/10.1007/b112982http://link.springer.com/10.1007/0-306-47598-7_7http://www.springerlink.com/index/pdf/10.1007/0-306-47598-7_7 %R 10.1007/b11298210.1007/0-306-47598-7_7 %0 Journal Article %J Genome Res %D 2002 %T Systematic learning of gene functional classes from DNA array expression data by using multilayer perceptrons %A A. Mateos %A Dopazo, J. %A Jansen, R. %A Tu, Y. %A Gerstein, M. %A Stolovitzky, G. %K Algorithms Artificial Intelligence Citric Acid Cycle/genetics Cluster Analysis Computational Biology/methods Gene Expression Profiling/*methods/statistics & numerical data Genes/*physiology Genetic Heterogeneity Neural Networks (Computer) Oligonucleotide %X Recent advances in microarray technology have opened new ways for functional annotation of previously uncharacterised genes on a genomic scale. This has been demonstrated by unsupervised clustering of co-expressed genes and, more importantly, by supervised learning algorithms. Using prior knowledge, these algorithms can assign functional annotations based on more complex expression signatures found in existing functional classes. Previously, support vector machines (SVMs) and other machine-learning methods have been applied to a limited number of functional classes for this purpose. Here we present, for the first time, the comprehensive application of supervised neural networks (SNNs) for functional annotation. Our study is novel in that we report systematic results for 100 classes in the Munich Information Center for Protein Sequences (MIPS) functional catalog. We found that only 10% of these are learnable (based on the rate of false negatives). A closer analysis reveals that false positives (and negatives) in a machine-learning context are not necessarily "false" in a biological sense. We show that the high degree of interconnections among functional classes confounds the signatures that ought to be learned for a unique class. We term this the "Borges effect" and introduce two new numerical indices for its quantification. Our analysis indicates that classification systems with a lower Borges effect are better suitable for machine learning. Furthermore, we introduce a learning procedure for combining false positives with the original class. We show that in a few iterations this process converges to a gene set that is learnable with considerably low rates of false positives and negatives and contains genes that are biologically related to the original class, allowing for a coarse reconstruction of the interactions between associated biological pathways. We exemplify this methodology using the well-studied tricarboxylic acid cycle. %B Genome Res %V 12 %P 1703-15 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12421757