Author: "Alain Viari" / Topic: genetics - Searchworks@Jio Institute Digital Library Search Results

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1. Peptimapper: proteogenomics workflow for the expert annotation of eukaryotic genomes

Author: Laetitia Guillot, Ludovic Delage, Alain Viari, Yves Vandenbrouck, Emmanuelle Com, Andrés Ritter, Régis Lavigne, Dominique Marie, Pierre Peterlongo, Philippe Potin, and Charles Pineau
Subjects: Bioinformatics, Genome annotation, Peptide sequence tag, Proteogenomics, Proteomics, Tandem mass spectrometry, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract: Abstract Background Accurate structural annotation of genomes is still a challenge, despite the progress made over the past decade. The prediction of gene structure remains difficult, especially for eukaryotic species, and is often erroneous and incomplete. We used a proteogenomics strategy, taking advantage of the combination of proteomics datasets and bioinformatics tools, to identify novel protein coding-genes and splice isoforms, assign correct start sites, and validate predicted exons and genes. Results Our proteogenomics workflow, Peptimapper, was applied to the genome annotation of Ectocarpus sp., a key reference genome for both the brown algal lineage and stramenopiles. We generated proteomics data from various life cycle stages of Ectocarpus sp. strains and sub-cellular fractions using a shotgun approach. First, we directly generated peptide sequence tags (PSTs) from the proteomics data. Second, we mapped PSTs onto the translated genomic sequence. Closely located hits (i.e., PSTs locations on the genome) were then clustered to detect potential coding regions based on parameters optimized for the organism. Third, we evaluated each cluster and compared it to gene predictions from existing conventional genome annotation approaches. Finally, we integrated cluster locations into GFF files to use a genome viewer. We identified two potential novel genes, a ribosomal protein L22 and an aryl sulfotransferase and corrected the gene structure of a dihydrolipoamide acetyltransferase. We experimentally validated the results by RT-PCR and using transcriptomics data. Conclusions Peptimapper is a complementary tool for the expert annotation of genomes. It is suitable for any organism and is distributed through a Docker image available on two public bioinformatics docker repositories: Docker Hub and BioShaDock. This workflow is also accessible through the Galaxy framework and for use by non-computer scientists at https://galaxy.protim.eu. Data are available via ProteomeXchange under identifier PXD010618.
Published: 2019
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2. The circular RNome of primary breast cancer

Author: Steven Van Laere, Colin A. Purdie, John A. Foekens, Gaëten MacGrogan, Marcel Smid, Andrew Futreal, Vanja de Weerd, Paul N. Span, Marc J. van de Vijver, Jorunn E. Eyfjord, Serena Nik-Zainal, F. Germán Rodríguez-González, Roberto Salgado, Peter T. Simpson, Christine Desmedt, Wendy J. C. Prager-van der Smissen, Fred C.G.J. Sweep, Tari A. King, Adam Butler, Michael R. Stratton, Carlos Caldas, Gert Van den Eynden, Sunil R. Lakhani, Saskia M. Wilting, Alastair M. Thompson, Angelo Paradiso, John W.M. Martens, Anne Vincent-Salomon, Johan Staaf, Anne van Galen, Sancha Martin, Hendrik G. Stunnenberg, Annegien Broeks, Andrea L. Richardson, Anne Lise Børresen-Dale, Helen Davies, Michelle van der Vlugt-Daane, Katharina Uhr, Stian Knappskog, Alain Viari, Anieta M. Sieuwerts, Medical Oncology, Smid, Marcel [0000-0003-0605-1901], Apollo - University of Cambridge Repository, Pathology, CCA - Cancer biology and immunology, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), The Wellcome Trust Sanger Institute [Cambridge], Lund University [Lund], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Dana-Farber Cancer Institute [Boston], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Institut Bergonié [Bordeaux], UNICANCER, Breast Cancer Translational Research Laboratory, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Translational Cancer Research Unit [Antwerp], Department of Pathology [Dundee], Ninewells Hospital and Medical School [Dundee], Radboud University Medical Center [Nijmegen], University of Southern Queensland (USQ), University of Antwerp (UA), Istituto Tumori 'Giovanni Paolo II' [Bari], University of Iceland [Reykjavik], Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), The University of Texas M.D. Anderson Cancer Center [Houston], University of Bergen (UiB), Haukeland University Hospital, Memorial Sloane Kettering Cancer Center [New York], Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institute for Cancer Research [Oslo], Oslo University Hospital [Oslo], Fondation Synergie Lyon Cancer [Lyon], Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: Génétique clinique, Proliferation index, [SDV]Life Sciences [q-bio], Transcriptome, Exon, Breast cancer, 0302 clinical medicine, Brjóstakrabbamein, MUTATIONAL PROCESSES, Genetics (clinical), Genetics & Heredity, 0303 health sciences, Gene knockdown, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], ABUNDANT, CREB-Binding Protein, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, GENOME, Chemistry, Lymphatic Metastasis, RNA splicing, MCF-7 Cells, Female, Engineering sciences. Technology, Biologie, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Breast Neoplasms, Biology, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, REVEALS, Biomarkers, Tumor, Genetics, medicine, Erfðafræði, Humans, TAMOXIFEN, Molecular Biology, Gene, SIGNATURES, 030304 developmental biology, Science & Technology, LANDSCAPE, Research, MICRORNA, Cancer, RNA, Circular, medicine.disease, DNA-rannsóknir, GENE, RNAs, Repressor Proteins, Biotechnology & Applied Microbiology, Cancer research, RNA, Human medicine, Carrier Proteins, 030217 neurology & neurosurgery
Abstract: Publisher's version (útgefin grein), Circular RNAs (circRNAs) are a class of RNAs that is under increasing scrutiny, although their functional roles are debated. We analyzed RNA-seq data of 348 primary breast cancers and developed a method to identify circRNAs that does not rely on unmapped reads or known splice junctions. We identified 95,843 circRNAs, of which 20,441 were found recurrently. Of the circRNAs that match exon boundaries of the same gene, 668 showed a poor or even negative (R < 0.2) correlation with the expression level of the linear gene. In silico analysis showed only a minority (8.5%) of circRNAs could be explained by known splicing events. Both these observations suggest that specific regulatory processes for circRNAs exist. We confirmed the presence of circRNAs of CNOT2, CREBBP, and RERE in an independent pool of primary breast cancers. We identified circRNA profiles associated with subgroups of breast cancers and with biological and clinical features, such as amount of tumor lymphocytic infiltrate and proliferation index. siRNA-mediated knockdown of circCNOT2 was shown to significantly reduce viability of the breast cancer cell lines MCF-7 and BT-474, further underlining the biological relevance of circRNAs. Furthermore, we found that circular, and not linear, CNOT2 levels are predictive for progression-free survival time to aromatase inhibitor (AI) therapy in advanced breast cancer patients, and found that circCNOT2 is detectable in cell-free RNA from plasma. We showed that circRNAs are abundantly present, show characteristics of being specifically regulated, are associated with clinical and biological properties, and thus are relevant in breast cancer., We thank the Erasmus MC Cancer Computational Biology Center for giving access to their IT infrastructure and the software that was used for the computations and data analysis in this study. We thank Sandra Albassam for her help with the first versions of the script to identify circular regions. We thank Maurice P.H.M. Jansen, Jean C. Helmijr, Inge de Kruijff, and Manouk K. Bos for their help in evaluating plasma samples that were gathered in the EU-FP7 CareMore (nr 601760) project. We thank for technical support Miriam Ragle Aure and Anita Langerød of the Oslo University Hospital, Norway; Ewan Birney of the European Bioinformatics Institute, UK; and Stefania Tommasi of the IRCCS Istituto Tumori “Giovanni Paolo II,” Bari, Italy. We thank the Oslo Breast Cancer Research Consortium (OSBREAC), Norway (https://www.ous-research.no/home/kgjebsen/home/14105) for contributing patient samples and Sabine Linn and Marleen Kok of The Netherlands Cancer Institute for contributing samples for the AI cohort. Finally, we thank all members of the ICGC Breast Cancer Working Group. This work has been funded through the ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (a European research project funded by the European Community’s Seventh Framework Programme (FP7/2010-2014) under the grant agreement number 242006) and the Triple Negative project funded by the Wellcome Trust (grant reference 077012/Z/05/Z). F.G.R.-G. and S.M. were funded by BASIS. J.A.F. was funded through an ERC Advanced Grant (ERC-2012-AdG-322737) and ERC Proof-of-Concept Grant (ERC-2017-PoC-767854). K.U. was funded by the Daniel den Hoed Foundation. S.N.-Z. is a Wellcome Beit Fellow and personally funded by a Wellcome Trust Intermediate Fellowship (WT100183MA). A.L.R. is partially supported by the Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer (NIH/NCI 5 P50 CA16 8504-02). A.M.S. was supported by Cancer Genomics Netherlands (CGC.nl) through a grant from the Netherlands Organization of Scientific research (NWO). M. Smid was supported by the EU-FP7-DDR response project. C.D. was supported by a grant from the Breast Cancer Research Foundation. J.E. was funded by The Icelandic Centre for Research (RANNIS).
Published: 2019

3. Genetic analysis of lung cancer reveals novel susceptibility loci and germline impact on somatic mutation burden

Author: Aurélie AG Gabriel, Joshua R Atkins, Ricardo CC Penha, Karl Smith-Byrne, Valerie Gaborieau, Catherine Voegele, Behnoush Abedi-Ardekani, Maja Milojevic, Robert Olaso, Vincent Meyer, Anne Boland, Jean François Deleuze, David Zaridze, Anush Mukeriya, Beata Swiatkowska, Vladimir Janout, Miriam Schejbalová, Dana Mates, Jelena Stojšić, Miodrag Ognjanovic, John S Witte, Sara R Rashkin, Linda Kachuri, Rayjean J Hung, Siddhartha Kar, Paul Brennan, Anne-Sophie Sertier, Anthony Ferrari, Alain Viari, Mattias Johansson, Christopher I Amos, Matthieu Foll, and James D McKay
Subjects: Genetics, Mutation, education.field_of_study, Population, Cancer, Genome-wide association study, Biology, medicine.disease_cause, medicine.disease, Germline, Germline mutation, Expression quantitative trait loci, medicine, education, Lung cancer
Abstract: Germline genetic variants are involved in lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated genes involved in smoking propensity and DNA repair but further work is required to identify additional LC susceptibility variants and to investigate LC disease development dynamics.We have undertaken a family history-based genome-wide association (GWAx) study of LC, analysing 48,843 European cases with a parent/sibling with LC compared to 195,387 controls from the UK Biobank. This was meta-analysed with previously described LC GWAS results. We performed Polygenic Risk Scores (PRS) analyses and further evaluated the PRS influence on the somatic environment in exome (N=736) and genome sequencing (N=61) profiled cohorts.Eight novel loci were identified including DNA repair genes (CHEK1, MDM4), metabolic genes (CYP1A1) and variants that were also associated with smoking propensity, such as both subunits of the neuronal α4β2 nicotinic acetylcholine receptor (CHRNA4 and CHRNB2). PRS analysis demonstrated that variants related to eQTLs and/or smoking propensity are enriched for susceptibility variants, including variants below genome-wide significant threshold. PRS of LC variants related to smoking propensity were associated with somatic mutation burden in two case cohorts, with individuals with higher polygenic genetic risk having increased numbers of somatic mutations in their lung tumours.This study has expanded the number of susceptibility loci linked with LC and provided insights into the molecular mechanisms by which these susceptibility variants contribute to the development of lung cancer.
Published: 2021

4. Acquired somatic MMR deficiency is a major cause of MSI tumor in patients suspected for 'Lynch-like syndrome' including young patients

Author: Cedrick Lefol, Christian Baudet, Pierre Naïbo, Qing Wang, Emilie Sohier, Chloé Grand-Masson, Alain Viari, and Eric Ruano
Subjects: Adult, congenital, hereditary, and neonatal diseases and abnormalities, Somatic cell, Adenomatous Polyposis Coli Protein, Loss of Heterozygosity, MLH1, DNA Mismatch Repair, Germline, Article, Malignant transformation, Loss of heterozygosity, Genetics, medicine, Humans, Gene, Genetics (clinical), Aged, business.industry, Microsatellite instability, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, MutS Homolog 2 Protein, MSH2, Cancer research, Microsatellite Instability, business, MutL Protein Homolog 1
Abstract: Patients with tumors displaying high microsatellite instability (MSI-H) but no germline MMR inactivation are suspected for Lynch-like syndrome (LLS). To explore the involvement of acquired somatic MMR alteration as a cause, we screened 113 patient tumor samples for MMR gene variations and loss of heterozygosity. Somatic MMR alterations were found in 85.8% of patients including "double hits" in 63.7% of patients, mainly diagnosed with colon and endometrial cancers. Interestingly, 37.5% of them were under the age of 50, and seven patients were under 30. Somatic alterations were mainly attributed to the MLH1, MSH2 genes, likely reflecting the functional importance of these key MMR genes. Pathogenic variants co-existed in other cancer genes in particular the APC gene displaying a characteristic MMR deficiency-related "mutational signature", indicating that it may be inactivated owing to MMR deficiency. We speculated that APC inactivation could trigger an accelerated malignant transformation underlying early-onset cancers. Our findings provide further insight into the mechanisms underlying LLS, somatic MMR inactivation being a major cause for early-onset LLS through pathways differing from those involved in late-onset sporadic cases.
Published: 2020

5. Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Author: Bailey, Matthew H, Meyerson, William U, Dursi, Lewis Jonathan, Wang, Liang-Bo, Dong, Guanlan, Liang, Wen-Wei, Weerasinghe, Amila, Shantao, Li, Kelso, Sean, Saksena, Gordon, Ellrott, Kyle, Wendl, Michael C, Wheeler, David A, Getz, Gad, Simpson, Jared T, Gerstein, Mark B, Ding, Lirehan, Akbani, Pavana, Anur, Matthew, H Bailey, Alex, Buchanan, Kami, Chiotti, Kyle, Covington, Allison, Creason, Ding, Li, Kyle, Ellrott, Fan, Yu, Steven, Foltz, Gad, Getz, Walker, Hale, David, Haussler, Julian, M Hess, Carolyn, M Hutter, Cyriac, Kandoth, Katayoon, Kasaian, Melpomeni, Kasapi, Dave, Larson, Ignaty, Leshchiner, John, Letaw, Singer, Ma, Michael, D McLellan, Yifei, Men, Gordon, B Mills, Beifang, Niu, Myron, Peto, Amie, Radenbaugh, Sheila, M Reynolds, Gordon, Saksena, Heidi, Sofia, Chip, Stewart, Adam, J Struck, Joshua, M Stuart, Wenyi, Wang, John, N Weinstein, David, A Wheeler, Christopher, K Wong, Liu, Xi, Kai, Ye, Matthias, Bieg, Paul, C Boutros, Ivo, Buchhalter, Adam, P Butler, Ken, Chen, Zechen, Chong, Oliver, Drechsel, Lewis Jonathan Dursi, Roland, Eils, Shadrielle M, G Espiritu, Robert, S Fulton, Shengjie, Gao, Josep L, L Gelpi, Mark, B Gerstein, Santiago, Gonzalez, Ivo, G Gut, Faraz, Hach, Michael, C Heinold, Jonathan, Hinton, Taobo, Hu, Vincent, Huang, Huang, Yi, Barbara, Hutter, David, R Jones, Jongsun, Jung, Natalie, Jäger, Hyung-Lae, Kim, Kortine, Kleinheinz, Sushant, Kumar, Yogesh, Kumar, Christopher, M Lalansingh, Ivica, Letunic, Dimitri, Livitz, Eric, Z Ma, Yosef, E Maruvka, R Jay Mashl, Andrew, Menzies, Ana, Milovanovic, Morten Muhlig Nielsen, Stephan, Ossowski, Nagarajan, Paramasivam, Jakob Skou Pedersen, Marc, D Perry, Montserrat, Puiggròs, Keiran, M Raine, Esther, Rheinbay, Romina, Royo, S Cenk Sahinalp, Iman, Sarrafi, Matthias, Schlesner, Jared, T Simpson, Lucy, Stebbings, Miranda, D Stobbe, Jon, W Teague, Grace, Tiao, David, Torrents, Jeremiah, A Wala, Jiayin, Wang, Sebastian, M Waszak, Joachim, Weischenfeldt, Michael, C Wendl, Johannes, Werner, Zhenggang, Wu, Hong, Xue, Sergei, Yakneen, Takafumi, N Yamaguchi, Venkata, D Yellapantula, Christina, K Yung, Junjun, Zhang, Lauri, A Aaltonen, Federico, Abascal, Adam, Abeshouse, Hiroyuki, Aburatani, David, J Adams, Nishant, Agrawal, Keun Soo Ahn, Sung-Min, Ahn, Hiroshi, Aikata, Rehan, Akbani, Kadir, C Akdemir, Hikmat, Al-Ahmadie, Sultan, T Al-Sedairy, Fatima, Al-Shahrour, Malik, Alawi, Monique, Albert, Kenneth, Aldape, Ludmil, B Alexandrov, Adrian, Ally, Kathryn, Alsop, Eva, G Alvarez, Fernanda, Amary, Samirkumar, B Amin, Brice, Aminou, Ole, Ammerpohl, Matthew, J Anderson, Yeng, Ang, Davide, Antonello, Samuel, Aparicio, Elizabeth, L Appelbaum, Yasuhito, Arai, Axel, Aretz, Koji, Arihiro, Shun-Ichi, Ariizumi, Joshua, Armenia, Laurent, Arnould, Sylvia, Asa, Yassen, Assenov, Gurnit, Atwal, Sietse, Aukema, J Todd Auman, Miriam, R Aure, Philip, Awadalla, Marta, Aymerich, Gary, D Bader, Adrian, Baez-Ortega, Peter, J Bailey, Miruna, Balasundaram, Saianand, Balu, Pratiti, Bandopadhayay, Rosamonde, E Banks, Stefano, Barbi, Andrew, P Barbour, Jonathan, Barenboim, Jill, Barnholtz-Sloan, Hugh, Barr, Elisabet, Barrera, John, Bartlett, Javier, Bartolome, Bassi, Claudio, Oliver, F Bathe, Daniel, Baumhoer, Prashant, Bavi, Stephen, B Baylin, Wojciech, Bazant, Duncan, Beardsmore, Timothy, A Beck, Sam, Behjati, Andreas, Behren, Cindy, Bell, Sergi, Beltran, Christopher, Benz, Andrew, Berchuck, Anke, K Bergmann, Erik, N Bergstrom, Benjamin, P Berman, Daniel, M Berney, Stephan, H Bernhart, Rameen, Beroukhim, Mario, Berrios, Samantha, Bersani, Johanna, Bertl, Miguel, Betancourt, Vinayak, Bhandari, Shriram, G Bhosle, Andrew, V Biankin, Darell, Bigner, Hans, Binder, Ewan, Birney, Michael, Birrer, Nidhan, K Biswas, Bodil, Bjerkehagen, Tom, Bodenheimer, Lori, Boice, Giada, Bonizzato, Johann, S De Bono, Arnoud, Boot, Moiz, S Bootwalla, Ake, Borg, Arndt, Borkhardt, Keith, A Boroevich, Ivan, Borozan, Christoph, Borst, Marcus, Bosenberg, Mattia, Bosio, Jacqueline, Boultwood, Guillaume, Bourque, G Steven Bova, David, T Bowen, Reanne, Bowlby, David D, L Bowtell, Sandrine, Boyault, Rich, Boyce, Jeffrey, Boyd, Alvis, Brazma, Paul, Brennan, Daniel, S Brewer, Arie, B Brinkman, Robert, G Bristow, Russell, R Broaddus, Jane, E Brock, Malcolm, Brock, Annegien, Broeks, Angela, N Brooks, Denise, Brooks, Benedikt, Brors, Søren, Brunak, Timothy J, C Bruxner, Alicia, L Bruzos, Christiane, Buchholz, Susan, Bullman, Hazel, Burke, Birgit, Burkhardt, Kathleen, H Burns, John, Busanovich, Carlos, D Bustamante, Atul, J Butte, Niall, J Byrne, Anne-Lise, Børresen-Dale, Samantha, J Caesar-Johnson, Andy, Cafferkey, Declan, Cahill, Claudia, Calabrese, Carlos, Caldas, Fabien, Calvo, Niedzica, Camacho, Peter, J Campbell, Elias, Campo, Cinzia, Cantù, Shaolong, Cao, Thomas, E Carey, Joana, Carlevaro-Fita, Rebecca, Carlsen, Ivana, Cataldo, Mario, Cazzola, Jonathan, Cebon, Robert, Cerfolio, Dianne, E Chadwick, Dimple, Chakravarty, Don, Chalmers, Calvin Wing Yiu Chan, Kin, Chan, Michelle, Chan-Seng-Yue, Vishal, S Chandan, David, K Chang, Stephen, J Chanock, Lorraine, A Chantrill, Aurélien, Chateigner, Nilanjan, Chatterjee, Kazuaki, Chayama, Hsiao-Wei, Chen, Jieming, Chen, Yiwen, Chen, Zhaohong, Chen, Andrew, D Cherniack, Jeremy, Chien, Yoke-Eng, Chiew, Suet-Feung, Chin, Juok, Cho, Sunghoon, Cho, Jung Kyoon Choi, Wan, Choi, Christine, Chomienne, Su Pin Choo, Angela, Chou, Angelika, N Christ, Elizabeth, L Christie, Eric, Chuah, Carrie, Cibulskis, Kristian, Cibulskis, Sara, Cingarlini, Peter, Clapham, Alexander, Claviez, Sean, Cleary, Nicole, Cloonan, Marek, Cmero, Colin, C Collins, Ashton, A Connor, Susanna, L Cooke, Colin, S Cooper, Leslie, Cope, Corbo, Vincenzo, Matthew, G Cordes, Stephen, M Cordner, Isidro, Cortés-Ciriano, Prue, A Cowin, Brian, Craft, David, Craft, Chad, J Creighton, Yupeng, Cun, Erin, Curley, Ioana, Cutcutache, Karolina, Czajka, Bogdan, Czerniak, Rebecca, A Dagg, Ludmila, Danilova, Maria Vittoria Davi, Natalie, R Davidson, Helen, Davies, Ian, J Davis, Brandi, N Davis-Dusenbery, Kevin, J Dawson, Francisco, M De La Vega, Ricardo De Paoli-Iseppi, Timothy, Defreitas, Angelo, P Dei Tos, Olivier, Delaneau, John, A Demchok, Jonas, Demeulemeester, German, M Demidov, Deniz, Demircioğlu, Nening, M Dennis, Robert, E Denroche, Stefan, C Dentro, Nikita, Desai, Vikram, Deshpande, Amit, G Deshwar, Christine, Desmedt, Jordi, Deu-Pons, Noreen, Dhalla, Neesha, C Dhani, Priyanka, Dhingra, Rajiv, Dhir, Anthony, Dibiase, Klev, Diamanti, Shuai, Ding, Huy, Q Dinh, Luc, Dirix, Harshavardhan, Doddapaneni, Nilgun, Donmez, Michelle, T Dow, Ronny, Drapkin, Ruben, M Drews, Serge, Serge, Tim, Dudderidge, Ana, Dueso-Barroso, Andrew, J Dunford, Michael, Dunn, Fraser, R Duthie, Ken, Dutton-Regester, Jenna, Eagles, Douglas, F Easton, Stuart, Edmonds, Paul, A Edwards, Sandra, E Edwards, Rosalind, A Eeles, Anna, Ehinger, Juergen, Eils, Adel, El-Naggar, Matthew, Eldridge, Serap, Erkek, Georgia, Escaramis, Xavier, Estivill, Dariush, Etemadmoghadam, Jorunn, E Eyfjord, Bishoy, M Faltas, Daiming, Fan, William, C Faquin, Claudiu, Farcas, Matteo, Fassan, Aquila, Fatima, Francesco, Favero, Nodirjon, Fayzullaev, Ina, Felau, Sian, Fereday, Martin, L Ferguson, Vincent, Ferretti, Lars, Feuerbach, Matthew, A Field, J Lynn Fink, Gaetano, Finocchiaro, Cyril, Fisher, Matthew, W Fittall, Anna, Fitzgerald, Rebecca, C Fitzgerald, Adrienne, M Flanagan, Neil, E Fleshner, Paul, Flicek, John, A Foekens, Kwun, M Fong, Nuno, A Fonseca, Christopher, S Foster, Natalie, S Fox, Michael, Fraser, Scott, Frazer, Milana, Frenkel-Morgenstern, William, Friedman, Joan, Frigola, Catrina, C Fronick, Akihiro, Fujimoto, Masashi, Fujita, Masashi, Fukayama, Lucinda, A Fulton, Mayuko, Furuta, P Andrew Futreal, Anja, Füllgrabe, Stacey, B Gabriel, Steven, Gallinger, Carlo, Gambacorti-Passerini, Jianjiong, Gao, Levi, Garraway, Øystein, Garred, Erik, Garrison, Dale, W Garsed, Nils, Gehlenborg, Joshy, George, Daniela, S Gerhard, Clarissa, Gerhauser, Jeffrey, E Gershenwald, Moritz, Gerstung, Mohammed, Ghori, Ronald, Ghossein, Nasra, H Giama, Richard, A Gibbs, Anthony, J Gill, Pelvender, Gill, Dilip, D Giri, Dominik, Glodzik, Vincent, J Gnanapragasam, Maria Elisabeth Goebler, Mary, J Goldman, Carmen, Gomez, Abel, Gonzalez-Perez, Dmitry, A Gordenin, James, Gossage, Kunihito, Gotoh, Ramaswamy, Govindan, Dorthe, Grabau, Janet, S Graham, Robert, C Grant, Anthony, R Green, Eric, Green, Liliana, Greger, Nicola, Grehan, Sonia, Grimaldi, Sean, M Grimmond, Robert, L Grossman, Adam, Grundhoff, Gunes, Gundem, Qianyun, Guo, Manaswi, Gupta, Shailja, Gupta, Marta, Gut, Jonathan, Göke, Gavin, Ha, Andrea, Haake, David, Haan, Siegfried, Haas, Kerstin, Haase, James, E Haber, Nina, Habermann, Syed, Haider, Natsuko, Hama, Freddie, C Hamdy, Anne, Hamilton, Mark, P Hamilton, Leng, Han, George, B Hanna, Martin, Hansmann, Nicholas, J Haradhvala, Olivier, Harismendy, Ivon, Harliwong, Arif, O Harmanci, Eoghan, Harrington, Takanori, Hasegawa, Steve, Hawkins, Shinya, Hayami, Shuto, Hayashi, D Neil Hayes, Stephen, J Hayes, Nicholas, K Hayward, Steven, Hazell, Yao, He, Allison, P Heath, Simon, C Heath, David, Hedley, Apurva, M Hegde, David, I Heiman, Zachary, Heins, Lawrence, E Heisler, Eva, Hellstrom-Lindberg, Mohamed, Helmy, Seong Gu Heo, Austin, J Hepperla, José María Heredia-Genestar, Carl, Herrmann, Peter, Hersey, Holmfridur, Hilmarsdottir, Satoshi, Hirano, Nobuyoshi, Hiraoka, Katherine, A Hoadley, Asger, Hobolth, Ermin, Hodzic, Jessica, I Hoell, Steve, Hoffmann, Oliver, Hofmann, Andrea, Holbrook, Aliaksei, Z Holik, Michael, A Hollingsworth, Oliver, Holmes, Robert, A Holt, Chen, Hong, Eun Pyo Hong, Jongwhi, H Hong, Gerrit, K Hooijer, Henrik, Hornshøj, Fumie, Hosoda, Yong, Hou, Volker, Hovestadt, William, Howat, Alan, P Hoyle, Ralph, H Hruban, Jianhong, Hu, Xing, Hua, Kuan-Lin, Huang, Mei, Huang, Mi Ni Huang, Wolfgang, Huber, Thomas, J Hudson, Michael, Hummel, Jillian, A Hung, David, Huntsman, Ted, R Hupp, Jason, Huse, Matthew, R Huska, Daniel, Hübschmann, Christine, A Iacobuzio-Donahue, Charles David Imbusch, Marcin, Imielinski, Seiya, Imoto, William, B Isaacs, Keren, Isaev, Shumpei, Ishikawa, Murat, Iskar, M Ashiqul Islam, S, Michael, Ittmann, Sinisa, Ivkovic, Jose M, G Izarzugaza, Jocelyne, Jacquemier, Valerie, Jakrot, Nigel, B Jamieson, Gun Ho Jang, Se Jin Jang, Joy, C Jayaseelan, Reyka, Jayasinghe, Stuart, R Jefferys, Karine, Jegalian, Jennifer, L Jennings, Seung-Hyup, Jeon, Lara, Jerman, Yuan, Ji, Wei, Jiao, Peter, A Johansson, Amber, L Johns, Jeremy, Johns, Rory, Johnson, Todd, A Johnson, Clemency, Jolly, Yann, Joly, Jon, G Jonasson, Corbin, D Jones, David T, W Jones, Nic, Jones, Steven J, M Jones, Jos, Jonkers, Young Seok Ju, Hartmut, Juhl, Malene, Juul, Randi Istrup Juul, Sissel, Juul, Rolf, Kabbe, Andre, Kahles, Abdullah, Kahraman, Vera, B Kaiser, Hojabr, Kakavand, Sangeetha, Kalimuthu, Christof von Kalle, Koo Jeong Kang, Katalin, Karaszi, Beth, Karlan, Rosa, Karlić, Dennis, Karsch, Karin, S Kassahn, Hitoshi, Katai, Mamoru, Kato, Hiroto, Katoh, Yoshiiku, Kawakami, Jonathan, D Kay, Stephen, H Kazakoff, Marat, D Kazanov, Maria, Keays, Electron, Kebebew, Richard, F Kefford, Manolis, Kellis, James, G Kench, Catherine, J Kennedy, Jules N, A Kerssemakers, David, Khoo, Vincent, Khoo, Narong, Khuntikeo, Ekta, Khurana, Helena, Kilpinen, Hark Kyun Kim, Hyung-Yong, Kim, Hyunghwan, Kim, Jaegil, Kim, Jihoon, Kim, Jong, K Kim, Youngwook, Kim, Tari, A King, Wolfram, Klapper, Leszek, J Klimczak, Stian, Knappskog, Michael, Kneba, Bartha, M Knoppers, Youngil, Koh, Jan, Komorowski, Daisuke, Komura, Mitsuhiro, Komura, Kong, Gu, Marcel, Kool, Jan, O Korbel, Viktoriya, Korchina, Andrey, Korshunov, Michael, Koscher, Roelof, Koster, Zsofia, Kote-Jarai, Antonios, Koures, Milena, Kovacevic, Barbara, Kremeyer, Helene, Kretzmer, Markus, Kreuz, Savitri, Krishnamurthy, Dieter, Kube, Kiran, Kumar, Pardeep, Kumar, Ritika, Kundra, Kirsten, Kübler, Ralf, Küppers, Jesper, Lagergren, Phillip, H Lai, Peter, W Laird, Sunil, R Lakhani, Emilie, Lalonde, Fabien, C Lamaze, Adam, Lambert, Eric, Lander, Pablo, Landgraf, Landoni, Luca, Anita, Langerød, Andrés, Lanzós, Denis, Larsimont, Erik, Larsson, Mark, Lathrop, Loretta M, S Lau, Chris, Lawerenz, Rita, T Lawlor, Michael, S Lawrence, Alexander, J Lazar, Xuan, Le, Darlene, Lee, Donghoon, Lee, Eunjung Alice Lee, Hee Jin Lee, Jake June-Koo Lee, Jeong-Yeon, Lee, Juhee, Lee, Ming Ta Michael Lee, Henry, Lee-Six, Kjong-Van, Lehmann, Hans, Lehrach, Dido, Lenze, Conrad, R Leonard, Daniel, A Leongamornlert, Louis, Letourneau, Douglas, A Levine, Lora, Lewis, Tim, Ley, Chang, Li, Constance, H Li, Haiyan Irene Li, Jun, Li, Lin, Li, Siliang, Li, Xiaobo, Li, Xiaotong, Li, Xinyue, Li, Yilong, Li, Han, Liang, Sheng-Ben, Liang, Peter, Lichter, Pei, Lin, Ziao, Lin, M Linehan, W, Ole Christian Lingjærde, Dongbing, Liu, Eric Minwei Liu, Fei-Fei, Liu, Fenglin, Liu, Jia, Liu, Xingmin, Liu, Julie, Livingstone, Naomi, Livni, Lucas, Lochovsky, Markus, Loeffler, Georgina, V Long, Armando, Lopez-Guillermo, Shaoke, Lou, David, N Louis, Laurence, B Lovat, Yiling, Lu, Yong-Jie, Lu, Youyong, Lu, Luchini, Claudio, Ilinca, Lungu, Xuemei, Luo, Hayley, J Luxton, Andy, G Lynch, Lisa, Lype, Cristina, López, Carlos, López-Otín, Yussanne, Ma, Gaetan, Macgrogan, Shona, Macrae, Geoff, Macintyre, Tobias, Madsen, Kazuhiro, Maejima, Andrea, Mafficini, Dennis, T Maglinte, Arindam, Maitra, Partha, P Majumder, Luca, Malcovati, Salem, Malikic, Malleo, Giuseppe, Graham, J Mann, Luisa, Mantovani-Löffler, Kathleen, Marchal, Giovanni, Marchegiani, Elaine, R Mardis, Adam, A Margolin, Maximillian, G Marin, Florian, Markowetz, Julia, Markowski, Jeffrey, Marks, Tomas, Marques-Bonet, Marco, A Marra, Luke, Marsden, John W, M Martens, Sancha, Martin, Jose, I Martin-Subero, Iñigo, Martincorena, Alexander, Martinez-Fundichely, Charlie, E Massie, Thomas, J Matthew, Lucy, Matthews, Erik, Mayer, Simon, Mayes, Michael, Mayo, Faridah, Mbabaali, Karen, Mccune, Ultan, Mcdermott, Patrick, D McGillivray, John, D McPherson, John, R McPherson, Treasa, A McPherson, Samuel, R Meier, Alice, Meng, Shaowu, Meng, Neil, D Merrett, Sue, Merson, Matthew, Meyerson, William, U Meyerson, Piotr, A Mieczkowski, George, L Mihaiescu, Sanja, Mijalkovic, Ana Mijalkovic Mijalkovic-Lazic, Tom, Mikkelsen, Milella, Michele, Linda, Mileshkin, Christopher, A Miller, David, K Miller, Jessica, K Miller, Sarah, Minner, Marco, Miotto, Gisela Mir Arnau, Lisa, Mirabello, Chris, Mitchell, Thomas, J Mitchell, Satoru, Miyano, Naoki, Miyoshi, Shinichi, Mizuno, Fruzsina, Molnár-Gábor, Malcolm, J Moore, Richard, A Moore, Sandro, Morganella, Quaid, D Morris, Carl, Morrison, Lisle, E Mose, Catherine, D Moser, Ferran, Muiños, Loris, Mularoni, Andrew, J Mungall, Karen, Mungall, Elizabeth, A Musgrove, Ville, Mustonen, David, Mutch, Francesc, Muyas, Donna, M Muzny, Alfonso, Muñoz, Jerome, Myers, Ola, Myklebost, Peter, Möller, Genta, Nagae, Adnan, M Nagrial, Hardeep, K Nahal-Bose, Hitoshi, Nakagama, Hidewaki, Nakagawa, Hiromi, Nakamura, Toru, Nakamura, Kaoru, Nakano, Tannistha, Nandi, Jyoti, Nangalia, Mia, Nastic, Arcadi, Navarro, Fabio C, P Navarro, David, E Neal, Gerd, Nettekoven, Felicity, Newell, Steven, J Newhouse, Yulia, Newton, Alvin Wei Tian Ng, Anthony, Ng, Jonathan, Nicholson, David, Nicol, Yongzhan, Nie, G Petur Nielsen, Serena, Nik-Zainal, Michael, S Noble, Katia, Nones, Paul, A Northcott, Faiyaz, Notta, Brian, D O'Connor, Peter, O'Donnell, Maria, O'Donovan, Sarah, O'Meara, Brian Patrick O'Neill, J Robert O'Neill, David, Ocana, Angelica, Ochoa, Layla, Oesper, Christopher, Ogden, Hideki, Ohdan, Kazuhiro, Ohi, Lucila, Ohno-Machado, Karin, A Oien, Akinyemi, I Ojesina, Hidenori, Ojima, Takuji, Okusaka, Larsson, Omberg, Choon Kiat Ong, German, Ott, F Francis Ouellette, B, Christine, P'Ng, Marta, Paczkowska, Paiella, Salvatore, Chawalit, Pairojkul, Marina, Pajic, Qiang, Pan-Hammarström, Elli, Papaemmanuil, Irene, Papatheodorou, Ji Wan Park, Joong-Won, Park, Keunchil, Park, Kiejung, Park, Peter, J Park, Joel, S Parker, Simon, L Parsons, Harvey, Pass, Danielle, Pasternack, Alessandro, Pastore, Ann-Marie, Patch, Iris, Pauporté, Antonio, Pea, John, V Pearson, Chandra Sekhar Pedamallu, Paolo, Pederzoli, Martin, Peifer, Nathan, A Pennell, Charles, M Perou, Gloria, M Petersen, Nicholas, Petrelli, Robert, Petryszak, Stefan, M Pfister, Mark, Phillips, Oriol, Pich, Hilda, A Pickett, Todd, D Pihl, Nischalan, Pillay, Sarah, Pinder, Mark, Pinese, Andreia, V Pinho, Esa, Pitkänen, Xavier, Pivot, Elena, Piñeiro-Yáñez, Laura, Planko, Christoph, Plass, Paz, Polak, Tirso, Pons, Irinel, Popescu, Olga, Potapova, Aparna, Prasad, Shaun, R Preston, Manuel, Prinz, Antonia, L Pritchard, Stephenie, D Prokopec, Elena, Provenzano, Xose, S Puente, Sonia, Puig, Sergio, Pulido-Tamayo, Gulietta, M Pupo, Colin, A Purdie, Michael, C Quinn, Raquel, Rabionet, Janet, S Rader, Bernhard, Radlwimmer, Petar, Radovic, Benjamin, Raeder, Manasa, Ramakrishna, Kamna, Ramakrishnan, Suresh, Ramalingam, Benjamin, J Raphael, W Kimryn Rathmell, Tobias, Rausch, Guido, Reifenberger, Jüri, Reimand, Jorge, Reis-Filho, Victor, Reuter, Iker, Reyes-Salazar, Matthew, A Reyna, Yasser, Riazalhosseini, Andrea, L Richardson, Julia, Richter, Matthew, Ringel, Markus, Ringnér, Yasushi, Rino, Karsten, Rippe, Jeffrey, Roach, Lewis, R Roberts, Nicola, D Roberts, Steven, A Roberts, A Gordon Robertson, Alan, J Robertson, Javier Bartolomé Rodriguez, Bernardo, Rodriguez-Martin, F Germán Rodríguez-González, Michael H, A Roehrl, Marius, Rohde, Hirofumi, Rokutan, Gilles, Romieu, Ilse, Rooman, Tom, Roques, Daniel, Rosebrock, Mara, Rosenberg, Philip, C Rosenstiel, Andreas, Rosenwald, Edward, W Rowe, Steven, G Rozen, Yulia, Rubanova, Mark, A Rubin, Carlota, Rubio-Perez, Vasilisa, A Rudneva, Borislav, C Rusev, Ruzzenente, Andrea, Gunnar, Rätsch, Radhakrishnan, Sabarinathan, Veronica, Y Sabelnykova, Sara, Sadeghi, Natalie, Saini, Mihoko, Saito-Adachi, Adriana, Salcedo, Roberto, Salgado, Leonidas, Salichos, Richard, Sallari, Charles, Saller, Salvia, Roberto, Michelle, Sam, Jaswinder, S Samra, Francisco, Sanchez-Vega, Chris, Sander, Grant, Sanders, Rajiv, Sarin, Aya, Sasaki-Oku, Torill, Sauer, Guido, Sauter, Robyn P, M Saw, Maria, Scardoni, Christopher, J Scarlett, Scarpa, Aldo, Ghislaine, Scelo, Dirk, Schadendorf, Jacqueline, E Schein, Markus, B Schilhabel, Thorsten, Schlomm, Heather, K Schmidt, Sarah-Jane, Schramm, Stefan, Schreiber, Nikolaus, Schultz, Steven, E Schumacher, Roland, F Schwarz, Richard, A Scolyer, David, Scott, Ralph, Scully, Raja, Seethala, Ayellet, V Segre, Iris, Selander, Colin, A Semple, Yasin, Senbabaoglu, Subhajit, Sengupta, Elisabetta, Sereni, Stefano, Serra, Dennis, C Sgroi, Mark, Shackleton, Nimish, C Shah, Sagedeh, Shahabi, Catherine, A Shang, Ping, Shang, Ofer, Shapira, Troy, Shelton, Ciyue, Shen, Hui, Shen, Rebecca, Shepherd, Ruian, Shi, Yan, Shi, Yu-Jia, Shiah, Tatsuhiro, Shibata, Juliann, Shih, Eigo, Shimizu, Kiyo, Shimizu, Seung Jun Shin, Yuichi, Shiraishi, Tal, Shmaya, Ilya, Shmulevich, Solomon, I Shorser, Charles, Short, Raunak, Shrestha, Suyash, S Shringarpure, Craig, Shriver, Shimin, Shuai, Nikos, Sidiropoulos, Reiner, Siebert, Anieta, M Sieuwerts, Lina, Sieverling, Sabina, Signoretti, Katarzyna, O Sikora, Michele, Simbolo, Ronald, Simon, Janae, V Simons, Peter, T Simpson, Samuel, Singer, Nasa, Sinnott-Armstrong, Payal, Sipahimalani, Tara, J Skelly, Marcel, Smid, Jaclyn, Smith, Karen, Smith-McCune, Nicholas, D Socci, Heidi, J Sofia, Matthew, G Soloway, Lei, Song, Anil, K Sood, Sharmila, Sothi, Christos, Sotiriou, Cameron, M Soulette, Paul, N Span, Paul, T Spellman, Sperandio, Nicola, Andrew, J Spillane, Oliver, Spiro, Jonathan, Spring, Johan, Staaf, Peter, F Stadler, Peter, Staib, Stefan, G Stark, Ólafur Andri Stefánsson, Oliver, Stegle, Lincoln, D Stein, Alasdair, Stenhouse, Stephan, Stilgenbauer, Michael, R Stratton, Jonathan, R Stretch, Henk, G Stunnenberg, Hong, Su, Xiaoping, Su, Ren, X Sun, Stephanie, Sungalee, Hana, Susak, Akihiro, Suzuki, Fred, Sweep, Monika, Szczepanowski, Holger, Sültmann, Takashi, Yugawa, Angela, Tam, David, Tamborero, Benita Kiat Tee Tan, Donghui, Tan, Patrick, Tan, Hiroko, Tanaka, Hirokazu, Taniguchi, Tomas, J Tanskanen, Maxime, Tarabichi, Roy, Tarnuzzer, Patrick, Tarpey, Morgan, L Taschuk, Kenji, Tatsuno, Simon, Tavaré, Darrin, F Taylor, Amaro, Taylor-Weiner, Bin Tean Teh, Varsha, Tembe, Javier, Temes, Kevin, Thai, Sarah, P Thayer, Nina, Thiessen, Gilles, Thomas, Sarah, Thomas, Alan, Thompson, Alastair, M Thompson, John, F Thompson, R Houston Thompson, Heather, Thorne, Leigh, B Thorne, Adrian, Thorogood, Nebojsa, Tijanic, Lee, E Timms, Roberto, Tirabosco, Marta, Tojo, Stefania, Tommasi, Christopher, W Toon, Umut, H Toprak, Giampaolo, Tortora, Jörg, Tost, Yasushi, Totoki, David, Townend, Nadia, Traficante, Isabelle, Treilleux, Jean-Rémi, Trotta, Lorenz H, P Trümper, Ming, Tsao, Tatsuhiko, Tsunoda, Jose M, C Tubio, Olga, Tucker, Richard, Turkington, Daniel, J Turner, Andrew, Tutt, Masaki, Ueno, Naoto, T Ueno, Christopher, Umbricht, Husen, M Umer, Timothy, J Underwood, Lara, Urban, Tomoko, Urushidate, Tetsuo, Ushiku, Liis, Uusküla-Reimand, Alfonso, Valencia, David, J Van Den Berg, Steven Van Laere, Peter Van Loo, Erwin, G Van Meir, Gert, G Van den Eynden, Theodorus Van der Kwast, Naveen, Vasudev, Miguel, Vazquez, Ravikiran, Vedururu, Umadevi, Veluvolu, Shankar, Vembu, Lieven P, C Verbeke, Peter, Vermeulen, Clare, Verrill, Alain, Viari, David, Vicente, Caterina, Vicentini, K Vijay Raghavan, Juris, Viksna, Ricardo, E Vilain, Izar, Villasante, Anne, Vincent-Salomon, Tapio, Visakorpi, Douglas, Voet, Paresh, Vyas, Ignacio, Vázquez-García, Nick, M Waddell, Nicola, Waddell, Claes, Wadelius, Lina, Wadi, Rabea, Wagener, Jian, Wang, Linghua, Wang, Wang, Qi, Yumeng, Wang, Zhining, Wang, Paul, M Waring, Hans-Jörg, Warnatz, Jonathan, Warrell, Anne, Y Warren, David, C Wedge, Dieter, Weichenhan, Paul, Weinberger, Daniel, J Weisenberger, Ian, Welch, Justin, P Whalley, Hayley, C Whitaker, Dennis, Wigle, Matthew, D Wilkerson, Ashley, Williams, James, S Wilmott, Gavin, W Wilson, Julie, M Wilson, Richard, K Wilson, Boris, Winterhoff, Jeffrey, A Wintersinger, Maciej, Wiznerowicz, Stephan, Wolf, Bernice, H Wong, Tina, Wong, Winghing, Wong, Youngchoon, Woo, Scott, Wood, Bradly, G Wouters, Adam, J Wright, Derek, W Wright, Mark, H Wright, Chin-Lee, Wu, Dai-Ying, Wu, Guanming, Wu, Jianmin, Wu, Kui, Wu, Yang, Wu, Tian, Xia, Qian, Xiang, Xiao, Xiao, Rui, Xing, Heng, Xiong, Qinying, Xu, Yanxun, Xu, Shinichi, Yachida, Rui, Yamaguchi, Masakazu, Yamamoto, Shogo, Yamamoto, Hiroki, Yamaue, Fan, Yang, Huanming, Yang, Jean, Y Yang, Liming, Yang, Lixing, Yang, Shanlin, Yang, Tsun-Po, Yang, Yang, Yang, Xiaotong, Yao, Marie-Laure, Yaspo, Lucy, Yates, Christina, Yau, Chen, Ye, Christopher, J Yoon, Sung-Soo, Yoon, Fouad, Yousif, Jun, Yu, Kaixian, Yu, Willie, Yu, Yingyan, Yu, Yuan, Ke, Yuan, Yuan, Denis, Yuen, Olga, Zaikova, Jorge, Zamora, Marc, Zapatka, Jean, C Zenklusen, Thorsten, Zenz, Nikolajs, Zeps, Cheng-Zhong, Zhang, Fan, Zhang, Hailei, Zhang, Hongwei, Zhang, Hongxin, Zhang, Jiashan, Zhang, Jing, Zhang, Xiuqing, Zhang, Xuanping, Zhang, Yan, Zhang, Zemin, Zhang, Zhongming, Zhao, Liangtao, Zheng, Xiuqing, Zheng, Wanding, Zhou, Yong, Zhou, Bin, Zhu, Hongtu, Zhu, Jingchun, Zhu, Shida, Zhu, Lihua, Zou, Xueqing, Zou, Anna, Defazio, Nicholas van As, Carolien H, M van Deurzen, Marc, J van de Vijver, L Van't Veer, Christian von Mering, Medical Oncology, Pathology, Bailey, Matthew H. [0000-0003-4526-9727], Dursi, Lewis Jonathan [0000-0002-4697-798X], Wang, Liang-Bo [0000-0001-6977-9348], Dong, Guanlan [0000-0002-4747-6036], Weerasinghe, Amila [0000-0003-3568-5823], Li, Shantao [0000-0002-5440-2780], Saksena, Gordon [0000-0001-6630-7935], Ellrott, Kyle [0000-0002-6573-5900], Wheeler, David A. [0000-0002-9056-6299], Getz, Gad [0000-0002-0936-0753], Gerstein, Mark B. [0000-0002-9746-3719], Apollo - University of Cambridge Repository, CCA - Cancer biology and immunology, Graduate School, Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, Bailey, M, Meyerson, W, Dursi, L, Wang, L, Dong, G, Liang, W, Weerasinghe, A, Li, S, Kelso, S, Akbani, R, Anur, P, Buchanan, A, Chiotti, K, Covington, K, Creason, A, Ding, L, Ellrott, K, Fan, Y, Foltz, S, Getz, G, Hale, W, Haussler, D, Hess, J, Hutter, C, Kandoth, C, Kasaian, K, Kasapi, M, Larson, D, Leshchiner, I, Letaw, J, Ma, S, Mclellan, M, Men, Y, Mills, G, Niu, B, Peto, M, Radenbaugh, A, Reynolds, S, Saksena, G, Sofia, H, Stewart, C, Struck, A, Stuart, J, Wang, W, Weinstein, J, Wheeler, D, Wong, C, Xi, L, Ye, K, Bieg, M, Boutros, P, Buchhalter, I, Butler, A, Chen, K, Chong, Z, Drechsel, O, Jonathan Dursi, L, Eils, R, Espiritu, S, Fulton, R, Gao, S, Gelpi, J, Gerstein, M, Gonzalez, S, Gut, I, Hach, F, Heinold, M, Hinton, J, Hu, T, Huang, V, Huang, Y, Hutter, B, Jones, D, Jung, J, Jager, N, Kim, H, Kleinheinz, K, Kumar, S, Kumar, Y, Lalansingh, C, Letunic, I, Livitz, D, Ma, E, Maruvka, Y, Mashl, R, Menzies, A, Milovanovic, A, Nielsen, M, Ossowski, S, Paramasivam, N, Pedersen, J, Perry, M, Puiggros, M, Raine, K, Rheinbay, E, Royo, R, Sahinalp, S, Sarrafi, I, Schlesner, M, Simpson, J, Stebbings, L, Stobbe, M, Teague, J, Tiao, G, Torrents, D, Wala, J, Wang, J, Waszak, S, Weischenfeldt, J, Wendl, M, Werner, J, Wu, Z, Xue, H, Yakneen, S, Yamaguchi, T, Yellapantula, V, Yung, C, Zhang, J, Aaltonen, L, Abascal, F, Abeshouse, A, Aburatani, H, Adams, D, Agrawal, N, Ahn, K, Ahn, S, Aikata, H, Akdemir, K, Al-Ahmadie, H, Al-Sedairy, S, Al-Shahrour, F, Alawi, M, Albert, M, Aldape, K, Alexandrov, L, Ally, A, Alsop, K, Alvarez, E, Amary, F, Amin, S, Aminou, B, Ammerpohl, O, Anderson, M, Ang, Y, Antonello, D, Aparicio, S, Appelbaum, E, Arai, Y, Aretz, A, Arihiro, K, Ariizumi, S, Armenia, J, Arnould, L, Asa, S, Assenov, Y, Atwal, G, Aukema, S, Auman, J, Aure, M, Awadalla, P, Aymerich, M, Bader, G, Baez-Ortega, A, Bailey, P, Balasundaram, M, Balu, S, Bandopadhayay, P, Banks, R, Barbi, S, Barbour, A, Barenboim, J, Barnholtz-Sloan, J, Barr, H, Barrera, E, Bartlett, J, Bartolome, J, Bassi, C, Bathe, O, Baumhoer, D, Bavi, P, Baylin, S, Bazant, W, Beardsmore, D, Beck, T, Behjati, S, Behren, A, Bell, C, Beltran, S, Benz, C, Berchuck, A, Bergmann, A, Bergstrom, E, Berman, B, Berney, D, Bernhart, S, Beroukhim, R, Berrios, M, Bersani, S, Bertl, J, Betancourt, M, Bhandari, V, Bhosle, S, Biankin, A, Bigner, D, Binder, H, Birney, E, Birrer, M, Biswas, N, Bjerkehagen, B, Bodenheimer, T, Boice, L, Bonizzato, G, De Bono, J, Boot, A, Bootwalla, M, Borg, A, Borkhardt, A, Boroevich, K, Borozan, I, Borst, C, Bosenberg, M, Bosio, M, Boultwood, J, Bourque, G, Bova, G, Bowen, D, Bowlby, R, Bowtell, D, Boyault, S, Boyce, R, Boyd, J, Brazma, A, Brennan, P, Brewer, D, Brinkman, A, Bristow, R, Broaddus, R, Brock, J, Brock, M, Broeks, A, Brooks, A, Brooks, D, Brors, B, Brunak, S, Bruxner, T, Bruzos, A, Buchholz, C, Bullman, S, Burke, H, Burkhardt, B, Burns, K, Busanovich, J, Bustamante, C, Butte, A, Byrne, N, Borresen-Dale, A, Caesar-Johnson, S, Cafferkey, A, Cahill, D, Calabrese, C, Caldas, C, Calvo, F, Camacho, N, Campbell, P, Campo, E, Cantu, C, Cao, S, Carey, T, Carlevaro-Fita, J, Carlsen, R, Cataldo, I, Cazzola, M, Cebon, J, Cerfolio, R, Chadwick, D, Chakravarty, D, Chalmers, D, Chan, C, Chan, K, Chan-Seng-Yue, M, Chandan, V, Chang, D, Chanock, S, Chantrill, L, Chateigner, A, Chatterjee, N, Chayama, K, Chen, H, Chen, J, Chen, Y, Chen, Z, Cherniack, A, Chien, J, Chiew, Y, Chin, S, Cho, J, Cho, S, Choi, J, Choi, W, Chomienne, C, Choo, S, Chou, A, Christ, A, Christie, E, Chuah, E, Cibulskis, C, Cibulskis, K, Cingarlini, S, Clapham, P, Claviez, A, Cleary, S, Cloonan, N, Cmero, M, Collins, C, Connor, A, Cooke, S, Cooper, C, Cope, L, Corbo, V, Cordes, M, Cordner, S, Cortes-Ciriano, I, Cowin, P, Craft, B, Craft, D, Creighton, C, Cun, Y, Curley, E, Cutcutache, I, Czajka, K, Czerniak, B, Dagg, R, Danilova, L, Davi, M, Davidson, N, Davies, H, Davis, I, Davis-Dusenbery, B, Dawson, K, De La Vega, F, De Paoli-Iseppi, R, Defreitas, T, Dei Tos, A, Delaneau, O, Demchok, J, Demeulemeester, J, Demidov, G, Demircioglu, D, Dennis, N, Denroche, R, Dentro, S, Desai, N, Deshpande, V, Deshwar, A, Desmedt, C, Deu-Pons, J, Dhalla, N, Dhani, N, Dhingra, P, Dhir, R, Dibiase, A, Diamanti, K, Ding, S, Dinh, H, Dirix, L, Doddapaneni, H, Donmez, N, Dow, M, Drapkin, R, Drews, R, Serge, S, Dudderidge, T, Dueso-Barroso, A, Dunford, A, Dunn, M, Duthie, F, Dutton-Regester, K, Eagles, J, Easton, D, Edmonds, S, Edwards, P, Edwards, S, Eeles, R, Ehinger, A, Eils, J, El-Naggar, A, Eldridge, M, Erkek, S, Escaramis, G, Estivill, X, Etemadmoghadam, D, Eyfjord, J, Faltas, B, Fan, D, Faquin, W, Farcas, C, Fassan, M, Fatima, A, Favero, F, Fayzullaev, N, Felau, I, Fereday, S, Ferguson, M, Ferretti, V, Feuerbach, L, Field, M, Fink, J, Finocchiaro, G, Fisher, C, Fittall, M, Fitzgerald, A, Fitzgerald, R, Flanagan, A, Fleshner, N, Flicek, P, Foekens, J, Fong, K, Fonseca, N, Foster, C, Fox, N, Fraser, M, Frazer, S, Frenkel-Morgenstern, M, Friedman, W, Frigola, J, Fronick, C, Fujimoto, A, Fujita, M, Fukayama, M, Fulton, L, Furuta, M, Futreal, P, Fullgrabe, A, Gabriel, S, Gallinger, S, Gambacorti Passerini, C, Gao, J, Garraway, L, Garred, O, Garrison, E, Garsed, D, Gehlenborg, N, George, J, Gerhard, D, Gerhauser, C, Gershenwald, J, Gerstung, M, Ghori, M, Ghossein, R, Giama, N, Gibbs, R, Gill, A, Gill, P, Giri, D, Glodzik, D, Gnanapragasam, V, Goebler, M, Goldman, M, Gomez, C, Gonzalez-Perez, A, Gordenin, D, Gossage, J, Gotoh, K, Govindan, R, Grabau, D, Graham, J, Grant, R, Green, A, Green, E, Greger, L, Grehan, N, Grimaldi, S, Grimmond, S, Grossman, R, Grundhoff, A, Gundem, G, Guo, Q, Gupta, M, Gupta, S, Gut, M, Goke, J, Ha, G, Haake, A, Haan, D, Haas, S, Haase, K, Haber, J, Habermann, N, Haider, S, Hama, N, Hamdy, F, Hamilton, A, Hamilton, M, Han, L, Hanna, G, Hansmann, M, Haradhvala, N, Harismendy, O, Harliwong, I, Harmanci, A, Harrington, E, Hasegawa, T, Hawkins, S, Hayami, S, Hayashi, S, Hayes, D, Hayes, S, Hayward, N, Hazell, S, He, Y, Heath, A, Heath, S, Hedley, D, Hegde, A, Heiman, D, Heins, Z, Heisler, L, Hellstrom-Lindberg, E, Helmy, M, Heo, S, Hepperla, A, Heredia-Genestar, J, Herrmann, C, Hersey, P, Hilmarsdottir, H, Hirano, S, Hiraoka, N, Hoadley, K, Hobolth, A, Hodzic, E, Hoell, J, Hoffmann, S, Hofmann, O, Holbrook, A, Holik, A, Hollingsworth, M, Holmes, O, Holt, R, Hong, C, Hong, E, Hong, J, Hooijer, G, Hornshoj, H, Hosoda, F, Hou, Y, Hovestadt, V, Howat, W, Hoyle, A, Hruban, R, Hu, J, Hua, X, Huang, K, Huang, M, Huber, W, Hudson, T, Hummel, M, Hung, J, Huntsman, D, Hupp, T, Huse, J, Huska, M, Hubschmann, D, Iacobuzio-Donahue, C, Imbusch, C, Imielinski, M, Imoto, S, Isaacs, W, Isaev, K, Ishikawa, S, Iskar, M, Islam, S, Ittmann, M, Ivkovic, S, Izarzugaza, J, Jacquemier, J, Jakrot, V, Jamieson, N, Jang, G, Jang, S, Jayaseelan, J, Jayasinghe, R, Jefferys, S, Jegalian, K, Jennings, J, Jeon, S, Jerman, L, Ji, Y, Jiao, W, Johansson, P, Johns, A, Johns, J, Johnson, R, Johnson, T, Jolly, C, Joly, Y, Jonasson, J, Jones, C, Jones, N, Jones, S, Jonkers, J, Ju, Y, Juhl, H, Juul, M, Juul, R, Juul, S, Kabbe, R, Kahles, A, Kahraman, A, Kaiser, V, Kakavand, H, Kalimuthu, S, von Kalle, C, Kang, K, Karaszi, K, Karlan, B, Karlic, R, Karsch, D, Kassahn, K, Katai, H, Kato, M, Katoh, H, Kawakami, Y, Kay, J, Kazakoff, S, Kazanov, M, Keays, M, Kebebew, E, Kefford, R, Kellis, M, Kench, J, Kennedy, C, Kerssemakers, J, Khoo, D, Khoo, V, Khuntikeo, N, Khurana, E, Kilpinen, H, Kim, J, Kim, Y, King, T, Klapper, W, Klimczak, L, Knappskog, S, Kneba, M, Knoppers, B, Koh, Y, Jan, K, Komura, D, Komura, M, Kong, G, Kool, M, Korbel, J, Korchina, V, Korshunov, A, Koscher, M, Koster, R, Kote-Jarai, Z, Koures, A, Kovacevic, M, Kremeyer, B, Kretzmer, H, Kreuz, M, Krishnamurthy, S, Kube, D, Kumar, K, Kumar, P, Kundra, R, Kubler, K, Kuppers, R, Lagergren, J, Lai, P, Laird, P, Lakhani, S, Lalonde, E, Lamaze, F, Lambert, A, Lander, E, Landgraf, P, Landoni, L, Langerod, A, Lanzos, A, Larsimont, D, Larsson, E, Lathrop, M, Lau, L, Lawerenz, C, Lawlor, R, Lawrence, M, Lazar, A, Le, X, Lee, D, Lee, E, Lee, H, Lee, J, Lee, M, Lee-Six, H, Lehmann, K, Lehrach, H, Lenze, D, Leonard, C, Leongamornlert, D, Letourneau, L, Levine, D, Lewis, L, Ley, T, Li, C, Li, H, Li, J, Li, L, Li, X, Li, Y, Liang, H, Liang, S, Lichter, P, Lin, P, Lin, Z, Linehan, W, Lingjaerde, O, Liu, D, Liu, E, Liu, F, Liu, J, Liu, X, Livingstone, J, Livni, N, Lochovsky, L, Loeffler, M, Long, G, Lopez-Guillermo, A, Lou, S, Louis, D, Lovat, L, Lu, Y, Luchini, C, Lungu, I, Luo, X, Luxton, H, Lynch, A, Lype, L, Lopez, C, Lopez-Otin, C, Ma, Y, Macgrogan, G, Macrae, S, Macintyre, G, Madsen, T, Maejima, K, Mafficini, A, Maglinte, D, Maitra, A, Majumder, P, Malcovati, L, Malikic, S, Malleo, G, Mann, G, Mantovani-Loffler, L, Marchal, K, Marchegiani, G, Mardis, E, Margolin, A, Marin, M, Markowetz, F, Markowski, J, Marks, J, Marques-Bonet, T, Marra, M, Marsden, L, Martens, J, Martin, S, Martin-Subero, J, Martincorena, I, Martinez-Fundichely, A, Massie, C, Matthew, T, Matthews, L, Mayer, E, Mayes, S, Mayo, M, Mbabaali, F, Mccune, K, Mcdermott, U, Mcgillivray, P, Mcpherson, J, Mcpherson, T, Meier, S, Meng, A, Meng, S, Merrett, N, Merson, S, Meyerson, M, Mieczkowski, P, Mihaiescu, G, Mijalkovic, S, Mijalkovic-Lazic, A, Mikkelsen, T, Milella, M, Mileshkin, L, Miller, C, Miller, D, Miller, J, Minner, S, Miotto, M, Arnau, G, Mirabello, L, Mitchell, C, Mitchell, T, Miyano, S, Miyoshi, N, Mizuno, S, Molnar-Gabor, F, Moore, M, Moore, R, Morganella, S, Morris, Q, Morrison, C, Mose, L, Moser, C, Muinos, F, Mularoni, L, Mungall, A, Mungall, K, Musgrove, E, Mustonen, V, Mutch, D, Muyas, F, Muzny, D, Munoz, A, Myers, J, Myklebost, O, Moller, P, Nagae, G, Nagrial, A, Nahal-Bose, H, Nakagama, H, Nakagawa, H, Nakamura, H, Nakamura, T, Nakano, K, Nandi, T, Nangalia, J, Nastic, M, Navarro, A, Navarro, F, Neal, D, Nettekoven, G, Newell, F, Newhouse, S, Newton, Y, Ng, A, Nicholson, J, Nicol, D, Nie, Y, Nielsen, G, Nik-Zainal, S, Noble, M, Nones, K, Northcott, P, Notta, F, O'Connor, B, O'Donnell, P, O'Donovan, M, O'Meara, S, O'Neill, B, O'Neill, J, Ocana, D, Ochoa, A, Oesper, L, Ogden, C, Ohdan, H, Ohi, K, Ohno-Machado, L, Oien, K, Ojesina, A, Ojima, H, Okusaka, T, Omberg, L, Ong, C, Ott, G, Ouellette, B, P'Ng, C, Paczkowska, M, Paiella, S, Pairojkul, C, Pajic, M, Pan-Hammarstrom, Q, Papaemmanuil, E, Papatheodorou, I, Park, J, Park, K, Park, P, Parker, J, Parsons, S, Pass, H, Pasternack, D, Pastore, A, Patch, A, Pauporte, I, Pea, A, Pearson, J, Pedamallu, C, Pederzoli, P, Peifer, M, Pennell, N, Perou, C, Petersen, G, Petrelli, N, Petryszak, R, Pfister, S, Phillips, M, Pich, O, Pickett, H, Pihl, T, Pillay, N, Pinder, S, Pinese, M, Pinho, A, Pitkanen, E, Pivot, X, Pineiro-Yanez, E, Planko, L, Plass, C, Polak, P, Pons, T, Popescu, I, Potapova, O, Prasad, A, Preston, S, Prinz, M, Pritchard, A, Prokopec, S, Provenzano, E, Puente, X, Puig, S, Pulido-Tamayo, S, Pupo, G, Purdie, C, Quinn, M, Rabionet, R, Rader, J, Radlwimmer, B, Radovic, P, Raeder, B, Ramakrishna, M, Ramakrishnan, K, Ramalingam, S, Raphael, B, Rathmell, W, Rausch, T, Reifenberger, G, Reimand, J, Reis-Filho, J, Reuter, V, Reyes-Salazar, I, Reyna, M, Riazalhosseini, Y, Richardson, A, Richter, J, Ringel, M, Ringner, M, Rino, Y, Rippe, K, Roach, J, Roberts, L, Roberts, N, Roberts, S, Robertson, A, Rodriguez, J, Rodriguez-Martin, B, Rodriguez-Gonzalez, F, Roehrl, M, Rohde, M, Rokutan, H, Romieu, G, Rooman, I, Roques, T, Rosebrock, D, Rosenberg, M, Rosenstiel, P, Rosenwald, A, Rowe, E, Rozen, S, Rubanova, Y, Rubin, M, Rubio-Perez, C, Rudneva, V, Rusev, B, Ruzzenente, A, Ratsch, G, Sabarinathan, R, Sabelnykova, V, Sadeghi, S, Saini, N, Saito-Adachi, M, Salcedo, A, Salgado, R, Salichos, L, Sallari, R, Saller, C, Salvia, R, Sam, M, Samra, J, Sanchez-Vega, F, Sander, C, Sanders, G, Sarin, R, Sasaki-Oku, A, Sauer, T, Sauter, G, Saw, R, Scardoni, M, Scarlett, C, Scarpa, A, Scelo, G, Schadendorf, D, Schein, J, Schilhabel, M, Schlomm, T, Schmidt, H, Schramm, S, Schreiber, S, Schultz, N, Schumacher, S, Schwarz, R, Scolyer, R, Scott, D, Scully, R, Seethala, R, Segre, A, Selander, I, Semple, C, Senbabaoglu, Y, Sengupta, S, Sereni, E, Serra, S, Sgroi, D, Shackleton, M, Shah, N, Shahabi, S, Shang, C, Shang, P, Shapira, O, Shelton, T, Shen, C, Shen, H, Shepherd, R, Shi, R, Shi, Y, Shiah, Y, Shibata, T, Shih, J, Shimizu, E, Shimizu, K, Shin, S, Shiraishi, Y, Shmaya, T, Shmulevich, I, Shorser, S, Short, C, Shrestha, R, Shringarpure, S, Shriver, C, Shuai, S, Sidiropoulos, N, Siebert, R, Sieuwerts, A, Sieverling, L, Signoretti, S, Sikora, K, Simbolo, M, Simon, R, Simons, J, Simpson, P, Singer, S, Sinnott-Armstrong, N, Sipahimalani, P, Skelly, T, Smid, M, Smith, J, Smith-McCune, K, Socci, N, Soloway, M, Song, L, Sood, A, Sothi, S, Sotiriou, C, Soulette, C, Span, P, Spellman, P, Sperandio, N, Spillane, A, Spiro, O, Spring, J, Staaf, J, Stadler, P, Staib, P, Stark, S, Stefansson, O, Stegle, O, Stein, L, Stenhouse, A, Stilgenbauer, S, Stratton, M, Stretch, J, Stunnenberg, H, Su, H, Su, X, Sun, R, Sungalee, S, Susak, H, Suzuki, A, Sweep, F, Szczepanowski, M, Sultmann, H, Yugawa, T, Tam, A, Tamborero, D, Tan, B, Tan, D, Tan, P, Tanaka, H, Taniguchi, H, Tanskanen, T, Tarabichi, M, Tarnuzzer, R, Tarpey, P, Taschuk, M, Tatsuno, K, Tavare, S, Taylor, D, Taylor-Weiner, A, Teh, B, Tembe, V, Temes, J, Thai, K, Thayer, S, Thiessen, N, Thomas, G, Thomas, S, Thompson, A, Thompson, J, Thompson, R, Thorne, H, Thorne, L, Thorogood, A, Tijanic, N, Timms, L, Tirabosco, R, Tojo, M, Tommasi, S, Toon, C, Toprak, U, Tortora, G, Tost, J, Totoki, Y, Townend, D, Traficante, N, Treilleux, I, Trotta, J, Trumper, L, Tsao, M, Tsunoda, T, Tubio, J, Tucker, O, Turkington, R, Turner, D, Tutt, A, Ueno, M, Ueno, N, Umbricht, C, Umer, H, Underwood, T, Urban, L, Urushidate, T, Ushiku, T, Uuskula-Reimand, L, Valencia, A, Van Den Berg, D, Van Laere, S, Van Loo, P, Van Meir, E, Van den Eynden, G, Van der Kwast, T, Vasudev, N, Vazquez, M, Vedururu, R, Veluvolu, U, Vembu, S, Verbeke, L, Vermeulen, P, Verrill, C, Viari, A, Vicente, D, Vicentini, C, Raghavan, K, Viksna, J, Vilain, R, Villasante, I, Vincent-Salomon, A, Visakorpi, T, Voet, D, Vyas, P, Vazquez-Garcia, I, Waddell, N, Wadelius, C, Wadi, L, Wagener, R, Wang, Q, Wang, Y, Wang, Z, Waring, P, Warnatz, H, Warrell, J, Warren, A, Wedge, D, Weichenhan, D, Weinberger, P, Weisenberger, D, Welch, I, Whalley, J, Whitaker, H, Wigle, D, Wilkerson, M, Williams, A, Wilmott, J, Wilson, G, Wilson, J, Wilson, R, Winterhoff, B, Wintersinger, J, Wiznerowicz, M, Wolf, S, Wong, B, Wong, T, Wong, W, Woo, Y, Wood, S, Wouters, B, Wright, A, Wright, D, Wright, M, Wu, C, Wu, D, Wu, G, Wu, J, Wu, K, Wu, Y, Xia, T, Xiang, Q, Xiao, X, Xing, R, Xiong, H, Xu, Q, Xu, Y, Yachida, S, Yamaguchi, R, Yamamoto, M, Yamamoto, S, Yamaue, H, Yang, F, Yang, H, Yang, J, Yang, L, Yang, S, Yang, T, Yang, Y, Yao, X, Yaspo, M, Yates, L, Yau, C, Ye, C, Yoon, C, Yoon, S, Yousif, F, Yu, J, Yu, K, Yu, W, Yu, Y, Yuan, K, Yuan, Y, Yuen, D, Zaikova, O, Zamora, J, Zapatka, M, Zenklusen, J, Zenz, T, Zeps, N, Zhang, C, Zhang, F, Zhang, H, Zhang, X, Zhang, Y, Zhang, Z, Zhao, Z, Zheng, L, Zheng, X, Zhou, W, Zhou, Y, Bin, Z, Zhu, H, Zhu, J, Zhu, S, Zou, L, Zou, X, Defazio, A, van As, N, van Deurzen, C, van de Vijver, M, van't Veer, L, von Mering, C, Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Tampere University, BioMediTech, TAYS Cancer Centre, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Cellular Medicine Division, University of St Andrews. Statistics, University of St Andrews. School of Medicine, University of Zurich, Gerstein, Mark B, Ding, Li, Bailey, Matthew H [0000-0003-4526-9727], Wheeler, David A [0000-0002-9056-6299], Gerstein, Mark B [0000-0002-9746-3719], Faculty of Economic and Social Sciences and Solvay Business School, Lauri Antti Aaltonen / Principal Investigator, Genome-Scale Biology (GSB) Research Program, Department of Medical and Clinical Genetics, Organismal and Evolutionary Biology Research Programme, Helsinki Institute for Information Technology, Institute of Biotechnology, Bioinformatics, Department of Computer Science, Faculty of Medicine, and HUS Helsinki and Uusimaa Hospital District
Subjects: VARIANTS, 0302 clinical medicine, 706/648/697/129/2043, Databases, Genetic, Cancer genomics, SOMATIC POINT MUTATIONS, Càncer, lcsh:Science, Exome, Exome sequencing, Cancer, Base Composition, Neoplasms -- genetics, 1184 Genetics, developmental biology, physiology, 3100 General Physics and Astronomy, 3. Good health, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Transformació genètica, Genetic databases, Erfðarannsóknir, Human, GENES, Science, 1600 General Chemistry, General Biochemistry, Genetics and Molecular Biology, RC0254, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, 1300 General Biochemistry, Genetics and Molecular Biology, Exome Sequencing, Genetics, Humans, Author Correction, Retrospective Studies, Whole genome sequencing, Comparative genomics, Science & Technology, RC0254 Neoplasms. Tumors. Oncology (including Cancer), INSERTIONS, DNA, PERFORMANCE, Human genetics, Communication and replication, Cancérologie, 692/4028/67/69, Genòmica, 030104 developmental biology, Mutation, Genome mutation, Human genome, lcsh:Q, COMPREHENSIVE CHARACTERIZATION, Genètica, 0301 basic medicine, Medizin, General Physics and Astronomy, Genome, Whole Exome Sequencing, Genetic transformation, International Cancer Genome Consortium, Neoplasms, 631/114/2399, Genamengi, Medicine and Health Sciences, Medicine(all), Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, 318 Medical biotechnology, Exome -- genetics, article, Exons, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Multidisciplinary Sciences, CAPTURE, 1181 Ecology, evolutionary biology, oncology, DNA, Intergenic, 139, Medical Genetics, Biotechnology, ICGC/TCGA Pan-Cancer Analysis, 3122 Cancers, 610 Medicine & health, 45/23, QH426 Genetics, Biology, MC3 Working Group, Databases, Germline mutation, PCAWG novel somatic mutation calling methods working group, Krabbameinsrannsóknir, Cancer Genome Atlas, Genome, Human -- genetics, ddc:610, QH426, Medicinsk genetik, Krabbamein, Intergenic, Whole Genome Sequencing, Genome, Human, Human Genome, PCAWG Consortium, DAS, General Chemistry, DELETIONS, Good Health and Well Being, 10032 Clinic for Oncology and Hematology, 3111 Biomedicine, 631/1647/2217/748
Abstract: MC3 Working Group: Rehan Akbani21, Pavana Anur22, Matthew H. Bailey1,2,3, Alex Buchanan9, Kami Chiotti9, Kyle Covington12,23, Allison Creason9, Li Ding1,2,3,20, Kyle Ellrott9, Yu Fan21, Steven Foltz1,2, Gad Getz8,14,15,16, Walker Hale12, David Haussler24,25, Julian M. Hess8,26, Carolyn M. Hutter27, Cyriac Kandoth28, Katayoon Kasaian29,30, Melpomeni Kasapi27, Dave Larson1 , Ignaty Leshchiner8, John Letaw31, Singer Ma32, Michael D. McLellan1,3,20, Yifei Men32, Gordon B. Mills33,34, Beifang Niu35, Myron Peto22, Amie Radenbaugh24, Sheila M. Reynolds36, Gordon Saksena8, Heidi Sofia27, Chip Stewart8, Adam J. Struck31, Joshua M. Stuart24,37, Wenyi Wang21, John N. Weinstein38, David A. Wheeler12,13, Christopher K. Wong24,39, Liu Xi12 & Kai Ye40,41 21Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 22Molecular and Medical Genetics, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. 23Castle Biosciences Inc, Friendswood, TX 77546, USA. 24UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 25Howard Hughes Medical Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 26Massachusetts General Hospital Center for Cancer Research, Charlestown, MA 02114, USA. 27National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20894, USA. 28Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. 29Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. 30Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 4S6, Canada. 31Computational Biology Program, School of Medicine, Oregon Health and Science University, Portland, OR 97239, USA. 32DNAnexus Inc, Mountain View, CA 94040, USA. 33Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USA. 34Precision Oncology, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. 35Computer Network Information Center, Chinese Academy of Sciences, Beijing, China. 36Institute for Systems Biology, Seattle, WA 98109, USA. 37Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 38Department of Bioinformatics and Computational Biology and Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 39Biomolecular Engineering Department, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 40School of Elect, PCAWG novel somatic mutation calling methods working group: Matthew H. Bailey1,2,3, Beifang Niu35, Matthias Bieg42,43, Paul C. Boutros6,44,45,46, Ivo Buchhalter43,47,48, Adam P. Butler49, Ken Chen50, Zechen Chong51, Li Ding1,2,3,20, Oliver Drechsel52,53, Lewis Jonathan Dursi6,7, Roland Eils47,48,54,55, Kyle Ellrott9, Shadrielle M. G. Espiritu6, Yu Fan21, Robert S. Fulton1,3,20, Shengjie Gao56, Josep L. l. Gelpi57,58, Mark B. Gerstein5,18,19, Gad Getz8,14,15,16, Santiago Gonzalez59,60, Ivo G. Gut52,61, Faraz Hach62,63, Michael C. Heinold47,48, Julian M. Hess8,26, Jonathan Hinton49, Taobo Hu64, Vincent Huang6, Yi Huang65,66, Barbara Hutter43,67,68, David R. Jones49, Jongsun Jung69, Natalie Jäger47, Hyung-Lae Kim70, Kortine Kleinheinz47,48, Sushant Kumar5,19, Yogesh Kumar64, Christopher M. Lalansingh6, Ignaty Leshchiner8, Ivica Letunic71, Dimitri Livitz8, Eric Z. Ma64, Yosef E. Maruvka8,26,72, R. Jay Mashl1,2, Michael D. McLellan1,3,20, Andrew Menzies49, Ana Milovanovic57, Morten Muhlig Nielsen73, Stephan Ossowski52,53,74, Nagarajan Paramasivam43,47, Jakob Skou Pedersen73,75, Marc D. Perry76,77, Montserrat Puiggròs57, Keiran M. Raine49, Esther Rheinbay8,14,72, Romina Royo57, S. Cenk Sahinalp62,78,79, Gordon Saksena8, Iman Sarrafi62,78, Matthias Schlesner47,80, Jared T. Simpson6,17, Lucy Stebbings49, Chip Stewart8, Miranda D. Stobbe52,61, Jon W. Teague49, Grace Tiao8, David Torrents57,81, Jeremiah A. Wala8,14,82, Jiayin Wang1,40,66, Wenyi Wang21, Sebastian M. Waszak60, Joachim Weischenfeldt60,83,84, Michael C. Wendl1,10,11, Johannes Werner47,85, Zhenggang Wu64, Hong Xue64, Sergei Yakneen60, Takafumi N. Yamaguchi6, Kai Ye40,41, Venkata D. Yellapantula20,86, Christina K. Yung76 & Junjun Zhang76, PCAWG Consortium: Lauri A. Aaltonen87, Federico Abascal49, Adam Abeshouse88, Hiroyuki Aburatani89, David J. Adams49, Nishant Agrawal90, Keun Soo Ahn91, Sung-Min Ahn92, Hiroshi Aikata93, Rehan Akbani21, Kadir C. Akdemir50, Hikmat Al-Ahmadie88, Sultan T. Al-Sedairy94, Fatima Al-Shahrour95, Malik Alawi96,97, Monique Albert98, Kenneth Aldape99,100, Ludmil B. Alexandrov49,101,102, Adrian Ally30, Kathryn Alsop103, Eva G. Alvarez104,105,106, Fernanda Amary107, Samirkumar B. Amin108,109,110, Brice Aminou76, Ole Ammerpohl111,112, Matthew J. Anderson113, Yeng Ang114, Davide Antonello115, Pavana Anur22, Samuel Aparicio116, Elizabeth L. Appelbaum1,117, Yasuhito Arai118, Axel Aretz119, Koji Arihiro93, Shun-ichi Ariizumi120, Joshua Armenia121, Laurent Arnould122, Sylvia Asa123,124, Yassen Assenov125, Gurnit Atwal6,126,127, Sietse Aukema112,128, J. Todd Auman129, Miriam R. Aure130, Philip Awadalla6,126, Marta Aymerich131, Gary D. Bader126, Adrian Baez-Ortega132, Matthew H. Bailey1,2,3, Peter J. Bailey133, Miruna Balasundaram30, Saianand Balu134, Pratiti Bandopadhayay8,135,136, Rosamonde E. Banks137, Stefano Barbi138, Andrew P. Barbour139,140, Jonathan Barenboim6, Jill Barnholtz-Sloan141,142, Hugh Barr143, Elisabet Barrera59, John Bartlett98,144, Javier Bartolome57, Claudio Bassi115, Oliver F. Bathe145,146, Daniel Baumhoer147, Prashant Bavi148, Stephen B. Baylin149,150, Wojciech Bazant59, Duncan Beardsmore151, Timothy A. Beck152,153, Sam Behjati49, Andreas Behren154, Beifang Niu35, Cindy Bell155, Sergi Beltran52,61, Christopher Benz156, Andrew Berchuck157, Anke K. Bergmann158, Erik N. Bergstrom101,102, Benjamin P. Berman159,160,161, Daniel M. Berney162, Stephan H. Bernhart163,164,165, Rameen Beroukhim8,14,82, Mario Berrios166, Samantha Bersani167, Johanna Bertl73,168, Miguel Betancourt169, Vinayak Bhandari6,44, Shriram G. Bhosle49, Andrew V. Biankin133,170,171,172, Matthias Bieg42,43, Darell Bigner173, Hans Binder163,164, Ewan Birney59, Michael Birrer72, Nidhan K. Biswas174, Bodil Bjerkehagen147,175, Tom Bodenheimer134, Lori Boice176, Giada Bonizzato177, Johann S. De Bono178, Arnoud Boot179,180, Moiz S. Bootwalla166, Ake Borg181, Arndt Borkhardt182, Keith A. Boroevich183,184, Ivan Borozan6, Christoph Borst185, Marcus Bosenberg186, Mattia Bosio52,53,57, Jacqueline Boultwood187, Guillaume Bourque188,189, Paul C. Boutros6,44,45,46, G. Steven Bova190, David T. Bowen49,191, Reanne Bowlby30, David D. L. Bowtell103, Sandrine Boyault192, Rich Boyce59, Jeffrey Boyd193, Alvis Brazma59, Paul Brennan194, Daniel S. Brewer195,196, Arie B. Brinkman197, Robert G. Bristow44,198,199,200,201, Russell R. Broaddus99, Jane E. Brock202, Malcolm Brock203, Annegien Broeks204, Angela N. Brooks8,24,37,82, Denise Brooks30, Benedikt Brors67,205,206, Søren Brunak207,208, Timothy J. C. Bruxner113,209, Alicia L. Bruzos104,105,106, Alex Buchanan9, Ivo Buchhalter43,47,48, Christiane Buchholz210, Susan Bullman8,82, Hazel Burke211, Birgit Burkhardt212, Kathleen H. Burns213,214, John Busanovich8,215, Carlos D. Bustamante216,217, Adam P. Butler49, Atul J. Butte218, Niall J. Byrne76, Anne-Lise Børresen-Dale130,219, Samantha J. Caesar-Johnson220, Andy Cafferkey59, Declan Cahill221, Claudia Calabrese59,60, Carlos Caldas222,223, Fabien Calvo224, Niedzica Camacho178, Peter J. Campbell49,225, Elias Campo226,227, Cinzia Cantù177, Shaolong Cao21, Thomas E. Carey228, Joana Carlevaro-Fita229,230,231, Rebecca Carlsen30, Ivana Cataldo167,177, Mario Cazzola232, Jonathan Cebon154, Robert Cerfolio233, Dianne E. Chadwick234, Dimple Chakravarty235, Don Chalmers236, Calvin Wing Yiu Chan47,237, Kin Chan238, Michelle Chan-Seng-Yue148, Vishal S. Chandan239, David K. Chang133,170, Stephen J. Chanock240, Lorraine A. Chantrill170,241, Aurélien Chateigner76,242, Nilanjan Chatterjee149,243, Kazuaki Chayama93, Hsiao-Wei Chen114,121, Jieming Chen218, Ken Chen50, Yiwen Chen21, Zhaohong Chen244, Andrew D. Cherniack8,82, Jeremy Chien245, Yoke-Eng Chiew246,247, Suet-Feung Chin222,223, Juok Cho8, Sunghoon Cho248, Jung Kyoon Choi249, Wan Choi250, Christine Chomienne251, Zechen Chong51, Su Pin Choo252, Angela Chou170,246, Angelika N. Christ113, Elizabeth L. Christie103, Eric Chuah30, Carrie Cibulskis8, Kristian Cibulskis8, Sara Cingarlini253, Peter Clapham49, Alexander Claviez254, Sean Cleary148,255, Nicole Cloonan256, Marek Cmero257,258,259, Colin C. Collins62, Ashton A. Connor255,260, Susanna L. Cooke133, Colin S. Cooper178,196,261, Leslie Cope149, Vincenzo Corbo138,177, Matthew G. Cordes1,262, Stephen M. Cordner263, Isidro Cortés-Ciriano264,265,266, Kyle Covington12,23, Prue A. Cowin267, Brian Craft24, David Craft8,268, Chad J. Creighton269, Yupeng Cun270, Erin Curley271, Ioana Cutcutache179,180, Karolina Czajka272, Bogdan Czerniak99,273, Rebecca A. Dagg274, Ludmila Danilova149, Maria Vittoria Davi275, Natalie R. Davidson276,277,278,279,280, Helen Davies49,281,282, Ian J. Davis283, Brandi N. Davis-Dusenbery284, Kevin J. Dawson49, Francisco M. De La Vega216,217,285, Ricardo De Paoli-Iseppi211, Timothy Defreitas8, Angelo P. Dei Tos286, Olivier Delaneau287,288,289, John A. Demchok220, Jonas Demeulemeester290,291, German M. Demidov52,53,74, Deniz Demircioğlu292,293, Nening M. Dennis221, Robert E. Denroche148, Stefan C. Dentro49,290,294, Nikita Desai76, Vikram Deshpande72, Amit G. Deshwar295, Christine Desmedt296,297, Jordi Deu-Pons298,299, Noreen Dhalla30, Neesha C. Dhani300, Priyanka Dhingra301,302, Rajiv Dhir303, Anthony DiBiase304, Klev Diamanti305, Li Ding1,2,3,20, Shuai Ding306, Huy Q. Dinh159, Luc Dirix307, HarshaVardhan Doddapaneni12, Nilgun Donmez62,78, Michelle T. Dow244, Ronny Drapkin308, Oliver Drechsel52,53, Ruben M. Drews223, Serge Serge49, Tim Dudderidge150,221, Ana Dueso-Barroso57, Andrew J. Dunford8, Michael Dunn309, Lewis Jonathan Dursi6,7, Fraser R. Duthie133,310, Ken Dutton-Regester311, Jenna Eagles272, Douglas F. Easton312,313, Stuart Edmonds314, Paul A. Edwards223,315, Sandra E. Edwards178, Rosalind A. Eeles178,221, Anna Ehinger316, Juergen Eils54,55, Roland Eils47,48,54,55, Adel El-Naggar99,273, Matthew Eldridge223, Kyle Ellrott9, Serap Erkek60, Georgia Escaramis53,317,318, Shadrielle M. G. Espiritu6, Xavier Estivill53,319, Dariush Etemadmoghadam103, Jorunn E. Eyfjord320, Bishoy M. Faltas280, Daiming Fan321, Yu Fan21, William C. Faquin72, Claudiu Farcas244, Matteo Fassan322, Aquila Fatima323, Francesco Favero324, Nodirjon Fayzullaev76, Ina Felau220, Sian Fereday103, Martin L. Ferguson325, Vincent Ferretti76,326, Lars Feuerbach205, Matthew A. Field327, J. Lynn Fink57,113, Gaetano Finocchiaro328, Cyril Fisher221, Matthew W. Fittall290, Anna Fitzgerald329, Rebecca C. Fitzgerald282, Adrienne M. Flanagan330, Neil E. Fleshner331, Paul Flicek59, John A. Foekens332, Kwun M. Fong333, Nuno A. Fonseca59,334, Christopher S. Foster335,336, Natalie S. Fox6, Michael Fraser6, Scott Frazer8, Milana Frenkel-Morgenstern337, William Friedman338, Joan Frigola298, Catrina C. Fronick1,262, Akihiro Fujimoto184, Masashi Fujita184, Masashi Fukayama339, Lucinda A. Fulton1 , Robert S. Fulton1,3,20, Mayuko Furuta184, P. Andrew Futreal340, Anja Füllgrabe59, Stacey B. Gabriel8, Steven Gallinger148,255,260, Carlo Gambacorti-Passerini341, Jianjiong Gao121, Shengjie Gao56, Levi Garraway82, Øystein Garred342, Erik Garrison49, Dale W. Garsed103, Nils Gehlenborg8,343, Josep L. l. Gelpi57,58, Joshy George110, Daniela S. Gerhard344, Clarissa Gerhauser345, Jeffrey E. Gershenwald346,347, Mark B. Gerstein5,18,19, Moritz Gerstung59,60, Gad Getz8,14,15,16, Mohammed Ghori49, Ronald Ghossein348, Nasra H. Giama349, Richard A. Gibbs12, Anthony J. Gill170,350, Pelvender Gill351, Dilip D. Giri348, Dominik Glodzik49, Vincent J. Gnanapragasam352,353, Maria Elisabeth Goebler354, Mary J. Goldman24, Carmen Gomez355, Santiago Gonzalez59,60, Abel Gonzalez-Perez298,299,356, Dmitry A. Gordenin357, James Gossage358, Kunihito Gotoh359, Ramaswamy Govindan3, Dorthe Grabau360, Janet S. Graham133,361, Robert C. Grant148,260, Anthony R. Green315, Eric Green27, Liliana Greger59, Nicola Grehan282, Sonia Grimaldi177, Sean M. Grimmond362, Robert L. Grossman363, Adam Grundhoff97,364, Gunes Gundem88, Qianyun Guo75, Manaswi Gupta8, Shailja Gupta365, Ivo G. Gut52,61, Marta Gut52,61, Jonathan Göke292,366, Gavin Ha8, Andrea Haake111, David Haan37, Siegfried Haas185, Kerstin Haase290, James E. Haber367, Nina Habermann60, Faraz Hach62,63, Syed Haider6, Natsuko Hama118, Freddie C. Hamdy351, Anne Hamilton267, Mark P. Hamilton368, Leng Han369, George B. Hanna370, Martin Hansmann371, Nicholas J. Haradhvala8,72, Olivier Harismendy102,372, Ivon Harliwong113, Arif O. Harmanci5,373, Eoghan Harrington374, Takanori Hasegawa375, David Haussler24,25, Steve Hawkins223, Shinya Hayami376, Shuto Hayashi375, D. Neil Hayes134,377,378, Stephen J. Hayes379,380, Nicholas K. Hayward211,311, Steven Hazell221, Yao He381, Allison P. Heath382, Simon C. Heath52,61, David Hedley300, Apurva M. Hegde38, David I. Heiman8, Michael C. Heinold47,48, Zachary Heins88, Lawrence E. Heisler152, Eva Hellstrom-Lindberg383, Mohamed Helmy384, Seong Gu Heo385, Austin J. Hepperla134, José María Heredia-Genestar386, Carl Herrmann47,48,387, Peter Hersey211, Julian M. Hess8,26, Holmfridur Hilmarsdottir320, Jonathan Hinton49, Satoshi Hirano388, Nobuyoshi Hiraoka389, Katherine A. Hoadley134,390, Asger Hobolth75,168, Ermin Hodzic78, Jessica I. Hoell182, Steve Hoffmann163,164,165,391, Oliver Hofmann392, Andrea Holbrook166, Aliaksei Z. Holik53, Michael A. Hollingsworth393, Oliver Holmes209,311, Robert A. Holt30, Chen Hong205,237, Eun Pyo Hong385, Jongwhi H. Hong394, Gerrit K. Hooijer395, Henrik Hornshøj73, Fumie Hosoda118, Yong Hou56,396, Volker Hovestadt397, William Howat352, Alan P. Hoyle134, Ralph H. Hruban149, Jianhong Hu12, Taobo Hu64, Xing Hua240, Kuan-lin Huang1,398, Mei Huang176, Mi Ni Huang179,180, Vincent Huang6, Yi Huang65,66, Wolfgang Huber60, Thomas J. Hudson272,399, Michael Hummel400, Jillian A. Hung246,247, David Huntsman401, Ted R. Hupp402, Jason Huse88, Matthew R. Huska403, Barbara Hutter43,67,68, Carolyn M. Hutter27, Daniel Hübschmann48,54,404,405,406, Christine A. Iacobuzio-Donahue348, Charles David Imbusch205, Marcin Imielinski407,408, Seiya Imoto375, William B. Isaacs409, Keren Isaev6,44, Shumpei Ishikawa410, Murat Iskar397, S. M. Ashiqul Islam244, Michael Ittmann411,412,413, Sinisa Ivkovic284, Jose M. G. Izarzugaza414, Jocelyne Jacquemier415, Valerie Jakrot211, Nigel B. Jamieson133,172,416, Gun Ho Jang148, Se Jin Jang417, Joy C. Jayaseelan12, Reyka Jayasinghe1 , Stuart R. Jefferys134, Karine Jegalian418, Jennifer L. Jennings419, Seung-Hyup Jeon250, Lara Jerman60,420, Yuan Ji421,422, Wei Jiao6, Peter A. Johansson311, Amber L. Johns170, Jeremy Johns272, Rory Johnson230,423, Todd A. Johnson183, Clemency Jolly290, Yann Joly424, Jon G. Jonasson320, Corbin D. Jones425, David R. Jones49, David T. W. Jones426,427, Nic Jones428, Steven J. M. Jones30, Jos Jonkers204, Young Seok Ju49,249, Hartmut Juhl429, Jongsun Jung69, Malene Juul73, Randi Istrup Juul73, Sissel Juul374, Natalie Jäger47, Rolf Kabbe47, Andre Kahles276,277,278,279,430, Abdullah Kahraman431,432,433, Vera B. Kaiser434, Hojabr Kakavand211, Sangeetha Kalimuthu148, Christof von Kalle405, Koo Jeong Kang91, Katalin Karaszi351, Beth Karlan435, Rosa Karlić436, Dennis Karsch437, Katayoon Kasaian29,30, Karin S. Kassahn113,438, Hitoshi Katai439, Mamoru Kato440, Hiroto Katoh410, Yoshiiku Kawakami93, Jonathan D. Kay117, Stephen H. Kazakoff209,311, Marat D. Kazanov441,442,443, Maria Keays59, Electron Kebebew444,445, Richard F. Kefford446, Manolis Kellis8,447, James G. Kench170,350,448, Catherine J. Kennedy246,247, Jules N. A. Kerssemakers47, David Khoo273, Vincent Khoo221, Narong Khuntikeo115,449, Ekta Khurana301,302,450,451, Helena Kilpinen117, Hark Kyun Kim452, Hyung-Lae Kim70, Hyung-Yong Kim415, Hyunghwan Kim250, Jaegil Kim8, Jihoon Kim453, Jong K. Kim454, Youngwook Kim455,456, Tari A. King457,458,459, Wolfram Klapper128, Kortine Kleinheinz47,48, Leszek J. Klimczak460, Stian Knappskog49,461, Michael Kneba437, Bartha M. Knoppers424, Youngil Koh462,463, Jan Komorowski305,464, Daisuke Komura410, Mitsuhiro Komura375, Gu Kong415, Marcel Kool426,465, Jan O. Korbel59,60, Viktoriya Korchina12, Andrey Korshunov465, Michael Koscher465, Roelof Koster466, Zsofia Kote-Jarai178, Antonios Koures244, Milena Kovacevic284, Barbara Kremeyer49, Helene Kretzmer164,165, Markus Kreuz467, Savitri Krishnamurthy99,468, Dieter Kube469, Kiran Kumar8, Pardeep Kumar221, Sushant Kumar5,19, Yogesh Kumar64, Ritika Kundra114,121, Kirsten Kübler8,14,72, Ralf Küppers470, Jesper Lagergren383,471, Phillip H. Lai166, Peter W. Laird472, Sunil R. Lakhani473, Christopher M. Lalansingh6, Emilie Lalonde6, Fabien C. Lamaze6, Adam Lambert351, Eric Lander8, Pablo Landgraf474,475, Luca Landoni115, Anita Langerød130, Andrés Lanzós230,231,423, Denis Larsimont476, Erik Larsson477, Mark Lathrop189, Loretta M. S. Lau478, Chris Lawerenz55, Rita T. Lawlor177, Michael S. Lawrence8,72,183, Alexander J. Lazar99,108, Xuan Le479, Darlene Lee30, Donghoon Lee5, Eunjung Alice Lee480, Hee Jin Lee417, Jake June-Koo Lee264,266, Jeong-Yeon Lee481, Juhee Lee482, Ming Ta Michael Lee340, Henry Lee-Six49, Kjong-Van Lehmann276,277,278,279,430, Hans Lehrach483, Dido Lenze400, Conrad R. Leonard209,311, Daniel A. Leongamornlert49,178, Ignaty Leshchiner8, Louis Letourneau484, Ivica Letunic71, Douglas A. Levine88,485, Lora Lewis12, Tim Ley486, Chang Li56,396, Constance H. Li6,44, Haiyan Irene Li30, Jun Li21, Lin Li56, Shantao Li5, Siliang Li56,396, Xiaobo Li56,396, Xiaotong Li5, Xinyue Li56, Yilong Li49, Han Liang21, Sheng-Ben Liang234, Peter Lichter68,397, Pei Lin8, Ziao Lin8,487, W. M. Linehan488, Ole Christian Lingjærde489, Dongbing Liu56,396, Eric Minwei Liu88,301,302, Fei-Fei Liu201,490, Fenglin Liu381,491, Jia Liu492, Xingmin Liu56,396, Julie Livingstone6, Dimitri Livitz8, Naomi Livni221, Lucas Lochovsky5,19,110, Markus Loeffler467, Georgina V. Long211, Armando Lopez-Guillermo493, Shaoke Lou5,19, David N. Louis72, Laurence B. Lovat117, Yiling Lu38, Yong-Jie Lu162,494, Youyong Lu495,496,497, Claudio Luchini167, Ilinca Lungu144,148, Xuemei Luo152, Hayley J. Luxton117, Andy G. Lynch223,315,498, Lisa Lype36, Cristina López111,112, Carlos López-Otín499, Eric Z. Ma64, Yussanne Ma30, Gaetan MacGrogan500, Shona MacRae501, Geoff Macintyre223, Tobias Madsen73, Kazuhiro Maejima184, Andrea Mafficini177, Dennis T. Maglinte166,502, Arindam Maitra174, Partha P. Majumder174, Luca Malcovati232, Salem Malikic62,78, Giuseppe Malleo115, Graham J. Mann211,246,503, Luisa Mantovani-Löffler504, Kathleen Marchal505,506, Giovanni Marchegiani115, Elaine R. Mardis1,193,507, Adam A. Margolin31, Maximillian G. Marin37, Florian Markowetz223,315, Julia Markowski403, Jeffrey Marks508, Tomas Marques-Bonet61,81,386,509, Marco A. Marra30, Luke Marsden351, John W. M. Martens332, Sancha Martin49,510, Jose I. Martin-Subero81,511, Iñigo Martincorena49, Alexander Martinez-Fundichely301,302,451 Yosef E. Maruvka8,26,72, R. Jay Mashl1,2, Charlie E. Massie223, Thomas J. Matthew37, Lucy Matthews178, Erik Mayer221,512, Simon Mayes513, Michael Mayo30, Faridah Mbabaali272, Karen McCune514, Ultan McDermott49, Patrick D. McGillivray19, Michael D. McLellan1,3,20, John D. McPherson148,272,515, John R. McPherson179,180, Treasa A. McPherson260, Samuel R. Meier8, Alice Meng516, Shaowu Meng134, Andrew Menzies49, Neil D. Merrett115,517, Sue Merson178, Matthew Meyerson8,14,82, William U. Meyerson4,5, Piotr A. Mieczkowski518, George L. Mihaiescu76, Sanja Mijalkovic284, Ana Mijalkovic Mijalkovic-Lazic284, Tom Mikkelsen519, Michele Milella253, Linda Mileshkin103, Christopher A. Miller1 , David K. Miller113,170, Jessica K. Miller272, Gordon B. Mills33,34, Ana Milovanovic57, Sarah Minner520, Marco Miotto115, Gisela Mir Arnau267, Lisa Mirabello240, Chris Mitchell103, Thomas J. Mitchell49,315,352, Satoru Miyano375, Naoki Miyoshi375, Shinichi Mizuno521, Fruzsina Molnár-Gábor522, Malcolm J. Moore300, Richard A. Moore30, Sandro Morganella49, Quaid D. Morris127,490, Carl Morrison523,524, Lisle E. Mose134, Catherine D. Moser349, Ferran Muiños298,299, Loris Mularoni298,299, Andrew J. Mungall30, Karen Mungall30, Elizabeth A. Musgrove133, Ville Mustonen525,526,527, David Mutch528, Francesc Muyas52,53,74, Donna M. Muzny12, Alfonso Muñoz59, Jerome Myers529, Ola Myklebost461, Peter Möller530, Genta Nagae89, Adnan M. Nagrial170, Hardeep K. Nahal-Bose76, Hitoshi Nakagama531, Hidewaki Nakagawa184, Hiromi Nakamura118, Toru Nakamura388, Kaoru Nakano184, Tannistha Nandi532, Jyoti Nangalia49, Mia Nastic284, Arcadi Navarro61,81,386, Fabio C. P. Navarro19, David E. Neal223,352, Gerd Nettekoven533, Felicity Newell209,311, Steven J. Newhouse59, Yulia Newton37, Alvin Wei Tian Ng534, Anthony Ng535, Jonathan Nicholson49, David Nicol221, Yongzhan Nie321,536, G. Petur Nielsen72, Morten Muhlig Nielsen73, Serena Nik-Zainal49,281,282,537, Michael S. Noble8, Katia Nones209,311, Paul A. Northcott538, Faiyaz Notta148,539, Brian D. O’Connor76,540, Peter O’Donnell541, Maria O’Donovan282, Sarah O’Meara49, Brian Patrick O’Neill542, J. Robert O’Neill543, David Ocana59, Angelica Ochoa88, Layla Oesper544, Christopher Ogden221, Hideki Ohdan93, Kazuhiro Ohi375, Lucila Ohno-Machado244, Karin A. Oien523,545, Akinyemi I. Ojesina546,547,548, Hidenori Ojima549, Takuji Okusaka550, Larsson Omberg551, Choon Kiat Ong552, Stephan Ossowski52,53,74, German Ott553, B. F. Francis Ouellette76,554, Christine P’ng6, Marta Paczkowska6, Salvatore Paiella115, Chawalit Pairojkul523, Marina Pajic170, Qiang Pan-Hammarström56,555, Elli Papaemmanuil49, Irene Papatheodorou59, Nagarajan Paramasivam43,47, Ji Wan Park385, Joong-Won Park556, Keunchil Park557,558, Kiejung Park559, Peter J. Park264,266, Joel S. Parker518, Simon L. Parsons124, Harvey Pass560, Danielle Pasternack272, Alessandro Pastore276, Ann-Marie Patch209,311, Iris Pauporté251, Antonio Pea115, John V. Pearson209,311, Chandra Sekhar Pedamallu8,14,82, Jakob Skou Pedersen73,75, Paolo Pederzoli115, Martin Peifer270, Nathan A. Pennell561, Charles M. Perou129,518, Marc D. Perry76,77, Gloria M. Petersen562, Myron Peto22, Nicholas Petrelli563, Robert Petryszak59, Stefan M. Pfister426,465,564, Mark Phillips424, Oriol Pich298,299, Hilda A. Pickett478, Todd D. Pihl565, Nischalan Pillay566, Sarah Pinder567, Mark Pinese170, Andreia V. Pinho568, Esa Pitkänen60, Xavier Pivot569, Elena Piñeiro-Yáñez95, Laura Planko533, Christoph Plass345, Paz Polak8,14,15, Tirso Pons570, Irinel Popescu571, Olga Potapova572, Aparna Prasad52, Shaun R. Preston573, Manuel Prinz47, Antonia L. Pritchard311, Stephenie D. Prokopec6, Elena Provenzano574, Xose S. Puente499, Sonia Puig176, Montserrat Puiggròs57, Sergio Pulido-Tamayo505,506, Gulietta M. Pupo246, Colin A. Purdie575, Michael C. Quinn209,311, Raquel Rabionet52,53,576, Janet S. Rader577, Bernhard Radlwimmer397, Petar Radovic284, Benjamin Raeder60, Keiran M. Raine49, Manasa Ramakrishna49, Kamna Ramakrishnan49, Suresh Ramalingam578, Benjamin J. Raphael579, W. Kimryn Rathmell580, Tobias Rausch60, Guido Reifenberger475, Jüri Reimand6,44, Jorge Reis-Filho348, Victor Reuter348, Iker Reyes-Salazar298, Matthew A. Reyna579, Sheila M. Reynolds36, Esther Rheinbay8,14,72, Yasser Riazalhosseini189, Andrea L. Richardson323, Julia Richter111,128, Matthew Ringel581, Markus Ringnér181, Yasushi Rino582, Karsten Rippe405, Jeffrey Roach583, Lewis R. Roberts349, Nicola D. Roberts49, Steven A. Roberts584, A. Gordon Robertson30, Alan J. Robertson113, Javier Bartolomé Rodriguez57, Bernardo Rodriguez-Martin104,105,106, F. Germán Rodríguez-González83,332, Michael H. A. Roehrl44,123,148,234,585,586, Marius Rohde587, Hirofumi Rokutan440, Gilles Romieu588, Ilse Rooman170, Tom Roques262, Daniel Rosebrock8, Mara Rosenberg8,72, Philip C. Rosenstiel589, Andreas Rosenwald590, Edward W. Rowe221,591, Romina Royo57, Steven G. Rozen179,180,592, Yulia Rubanova17,127, Mark A. Rubin423,593,594,595,596, Carlota Rubio-Perez298,299,597, Vasilisa A. Rudneva60, Borislav C. Rusev177, Andrea Ruzzenente598, Gunnar Rätsch276,277,278,279,280,430, Radhakrishnan Sabarinathan298,299,599, Veronica Y. Sabelnykova6, Sara Sadeghi30, S. Cenk Sahinalp62,78,79, Natalie Saini357, Mihoko Saito-Adachi440, Gordon Saksena8, Adriana Salcedo6, Roberto Salgado600, Leonidas Salichos5,19, Richard Sallari8, Charles Saller601, Roberto Salvia115, Michelle Sam272, Jaswinder S. Samra115,602, Francisco Sanchez-Vega114,121, Chris Sander276,603,604, Grant Sanders134, Rajiv Sarin605, Iman Sarrafi62,78, Aya Sasaki-Oku184, Torill Sauer489, Guido Sauter520, Robyn P. M. Saw211, Maria Scardoni167, Christopher J. Scarlett170,606, Aldo Scarpa177, Ghislaine Scelo194, Dirk Schadendorf68,607, Jacqueline E. Schein30, Markus B. Schilhabel589, Matthias Schlesner47,80, Thorsten Schlomm84,608, Heather K. Schmidt1 , Sarah-Jane Schramm246, Stefan Schreiber609, Nikolaus Schultz121, Steven E. Schumacher8,323, Roland F. Schwarz59,403,405,610, Richard A. Scolyer211,448,602, David Scott428, Ralph Scully611, Raja Seethala612, Ayellet V. Segre8,613, Iris Selander260, Colin A. Semple434, Yasin Senbabaoglu276, Subhajit Sengupta614, Elisabetta Sereni115, Stefano Serra585, Dennis C. Sgroi72, Mark Shackleton103, Nimish C. Shah352, Sagedeh Shahabi234, Catherine A. Shang329, Ping Shang211, Ofer Shapira8,323, Troy Shelton271, Ciyue Shen603,604, Hui Shen615, Rebecca Shepherd49, Ruian Shi490, Yan Shi134, Yu-Jia Shiah6, Tatsuhiro Shibata118,616, Juliann Shih8,82, Eigo Shimizu375, Kiyo Shimizu617, Seung Jun Shin618, Yuichi Shiraishi375, Tal Shmaya285, Ilya Shmulevich36, Solomon I. Shorser6, Charles Short59, Raunak Shrestha62, Suyash S. Shringarpure217, Craig Shriver619, Shimin Shuai6,126, Nikos Sidiropoulos83, Reiner Siebert112,620, Anieta M. Sieuwerts332, Lina Sieverling205,237, Sabina Signoretti202,621, Katarzyna O. Sikora177, Michele Simbolo138, Ronald Simon520, Janae V. Simons134, Jared T. Simpson6,17, Peter T. Simpson473, Samuel Singer115,458, Nasa Sinnott-Armstrong8,217, Payal Sipahimalani30, Tara J. Skelly390, Marcel Smid332, Jaclyn Smith622, Karen Smith-McCune514, Nicholas D. Socci276, Heidi J. Sofia27, Matthew G. Soloway134, Lei Song240, Anil K. Sood623,624,625, Sharmila Sothi626, Christos Sotiriou244, Cameron M. Soulette37, Paul N. Span627, Paul T. Spellman22, Nicola Sperandio177, Andrew J. Spillane211, Oliver Spiro8, Jonathan Spring628, Johan Staaf181, Peter F. Stadler163,164,165, Peter Staib629, Stefan G. Stark277,279,618,630, Lucy Stebbings49, Ólafur Andri Stefánsson631, Oliver Stegle59,60,632, Lincoln D. Stein6,126, Alasdair Stenhouse633, Chip Stewart8, Stephan Stilgenbauer634, Miranda D. Stobbe52,61, Michael R. Stratton49, Jonathan R. Stretch211, Adam J. Struck31, Joshua M. Stuart24,37, Henk G. Stunnenberg396,635, Hong Su56,396, Xiaoping Su99, Ren X. Sun6, Stephanie Sungalee60, Hana Susak52,53, Akihiro Suzuki89,636, Fred Sweep637, Monika Szczepanowski128, Holger Sültmann67,638, Takashi Yugawa617, Angela Tam30, David Tamborero298,299, Benita Kiat Tee Tan639, Donghui Tan518, Patrick Tan180,532,592,640, Hiroko Tanaka375, Hirokazu Taniguchi616, Tomas J. Tanskanen641, Maxime Tarabichi49,290, Roy Tarnuzzer220, Patrick Tarpey642, Morgan L. Taschuk152, Kenji Tatsuno89, Simon Tavaré223,643, Darrin F. Taylor113, Amaro Taylor-Weiner8, Jon W. Teague49, Bin Tean Teh180,592,640,644,645, Varsha Tembe246, Javier Temes104,105, Kevin Thai76, Sarah P. Thayer393, Nina Thiessen30, Gilles Thomas646, Sarah Thomas221, Alan Thompson221, Alastair M. Thompson633, John F. Thompson211, R. Houston Thompson647, Heather Thorne103, Leigh B. Thorne176, Adrian Thorogood424, Grace Tiao8, Nebojsa Tijanic284, Lee E. Timms272, Roberto Tirabosco648, Marta Tojo106, Stefania Tommasi649, Christopher W. Toon170, Umut H. Toprak48,650, David Torrents57,81, Giampaolo Tortora651,652, Jörg Tost653, Yasushi Totoki118, David Townend654, Nadia Traficante103, Isabelle Treilleux655,656, Jean-Rémi Trotta61, Lorenz H. P. Trümper469, Ming Tsao124,539, Tatsuhiko Tsunoda183,657,658,659, Jose M. C. Tubio104,105,106, Olga Tucker660, Richard Turkington661, Daniel J. Turner513, Andrew Tutt323, Masaki Ueno376, Naoto T. Ueno662, Christopher Umbricht151,213,663, Husen M. Umer305,664, Timothy J. Underwood665, Lara Urban59,60, Tomoko Urushidate616, Tetsuo Ushiku339, Liis Uusküla-Reimand666,667, Alfonso Valencia57,81, David J. Van Den Berg166, Steven Van Laere307, Peter Van Loo290,291, Erwin G. Van Meir668, Gert G. Van den Eynden307, Theodorus Van der Kwast123, Naveen Vasudev137, Miguel Vazquez57,669, Ravikiran Vedururu267, Umadevi Veluvolu518, Shankar Vembu490,670, Lieven P. C. Verbeke506,671, Peter Vermeulen307, Clare Verrill351,672, Alain Viari177, David Vicente57, Caterina Vicentini177, K. Vijay Raghavan365, Juris Viksna673, Ricardo E. Vilain674, Izar Villasante57, Anne Vincent-Salomon635, Tapio Visakorpi190, Douglas Voet8, Paresh Vyas311,351, Ignacio Vázquez-García49,86,675,676, Nick M. Waddell209, Nicola Waddell209,311, Claes Wadelius677, Lina Wadi6, Rabea Wagener111,112, Jeremiah A. Wala8,14,82, Jian Wang56, Jiayin Wang1,40,66, Linghua Wang12, Qi Wang465, Wenyi Wang21, Yumeng Wang21, Zhining Wang220, Paul M. Waring523, Hans-Jörg Warnatz483, Jonathan Warrell5,19, Anne Y. Warren352,678, Sebastian M. Waszak60, David C. Wedge49,294,679, Dieter Weichenhan345, Paul Weinberger680, John N. Weinstein38, Joachim Weischenfeldt60,83,84, Daniel J. Weisenberger166, Ian Welch681, Michael C. Wendl1,10,11, Johannes Werner47,85, Justin P. Whalley61,682, David A. Wheeler12,13, Hayley C. Whitaker117, Dennis Wigle683, Matthew D. Wilkerson518, Ashley Williams244, James S. Wilmott211, Gavin W. Wilson6,148, Julie M. Wilson148, Richard K. Wilson1,684, Boris Winterhoff685, Jeffrey A. Wintersinger17,127,384, Maciej Wiznerowicz686,687, Stephan Wolf688, Bernice H. Wong689, Tina Wong1,30, Winghing Wong690, Youngchoon Woo250, Scott Wood209,311, Bradly G. Wouters44, Adam J. Wright6, Derek W. Wright133,691, Mark H. Wright217, Chin-Lee Wu72, Dai-Ying Wu285, Guanming Wu692, Jianmin Wu170, Kui Wu56,396, Yang Wu179,180, Zhenggang Wu64, Liu Xi12, Tian Xia693, Qian Xiang76, Xiao Xiao66, Rui Xing497, Heng Xiong56,396, Qinying Xu209,311, Yanxun Xu694, Hong Xue64, Shinichi Yachida118,695, Sergei Yakneen60, Rui Yamaguchi375, Takafumi N. Yamaguchi6, Masakazu Yamamoto120, Shogo Yamamoto89, Hiroki Yamaue376, Fan Yang490, Huanming Yang56, Jean Y. Yang696, Liming Yang220, Lixing Yang697, Shanlin Yang306, Tsun-Po Yang270, Yang Yang369, Xiaotong Yao408,698, Marie-Laure Yaspo483, Lucy Yates49, Christina Yau156, Chen Ye56,396, Kai Ye40,41, Venkata D. Yellapantula20,86, Christopher J. Yoon249, Sung-Soo Yoon463, Fouad Yousif6, Jun Yu699, Kaixian Yu700, Willie Yu701, Yingyan Yu702, Ke Yuan223,510,703, Yuan Yuan21, Denis Yuen6, Takashi Yugawa617, Christina K. Yung76, Olga Zaikova704, Jorge Zamora49,104,105,106, Marc Zapatka397, Jean C. Zenklusen220, Thorsten Zenz67, Nikolajs Zeps705,706, Cheng-Zhong Zhang8,707, Fan Zhang381, Hailei Zhang8, Hongwei Zhang494, Hongxin Zhang121, Jiashan Zhang220, Jing Zhang5, Junjun Zhang76, Xiuqing Zhang56, Xuanping Zhang66,369, Yan Zhang5,708,709, Zemin Zhang381,710, Zhongming Zhao711, Liangtao Zheng381, Xiuqing Zheng381, Wanding Zhou615, Yong Zhou56, Bin Zhu240, Hongtu Zhu700,712, Jingchun Zhu24, Shida Zhu56,396, Lihua Zou713, Xueqing Zou49, Anna deFazio246,247,714, Nicholas van As221, Carolien H. M. van Deurzen715, Marc J. van de Vijver523, L. van’t Veer716 & Christian von Mering433,717, The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.
Published: 2020

6. Biased mutational pattern and quasispecies hypothesis in H5N1 virus

Author: Ramona Alikiiteaga Gutiérrez, Alain Viari, Philippe Buchy, Bernard Godelle, Roger Frutos, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), An algorithmic view on genomes, cells, and environments (BAMBOO), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 2 - Sciences et Techniques (UM2), Interaction hôtes vecteurs parasites dans les infections par des trypanosomatidae (UMR InterTryp ), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD), This work was supported by the French Ministry of Research and by the Office of the Assistant Secretary for Preparedness and Response within the U.S. Department of Health and Human Services. Ramona Gutiérrez received a scholarship from the Government of New-Caledonia. Alain Viari, Bernard Godelle and Roger Frutos were supported in part by the PHC-Siam Grant 20624VK from the French Ministry of Foreign and European Affairs., Gutiérrez RA, Viari A, Godelle B, Frutos R, Buchy P., Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), and Institut de Recherche pour le Développement (IRD)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)
Subjects: Mutation rate, Polymorphisme génétique, viruses, DNA Mutational Analysis, L73 - Maladies des animaux, medicine.disease_cause, influenza virus, Mutation Rate, Génétique des populations, Influenza A virus, Phylogeny, Genetics, 0303 health sciences, virus diseases, H5N1, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, biased mutational pattern, Infectious Diseases, Infection, Microbiology (medical), Modèle, olymorphism, Hemagglutinin (influenza), Viral quasispecies, Biology, Microbiology, Article, Volaille, Virus, Viral Proteins, 03 medical and health sciences, medicine, Animals, Influenzavirus aviaire, Polymorphism, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Influenza A Virus, H5N1 Subtype, 030306 microbiology, RNA, quasispecies, Virology, Influenza A virus subtype H5N1, Influenza in Birds, Mutation, biology.protein, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Chickens
Abstract: International audience; Like other RNA viruses, influenza viruses are subject to high mutation rates. Carrying segmented RNA genomes, their genetic variability is even higher. We aimed at analyzing the mutational events occurring during the infection of chickens by the Highly Pathogenic Avian Influenza (HPAI) H5N1 virus. We therefore studied the different sequences of two surface proteins, hemagglutinin (HA) and neuraminidase (NA), as well as two internal proteins, PB2 and NS. Three organs (lung, spleen, brain) were obtained from a chicken, experimentally infected with a lethal dose of HPAI H5N1 virus. Cloning these PCR fragments enabled us to investigate the mutations undergone by the virus after several replicative cycles. The first outcome is the presence of a strong mutational bias, resembling host-driven ADAR1 adenosine deamination, which is responsible for 81% of all mutations. Whereas the frequency of RNA dependent RNA polymerase-related mutations is compatible with the survival of the virus, the ADAR1-like activity usually strongly increases the mutation frequency into a level of "error catastrophe" in theory incompatible with virus survival. Nevertheless, the virus was successfully infective. HPAI H5N1 virus displayed traits in agreement with the quasispecies theory. The role of this quasispecies structure in successful infection and the superposition with the ADAR1-like response is discussed.
Published: 2013

7. Complex dynamic of dengue virus serotypes 2 and 3 in Cambodia following series of climate disasters

Author: Alain Viari, Chantha Ngan, Vincent Deubel, Sowath Ly, Sivuth Ong, Veasna Duong, Bunthin Y, Rekol Huy, Niall J. Lennon, Philippe Buchy, Matthew R. Henn, Bruce W. Birren, Jeremy Farrar, Laurent Gavotte, Roger Frutos, Cameron P. Simmons, Sirenda Vong, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), National Center of Parasitology (CNM), National Malaria Center [Phnom Penh], Université Montpellier 2 - Sciences et Techniques (UM2), An algorithmic view on genomes, cells, and environments (BAMBOO), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria), Interactions hôtes-vecteurs-parasites-environnement dans les maladies tropicales négligées dues aux trypanosomatides (UMR INTERTRYP), Université de Bordeaux (UB)-Institut de Recherche pour le Développement (IRD)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), This study was funded in part by the Wellcome Trust UK. Roger Frutos was supported in part by the PHC Grant 20624 VK and the FP7 Erasmus Mundus project MAHEVA. Alain Viari was supported in part by the PHC Grant 20624 VK. We are very grateful to the Doctorate School SIBAGHE (University Montpellier 2) and the French Ministry of Foreign Affairs for providing scholarships supporting in part Veasna Duong., Duong V, Henn MR, Ly S, Vong S, Birren BW, Farrar JJ, Deubel V, Frutos R, Buchy P., Simmons C, Ngan C, Y B, Gavotte L, Viari A, Ong S, Huy R, Lennon NJ, Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université de Bordeaux (UB)
Subjects: Serotype, Genes, Viral, Climate, viruses, Lineage (evolution), Dengue virus, Accident climatique, Facteur climatique, medicine.disease_cause, Dengue fever, Dengue, Disasters, 0302 clinical medicine, Lignée, Case fatality rate, Child, Phylogeny, Diversity, 0303 health sciences, education.field_of_study, biology, virus diseases, Middle Aged, 3. Good health, Flavivirus, Infectious Diseases, S50 - Santé humaine, Child, Preschool, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cambodia, épidémie, Adult, Microbiology (medical), Adolescent, Molecular Sequence Data, 030231 tropical medicine, Population, Descendance, Genome, Viral, Catastrophe naturelle, Microbiology, Open Reading Frames, Young Adult, 03 medical and health sciences, Variation génétique, Genetics, medicine, Humans, Amino Acid Sequence, Selection, Genetic, Serotyping, education, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Aged, 030304 developmental biology, Polymorphism, Genetic, Base Sequence, DENV-2, Infant, DENV-3, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, medicine.disease, Virology, Sérotype, Lineage dynamics, Vector (epidemiology), Mutation
Abstract: Lien vers le texte intégral : http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=22677620; International audience; The Dengue National Control Program was established in Cambodia in 2000 and has reported between 10,000 and 40,000 dengue cases per year with a case fatality rate ranging from 0.7 to 1.7. In this study 39 DENV-2 and 57 DENV-3 viruses isolated from patients between 2000 and were fully sequenced. Five DENV2 and four DENV3 distinct lineages with different dynamics were identified. Each lineage was characterized by the presence of specific mutations with no evidence of recombination. In both DENV-2 and DENV-3 the lineages present prior to 2003 were replaced after that date by unrelated lineages. After 2003, DENV-2 lineages D2-3 and D2-4 cocirculated until 2007 when they were almost completely replaced by a lineage D2-5 which emerged from Conversely, all DENV-3 lineages remained, diversified and cocirculated with novel lineages emerging. Years 2006 and 2007 were marked by a high prevalence of DENV-3 and 2007 with a large dengue outbreak and a high proportion of patients with severe disease. Selective sweeps in DENV-1 and DENV-2 were linked to immunological escape to a predominately DENV-3-driven immunological response. The complex dynamic of dengue in Cambodia in the last ten years has been associated with a combination of stochastic climatic events, cocirculation, coevolution, adaptation to different vector populations, and with the human population immunological landscape.
Published: 2013

8. Abstract P6-08-10: Mutational signatures impact the breast cancer transcriptome and distinguish mitotic from immune response pathways

Author: Ramakrishna, A-L Børresen-Dale, M.E. Meijer-van Gelder, Alain Viari, Adam Butler, M.J. van de Vijver, Reno Debets, Henk Stunnenberg, Ewan Birney, Anne Louise Richardson, Germán Fg Rodríguez-González, Arend Brinkman, Marcel Smid, A van Galen, Kim Berentsen, Serena Nik-Zainal, Jwm Martens, HD Davies, J.A. Foekens, AM Sieuwerts, Wjc Prager-Van der Smissen, Markus Ringnér, M van der Vlugt – Daane, Stewart G. Martin, Johan Staaf, Chm van Deurzen, Michael R. Stratton, and Carlos Caldas
Subjects: Genetics, Cancer Research, biology, Tumor-infiltrating lymphocytes, Cancer, Context (language use), Cell cycle, medicine.disease, Transcriptome, Breast cancer, Oncology, biology.protein, medicine, PTEN, Cancer immunology
Abstract: A comprehensive whole genome analysis of a large breast cancer cohort of 560 cases (Nik-Zainal et al, submitted 2015) reports novel and existing DNA substitution and rearrangement signatures next a comprehensive list of events driving the breast cancer cell to its malignant potency. In the current study, we linked the observed genetic diversity to the breast cancer transcriptome for 260 cases for which whole genome and whole transcriptome data were both available. Cluster analysis of the global gene expression showed the familiar view of a coherent basal-like and a heterogeneous luminal subgroup. New and previously reported1 subtype-specific aberrations with concordant expression changes were found in TP53, PIK3CA, PTEN, CCND1, CDH1 and GATA3, and mutations in PIK3CA, PTEN, AKT1 and AKT2 were mutually exclusive confirming they are active in the same pathway in breast cancer. Integrating the identified DNA substitutions signatures with the transcriptome, we observed that the total number of substitutions in a cancer, irrespective of substitution type, was positively associated with cell cycle regulated gene expression and with adverse outcome. In addition and more remarkably, we observed that the number substitution of two substitution signatures2 particularly associated with immune-response specific gene expression, with increased amount of tumor infiltrating lymphocytes and with a better outcome. These two signatures comprised 1) mutations of the APOBEC-type (predominant C>G in a TCN context), and 2) mutations which lacks specific features but which are strongly associated with genetic and epigenetic inactivating aberrations in BRCA1 and BRCA2. Thus, while earlier reports3-5 imply that the sheer number of driver events triggers an immune-response, we refine this statement by observing that substitutions of a particular type are much very effective in doing so explaining the superior outcome of cancer having these particular types of substitutions. This result also implies that purposefully augmenting T-cell reactivity against amino-acid substitutions resulting from either of these two DNA substitution types could potentially improve immunotherapies in breast cancer. 1. Comprehensive molecular portraits of human breast tumours. Nature 490, 61-70 (2012). 2. Alexandrov, L.B., et al. Signatures of mutational processes in human cancer. Nature 500, 415-421 (2013). 3. Rizvi, N.A., et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124-128 (2015). 4. Schumacher, T.N. & Schreiber, R.D. Neoantigens in cancer immunotherapy. Science 348, 69-74 (2015). 5. Snyder, A., et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371, 2189-2199 (2014). Citation Format: Martens JWM, Smid M, Rodríguez-González G, Sieuwerts AM, Prager-Van der Smissen WJC, Van Der Vlugt - Daane M, Van Galen A, Nik-Zainal S, Staaf J, Brinkman AB, Van de Vijver MJ, Richardson AL, Berentsen K, Caldas C, Butler A, Martin S, Davies HD, Debets R, Meijer-Van Gelder ME, Van Deurzen CHM, Ramakrishna MR, Ringnér M, Viari A, Birney E, Børresen-Dale A-L, Stunnenberg HG, Stratton M, Foekens JA. Mutational signatures impact the breast cancer transcriptome and distinguish mitotic from immune response pathways. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-08-10.
Published: 2016

9. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures

Author: Anieta M. Sieuwerts, Gu Kong, Christos Sotiriou, Sandrine Boyault, John W.M. Martens, Sunil R. Lakhani, Steven Van Laere, Peter J. Campbell, Andrew Tutt, Keiran Raine, Michael R. Stratton, Peter T. Simpson, Sancha Martin, Paul N. Span, Ewan Birney, Jorunn E. Eyfjord, Sandro Morganella, Lucy R. Yates, Marc J. van de Vijver, Alain Viari, Johan Staaf, Hendrik G. Stunnenberg, Anne Vincent-Salomon, Manasa Ramakrishna, Xueqing Zou, Dominik Glodzik, Tari A Ta King, Andrea L. Richardson, Serena Nik-Zainal, Anne Lise Børresen-Dale, Åke Borg, Alastair M Thompson, Helen Davies, The Wellcome Trust Sanger Institute [Cambridge], Guy's and St Thomas' Hospital [London], Lund University [Lund], AstraZeneca, Centre Léon Bérard [Lyon], Department of Medical Oncology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre for Clinical Research [Brisbane], University of Queensland [Brisbane], Memorial Sloane Kettering Cancer Center [New York], University of Iceland [Reykjavik], Hanyang University, Department of Molecular Biology [Nijmegen], Radboud University Medical Center [Nijmegen], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Oslo (UiO), Oslo University Hospital [Oslo], European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Breakthrough Breast Cancer Centre, London Institute of Cancer, The University of Texas M.D. Anderson Cancer Center [Houston], HistoGeneX, Brigham and Women's Hospital [Boston], Dana-Farber Cancer Institute [Boston], Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Baobab, Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Pathology, CCA - Cancer biology and immunology, Medical Oncology, Sieuwerts, Anieta M [0000-0003-1341-5400], Raine, Keiran [0000-0002-5634-1539], Martens, John WM [0000-0002-3428-3366], Tutt, Andrew [0000-0001-8715-2901], and Apollo - University of Cambridge Repository
Subjects: Male, 0301 basic medicine, endocrine system diseases, Somatic cell, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Breast Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Poly (ADP-Ribose) Polymerase Inhibitor, Article, General Biochemistry, Genetics and Molecular Biology, Germline, Breast Neoplasms, Male, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Cancer genomics, Humans, skin and connective tissue diseases, Biology, Molecular Biology, Polymerase, BRCA2 Protein, Ovarian Neoplasms, Genetics, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Models, Genetic, biology, BRCA1 Protein, Area under the curve, General Medicine, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, Pancreatic Neoplasms, Chemistry, Logistic Models, 030104 developmental biology, Area Under Curve, 030220 oncology & carcinogenesis, Mutation, biology.protein, Cancer research, Female, Human medicine
Abstract: International audience; Approximately 1–5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (~1–5%) who could have selective therapeutic sensitivity to PARP inhibition.
Published: 2017

10. Corrigendum: A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Author: Dominik Glodzik, Sandro Morganella, Helen Davies, Peter T Simpson, Yilong Li, Xueqing Zou, Javier Diez-Perez, Johan Staaf, Ludmil B Alexandrov, Marcel Smid, Arie B Brinkman, Inga Hansine Rye, Hege Russnes, Keiran Raine, Colin A Purdie, Sunil R Lakhani, Alastair M Thompson, Ewan Birney, Hendrik G Stunnenberg, Marc J van de Vijver, John W M Martens, Anne-Lise Børresen-Dale, Andrea L Richardson, Gu Kong, Alain Viari, Douglas Easton, Gerard Evan, Peter J Campbell, Michael R Stratton, Serena Nik-Zainal, Pathology, and CCA - Cancer biology and immunology
Subjects: Genetics, Article
Abstract: Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific ‘super-enhancer’ regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.
Published: 2017

11. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo

Author: Andrea L. Richardson, Anne Lise Børresen-Dale, Christos Sotiriou, Benita Kiat Tee Bk Tan, Laura Van't Veer, Andrew Tutt, Mia Petljak, David C. Wedge, Michael R. Stratton, Ludmil B. Alexandrov, Carlos Caldas, Åke Borg, Raheleh Rahbari, Inigo Martincorena, Alastair M Thompson, Henk Stunnenberg, Sancha Martin, Stian Knappskog, Marc J. van de Vijver, John W.M. Martens, Colin A. Purdie, Nikita Patel, Sarah O’Meara, Naoto T. Ueno, Peter J. Campbell, Matthew Me Hurles, Christopher Alder, Paul N. Span, Jorunn E. Eyfjord, Torril Sauer, Manasa Ramakrishna, Anthony Fullam, Steve Gamble, Helen Davies, S. Pinder, Alain Viari, Dilip Giri, Serena Nik-Zainal, Young Seok Ju, Moritz Gerstung, Sunil R. Lakhani, Medical Oncology, Korea Advanced Institute of Science and Technology (KAIST), The Wellcome Trust Sanger Institute [Cambridge], European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Los Alamos National Laboratory (LANL), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Memorial Sloane Kettering Cancer Center [New York], University of Oslo (UiO), Akershus University Hospital [Lørenskog], King’s Health Partners Cancer Biobank [London], Guy's Hospital [London], Department of Pathology [Dundee], Ninewells Hospital and Medical School [Dundee], BioCare [Lund], Department of Oncology and Pathology [Lund], Lund University [Lund]-Lund University [Lund], Department of Molecular Biology [Nijmegen], Radboud University Medical Center [Nijmegen], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), National Cancer Centre Singapore (NCCS), National Cancer Centre Singapore, University of Cambridge [UK] (CAM), Breakthrough Breast Cancer Centre, London Institute of Cancer, Department of Breast Medical Oncology [Houston], The University of Texas M.D. Anderson Cancer Center [Houston], Helen Diller Family Comprehensive Cancer Center [San Francisco], Department of Medical Oncology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), University of Bergen (UiB), University of Queensland [Brisbane], University of Iceland [Reykjavik], Institute for Cancer Research [Oslo], Oslo University Hospital [Oslo], Johns Hopkins University School of Medicine [Baltimore], Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Baobab, Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), University of Oxford [Oxford], Caldas, Carlos [0000-0003-3547-1489], Nik-Zainal Abidin, Serena [0000-0001-5054-1727], Apollo - University of Cambridge Repository, and Pathology
Subjects: 0301 basic medicine, Mutation rate, Somatic cell, [SDV]Life Sciences [q-bio], medicine.disease_cause, Germ-Line Mutation/genetics, Mutation Rate, Human embryogenesis, Embryonic Development/genetics, Blood Cells/metabolism, Genetics, Mutation, Multidisciplinary, Genome, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Manchester Cancer Research Centre, Mosaicism, Embryo, Mammalian/cytology, Embryo, Human, Adult, General Science & Technology, 1.1 Normal biological development and functioning, Embryonic Development, Biology, Article, 03 medical and health sciences, Germline mutation, Cell Lineage/genetics, Underpinning research, medicine, Humans, Cell Lineage, Gene, Molecular Biology, Germ-Line Mutation, Blood Cells, Genome, Human, Mammalian, ResearchInstitutes_Networks_Beacons/mcrc, Human Genome, Embryo, Mammalian, Embryonic stem cell, Human genetics, 030104 developmental biology, Mutagenesis, Genome, Human/genetics, Generic health relevance, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: International audience; Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.
Published: 2017

12. A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Author: Johan Staaf, Helen Davies, Ewan Birney, Hendrik G. Stunnenberg, Michael R. Stratton, Yang Li, Inga H. Rye, John W.M. Martens, Sunil R. Lakhani, Douglas F. Easton, Peter T. Simpson, Javier Diez-Perez, Andrea L. Richardson, Marc J. van de Vijver, Anne Lise Børresen-Dale, Marcel Smid, Sandro Morganella, Gerard I. Evan, Alain Viari, Serena Nik-Zainal, Ludmil B. Alexandrov, Hege G. Russnes, Alastair M. Thompson, Colin A. Purdie, Arie B. Brinkman, Dominik Glodzik, Xueqing Zou, Gu Kong, Peter J. Campbell, Keiran Raine, Pathology, CCA - Cancer biology and immunology, Medical Oncology, The Wellcome Trust Sanger Institute [Cambridge], Centre for Clinical Research [Brisbane], University of Queensland [Brisbane], Lund University [Lund], Los Alamos National Laboratory (LANL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Radboud university [Nijmegen], Institute for Cancer Research [Oslo], Oslo University Hospital [Oslo], University of Oslo (UiO), Department of Pathology [Dundee], Ninewells Hospital and Medical School [Dundee], The University of Texas M.D. Anderson Cancer Center [Houston], European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Oslo University Hospital Radiumhospitalet, Brigham and Women's Hospital [Boston], Dana-Farber Cancer Institute [Boston], Hanyang University, Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Baobab, Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre for Cancer Genetic Epidemiology [Cambridge], University of Cambridge [UK] (CAM)-Department of Oncology, Department of Biochemistry [Cambridge], University of Cambridge [UK] (CAM), Cambridge University Hospitals - NHS (CUH), Radboud University [Nijmegen], Zou, Xueqing [0000-0003-1143-1028], Easton, Douglas [0000-0003-2444-3247], Evan, Gerard [0000-0003-0412-1216], Nik-Zainal Abidin, Serena [0000-0001-5054-1727], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, DNA Repair, Somatic cell, [SDV]Life Sciences [q-bio], Gene Expression, Breast Neoplasms, Genomics, Regulatory Sequences, Nucleic Acid, Biology, medicine.disease_cause, Genome, Germline, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, genomics, Genetics, medicine, Humans, DNA Breaks, Double-Stranded, Molecular Biology, Gene, Mutation, Cancer, medicine.disease, 3. Good health, genetics research, 030104 developmental biology, Genetic Loci, Regulatory sequence, Female, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Transcriptome
Abstract: International audience; Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.
Published: 2017

13. Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency

Author: Colin A. Purdie, Michael R. Stratton, Xueqing Zou, Gu Kong, Jorunn E. Eyfjord, Elin Borgen, Se Jin Jang, Sandro Morganella, Hege G. Russnes, Alain Viari, Alastair M. Thompson, Dominik Glodzik, Helen Davies, Serena Nik-Zainal, Andrea L. Richardson, Anne Lise Børresen-Dale, The Wellcome Trust Sanger Institute [Cambridge], Department of Pathology [Dundee], Ninewells Hospital and Medical School [Dundee], University of Ulsan, Department of Pathology [Oslo], Oslo University Hospital [Oslo], University of Oslo (UiO), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Dana-Farber Cancer Institute [Boston], Department of Cancer Genetics [Oslo], Institute for Cancer Research [Oslo], Oslo University Hospital [Oslo]-Oslo University Hospital [Oslo], Department of Breast Surgical Oncology [Houston], The University of Texas M.D. Anderson Cancer Center [Houston], University of Iceland [Reykjavik], and Hanyang University
Subjects: 0301 basic medicine, APOBEC, Cancer Research, congenital, hereditary, and neonatal diseases and abnormalities, [SDV]Life Sciences [q-bio], Mutagenesis (molecular biology technique), Breast Neoplasms, Biology, DNA Mismatch Repair, complex mixtures, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, medicine, Humans, Gene, Whole genome sequencing, Genetics, Genome, Human, High-Throughput Nucleotide Sequencing, Cancer, DNA, Neoplasm, Sequence Analysis, DNA, medicine.disease, Lynch syndrome, digestive system diseases, 3. Good health, DNA Repair Enzymes, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Female, DNA mismatch repair
Abstract: Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 4755–62. ©2017 AACR.
Published: 2017

14. Landscape of somatic mutations in 560 breast cancer whole-genome sequences

Author: John W.M. Martens, Sandrine Boyault, David Jones, Stefania Tommasi, Jeong-Yeon Lee, Germán Fg Rodríguez-González, Inigo Martincorena, Sung-Min Ahn, Alastair M Thompson, Manasa Ramakrishna, Gilles Thomas, Helen Davies, Savitri Krishnamurthy, Stian Knappskog, Steven Van Laere, Lucy Stebbings, Andrea L. Richardson, Andrew Tutt, Anne Lise Børresen-Dale, Olafur Oa Stefansson, Sunil R. Lakhani, Michiel M. Smid, Gerrit Gk Hooijer, Young Seok Ju, Tari Ta King, Rebecca Shepherd, Luc Dirix, Xavier Pivot, Adam Butler, Aquila Fatima, Peter Pt Simpson, Serena Nik-Zainal, Sancha Martin, Hyung-Yong Kim, Hendrik G. Stunnenberg, Jos Jonkers, Michael R. Stratton, Jon W. Teague, Se Jin Jang, Sandro Morganella, Ville Mustonen, Moritz Gerstung, Gu Kong, Carlos Caldas, Anne Vincent-Salomon, Anieta M. Sieuwerts, Lucy R. Yates, Sarah O’Meara, Peter B. Vermeulen, Dominik Glodzik, Peter Van Loo, Naoto T. Ueno, Arie B. Brinkman, Stuart McLaren, Yang Li, Marc J. van de Vijver, Laura Van't Veer, P. Andrew Futreal, Markus Ringnér, Christos Sotiriou, Ewan Birney, Kamna Ramakrishnan, Miriam Ragle Aure, Johan Staaf, Jane E. Brock, Benita Kiat Tee Bk Tan, Alain Viari, Xueqing Zou, Anita Langerød, David C. Wedge, Hee Jin Lee, Christine Desmedt, Gilles Romieu, Paul N. Span, Jorunn E. Eyfjord, Annegien Broeks, Isabelle Treilleux, Åke Borg, Colin Ca Purdie, Ole Christian Lingjærde, Gert Van den Eynden, John A. Foekens, Serge Dronov, Andrew Menzies, Peter J. Campbell, Iris Pauporté, Ludmil B. Alexandrov, Keiran Raine, The Wellcome Trust Sanger Institute [Cambridge], Lund University [Lund], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Radboud university [Nijmegen], Oslo University Hospital Radiumhospitalet, University of Oslo (UiO), Gachon University Hospital, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Brigham and Women's Hospital [Boston], Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Breast Cancer Translational Research Laboratory, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Algemeen Ziekenhuis St Augustinus Oncology, Dana-Farber Cancer Institute [Boston], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Ulsan, NASA Johnson Space Center (JSC), NASA, University of Stuttgart, Esso UK Ltd, Department of Exploration, Esso UK Ltd, Department of Computer Science & Engineering [Riverside] (CSE), University of California [Riverside] (UCR), University of California-University of California, Department of Geriatric Medicine [Singapore] (Alexandra Hospital), Institut national du cancer [Boulogne] (INCA), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Department of Pathology [Dundee], Ninewells Hospital and Medical School [Dundee], Canary Institute for Cancer Research (ICIC), Department of Biochemistry and Physiology, Faculty of Health Sciences, University of Las Palmas de Gran Canaria (ULPGC), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Department of Medical Oncology [Rotterdam], Cancer Genomics Centre, University of Queensland [Brisbane], University of Iceland [Reykjavik], Beckman Research Institute [Duarte, CA], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Antwerp (UA), European Central Bank (ECB), European Central Bank, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Tumor Biology, Institut Curie [Paris], University of Cambridge [UK] (CAM), Division of Diagnostic Oncology, Netherlands Cancer Institute, Agendia BV, Breakthrough Breast Cancer Centre, London Institute of Cancer, University of Bergen (UiB), National Cancer Centre Singapore (NCCS), National Cancer Centre Singapore, Division of Molecular Biology, National Institutes of Natural Sciences, The Graduate University for Advanced Studies, Baobab, Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Department of Radiation Oncology 874, Radboud University Medical Center [Nijmegen], Department of Laboratory Medicine, Department Medical Oncology, Department of Pathology, Ospedale 'Mater Salutis', Goddard Earth Sciences and Technology and Research (GESTAR), NASA-Universities Space Research Association (USRA), Department of Molecular Biology [Nijmegen], Department of Organismic and Evolutionary Biology [Cambridge] (OEB), Harvard University [Cambridge], Department of Computing [London], Biomedical Image Analysis Group [London] (BioMedIA), Imperial College London-Imperial College London, Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Sagot, Marie-France, Radboud University [Nijmegen], University of California [Riverside] (UC Riverside), University of California (UC)-University of California (UC), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nik-Zainal, Serena [0000-0001-5054-1727], Zou, Xueqing [0000-0003-1143-1028], Caldas, Carlos [0000-0003-3547-1489], Apollo - University of Cambridge Repository, Medical Oncology, Harvard University, Fondation Synergie Lyon Cancer [Lyon], CCA -Cancer Center Amsterdam, Pathology, Erasmus University Medical Center [Rotterdam], University of Oslo ( UiO ), Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Netherlands Cancer Institute ( NKI ), Institut Jules Bordet, Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ), NASA Johnson Space Center ( JSC ), Department of Computer Science & Engineering [Riverside] ( CSE ), University of California [Riverside] ( UCR ), Institut national du cancer [Boulogne] ( INCA ), Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Department of Medical Oncology, Erasmus Medical Center Rotterdam, Josephine Nefkens Institute and Cancer Genomics Centre, University of Las Palmas de Gran Canaria ( ULPGC ), Institut de Recherche en Cancérologie de Montpellier ( IRCM - U1194 Inserm - UM ), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Erasmus MC, Beckman Research Institute, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University of Antwerp ( UA ), European Central Bank ( ECB ), U 830, Institut National de la Santé et de la Recherche Médicale, Institut Curie, University of Cambridge [UK] ( CAM ), University of Bergen ( UIB ), National Cancer Centre Singapore ( NCCS ), Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale ( ERABLE ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ), Goddard Earth Sciences and Technology and Research ( GESTAR ), NASA-Universities Space Research Association ( USRA ), Department of Organismic and Evolutionary Biology ( OEB ), and Biomedical Image Analysis Group [London] ( BioMedIA )
Subjects: 0301 basic medicine, DNA Replication, Male, Mutation rate, DNA repair, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, Biology, medicine.disease_cause, Genome, Cohort Studies, 03 medical and health sciences, Germline mutation, SDG 3 - Good Health and Well-being, Mutation Rate, medicine, Humans, Gene, Molecular Biology, Genetics, Mutation, Multidisciplinary, [ SDV ] Life Sciences [q-bio], Genome, Human, Recombinational DNA Repair, DNA, Neoplasm, Genomics, Oncogenes, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Mutagenesis, Human genome, Female, Engineering sciences. Technology
Abstract: Item does not contain fulltext We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
Published: 2016

15. A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers

Author: Marta Gut, Iris Pauporté, Cécile Mannina, Sancha Martin, Michael R. Stratton, Frédérique Penault-Llorca, Vincent Le Texier, Laurent Arnould, Pierre Saintigny, Marie-Christine Mathieu, P. Fumoleau, Xavier Pivot, Jean-François Deleuze, Hélène Blanché, Anthony Ferrari, Janice Kielbassa, Eskeatnaf Mulugeta, Olivier Tredan, Sandrine Boyault, Anne Vincent-Salomon, Thomas Bachelot, Emilie Thomas, Jean-Yves Pierga, Odette Mariani, Suzette Delaloge, Ivo Gut, Hervé Bonnefoi, Fabien Calvo, Frédéric Bibeau, Alain Viari, Serena Nik-Zainal, Anne-Sophie Sertier, Gilles Romieu, Maria Rios, Gaëtan MacGrogan, Jocelyne Jacquemier, Laurie Tonon, Gilles Thomas, Jean-Marc Ferrero, Isabelle Treilleux, Daniel Birnbaum, Catherine Bouteille, Carole Tarpin, Centre Léon Bérard [Lyon], Génétique et Biologie du Développement, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Gustave Roussy (IGR), Equipe de recherche sur les traitements individualisés des cancers (ERTICa), Université d'Auvergne - Clermont-Ferrand I (UdA), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Ressources Biologiques [Paris], Institut Curie [Paris], Département de pathologie, Physico-Chimie-Curie (PCC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Department of Medical Oncology [Lyon], UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, UNICANCER, Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Pôle de Chirurgie Oncologique générale, Gynécologique et Mammaire [Centre Antoine-Lacassagne], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chirurgie gynécologique, mammaire et réparatrice [Saint-Etienne], Clinique Mutualiste Chirurgicale [Saint-Étienne], Direction de la recherche [Gustave Roussy], Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), The Wellcome Trust Sanger Institute [Cambridge], Institut National du Cancer [Boulogne Billancourt] (INC), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) ( HOTE GREFFON ), Université de Franche-Comté ( UFC ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Validation et identification de nouvelles cibles en oncologie ( VINCO ), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Institut Gustave Roussy ( IGR ), Equipe de recherche sur les traitements individualisés des cancers ( ERTICa ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), UNICANCER - Institut régional du Cancer [Montpellier] ( ICM ), Institut Curie, Institut Bergonié - CRLCC Bordeaux, Physico-Chimie-Curie ( PCC ), Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut de Cancérologie de Lorraine - Alexis Vautrin ( ICL ), CRLCC Antoine Lacassagne, Centre de Recherche en Cancérologie de Marseille ( CRCM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université ( AMU ), Centre for Genomic Regulation [Barcelona] ( CRG ), Universitat Pompeu Fabra [Barcelona]-Centro Nacional de Analisis Genomico [Barcelona] ( CNAG ), Institut National du Cancer [Boulogne Billancourt] ( INC ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale ( ERABLE ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ), Nik-Zainal Abidin, Serena [0000-0001-5054-1727], Apollo - University of Cambridge Repository, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Sagot, Marie-France, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Institut Paoli Calmettes, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes-Aix Marseille Université ( AMU ), Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: 0301 basic medicine, DNA Copy Number Variations, Receptor, ErbB-2, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Breast Neoplasms, Biology, Genome, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Germline mutation, Gene duplication, medicine, Humans, Copy-number variation, skin and connective tissue diseases, Genetics, Multidisciplinary, Whole Genome Sequencing, [ SDV ] Life Sciences [q-bio], Gene Expression Profiling, Estrogen Receptor alpha, Gene Amplification, General Chemistry, Amplicon, medicine.disease, 3. Good health, Gene expression profiling, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Human genome, Female, Receptors, Progesterone, Transcriptome
Abstract: HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal–basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage–fusion–bridge mechanism., Breast cancer is separated into multiple subtypes based on the expression of HER2 and hormone receptors. Here, the authors report the whole genome sequence of 64 HER2 positive tumours and show that these can be further separated into four groups with different gene expression profiles and genomic features.
Published: 2016

16. Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration

Author: Stefania Tommasi, Johan Staaf, Ewan Birney, Steven Van Laere, Sunil R. Lakhani, Marcel Smid, Tari Ta King, Serena Nik-Zainal, Peter T. Simpson, Gert Van den Eynden, Andrea L. Richardson, Annegien Broeks, Adam A Butler, John A. Foekens, Alain Viari, Reno Debets, Gaëtan MacGrogan, Anne Lise Børresen-Dale, Colin A. Purdie, Mike M Stratton, Arie B. Brinkman, Hendrik G. Stunnenberg, Sancha Martin, Gilles Thomas, P. Andrew Futreal, Anne A van Galen, Carlos Caldas, Anne Vincent-Salomon, John W.M. Martens, Germán Fg Rodríguez-González, Anita Langerød, Christine Desmedt, Helen Davies, Aquila Fatima, Anieta M. Sieuwerts, Kim Berentsen, Jorunn J Eyford, Michelle van der Vlugt-Daane, Marc J. van de Vijver, Wendy Wj Prager-Van der Smissen, Alastair M Thompson, Stian Knappskog, Markus Ringnér, Carolien Ch van Deurzen, Paul N. Span, Marion E Meijer-Van Me Gelder, Roberto Salgado, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Breast Cancer Translational Research Laboratory, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), The Wellcome Trust Sanger Institute [Cambridge], Lund University [Lund], Radboud university [Nijmegen], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Dana-Farber Cancer Institute [Boston], Department of Medical Oncology, Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pathology [Dundee], Ninewells Hospital and Medical School [Dundee], University of Cambridge [UK] (CAM), Department of Radiation Oncology 874, Radboud University Medical Center [Nijmegen], Department of Laboratory Medicine, University of Queensland [Brisbane], Department Medical Oncology, University of Antwerp (UA), Department of Pathology, Ospedale 'Mater Salutis', Beckman Research Institute [Duarte, CA], University of Iceland [Reykjavik], Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Department of Tumor Biology, Institut Curie [Paris], MD Anderson Cancer Center [Houston], The University of Texas Health Science Center at Houston (UTHealth), University of Bergen (UiB), Esso UK Ltd, Department of Exploration, Esso UK Ltd, Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Baobab, Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Oslo University Hospital Radiumhospitalet, Department of Molecular Biology [Nijmegen], Sagot, Marie-France, Radboud University [Nijmegen], Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Medical Oncology, Pathology, Fondation Synergie Lyon Cancer [Lyon], CCA -Cancer Center Amsterdam, Lakhani, Sunil R [0000-0003-1879-2555], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Biomedical, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Genome, Article, General Biochemistry, Genetics and Molecular Biology, CDH1, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Basic Science, SDG 3 - Good Health and Well-being, Breast Cancer, Genetics, medicine, PTEN, 1112 Oncology and Carcinogenesis, Molecular Biology, Cancer, 0604 Genetics, Multidisciplinary, Oncogene, biology, Human Genome, GATA3, Médecine pathologie humaine, General Chemistry, Sciences bio-médicales et agricoles, medicine.disease, Cell Cycle Gene, 3. Good health, Cancérologie, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Engineering sciences. Technology
Abstract: A recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP53, PIK3CA, PTEN, CCND1 and CDH1. We find that CCND3 expression levels do not correlate with amplification, while increased GATA3 expression in mutant GATA3 cancers suggests GATA3 is an oncogene. In luminal cases the total number of substitutions, irrespective of type, associates with cell cycle gene expression and adverse outcome, whereas the number of mutations of signatures 3 and 13 associates with immune-response specific gene expression, increased numbers of tumour-infiltrating lymphocytes and better outcome. Thus, while earlier reports imply that the sheer number of somatic aberrations could trigger an immune-response, our data suggests that substitutions of a particular type are more effective in doing so than others., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2016

17. Ehrlichia ruminantium: genomic and evolutionary features

Author: Nathalie Vachiery, Roger Frutos, Dominique Martinez, Frédéric Boyer, and Alain Viari
Subjects: Séquence nucléotidique, animal structures, Pseudogene, Molecular Sequence Data, Ehrlichia, L73 - Maladies des animaux, Ehrlichia ruminantium, Genome, Conserved sequence, Evolution, Molecular, Intergenic region, Species Specificity, Tandem repeat, parasitic diseases, Gene, Conserved Sequence, Adaptabilité, Genetics, Génome, biology, Genetic Variation, biology.organism_classification, Infectious Diseases, Mutagenesis, Tandem Repeat Sequences, DNA, Intergenic, Parasitology, Genome, Bacterial
Abstract: Ehrlichia ruminantium is the causative agent of heartwater, an important tick-borne disease of livestock in Africa and the Caribbean that threatens the American mainland. The genome sequences of three strains of E. ruminantium have recently been published, revealing the presence of specific features related to genomic plasticity. E. ruminantium strains have traces of active genomic modifications, such as high substitution rates, truncated genes and the presence of pseudogenes and many tandem repeats. The most specific feature is the presence in all Ehrlichia of independent long-period tandem repeats, which are associated with expansion or contraction of intergenic regions.
Published: 2007

18. Comparative Genomics of Three Strains ofEhrlichia ruminantium

Author: Jacques Demaille, Nathalie Vachiery, Alain Viari, Dominique Martinez, Roger Frutos, Conchita Ferraz, Frédéric Boyer, Eric Coissac, Albert Bensaid, and Anne Morgat
Subjects: Comparative genomics, Genetics, 0303 health sciences, 030306 microbiology, General Neuroscience, Biology, Ehrlichia ruminantium, biology.organism_classification, Genome, General Biochemistry, Genetics and Molecular Biology, Conserved sequence, 03 medical and health sciences, Intergenic region, History and Philosophy of Science, Tandem repeat, Codon usage bias, Gene, 030304 developmental biology
Abstract: The tick-borne Rickettsiale Ehrlichia ruminantium (E. ruminantium) is the causative agent of heartwater in Africa and the Caribbean. Heartwater, responsible for major losses on livestock in Africa represents also a threat for the American mainland. Three complete genomes corresponding to two different groups of differing phenotypes, Gardel and Welgevonden, have been recently described. One genome (Erga) represents the Gardel group from Guadeloupe Island and two genomes (Erwo and Erwe) belong to the Welgevonden group. Erwo, isolated in South Africa, is the parental strain of Erwe, which was maintained for 18 years in Guadeloupe under different culture conditions than Erwo. The three strains display genomes of differing sizes with 1,499,920 bp, 1,512,977 bp, and 1,516,355 bp for Erga, Erwe, and Erwo, respectively. Gene sequences and order are highly conserved between the three strains, although several gene truncations could be pinpointed, most of them occurring within three regions of accumulated differences (RAD). E. ruminantium displays a strong leading/lagging compositional bias inducing a strand-specific codon usage. Finally, a striking feature of E. ruminantium is the presence of long intergenic regions containing tandem repeats. These repeats are at the origin of an active process, specific to E. ruminantium, of genome expansion/contraction based on the addition or removal of tandem units.
Published: 2006

19. Chemical and biological insecticides select distinct gene expression patterns in Aedes aegypti mosquito

Author: Guillaume Tetreau, Margot Paris, Muhammad Riaz, Laurence Després, Alain Viari, Aurélie Bonin, Frédéric Faucon, Rodolphe Poupardin, Renaud Stalinski, Jean-Philippe David, Stéphane Reynaud, Vincent Navratil, Laboratoire d'Ecologie Alpine (LECA), Université Joseph Fourier - Grenoble 1 (UJF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), 149 rue de Bercy, Institut de l'élevage (IDELE), Baobab, Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Institut des Matériaux Jean Rouxel (IMN), Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), EDF (EDF), Laboratoire Hubert Curien [Saint Etienne] (LHC), Institut d'Optique Graduate School (IOGS)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Institut des Sciences Analytiques (ISA), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS)-Institut d'Optique Graduate School (IOGS)
Subjects: 0106 biological sciences, Subject Areas: evolution, Insecticides, [SDV]Life Sciences [q-bio], Genes, Insect, Aedes aegypti, 01 natural sciences, 03 medical and health sciences, Immunity, Aedes, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], cross resistance, Bioassay, molecular biology, Animals, detoxification, Pest Control, Biological, Gene, Cross-resistance, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, Evolutionary Biology, biology, business.industry, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Gene Expression Profiling, Bacillus thuringiensis israelensis, biology.organism_classification, Agricultural and Biological Sciences (miscellaneous), immunity, 3. Good health, Biotechnology, Gene expression profiling, ecology Keywords: transcriptomics, 010602 entomology, Metabolic pathway, General Agricultural and Biological Sciences, business, [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis
Abstract: Worldwide evolution of mosquito resistance to chemical insecticides represents a major challenge for public health, and the future of vector control largely relies on the development of biological insecticides that can be used in combination with chemicals (integrated management), with the expectation that populations already resistant to chemicals will not become readily resistant to biological insecticides. However, little is known about the metabolic pathways affected by selection with chemical or biological insecticides. Here we show that Aedes aegypti , a laboratory mosquito strain selected with a biological insecticide ( Bacillus thuringiensis israelensis , Bti) evolved increased transcription of many genes coding for endopeptidases while most genes coding for detoxification enzymes were under-expressed. By contrast, in strains selected with chemicals, genes encoding detoxification enzymes were mostly over-expressed. In all the resistant strains, genes involved in immune response were under-transcribed, suggesting that basal immunity might be a general adjustment variable to compensate metabolic costs caused by insecticide selection. Bioassays generally showed no evidence for an increased susceptibility of selected strains towards the other insecticide type, and all chemical-resistant strains were as susceptible to Bti as the unselected parent strain, which is a good premise for sustainable integrated management of mosquito populations resistant to chemicals.
Published: 2014

20. Genetic diversity and lineage dynamic of dengue virus serotype 1 (DENV-1) in Cambodia

Author: Sirenda Vong, Ngan Chantha, Jeremy Farrar, Veasna Duong, Roger Frutos, Philippe Buchy, Alain Viari, Cameron P. Simmons, Matthew R. Henn, Bruce W. Birren, Laurent Gavotte, Vincent Deubel, Niall J. Lennon, Sivuth Ong, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Hospital for Tropical Diseases, Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), Université Montpellier 2 - Sciences et Techniques (UM2), An algorithmic view on genomes, cells, and environments (BAMBOO), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), National Center of Parasitology (CNM), National Malaria Center [Phnom Penh], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Interactions hôtes-vecteurs-parasites-environnement dans les maladies tropicales négligées dues aux trypanosomatides (UMR INTERTRYP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université de Bordeaux (UB), This study was funded in part by the Wellcome Trust (www.wellcome.ac.uk). Dr. Roger Frutos and Dr. Alain Viari were supported in part by the PHC Grant 20624 VK. We are very grateful to the Doctorate School SIBAGHE (University Montpellier 2) and the French Ministry of Foreign Affairs for providing scholarships supporting in part Dr. Veasna Duong, Duong V, Simmons C, Henn MR, Deubel V, Frutos R, Buchy P., Gavotte L, Viari A, Ong S, Chantha N, Lennon NJ, Birren BW, Vong S, Farrar JJ, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria), Université de Bordeaux (UB)-Institut de Recherche pour le Développement (IRD)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)
Subjects: Serotype, Genes, Viral, Lineage (evolution), viruses, genome sequence, Dengue virus, medicine.disease_cause, Dengue fever, Dengue, 0302 clinical medicine, Génétique des populations, Lignée, Child, Phylogeny, Genetics, 0303 health sciences, biology, virus diseases, 3. Good health, Flavivirus, Infectious Diseases, S50 - Santé humaine, Child, Preschool, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, RNA, Viral, Cambodia, Microbiology (medical), Adult, Séquence nucléotidique, Adolescent, 030231 tropical medicine, Molecular Sequence Data, Descendance, Genome, Viral, Microbiology, diversity, Evolution, Molecular, 03 medical and health sciences, Open Reading Frames, Young Adult, Variation génétique, Quantitative Trait, Heritable, Phylogenetics, medicine, Humans, Selection, Genetic, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Polymorphism, Genetic, Molecular epidemiology, DENV-1, Genetic Variation, Infant, Dengue Virus, biology.organism_classification, medicine.disease, Virology, Sérotype, Lineage dynamics, Selective sweep
Abstract: In Cambodia, dengue virus (DENV) was first isolated in 1963 and has become endemic with peak epidemic during raining season. Since 2000, the Dengue National Control Program has reported from 10,000 to 40,000 cases per year with fatality rates ranging from 0.7 to 1.7. All four dengue serotypes are found circulating in Cambodia with alternative predominance of serotypes DENV-2 and DENV-3. The DENV-1 represents from 5% to 20% of all circulating viruses, depending upon the year. In this work, 79 clinical strains of DENV-1 were isolated between 2000 and 2009 and their genome fully sequenced. Four distinct lineages with different dynamics were identified. The main evolutionary drive was negative selective pressure but each lineage was characterized by the presence of specific mutations acquired through evolution. Coexistence, extinction and replacement of lineages occurred over the 10-year period. Lineages 1, 2 and 3 were all detected since 2000–2002 and disappeared in 2003, 2004–2005 and 2007, respectively. Lineages 1 and 2 displayed different dynamics. Lineage 1 was very diverse whereas lineage 2 was very homogeneous. Lineage 4 which derived from lineage 3 in 2003 remained the only one at the end of the sampling period in 2008–2009 owing to a selective sweep. The lineages dynamic of DENV-1 viruses and consequences for molecular epidemiology are discussed.
Published: 2011

21. Abstract P6-07-13: New insights on HER2 amplification from the constitutional and somatic standpoints: Results from the ICGC and SIGNAL/Phare studies

Author: Pierre Saintigny, Gaëtan MacGrogan, D Birbaum, Xavier Pivot, V Letexier, G Romieux, Laurent Arnould, Alain Viari, Anne Vincent-Salomon, Iris Pauporté, S Boyault, A Ferrari, A-S Sertier, David Cox, Isabelle Treilleux, Janice Kielbassa, Emilie Thomas, and Laurie Tonon
Subjects: Genetics, Whole genome sequencing, Cancer Research, Genetic heterogeneity, Cancer, Genome-wide association study, Amplicon, Biology, medicine.disease_cause, medicine.disease, Genome, Breast cancer, Oncology, medicine, skin and connective tissue diseases, Carcinogenesis
Abstract: Background: HER2-positive (HER2+) breast cancers are defined by the amplification and/or overexpression of the human epidermal growth factor receptor (HER2/ERBB2) gene on chromosome region 17q12. Although anti-HER2 targeted therapies have greatly improved treatment of HER2+ breast cancer, the magnitude of benefit varies widely between patients. Deciphering the genomic and genetic heterogeneity of HER2+ breast cancer may provide a basis to better understand their natural history, opening new avenues of treatment. Methods: As part of the ICGC Breast Cancer Working Group effort, we combined whole genome sequencing and transcriptomic analyses of 64 HER2+ primary invasive carcinomas, and a genome wide association study (GWAS) of over 9.836 breast cancer patients in the prospective SIGNAL/PHARE cohort (NCT00381901 – RECF1098). Results: Using WGS data we precisely delineate the ERBB2 amplicon as a 106 kb region involving six genes and show that the amplification mechanism was consistent with breakage-fusion-bridge (BFB) cycles. Four RNA expression-based groups were identified, displaying specific genomic alterations in terms of amplification, rearrangements and mutations. On other hand, GWAS analyses failed to identify any constitutional variants associated with HER2 amplification. Discussion: By combining whole genome sequencing and expression analysis, we provide evidence showing that HER2+ tumours display considerably more molecular heterogeneity than previously reported. These results are reinforced with the lack of association between any genetic variants and HER2 amplification from GWAS analyses. Taken as a whole, these results suggest that HER2+ breast cancers do not represent per se a homogeneous subtype, but are distributed along the whole breast cancer spectrum, from ER-positive luminal to ER-negative basal phenotype. Genome alterations present in HER2+ tumors are in accordance with these phenotypes, and it is likely that the HER2 amplification is a secondary event in the course of tumorigenesis, not favored by any particular constitutional or somatic genetic variants. Citation Format: Vincent-Salomon A, Ferrari A, Pivot X, Macgrogan G, Arnould L, Treilleux I, Romieux G, Sertier A-S, Thomas E, Tonon L, Boyault S, Kielbassa J, Letexier V, Pauporte I, Birbaum D, Saintigny P, Cox D, Viari A. New insights on HER2 amplification from the constitutional and somatic standpoints: Results from the ICGC and SIGNAL/Phare studies. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-07-13.
Published: 2016

22. Evolutionary Role of Restriction/Modification Systems as Revealed by Comparative Genome Analysis

Author: Antoine Danchin, Eduardo P. C. Rocha, and Alain Viari
Subjects: Genome evolution, Genome, Viral, Genome, Bacteriophage, Evolution, Molecular, Genome, Archaeal, Genetics, Bacteriophages, Deoxyribonucleases, Type II Site-Specific, DNA Modification Methylases, Genetics (clinical), Comparative genomics, Mutualism (biology), Base Composition, biology, Bacteria, Palindrome, Nucleic Acid Hybridization, Sequence Analysis, DNA, biology.organism_classification, AT Rich Sequence, Archaea, Markov Chains, GC Rich Sequence, Restriction site, Evolutionary biology, Genome, Bacterial
Abstract: Type II restriction modification systems (RMSs) have been regarded either as defense tools or as molecular parasites of bacteria. We extensively analyzed their evolutionary role from the study of their impact in the complete genomes of 26 bacteria and 35 phages in terms of palindrome avoidance. This analysis reveals that palindrome avoidance is not universally spread among bacterial species and that it does not correlate with taxonomic proximity. Palindrome avoidance is also not universal among bacteriophage, even when their hosts code for RMSs, and depends strongly on the genetic material of the phage. Interestingly, palindrome avoidance is intimately correlated with the infective behavior of the phage. We observe that the degree of palindrome and restriction site avoidance is significantly and consistently less important in phages than in their bacterial hosts. This result brings to the fore a larger selective load for palindrome and restriction site avoidance on the bacterial hosts than on their infecting phages. It is then consistent with a view where type II RMSs are considered as parasites possibly at the verge of mutualism. As a consequence, RMSs constitute a nontrivial third player in the host–parasite relationship between bacteria and phages.
Published: 2001

23. Searching genomes for sequences with the potential to form intrastrand triple helices

Author: Alain Viari, Paula Rodrigues Hoyne, Lindsay M Edwards, and L. James Maher
Subjects: DNA, Bacterial, Hot Temperature, Databases, Factual, Stereochemistry, Molecular Sequence Data, Sequence alignment, Regulatory Sequences, Nucleic Acid, Biology, Nucleic Acid Denaturation, Pattern Recognition, Automated, chemistry.chemical_compound, Structural Biology, Escherichia coli, Magnesium, Molecular Biology, Genetics, Base Sequence, Computational Biology, RNA, Nucleic Acid Strand, DNA, Genomics, Chromosomes, Bacterial, Hydrogen-Ion Concentration, Physical Chromosome Mapping, Oligodeoxyribonucleotides, chemistry, Genes, Bacterial, Helix, Nucleic acid, Nucleic Acid Conformation, Spectrophotometry, Ultraviolet, Sequence Alignment, Algorithms, Genome, Bacterial, Software, Triple helix
Abstract: The canonical double-helix form of DNA is thought to predominate both in dilute solution and in living cells. Sequence-dependent fluctuations in local DNA shape occur within the double helix. Besides these relatively modest variations in shape, more extreme and remarkable structures have been detected in which some bases become unpaired. Examples include unusual three-stranded structures such as H-DNA. Certain RNA and DNA strands can also fold onto themselves to form intrastrand triplexes. Although they have been extensively studied in vitro, it remains unknown whether nucleic acid triplexes play natural roles in cells. If natural nucleic acid triplexes were identified in cells, much could be learned by examining the formation, stabilization, and function of such structures. With these goals in mind, we adapted a pattern-recognition program to search genetic databases for a type of potential triplex structure whose presence in genomes has not been previously investigated. We term these sequences Potential Intrastrand Triplex (PIT) elements. The formation of an intrastrand triplex requires three consecutive sequence domains with appropriate symmetry along a single nucleic acid strand. It is remarkable that we discovered multiple copies of sequence elements with the potential to form one particular class of intrastrand triplexes in the fully sequenced genomes of several bacteria. We then focused on the characterization of the 25 copies of a particular approximately 37 nt PIT sequence detected in Escherichia coli. Through biochemical studies, we demonstrate that an isolated DNA strand from this family of E. coli PIT elements forms a stable intrastrand triplex at physiological temperature and pH in the presence of physiological concentrations of Mg(2+).
Published: 2000

24. Implication of gene distribution in the bacterial chromosome for the bacterial cell factory

Author: Ivan Moszer, Antoine Danchin, Pascale Guerdoux-Jamet, Alain Viari, and Eduardo P. C. Rocha
Subjects: Genetics, Bacteria, Models, Genetic, In silico, Circular bacterial chromosome, Gene Expression, Bioengineering, Genomics, General Medicine, Genome project, Bacterial genome size, Chromosomes, Bacterial, Biology, Applied Microbiology and Biotechnology, Genome, Cell Compartmentation, Genes, Bacterial, Operon, Codon, Gene, Genome, Bacterial, Biotechnology, Genomic organization
Abstract: As bacterial genome sequences accumulate, more and more pieces of data suggest that there is a significant correlation between the distribution of genes along the chromosome and the physical architecture of the cell, suggesting that the map of the cell is in the chromosome. Considering sequences and experimental data indicative of cell compartmentalisation, mRNA folding and turnover, as well as known structural features of protein and membrane complexes, we show that preliminary in silico analysis of whole genome sequences strongly substantiates this hypothesis. If there is a correlation between the genome sequence and the cell architecture, it must derive from some selection pressure in the organisms growing in the wild. As a consequence, the underlying constraints should be optimised in genetically modified organisms if one is to expect high product yields. Consequences in terms of gene expression for biotechnology are straightforward: knocking genes out and in genomes should not be randomly performed, but should follow the rules of chromosome organisation.
Published: 2000

25. Detecting and Analyzing DNA Sequencing Errors: Toward a Higher Quality of the Bacillus subtilis Genome Sequence

Author: Alain Viari, Antoine Danchin, Claudine Médigue, and Matthias Rose
Subjects: DNA, Bacterial, Quality Control, Whole genome sequencing, Genetics, Sequence analysis, DNA Mutational Analysis, Frameshifting, Ribosomal, Sequence Analysis, DNA, Genome project, Biology, DNA sequencing, Sequence-tagged site, Methods, Primer walking, Human genome, Gene, Genome, Bacterial, Software, Genetics (clinical), Bacillus subtilis
Abstract: During the determination of a DNA sequence, the introduction of artifactual frameshifts and/or in-frame stop codons in putative genes can lead to misprediction of gene products. Detection of such errors with a method based on protein similarity matching is only possible when related sequences are available in databases. Here, we present a method to detect frameshift errors in DNA sequences that is based on the intrinsic properties of the coding sequences. It combines the results of two analyses, the search for translational initiation/termination sites and the prediction of coding regions. This method was used to screen the complete Bacillus subtilisgenome sequence and the regions flanking putative errors were resequenced for verification. This procedure allowed us to correct the sequence and to analyze in detail the nature of the errors. Interestingly, in several cases in-frame termination codons or frameshifts were not sequencing errors but confirmed to be present in the chromosome, indicating that the genes are either nonfunctional (pseudogenes) or subject to regulatory processes such as programmed translational frameshifts. The method can be used for checking the quality of the sequences produced by any prokaryotic genome sequencing project.
Published: 1999

26. Analysis of long repeats in bacterial genomes reveals alternative evolutionary mechanisms in Bacillus subtilis and other competent prokaryotes

Author: Antoine Danchin, Alain Viari, and Eduardo P. C. Rocha
Subjects: Zoology, Computational biology, Bacillus subtilis, Bacterial genome size, Genome, DNA sequencing, Evolution, Molecular, chemistry.chemical_compound, Mycoplasma, Species Specificity, Escherichia coli, Genetics, Insertion sequence, Molecular Biology, Genome size, Ecology, Evolution, Behavior and Systematics, Repetitive Sequences, Nucleic Acid, Models, Genetic, biology, Methanobacterium, Chromosome, biology.organism_classification, Antigenic Variation, Prokaryotic Cells, chemistry, Genome, Bacterial, DNA
Abstract: Prokaryotic genomes seem to be optimized toward compactness and have therefore been thought to lack long redundant DNA sequences. However, we identified a large number of long strict repeats in eight prokaryotic complete genomes and found that their density is negatively correlated with genome size. A detailed analysis of the long repeats present in the genome of Bacillus subtilis revealed a very strict constraint on the spatial distribution of repeats in this genome. We interpret this as the hallmark of selection processes leading to the addition of new genetic information. Such addition is independent of insertion sequences and relies on the nonspecific DNA uptake by the competent cell and its subsequent integration in the chromosome in a circular form through a Campbell-like mechanism. Similar patterns are found in other competent genomes of Gram-negative bacteria and Archaea, suggesting a similar evolutionary mechanism. The correlation of the spatial distribution of repeats and the absence of insertion sequences in a genome may indicate, in the framework of our model, that mechanisms aiming at their avoidance/elimination have been developed.
Published: 1999

27. A phenotypic and mechanistic perspective on heterogeneity of HER2-positive breast cancers

Author: Alain Viari, Anne Vincent-Salomon, Pierre Saintigny, Iris Pauporté, Xavier Pivot, Daniel Birnbaum, Anthony Ferrari, and Anne-Sophie Sertier
Subjects: 0301 basic medicine, Genetics, Cancer Research, Chromothripsis, Human epidermal growth factor, Cell of origin, Perspective (graphical), Biology, medicine.disease, Phenotype, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Gene expression, Cancer research, medicine, Molecular Medicine, HER2 Amplification, skin and connective tissue diseases, Author's View
Abstract: Analysis of gene expression and whole-genome features of 64 human epidermal growth factor 2 (HER2)-positive breast tumors supports the idea that their intrinsic heterogeneity actually reflects their cell of origin, suggesting that HER2 amplification is an embedded event in the natural history of these tumors. Possible mechanisms for this event involve breakage-fusion-bridge and chromothripsis.
Published: 2016

28. UniPathway: a resource for the exploration and annotation of metabolic pathways

Author: Alain Viari, Kristian B. Axelsen, Anne Morgat, Lydie Bougueleret, Guillaume Keller, Ioannis Xenarios, Amos Marc Bairoch, Alan Bridge, Eric Coissac, Elisabeth Coudert, An algorithmic view on genomes, cells, and environments (BAMBOO), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Swiss-Prot Group, Swiss Institute of Bioinformatics [Genève] (SIB), Laboratoire d'Ecologie Alpine (LECA), Université Joseph Fourier - Grenoble 1 (UJF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Vital-IT, European Project: 247073,EC:FP7:ERC,ERC-2009-AdG,SISYPHE(2010), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria), and Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])
Subjects: Databases, Factual, Computational biology, Biology, Bioinformatics, 03 medical and health sciences, Annotation, Resource (project management), Controlled vocabulary, Databases, Protein, Enzymes/metabolism, Lysine/biosynthesis, Metabolic Networks and Pathways, Molecular Sequence Annotation, Genetics, ddc:576, KEGG, 030304 developmental biology, 0303 health sciences, Lysine, 030302 biochemistry & molecular biology, MetaCyc, Articles, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Enzymes, Metabolic pathway, UniProt, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: International audience; UniPathway (http://www.unipathway.org) is a fully manually curated resource for the representation and annotation of metabolic pathways. UniPathway provides explicit representations of enzyme-catalyzed and spontaneous chemical reactions, as well as a hierarchical representation of metabolic pathways. This hierarchy uses linear subpathways as the basic building block for the assembly of larger and more complex pathways, including species-specific pathway variants. All of the pathway data in UniPathway has been extensively cross-linked to existing pathway resources such as KEGG and MetaCyc, as well as sequence resources such as the UniProt KnowledgeBase (UniProtKB), for which UniPathway provides a controlled vocabulary for pathway annotation. We introduce here the basic concepts underlying the UniPathway resource, with the aim of allowing users to fully exploit the information provided by UniPathway.
Published: 2012

29. ecoPrimers: inference of new DNA barcode markers from whole genome sequence analysis

Author: François Pompanon, Tiayyba Riaz, Wasim Shehzad, Pierre Taberlet, Eric Coissac, Alain Viari, Laboratoire d'Ecologie Alpine (LECA), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), An algorithmic view on genomes, cells, and environments (BAMBOO), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria), Université Joseph Fourier - Grenoble 1 (UJF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), and Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0106 biological sciences, Genetic Markers, Sequence analysis, Genomics, Bacterial genome size, Computational biology, Biology, Barcode, 010603 evolutionary biology, 01 natural sciences, DNA barcoding, Genome, Polymerase Chain Reaction, law.invention, 03 medical and health sciences, law, Genetics, Animals, DNA Barcoding, Taxonomic, Data Mining, Genome, Chloroplast, 030304 developmental biology, DNA Primers, 0303 health sciences, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Genetic marker, Genome, Mitochondrial, Vertebrates, Methods Online, Identification (biology), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Algorithms, Genome, Bacterial, Software
Abstract: International audience; Using non-conventional markers, DNA metabarcoding allows biodiversity assessment from complex substrates. In this article, we present ecoPrimers, a software for identifying new barcode markers and their associated PCR primers. ecoPrimers scans whole genomes to find such markers without a priori knowledge. ecoPrimers optimizes two quality indices measuring taxonomical range and discrimination to select the most efficient markers from a set of reference sequences, according to specific experimental constraints such as marker length or specifically targeted taxa. The key step of the algorithm is the identification of conserved regions among reference sequences for anchoring primers. We propose an efficient algorithm based on data mining, that allows the analysis of huge sets of sequences. We evaluate the efficiency of ecoPrimers by running it on three different sequence sets: mitochondrial, chloroplast and bacterial genomes. Identified barcode markers correspond either to barcode regions already in use for plants or animals, or to new potential barcodes. Results from empirical experiments carried out on a promising new barcode for analyzing vertebrate diversity fully agree with expectations based on bioinformatics analysis. These tests demonstrate the efficiency of ecoPrimers for inferring new barcodes fitting with diverse experimental contexts. ecoPrimers is available as an open source project at: http://www.grenoble.prabi.fr/trac/ecoPrimers.
Published: 2011

30. Innovative approach for transcriptomic analysis of obligate intracellular pathogen: selective capture of transcribed sequences of Ehrlichia ruminantium

Author: Loïc Emboulé, France Daigle, Damien F Meyer, Bernard Mari, Valérie Pinarello, Christian Sheikboudou, Virginie Magnone, Roger Frutos, Alain Viari, Pascal Barbry, Dominique Martinez, Thierry Lefrançois, Nathalie Vachiéry, Emboulé, Loïc, Vachiery, Nathalie, Contrôle des maladies animales exotiques et émergentes (UMR CMAEE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA), Université de Montréal (UdeM), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Computer science and genomics (HELIX), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), European Union, INRA, CIRAD, 'Fonds France-Canada pour la Recherche', and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
Subjects: Transcription, Genetic, [SDV]Life Sciences [q-bio], Rickettsiales, Methodology article, L73 - Maladies des animaux, Genome, Pathogénèse, Expression des gènes, Ehrlichia ruminantium, Pathogen, Cells, Cultured, 2. Zero hunger, Genetics, 0303 health sciences, biology, Ehrlichia, lcsh:Cytology, Goats, Amblyomma variegatum, DNA, Bacterial, Arn messager, DNA, Complementary, Séquence nucléotidique, Méthodologie, lcsh:QH426-470, Ruminant, Pouvoir pathogène, Relation hôte pathogène, Agent pathogène, 03 medical and health sciences, parasitic diseases, Animals, lcsh:QH573-671, Gene, Molecular Biology, 030304 developmental biology, Génie génétique, Bovin, Obligate, 030306 microbiology, Transcription génique, Intracellular parasite, Gene Expression Profiling, Sequence Analysis, DNA, biology.organism_classification, lcsh:Genetics, Cattle, U30 - Méthodes de recherche
Abstract: Background Whole genome transcriptomic analysis is a powerful approach to elucidate the molecular mechanisms controlling the pathogenesis of obligate intracellular bacteria. However, the major hurdle resides in the low quantity of prokaryotic mRNAs extracted from host cells. Our model Ehrlichia ruminantium (ER), the causative agent of heartwater, is transmitted by tick Amblyomma variegatum. This bacterium affects wild and domestic ruminants and is present in Sub-Saharan Africa and the Caribbean islands. Because of its strictly intracellular location, which constitutes a limitation for its extensive study, the molecular mechanisms involved in its pathogenicity are still poorly understood. Results We successfully adapted the SCOTS method (Selective Capture of Transcribed Sequences) on the model Rickettsiales ER to capture mRNAs. Southern Blots and RT-PCR revealed an enrichment of ER's cDNAs and a diminution of ribosomal contaminants after three rounds of capture. qRT-PCR and whole-genome ER microarrays hybridizations demonstrated that SCOTS method introduced only a limited bias on gene expression. Indeed, we confirmed the differential gene expression between poorly and highly expressed genes before and after SCOTS captures. The comparative gene expression obtained from ER microarrays data, on samples before and after SCOTS at 96 hpi was significantly correlated (R2 = 0.7). Moreover, SCOTS method is crucial for microarrays analysis of ER, especially for early time points post-infection. There was low detection of transcripts for untreated samples whereas 24% and 70.7% were revealed for SCOTS samples at 24 and 96 hpi respectively. Conclusions We conclude that this SCOTS method has a key importance for the transcriptomic analysis of ER and can be potentially used for other Rickettsiales. This study constitutes the first step for further gene expression analyses that will lead to a better understanding of both ER pathogenicity and the adaptation of obligate intracellular bacteria to their environment.
Published: 2009

31. PepLine: A Software Pipeline for High-Throughput Direct Mapping of Tandem Mass Spectrometry Data on Genomic Sequences

Author: Jérôme Garin, Thierry Vermat, Marielle Vigouroux, Marianne Tardif, Romain Cahuzac, Christophe Bruley, Erwan Reguer, Yves Vandenbrouck, Myriam Ferro, Alain Viari, Estelle Nugues, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire d'étude de la dynamique des protéomes (LEDyP), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), John Innes Centre [Norwich], Biotechnology and Biological Sciences Research Council (BBSRC), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: Chloroplasts, [SDV]Life Sciences [q-bio], Molecular Sequence Data, [INFO.INFO-DS]Computer Science [cs]/Data Structures and Algorithms [cs.DS], Arabidopsis, Computational biology, Biology, Tandem mass spectrometry, Proteomics, 01 natural sciences, Biochemistry, Genome, Mass Spectrometry, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Coding region, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, ORFS, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, Base Sequence, Arabidopsis Proteins, 010401 analytical chemistry, Peptide sequence tag, General Chemistry, Genome project, 0104 chemical sciences, genomic DNA, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Peptides, Sequence Alignment, Algorithms, Software
Abstract: PepLine is a fully automated software which maps MS/MS fragmentation spectra of trypsic peptides to genomic DNA sequences. The approach is based on Peptide Sequence Tags (PSTs) obtained from partial interpretation of QTOF MS/MS spectra (first module). PSTs are then mapped on the six-frame translations of genomic sequences (second module) giving hits. Hits are then clustered to detect potential coding regions (third module). Our work aimed at optimizing the algorithms of each component to allow the whole pipeline to proceed in a fully automated manner using raw nucleic acid sequences (i.e., genomes that have not been "reduced" to a database of ORFs or putative exons sequences). The whole pipeline was tested on controlled MS/MS spectra sets from standard proteins and from Arabidopsis thaliana envelope chloroplast samples. Our results demonstrate that PepLine competed with protein database searching softwares and was fast enough to potentially tackle large data sets and/or high size genomes. We also illustrate the potential of this approach for the detection of the intron/exon structure of genes.
Published: 2008

32. Differential strain-specific diagnosis of the heartwater agent: Ehrlichia ruminantium

Author: Thierry Lefrançois, Hassane Adakal, Frédéric Boyer, Nathalie Vachiery, Conchita Ferraz, Eric Coissac, Alain Viari, Gaël Darren Maganga, Frédéric Stachurski, Albert Bensaid, Roger Frutos, Jacques Demaille, Yane Kandassamy, Dominique Martinez, Anne Morgat, Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Computer science and genomics (HELIX), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Inconnu, Rétrovirus et Pathologie Comparée (RPC), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL), and ProdInra, Migration
Subjects: Identification, [SDV]Life Sciences [q-bio], L73 - Maladies des animaux, Genome, Mice, Ehrlichia ruminantium, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Geography, biology, Ehrlichia, Goats, Strain (biology), Phenotype, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, Provenance, Female, Heartwater Disease, DNA, Bacterial, Microbiology (medical), animal structures, Séquence nucléotidique, Cattle Diseases, Microbiology, 03 medical and health sciences, Species Specificity, Animals, Diagnostic, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Whole genome sequencing, Comparative genomics, Génie génétique, [SDV.GEN]Life Sciences [q-bio]/Genetics, Sheep, Génome, 030306 microbiology, biology.organism_classification, Maladie bactérienne, Cattle, Genome, Bacterial
Abstract: Ehrlichia ruminantium is the causative agent of heartwater, a major tick-borne disease of livestock in Africa introduced in the Caribbean and threatening to emerge and spread in the American mainland. Complete genome sequencing was done for two isolates of E. ruminantium of differing phenotype, isolates Gardel (Erga) from Guadeloupe Island and Welgevonden (Erwe) originating from South Africa and maintained in Guadeloupe. The type strain of E. ruminantium (Erwo), previously isolated and sequenced in South Africa; is identical to Erwe with respect to target genes. They make the Erwe/Erwo complex. Comparative analysis of the genomes shows the presence of 49 unique CDS and 28 truncated CDS differentiating Erga from Erwe/Erwo. Three regions of accumulated differences (RAD) acting as mutational hot spots were identified in E. ruminantium. Ten CDS, six unique CDS and four truncated CDS corresponding to major genomic changes (deletions or extensive mutations) were considered as targets for differential diagnosis on four isolates of E. ruminantium: Erga, Erwe/Erwo, Senegal and Umpala. Pairs of PCR primers were developed for each target gene. PCR analysis of the target genes generated strain-specific patterns on Erga and Erwe/Erwo as predicted by comparative genomics, but also for isolates Senegal and Umpala. The target genes identified by bacterial comparative genomics are shown to be highly efficient for strain-specific PCR diagnosis of E. ruminantium and further vaccine management tools.
Published: 2008

33. Comparative genomic analysis of three strains of Ehrlichia ruminantium reveals an active process of genome size plasticity

Author: Nathalie Vachiery, Alain Viari, Albert Bensaid, Roger Frutos, Sophie Eychenié, Eric Coissac, Conchita Ferraz, Dominique Martinez, Isabelle Chantal, Jacques Demaille, Yane Kandassamy, Anne Morgat, Computer science and genomics (HELIX), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Genomics and Proteomics, Molecular Sequence Data, Ehrlichia ruminantium, L73 - Maladies des animaux, Microbiology, Genome, Evolution, Molecular, 03 medical and health sciences, Intergenic region, Tandem repeat, Species Specificity, Gene Order, Anaplasma, L50 - Physiologie et biochimie animales, Molecular Biology, Conserved Sequence, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 2. Zero hunger, Genetics, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, 030306 microbiology, Ehrlichia, Genetic Variation, biology.organism_classification, Phenotype, Ehrlichiaceae, Mutagenesis, Tandem Repeat Sequences, Rickettsiales, Genome, Bacterial
Abstract: Ehrlichia ruminantium is the causative agent of heartwater, a major tick-borne disease of livestock in Africa that has been introduced in the Caribbean and is threatening to emerge and spread on the American mainland. We sequenced the complete genomes of two strains of E. ruminantium of differing phenotypes, strains Gardel (Erga; 1,499,920 bp), from the island of Guadeloupe, and Welgevonden (Erwe; 1,512,977 bp), originating in South Africa and maintained in Guadeloupe in a different cell environment. Comparative genomic analysis of these two strains was performed with the recently published parent strain of Erwe (Erwo) and other Rickettsiales ( Anaplasma , Wolbachia , and Rickettsia spp.). Gene order is highly conserved between the E. ruminantium strains and with A. marginale . In contrast, there is very little conservation of gene order with members of the Rickettsiaceae . However, gene order may be locally conserved, as illustrated by the tuf operons. Eighteen truncated protein-encoding sequences (CDSs) differentiate Erga from Erwe / Erwo, whereas four other truncated CDSs differentiate Erwe from Erwo. Moreover, E. ruminantium displays the lowest coding ratio observed among bacteria due to unusually long intergenic regions. This is related to an active process of genome expansion/contraction targeted at tandem repeats in noncoding regions and based on the addition or removal of ca. 150-bp tandem units. This process seems to be specific to E. ruminantium and is not observed in the other Rickettsiales .
Published: 2006

34. The complete genome sequence of the murine respiratory pathogen Mycoplasma pulmonis

Author: Delphine Samson, Ivan Moszer, Isabelle Chambaud, Alain Blanchard, Eduardo P. C. Rocha, Kevin Dybvig, Stéphane Ferris, Frédérique Galisson, Alain Viari, Henri Wróblewski, Roland Heilig, Valérie Barbe, Génomique, développement et pouvoir pathogène (GD2P), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA), Oncologie virale, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Ressources en Information Scientifique (CeRIS), Institut Pasteur [Paris] (IP), Régulation de l'Expression Génétique (REG), University of Alabama at Birmingham [ Birmingham] (UAB), Université de Rennes (UR), Computer science and genomics (HELIX), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Atelier de BioInformatique (ABI), Université Pierre et Marie Curie - Paris 6 (UPMC), This work was funded by the Institut Pasteur, Genoscope, INRA, Région Aquitaine and the Université Victor Segalen Bordeaux 2. It was also supported in part by the US Public Health Service grant AI41113 to K.D. from the National Institutes of Health., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)
Subjects: Sequence analysis, Lipoproteins, Molecular Sequence Data, Respiratory System, Replication Origin, medicine.disease_cause, Genome, Article, Evolution, Molecular, 03 medical and health sciences, Mice, Open Reading Frames, Mycoplasma, Genetics, medicine, Animals, Humans, Genomic library, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Gene, 030304 developmental biology, Repetitive Sequences, Nucleic Acid, Whole genome sequencing, Recombination, Genetic, 0303 health sciences, Antigens, Bacterial, Base Composition, Genomic Library, Internet, Polymorphism, Genetic, biology, Virulence, 030306 microbiology, Computational Biology, biology.organism_classification, RNA, Bacterial, Genetic Code, Mutation, Mollicutes, Mycoplasma pulmonis, Codon, Terminator
Abstract: International audience; Mycoplasma pulmonis is a wall-less eubacterium belonging to the Mollicutes (trivial name, mycoplasmas) and responsible for murine respiratory diseases. The genome of strain UAB CTIP is composed of a single circular 963 879 bp chromosome with a G + C content of 26.6 mol%, i.e. the lowest reported among bacteria, Ureaplasma urealyticum apart. This genome contains 782 putative coding sequences (CDSs) covering 91.4% of its length and a function could be assigned to 486 CDSs whilst 92 matched the gene sequences of hypothetical proteins, leaving 204 CDSs without significant database match. The genome contains a single set of rRNA genes and only 29 tRNAs genes. The replication origin oriC was localized by sequence analysis and by using the G + C skew method. Sequence polymorphisms within stretches of repeated nucleotides generate phase-variable protein antigens whilst a recombinase gene is likely to catalyse the site-specific DNA inversions in major M.pulmonis surface antigens. Furthermore, a hemolysin, secreted nucleases and a glyco-protease are predicted virulence factors. Surprisingly, several of the genes previously reported to be essential for a self-replicating minimal cell are missing in the M.pulmonis genome although this one is larger than the other mycoplasma genomes fully sequenced until now.
Published: 2001

35. Analysis of intrachromosomal duplications in yeast Saccharomyces cerevisiae: a possible model for their origin

Author: Eric Coissac, Pierre Netter, Guillaume Achaz, and Alain Viari
Subjects: Genetics, biology, Models, Genetic, Inverted repeat, Saccharomyces cerevisiae, Fungal genetics, biology.organism_classification, Positive correlation, Genome, Yeast, Evolution, Molecular, Gene Duplication, Gene duplication, Direct repeat, Chromosomes, Fungal, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Repetitive Sequences, Nucleic Acid
Abstract: The complete genome of the yeast Saccharomyces cerevisiae was investigated for intrachromosomal duplications at the level of nucleotide sequences. The analysis was performed by looking for long approximate repeats (from 30 to 3,885 bp) present on each of the chromosomes. We show that direct and inverted repeats exhibit very different characteristics: the two copies of direct repeats are more similar and longer than those of inverted repeats. Furthermore, contrary to the inverted repeats, a large majority of direct repeats appear to be closely spaced. The distance (delta) between the two copies is generally smaller than 1 kb. Further analysis of these "close direct repeats" shows a negative correlation between delta and the percentage of identity between the two copies, and a positive correlation between delta and repeat length. Moreover, contrary to the other categories of repeats, close direct repeats are mostly located within coding sequences (CDSs). We propose two hypotheses in order to interpret these observations: first, the deletion/conversion rate is negatively correlated with delta; second, there exists an active duplication mechanism which continuously creates close direct repeats, the other intrachromosomal repeats being the result, by chromosomal rearrangements of these "primary repeats."
Published: 2000

36. Universal replication biases in bacteria

Author: Antoine Danchin, Eduardo P. C. Rocha, and Alain Viari
Subjects: chemistry.chemical_classification, Genetics, DNA Replication, Bacteria, Models, Genetic, Circular bacterial chromosome, DNA replication, GC skew, Replication Origin, Biology, Chromosomes, Bacterial, Microbiology, Amino acid, chemistry, Codon usage bias, Amino Acids, Synonymous substitution, Codon, Molecular Biology, Gene, Sequence (medicine)
Abstract: Analysis of 15 complete bacterial chromosomes revealed important biases in gene organization. Strong compositional asymmetries between the genes lying on the leading versus lagging strands were observed at the level of nucleotides, codons and, surprisingly, amino acids. For some species, the bias is so high that the sole knowledge of a protein sequence allows one to predict with almost no errors whether the gene is transcribed from one strand or the other. Furthermore, we show that these biases are not species specific but appear to be universal. These findings may have important consequences in our understanding of fundamental biological processes in bacteria, such as replication fidelity, codon usage in genes and even amino acid usage in proteins.
Published: 1999

37. Oligonucleotide bias in Bacillus subtilis: general trends and taxonomic comparisons

Author: Alain Viari, Eduardo P. C. Rocha, and Antoine Danchin
Subjects: Genetics, DNA, Bacterial, Methanococcus, Base Composition, biology, Base Sequence, Palindrome, Oligonucleotides, Bacillus subtilis, biology.organism_classification, Genome, DNA Restriction-Modification Enzymes, Markov Chains, Restriction site, chemistry.chemical_compound, chemistry, Gene, DNA, Genome, Bacterial, Research Article
Abstract: We present a general analysis of oligonucleotide usage in the complete genome of Bacillus subtilis . Several datasets were built in order to assign various biological contexts to the biased use of words and to reveal local asymmetries in word usage that may be coupled with replication, the control of gene expression and the restriction/modification system. This analysis was complemented by cross-comparisons with the complete genomes of Escherichia coli , Haemophilus influenzae and Methanococcus jannaschii . We have observed a large number of biased oligonucleotides for words of size up to 8, throughout the datasets and species, indicating that such long strict words play an important role as biological signals. We speculate that some of them are involved in interactions with DNA and/or RNA polymerases. An extensive analysis of palindrome abundances and distributions provides the surprising result that prophage-like elements embedded in the genome exhibit a smaller avoidance of restriction sites. This may reinforce a recently proposed hypothesis of a selfish gene phenomena in the transfer of restriction/modification systems in bacteria.
Published: 1998

38. Pairwise and multiple identification of three-dimensional common substructures in proteins

Author: Henri Soldano, Alain Viari, Vincent Escalier, and Joël Pothier
Subjects: Models, Molecular, Biological data, Branch and bound, Computers, Molecular Sequence Data, Exponential function, Globins, Protein Structure, Tertiary, Combinatorics, Set (abstract data type), Computational Mathematics, Identification (information), Computational Theory and Mathematics, Modeling and Simulation, Multiple comparisons problem, Core (graph theory), Genetics, Animals, Pairwise comparison, Amino Acid Sequence, Molecular Biology, Sequence Alignment, Algorithms, Software, Mathematics
Abstract: In this paper, we present an algorithm to find three-dimensional substructures common to two or more molecules. The basic algorithm is devoted to pairwise structural comparison. Given two sets of atomic coordinates, it finds the largest subsets of atoms which are "similar" in the sense that all internal distances are approximately conserved. The basic idea of the algorithm is to recursively build subsets of increasing sizes, combining two sets of size k to build a set of size k + 1. The algorithm can be used "as is" for small molecules or local parts of proteins (about 30 atoms). When a high number of atoms is involved, we use a two step procedure. First we look for common "local" fragments by using the previous algorithm, and then we gather these fragments by using a Branch and Bound technique. We also extend the basic algorithm to perform multiple comparisons, by using one of the structures as a reference point (pivot) to which all other structures are compared. The solution is the largest subsets of atoms common to the pivot and at least q other structures. Although both algorithms are theoretically exponential in the number of atoms, experiments performed on biological data and using realistic parameters show that the solution is obtained within a few minutes. Finally, an application to the determination of the structural core of seven globins is presented.
Published: 1998

39. The complete genome sequence of the gram-positive bacterium Bacillus subtilis

Author: Daniel Portetelle, Angelo Tognoni, Vladimir Lazarevic, Hiroshi Yoshikawa, Carlo V. Bruschi, A. Düsterhöft, H. Wedler, J.-J. Codani, S. C. Brignell, Masaya Fujita, B. Roche, Motoki Mizuno, Junichi Sekiguchi, P. Koetter, Miyuki Kumano, K. Yoshida, Richard A. Daniel, Alain Brans, Y. Kobayashi, Jeff Errington, B.-S. Shin, BJ Guy, Simone J. Séror, Peter Terpstra, S. Fuma, Y. Kasahara, Mary O'Reilly, F Scoffone, Claudine Médigue, R. Wambutt, Matthias Rose, G. Koningstein, Nathalie Galleron, M. G. Bertero, M. Klaerr-Blanchard, Bernard Joris, B. Oudega, Michael A. Rieger, G. Alloni, Mitsuhiro Itaya, Simon Ming-Yuen Lee, Bénédicte Purnelle, Steffen Porwollik, Marie-Françoise Hullo, Alla Lapidus, Valentina Tosato, Colin R. Harwood, N. Medina, Catherine Mauël, Kevin M. Devine, Kanako Kurita, Ken-Ichi Takemaru, Nicola J. Cummings, Susanne Krogh, Louis M. Jones, Micheline Vandenbol, Rainer Borriss, K. Ogawa, Alain Levine, E. Presecan, Bolotin Ap, E. Scanlan, Hisashi Yoshikawa, Michio Takeuchi, G. Guiseppi, J. Lauber, Stanislav Dusko Ehrlich, Ivan Moszer, D. Moestl, K. Yasumoto, S. Schleich, S. Hosono, E. Tacconi, E. Wedler, Georges Rapoport, E. J. Golightly, Sierd Bron, T. Takagi, Shigeki Uchiyama, C. Fabret, Kazuko Haga, Alexei Sorokin, L. Boursier, Pascale Serror, Vasco Azevedo, Guido Grandi, Petar Pujic, A. M. Prescott, Sa Youl Ghim, A. Ogiwara, François Denizot, Hiroki Yamamoto, Blazenka Soldo, R. Schroeter, S. Masuda, S. Brouillet, André Goffeau, Agnieszka Sekowska, A. Tamakoshi, Naotake Ogasawara, Alain Viari, Eugenio Ferrari, V. Capuano, Eduardo P. C. Rocha, Dimitri Karamata, S. Lardinois, D. Foulger, Michiel A. Noback, Ian F. Connerton, Katsunori Yata, Victor Parro, Alessandra M. Albertini, Alain Hénaut, Carsten Klein, C. Fritz, Toshitada Sato, P. Winters, Alessandro Galizzi, Yoshito Sadaie, Stacey Reynolds, H. Liu, Hideyuki Takahashi, Tetsu Tanaka, David Noone, S. Borchert, S. Nakai, T. Weitzenegger, Kunio Yamane, F. Kunst, S.-H. Park, P. T. Emmerson, M. Braun, Emmanuelle Zumstein, Yasutaro Fujita, Philippe Bessières, Noel Carter, Antoine Danchin, A. Vassarotti, B. Caldwell, M. Rey, Françoise Vannier, Carlo Rivolta, Thomas Pohl, Rafael P. Mellado, H. Hilbert, K. D. Entian, Jacques Haiech, Siger Holsappel, Soo Keun Choi, Philippe Glaser, and Anil Wipat
Subjects: DNA, Bacterial, Cloning, Organism, Molecular Sequence Data, Bacillus subtilis, Biology, TERMINATORS, Genome, REGION, Microbiology, Bacterial Proteins, STRANDS, Gene density, Gene family, YEAST ARTIFICIAL CHROMOSOMES, Gene, Prophage, Genetics, Multidisciplinary, COMPETENCE, ACIDS, biology.organism_classification, DNA-SEQUENCES, REPLICATION, Horizontal gene transfer, Minimal genome, PROJECT, Genome, Bacterial
Abstract: Bacillus subtilis is the best-characterized member of the Gram-positive bacteria. Its genome of 4,214,810 base pairs comprises 4,100 protein-coding genes. Of these protein-coding genes, 53% are represented once, while a quarter of the genome corresponds to several gene families that have been greatly expanded by gene duplication, the largest family containing 77 putative ATP-binding transport proteins. In addition, a large proportion of the genetic capacity is devoted to the utilization of a variety of carbon sources, including many plant-derived molecules. The identification of five signal peptidase genes, as well as several genes for components of the secretion apparatus, is important given the capacity of Bacillus strains to secrete large amounts of industrially important enzymes. Many of the genes are involved in the synthesis of secondary metabolites, including antibiotics, that are more typically associated with Streptomyces species. The genome contains at least ten prophages or remnants of prophages, indicating that bacteriophage infection has played an important evolutionary role in horizontal gene transfer, in particular in the propagation of bacterial pathogenesis.
Published: 1997

40. Palingol: a declarative programming language to describe nucleic acids' secondary structures and to scan sequence database

Author: Alain Viari, Milutin Kontic, and Bernard Billoud
Subjects: Structure (mathematical logic), Sequence, Focus (computing), Database, Base Sequence, Databases, Factual, Process (engineering), Iron, Molecular Sequence Data, DNA, Biology, Regulatory Sequences, Nucleic Acid, computer.software_genre, Data type, RNA, Bacterial, General purpose, RNA, Transfer, Genetics, Nucleic Acid Conformation, Programming Languages, Representation (mathematics), computer, Declarative programming, Research Article
Abstract: At the DNA/RNA level, biological signals are defined by a combination of spatial structures and sequence motifs. Until now, few attempts had been made in writing general purpose search programs that take into account both sequence and structure criteria. Indeed, the most successful structure scanning programs are usually dedicated to particular structures and are written using general purpose programming languages through a complex and time consuming process where the biological problem of defining the structure and the computer engineering problem of looking for it are intimately intertwined. In this paper, we describe a general representation of structures, suitable for database scanning, together with a programming language, Palingol, designed to manipulate it. Palingol has specific data types, corresponding to structural elements-basically helices-that can be arranged in any way to form a complex structure. As a consequence of the declarative approach used in Palingol, the user should only focus on 'what to search for' while the language engine takes care of 'how to look for it'. Therefore, it becomes simpler to write a scanning program and the structural constraints that define the required structure are more clearly identified.
Published: 1996

41. Analysis of a Bacillus subtilis genome fragment using a co-operative computer system prototype

Author: Antoine Danchin, Claudine Médigue, Alain Viari, and Ivan Moszer
Subjects: Genetics, Biological data, Knowledge representation and reasoning, Base Sequence, Molecular Sequence Data, General Medicine, Biology, computer.software_genre, Genome, DNA sequencing, Annotation, Data mining, Software system, User interface, computer, Large-Scale Sequencing, Sequence Analysis, Genome, Bacterial, Software, Bacillus subtilis
Abstract: Analysis of the huge volume of data generated by large scale sequencing projects requires the construction of new, sophisticated computer systems. These systems should be able to manage the biological data as well as the results of their analysis. They should also help the user to choose the most appropriate methods, and to string them together in order to solve a global analysis task. In this paper we present the prototype of a software system providing an environment for the analysis of large-scale sequence data. As a first step toward this end, this environment has been put to the test within the Bacillus subtilis genome sequencing project. This system integrates both the descriptive knowledge of the entities involved (genes, regulatory signals and the like) and the methodological knowledge comprising an extensible set of analytical methods. A knowledge representation based on two existing object-oriented models is used to implement this integrated system. In addition, the present prototype provides a suitable user interface both for displaying simultaneously the results generated by several methods and for interacting with the objects. We present in this paper the analysis of a B. subtilis genome fragment, present in data libraries but not annotated. Annotation of the genes present in the fragment allowed us to combine the results of several methods used for predicting coding sequences, and to characterize it as comprising a cryptic phage, the skin element. Comparison between the annotation of the skin element and a standard region of the chromosome indicated that local features of the nucleotide sequence could discriminate between phage and non-phage DNA sequence.
Published: 1995

42. The CanOE Strategy: Integrating Genomic and Metabolic Contexts across Multiple Prokaryote Genomes to Find Candidate Genes for Orphan Enzymes

Author: David Vallenet, Claudine Médigue, Alain Viari, Eugeni Belda, Adam Alexander T. Smith, Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Swiss-Prot Group, Swiss Institute of Bioinformatics [Genève] (SIB), An algorithmic view on genomes, cells, and environments (BAMBOO), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria), Génomique métabolique (UMR 8030), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), and Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Candidate gene, QH301-705.5, Archaeal Proteins, Genomics, Biology, Biochemistry, Genome, 03 medical and health sciences, Cellular and Molecular Neuroscience, Protein sequencing, Metabolomics, Bacterial Proteins, Genome, Archaeal, Databases, Genetic, Genetics, Gene family, Biology (General), Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 0303 health sciences, Models, Genetic, Ecology, 030302 biochemistry & molecular biology, Computational Biology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Enzymes, Metabolic pathway, Metabolism, Computational Theory and Mathematics, Modeling and Simulation, Metabolome, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Genome, Bacterial, Research Article
Abstract: Of all biochemically characterized metabolic reactions formalized by the IUBMB, over one out of four have yet to be associated with a nucleic or protein sequence, i.e. are sequence-orphan enzymatic activities. Few bioinformatics annotation tools are able to propose candidate genes for such activities by exploiting context-dependent rather than sequence-dependent data, and none are readily accessible and propose result integration across multiple genomes. Here, we present CanOE (Candidate genes for Orphan Enzymes), a four-step bioinformatics strategy that proposes ranked candidate genes for sequence-orphan enzymatic activities (or orphan enzymes for short). The first step locates “genomic metabolons”, i.e. groups of co-localized genes coding proteins catalyzing reactions linked by shared metabolites, in one genome at a time. These metabolons can be particularly helpful for aiding bioanalysts to visualize relevant metabolic data. In the second step, they are used to generate candidate associations between un-annotated genes and gene-less reactions. The third step integrates these gene-reaction associations over several genomes using gene families, and summarizes the strength of family-reaction associations by several scores. In the final step, these scores are used to rank members of gene families which are proposed for metabolic reactions. These associations are of particular interest when the metabolic reaction is a sequence-orphan enzymatic activity. Our strategy found over 60,000 genomic metabolons in more than 1,000 prokaryote organisms from the MicroScope platform, generating candidate genes for many metabolic reactions, of which more than 70 distinct orphan reactions. A computational validation of the approach is discussed. Finally, we present a case study on the anaerobic allantoin degradation pathway in Escherichia coli K-12., Author Summary The discovery of the various metabolic functions catalyzed by enzymes encoded by the genes from the exponentially increasing number of sequenced genomes is one of the main focuses of bioinformatics tools today. However, most of these tools rely on already identified enzyme-coding gene or protein sequence information to predict known enzymatic activities in new genomes. Therefore, they cannot be used to reveal metabolic activities without any corresponding sequenced genes, dubbed “sequence-orphan activities”. In such cases, the best approach is the bioanalysis of target genes by human expert curators, manually integrating so-called “context-based information” (such as gene co-localization on the genome, or the presence of incomplete metabolic pathways) to infer novel functions. Few bioinformatics tools exploit such information and render accessible results in an automated way. Here, we present “CanOE”, a strategy that uses contextual information to propose and rank Candidate genes for Orphan Enzymes in Bacteria and Archaea. Beyond the merit of extending our knowledge and comprehension of prokaryote metabolism, identifying coding genes for sequence-orphan activities opens new opportunities for functional annotation (homology-based transfer made accessible), drug design (new metabolic targets), synthetic biology (new building blocks) and biotechnology applications (new biocatalysts).
Published: 2012

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