Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics

Martin Hrabě de Angelis, George Nicholson, Mohammed Selloum, Jacqueline K White, Hugh Morgan, Ramiro Ramirez-Solis, Tania Sorg, Sara Wells, Helmut Fuchs, Martin Fray, David J Adams, Niels C Adams, Thure Adler, Antonio Aguilar-Pimentel, Dalila Ali-Hadji, Gregory Amann, Philippe André, Sarah Atkins, Aurelie Auburtin, Abdel AyadiJulien Becker, Lore Becker, Elodie Bedu, Raffi Bekeredjian, Marie-Christine Birling, Andrew Blake, Joanna Bottomley, Michael R Bowl, Véronique Brault, Dirk H Busch, James N Bussell, Julia Calzada-Wack, Heather Cater, Marie-France Champy, Philippe Charles, Claire Chevalier, Francesco Chiani, Gemma F Codner, Roy Combe, Roger Cox, Emilie Dalloneau, André Dierich, Armida Di Fenza, Brendan Doe, Arnaud Duchon, Oliver Eickelberg, Chris T Esapa, Lahcen El Fertak, Tanja Feigel, Irina Emelyanova, Jeanne Estabel, Jack Favor, Ann Flenniken, Alessia Gambadoro, Lilian Garrett, Hilary Gates, Anna-Karin Gerdin, George Gkoutos, Simon Greenaway, Lisa Glasl, Patrice Goetz, Isabelle Goncalves Da Cruz, Alexander Götz, Jochen Graw, Alain Guimond, Wolfgang Hans, Geoff Hicks, Sabine M Hölter, Heinz Höfler, John M Hancock, Robert Hoehndorf, Tertius Hough, Richard Houghton, Anja Hurt, Boris Ivandic, Hughes Jacobs, Sylvie Jacquot, Nora Jones, Natasha A Karp, Hugo A Katus, Sharon Kitchen, Tanja Klein-Rodewald, Martin Klingenspor, Thomas Klopstock, Valerie Lalanne, Sophie Leblanc, Christoph Lengger, Elise le Marchand, Tonia Ludwig, Aline Lux, Colin McKerlie, Holger Maier, Jean-Louis Mandel, Susan Marschall, Manuel Mark, David G Melvin, Hamid Meziane, Kateryna Micklich, Christophe Mittelhauser, Laurent Monassier, David Moulaert, Stéphanie Muller, Beatrix Naton, Frauke Neff, Patrick M Nolan, Lauryl M J Nutter, Markus Ollert, Guillaume Pavlovic, Natalia S Pellegata, Emilie Peter, Benoit Petit-Demoulière, Amanda Pickard, Christine Podrini, Paul Potter, Laurent Pouilly, Oliver Puk, David Richardson, Stephane Rousseau, Leticia Quintanilla-Fend, Mohamed M Quwailid, Ildiko Racz, Birgit Rathkolb, Fabrice Riet, Janet Rossant, Michel Roux, Jan Rozman, Edward Ryder, Jennifer Salisbury, Luis Santos, Karl-Heinz Schäble, Evelyn Schiller, Anja Schrewe, Holger Schulz, Ralf Steinkamp, Michelle Simon, Michelle Stewart, Claudia Stöger, Tobias Stöger, Minxuan Sun, David Sunter, Lydia Teboul, Isabelle Tilly, Glauco P Tocchini-Valentini, Monica Tost, Irina Treise, Laurent Vasseur, Emilie Velot, Daniela Vogt-Weisenhorn, Christelle Wagner, Alison Walling, Marie Wattenhofer-Donze, Bruno Weber, Olivia Wendling, Henrik Westerberg, Monja Willershäuser, Eckhard Wolf, Anne Wolter, Joe Wood, Wolfgang Wurst, Ali Önder Yildirim, Ramona Zeh, Andreas Zimmer, Annemarie Zimprich, Chris Holmes, Karen P Steel, Yann Herault, Valérie Gailus-Durner, Ann-Marie Mallon, Steve D M Brown

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87 Scopus citations

Abstract

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.
Original languageEnglish (US)
Pages (from-to)969-978
Number of pages10
JournalNature Genetics
Volume47
Issue number9
DOIs
StatePublished - Jul 27 2015

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