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, Markus Ollert, EUMODIC Consortium

Research output: Contribution to journalArticleResearchpeer-review

106 Citations (Scopus)

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
Pages (from-to)969-978
Number of pages10
JournalNature Genetics
Volume47
Issue number9
DOIs
Publication statusPublished - 27 Aug 2015
Externally publishedYes

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