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Nat Genet. 2015 Sep;47(9):969-978. doi: 10.1038/ng.3360. Epub 2015 Jul 27.

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

de Angelis MH#1,2,3, Nicholson G#4, Selloum M#5,6,7,8, White J#9, Morgan H#10, Ramirez-Solis R#9, Sorg T#5,6,7,8, Wells S#10, Fuchs H#1, Fray M#10, Adams DJ9, Adams NC9, Adler T1,11, Aguilar-Pimentel A1,12, Ali-Hadji D5,6,7,8, Amann G5,6,7,8, André P5,6,7,8, Atkins S10, Auburtin A5,6,7,8, Ayadi A5,6,7,8, Becker J5,6,7,8, Becker L1,13, Bedu E5,6,7,8, Bekeredjian R1,14, Birling MC5,6,7,8, Blake A10, Bottomley J9, Bowl M10, Brault V15,6,7,8, Busch DH11, Bussell JN9, Calzada-Wack J16, Cater H10, Champy MF5,6,7,8, Charles P5,6,7,8, Chevalier C15,6,7,8, Chiani F17, Codner GF10, Combe R5,6,7,8, Cox R10, Dalloneau E15,6,7,8, Dierich A5,6,7,8, Di Fenza A10, Doe B17, Duchon A15,6,7,8, Eickelberg O18, Esapa CT10, El Fertak L5,6,7,8, Feigel T10, Emelyanova I10, Estabel J9, Favor J19, Flenniken A20, Gambadoro A17, Garrett L21, Gates H10, Gerdin AK9, Gkoutos G22, Greenaway S10, Glasl L21, Goetz P5,6,7,8, Da Cruz IG5,6,7,8, Götz A18, Graw J21, Guimond A5,6,7,8, Hans W1, Hicks G23, Hölter SM21, Höfler H13, Hancock JM10, Hoehndorf R24, Hough T10, Houghton R9, Hurt A1, Ivandic B1,14, Jacobs H5,6,7,8, Jacquot S5,6,7,8, Jones N20, Karp NA9, Katus HA1,14, Kitchen S10, Klein-Rodewald T16, Klingenspor M1,25, Klopstock T1,13, Lalanne V5,6,7,8, Leblanc S5,6,7,8, Lengger C1, le Marchand E5,6,7,8, Ludwig T1, Lux A5,6,7,8, McKerlie C26,27, Maier H1, Mandel JL5,15,6,7,8, Marschall S1, Mark M5,15,6,7,8, Melvin DG9, Meziane H5,6,7,8, Micklich K1, Mittelhauser C5,6,7,8, Monassier L5,6,7,8, Moulaert D5,6,7,8, Muller S5,6,7,8, Naton B1, Neff F16, Nolan PM10, Nutter LM27, Ollert M1,12, Pavlovic G5,6,7,8, Pellegata NS16, Peter E5,6,7,8, Petit-Demoulière B5,6,7,8, Pickard A10, Podrini C9, Potter P10, Pouilly L5,6,7,8, Puk O21, Richardson D9, Rousseau S5,6,7,8, Quintanilla-Fend L16, Quwailid MM10, Racz I1,28, Rathkolb B1,29, Riet F5,6,7,8, Rossant J27, Roux M5,15,6,7,8, Rozman J1,25, Ryder E9, Salisbury J9, Santos L10, Schäble KH1, Schiller E1, Schrewe A1, Schulz H18, Steinkamp R1, Simon M10, Stewart M10, Stöger C1, Stöger T18, Sun M21, Sunter D9, Teboul L10, Tilly I5,6,7,8, Tocchini-Valentini GP17, Tost M16, Treise I1, Vasseur L5,6,7,8, Velot E15,6,7,8, Vogt-Weisenhorn D21, Wagner C5,15,6,7,8, Walling A10, Weber B5,6,7,8, Wendling O5,15,6,7,8, Westerberg H10, Willershäuser M1, Wolf E29,1, Wolter A5,6,7,8, Wood J10, Wurst W21,2,30,31, Yildirim AÖ18, Zeh R1, Zimmer A1,28, Zimprich A21; EUMODIC Consortium, Holmes C#4, Steel KP#9, Herault Y#5,15,6,7,8, Gailus-Durner V#1, Mallon AM#10, Brown SD#10.

Author information

1
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), München/Neuherberg, Germany.
2
School of Life Sciences Weihenstephan, Technische Universität München, Freising, Germany.
3
German Center for Diabetes Research (DZD), Neuherberg, Germany.
4
Department of Statistics, University of Oxford, Oxford, UK.
5
Institut Clinique de la Souris , PHENOMIN, GIE CERBMIllkirch, France.
6
Centre National de la Recherche Scientifique, Illkirch, France.
7
Institut National de la Santé et de la Recherche Médicale, Illkirch, France.
8
Université de Strasbourg, Illkirch, France.
9
The Wellcome Trust Sanger Institute, Hinxton, UK.
10
MRC Harwell, Medical Research Council, Harwell, UK.
11
Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.
12
Division of Environmental Dermatology and Allergy (UDA), Helmholtz Zentrum München/ Technische Universität München, and Clinical Research Division of Molecular and Clinical Allergotoxicology, Department of Dermatology and Allergy, Technische Universität München, Munich, Germany.
13
Deptartment of Neurology, Klinikum der Ludwig-Maximilians-Universität München, Germany.
14
Department of Cardiology, Angiology and Pneumology, Heidelberg University Hospital, Heidelberg, Germany.
15
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
16
Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), München/Neuherberg, Germany.
17
Institute of Cell Biology and Neurology, CNR (National Research Council), Rome, Italy.
18
Institute of Lung Biology and Disease, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), München/Neuherberg, Germany.
19
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), München/Neuherberg, Germany.
20
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
21
Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), München/Neuherberg, Germany.
22
Department of Computer Science, University of Aberystwyth, UK.
23
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada.
24
Computational Bioscience Research Center, King Abdullah University of Science and Technology, Kingdom of Saudi Arabia.
25
Else Kröner-Fresenius Center for Nutrional Medicine, Technische Universität München, Freising-Weihenstephan, Germany.
26
Toronto Centre for Phenogenomics, Toronto, Canada.
27
The Hospital for Sick Children, Toronto, Canada.
28
Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany.
29
Institute of Molecular Animal Breeding and Biotechnology, Ludwigs-Maximilians-University Munich, Munich, Germany.
30
Max-Planck-Institute of Psychiatry, Munich, Germany.
31
Deutsches Zentrum für Neurodegenerative Erkrankungen, Munich, Germany.
#
Contributed equally

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.

Comment in

PMID:
26214591
PMCID:
PMC4564951
DOI:
10.1038/ng.3360
[Indexed for MEDLINE]
Free PMC Article

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