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Nature. 2016 Sep 22;537(7621):508-514. doi: 10.1038/nature19356. Epub 2016 Sep 14.

High-throughput discovery of novel developmental phenotypes.

Author information

1
Department of Molecular Physiology and Biophysics, Houston, Texas 77030, USA.
2
The Toronto Centre for Phenogenomics, Toronto, Ontario M5T 3H7, Canada.
3
Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
4
Genomics and Computational Biology Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
5
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
6
Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario M5T 3H7, Canada.
7
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
8
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
9
Centre for Anatomy and Cell Biology, Medical University of Vienna, Vienna A-1090, Austria.
10
The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
11
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
12
Mouse Biology Program, University of California, Davis, California 95618, USA.
13
Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology, Monterotondo Scalo I-00015, Italy.
14
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
15
Program in Medical and Population Genetics, Broad Institute MIT and Harvard, Cambridge, Massachusetts 02142, USA.
16
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics and German Mouse Clinic, Neuherberg 85764, Germany.
17
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
18
SKL of Pharmaceutical Biotechnology and Model Animal Research Center, Collaborative Innovation Center for Genetics and Development, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China.
19
Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS), et Institut de Génétique Biologie Moléculaire et Cellulaire (IGBMC) CNRS, INSERM, University of Strasbourg, Illkirch-Graffenstaden 67404, France.
20
RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan.
21
Children's Hospital Oakland Research Institute, Oakland, California 94609, USA.
22
IMPC, San Anselmo, California 94960, USA.
23
Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising 81675, Germany.
24
German Center for Diabetes Research (DZD), Neuherberg 85764, Germany.
25
The Francis Crick Institute Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW1 1AT, UK.
26
Departments of Genetics and Psychiatry, Perlman School of Medicine, University of Pennsylvania, Philadelphia Pennsylvania 19104, USA.

Abstract

Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

PMID:
27626380
PMCID:
PMC5295821
DOI:
10.1038/nature19356
[Indexed for MEDLINE]
Free PMC Article
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