PgmNr M252: Large-scale discovery of embryonic lethal phenotypes in mice.
Authors:
S. A. Murray
1 ; A. M. Flenniken
2,13 ; X. Ji
3 ; L. Teboul
4 ; M. D. Wong
2,11 ; J. K. White
5 ; T. F. Meehan
6 ; H. Westerberg
4 ; M. Justice
7,14 ; M. Hrabe de Angelis
8,17,18 ; Y. Herault
9 ; T. Mohun
10 ; R. M. Henkelman
2,11 ; S. D. Brown
4 ; K. C. Lloyd
12 ; C. McKerlie
2,13 ; D. Adams
5 ; A. L. Beaudet
14 ; M. Bucan
15 ; M. E. Dickinson
16 ; The International Mouse Phenotyping Consortium
Institutes
1) The Jackson Laboratory, Bar Harbor, ME; 2) Toronto Centre for Phenogenomics, Toronto, Ontario, Canada; 3) Genomics and Computational Biology Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104; 4) Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire, UK; 5) The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; 6) European Molecular Biology Laboratory- European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; 7) The Hospital for Sick Children, Toronto Ontario, Canada; 8) Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics and German Mouse Clinic, Neuherberg, Germany; 9) Institut Clinique de la Souris (ICS), PHENOMIN, Illkirch, Cedex, France; 10) The Francis Crick Institute Mill Hill Laboratory, The Ridgeway, Mill Hill, London A, UK; 11) Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, M5T 3H7, Canada; 12) Mouse Biology Program, University of California, Davis; 13) Mount Sinai Hospital, Toronto, Ontario, Canada; 14) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA; 15) Departments of Genetics and Psychiatry, Perlman School of Medicine, University of Pennsylvania, Philadelphia PA 19104; 16) Department of Molecular Physiology and Biophysics, Houston, Texas, USA; 17) Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising; 18) German Center for Diabetes Research (DZD), Neuherberg, Germany. Abstract: Nearly one third of all mammalian genes are essential. Embryonic lethal genes identified and characterized through mouse knockouts (KO) have greatly furthered our understanding of gene and pathway function. The overarching goal of the Knockout Mouse Phenotyping Program (KOMP2) and its partners in the IMPC International Mouse Phenotyping Consortium (IMPC) is to generate an encyclopedia of gene function through genome-wide generation and phenotyping of knockout mice. Collectively, the consortium has produced over 5000 knockout strains and identified over 400 embryonic lethal genes. To characterize the lethal lines, we have built and implemented a high-throughput embryo phenotyping pipeline, which includes the use of high-resolution 3D imaging for the generation of rich datasets that are distributed to the scientific community. The screen has revealed numerous phenotypes in genes with no previously ascribed function, and added new annotations to a subset of genes with prior knockout data. Unexpectedly, our analysis reveals frequent incomplete penetrance and variable expressivity of developmental phenotypes despite a defined genetic background. In addition, we found that human disease genes are highly enriched for in the essential genes identified in our screen, thus providing a novel dataset that facilitates prioritization and validation of mutations identified in clinical sequencing efforts.