High-throughput discovery of novel developmental phenotypes

Mary E. Dickinson, Ann M. Flenniken, Xiao Ji, Lydia Teboul, Michael D. Wong, Jacqueline K. White, Terrence F. Meehan, Wolfgang J. Weninger, Henrik Westerberg, Hibret Adissu, Candice N. Baker, Lynette Bower, James M. Brown, L. Brianna Caddle, Francesco Chiani, Dave Clary, James Cleak, Mark J. Daly, James M. Denegre, Brendan Doe, Mary E. Dolan, Sarah M. Edie, Helmut Fuchs, Valerie Gailus-Durner, Antonella Galli, Alessia Gambadoro, Juan Gallegos, Shiying Guo, Neil R. Horner, Chih-Wei Hsu, Sara J. Johnson, Sowmya Kalaga, Lance C. Keith, Louise Lanoue, Thomas N. Lawson, Monkol Lek, Manuel Mark, Susan Marschall, Jeremy Mason, Melissa L. McElwee, Susan Newbigging, Lauryl M. J. Nutter, Kevin A. Peterson, Ramiro Ramirez-Solis, Douglas J. Rowland, Edward Ryder, Kaitlin E. Samocha, John R. Seavitt, Mohammed Selloum, Zsombor Szoke-Kovacs, Masaru Tamura, Amanda G. Trainor, Ilinca Tudose, Shigeharu Wakana, Jonathan Warren, Olivia Wendling, David B. West, Leeyean Wong, Atsushi Yoshiki, Wolfgang Wurst, Daniel G. MacArthur, Glauco P. Tocchini-Valentini, Xiang Gao, Paul Flicek, Allan Bradley, William C. Skarnes, Monica J. Justice, Helen E. Parkinson, Mark Moore, Sara Wells, Robert E. Braun, Karen L. Svenson, Martin Hrabe de Angelis, Yann Herault, Tim Mohun, Ann-Marie Mallon, R. Mark Henkelman, Steve D. M. Brown, David J. Adams, K. C. Kent Lloyd, Colin McKerlie, Arthur L. Beaudet, Maja Bućan and Stephen A. Murray ()
Additional contact information
Mary E. Dickinson: Department of Molecular Physiology and Biophysics
Ann M. Flenniken: The Toronto Centre for Phenogenomics
Xiao Ji: Genomics and Computational Biology Program, Perelman School of Medicine, University of Pennsylvania
Lydia Teboul: Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre)
Michael D. Wong: The Toronto Centre for Phenogenomics
Jacqueline K. White: The Wellcome Trust Sanger Institute
Terrence F. Meehan: European Molecular Biology Laboratory, European Bioinformatics Institute
Wolfgang J. Weninger: Centre for Anatomy and Cell Biology, Medical University of Vienna
Henrik Westerberg: Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre)
Hibret Adissu: The Toronto Centre for Phenogenomics
Candice N. Baker: The Jackson Laboratory
Lynette Bower: Mouse Biology Program, University of California
James M. Brown: Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre)
L. Brianna Caddle: The Jackson Laboratory
Francesco Chiani: Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology
Dave Clary: Mouse Biology Program, University of California
James Cleak: Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre)
Mark J. Daly: Analytic and Translational Genetics Unit, Massachusetts General Hospital
James M. Denegre: The Jackson Laboratory
Brendan Doe: The Wellcome Trust Sanger Institute
Mary E. Dolan: The Jackson Laboratory
Sarah M. Edie: The Jackson Laboratory
Helmut Fuchs: Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics and German Mouse Clinic
Valerie Gailus-Durner: Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics and German Mouse Clinic
Antonella Galli: The Wellcome Trust Sanger Institute
Alessia Gambadoro: Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology
Juan Gallegos: Baylor College of Medicine
Shiying Guo: SKL of Pharmaceutical Biotechnology and Model Animal Research Center, Collaborative Innovation Center for Genetics and Development, Nanjing Biomedical Research Institute, Nanjing University
Neil R. Horner: Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre)
Chih-Wei Hsu: Department of Molecular Physiology and Biophysics
Sara J. Johnson: Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre)
Sowmya Kalaga: Department of Molecular Physiology and Biophysics
Lance C. Keith: Department of Molecular Physiology and Biophysics
Louise Lanoue: Mouse Biology Program, University of California
Thomas N. Lawson: Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre)
Monkol Lek: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Manuel Mark: Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS), et Institut de Génétique Biologie Moléculaire et Cellulaire (IGBMC) CNRS, INSERM, University of Strasbourg
Susan Marschall: Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics and German Mouse Clinic
Jeremy Mason: European Molecular Biology Laboratory, European Bioinformatics Institute
Melissa L. McElwee: Department of Molecular Physiology and Biophysics
Susan Newbigging: The Toronto Centre for Phenogenomics
Lauryl M. J. Nutter: The Toronto Centre for Phenogenomics
Kevin A. Peterson: The Jackson Laboratory
Ramiro Ramirez-Solis: The Wellcome Trust Sanger Institute
Douglas J. Rowland: Mouse Biology Program, University of California
Edward Ryder: The Wellcome Trust Sanger Institute
Kaitlin E. Samocha: Analytic and Translational Genetics Unit, Massachusetts General Hospital
John R. Seavitt: Baylor College of Medicine
Mohammed Selloum: Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS), et Institut de Génétique Biologie Moléculaire et Cellulaire (IGBMC) CNRS, INSERM, University of Strasbourg
Zsombor Szoke-Kovacs: Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre)
Masaru Tamura: RIKEN BioResource Center
Amanda G. Trainor: Mouse Biology Program, University of California
Ilinca Tudose: European Molecular Biology Laboratory, European Bioinformatics Institute
Shigeharu Wakana: RIKEN BioResource Center
Jonathan Warren: European Molecular Biology Laboratory, European Bioinformatics Institute
Olivia Wendling: Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS), et Institut de Génétique Biologie Moléculaire et Cellulaire (IGBMC) CNRS, INSERM, University of Strasbourg
David B. West: Children’s Hospital Oakland Research Institute
Leeyean Wong: Department of Molecular Physiology and Biophysics
Atsushi Yoshiki: RIKEN BioResource Center
Wolfgang Wurst: HelmholtzZentrum Munich, Institute of Developmental Genetics
Daniel G. MacArthur: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Glauco P. Tocchini-Valentini: Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology
Xiang Gao: SKL of Pharmaceutical Biotechnology and Model Animal Research Center, Collaborative Innovation Center for Genetics and Development, Nanjing Biomedical Research Institute, Nanjing University
Paul Flicek: European Molecular Biology Laboratory, European Bioinformatics Institute
Allan Bradley: The Wellcome Trust Sanger Institute
William C. Skarnes: The Wellcome Trust Sanger Institute
Monica J. Justice: The Hospital for Sick Children
Helen E. Parkinson: European Molecular Biology Laboratory, European Bioinformatics Institute
Mark Moore: IMPC
Sara Wells: Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre)
Robert E. Braun: The Jackson Laboratory
Karen L. Svenson: The Jackson Laboratory
Martin Hrabe de Angelis: Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics and German Mouse Clinic
Yann Herault: Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS), et Institut de Génétique Biologie Moléculaire et Cellulaire (IGBMC) CNRS, INSERM, University of Strasbourg
Tim Mohun: The Francis Crick Institute Mill Hill Laboratory, The Ridgeway
Ann-Marie Mallon: Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre)
R. Mark Henkelman: The Toronto Centre for Phenogenomics
Steve D. M. Brown: Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre)
David J. Adams: The Wellcome Trust Sanger Institute
K. C. Kent Lloyd: Mouse Biology Program, University of California
Colin McKerlie: The Toronto Centre for Phenogenomics
Arthur L. Beaudet: Baylor College of Medicine
Maja Bućan: Perlman School of Medicine, University of Pennsylvania
Stephen A. Murray: The Jackson Laboratory

Nature, 2016, vol. 537, issue 7621, 508-514

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature19356

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