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High-throughput discovery of novel developmental phenotypes

Author

Listed:
  • Mary E. Dickinson

    (Department of Molecular Physiology and Biophysics)

  • Ann M. Flenniken

    (The Toronto Centre for Phenogenomics
    Mount Sinai Hospital)

  • 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
    Mouse Imaging Centre, The Hospital for Sick Children)

  • 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
    The Hospital for Sick Children)

  • 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
    Program in Medical and Population Genetics, Broad Institute MIT and Harvard)

  • 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
    Program in Medical and Population Genetics, Broad Institute MIT and Harvard)

  • 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
    The Hospital for Sick Children)

  • Lauryl M. J. Nutter

    (The Toronto Centre for Phenogenomics
    The Hospital for Sick Children)

  • 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
    Program in Medical and Population Genetics, Broad Institute MIT and Harvard)

  • 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
    Technical University of Munich, Chair of Developmental Genetics
    German Center for Neurodegenerative Diseases (DZNE) Site Munich,
    Munich Cluster for Systems Neurology (SyNergy))

  • Daniel G. MacArthur

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute MIT and Harvard)

  • 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
    Baylor College of Medicine)

  • 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
    Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München
    German Center for Diabetes Research (DZD))

  • 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
    Mouse Imaging Centre, The Hospital for Sick Children)

  • 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
    The Hospital for Sick Children)

  • Arthur L. Beaudet

    (Baylor College of Medicine)

  • Maja Bućan

    (Perlman School of Medicine, University of Pennsylvania)

  • Stephen A. Murray

    (The Jackson Laboratory)

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.

Suggested Citation

  • 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, 2016. "High-throughput discovery of novel developmental phenotypes," Nature, Nature, vol. 537(7621), pages 508-514, September.
  • Handle: RePEc:nat:nature:v:537:y:2016:i:7621:d:10.1038_nature19356
    DOI: 10.1038/nature19356
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