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Human and mouse essentiality screens as a resource for disease gene discovery

Author

Listed:
  • Pilar Cacheiro

    (Queen Mary University of London)

  • Violeta Muñoz-Fuentes

    (European Bioinformatics Institute (EMBL-EBI))

  • Stephen A. Murray

    (The Jackson Laboratory)

  • Mary E. Dickinson

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Maja Bucan

    (University of Pennsylvania)

  • Lauryl M. J. Nutter

    (The Hospital for Sick Children)

  • Kevin A. Peterson

    (The Jackson Laboratory)

  • Hamed Haselimashhadi

    (European Bioinformatics Institute (EMBL-EBI))

  • Ann M. Flenniken

    (Mount Sinai Hospital)

  • Hugh Morgan

    (Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre))

  • Henrik Westerberg

    (Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre))

  • Tomasz Konopka

    (Queen Mary University of London)

  • Chih-Wei Hsu

    (Baylor College of Medicine)

  • Audrey Christiansen

    (Baylor College of Medicine)

  • Denise G. Lanza

    (Baylor College of Medicine)

  • Arthur L. Beaudet

    (Baylor College of Medicine)

  • Jason D. Heaney

    (Baylor College of Medicine)

  • Helmut Fuchs

    (German Research Center for Environmental Health)

  • Valerie Gailus-Durner

    (German Research Center for Environmental Health)

  • Tania Sorg

    (Université de Strasbourg, CNRS, INSERM, Institut Clinique de la Souris, PHENOMIN-ICS)

  • Jan Prochazka

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Vendula Novosadova

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Christopher J. Lelliott

    (Wellcome Trust Sanger Institute)

  • Hannah Wardle-Jones

    (Wellcome Trust Sanger Institute)

  • Sara Wells

    (Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre))

  • Lydia Teboul

    (Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre))

  • Heather Cater

    (Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre))

  • Michelle Stewart

    (Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre))

  • Tertius Hough

    (Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre))

  • Wolfgang Wurst

    (German Research Center for Environmental Health GmbH
    Technische Universität München
    Ludwig-Maximilians-Universität München)

  • Radislav Sedlacek

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • David J. Adams

    (Wellcome Trust Sanger Institute)

  • John R. Seavitt

    (Baylor College of Medicine)

  • Glauco Tocchini-Valentini

    (Institute of Cell Biology and Neurobiology)

  • Fabio Mammano

    (Institute of Cell Biology and Neurobiology)

  • Robert E. Braun

    (The Jackson Laboratory)

  • Colin McKerlie

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Yann Herault

    (Université de Strasbourg, CNRS, INSERM, Institut de Génétique, Biologie Moléculaire et Cellulaire, Institut Clinique de la Souris, IGBMC, PHENOMIN-ICS)

  • Martin Hrabě Angelis

    (German Research Center for Environmental Health
    Technische Universität München
    German Center for Diabetes Research (DZD))

  • Ann-Marie Mallon

    (Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre))

  • K. C. Kent Lloyd

    (University of California)

  • Steve D. M. Brown

    (Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre))

  • Helen Parkinson

    (European Bioinformatics Institute (EMBL-EBI))

  • Terrence F. Meehan

    (European Bioinformatics Institute (EMBL-EBI))

  • Damian Smedley

    (Queen Mary University of London)

Abstract

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.

Suggested Citation

  • Pilar Cacheiro & Violeta Muñoz-Fuentes & Stephen A. Murray & Mary E. Dickinson & Maja Bucan & Lauryl M. J. Nutter & Kevin A. Peterson & Hamed Haselimashhadi & Ann M. Flenniken & Hugh Morgan & Henrik W, 2020. "Human and mouse essentiality screens as a resource for disease gene discovery," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14284-2
    DOI: 10.1038/s41467-020-14284-2
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    Cited by:

    1. Asmundur Oddsson & Patrick Sulem & Gardar Sveinbjornsson & Gudny A. Arnadottir & Valgerdur Steinthorsdottir & Gisli H. Halldorsson & Bjarni A. Atlason & Gudjon R. Oskarsson & Hannes Helgason & Henriet, 2023. "Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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