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

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 Westerberg, Tomasz Konopka, Chih-Wei Hsu, Audrey Christiansen, Denise G. Lanza, Arthur L. Beaudet, Jason D. Heaney, Helmut Fuchs, Valerie Gailus-Durner, Tania Sorg, Jan Prochazka, Vendula Novosadova, Christopher J. Lelliott, Hannah Wardle-Jones, Sara Wells, Lydia Teboul, Heather Cater, Michelle Stewart, Tertius Hough, Wolfgang Wurst, Radislav Sedlacek, David J. Adams, John R. Seavitt, Glauco Tocchini-Valentini, Fabio Mammano, Robert E. Braun, Colin McKerlie, Yann Herault, Martin Hrabě Angelis, Ann-Marie Mallon, K. C. Kent Lloyd, Steve D. M. Brown, Helen Parkinson, Terrence F. Meehan and Damian Smedley ()
Additional contact information
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
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
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
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
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

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14284-2

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