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

P. Cacheiro, V. Muñoz-Fuentes, SA. Murray, ME. Dickinson, M. Bucan, LMJ. Nutter, KA. Peterson, H. Haselimashhadi, AM. Flenniken, H. Morgan, H. Westerberg, T. Konopka, CW. Hsu, A. Christiansen, DG. Lanza, AL. Beaudet, JD. Heaney, H. Fuchs, V....

. 2020 ; 11 (1) : 655. [pub] 20200131

Jazyk angličtina Země Velká Británie

Typ dokumentu hodnotící studie, časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20023208

Grantová podpora
UM1 OD023221 NIH HHS - United States
UM1 HG006348 NHGRI NIH HHS - United States
MC_U142684172 Medical Research Council - United Kingdom
UM1 HG006370 NHGRI NIH HHS - United States
MR/S006753/1 Medical Research Council - United Kingdom
MC_U142684171 Medical Research Council - United Kingdom

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.

Clinical Pharmacology William Harvey Research Institute School of Medicine and Dentistry Queen Mary University of London London EC1M 6BQ UK

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Vestec 252 50 Prague Czech Republic

Department of Genetics Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA

Departments of Molecular and Human Genetics Baylor College of Medicine Houston TX 77030 USA

Departments of Molecular Physiology and Biophysics Baylor College of Medicine Houston TX 77030 USA

Departments of Molecular Physiology and Biophysics Baylor College of Medicine Houston TX 77030 USA Departments of Molecular and Human Genetics Baylor College of Medicine Houston TX 77030 USA

European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Genome Campus Hinxton Cambridge CB10 1SD UK

German Mouse Clinic Institute of Experimental Genetics Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg Germany

German Mouse Clinic Institute of Experimental Genetics Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg Germany Department of Experimental Genetics Center of Life and Food Sciences Weihenstephan Technische Universität München 85354 Freising Weihenstephan Germany German Center for Diabetes Research 85764 Neuherberg Germany

Institute of Developmental Genetics Helmholtz Zentrum München German Research Center for Environmental Health GmbH 85764 Neuherberg Germany Department of Developmental Genetics Center of Life and Food Sciences Weihenstephan Technische Universität München 85764 Neuherberg Germany Deutsches Institut für Neurodegenerative Erkrankungen Adolf Butenandt Institut Ludwig Maximilians Universität München 80336 Munich Germany

Medical Research Council Harwell Institute Harwell Oxfordshire OX11 0RD UK

Monterotondo Mouse Clinic Italian National Research Council Institute of Cell Biology and Neurobiology 00015 Monterotondo Scalo Italy

Mouse Biology Program University of California Davis CA 95618 USA

The Centre for Phenogenomics Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital Toronto ON M5T 3H7 Canada

The Centre for Phenogenomics The Hospital for Sick Children Toronto ON M5T 3H7 Canada

The Centre for Phenogenomics The Hospital for Sick Children Toronto ON M5T 3H7 Canada Translational Medicine The Hospital for Sick Children Toronto ON M5T 3H7 Canada

The Jackson Laboratory Bar Harbor ME 4609 USA

Université de Strasbourg CNRS INSERM Institut Clinique de la Souris PHENOMIN ICS 67404 Illkirch France

Université de Strasbourg CNRS INSERM Institut de Génétique Biologie Moléculaire et Cellulaire Institut Clinique de la Souris IGBMC PHENOMIN ICS 67404 Illkirch France

Wellcome Trust Sanger Institute Hinxton Cambridge CB10 1SA UK

Citace poskytuje Crossref.org

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