The landscape of tolerated genetic variation in humans and primates
Hong Gao(Illumina (United States)), Tobias Hamp(Illumina (United States)), Jeffrey M. Ede(Illumina (United States)), Joshua G. Schraiber(Illumina (United States)), Jeremy F. McRae(Illumina (United States)), Moriel Singer‐Berk(Broad Institute), Yanshen Yang(Illumina (United States)), Anastasia S. D. Dietrich(Illumina (United States)), Petko Fiziev(Illumina (United States)), Lukas F. K. Kuderna(Illumina (United States)), Laksshman Sundaram(Illumina (United States)), Yibing Wu(Illumina (United States)), Aashish N. Adhikari(Illumina (United States)), Yair Field(Illumina (United States)), Chen Chen(Illumina (United States)), Serafim Batzoglou(Illumina (United States)), François Aguet(Illumina (United States)), Gabrielle Lemire(Broad Institute), Rebecca Reimers(Boston Children's Hospital), Daniel J. Balick(Brigham and Women's Hospital), Mareike C. Janiak(University of Salford), Martin Kuhlwilm(University of Vienna), Joseph D. Orkin(Institut de Biologia Evolutiva), Shivakumara Manu(Centre for Cellular and Molecular Biology), Alejandro Valenzuela(Institut de Biologia Evolutiva), Juraj Bergman(Aarhus University), Marjolaine Rousselle(Aarhus University), Felipe Ennes Silva(Université Libre de Bruxelles), Lídia Águeda(Centre for Genomic Regulation), Julie Blanc(Centre for Genomic Regulation), Marta Gut(Centre for Genomic Regulation), Dorien de Vries(University of Salford), Ian Goodhead(University of Salford), R. Alan Harris(Baylor College of Medicine), Muthuswamy Raveendran(Baylor College of Medicine), Axel Jensen(Uppsala University), Idriss S. Chuma(Tanzania National Parks), Julie E. Horvath(University of North Carolina at Chapel Hill), Christina Hvilsom(Copenhagen Zoo), David Juan(Institut de Biologia Evolutiva), Peter Frandsen(Copenhagen Zoo), Fabiano Rodrigues de Melo(Universidade Federal de Viçosa), Fabrício Bertuol(Universidade Federal do Amazonas), Hazel Byrne(University of Utah), Iracilda Sampaio(Universidade Federal do Pará), Izeni Pires Farias(Universidade Federal do Amazonas), João Valsecchi(Instituto Nacional de Pesquisas da Amazônia), Mariluce Rezende Messias(Universidade Federal de Rondônia), Maria Nazareth Ferreira da Silva(Instituto Nacional de Pesquisas da Amazônia), Mihir Trivedi(Centre for Cellular and Molecular Biology), Rogério Vieira Rossi(Universidade Federal de Mato Grosso), Tomas Hrbek(Trinity University), Nicole Andriaholinirina(Université de Mahajanga), C. Rabarivola(Université de Mahajanga), Alphonse Zaramody(Université de Mahajanga), Clifford J. Jolly(New York University), Jane E. Phillips‐Conroy(Washington University in St. Louis), Gregory K. Wilkerson(The University of Texas MD Anderson Cancer Center), Christian R. Abee(The University of Texas MD Anderson Cancer Center), Joe H. Simmons(The University of Texas MD Anderson Cancer Center), Eduardo Fernández‐Duque(Yale University), Sree Kanthaswamy(Arizona State University), Fekadu Shiferaw(The Carter Center), Dong‐Dong Wu(Kunming Institute of Zoology), Long Zhou(Zhejiang University), Yong Shao(Kunming Institute of Zoology), Guojie Zhang(University of Copenhagen), Julius D. Keyyu(Tanzania Wildlife Research Institute), Sascha Knauf(Friedrich-Loeffler-Institut), Minh Đức Lê(VNU Central Institute for Natural Resources and Environmental Studies), Esther Lizano(Institució Catalana de Recerca i Estudis Avançats), Stefan Merker(Staatliches Museum für Naturkunde Stuttgart), Arcadi Navarro(Universitat Autònoma de Barcelona), Thomas Bataillon(Aarhus University), Tilo Nadler(Cat Tien National Park), Chiea Chuen Khor(Agency for Science, Technology and Research), Jessica Lee(Ministry of Manpower), Patrick Tan(Agency for Science, Technology and Research), Weng Khong Lim(SingHealth), Andrew C. Kitchener(National Museums Scotland), Dietmar Zinner(German Primate Center), Marta Gut(Universitat Pompeu Fabra), Amanda Melin(University of Calgary), Katerina Guschanski(Uppsala University), Mikkel Heide Schierup(Aarhus University), Robin M. D. Beck(University of Salford), Govindhaswamy Umapathy(Centre for Cellular and Molecular Biology), Christian Roos(German Primate Center), Jean P. Boubli(University of Salford), Monkol Lek(Yale University), Shamil Sunyaev(Brigham and Women's Hospital), Anne O’Donnell‐Luria(Broad Institute), Heidi L. Rehm(Broad Institute), Jinbo Xu(Toyota Technological Institute at Chicago), Jeffrey Rogers(Baylor College of Medicine), Tomàs Marquès‐Bonet(Institució Catalana de Recerca i Estudis Avançats), Kyle Kai‐How Farh(Illumina (United States))
Cited by 175Open Access
Abstract
Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.
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