The landscape of tolerated genetic variation in humans and primates
Hong Gao, Tobias Hamp, Jeffrey M. Ede, Joshua G. Schraiber, Jeremy F. McRae, Moriel Singer‐Berk, Yanshen Yang, Anastasia S. D. Dietrich, Petko Fiziev, Lukas F. K. Kuderna, Laksshman Sundaram, Yibing Wu, Aashish N. Adhikari, Yair Field, Chen Chen, Serafim Batzoglou, François Aguet, Gabrielle Lemire, Rebecca Reimers, Daniel J. Balick, Mareike C. Janiak, Martin Kuhlwilm, Joseph D. Orkin, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rousselle, Felipe Ennes Silva, Lídia Águeda, Julie Blanc, Marta Gut, Dorien de Vries, Ian Goodhead, R. Alan Harris, Muthuswamy Raveendran, Axel Jensen, Idriss S. Chuma, Julie E. Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Fabiano Rodrigues de Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Pires Farias, João Valsecchi, Mariluce Rezende Messias, Maria Nazareth Ferreira da Silva, Mihir Trivedi, Rogério Vieira Rossi, Tomas Hrbek, Nicole Andriaholinirina, C. Rabarivola, Alphonse Zaramody, Clifford J. Jolly, Jane E. Phillips‐Conroy, Gregory K. Wilkerson, Christian R. Abee, Joe H. Simmons, Eduardo Fernández‐Duque, Sree Kanthaswamy, Fekadu Shiferaw, Dong‐Dong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D. Keyyu, Sascha Knauf, Minh Đức Lê, Esther Lizano, Stefan Merker, Arcadi Navarro, Thomas Bataillon, Tilo Nadler, Chiea Chuen Khor, Jessica Lee, Patrick Tan, Weng Khong Lim, Andrew C. Kitchener, Dietmar Zinner, Marta Gut, Amanda Melin, Katerina Guschanski, Mikkel Heide Schierup, Robin M. D. Beck, Govindhaswamy Umapathy, Christian Roos, Jean P. Boubli, Monkol Lek, Shamil Sunyaev, Anne O’Donnell‐Luria, Heidi L. Rehm, Jinbo Xu, Jeffrey Rogers, Tomàs Marquès‐Bonet, Kyle Kai‐How Farh
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.