The landscape of tolerated genetic variation in humans and primates

The landscape of tolerated genetic variation in humans and primates

Science

10.1126/science.abn8197

https://doi.org/10.1126/science.abn8197

Hong Gao, Tobias Hamp, Jeffrey Ede, Joshua G. Schraiber, Jeremy McRae, Moriel Singer-Berk, Yanshen Yang, Anastasia S. D. Dietrich, Petko P. Fiziev, Lukas F. K. Kuderna, Laksshman Sundaram, Yibing Wu, Aashish Adhikari, Yair Field, Chen Chen, Serafim Batzoglou, Francois Aguet, Gabrielle Lemire, Rebecca Reimers, Daniel Balick, Mareike C. Janiak, Martin Kuhlwilm, Joseph D. Orkin, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rousselle, Felipe Ennes Silva, Lidia Agueda, 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 R. de Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, João Valsecchi do Amaral, Mariluce Messias, Maria N. F. da Silva, Mihir Trivedi, Rogerio Rossi, Tomas Hrbek, Nicole Andriaholinirina, Clément J. Rabarivola, Alphonse Zaramody, Clifford J. Jolly, Jane Phillips-Conroy, Gregory Wilkerson, Christian Abee, Joe H. Simmons, Eduardo Fernandez-Duque, Sree Kanthaswamy, Fekadu Shiferaw, Dongdong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D. Keyyu, Sascha Knauf, Minh D. Le, 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, Ivo 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, Tomas Marques-Bonet, Kyle Kai-How Farh

02 June 2023

Gao, H., Hamp, T., Ede, J., Schraiber, J. G., McRae, J., Singer-Berk, M., Yang, Y., Dietrich, A. S. D., Fiziev, P. P., Kuderna, L. F. K., Sundaram, L., Wu, Y., Adhikari, A., Field, Y., Chen, C., Batzoglou, S., Aguet, F., Lemire, G., Reimers, R., … Farh, K. K.-H. (2023). The landscape of tolerated genetic variation in humans and primates. Science, 380(6648). https://doi.org/10.1126/science.abn8197

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.

Publisher Copyright

There was no specific funding for the research done

Copyright © 2023 the authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original US government works. https://www.sciencemag.org/about/ science-licenses-journal-article-reuse

https://oar.a-star.edu.sg/communities-collections/articles/22593

0036-8075
1095-9203

Genome Institute of Singapore

https://doi.org/10.1126/science.abn8197