The landscape of tolerated genetic variation in humans and primates

Hong Gao; Tobias Hamp; Jeffrey Ede; Joshua G. Schraiber; Jeremy McRae; Moriel Singer-Berk; Yanshen Yang; Anastasia Susanna Dagmar Dietrich; Petko Fiziev; Lukas F.K. Kuderna; Laksshman Sundaram; Yibing Wu; Aashish N. Adhikari; Yair Field; Serafim Batzoglou; Francois Aguet; Gabrielle Lemire; Rebecca Reimers; Daniel Balick; Mareike Janiak; Martin Kuhlwilm; Joseph Orkin; Shivakumara Manu; Alejandro Valenzuela; Juraj Bergman; Marjolaine Rousselle; FE Silva; Lidia Agueda Calpena; Julie Blanc; Marta Gut; Dorien de Vries; Ian Goodhead; Ronald Harris; Muthuswamy Raveendran; Axel Jensen; Idrissa Chuma; Julie Horvath; Christina Hvilsom; David Juan; Peter Frandsen; Fabiano R. de Melo; Fabrício Bertuol; Hazel Byrne; Iracilda Sampaio; Izeni Pires Farias; João Valsecchi; Mariluce Messias; Maria Nazareth Ferreira da Silva; Mihir Trivedi; Rogerio Vieira Rossi

doi:10.1126/science.abn8197

The landscape of tolerated genetic variation in humans and primates

Hong Gao, Tobias Hamp, Jeffrey Ede, Joshua G. Schraiber, Jeremy McRae, Moriel Singer-Berk, Yanshen Yang, Anastasia Susanna Dagmar Dietrich, Petko Fiziev, Lukas F.K. Kuderna, Laksshman Sundaram, Yibing Wu, Aashish N. Adhikari, Yair Field, Serafim Batzoglou, Francois Aguet, Gabrielle Lemire, Rebecca Reimers, Daniel Balick, Mareike JaniakMartin Kuhlwilm, Joseph Orkin, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rousselle, FE Silva, Lidia Agueda Calpena, Julie Blanc, Marta Gut, Dorien de Vries, Ian Goodhead, Ronald Harris, Muthuswamy Raveendran, Axel Jensen, Idrissa Chuma, Julie Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Fabiano R. de Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Pires Farias, João Valsecchi, Mariluce Messias, Maria Nazareth Ferreira da Silva, Mihir Trivedi, Rogerio Vieira Rossi

Publications: Contribution to journal › Article › Peer Reviewed

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.

Original language	English
Article number	eabn8197
Journal	Science
Volume	380
Issue number	6648
DOIs	https://doi.org/10.1126/science.abn8197
Publication status	Published - 2 Jun 2023

Austrian Fields of Science 2012

106014 Genomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Gao, H., Hamp, T., Ede, J., Schraiber, J. G., McRae, J., Singer-Berk, M., Yang, Y., Dietrich, A. S. D., Fiziev, P., Kuderna, L. F. K., Sundaram, L., Wu, Y., Adhikari, A. N., Field, Y., Batzoglou, S., Aguet, F., Lemire, G., Reimers, R., Balick, D., ... Rossi, R. V. (2023). The landscape of tolerated genetic variation in humans and primates. Science, 380(6648), Article eabn8197. https://doi.org/10.1126/science.abn8197

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title = "The landscape of tolerated genetic variation in humans and primates",

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.",

author = "Hong Gao and Tobias Hamp and Jeffrey Ede and Schraiber, {Joshua G.} and Jeremy McRae and Moriel Singer-Berk and Yanshen Yang and Dietrich, {Anastasia Susanna Dagmar} and Petko Fiziev and Kuderna, {Lukas F.K.} and Laksshman Sundaram and Yibing Wu and Adhikari, {Aashish N.} and Yair Field and Serafim Batzoglou and Francois Aguet and Gabrielle Lemire and Rebecca Reimers and Daniel Balick and Mareike Janiak and Martin Kuhlwilm and Joseph Orkin and Shivakumara Manu and Alejandro Valenzuela and Juraj Bergman and Marjolaine Rousselle and FE Silva and Calpena, {Lidia Agueda} and Julie Blanc and Marta Gut and Vries, {Dorien de} and Ian Goodhead and Ronald Harris and Muthuswamy Raveendran and Axel Jensen and Idrissa Chuma and Julie Horvath and Christina Hvilsom and David Juan and Peter Frandsen and Melo, {Fabiano R. de} and Fabr{\'i}cio Bertuol and Hazel Byrne and Iracilda Sampaio and Farias, {Izeni Pires} and Jo{\~a}o Valsecchi and Mariluce Messias and Silva, {Maria Nazareth Ferreira da} and Mihir Trivedi and Rossi, {Rogerio Vieira}",

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Gao, H, Hamp, T, Ede, J, Schraiber, JG, McRae, J, Singer-Berk, M, Yang, Y, Dietrich, ASD, Fiziev, P, Kuderna, LFK, Sundaram, L, Wu, Y, Adhikari, AN, Field, Y, Batzoglou, S, Aguet, F, Lemire, G, Reimers, R, Balick, D, Janiak, M, Kuhlwilm, M, Orkin, J, Manu, S, Valenzuela, A, Bergman, J, Rousselle, M, Silva, FE, Calpena, LA, Blanc, J, Gut, M, Vries, DD, Goodhead, I, Harris, R, Raveendran, M, Jensen, A, Chuma, I, Horvath, J, Hvilsom, C, Juan, D, Frandsen, P, Melo, FRD, Bertuol, F, Byrne, H, Sampaio, I, Farias, IP, Valsecchi, J, Messias, M, Silva, MNFD, Trivedi, M & Rossi, RV 2023, 'The landscape of tolerated genetic variation in humans and primates', Science, vol. 380, no. 6648, eabn8197. https://doi.org/10.1126/science.abn8197

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AU - Fiziev, Petko

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AU - Orkin, Joseph

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AU - Gut, Marta

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AU - Chuma, Idrissa

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AU - Hvilsom, Christina

AU - Juan, David

AU - Frandsen, Peter

AU - Melo, Fabiano R. de

AU - Bertuol, Fabrício

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The landscape of tolerated genetic variation in humans and primates

Abstract

Austrian Fields of Science 2012

UN SDGs

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