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 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

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 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 BalickMareike 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

Research output: Contribution to journal › Article › peer-review

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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 (US)
Article number	eabn8197
Journal	Science
Volume	380
Issue number	6648
DOIs	https://doi.org/10.1126/science.abn8197
State	Published - Jun 2 2023
Externally published	Yes

ASJC Scopus subject areas

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10.1126/science.abn8197

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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. 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), Article eabn8197. https://doi.org/10.1126/science.abn8197

Gao, H, Hamp, T, Ede, J, Schraiber, JG, McRae, J, Singer-Berk, M, Yang, Y, Dietrich, ASD, Fiziev, PP, Kuderna, LFK, Sundaram, L, Wu, Y, Adhikari, A, Field, Y, Chen, C, Batzoglou, S, Aguet, F, Lemire, G, Reimers, R, Balick, D, Janiak, MC, Kuhlwilm, M, Orkin, JD, Manu, S, Valenzuela, A, Bergman, J, Rousselle, M, Silva, FE, Agueda, L, Blanc, J, Gut, M, de Vries, D, Goodhead, I, Harris, RA, Raveendran, M, Jensen, A, Chuma, IS, Horvath, JE, Hvilsom, C, Juan, D, Frandsen, P, de Melo, FR, Bertuol, F, Byrne, H, Sampaio, I, Farias, I, do Amaral, JV, Messias, M, da Silva, MNF, Trivedi, M, Rossi, R, Hrbek, T, Andriaholinirina, N, Rabarivola, CJ, Zaramody, A, Jolly, CJ, Phillips-Conroy, J, Wilkerson, G, Abee, C, Simmons, JH, Fernandez-Duque, E, Kanthaswamy, S, Shiferaw, F, Wu, D, Zhou, L, Shao, Y, Zhang, G, Keyyu, JD, Knauf, S, Le, MD, Lizano, E, Merker, S, Navarro, A, Bataillon, T, Nadler, T, Khor, CC, Lee, J, Tan, P, Lim, WK, Kitchener, AC, Zinner, D, Gut, I, Melin, A, Guschanski, K, Schierup, MH, Beck, RMD, Umapathy, G, Roos, C, Boubli, JP, Lek, M, Sunyaev, S, O’Donnell-Luria, A, Rehm, HL, Xu, J, Rogers, J, Marques-Bonet, T & Farh, KKH 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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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 S.D.} and Fiziev, {Petko P.} and Kuderna, {Lukas F.K.} and Laksshman Sundaram and Yibing Wu and Aashish Adhikari and Yair Field and Chen Chen and Serafim Batzoglou and Francois Aguet and Gabrielle Lemire and Rebecca Reimers and Daniel Balick and Janiak, {Mareike C.} and Martin Kuhlwilm and Orkin, {Joseph D.} and Shivakumara Manu and Alejandro Valenzuela and Juraj Bergman and Marjolaine Rousselle and Silva, {Felipe Ennes} and Lidia Agueda and Julie Blanc and Marta Gut and {de Vries}, Dorien and Ian Goodhead and Harris, {R. Alan} and Muthuswamy Raveendran and Axel Jensen and Chuma, {Idriss S.} and Horvath, {Julie E.} and Christina Hvilsom and David Juan and Peter Frandsen and {de Melo}, {Fabiano R.} and Fabr{\'i}cio Bertuol and Hazel Byrne and Iracilda Sampaio and Izeni Farias and {do Amaral}, {Jo{\~a}o Valsecchi} and Mariluce Messias and {da Silva}, {Maria N.F.} and Mihir Trivedi and Rogerio Rossi and Tomas Hrbek and Nicole Andriaholinirina and Rabarivola, {Cl{\'e}ment J.} and Alphonse Zaramody and Jolly, {Clifford J.} and Jane Phillips-Conroy and Gregory Wilkerson and Christian Abee and Simmons, {Joe H.} and Eduardo Fernandez-Duque and Sree Kanthaswamy and Fekadu Shiferaw and Dongdong Wu and Long Zhou and Yong Shao and Guojie Zhang and Keyyu, {Julius D.} and Sascha Knauf and Le, {Minh D.} and Esther Lizano and Stefan Merker and Arcadi Navarro and Thomas Bataillon and Tilo Nadler and Khor, {Chiea Chuen} and Jessica Lee and Patrick Tan and Lim, {Weng Khong} and Kitchener, {Andrew C.} and Dietmar Zinner and Ivo Gut and Amanda Melin and Katerina Guschanski and Schierup, {Mikkel Heide} and Beck, {Robin M.D.} and Govindhaswamy Umapathy and Christian Roos and Boubli, {Jean P.} and Monkol Lek and Shamil Sunyaev and Anne O{\textquoteright}Donnell-Luria and Rehm, {Heidi L.} and Jinbo Xu and Jeffrey Rogers and Tomas Marques-Bonet and Farh, {Kyle Kai How}",

year = "2023",

month = jun,

day = "2",

doi = "10.1126/science.abn8197",

language = "English (US)",

volume = "380",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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T1 - The landscape of tolerated genetic variation in humans and primates

AU - Gao, Hong

AU - Hamp, Tobias

AU - Ede, Jeffrey

AU - Schraiber, Joshua G.

AU - McRae, Jeremy

AU - Singer-Berk, Moriel

AU - Yang, Yanshen

AU - Dietrich, Anastasia S.D.

AU - Fiziev, Petko P.

AU - Kuderna, Lukas F.K.

AU - Sundaram, Laksshman

AU - Wu, Yibing

AU - Adhikari, Aashish

AU - Field, Yair

AU - Chen, Chen

AU - Batzoglou, Serafim

AU - Aguet, Francois

AU - Lemire, Gabrielle

AU - Reimers, Rebecca

AU - Balick, Daniel

AU - Janiak, Mareike C.

AU - Kuhlwilm, Martin

AU - Orkin, Joseph D.

AU - Manu, Shivakumara

AU - Valenzuela, Alejandro

AU - Bergman, Juraj

AU - Rousselle, Marjolaine

AU - Silva, Felipe Ennes

AU - Agueda, Lidia

AU - Blanc, Julie

AU - Gut, Marta

AU - de Vries, Dorien

AU - Goodhead, Ian

AU - Harris, R. Alan

AU - Raveendran, Muthuswamy

AU - Jensen, Axel

AU - Chuma, Idriss S.

AU - Horvath, Julie E.

AU - Hvilsom, Christina

AU - Juan, David

AU - Frandsen, Peter

AU - de Melo, Fabiano R.

AU - Bertuol, Fabrício

AU - Byrne, Hazel

AU - Sampaio, Iracilda

AU - Farias, Izeni

AU - do Amaral, João Valsecchi

AU - Messias, Mariluce

AU - da Silva, Maria N.F.

AU - Trivedi, Mihir

AU - Rossi, Rogerio

AU - Hrbek, Tomas

AU - Andriaholinirina, Nicole

AU - Rabarivola, Clément J.

AU - Zaramody, Alphonse

AU - Jolly, Clifford J.

AU - Phillips-Conroy, Jane

AU - Wilkerson, Gregory

AU - Abee, Christian

AU - Simmons, Joe H.

AU - Fernandez-Duque, Eduardo

AU - Kanthaswamy, Sree

AU - Shiferaw, Fekadu

AU - Wu, Dongdong

AU - Zhou, Long

AU - Shao, Yong

AU - Zhang, Guojie

AU - Keyyu, Julius D.

AU - Knauf, Sascha

AU - Le, Minh D.

AU - Lizano, Esther

AU - Merker, Stefan

AU - Navarro, Arcadi

AU - Bataillon, Thomas

AU - Nadler, Tilo

AU - Khor, Chiea Chuen

AU - Lee, Jessica

AU - Tan, Patrick

AU - Lim, Weng Khong

AU - Kitchener, Andrew C.

AU - Zinner, Dietmar

AU - Gut, Ivo

AU - Melin, Amanda

AU - Guschanski, Katerina

AU - Schierup, Mikkel Heide

AU - Beck, Robin M.D.

AU - Umapathy, Govindhaswamy

AU - Roos, Christian

AU - Boubli, Jean P.

AU - Lek, Monkol

AU - Sunyaev, Shamil

AU - O’Donnell-Luria, Anne

AU - Rehm, Heidi L.

AU - Xu, Jinbo

AU - Rogers, Jeffrey

AU - Marques-Bonet, Tomas

AU - Farh, Kyle Kai How

PY - 2023/6/2

Y1 - 2023/6/2

N2 - 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.

AB - 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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DO - 10.1126/science.abn8197

M3 - Article

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AN - SCOPUS:85160969495

SN - 0036-8075

VL - 380

JO - Science

JF - Science

IS - 6648

M1 - eabn8197

ER -

The landscape of tolerated genetic variation in humans and primates

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