The landscape of tolerated genetic variation in humans and primates

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• dc.contributor.author Gao, Hong
• dc.contributor.author Kuderna, Lukas, 1989-
• dc.contributor.author Kuhlwilm, Martin
• dc.contributor.author Orkin, Joseph D.
• dc.contributor.author Águeda, Lidia
• dc.contributor.author Blanc, Julie
• dc.contributor.author Gut, Marta
• dc.contributor.author Juan, David
• dc.contributor.author Navarro i Cuartiellas, Arcadi, 1969-
• dc.contributor.author Gut, Ivo Glynne
• dc.contributor.author Marquès i Bonet, Tomàs, 1975-
• dc.contributor.author Kai-How Farh, Kyle
• dc.date.accessioned 2025-01-21T14:17:29Z
• dc.date.available 2025-01-21T14:17:29Z
• dc.date.issued 2023
• dc.description.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.
• dc.description.sponsorship L.F.K.K. was supported by an EMBO STF 8286 (to L.F.K.K.). R.R. was supported by an NIH training grant NIH T32 GM007748. M.K. was supported by “la Caixa” Foundation (ID 100010434 to M.K.), fellowship code LCF/BQ/PR19/11700002 (to M.K.), and the Vienna Science and Technology Fund (WWTF) [10.47379/VRG20001] (to M.K.). J.D.O. was supported by “la Caixa” Foundation (ID 100010434) and the European Union’s Horizon 2020 research and innovation programme under the Marie SkŽodowska-Curie grant agreement 847648. The fellowship code is LCF/BQ/PI20/11760004. F.E.S. has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie SkŽodowska-Curie grant agreement No 801505. F.E.S. also received funds from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (Process nos.: 303286/2014-8, 303579/2014-5, 200502/2015-8, 302140/2020-4, 300365/2021-7, 301407/2021-5, 301925/2021-6,; the International Primatological Society (Conservation grant), The Rufford Foundation (14861-1, 23117-2, 38786-B), the Margot Marsh Biodiversity Foundation (SMA-CCO-G0023, SMA-CCOG0037), and Primate Conservation Inc. (#1713 and #1689). The Mamirauá Institute for Sustainable Development received funds from the Gordon and Betty Moore Foundation (grant 5344 to J.V.A. and F.E.S.) Fieldwork for samples collected in the Brazilian Amazon was funded by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/SISBIOTA Program 563348/2010-0 to I.P.F.), Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM/SISBIOTA 2317/2011 to I.P.F.), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES AUX 3261/2013) to I.P.F. Sampling of nonhuman primates in Tanzania was funded by the German Research Foundation (KN1097/3-1 to S.K. and RO3055/2-1 to C.R.) and by the US National Science Foundation (BNS83-03506 to J.P.C.) No animals in Tanzania were sampled purposely for this study. Details of the original study on Treponema pallidum infection can be requested from S.K. Sampling of baboons in Zambia was funded by US NSF grant BCS-1029451 to J.P.C., C.J.J., and J.R. The research reported in this manuscript was also funded by the Vietnamese Ministry of Science and Technology’s Program 562 (grant ĐTĐL.CN-64/19). A.N.C. is supported by I+D+i project PID2021-127792NB-I00 funded by MCIN/AEI/10.13039/501100011033 (FEDER Una manera de hacer Europa)” and by “Unidad de Excelencia María de Maeztu”, funded by the AEI (CEX2018-000792-M) and Departament de Recerca i Universitats de la Generalitat de Catalunya (GRC 2021 SGR 0467). A.D.M. was supported by the National Sciences and Engineering Research Council of Canada and Canada Research Chairs program. The authors thank the Veterinary and Zoology staff at Wildlife Reserves Singapore for their help in obtaining the tissue samples, as well as the Lee Kong Chian Natural History Museum for storage and provision of the tissue samples. We thank H. Doddapaneni, D. M. Muzny, and M. C. Gingras for their support of sequencing at the Baylor College of Medicine Human Genome Sequencing Center. We greatly appreciate the support of R. Gibbs, director of HGSC, for this project and thank the Baylor College of Medicine for internal funding. T.M.B. is supported by funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement 864203 to T.M.B.), PID2021-126004NB-100 (MICIIN/FEDER, UE) and Secretaria d’Universitats i Recerca and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2021 SGR 00177). H.L.R. receives funding from Illumina, Inc to support rare disease gene discovery and diagnosis. M.C.J, D.d.V. I.G., R.M.D.B., and J.P.B. were supported by a UKRI NERC standard grant (NE/T000341/1). We thank P. Karanth (IISc) and H. N. Kumara (SACON) for collecting and providing us with some of the samples from India. S.M.A. was supported by a BINC fellowship from the Department of Biotechnology (DBT), India. We acknowledge the support provided by the Council of Scientific and Industrial Research (CSIR), India, to G.U. for the sequencing at the Centre for Cellular and Molecular Biology (CCMB), India. We acknowledge the Duke Lemur Center for collecting primate samples. This is Duke Lemur Center publication #1560. Samples from Amazônia, Brazil, were accessed under SisGen no. A8F3D55. Aotus azarae samples from Argentina were obtained with grant support to E.F.D. from the Zoological Society of San Diego, the Wenner-Gren Foundation, the L.S.B. Leakey Foundation, the National Geographic Society, the US National Science Foundation (NSF-BCS-0621020, 1232349, 1503753, 1848954; NSF-RAPID-1219368, NSF-FAIN-1952072; NSF-DDIG-1540255; NSF-REU 0837921, 0924352, 1026991) and the US National Institute on Aging (NIA- P30 AG012836-19, NICHD R24 HD-044964-11). E.F.D. thanks the Ministry of Production and the Environment of Formosa Province in Argentina for the research presented here. J.H.S. was supported in part by the NIH under award number P40OD024628 - SPF Baboon Research Resource. This research is supported by the National Research Foundation Singapore under its National Precision Medicine Programme (NPM) Phase II Funding (MOH-000588 to P.T. and W.K.L.) and administered by the Singapore Ministry of Health’s National Medical Research Council. J.R. is also a Core Scientist at the Wisconsin National Primate Research Center, Univ. of Wisconsin, Madison. K.G. was supported by the Swedish Research Council VR (2020-03398). We acknowledge the institutional support of the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III and the 2014–2020 Smart Growth Operating Program, to the EMBL partnership and institutional cofinancing with the European Regional Development Fund (MINECO/FEDER, BIO2015-71792-P). We also acknowledge the support of the Centro de Excelencia Severo Ochoa, and the Generalitat de Catalunya through the Departament de Salut, Departament d’Empresa i Coneixement and the CERCA Programme to the institute. The research reported in this manuscript was also funded by the Vietnamese Ministry of Science and Technology’s Program 562 (grant no. ĐTĐL.CN-64/19) to M.D.L.
• dc.format.mimetype application/pdf
• dc.identifier.citation Gao H, Hamp T, Ede J, Schraiber JG, McRae J, Singer-Berk M, Yang Y, et al. The landscape of tolerated genetic variation in humans and primates. Science. 2023 Jun 2;380(6648):eabn8153. DOI: 10.1126/science.abn8197
• dc.identifier.doi http://dx.doi.org/10.1126/science.abn8197
• dc.identifier.issn 0036-8075
• dc.identifier.uri http://hdl.handle.net/10230/69224
• dc.language.iso eng
• dc.publisher American Association for the Advancement of Science (AAAS)
• dc.relation.ispartof Science. 2023 Jun 2;380(6648):eabn8153
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/847648
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/801505
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/864203
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-126004NB-100
• dc.rights This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on 2023 Jun 2;380(6648):eabn8153, DOI: 10.1126/science.abn8197.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.other Genètica humana
• dc.title The landscape of tolerated genetic variation in humans and primates
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion