Identification of constrained sequence elements across 239 primate genomes

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• dc.contributor.author Kuderna, Lukas, 1989-
• dc.contributor.author Valenzuela, Alejandro
• dc.contributor.author Navarro i Cuartiellas, Arcadi, 1969-
• dc.contributor.author Marquès i Bonet, Tomàs, 1975-
• dc.contributor.author Kai-How Farh, Kyle
• dc.date.accessioned 2024-02-06T07:24:46Z
• dc.date.available 2024-02-06T07:24:46Z
• dc.date.issued 2023
• dc.description.abstract Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3-9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.
• dc.description.sponsorship The authors thank H. Chang, O. Ryder, S. Reilly and E. Karlsson for helpful discussions. Funding: M.C.J., D.d.V., I. Goodhead, R.M.D.B. and J.P.B. were supported by a UKRI NERC standard grant (NE/T000341/1). H.C. and M.H. were supported by NHGRI U24HG002371. M.K. was supported by la Caixa Foundation (ID 100010434), fellowship code LCF/BQ/PR19/11700002, and by the Vienna Science and Technology Fund (WWTF) and the City of Vienna through project VRG20-001. 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 Skłodowska-Curie grant agreement no. 847648. The fellowship code is LCF/BQ/PI20/11760004. F.E.S. was supported by Brazilian National Council for Scientific and Technological Development (CNPq) (Processes 303286/2014-8, 303579/2014-5, 200502/2015-8, 302140/2020-4, 300365/2021-7, 301407/2021-5 and 301925/2021-6), by the Fonds de la Recherche Scientifique - FNRS (#40017464), and by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 801505. 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), Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM/SISBIOTA #2317/2011), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES AUX # 3261/2013) to I.F. Samples from Amazônia, Brazil were accessed under SisGen no. A8F3D55. Sampling of non-human primates in Tanzania was funded by the German Research Foundation (KN1097/3-1 to S. Knauf and RO3055/2-1 to CR). No animals in Tanzania were sampled purposely for this study. Details of the original study on Treponema pallidum infection can be requested from S. Knauf. This research was funded by the Vietnamese Ministry of Science and Technology’s Program 562 (grant no. ĐTĐL.CN-64/19). A.N. is supported by AEI-PGC2018-101927-BI00 704 (FEDER/UE), FEDER (Fondo Europeo de Desarrollo Regional)/FSE (Fondo Social Europeo), Unidad de Excelencia María de Maeztu, funded by the AEI (CEX2018-000792-M) and Secretaria d’Universitats i Recerca and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880). A.D.M. was supported by the National Sciences and Engineering Research Council of Canada and Canada Research Chairs program. Aotus azarae samples from Argentina were obtained with grant support to E.F.-D. from the Zoological Society of San Diego, 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). J.H.S. was supported in part by the NIH under award number P40OD024628 - SPF Baboon Research Resource. K.G. was supported by the Swedish Research Council VR (2020-03398). We thank C. Escudé and B. Bed’Homme, and L. Cacheux and J.-P. Gautier for providing guenon cell culture and tissue samples. 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. The authors thank the Veterinary and Zoology staff at Wildlife Reserves Singapore for their help in obtaining the tissue samples, and the Lee Kong Chian Natural History Museum for storage and provision of the tissue samples. 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 no. 864203), 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). K.L.-T. is a recipient of Distinguished Professor award from the Swedish Research Council and the Knut and Wallenberg Foundation.
• dc.format.mimetype application/pdf
• dc.identifier.citation Kuderna LFK, Ulirsch JC, Rashid S, Ameen M, Sundaram L, Hickey G et al. Identification of constrained sequence elements across 239 primate genomes. Nature. 2024 Jan;625(7996):735-42. DOI: 10.1038/s41586-023-06798-
• dc.identifier.doi http://dx.doi.org/10.1038/s41586-023-06798-8
• dc.identifier.issn 0028-0836
• dc.identifier.uri http://hdl.handle.net/10230/58960
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nature. 2024 Jan;625(7996):735-42
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/847648
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/864203
• dc.rights © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Comparative genomics
• dc.subject.keyword Evolutionary genetics
• dc.subject.keyword Genetic variation
• dc.subject.keyword Genome evolution
• dc.subject.keyword Transcriptional regulatory elements
• dc.title Identification of constrained sequence elements across 239 primate genomes
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion