Title | Identification of constrained sequence elements across 239 primate genomes. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Kuderna, LFK, Ulirsch, JC, Rashid, S, Ameen, M, Sundaram, L, Hickey, G, Cox, AJ, Gao, H, Kumar, A, Aguet, F, Christmas, MJ, Clawson, H, Haeussler, M, Janiak, MC, Kuhlwilm, M, Orkin, JD, Bataillon, T, Manu, S, Valenzuela, A, Bergman, J, Rouselle, M, Silva, FEnnes, 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, Schraiber, JG, de Melo, FR, Bertuol, F, Byrne, H, Sampaio, I, Farias, I, Valsecchi, J, 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, Nadler, T, Khor, CChuen, Lee, J, Tan, P, Lim, WKhong, Kitchener, AC, Zinner, D, Gut, I, Melin, AD, Guschanski, K, Schierup, MHeide, Beck, RMD, Karakikes, I, Wang, KC, Umapathy, G, Roos, C, Boubli, JP, Siepel, A, Kundaje, A, Paten, B, Lindblad-Toh, K, Rogers, J, Bonet, TMarques, Farh, KKai-How |
Journal | Nature |
Volume | 625 |
Issue | 7996 |
Pagination | 735-742 |
Date Published | 2024 Jan |
ISSN | 1476-4687 |
Keywords | Animals, Conserved Sequence, Deoxyribonuclease I, DNA, Evolution, Molecular, Female, Gene Expression Regulation, Genome, Humans, Mammals, Placenta, Pregnancy, Primates, Proteins, Regulatory Sequences, Nucleic Acid, Reproducibility of Results, Transcription Factors |
Abstract | Noncoding DNA is central to our understanding of human gene regulation and complex diseases, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome. 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 DNA, the relatively short timescales separating primate species, and the previously limited availability of whole-genome sequences. 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. |
DOI | 10.1038/s41586-023-06798-8 |
Alternate Journal | Nature |
PubMed ID | 38030727 |
PubMed Central ID | PMC10808062 |
Grant List | P30 AG012836 / AG / NIA NIH HHS / United States P40 OD024628 / OD / NIH HHS / United States R24 HD044964 / HD / NICHD NIH HHS / United States U24 HG002371 / HG / NHGRI NIH HHS / United States |
Identification of constrained sequence elements across 239 primate genomes.
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