Identification of constrained sequence elements across 239 primate genomes.

TitleIdentification of constrained sequence elements across 239 primate genomes.
Publication TypeJournal Article
Year of Publication2024
AuthorsKuderna, 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
Date Published2024 Jan
KeywordsAnimals, 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

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.

Alternate JournalNature
PubMed ID38030727
PubMed Central IDPMC10808062
Grant ListU24 HG002371 / HG / NHGRI NIH HHS / United States
P30 AG012836 / AG / NIA NIH HHS / United States
R24 HD044964 / HD / NICHD NIH HHS / United States
U24 HG011853 / HG / NHGRI NIH HHS / United States
P40 OD024628 / OD / NIH HHS / United States

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