Journal Article

Identification of constrained sequence elements across 239 primate genomes

Christmas, Matthew J., Lee, Jessica, Ameen, Mohamed, Raveendran, Muthuswamy, Chuma, Idriss S., Marques Bonet, Tomas, Horvath, Julie E., Trivedi, Mihir, Guschanski, Katerina, Gao, Hong, Silva, Felipe Ennes, Goodhead, Ian, Blanc, Julie, Gut, Marta, Zaramody, Alphonse, Siepel, Adam, Aguet, Francois, Beck, Robin M. D., Le, Minh D., Umapathy, Govindhaswamy, Manu, Shivakumara, Hrbek, Tomas, Kundaje, Anshul, Sampaio, Iracilda, Valenzuela, Alejandro, Hvilsom, Christina, Kuhlwilm, Martin, Harris, R. Alan, Knauf, Sascha, Kumar, Arvind, Kitchener, Andrew C., Abee, Christian, Paten, Benedict, Jolly, Clifford J., Phillips-Conroy, Jane, Messias, Malu, Zhou, Long, Bertuol, Fabrício, Zinner, Dietmar, Valsecchi, João, Haeussler, Maximilian, Schierup, Mikkel Heide, Lim, Weng Khong, Agueda, Lidia, Shao, Yong, Karakikes, Ioannis, Cox, Anthony J., Schraiber, Joshua G., Zhang, Guojie, Rogers, Jeffrey, Byrne, Hazel, Rossi, Rogerio, Lizano, Esther, Rashid, Sabrina, Frandsen, Peter, Melin, Amanda D., Ulirsch, Jacob C., da Silva, Maria N. F., Merker, Stefan, Khor, Chiea Chuen, de Melo, Fabiano R., Rabarivola, Clément J., Wu, Dongdon

2024

Overview

Noncoding DNA is central to our understanding of human gene regulation and complex diseases 1 , 2 , and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome 3 – 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 DNA 10 , the relatively short timescales separating primate species 11 , and the previously limited availability of whole-genome sequences 12 . 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. Whole-genome alignment of 239 primate species reveals noncoding regulatory elements that are under selective constraint in primates but not in other placental mammals, that are enriched for variants that affect human gene expression and complex traits in diseases.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/23 / 631/181/2474 / 631/181/457/649 / 631/208/212/2304 / 631/208/212/748 / 631/337/572/2102 / Animals / Binding sites / Biological evolution / Conserved Sequence - genetics / Constraints / Deoxyribonuclease / Deoxyribonuclease I - metabolism / Deoxyribonucleic acid / DNA / DNA - genetics / DNA - metabolism / Evolution / Evolution, Molecular / Female / Gene expression / Gene Expression Regulation - genetics / Gene regulation / Genetic diversity / Genetic variance / Genome - genetics / Genomes / Genomics / Humanities and Social Sciences / Humans / Hypersensitivity / Mammals / Mammals - classification / Mammals - genetics / Monkeys & apes / multidisciplinary / Mutation / Nucleotide sequence / Phylogenetics / Placenta / Placentalia / Pregnancy / Primates / Primates - classification / Primates - genetics / Proteins / Proteins - genetics / Regulatory sequences / Regulatory Sequences, Nucleic Acid - genetics / Reproducibility of Results / Science / Science (multidisciplinary) / Transcription factors / Transcription Factors - metabolism / Vertebrates