Identification of constrained sequence elements across 239 primate genomes

Kuderna, Lukas F. K. and Ulirsch, Jacob C. and Rashid, Sabrina and Ameen, Mohamed and Sundaram, Laksshman and Hickey, Glenn and Cox, Anthony J. and Gao, Hong and Kumar, Arvind and Aguet, Francois and Christmas, Matthew J. and Clawson, Hiram and Haeussler, Maximilian and Janiak, Mareike C. and Kuhlwilm, Martin and Orkin, Joseph D. and Bataillon, Thomas and Manu, Shivakumara and Valenzuela, Alejandro and Bergman, Juraj and Rouselle, Marjolaine and Silva, Felipe Ennes and Agueda, Lidia and Blanc, Julie and Gut, Marta and de Vries, Dorien and Goodhead, Ian and Harris, R. Alan and Raveendran, Muthuswamy and Jensen, Axel and Chuma, Idriss S. and Horvath, Julie E. and Hvilsom, Christina and Juan, David and Frandsen, Peter and Schraiber, Joshua G. and de Melo, Fabiano R. and Bertuol, Fabrício and Byrne, Hazel and Sampaio, Iracilda and Farias, Izeni and Valsecchi, João and Messias, Malu and da Silva, Maria N. F. and Trivedi, Mihir and Rossi, Rogerio and Hrbek, Tomas and Andriaholinirina, Nicole and Rabarivola, Clément J. and Zaramody, Alphonse and Jolly, Clifford J. and Phillips-Conroy, Jane and Wilkerson, Gregory and Abee, Christian and Simmons, Joe H. and Fernandez-Duque, Eduardo and Kanthaswamy, Sree and Shiferaw, Fekadu and Wu, Dongdong and Zhou, Long and Shao, Yong and Zhang, Guojie and Keyyu, Julius D. and Knauf, Sascha and Le, Minh D. and Lizano, Esther and Merker, Stefan and Navarro, Arcadi and Nadler, Tilo and Khor, Chiea Chuen and Lee, Jessica and Tan, Patrick and Lim, Weng Khong and Kitchener, Andrew C. and Zinner, Dietmar and Gut, Ivo and Melin, Amanda D. and Guschanski, Katerina and Schierup, Mikkel Heide and Beck, Robin M. D. and Karakikes, Ioannis and Wang, Kevin C. and Umapathy, Govindhaswamy and Roos, Christian and Boubli, Jean P. and Siepel, Adam and Kundaje, Anshul and Paten, Benedict and Lindblad-Toh, Kerstin and Rogers, Jeffrey and Marques Bonet, Tomas and Farh, Kyle Kai-How (2023) Identification of constrained sequence elements across 239 primate genomes. Nature. ISSN 0028-0836

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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 genome3,4,5,6,7,8,9. 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.

Item Type: Article
Subjects: European Repository > Geological Science
Depositing User: Managing Editor
Date Deposited: 14 Dec 2023 12:06
Last Modified: 14 Dec 2023 12:06
URI: http://go7publish.com/id/eprint/3961

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