Identification of constrained sequence elements across 239 primate genomes

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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)735-742
Number of pages8
JournalNature
Volume625
Issue number7996
DOIs
StatePublished - Jan 25 2024

ASJC Scopus subject areas

  • General

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