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 Bergman, Marjolaine Rouselle, Felipe Ennes Silva, Lidia Agueda, Julie Blanc, Marta Gut, Dorien 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. Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, João Valsecchi, Malu Messias, Maria N. F. 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 () and Kyle Kai-How Farh ()
Additional contact information
Lukas F. K. Kuderna: Illumina
Jacob C. Ulirsch: Illumina
Sabrina Rashid: Illumina
Mohamed Ameen: Illumina
Laksshman Sundaram: Illumina
Glenn Hickey: University of California
Anthony J. Cox: Illumina
Hong Gao: Illumina
Arvind Kumar: Illumina
Francois Aguet: Illumina
Matthew J. Christmas: Uppsala University
Hiram Clawson: University of California
Maximilian Haeussler: University of California
Mareike C. Janiak: University of Salford
Martin Kuhlwilm: University of Vienna
Joseph D. Orkin: Université de Montréal
Thomas Bataillon: Aarhus University
Shivakumara Manu: Academy of Scientific and Innovative Research (AcSIR)
Alejandro Valenzuela: Universitat Pompeu Fabra
Juraj Bergman: Aarhus University
Marjolaine Rouselle: Aarhus University
Felipe Ennes Silva: Research Group on Primate Biology and Conservation, Mamirauá Institute for Sustainable Development
Lidia Agueda: Centro Nacional de Analisis Genomico (CNAG)
Julie Blanc: Centro Nacional de Analisis Genomico (CNAG)
Marta Gut: Centro Nacional de Analisis Genomico (CNAG)
Dorien Vries: University of Salford
Ian Goodhead: University of Salford
R. Alan Harris: Baylor College of Medicine
Muthuswamy Raveendran: Baylor College of Medicine
Axel Jensen: Uppsala University
Idriss S. Chuma: Tanzania National Parks
Julie E. Horvath: North Carolina Museum of Natural Sciences
Christina Hvilsom: Copenhagen Zoo
David Juan: Universitat Pompeu Fabra
Peter Frandsen: Copenhagen Zoo
Joshua G. Schraiber: Illumina
Fabiano R. Melo: Universidade Federal de Viçosa
Fabrício Bertuol: Universidade Federal do Amazonas, Departamento de Genética, Laboratório de Evolução e Genética Animal (LEGAL)
Hazel Byrne: University of Utah
Iracilda Sampaio: Universidade Federal do Para
Izeni Farias: Universidade Federal do Amazonas, Departamento de Genética, Laboratório de Evolução e Genética Animal (LEGAL)
João Valsecchi: Research Group on Terrestrial Vertebrate Ecology, Mamirauá Institute for Sustainable Development
Malu Messias: Universidade Federal de Rondônia
Maria N. F. Silva: Instituto Nacional de Pesquisas da Amazônia
Mihir Trivedi: CSIR-Centre for Cellular and Molecular Biology
Rogerio Rossi: Universidade Federal do Mato Grosso
Tomas Hrbek: Universidade Federal do Amazonas, Departamento de Genética, Laboratório de Evolução e Genética Animal (LEGAL)
Nicole Andriaholinirina: University of Mahajanga
Clément J. Rabarivola: University of Mahajanga
Alphonse Zaramody: University of Mahajanga
Clifford J. Jolly: New York University
Jane Phillips-Conroy: Washington University School of Medicine in St Louis
Gregory Wilkerson: MD Anderson Cancer Center
Christian Abee: MD Anderson Cancer Center
Joe H. Simmons: MD Anderson Cancer Center
Eduardo Fernandez-Duque: Yale University
Sree Kanthaswamy: Arizona State University
Fekadu Shiferaw: Guinea Worm Eradication Program, The Carter Center Ethiopia
Dongdong Wu: Chinese Academy of Sciences
Long Zhou: Zhejiang University School of Medicine
Yong Shao: Chinese Academy of Sciences
Guojie Zhang: Chinese Academy of Sciences
Julius D. Keyyu: Tanzania Wildlife Research Institute (TAWIRI)
Sascha Knauf: Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health
Minh D. Le: University of Science and Central Institute for Natural Resources and Environmental Studies, Vietnam National University
Esther Lizano: Universitat Pompeu Fabra
Stefan Merker: State Museum of Natural History Stuttgart
Arcadi Navarro: Universitat Pompeu Fabra
Tilo Nadler: Cuc Phuong Commune
Chiea Chuen Khor: Agency for Science, Technology and Research
Jessica Lee: Mandai Nature
Patrick Tan: Agency for Science, Technology and Research
Weng Khong Lim: SingHealth Duke–NUS Institute of Precision Medicine (PRISM)
Andrew C. Kitchener: National Museums Scotland
Dietmar Zinner: Leibniz Institute for Primate Research
Ivo Gut: Centro Nacional de Analisis Genomico (CNAG)
Amanda D. Melin: University of Calgary
Katerina Guschanski: Uppsala University
Mikkel Heide Schierup: Aarhus University
Robin M. D. Beck: University of Salford
Ioannis Karakikes: Stanford University
Kevin C. Wang: Stanford University
Govindhaswamy Umapathy: Academy of Scientific and Innovative Research (AcSIR)
Christian Roos: Leibniz Institute for Primate Research
Jean P. Boubli: University of Salford
Adam Siepel: Cold Spring Harbor Laboratory
Anshul Kundaje: Stanford University
Benedict Paten: University of California
Kerstin Lindblad-Toh: Uppsala University
Jeffrey Rogers: Baylor College of Medicine
Tomas Marques Bonet: Universitat Pompeu Fabra
Kyle Kai-How Farh: Illumina

Nature, 2024, vol. 625, issue 7996, 735-742

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-023-06798-8

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