Identification of constrained sequence elements across 239 primate genomes

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 spe...

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Detalles Bibliográficos
Autores: Kuderna, Lukas F. K.|||0000-0002-9992-9295, Ulirsch, Jacob C., Rashid, Sabrina, Ameen, Mohamed, Sundaram, Laksshman, Hickey, Glenn, Cox, Anthony J., Gao, Hong, Kumar, Arvind, Aguet, Francois|||0000-0001-9414-300X, Christmas, Matthew J., Clawson, Hiram, Haeussler, Maximilian, Janiak, Mareike|||0000-0002-7759-2556, Kuhlwilm, Martin|||0000-0002-0115-1797, Orkin, Joseph|||0000-0001-6922-2072, Bataillon, Thomas, Shivakumara, Manu, Valenzuela Oliver, Alejandro|||0000-0001-6120-6246, Bergman, Juraj, Rouselle, Marjolaine, Silva, Felipe Ennes, Agueda Calpena, Lidia|||0000-0003-3358-2759, Blanc, Julie, Gut, Marta|||0000-0002-4063-7159, de Vries, Dorien|||0000-0002-6809-0052, Goodhead, Ian|||0000-0002-3110-9442, Harris, R. Alan|||0000-0002-7333-4752, Raveendran, Muthuswamy|||0000-0001-6185-4059, Jensen, Axel|||0000-0003-1766-560X, Chuma, Idriss S., Horvath, Julie E., Hvilsom, Christina, Juan, David|||0000-0003-1912-9667, Frandsen, Peter, Schraiber, Joshua G., de Melo, Fabiano R.|||0000-0001-9958-2036, Bertuol, Fabrício|||0000-0001-6431-6950, Byrne, Hazel, Sampaio, Iracilda|||0000-0002-2137-4656, Pires Farias, Izeni|||0000-0002-1416-4351, Valsecchi, João|||0000-0002-9138-0381, Messias, Mariluce|||0000-0002-8322-3327, da Silva, Maria N. F., Trivedi, Mihir, Rossi, Rogerio, Hrbek, Tomas|||0000-0003-3239-7068, Andriaholinirina, Nicole, Rabarivola, Clément J., Zaramody, Alphonse, Jolly, Clifford J., Phillips-Conroy, Jane, Wilkerson, Gregory|||0000-0002-3773-1064, Abbee, C., Simmons, Joe H.|||0000-0003-1815-6831, Fernandez-Duque, Eduardo|||0000-0002-3993-7912, Kanthaswamy, Sree, Shiferaw, Fekadu, Wu, Dong-Dong|||0000-0001-7101-7297, Zhou, Long|||0000-0001-7596-2691, Shao, Yong|||0000-0003-1704-8425, Zhang, Guojie|||0000-0001-6860-1521, Keyyu, Julius D., Knauf, Sascha|||0000-0001-5744-4946, Le, Minh D., Lizano, Esther|||0000-0003-3304-9807, Merker, Stefan|||0000-0003-3142-7720, Navarro, Arcadi|||0000-0003-2162-8246, Nadler, Tilo, Khor, Chiea Chuen|||0000-0002-1128-4729, Lee, Jessica, Tan, Patrick, Lim, Weng Khong, Kitchener, Andrew C., Zinner, Dietmar, Gut, Ivo|||0000-0001-7219-632X, Melin, Amanda D.|||0000-0002-0612-2514, Guschanski, Katerina|||0000-0002-8493-5457, Schierup, Mikkel Heide|||0000-0002-5028-1790, Beck, Robin|||0000-0002-7050-7072, Karakikes, Ioannis, Wang, Kevin C., Umapathy, Govindhaswamy, Roos, Christian|||0000-0003-0190-4266, Boubli, Jean|||0000-0002-5833-9264, Siepel, Adam|||0000-0002-3557-7219, Kundaje, Anshul|||0000-0003-3084-2287, Paten, Benedict|||0000-0001-8863-3539, Lindblad-Toh, Kerstin|||0000-0001-8338-0253, Rogers, Jeffrey|||0000-0002-7374-6490, Marquès i Bonet, Tomàs|||0000-0002-5597-3075, Farh, Kyle Kai-How|||0000-0001-6947-8537
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:285370
Acceso en línea:https://ddd.uab.cat/record/285370
https://dx.doi.org/urn:doi:10.1038/s41586-023-06798-8
Access Level:acceso abierto
Palabra clave:Comparative genomics
Evolutionary genetics
Genetic variation
Genome evolution
Transcriptional regulatory elements
Descripción
Sumario: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 DNA10, the relatively short timescales separating primate species, 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.

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