Mammalian evolution of human cis-regulatory elements and transcription factor binding sites
Author:
Andrews Gregory1ORCID, Fan Kaili1ORCID, Pratt Henry E.1ORCID, Phalke Nishigandha1, Karlsson Elinor K.123ORCID, Lindblad-Toh Kerstin24ORCID, Gazal Steven56ORCID, Moore Jill E.1ORCID, Weng Zhiping1ORCID, Andrews Gregory, Armstrong Joel C., Bianchi Matteo, Birren Bruce W., Bredemeyer Kevin R., Breit Ana M., Christmas Matthew J., Clawson Hiram, Damas Joana, Di Palma Federica, Diekhans Mark, Dong Michael X., Eizirik Eduardo, Fan Kaili, Fanter Cornelia, Foley Nicole M., Forsberg-Nilsson Karin, Garcia Carlos J., Gatesy John, Gazal Steven, Genereux Diane P., Goodman Linda, Grimshaw Jenna, Halsey Michaela K., Harris Andrew J., Hickey Glenn, Hiller Michael, Hindle Allyson G., Hubley Robert M., Hughes Graham M., Johnson Jeremy, Juan David, Kaplow Irene M., Karlsson Elinor K., Keough Kathleen C., Kirilenko Bogdan, Koepfli Klaus-Peter, Korstian Jennifer M., Kowalczyk Amanda, Kozyrev Sergey V., Lawler Alyssa J., Lawless Colleen, Lehmann Thomas, Levesque Danielle L., Lewin Harris A., Li Xue, Lind Abigail, Lindblad-Toh Kerstin, Mackay-Smith Ava, Marinescu Voichita D., Marques-Bonet Tomas, Mason Victor C., Meadows Jennifer R. S., Meyer Wynn K., Moore Jill E., Moreira Lucas R., Moreno-Santillan Diana D., Morrill Kathleen M., Muntané Gerard, Murphy William J., Navarro Arcadi, Nweeia Martin, Ortmann Sylvia, Osmanski Austin, Paten Benedict, Paulat Nicole S., Pfenning Andreas R., Phan BaDoi N., Pollard Katherine S., Pratt Henry E., Ray David A., Reilly Steven K., Rosen Jeb R., Ruf Irina, Ryan Louise, Ryder Oliver A., Sabeti Pardis C., Schäffer Daniel E., Serres Aitor, Shapiro Beth, Smit Arian F. A., Springer Mark, Srinivasan Chaitanya, Steiner Cynthia, Storer Jessica M., Sullivan Kevin A. M., Sullivan Patrick F., Sundström Elisabeth, Supple Megan A., Swofford Ross, Talbot Joy-El, Teeling Emma, Turner-Maier Jason, Valenzuela Alejandro, Wagner Franziska, Wallerman Ola, Wang Chao, Wang Juehan, Weng Zhiping, Wilder Aryn P., Wirthlin Morgan E., Xue James R., Zhang Xiaomeng,
Affiliation:
1. Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA. 2. Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA. 3. Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605, USA. 4. Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 75132 Uppsala, Sweden. 5. Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. 6. Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Abstract
Understanding the regulatory landscape of the human genome is a long-standing objective of modern biology. Using the reference-free alignment across 241 mammalian genomes produced by the Zoonomia Consortium, we charted evolutionary trajectories for 0.92 million human candidate cis-regulatory elements (cCREs) and 15.6 million human transcription factor binding sites (TFBSs). We identified 439,461 cCREs and 2,024,062 TFBSs under evolutionary constraint. Genes near constrained elements perform fundamental cellular processes, whereas genes near primate-specific elements are involved in environmental interaction, including odor perception and immune response. About 20% of TFBSs are transposable element–derived and exhibit intricate patterns of gains and losses during primate evolution whereas sequence variants associated with complex traits are enriched in constrained TFBSs. Our annotations illuminate the regulatory functions of the human genome.
Publisher
American Association for the Advancement of Science (AAAS)
Subject
Multidisciplinary
Cited by
16 articles.
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