The functional and evolutionary impacts of human-specific deletions in conserved elements
Author:
Xue James R.12ORCID, Mackay-Smith Ava3ORCID, Mouri Kousuke4ORCID, Garcia Meilin Fernandez5ORCID, Dong Michael X.6ORCID, Akers Jared F.3ORCID, Noble Mark3ORCID, Li Xue178ORCID, Lindblad-Toh Kerstin16ORCID, Karlsson Elinor K.178ORCID, Noonan James P.3910ORCID, Capellini Terence D.111ORCID, Brennand Kristen J.35ORCID, Tewhey Ryan41213ORCID, Sabeti Pardis C.121415ORCID, Reilly Steven K.3ORCID, 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. Broad Institute of MIT and Harvard, Cambridge, MA, USA. 2. Center for System Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA. 3. Department of Genetics, Yale School of Medicine, New Haven, CT, USA. 4. The Jackson Laboratory, Bar Harbor, ME, USA. 5. Department of Psychiatry, Yale University, New Haven, CT, USA. 6. Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. 7. Program in Bioinformatics and Integrative Biology, UMass Chan Medical School, Worcester, MA, USA. 8. Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA, USA. 9. Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA. 10. Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA. 11. Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. 12. Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, USA. 13. Graduate School of Biomedical Sciences Tufts University School of Medicine, Boston, MA, USA. 14. Howard Hughes Medical Institute, Chevy Chase, MD, USA. 15. Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Abstract
Conserved genomic sequences disrupted in humans may underlie uniquely human phenotypic traits. We identified and characterized 10,032 human-specific conserved deletions (hCONDELs). These short (average 2.56 base pairs) deletions are enriched for human brain functions across genetic, epigenomic, and transcriptomic datasets. Using massively parallel reporter assays in six cell types, we discovered 800 hCONDELs conferring significant differences in regulatory activity, half of which enhance rather than disrupt regulatory function. We highlight several hCONDELs with putative human-specific effects on brain development, including
HDAC5
,
CPEB4
, and
PPP2CA
. Reverting an hCONDEL to the ancestral sequence alters the expression of
LOXL2
and developmental genes involved in myelination and synaptic function. Our data provide a rich resource to investigate the evolutionary mechanisms driving new traits in humans and other species.
Publisher
American Association for the Advancement of Science (AAAS)
Subject
Multidisciplinary
Cited by
21 articles.
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