Adaptive sequence divergence forged new neurodevelopmental enhancers in humans.

Autor:	Mangan RJ; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Alsina FC; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Mosti F; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Sotelo-Fonseca JE; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Snellings DA; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Au EH; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Carvalho J; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Sathyan L; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Johnson GD; Center for Genomic and Computational Biology, Duke University, Durham, NC 27705, USA; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710, USA., Reddy TE; Center for Genomic and Computational Biology, Duke University, Durham, NC 27705, USA; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710, USA., Silver DL; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Duke Institute for Brain Sciences and Duke Regeneration Center, Duke University Medical Center, Durham, NC 27710, USA; Departments of Cell Biology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA., Lowe CB; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Center for Genomic and Computational Biology, Duke University, Durham, NC 27705, USA. Electronic address: craig.lowe@duke.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2022 Nov 23; Vol. 185 (24), pp. 4587-4603.e23.
DOI:	10.1016/j.cell.2022.10.016
Abstrakt:	Searches for the genetic underpinnings of uniquely human traits have focused on human-specific divergence in conserved genomic regions, which reflects adaptive modifications of existing functional elements. However, the study of conserved regions excludes functional elements that descended from previously neutral regions. Here, we demonstrate that the fastest-evolved regions of the human genome, which we term "human ancestor quickly evolved regions" (HAQERs), rapidly diverged in an episodic burst of directional positive selection prior to the human-Neanderthal split, before transitioning to constraint within hominins. HAQERs are enriched for bivalent chromatin states, particularly in gastrointestinal and neurodevelopmental tissues, and genetic variants linked to neurodevelopmental disease. We developed a multiplex, single-cell in vivo enhancer assay to discover that rapid sequence divergence in HAQERs generated hominin-unique enhancers in the developing cerebral cortex. We propose that a lack of pleiotropic constraints and elevated mutation rates poised HAQERs for rapid adaptation and subsequent susceptibility to disease. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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