气候变化领域集成服务门户(CCPortal): Massively parallel discovery of human-specific substitutions that alter enhancer activity

CCPortal

DOI	10.1073/pnas.2007049118
	Massively parallel discovery of human-specific substitutions that alter enhancer activity
	Uebbing S.; Gockley J.; Reilly S.K.; Kocher A.A.; Geller E.; Gandotra N.; Scharfe C.; Cotney J.; Noonan J.P.
发表日期	2021
ISSN	00278424
卷号	118 期号:2
英文摘要	Genetic changes that altered the function of gene regulatory elements have been implicated in the evolution of human traits such as the expansion of the cerebral cortex. However, identifying the particular changes that modified regulatory activity during human evolution remain challenging. Here we used massively parallel enhancer assays in neural stem cells to quantify the functional impact of >32,000 human-specific substitutions in >4,300 human accelerated regions (HARs) and human gain enhancers (HGEs), which include enhancers with novel activities in humans. We found that >30% of active HARs and HGEs exhibited differential activity between human and chimpanzee. We isolated the effects of human-specific substitutions from background genetic variation to identify the effects of genetic changes most relevant to human evolution. We found that substitutions interacted in both additive and nonadditive ways to modify enhancer function. Substitutions within HARs, which are highly constrained compared to HGEs, showed smaller effects on enhancer activity, suggesting that the impact of human-specific substitutions is buffered in enhancers with constrained ancestral functions. Our findings yield insight into how human-specific genetic changes altered enhancer function and provide a rich set of candidates for studies of regulatory evolution in humans. © This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
英文关键词	Enhancer evolution; Gene regulation; Human accelerated regions; Massively parallel enhancer assay; Neurodevelopment
语种	英语
scopus关键词	article; chimpanzee; controlled study; enhancer region; gene control; genetic variation; human; human cell; nervous system development; neural stem cell; nonhuman
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/181059
作者单位	Department of Genetics, Yale School of Medicine, New Haven, CT 06510, United States; Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06520, United States; Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, United States; Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, United States
推荐引用方式 GB/T 7714	Uebbing S.,Gockley J.,Reilly S.K.,et al. Massively parallel discovery of human-specific substitutions that alter enhancer activity[J],2021,118(2).
APA	Uebbing S..,Gockley J..,Reilly S.K..,Kocher A.A..,Geller E..,...&Noonan J.P..(2021).Massively parallel discovery of human-specific substitutions that alter enhancer activity.Proceedings of the National Academy of Sciences of the United States of America,118(2).
MLA	Uebbing S.,et al."Massively parallel discovery of human-specific substitutions that alter enhancer activity".Proceedings of the National Academy of Sciences of the United States of America 118.2(2021).