气候变化领域集成服务门户(CCPortal): Repeated mutation of a developmental enhancer contributed to human thermoregulatory evolution

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DOI	10.1073/pnas.2021722118
	Repeated mutation of a developmental enhancer contributed to human thermoregulatory evolution
	Aldea D.; Atsuta Y.; Kokalari B.; Schaffner S.F.; Prasasya R.D.; Aharoni A.; Dingwall H.L.; Warder B.; Kamberov Y.G.
发表日期	2021
ISSN	00278424
卷号	118 期号:16
英文摘要	Humans sweat to cool their bodies and have by far the highest eccrine sweat gland density among primates. Humans' high eccrine gland density has long been recognized as a hallmark human evolutionary adaptation, but its genetic basis has been unknown. In humans, expression of the Engrailed 1 (EN1) transcription factor correlates with the onset of eccrine gland formation. In mice, regulation of ectodermal En1 expression is a major determinant of natural variation in eccrine gland density between strains, and increased En1 expression promotes the specification of more eccrine glands. Here, we show that regulation of EN1 has evolved specifically on the human lineage to promote eccrine gland formation. Using comparative genomics and validation of ectodermal enhancer activity in mice, we identified a human EN1 skin enhancer, hECE18. We showed that multiple epistatically interacting derived substitutions in the human ECE18 enhancer increased its activity compared with nonhuman ape orthologs in cultured keratinocytes. Repression of hECE18 in human cultured keratinocytes specifically attenuated EN1 expression, indicating this element positively regulates EN1 in this context. In a humanized enhancer knock-in mouse, hECE18 increased developmental En1 expression in the skin to induce the formation of more eccrine glands. Our study uncovers a genetic basis contributing to the evolution of one of the most singular human adaptations and implicates multiple interacting mutations in a single enhancer as a mechanism for human evolutionary change. © This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
英文关键词	Eccrine gland; Engrailed 1; Human evolution; Regulatory evolution; Sweat
语种	英语
scopus关键词	animal cell; animal experiment; animal model; article; cell culture; comparative genomics; controlled study; eccrine gland; ectoderm; enhancer region; human; keratinocyte; male; mouse; nonhuman; orthology; protein expression
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/179832
作者单位	Department of Genetics, Perelman School of Medicine, Philadelphia, PA 19104, United States; Genetics Department, Harvard Medical School, Boston, MA 02115, United States; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02138, United States; Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, Philadelphia, PA 19104, United States
推荐引用方式 GB/T 7714	Aldea D.,Atsuta Y.,Kokalari B.,et al. Repeated mutation of a developmental enhancer contributed to human thermoregulatory evolution[J],2021,118(16).
APA	Aldea D..,Atsuta Y..,Kokalari B..,Schaffner S.F..,Prasasya R.D..,...&Kamberov Y.G..(2021).Repeated mutation of a developmental enhancer contributed to human thermoregulatory evolution.Proceedings of the National Academy of Sciences of the United States of America,118(16).
MLA	Aldea D.,et al."Repeated mutation of a developmental enhancer contributed to human thermoregulatory evolution".Proceedings of the National Academy of Sciences of the United States of America 118.16(2021).