Repeated mutation of a developmental enhancer contributed to human thermoregulatory evolution
| العنوان: | Repeated mutation of a developmental enhancer contributed to human thermoregulatory evolution |
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| المؤلفون: | Bailey Warder, Daniel Aldea, Heather L. Dingwall, Adam Aharoni, Yana G. Kamberov, Yuji Atsuta, Rexxi D. Prasasya, Blerina Kokalari, Stephen F. Schaffner |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Keratinocytes, Lineage (genetic), Evolution, Mice, Transgenic, Sweating, Context (language use), Eccrine Glands, Regulatory Sequences, Nucleic Acid, Biology, medicine.disease_cause, Evolution, Molecular, Mice, human evolution, Engrailed 1, eccrine gland, regulatory evolution, Ectoderm, medicine, Animals, Humans, Eccrine sweat gland, Enhancer, Psychological repression, Transcription factor, Skin, Homeodomain Proteins, Comparative genomics, Mutation, Multidisciplinary, integumentary system, Biological Sciences, Biological Evolution, Cell biology, Mice, Inbred C57BL, sweat, Enhancer Elements, Genetic, medicine.anatomical_structure, Body Temperature Regulation, Transcription Factors |
| الوصف: | Significance One of the most distinctive physiological traits differentiating humans from other primates is a reliance on sweating to cool off. The effectiveness of human thermoregulatory sweating is underlain by the evolution of a dramatically increased density of water-secreting eccrine sweat glands in human skin relative to that of other primates. Here, we show that the accumulation of human-specific mutations in a developmental enhancer collectively promoted the production of eccrine glands in humans by up-regulating the expression of the Engrailed 1 transcription factor in the skin. This study reveals a mechanism that contributed to the evolution of humans’ signature thermoregulatory capabilities and underscores the importance of regulatory evolution in generating the modern human form. 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. |
| تدمد: | 1091-6490 0027-8424 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::54bf2ebc324165ab159309023d0150e6Test https://doi.org/10.1073/pnas.2021722118Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....54bf2ebc324165ab159309023d0150e6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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