The Genetic Basis for the Evolution of Adaptive Skin Appendage Traits in Humans

人类皮肤的“裸露”外观是人类区别于所有其他灵长类动物的特征。这种引人注目的外表是由于体毛的缩小和汗腺密度的增加（大约是黑猩猩的10倍）。这些适应使人类能够通过增加皮肤上的空气流动和皮肤表面的水分蒸发来降低体温。该项目将发现并解释人类特定的头发和汗腺组成的进化修饰背后的基因组变化。生物学的见解，以及作为该研究计划的一部分而开发的数据、方法和工具，将为更广泛地改变对其他适应性皮肤特征和皮肤生理学的遗传基础的研究提供新的资产。该项目产生的数据还将推动正在进行的在体外构建和正确模式头发和汗腺的努力，这是全面的人类皮肤再生的主要障碍。此外，该项目将支持培训代表性不足的少数民族学生和研究人员，并资助开发一个关于人类皮肤进化的公共教育网站，该网站将突出皮肤进化中的突出问题，并整理有关该主题的正在进行的和新的发现。这个研究项目建立在研究小组最近发现的基础上，即增加内分泌腺密度的生物信号子集也会改变头发的发育，导致头发大小减少。该项目的工作假设是，相对于其他灵长类动物，人类已经获得了调控序列的进化突变，导致伴随的分泌腺密度增加和毛发大小减少。研究人员将(i)绘制出控制关键发育因子En1表达的调控序列或增强子，En1相互调节内分泌汗腺密度和头发大小；（ii）通过使用不同的人类和黑猩猩调节序列的基因组编辑小鼠模型，研究人类特异性变化的功能意义，定义这些增强子内的基因组变化，这些增强子促成了人类独特的毛发和汗腺特征。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The "bare" appearance of human skin is a trait that distinguishes humans from all other primates. This striking appearance results from miniaturized body hair and increased sweat gland density (approximately 10 times higher than that of a chimpanzee). These adaptations allow humans to cool their body temperature through increased air flow over the skin and evaporation of water from the skin surface. This project will find and explain the genomic changes underlying the human-specific evolutionary modifications to hair and sweat gland composition. The biological insights, as well as the data, methods and tools developed as part of this research program, will provide novel assets to transform the investigation of the genetic bases of other adaptive skin traits and skin physiology more generally. The data generated by this project also will advance ongoing efforts to build and properly pattern hair and eccrine glands in vitro, a major obstacle in comprehensive human skin regeneration. In addition, this project will support the training of under-represented minority students and researchers, and fund the development of a public, educational website on human skin evolution, which will highlight outstanding questions in skin evolution and curate ongoing and new discoveries on this topic.This research program builds on the recent discovery by the research team that a subset of biological signals that increase eccrine gland density also alter hair development, leading to diminished hair size. The working hypothesis of this project is that humans have acquired evolutionary mutations in regulatory sequences leading to concomitantly increased eccrine gland density and diminished hair size relative to other primates. The researchers will (i) map out the regulatory sequences, or enhancers, that control the expression of a key developmental factor, En1, that reciprocally regulates eccrine sweat gland density and hair size; (ii) define the genomic changes within these enhancers that contributed to unique hair and sweat gland traits in humans, by investigating the functional significance of human-specific changes using genome edited mouse models of diverged human and chimpanzee regulatory sequences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.