The adaptive variation of human skin: A comprehensive anthropological genetics examination of epidermal differentiation complex

皮肤是人类最明显和最显著的特征之一，了解人类皮肤的变化对人类生物学领域具有重要意义。事实上，在过去十年中，在皮肤色素沉着的遗传和发育基础方面取得了很大进展，解释了人类群体内和人群之间皮肤颜色的变化。然而，皮肤的其他重要性质，特别是其屏障功能的变化，还没有得到很好的表征。这项建议使用最先进的基因组方法来确定皮肤屏障变异的程度和进化相关性，并解决为什么人类群体中仍然存在潜在的有害变异。这项拟议的研究是将新的基因组和计算技术应用于人类学问题的前沿。在这一项目的背景下设计了具体的课程和讲习班，以建立一个主要的中心，培训本科生和研究生的下一代生物人类学家。此外，通过不断的公共互动，这项研究有助于更好地理解皮肤的生物进化是如何独立于身份的文化构建的。最近可用的现代和古代基因组使人们能够全面了解人类基因组中的进化签名。此外，长读测序技术现在可以对基因组结构变异(例如DNA片段的缺失和复制)进行准确的研究，这些变异对人类进化和生物变异具有过大的影响。这项拟议的研究利用这些新的可用资源来研究表皮分化复合体的进化，表皮分化复合体是人类1号染色体上的一个2Mb区域，包含50多个已知在皮肤发育和功能中起作用的基因。这个复合体中的基因参与了几个重要的功能，如免疫反应、隔绝紫外线、热、湿和伤口愈合。初步工作表明，包括致病压力在内的多种特定地理适应力量的存在，塑造了该地区的遗传变异，为人类皮肤屏障功能的进化提供了一瞥。该项目就是在这一前提下展开的，目的是提供迄今为止对作用于表皮分化复合体基因的进化力量的最全面的理解。此外，该项目还确定了对人类皮肤表型变异具有人类学意义的遗传变异，因此是下游功能研究的完美目标。该项目还将为未来的人类学遗传学研究，特别是与人类基因组结构变异有关的研究奠定方法论基础。

Skin is one of the most visible and distinguishing characteristics of humans, and understanding skin variation among humans is of central importance to the field of human biology. Indeed, there have been great advances in the last decade with regards to the genetic and developmental bases of pigmentation of the skin, explaining variation of skin color within and among human populations. However, variation in other important properties of skin, especially its barrier function, has not been well characterized. This proposal uses state-of-the-art genomic approaches to determine the extent and evolutionary relevance of skin barrier variation and address why potentially detrimental variants remain in human populations. The proposed study is at the forefront of applying novel genomic and computational technologies to anthropological questions. Specific courses and workshops are designed within the context of this project to create a major hub for training the next generation of biological anthropologists, both at the undergraduate and graduate levels. In addition, with constant public interaction, the research contributes to a better understanding of how biological evolution of the skin is independent of the cultural constructs of identity.Recently available modern and ancient genomes allow for a comprehensive look at the evolutionary signatures in the human genome. In addition, long-read sequencing technologies now permit accurate investigation of genomic structural variants (e.g., deletions and duplications of DNA segments), which have an outsized impact on human evolution and biological variation. The proposed study uses these newly available resources to investigate the evolution of the epidermal differentiation complex, a 2Mb region on human chromosome 1, which harbors more than 50 genes with known roles in skin development and function. The genes in this complex are involved in several important functions, such as immune response, insulation from UV light, heat, moisture, and wound healing. Preliminary work indicates the presence of multiple geography-specific adaptive forces, including pathogenic pressures, shaping the genetic variation in this region, providing a glimpse of the evolution of skin barrier function in humans. The proposed project expands on this premise, to provide the most comprehensive understanding to date of the evolutionary forces acting on epidermal differentiation complex genes. In addition, the project identifies genetic variants that are of anthropological significance for human skin phenotypic variation, and are thus perfect targets for downstream functional studies. The project will also lay a methodological groundwork for future anthropological genetic studies, especially pertaining to structural variation in the human genome.