亚欧人群色素相关表型的进化与多基因作用机制

Pigmentation related phenotypes (e.g. skin color, hair color, eye color) are important adaptive traits in human evolution, with significant phenotypic diversity and genetic variation. Most genetic studies on pigmentation related phenotypes have been performed in European populations. However, the mechanisms of how genetic variants affecting the pigmentation related phenotypes could be different among populations. Therefore, studies combining multiple populations and studies on admixed populations could help us better understand the genetic and evolutionary mechanisms of pigmentation related phenotypes. In this proposal, we plan to perform genome-wide scans for genetic variants associated with pigmentation related phenotypes in East Asians; compare the associated variants with those discovered in Europeans to uncover the systematic differences; evaluate the relative contribution of those variants in an admixed population of East Asian and European ancestries. Through deep sequencing on targeted genes in the admixed population, we aim to further examine the genetic contribution of rare variants on the pigmentation related phenotypes. From the above results, as well as a meta-analysis combining all the available populations with genome-wide scan data, we will choose the most plausible signals for further functional validations. We will also infer the selection time and coefficient for the responsible variants and systematically compare the difference among populations. This study is only feasible because of the availability of a large amount of samples, data and methods, mostly generated by several fostering projects. By compiling a strong team with various expertise, we ultimately aim to illustrate the general genetic mechanism and evolutionary history of the human pigmentation related phenotypes.

人类色素相关表型（如肤色、发色、眼色）有明显的表型多样性及遗传差异性，是重要的适应性进化特征。针对色素相关表型的遗传研究多在欧洲人群中展开，但造成色素相关表型差异的原因与机制可能存在显著的群体特异性。所以，针对多人群及混合人群进行系统研究，才能更完整地揭示色素相关表型的多基因作用机制与适应性进化规律。本项目计划通过全基因组关联分析定位东亚人群中与色素相关表型关联的遗传变异，比较亚欧人群间色素关联遗传变异的系统性差别，并在亚欧混合人群中定量分析各基因的相对贡献及其多基因互作机制；通过深度测序解析罕见变异对色素相关表型的遗传贡献；整合全基因组关联分析、深度测序分析及荟萃分析的结果，对候选遗传变异进行功能验证；比较候选遗传变异在不同人群中的受选择时间和选择压力。本项目拟利用多个培育项目在样本、数据及方法上的基础，发挥集成优势，通过多角度的研究，最终揭示人类色素相关表型的整体进化规律与遗传机制。

人类色素相关表型（如肤色、眼色、发色）有明显的表型多样性及遗传差异性，是重要的适应性进化特征。针对色素相关表型的遗传研究多在欧洲人群中展开，但造成色素相关表型差异的原因与机制可能存在显著的群体特异性。本项目针对东亚人群、欧洲人群、亚欧混合人群等多个群体进行系统研究，通过全基因组关联分析定位与色素相关表型关联的遗传变异，更完整地揭示了色素相关表型的多基因作用机制与适应性进化规律。汉族人群肤色的全基因组关联分析发现了三个相关位点，其中在SLC24A2基因附近发现了与肤色相关的新位点。通过对肤色相关基因KITLG的适应性进化研究，发现在欧亚人群中自然选择作用于不同的KITLG序列变异，有助于肤色变浅与体温调节以适应高纬度地区的紫外线辐射和冬季低温。汉族人群眼色的全基因组关联分析发现了三个独立的相关位点，其中在OCA2基因上发现了新的与眼色相关的非同义突变位点，分子动力学模拟显示其具有较强的功能性。在对亚欧混合人群的眼色研究中进而发现了五个独立的相关位点，发现其在不同人群中所受到的选择压有显著差异，而这一差异最有可能来源于适应紫外线强度的自然选择。通过多种族发色与眉毛颜色的全基因组关联分析发现了一系列新的关联基因，揭示其多基因互作机制。另外，全基因组关联分析还揭示了耳垂附着程度、毛发形状、眉毛浓度、面部形态等复杂表型的多基因互作机制、受到自然选择的状况，及其在欧亚人群中相关基因的异同，取得一系列重要的微进化相关研究结果。