Identifying the genetic architecture of pigmentary traits in populations of diverse ancestry

在人群中观察到的皮肤、毛发和虹膜色素沉着的显著变化是由于黑色素的数量、类型和分布的差异，黑色素是由称为黑素细胞的专门细胞合成的。关于这些特征所涉及的基因的详细情况还远未完成。特别是，很少有研究集中在非欧洲人群的色素沉着的遗传学，尽管这些人群的皮肤，头发和虹膜颜色的定量研究表明，这些特征有很大的多样性。** 在这个项目中，我建议在一个大样本的不同血统的个体（东亚，欧洲和南亚血统的3,000人，每组1,000人）中确定负责皮肤，头发和虹膜颜色以及虹膜结构正常变化的遗传标记。将获得每个人的皮肤和毛发色素沉着（使用反射光谱法）以及虹膜颜色和结构（使用高分辨率摄影）的详细定量测量，并将使用微阵列来表征整个基因组中超过170万个遗传标记。这将使得有可能评估遗传标记与色素性状和虹膜结构的关联。** 色素沉着是一个特别迷人的表型研究在人类群体中，因为在许多方面，它是一个非典型的性状。许多遗传学研究表明，由于主要大陆群体之间的差异而产生的遗传变异的平均比例仅占总遗传变异的10-15%。相反，猪的性状在大陆种群之间表现出很大的差异。造成这种差异的原因主要可以追溯到自然选择的强烈影响，自然选择根据明显的纬度梯度塑造了色素的分布。从进化、遗传和人类学的角度来看，对不同祖先群体中色素沉着表型的系统研究是很重要的;它将澄清在我们物种中观察到的分子变异和表型多样性之间的联系，同时提供关于不同因素（特别是自然选择）如何塑造色素沉着和色素沉着基因进化的见解。从生物医学的角度来看，这项研究也是相关的，因为许多与常见色素变化相关的变异也与皮肤癌风险相关。最后，本项目将探索虹膜结构的遗传结构（例如，收缩沟、Fuchs隐窝、痣和Wolfflin结节）。这些特征在人群中表现出很大的差异，但很少有研究致力于识别这种差异背后的遗传因素。

The remarkable variation in skin, hair and iris pigmentation observed in human populations is due to differences in the amount, type and distribution of melanin, which is synthesized by specialized cells known as melanocytes. The detailed picture of the genes involved in these traits remains far from complete. In particular, very few studies have focused on the genetics of pigmentation in non-European populations, in spite of the fact that quantitative studies of skin, hair and iris color in these populations show that there is substantial diversity in these traits. ******In this project, I propose to identify genetic markers responsible for normal variation in skin, hair and iris colour, as well as iris structure, in a large sample of individuals of diverse ancestry (3,000 individuals of East Asian, European and South Asian ancestry, 1,000 per group). Detailed quantitative measures of skin and hair pigmentation (using reflectance spectroscopy), and iris colour and structure (using high-resolution photography), will be obtained for each individual, and a microarray will be used to characterize more than 1.7 million genetic markers throughout the genome. This will make it possible to evaluate the association of the genetic markers with pigmentary traits and iris structure. ******Pigmentation is a particularly fascinating phenotype to study in human populations, because in many respects it is an atypical trait. Numerous genetic studies have indicated that the average proportion of genetic variation due to differences between major continental groups is just 10-15% of the total genetic variation. In contrast, pigmentary traits show large differences between continental populations. The reasons for this discrepancy can be traced back primarily to the strong influence of natural selection, which has shaped the distribution of pigmentation according to a clear latitudinal gradient. The proposed systematic study of pigmentary phenotypes in populations of diverse ancestry is important from evolutionary, genetic, and anthropological points of view; it will clarify the connection between the molecular variation and the phenotypic diversity observed in our species, while providing insights on how diverse factors (particularly natural selection) have shaped the evolution of pigmentation and pigmentation genes. The research is also relevant from a biomedical perspective, given that many variants associated with common pigmentation variation are also associated with skin cancer risk. Finally, this project will explore the genetic architecture of iris structure (e.g., contraction furrows, Fuchs' crypts, nevi, and Wolfflin nodules). These traits show substantial variation in human populations, but very few studies have been devoted to the identification of the genetic factors underlying this variation.