Genetic and molecular basis for variation in human skin pigmentation

表皮色素的变化是人类群体最显著的特征之一，对 防止紫外线辐射的有害影响。许多控制色素沉着的基因一直是 在动物模型中被证实，但人们对正常人类皮肤色素变异的遗传基础知之甚少。 填补这一知识空白可能会揭示黑素细胞背后的新分子和细胞机制 生物学、黑色素瘤风险和罕见的遗传性疾病。因为它们具有高度的遗传多样性和广谱 在肤色方面，非洲人在发现调节色素沉着的基因方面尤其有用。 因此，我们的团队最近使用了全基因组关联研究和自然选择扫描 来自1600名不同种族的非洲人的独特数据集，用于识别影响非洲人肤色的基因变异 非洲人。这些基因包括之前未知的色素沉着功能基因，如MFSD12，编码 一种预测的跨膜转运蛋白，定位于溶酶体而不是黑色素体，从而调节 通过一种新的机制进行着色。初步分析还确定了其他候选运输商和 受体介导的信号调节因子，不知道在色素沉着中起作用，可能 以新奇的方式调节黑色素的生成。在这里，雇佣了一个由人类遗传学专家领导的多PI团队， 膜转运/细胞器生物学和膜信号/离子转运 其他专家，我们建议在3000名非洲人中发现(I)新的色素沉着基因 我们有全基因组序列数据，以及(Ii)产品的细胞和分子机制 其中，这些基因控制着人类皮肤的色素沉着。我们将通过整合人类基因组来实现我们的目标 和我们独特的非洲队列中的色素沉着数据，遗传分析了非编码序列的影响 基因表达变异，以及黑素细胞生物学和生理学的细胞培养研究。三位一体 特定的目标将检验我们的假设，即色素沉着的变化是由 编码可直接或间接改变黑素瘤环境的蛋白质的基因的调节元件 通过黑素皮质素-1受体(MC1R)等受体介导的信号传导。具体地说，我们将聘用 以下三个具体目标： 1.识别影响皮肤色素沉着的新的遗传变异，并测试这些变异是否会影响 邻近基因的基因表达； 2.确定溶酶体或黑素体转运蛋白影响的新机制 通过定义MFSD12和其他新发现的转运蛋白如何影响黑素生成来实现色素沉着； 3.确定新发现的受体介导的信号蛋白的功能 我们的新分析产生了色素沉着，并测试它们是否以及如何影响MC1R信号。

Variation in epidermal pigmentation is one of the most striking features of human populations and is critical for protection against the harmful effects of ultraviolet radiation. Many genes that control pigmentation have been identified in animal models, but little is known about the genetic basis of normal human skin pigment variation. Filling this knowledge gap will likely reveal novel molecular and cellular mechanisms underlying melanocyte biology, melanoma risk and rare genetic diseases. Because of their high genetic diversity and wide spectrum of skin tone, African populations are particularly informative for discovering genes that regulate pigmentation. Accordingly, our team recently used a genome wide association study and scans of natural selection in a unique dataset from 1600 ethnically diverse Africans to identify genetic variants that affect skin tone in Africans. These included genes with previously unknown functions in pigmentation such as MFSD12, encoding a predicted transmembrane transporter that localizes to lysosomes but not to melanosomes and thus regulates pigmentation by a novel mechanism. Preliminary analyses also identified additional candidate transporters and regulators of receptor-mediated signaling that were not known to function in pigmentation and that may regulate melanogenesis in novel ways. Here, employing a multi-PI team headed by experts in human genetics, membrane trafficking/ organelle biology, and membrane signaling/ ion transport in collaboration with three additional experts, we propose to identify (i) new pigmentation genes in a larger set of 3,000 Africans for which we have whole genome sequence data, and (ii) the cellular and molecular mechanisms by which the products of these genes control human skin pigmentation. We will accomplish our goal by integrating human genomic and pigmentation data in our unique African cohort, genetic analyses of the impact of non-coding sequence variants on gene expression, and cell culture studies of melanocyte cell biology and physiology. The three specific aims will test our hypotheses that variation in pigmentation results from genetic variations in the regulatory elements of genes encoding proteins that alter either the melanosomal milieu directly or indirectly via signaling mediated by receptors such as the melanocortin-1 receptor (MC1R). Specifically, we will employ the following three specific aims: 1. Identify novel genetic variants influencing skin pigmentation and test whether the variants influence gene expression from nearby genes; 2. Define novel mechanisms by which transporters in lysosomes or melanosomes influence pigmentation by defining how MFSD12 and other newly identified transporters impact melanogenesis; 3. Determine the function of newly identified receptor-mediated signaling proteins that regulate pigmentation resulting from our new analyses and test whether and how they influence MC1R signaling.