Genetic and molecular basis for variation in human skin pigmentation

表皮色素沉着的变化是人类群体最显著的特征之一，并且对于 防止紫外线辐射的有害影响。许多控制色素沉着的基因 在动物模型中发现，但对正常人类皮肤色素变异的遗传基础知之甚少。 填补这一知识空白将可能揭示黑素细胞的新的分子和细胞机制 生物学、黑色素瘤风险和罕见遗传疾病。由于其高度的遗传多样性和广泛的谱 由于肤色的差异，非洲人群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名种族多样的非洲人的独特数据集，以确定影响肤色的遗传变异， 非洲人这些基因包括以前未知的色素沉着功能，如MFSD 12，编码 一种预测的跨膜转运蛋白，定位于溶酶体但不定位于黑素体，从而调节 通过一种新的机制来着色。初步分析还确定了其他候选运输者， 受体介导的信号调节剂，不知道在色素沉着中起作用， 以新的方式调节黑素生成。在这里，聘请了由人类遗传学专家领导的多PI团队， 膜运输/细胞器生物学和膜信号传导/离子转运与三个合作 我们建议在3,000名非洲人中确定新的色素沉着基因， 我们有全基因组序列数据，（ii）产品的细胞和分子机制 这些基因控制人类皮肤色素沉着。我们将通过整合人类基因组 和色素沉着数据在我们独特的非洲队列，非编码序列的影响的遗传分析， 基因表达的变异，以及黑素细胞生物学和生理学的细胞培养研究。三 具体的目标将测试我们的假设，即色素沉着的变化是由遗传变异引起的。 编码直接或间接改变黑素体环境的蛋白质的基因的调节元件 通过受体介导的信号传导，例如黑皮质素-1受体（MC 1 R）。具体来说，我们将采用 以下三个具体目标： 1.识别影响皮肤色素沉着的新遗传变异，并测试这些变异是否影响 来自邻近基因的基因表达; 2.定义溶酶体或黑素体中转运蛋白影响 通过定义MFSD 12和其他新发现的转运蛋白如何影响黑素生成来确定色素沉着; 3.确定新鉴定的受体介导的信号蛋白的功能， 色素沉着导致我们的新的分析和测试是否以及如何影响MC 1 R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.