Genetic and molecular basis for variation in human skin pigmentation

人类皮肤色素沉着变化的遗传和分子基础

• 批准号: 10615919
• 负责人: Michael S Marks
• 金额: $ 111.02万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615919
• 关键词: Address; Affect; African; Animal Model; Biological Assay; Biology; CRISPR/Cas technology; Candidate Disease Gene; Carrier Proteins; Cell Culture Techniques; Cell physiology; Cells; Cellular biology; Chromatin; Code; Collaborations; Cytoplasm; Data; Data Set; Disease; Ethnic Population; European; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic Variation; Genome; Genomic Segment; Genomics; Goals; Hair; Human; Human Genetics; Hypersensitivity skin testing; Ion Transport; Knowledge; Link; Luciferases; Lysosomes; Maps; Melanins; Melanocortin 1 Receptor; Melanogenesis; Melanosomes; Membrane; Membrane Transport Proteins; Microscopy; Modernization; Molecular; Molecular Mechanisms of Action; Mus; Mutagenesis; Natural Selections; Neoplasm Metastasis; Nucleic Acid Regulatory Sequences; Organelles; Pathologic; Phenotype; Physiological; Pigmentation physiologic function; Pigments; Population; Production; Prognosis; Protein Subunits; Proteins; Publishing; Receptor Signaling; Regulatory Element; Risk; SNP array; Sample Size; Scanning; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Skin; Skin Pigmentation; Testing; Ultraviolet Rays; Untranslated RNA; Variant; candidate identification; cohort; enzyme activity; ethnic diversity; gene discovery; gene product; genetic analysis; genetic variant; genome wide association study; melanocyte; melanoma; migration; new therapeutic target; novel; patch clamp; rare genetic disorder; receptor; receptor-mediated signaling; solute; success; trafficking; trait; whole genome

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.

表皮色素沉着的变化是人类种群最引人注目的特征之一，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已经 在动物模型中鉴定出来，但对正常人皮肤色素变异的遗传基础知之甚少。 填补这一知识差距可能会揭示黑色素细胞下的新分子和细胞机制 生物学，黑色素瘤风险和罕见的遗传疾病。由于它们的遗传多样性高和广泛 肤色，非洲人群在发现调节色素沉着的基因方面特别有用。 因此，我们的团队最近使用了一项基因组广泛的关联研究和扫描自然选择 来自1600个种族多元化的非洲人的独特数据集，以识别影响肤色的遗传变异体 非洲人。其中包括具有以前未知功能在色素沉着（例如MFSD12）中的基因，编码 一种预测的跨膜转运蛋白，该转运蛋白定位于溶酶体，但不适合黑色素体，因此调节 通过一种新型机制的色素沉着。初步分析还确定了其他候选转运蛋白和 受体介导的信号传导的调节剂，这些信号传导在色素沉着中起作用，并且可能 以新颖的方式调节黑色素发生。在这里，雇用了一个由人类遗传学专家领导的多PI团队， 膜贩运/细胞器生物学和膜信号传导/离子运输与三个 其他专家，我们建议在3,000个非洲人中识别（i）（i）新的色素沉着基因 我们拥有整个基因组序列数据，以及（ii）产物的细胞和分子机制 这些基因控制着人类皮肤色素沉着。我们将通过整合人类基因组来实现我们的目标 和色素沉着数据在我们独特的非洲队列中，对非编码序列影响的遗传分析 关于基因表达的变体以及黑素细胞生物学和生理学的细胞培养研究。三个 具体目的将检验我们的假设，即色素沉着的变化是由遗传变异引起的 编码蛋白质的基因的调节元素，这些蛋白质直接或间接改变黑色素体环境 通过受体介导的信号传导，例如黑色素皮质素-1受体（MC1R）。具体来说，我们将雇用 以下三个具体目标： 1。确定新的遗传变异体影响皮肤色素沉着并测试变体是否影响 来自附近基因的基因表达； 2。定义新的机制，溶酶体或黑色素体中的转运蛋白会影响 通过定义MFSD12和其他新鉴定的转运蛋白如何影响黑色素发生来进行色素沉着； 3。确定调节的新鉴定的受体介导的信号蛋白的功能 我们的新分析产生色素沉着，并测试它们是否以及如何影响MC1R信号传导。