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

基本信息

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
项目类别：
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

项目摘要

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最显着的特征之一，对于人类健康至关重要防止紫外线辐射的有害影响。许多控制色素沉着的基因已被证实在动物模型中发现，但人们对正常人类皮肤色素变异的遗传基础知之甚少。填补这一知识空白将可能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遗传病。由于其遗传多样性高且谱系广非洲人群对于发现调节色素沉着的基因尤其了解肤色。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 个不同种族的非洲人的独特数据集，用于识别影响肤色的基因变异非洲人。其中包括具有以前未知的色素沉着功能的基因，例如 MFSD12，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进行色素沉着。初步分析还确定了其他候选转运蛋白和受体介导的信号调节剂，目前尚不清楚其在色素沉着中的作用，但可能以新颖的方式调节黑色素生成。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，膜信号传导/离子运输与三个合作另外，我们建议在 3,000 名非洲人的更大范围内确定 (i) 新的色素沉着基因，其中我们拥有全基因组序列数据，以及（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，非编码序列影响的遗传分析基因表达变异，以及黑素细胞生物学和生理学的细胞培养研究。三个具体目标将检验我们的假设，即色素沉着的变化是由基因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黑皮质素-1 受体 (MC1R) 等受体介导的信号传导。具体来说，我们将聘请以下三个具体目标： 1. 识别影响皮肤色素沉着的新基因变异并测试这些变异是否影响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色素生成来调节色素沉着； 3. 确定新发现的受体介导信号蛋白的功能我们的新分析产生的色素沉着，并测试它们是否以及如何影响 MC1R 信号传导。