小年 (2024-01-31 19:56):
#paper Feng, Y., Xie, N., Inoue, F. et al. Integrative functional genomic analyses identify genetic variants influencing skin pigmentation in Africans. Nat Genet (2024). https://doi.org/10.1038/s41588-023-01626-1. 肤色是人类群体间一个显著的差异性状,具有高度遗传性的复杂性状,受到数百个基因位点的影响,其遗传基础尚未完全阐明。本篇文章作者采用了综合的功能基因组学分析方法,揭示了影响非洲人群肤色的遗传变异。该研究团队通过全基因组关联分析(GWAS)和自然选择扫描,鉴定了与肤色相关的单核苷酸多态性(SNP),利用大规模平行报告基因检测技术(MPRA),他们测试了这些SNP的调控活性。作者进一步使用 Hi-C 和 H3K27ac HiChIP 技术,构建了高分辨率的染色质相互作用图谱,以确定这些SNP的潜在靶基因。该研究通过荧光素酶报告基因检测、CRISPR基因编辑、转录组分析和黑色素丰度检测等技术,发现MITF 附近的 rs111969762、LEF1 附近的 rs17038630 和 TRPS1 附近的 rs11985280,这三个Di-SNP均能显著影响增强子活性及其靶基因的表达,可能对桑人皮肤色素的适应性进化发挥了作用。总得来说,本项研究发现了多个新的影响黑色素细胞中黑色素水平的新基因,这些发现有助于深入理解人类肤色的遗传机制,并为研究其他复杂性状的遗传因素提供了有价值的方法论。
IF:31.700Q1 Nature genetics, 2024-Feb. DOI: 10.1038/s41588-023-01626-1 PMID: 38200130 PMCID:PMC11005318
Integrative functional genomic analyses identify genetic variants influencing skin pigmentation in Africans
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Abstract:
Skin color is highly variable in Africans, yet little is known about the underlying molecular mechanism. Here we applied massively parallel reporter assays to screen 1,157 candidate variants influencing skin pigmentation in Africans and identified 165 single-nucleotide polymorphisms showing differential regulatory activities between alleles. We combine Hi-C, genome editing and melanin assays to identify regulatory elements for MFSD12, HMG20B, OCA2, MITF, LEF1, TRPS1, BLOC1S6 and CYB561A3 that impact melanin levels in vitro and modulate human skin color. We found that independent mutations in an OCA2 enhancer contribute to the evolution of human skin color diversity and detect signals of local adaptation at enhancers of MITF, LEF1 and TRPS1, which may contribute to the light skin color of Khoesan-speaking populations from Southern Africa. Additionally, we identified CYB561A3 as a novel pigmentation regulator that impacts genes involved in oxidative phosphorylation and melanogenesis. These results provide insights into the mechanisms underlying human skin color diversity and adaptive evolution.
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