Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
Nat Genet. 2024 Feb;56(2):258-272. doi: 10.1038/s41588-023-01626-1. Epub 2024 Jan 10.
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.
皮肤颜色在非洲人中高度可变,但对其潜在的分子机制知之甚少。在这里,我们应用大规模平行报告基因检测筛选了 1157 个影响非洲人皮肤色素沉着的候选变体,并鉴定了 165 个单核苷酸多态性,这些多态性显示出等位基因之间的差异调控活性。我们结合 Hi-C、基因组编辑和黑色素测定法,鉴定了 MFSD12、HMG20B、OCA2、MITF、LEF1、TRPS1、BLOC1S6 和 CYB561A3 的调控元件,这些元件影响体外的黑色素水平,并调节人类肤色。我们发现,OCA2 增强子中的独立突变有助于人类肤色多样性的进化,并检测到 MITF、LEF1 和 TRPS1 增强子中局部适应的信号,这可能有助于来自南非的科伊桑语系人群的浅色皮肤。此外,我们还确定了 CYB561A3 作为一种新的色素沉着调节剂,影响参与氧化磷酸化和黑色素生成的基因。这些结果为人类皮肤颜色多样性和适应性进化的机制提供了深入的了解。