The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK.
Centre for Genetic Disorders, Institute of Science, Banaras Hindu University, Varanasi, India.
Eur J Hum Genet. 2020 Dec;28(12):1694-1702. doi: 10.1038/s41431-020-0660-6. Epub 2020 Jun 4.
Ectodysplasin A1 receptor (EDAR) is a TNF receptor family member with roles in the development and growth of hair, teeth and glands. A derived allele of EDAR, single-nucleotide variant rs3827760, encodes EDAR:p.(Val370Ala), a receptor with more potent signalling effects than the ancestral EDAR370Val. This allele of rs3827760 is at very high frequency in modern East Asian and Native American populations as a result of ancient positive selection and has been associated with straighter, thicker hair fibres, alteration of tooth and ear shape, reduced chin protrusion and increased fingertip sweat gland density. Here we report the characterisation of another SNV in EDAR, rs146567337, encoding EDAR:p.(Ser380Arg). The derived allele of this SNV is at its highest global frequency, of up to 5%, in populations of southern China, Vietnam, the Philippines, Malaysia and Indonesia. Using haplotype analyses, we find that the rs3827760 and rs146567337 SNVs arose on distinct haplotypes and that rs146567337 does not show the same signs of positive selection as rs3827760. From functional studies in cultured cells, we find that EDAR:p.(Ser380Arg) displays increased EDAR signalling output, at a similar level to that of EDAR:p.(Val370Ala). The existence of a second SNV with partly overlapping geographic distribution, the same in vitro functional effect and similar evolutionary age as the derived allele of rs3827760, but of independent origin and not exhibiting the same signs of strong selection, suggests a northern focus of positive selection on EDAR function in East Asia.
外胚层发育不良蛋白 A1 受体（EDAR）是 TNF 受体家族成员，在毛发、牙齿和腺体的发育和生长中发挥作用。EDAR 的一个衍生等位基因，单核苷酸变体 rs3827760，编码 EDAR:p.(Val370Ala)，这是一种受体，其信号传导效果比原始的 EDAR370Val 更强。由于古代的正选择，这个 rs3827760 等位基因在现代东亚和美洲原住民中非常高频，并且与更直、更粗的毛发纤维、牙齿和耳朵形状的改变、下巴突出度降低以及指尖汗腺密度增加有关。在这里，我们报告了 EDAR 中的另一个 SNV，rs146567337，编码 EDAR:p.(Ser380Arg)的特征。这个 SNV 的衍生等位基因在其最高全球频率中，高达 5%，出现在中国南方、越南、菲律宾、马来西亚和印度尼西亚的人群中。通过单倍型分析，我们发现 rs3827760 和 rs146567337 SNVs 出现在不同的单倍型上，并且 rs146567337 没有表现出与 rs3827760 相同的正选择迹象。从培养细胞的功能研究中，我们发现 EDAR:p.(Ser380Arg)显示出增强的 EDAR 信号输出，与 EDAR:p.(Val370Ala)的水平相似。第二个 SNV 的存在，其地理分布部分重叠，具有相同的体外功能效应，与 rs3827760 衍生等位基因的进化年龄相似，但起源独立，没有表现出强烈选择的相同迹象，表明东亚 EDAR 功能的正选择集中在北部。
