Characterisation of a second gain of function EDAR variant, encoding EDAR380R, in East Asia

• Published in: European journal of human genetics : EJHG 2020-12, Vol.28 (12), p.1694-1702
• Main Authors: Riddell, Jon, Basu Mallick, Chandana, Jacobs, Guy S, Schoenebeck, Jeffrey J, Headon, Denis J
• Format: Article
• Language: English
• Subjects: Alleles; Asia, Southeastern; Ectodysplasin; Edar Receptor - chemistry; Edar Receptor - genetics; Edar Receptor - metabolism; Evolution, Molecular; Gain of Function Mutation; Gene Frequency; Geographical distribution; HaCaT Cells; Hair; Haplotypes; HEK293 Cells; Humans; Minority & ethnic groups; Molecular Dynamics Simulation; Polymorphism, Single Nucleotide; Positive selection; Selection, Genetic; Sweat gland; Tumor necrosis factor receptors
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/s41431-020-0660-6

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.