A Tale of Two Haplotypes: The EDA2R/AR Intergenic Region is the Most Divergent Genomic Segment between Africans and East Asians in the Human Genome

Abstract

Single nucleotide polymorphisms (SNPs) with large allele frequency differences between human populations are relatively rare. The longest run of SNPs with an allele frequency difference of one between the Yoruba of Nigeria and the Han Chinese is found on the long arm of the X chromosome in the intergenic region separating the EDA2R and AR genes. It has been proposed that the unusual allele frequency distributions of these SNPs are the result of a selective sweep affecting African populations that occurred after the Out-of-Africa migration. To investigate the evolutionary history of the EDA2R/AR intergenic region, we characterized the haplotype structure of 52 of its highly-differentiated SNPs. Using a publicly-available dataset of 3,000 X chromosomes from 65 human populations, we found that nearly all human X chromosomes carry one of two modal haplotypes for these 52 SNPs. The predominance of two highly divergent haplotypes at this locus was confirmed using a subset of individuals sequenced to high coverage. The first of these haplotypes, the α haplotype, is at high frequencies in most of the African populations surveyed and likely arose prior to the separation of African populations into distinct genetic entities. The second, the β haplotype, is frequent or fixed in all non-African populations and likely arose in East Africa prior to the Out-of-Africa migration. We also observed a small group of rare haplotypes with no clear relationship to the α and β haplotypes.These haplotypes occur at relatively high frequencies in African hunter-gatherer populations, like the San and Mbuti Pygmies. Our analysis indicates that these haplotypes are part of a pool of diverse, ancestral haplotypes that have now been almost entirely replaced by the α and β haplotypes. We suggest that the rise of the α and β haplotypes was the result of the demographic forces that human populations experienced during the formation of modern African populations and the Out-of-Africa migration. However, we also present evidence that this region is the target Pre-print version. Visit http://digitalcommons.wayne.edu/humbiol/ after 1 February 2013 to acquire final version.3 of selection in the form of positive selection on the α and β haplotypes and of purifying selection against α/β recombinants.

Uncovering the genetic architecture and evolutionary roots of androgenetic alopecia in African men

“…Multiple X-linked variants that are associated with MPB are evolutionary outliers. 52,53 Key associations near the EDA2R and AR genes are rs12558842 in Hagenaars et al, rs2497911 in Heilmann-Heimbach et al, and rs1204041 in our study. Although the derived A allele at rs12558842 is nearly fixed in East Asian genomes, it is uncommon in Africa (1KGP allele frequencies of 0.998 in East Asia, 0.836 in Europe, and 0.060 in Africa).…”

“…Multiple X-linked variants that are associated with MPB are evolutionary outliers. 52,53 Key associations near the EDA2R and AR genes are rs12558842 in Hagenaars et al, rs2497911 in Heilmann-Heimbach et al, and rs1204041 in our study.…”

Comparison of the Transcriptional Profiles of Melanocytes from Dark and Light Skinned Individuals under Basal Conditions and Following Ultraviolet-B Irradiation

“…EDA2R has been reported to be affected by recent natural positive selection [ 38 – 39 ], and its paralog, EDAR , has been strongly associated with skin pigmentation variability in humans [ 40 ]. Strikingly, the intergenic region between EDA2R and the next gene on the same chromosome ( AR) is the most divergent genomic segment between Africans and East Asians in the human genome [ 41 ].…”

Coevolution between Human's Anticancer Activities and Functional Foods from Crop Origin Center in the World

“…The western Eurasian genetic signatures in modern-day Native Americans derive from post-Columbian admixture and a mixed ancestry of the First Americans (Raghavan et al, 2014). An allele frequency difference between Yoruba of Nigeria and Han Chinese is found for EDA2R and AR genes (Casto et al, 2012). Modern humans migration was the earliest coastal route from Africa into Southeast Asia by way of Indian subcontinent some 60 kya .…”