The Light Skin Allele of SLC24A5 in South Asians and Europeans Shares Identity by Descent

Abstract

Skin pigmentation is one of the most variable phenotypic traits in humans. A non-synonymous substitution (rs1426654) in the third exon of SLC24A5 accounts for lighter skin in Europeans but not in East Asians. A previous genome-wide association study carried out in a heterogeneous sample of UK immigrants of South Asian descent suggested that this gene also contributes significantly to skin pigmentation variation among South Asians. In the present study, we have quantitatively assessed skin pigmentation for a largely homogeneous cohort of 1228 individuals from the Southern region of the Indian subcontinent. Our data confirm significant association of rs1426654 SNP with skin pigmentation, explaining about 27% of total phenotypic variation in the cohort studied. Our extensive survey of the polymorphism in 1573 individuals from 54 ethnic populations across the Indian subcontinent reveals wide presence of the derived-A allele, although the frequencies vary substantially among populations. We also show that the geospatial pattern of this allele is complex, but most importantly, reflects strong influence of language, geography and demographic history of the populations. Sequencing 11.74 kb of SLC24A5 in 95 individuals worldwide reveals that the rs1426654-A alleles in South Asian and West Eurasian populations are monophyletic and occur on the background of a common haplotype that is characterized by low genetic diversity. We date the coalescence of the light skin associated allele at 22–28 KYA. Both our sequence and genome-wide genotype data confirm that this gene has been a target for positive selection among Europeans. However, the latter also shows additional evidence of selection in populations of the Middle East, Central Asia, Pakistan and North India but not in South India.

Skin Pigmentation Diversity in Central East Indian Populations and its Correlation with Mitochondrial Haplogroups

“…Previous report, observed the significant association with rs1426654, with skin pigmentation in populations living specifically in India [8]. Recent study on same region (middle gangetic regions of central east part of India) had well established the association with pigmentation India is well known for its cultural, social, ecological and genetic diversity in South Asia.…”

“…There were several pigmentation studies revealing association with pigmentation candidate gene in South Asia and they have approved the act of natural selection process of human populations [7][8][9][10][11][12]. Previous report, observed the significant association with rs1426654, with skin pigmentation in populations living specifically in India [8].…”

“…Pigmentation studies were helpful in understanding the evolutionary processes. Study shows that role of melanin is very important in pigmentation variation, where it is performing dual role and make delicate balance between the skin being light enough at low UVR zones (to allow sufficient production of vitamin D) and dark enough at high UVR zones (for protection against sun burn and degradation of folate) [8][9][10]. Any imbalance between these dual procedures would have wide-range of effects on human health (reproductive fitness, skin cancer, anaemia, fetal abnormalities, spermatogenesis, rickets and vitamin D deficiency) [9].…”

Discovery of copy number variants by multiplex amplifiable probe hybridization (MAPH) in candidate pigmentation genes

“…Thus, we assessed the diversity at this locus (where the CNV was found) in the European samples from the 1000 Genomes Project (1KGP) and we compared it to that corresponding to a region around SLC24A5 exon 3, where SNP rs1426654 locates. This SNP is particularly relevant as it has been strongly associated with human pigmentation (Lamason et al, 2005) and has also been reported to be under the action of positive selection (Basu Mallick et al, 2013;Norton et al, 2010;Sabeti et al, 2010). As positive selection also results in a drop in diversity (actually SNP rs1426654 is almost fixed in Europeans) we wanted to compare the profiles of diversity between these two loci in order to assess if it would be possible to identify a specific diversity signature for unaccounted (cryptic) copy number variation.…”

Polymorphisms in vitamin D-related genes and risk of uterine leiomyomata

“…In a large cohort of African American women, we examined UL risk in relation to twelve polymorphisms in eight genes: two in GC (12,16,17), two in VDR (18), two in CYP2R1 (12,19), two near DHCR7 (12,19), and one each in SLC24A5 (20,21), OCA2 (22), ASIP (23), and CYP24A1 (18). The selected SNPs have been associated with vitamin D levels in previously-described GWAS (12,13), or with vitamin D levels (14-19, 24, 25) and skin pigmentation (14,(20)(21)(22)(23)26) in other studies.…”