BMC Genetics 2008, 9:31doi:10.1186/1471-2156-9-31
Nucleotide diversity and population differentiation of the Melanocortin 1 Receptor gene, MC1R
Sharon A Savage et al.
The melanocortin 1 receptor gene (MC1R) is responsible for normal pigment variation in humans and is highly polymorphic with numerous population-specific alleles. Some MC1R variants have been associated with skin cancer risk.
Allele frequency data were compiled on 55 single nucleotide polymorphisms from seven geographically distinct human populations (n = 2306 individuals). MC1R nucleotide diversity, ?, was much higher (10.1 × 10-4) than in other genes for all subjects. A large degree of population differentiation, determined by FST, was also present, particularly between Asia and all other populations, due to the p.R163Q (c.488 G>A) polymorphism. The least amount of differentiation was between the United States, Northern Europe, and Southern Europe. Tajima's D statistic suggested the presence of positive selection in individuals from Europe.
This study further quantifies the degree of population-specific genetic variation and suggests that positive selection may be present in European populations in MC1R.
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Numerous studies have demonstrated associations between specific MC1R variants and red hair, light skin, poor tanning ability and heavy freckling [4-9]. A recent genome-wide association scan confirmed the role of MC1R SNPs in hair, eye, and skin pigmentation. The functional role of many of these variants has been described [10-13]. Several MC1R variants are also associated with increased risk of malignant melanoma in a variety of populations [14-22] The effect of MC1R polymorphisms in melanoma risk appears to extend beyond its effect on pigmentation in most of these investigations, and to be linked to melanomas harboring mutations in the BRAF oncogene.
Several hypotheses have been generated in an effort to understand the evolutionary history of skin pigmentation in humans. It has been suggested that as humans migrated out of Africa to climates with more limited exposure to sunlight, relaxation of functional constraints in pigmentation genes, including MC1R, or selection for functionally relevant variants that led to lighter skin pigmentation occurred. This could result in an improved ability to synthesize vitamin D in the presence of limited sunlight exposures [25-27]. It has also been suggested that darker skin is favored in regions closer to the equator for protection against ultraviolet radiation. In addition, differences in skin pigmentation could protect against pathogens and cold injury, and may have also been important in sexual selection.
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Several studies have evaluated genetic adaptation of the MC1R gene for evidence of positive selection with conflicting results. Some studies suggested that purifying selection is present in Africa and that relaxation of functional constraint in non-African populations, instead of positive selection, is present[25,27,40]. On the other hand, most recent studies have found evidence of positive selection at other pigmentation genes. For example, Myles et al  found evidence for positive selection in the DCT gene among individuals of Chinese ancestry. In their study, MC1R interpretations were limited because of the different SNPs genotyped between the Perlegen and HapMap data sets studied. In a study of 118 putative skin pigmentation genes, data were consistent with positive selection in subjects from Europe (OCA2, TYRP1, and KITLG) and in Asians (DCT, EGFR, and DRD2). Unfortunately, MC1R could not be evaluated in that study due to ascertainment criteria. It was also suggested that at least weak, recent positive selection may be present in MC1R, based on the AF variability between CEPH Utah and East Asian HapMap samples. Our data suggest that MC1R may be under positive selection in some populations, although additional studies are needed to further evaluate this finding.