- Genetic Heterogeneity of Variation in Skin/Hair/Eye Pigmentation
Multiple genes influence normal human skin, hair, and/or eye pigmentation. Pigmentation phenotypes influenced by variation in the OCA2 gene are termed SHEP1. The SHEP2 association (266300) is determined ... - Genetic Heterogeneity of Variation in Skin/Hair/Eye Pigmentation Multiple genes influence normal human skin, hair, and/or eye pigmentation. Pigmentation phenotypes influenced by variation in the OCA2 gene are termed SHEP1. The SHEP2 association (266300) is determined by variation at the MC1R locus (155555) and describes a phenotype predominantly characterized by red hair and fair skin. SHEP3 (601800) encompasses pigment variation influenced by the TYR gene (606933); SHEP4 (113750), that influenced by the SLC24A5 gene (609802). Variation in the SLC45A2 (606202) and SLC24A4 (609840) genes result in the phenotypic associations SHEP5 (227240) and SHEP6 (210750), respectively. Sequence variation thought to affect expression of KITLG (184745) results in the SHEP7 (611664) phenotypic association, and SHEP8 (611724) has been associated with single-nucleotide polymorphisms (SNPs) at chromosome 6p25.3. Polymorphism in the 3-prime-untranslated region of the ASIP gene (600201) influences the SHEP9 association (611742). The SHEP10 association (612267) comprises variation in the TPCN2 gene (612163), and SHEP11 (612271) is associated with polymorphism near the TYRP1 gene (115501).
Pigmentation of hair, eye, and skin is among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. Pigmentation in human tissues is attributable to the number, type, ... Pigmentation of hair, eye, and skin is among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. Pigmentation in human tissues is attributable to the number, type, and cellular distribution of melanosomes (subcellular compartments produced by melanocytes that synthesize and store the light-absorbing polymer melanin) (Sulem et al., 2007). Variation in pigmentation among individuals is thought to be caused by biochemical differences that affect the number of melanosomes produced, the type of melanin synthesized (either black-brown eumelanin or red-yellow pheomelanin), and the size and shape of the melanosomes. The key physiologic role of skin pigmentation seems to be to absorb ultraviolet radiation (UVR). This protective role must be weighted against the reduced amount of UVR available for the synthesis of vitamin D3. It is generally believed that the geographic distribution of human skin pigmentation reflects a history of adaptation to latitude-dependent levels of UVR, with individuals tending to have lighter pigmentation with increasing distance from the equator (Relethford, 1997). The majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair (Sulem et al., 2007). Stokowski et al. (2007) cited studies suggesting that the genetic factors influencing lighter pigmentation in Europeans may be far different from the mechanism for lighter pigmentation in East Asians (Relethford, 1997; Norton et al., 2006; Myles et al., 2007). Given the direct correlation between skin pigmentation and incident UV exposure, it has long been postulated that it is a trait under intense selective pressure (Stokowski et al., 2007). Pigmentary mutants in model organisms and human disorders of pigmentation have been the main source for the discovery of genes involved in skin color. More than 100 pigmentation genes have been identified in mouse alone, most with identified human orthologs, and at least 18 genes had been implicated in human albinism.
Two OCA2 coding region variant alleles, arg305 to trp (R305W; 611409.0011) and arg419 to gln (R419Q; 611409.0012), were shown to be associated with brown and green/hazel eye colors, respectively (Rebbeck et al., 2002; Jannot et al., 2005), and ... Two OCA2 coding region variant alleles, arg305 to trp (R305W; 611409.0011) and arg419 to gln (R419Q; 611409.0012), were shown to be associated with brown and green/hazel eye colors, respectively (Rebbeck et al., 2002; Jannot et al., 2005), and blue eye color was also shown to be linked to the OCA2 locus through use of microsatellite (Posthuma et al., 2006; Frudakis et al., 2003) and single-nucleotide polymorphism (SNP) (International HapMap Consortium, 2005) markers. Duffy et al. (2007) found that 3 SNPs in intron 1 of the OCA2 gene have the highest statistical association with blue eye color. Moreover, these are found in a tight linkage disequilibrium block, with the TGT haplotype 1 (611409.0013) representing 78.4% of alleles in their sample. Given that nonbrown eye colors are found at high frequency only in white populations, Duffy et al. (2007) considered it notable that haplotype 1 was found at 82.5% in Europeans and at only minor frequencies (7.4% in those of African and 12.1% in those of East Asian descent) in others, suggesting strong positive selection for TGT in Europeans. The TGT/TGT diplotype of OCA2 was found in 62.2% of samples and was the major genotype seen to modify eye color, with a frequency of 0.905 in blue or green compared with only 0.095 in brown eye color. This genotype was also at highest frequency in subjects with light brown hair and was more frequent in fair and medium skin types, consistent with the TGT haplotype acting as a recessive modifier of lighter pigmentary phenotypes. Duffy et al. (2007) found only minor population impact of the R305W and R419Q associated with nonblue eyes, as contrasted with the tight linkage of the major TGT haplotype within intron 1 of OCA2 with blue eye color and lighter hair and skin tones, which suggested that differences within the 5-prime proximal regulatory control region of the OCA2 gene alter expression or mRNA transcript levels and may be responsible for these associations. Among 2,986 Icelanders, Sulem et al. (2007) carried out a genomewide association scan for variants associated with hair and eye pigmentation, skin sensitivity to sun, and freckling. The most closely associated SNPs from 6 regions were then tested for replication in a second sample of 2,718 Icelanders and a sample of 1,214 Dutch. A 1-Mb region on chromosome 15 overlapping the OCA2 gene and containing 16 SNPs showed association with blue versus brown eyes, blue versus green eyes, blond versus brown hair, or some combination of these traits in the Icelandic sample that reached genomewide significance. The 3 common variants in intron 1 of OCA2, dbSNP rs7495174, dbSNP rs4778241, and dbSNP rs4778138, reported by Duffy et al. (2007) as strongly associated with skin, hair, and eye pigmentation in populations of European ancestry, were among the 16 detected in the genomewide scan. However, the SNP that showed the strongest association was dbSNP rs1667394 (OR = 35.42, P = 1.4 x 10(-124) for blue versus brown eyes; OR = 7.02, P = 5.1 x 10(-25) for blue versus green eyes; OR = 5.62, P = 4.4 x 10(-16) for blond versus brown hair). This SNP is located 200 kb downstream of OCA2, within intron 4 of the HERC2 gene (605837.0001). Given the established relationship between OCA2 and pigmentation, Sulem et al. (2007) considered it unlikely that the association signal provided by this SNP was due to a functional effect on HERC2. Rather, they suggested that perhaps sequence variation in the introns of HERC2 affects the expression of OCA2, or that functional variants exist within OCA2 that correlate with dbSNP rs1667394. In European populations, Kayser et al. (2008) and Sturm et al. (2008) identified variants in introns of the HERC2 gene (605837.0002, 605837.0003) that were better predictors of blue eye color than were the variants found by Duffy et al. (2007) in intron 1 of OCA2 (611409.0013). Sturm et al. (2008) identified the R419Q variant of OCA2 (611409.0012) as a penetrance modifier of the HERC2 variant dbSNP rs12913832 (605837.0003) and of the risk of malignant melanoma. In a 3-generation Danish family segregating blue and brown eye color, Eiberg et al. (2008) used fine mapping to identify a 166-kb candidate region within the HERC2 gene. Further studies of SNPs within this region among 144 blue-eyed and 45 brown-eyed individuals identified 2 SNPs, dbSNP rs1129038 and the strongly conserved dbSNP rs12913832, that showed significant associations with the blue-eyed phenotype (p = 6.2 x 10(-46)). A common founder haplotype containing these SNPs was identified among blue-eyed persons from Denmark, Turkey, and Jordan. In a study of eye color variation in a cohort of 718 individuals of European descent, Pospiech et al. (2011) used multifactor dimensionality reduction and logistic regression to examine gene-gene interactions based on SNPs in 11 known pigmentation genes. Significant interaction effects were found for 3 gene pairs: dbSNP rs12913832 in HERC2 and dbSNP rs1800407 in OCA2 for hazel versus nonhazel and for green versus nongreen eye color; dbSNP rs12913832 in HERC2 and dbSNP rs12896399 in SLC24A4 for blue versus nonblue; and dbSNP rs12913832 in HERC2 and dbSNP rs1408799 in TYRP1 for green versus nongreen color. The interaction of the HERC2 and OCA2 genes and the HERC2 and TYRP1 genes showed a synergistic effect for green eye color. The findings confirmed that the HERC2 and OCA2 genes have a predominant role in eye color inheritance. Donnelly et al. (2012) genotyped 3,432 individuals from 72 populations for 21 SNPs in the OCA2-HERC2 region, and found that blue-eye-associated alleles in all 3 haplotypes that previously had been associated with eye pigmentation in Europeans occurred at high frequencies in Europe; however, 1 was restricted to Europe and surrounding regions, whereas the other 2 were found at moderate to high frequencies throughout the world. Their data suggested that the TG allele of the haplotype restricted to Europe, consisting of the SNPs dbSNP rs1129038 and dbSNP rs12913832 and which they designated 'BEH2,' was the best marker for blue eyes.