Skin/hair/eye pigmentation, variation in, 8

Skin/hair/eye pigmentation (acronym: SHEP) is a classification system that refers to the genetically detectable and known polymorphisms in the genes that have been shown to determine the pigmentation system of skin, hair and iris. Skin/hair/eye pigmentation, variation in, 8, abbreviated SHEP8 (611724), is a form of pigmentation associated with a variation in the IRF4 gene (601900).

Pigmentation of hair, eyes, and skin is among the most visible examples of human phenotypic variation, with a wide normal range subject to considerable geographic stratification. Pigmentation in human tissues is due to the number, type, and cellular distribution of melanosomes (subcellular compartments formed by melanocytes that synthesize and store the light-absorbing polymer melanin) (Sulem et al. 2007). The variation in pigmentation from person to person is thought to be due to 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 melanosomes. The most important physiological function of skin pigmentation seems to be the absorption of ultraviolet radiation (UVR). This protective function must be balanced against the lower amount of UVR available for the synthesis of vitamin D3.

It is generally believed that the geographic distribution of human skin color reflects an adaptation to latitude-dependent UVR, with individuals tending to have lighter pigmentation with increasing distance from the equator (Relethford, 1997). Most variation in human eye and hair color is found in people of European ancestry, while most other human populations are fixed to brown eyes and black hair (Sulem et al., 2007). The studies cited by Stokowski et al. (2007) suggest that the genetic factors influencing lighter pigmentation in Europeans differ markedly from the mechanisms for lighter pigmentation in East Asians (Relethford, 1997; Norton et al. 2006; Myles et al. 2007).

Given the direct relationship between skin pigmentation and UV exposure, it has long been postulated that skin pigmentation is a trait under strong selection pressure (Stokowski et al. 2007). Pigment mutants in model organisms and human pigment disorders have been the main source of discovery of genes involved in skin color. In mice alone, more than 100 pigmentation genes have been identified. Thus, at least 18 genes have been linked to human albinism (see Albinism below).

Sulem et al. (2007) conducted a genome-wide association study (GWAS) in 2,986 Icelanders to find variants associated with hair and eye pigmentation, skin sun sensitivity, and freckling. The most strongly associated SNPs were then tested for replication in a second sample of 2,718 Icelanders and a sample of 1,214 Dutch. Sulem et al. (2007) found an association of the A allele of a single nucleotide polymorphism (SNP), rs1540771, on chromosome 6p25.3 between the IRF4 and SEC5L1 genes (615329), with the presence of freckles in Icelandic and Dutch population samples (discovery odds ratio (OR) = 1.40, p = 3.7 x 10(-18)). Secondary associations of this allele were found with brown rather than blond hair and with sun sensitivity of the skin. The frequency of rs1540771 is approximately 50% in European populations, but 30% and 5% in East Asian and Nigerian Yoruba HapMap samples, respectively.

Numerous genes influence the normal pigmentation of skin, hair and/or eyes in humans:

• SHEP1-associated pigmentation phenotypes are influenced by variations in the OCA2 gene.
• SHEP2 association (266300) is determined by variations at the MC1R locus (155555) and describes a phenotype characterized predominantly by red hair and fair skin.
• SHEP3 (601800) includes pigment variation influenced by the TYR gene (606933).
• SHEP4 association (113750) is influenced by variations at the SLC24A5 gene (609802).
• SHEP5 (227240) is associated with variations in the SLC245A2 gene (609840).
• SHEP6 (210750)- associated are variations in the SLC24A4 genes (609840).
• SHEP7 (611664) is a sequence variation thought to affect KITLG (184745) expression.
• SHEP8 (611724) is associated with a variation in the IRF4 gene (601900). SHEP9 (611742)is affected by polymorphism in the 3-prime untranslated region of the ASIP gene (600201).
• SHEP10 association (612267) involves variations in the TPCN2 gene (612163).
• SHEP11 (612271) is associated with a polymorphism near the TYRP1 gene (115501).

1. Praetorius C et al. (2013) A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. Cell 155:1022-1033.
2. Sulem, P et al. (2007) Genetic determinants of hair, eye and skin pigmentation in Europeans. Nature Genet 39: 1443-1452.