Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q12-q13.1 | [Skin/hair/eye pigmentation 1, blond/brown hair] | 227220 | Autosomal recessive | 3 | OCA2 | 611409 |
| 15q12-q13.1 | [Skin/hair/eye pigmentation 1, blue/nonblue eyes] | 227220 | Autosomal recessive | 3 | OCA2 | 611409 |
| 15q13.1 | [Skin/hair/eye pigmentation 1, blond/brown hair] | 227220 | Autosomal recessive | 3 | HERC2 | 605837 |
| 15q13.1 | [Skin/hair/eye pigmentation 1, blue/nonblue eyes] | 227220 | Autosomal recessive | 3 | HERC2 | 605837 |
A number sign (#) is used with this entry because of evidence that variants of the OCA2 gene (611409) play a role in determining blue versus nonblue eye color and blond versus brown hair. Noncoding variants in the HERC2 gene (605837) 200 kb downstream of OCA2 that are thought to affect OCA2 expression have also been associated.
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. SHEP8 (611724) is associated with variation in the IRF4 gene (601900). 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, 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.
Eiberg and Mohr (1996) sought the location of the BEY2 locus for brown eye color through an inquiry using data on eye color and hair color in 832 families from the Copenhagen area. By exclusion mapping with 80 markers in 120 segregating families and 290 markers in 5 segregating families, they obtained some indication of a locus BEY2 for brown eye color on chromosome 15. For possible confirmation, they selected a total of 45 families from their DNA bank segregating for BEY. All these were tested for chromosome 15 markers in the area between D15S11 and CYP19 (107910). They found a strong indication of linkage with the DNA polymorphism D15S165 and with flanking markers D15S156 and D15S144. A multipoint lod score of 32.2 was obtained for location in this interval. These markers had been assigned to the 15q11-q21 region.
Eiberg and Mohr (1996) obtained a lod score of 9.93 at theta (M = Z) = 0.10 for linkage of a locus for brown hair color (HCL3) to a locus for brown eye color (BEY2) that they mapped to 15q11-q21. The studies were done in 45 families from the Copenhagen area segregating for brown eye color. They found 56 matings informative for brown eye color and hair color; in 51 of these families the 2 traits were inherited together (in cis), while in 5 families the 2 traits were separated when transmitted to the offspring (in trans). They analyzed 3 of the 'trans' families and found that BEY2 and HCL3 segregated with chromosome 15 markers. This supported the assumption of linkage disequilibrium between BEY2 and HCL3, due presumably to recent immigration of people with brown hair and brown eye color, as an explanation for the excess of the apparent phase cis. There was an association between brown eye color and brown hair color in the 45 selected families; among 46 parents with brown eye color 44 had brown hair color, while among 44 spouses with blue eye color only 26 had brown hair color. Eiberg and Mohr (1996) suggested the P gene (OCA2; 611409), which resides in the 15q11-q21 region and which is the site of mutations causing type II oculocutaneous albinism (203200), as a candidate gene for brown eye and hair color.
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, rs7495174, rs4778241, and 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 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 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 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, rs1129038 and the strongly conserved 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: rs12913832 in HERC2 and rs1800407 in OCA2 for hazel versus nonhazel and for green versus nongreen eye color; rs12913832 in HERC2 and rs12896399 in SLC24A4 for blue versus nonblue; and rs12913832 in HERC2 and 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 rs1129038 and rs12913832 and which they designated 'BEH2,' was the best marker for blue eyes.
By examining 1,570 ethnically diverse African genomes from individuals with quantified pigmentation levels, Crawford et al. (2017) identified 10 SNPs in the OCA2/HERC2 region that were highly associated with pigmentation. The SNPs with the highest probability of being causal were rs1800404 (p = 1.6 x 10(-8)), a synonymous variant within exon 10 of OCA2, and rs4932620 (p = 3.2 x 10(-9)), located within intron 11 of HERC2. The ancestral rs1800404C allele, associated with dark pigmentation, is common in most Africans as well as southern and eastern Asians and Australo-Melanesians, whereas the derived T allele, associated with light pigmentation, is most common (greater than 70%) in Europeans and San. The derived rs4932620T allele, associated with dark skin pigmentation, is most common in Ethiopian populations with high levels of Nilo-Saharan ancestry and is at moderate frequency in other Ethiopian, Hadza, and Tanzania Nilo-Saharan populations. The variants associated with dark pigmentation are identical by descent in South Asian and Australo-Melanesian populations. Crawford et al. (2017) noted the extensive linkage disequilibrium among SNPs in the OCA2/HERC2 region.
Iris color was one of the first human traits used in investigating mendelian inheritance in humans. Davenport and Davenport (1907) outlined what was long taught in schools as a beginner's guide to genetics, that brown eye color is always dominant to blue, with 2 blue-eyed parents always producing a blue-eyed child, never one with brown eyes. As with many physical traits, the simplistic model does not convey the fact that eye color is inherited as a polygenic, not as a monogenic, trait (Sturm and Frudakis, 2004). The early view that blue is a simple recessive has been repeatedly shown to be wrong by observation of brown-eyed offspring of 2 blue-eyed parents. My monozygotic twin brother and I, brown-eyed, had blue-eyed parents and blue-eyed sibs (VAM). Blue-eyed offspring from 2 brown-eyed parents is a more frequent finding.
In some Norwegian families, Gedde-Dahl (1981) found diffusely brown eyes or centrally brown eyes segregating as simple dominant traits, symbolized BEY1. Possible linkage to Km (Inv) and to Co was found, suggesting the order Jk--Km--BEY1--Co. (Co and Km are not measurably linked.)
Gedde-Dahl et al. (1982) found positive lod scores between brown eye color BEY1 (later described as central brown eye color) and the blood groups Colton (CO; 110450, which maps to chromosome 7) and Kidd (JK; 111000, which maps to chromosome 18, Eiberg (1997)). Another phenotype, green eye color (GEY; see 601800), mapped to chromosome 19 by linkage to secretor (SE; 182100) and Lutheran (LU; 111150). A gene for brown hair color segregated with GEY (maximum lod = 5.6 at theta = 0.010) in the data of Eiberg and Mohr (1987).
Eiberg and Mohr (1987) found a lod score of 5.06 for linkage of GEY to brown hair color (BRHC, HCL1). Of interest is the fact that 6 loci on chromosome 19 in man have their homologs on chromosome 7 in the mouse. Chromosome 7 carries at least 3 'pigment loci,' namely, ruby-2 (ru-2), pink-eyed dilution (p; see 611409), and albino (c).
Eiberg (1997) stated that both cis and trans segregations of green eye color and brown hair color were found in families chosen primarily for segregation for green eye color.
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