Alternative titles; symbols
Other entities represented in this entry:
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q14.3 | [Skin/hair/eye pigmentation 3, blue/green eyes] | 601800 | Autosomal dominant | 3 | TYR | 606933 |
| 11q14.3 | [Skin/hair/eye pigmentation 3, light/dark/freckling skin] | 601800 | Autosomal dominant | 3 | TYR | 606933 |
| 11q14.3 | {Melanoma, cutaneous malignant, susceptibility to, 8} | 601800 | Autosomal dominant | 3 | TYR | 606933 |
A number sign (#) is used with this entry because of evidence that variation in the TYR gene (606933) influences skin, hair, and eye pigmentation.
For a general phenotypic description and a discussion of genetic heterogeneity of variation in skin, hair, and eye pigmentation, see 227220.
Stokowski et al. (2007) conducted a multistage genomewide association study using 1,620,742 SNPs to systematically investigate the genetic factors influencing intrinsic skin pigmentation in a population of South Asian descent. The melanin contribution to skin pigmentation was measured by reflectance spectrophotometry. They found association of the TYR SNP rs1042602 (S192Y; 606933.0008) with skin pigmentation in a cohort of 395 individuals (OR = 4.36, P = 4.48 x 10(-10)). The association was replicated in a second independent cohort of 235 individuals. The odds ratio, calculated for allele 1 (C), represented the ratio of the likelihood of an individual being in the low-reflectance group (darker skin) to the likelihood of being in the high-reflectance group (lighter skin). Stokowski et al. (2007) also found that polymorphism in the SLC24A5 (A111T; 609802.0001) and SLC45A2 (L374F; 606202.0008) genes yielded highly significant replicated associations with skin-reflectance measurements, which is an indirect measure of melanin content in the skin. The association detected in these 3 genes, in an additive manner, collectively accounted for a large fraction of the natural variation of skin pigmentation in the South Asian population. SLC24A5 contained the primary associated SNP. 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).
In a discovery sample of 2,986 Icelanders and replication samples of 2,718 Icelanders and 1,214 Dutch, Sulem et al. (2007) found an association of the TYR SNP rs1042602 (S192Y; 606933.0008) with freckling. In contrast with previous studies (Shriver et al., 2003, Frudakis et al., 2003), no association was found between this SNP and skin or eye color. Based on analysis of HapMap samples, the A allele of rs1042602, associated with the absence of freckles, is found at a frequency of approximately 35% in European populations, while the ancestral C allele is fixed in Asian and Nigerian Yoruba populations. There was evidence that the A allele has been subject to positive selection in European populations. Sulem et al. (2007) also found strong correlation of the TYR SNP rs1393350 with rs1126809 (R402Q; 606933.0009). The association of the rs1393350 A allele with blue versus green eye color was close to reaching genomewide significance (OR = 1.52, P = 2.0 x 10-(6)), which was confirmed in replication samples (combined P = 3.3 x 10(-12)). The authors also detected possible secondary associations of this SNP with blond versus brown hair and with skin sensitivity to sun.
Sulem et al. (2008) presented results from a genomewide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. The TYR rs1126809 R402Q variant showed genomewide significance for association with skin sensitivity to sun (p = 7.1 x 10(-13)) and blue versus green eye color (p = 4.6 x 10(-21)).
Association with Susceptibility to Cutaneous Malignant Melanoma
In a study of the effect of pigmentation-associated genetic sequence variants on risk of cutaneous melanoma and basal cell carcinoma, Gudbjartsson et al. (2008) found that the R402Q variant of TYR, previously shown to affect eye color and tanning response, conferred risk of cutaneous melanoma (odds ratio = 1.21, P = 2.8 x 10(-7)) and basal cell carcinoma (odds ratio = 1.14, P = 6.1 x 10(-4)).
Bishop et al. (2009) reported a genomewide association study of melanoma conducted by the GenoMEL consortium based on 317,000 tagging SNPs for 1,650 selected cases and 4,336 controls, with replication in an additional 2 cohorts (1,149 selected cases and 964 controls from GenoMEL, and a population-based case-control study in Leeds of 1,163 cases and 903 controls). The genomewide screen identified 5 loci with genotypes or imputed SNPs reaching P less than 5 x 10(-7). Three of these loci were replicated: 16q24 encompassing MC1R (155555) (combined P = 2.54 x 10(27) for rs258322), 11q14-q21 encompassing TYR (P = 2.41 x 10(-14) for rs1393350), and 9p21 adjacent to MTAP (156540) and flanking CDKN2A (600160) (P = 4.03 x 10(-7) for rs7023329) (see 155601). MC1R and TYR are associated with pigmentation, freckling, and cutaneous sun sensitivity, well-recognized melanoma risk factors. Bishop et al. (2009) concluded that despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and show independent association to disease risk.
In a linkage study, Eiberg et al. (1986) scored eye color in a questionnaire as purely blue, green, gray, brown, or 'don't know.' The presence of brown areas or spots were also noted. For the purpose of linkage analysis, they assumed 2 main loci: (1) a 'green/blue' locus (GEY) with a dominant allele for green and a recessive allele for blue, and (2) a 'brown/blue' locus (BEY) with a dominant allele for brown and a recessive for blue. Linkage of GEY with Lutheran (111200) and secretor (182100), both located on chromosome 19, was found. They reported a lod score of 3.37 (theta = 0.0 for males and 0.07 for females) against Lutheran and of 1.79 (at theta = 0.1 in males) against secretor, from observations largely in different families. In the full report, Eiberg and Mohr (1987) reported a combined lod score of 9.19 for linkage between GEY and the Lutheran-secretor systems. They also found evidence for linkage of GEY to brown hair color with a lod score of 5.06.
Eiberg (1997) suspected that green eye color is heterogeneous (perhaps with more than 2 loci), because he had observed families segregating with chromosome 19 and others not segregating with chromosome 19.
Bishop, D. T., Demenais, F., Iles, M. M., Harland, M., Taylor, J. C., Corda, E., Randerson-Moor, J., Aitken, J. F., Avril, M.-F., Azizi, E., Bakker, B., Bianchi-Scarra, G., and 41 others. Genome-wide association study identifies three loci associated with melanoma risk. Nature Genet. 41: 920-925, 2009. [PubMed: 19578364] [Full Text: https://doi.org/10.1038/ng.411]
Eiberg, H., Mohr, J. Major genes of eye color and hair color linked to LU and SE. Clin. Genet. 31: 186-191, 1987. [PubMed: 3568446] [Full Text: https://doi.org/10.1111/j.1399-0004.1987.tb02793.x]
Eiberg, H., Moller, N., Niebuhr, E., Nielsen, L. S., Mohr, J. Linkage of 'green/blue' eye colour (GEY) to blood group Lu-Se and transcobalamin II to blood group P. (Abstract) 7th International Congress of Human Genetics, Berlin 1986. Pp. 623-624.
Eiberg, H. Personal Communication. Copenhagen, Denmark 5/9/1997.
Frudakis, T., Thomas, M., Gaskin, Z., Venkateswarlu, K., Chandra, K. S., Ginjupalli, S., Gunturi, S., Natrajan, S., Ponnuswamy, V. K., Ponnuswamy, K. N. Sequences associated with human iris pigmentation. Genetics 165: 2071-2083, 2003. [PubMed: 14704187] [Full Text: https://doi.org/10.1093/genetics/165.4.2071]
Gudbjartsson, D. F., Sulem, P., Stacey, S. N., Goldstein, A. M., Rafner, T., Sigurgeirsson, B., Benediktsdottir, K. R., Thorisdottir, K., Ragnarsson, R., Sveinsdottir, S. G., Magnusson, V., Lindblom, A., and 26 others. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nature Genet. 40: 886-891, 2008. Note: Erratum: Nature Genet. 40: 1029 only, 2008. [PubMed: 18488027] [Full Text: https://doi.org/10.1038/ng.161]
Myles, S., Somel, M., Tank, K., Kelso, J., Stoneking, M. Identifying genes underlying skin pigmentation differences among human populations. Hum. Genet. 120: 613-621, 2007. [PubMed: 16977434] [Full Text: https://doi.org/10.1007/s00439-006-0256-4]
Norton, H. L., Kittles, R. A., Parra, E., McKeigue, P., Mao, X., Cheng, K., Canfield, V. A., Bradley, D. G., McEvoy, B., Shriver, M. D. Genetic evidence for the convergent evolution of light skin in Europeans and East Asians. Molec. Biol. Evol. 24: 710-722, 2006. [PubMed: 17182896] [Full Text: https://doi.org/10.1093/molbev/msl203]
Relethford, J. H. Hemispheric difference in human skin color. Am. J. Physiol. Anthrop. 104: 449-457, 1997. [PubMed: 9453695] [Full Text: https://doi.org/10.1002/(SICI)1096-8644(199712)104:4<449::AID-AJPA2>3.0.CO;2-N]
Shriver, M. D., Parra, E. J., Dios, S., Bonilla, C., Norton, H., Jovel, C., Pfaff, C., Jones, C., Massac, A., Cameron, N., Baron, A., Jackson, T., Argyropoulos, G., Jin, L., Hoggart, C. J., McKeigue, P. M., Kittles, R. A. Skin pigmentation, biogeographical ancestry and admixture mapping. Hum. Genet. 112: 387-399, 2003. [PubMed: 12579416] [Full Text: https://doi.org/10.1007/s00439-002-0896-y]
Stokowski, R. P., Pant, P. V. K., Dadd, T., Fereday, A., Hinds, D. A., Jarman, C., Filsell, W., Ginger, R. S., Green, M. R., van der Ouderaa, F. J., Cox, D. R. A genomewide association study of skin pigmentation in a South Asian population. Am. J. Hum. Genet. 81: 1119-1132, 2007. [PubMed: 17999355] [Full Text: https://doi.org/10.1086/522235]
Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Jakobsdottir, M., Steinberg, S., Gudjonsson, S. A., Palsson, A., Thorleifsson, G., Palsson, S., Sigurgeirsson, B., and 13 others. Two newly identified genetic determinants of pigmentation in Europeans. Nature Genet. 40: 835-837, 2008. [PubMed: 18488028] [Full Text: https://doi.org/10.1038/ng.160]
Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Magnusson, K. P., Manolescu, A., Karason, A., Palsson, A., Thorleifsson, G., Jakobsdottir, M., Steinberg, S., and 13 others. Genetic determinants of hair, eye and skin pigmentation in Europeans. Nature Genet. 39: 1443-1452, 2007. [PubMed: 17952075] [Full Text: https://doi.org/10.1038/ng.2007.13]