The human eye color is a quantitative trait displaying multifactorial inheritance. Several studies have shown that the OCA2 locus is the major contributor to the human eye color variation. By linkage analysis of a large Danish family, we finemapped the blue eye color locus to a 166 Kbp region within the HERC2 gene. By association analyses, we identified two SNPs within this region that were perfectly associated with the blue and brown eye colors: rs12913832 and rs1129038. Of these, rs12913832 is located 21.152 bp upstream from the OCA2 promoter in a highly conserved sequence in intron 86 of HERC2. The brown eye color allele of rs12913832 is highly conserved throughout a number of species. As shown by a Luciferase assays in cell cultures, the element significantly reduces the activity of the OCA2 promoter and electrophoretic mobility shift assays demonstrate that the two alleles bind different subsets of nuclear extracts. One single haplotype, represented by six polymorphic SNPs covering half of the 3′ end of the HERC2 gene, was found in 155 blue-eyed individuals from Denmark, and in 5 and 2 blue-eyed individuals from Turkey and Jordan, respectively. Hence, our data suggest a common founder mutation in an OCA2 inhibiting regulatory element as the cause of blue eye color in humans. In addition, an LOD score of Z = 4.21 between hair color and D14S72 was obtained in the large family, indicating that RABGGTA is a candidate gene for hair color.
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Ancans J, Tobin DJ, Hoogduijn MJ, Smit NP, Wakamatsu K, Thody AJ (2001). Melanosomal pH controls rate of melanogenesis, eumelanin/ phaeomelanin ratio and melanosome maturation in melanocytes and melanoma cells. Exp Cell Res 268:26–35
Carter D, Chakalova L, Osborne CS, Dai Y-F, Fraser P (2002). Long-range chromatin regulatory interactions in vivo. Nat Genet 32:623–626
Cavalli-Sforza LL, Menozzi P, Piazza A (1994). The History and geography of Human genes. Princeton University Press, Princeton
Duffy DL, Box NF, Chen W, Palmer JS, Montgomery GW, James MR, Hayward NK, Nicholas G, Martin NG, Sturm RA (2007). A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation. Am J Hum Genet 80:241–252
Eiberg H, Mohr J (1996). Assignment of genes coding for brown eye colour (BEY2) and brown hair colour (HCL3) on chromosome 15q. Eur J Hum Genet 4:237–241
Eiberg H, Nielsen LS, Klausen J, Dahlén M, Kristensen M, Bisgaard ML, Møller N, Mohr J (1989). Linkage between serum cholinesterase 2 (CHE2) and δ-crystalline gene cluster (CRYG): assignment to chromosome 2. Clin Genet 35:313-321
Frudakis T, Thomas M, Gaskin Z, Venkateswarlu K, Chandra KS, Ginjupalli S, Gunturi S, Natrajan S, Ponnuswamy VK, Ponnuswamy KN (2003). Sequences associated with Human iris pigmentation. Genetics 165:2071–2083
Frudakis T, Terravainen T, Thomas M (2007) Multilocus OCA2 genotypes specify human iris colors. Hum Genet 122:311–326. doi:10.1007/s00439-007-0401-8
Heinemeyer T, Wingender E, Reuter I, Hermjakob H, Kel AE, Kel OV, Ignatieva EV, Ananko EA, Podkolodnaya OA, Kolpakov FA et al (1998) Databases on transcriptional regulation: TRANSFAC, TRRD, and COMPEL. Nucleic Acids Res 26:364–370
Lamoreux ML, Zhou BK, Rosemblat S, Orlow SJ (1995) The pinkeyed-dilution protein and the eumelanin/pheomelanin switch: in support of a unifying hypothesis. Pigment Cell Res 8:263–270
Lee ST, Nicholls RD, Jong MT, Fukai K, Spritz RA (1995). Organization and sequence of the human P gene and identification of a new family of transport proteins. Genomics 20:354–63
Lehman AL, Nakatsu Y, Ching A, Bronson RT, Oakey RJ, Keiper-Hrynko N, Finger JN, Durham-Pierre D, Horton DB (1998) A very large protein with diverse functional motifs is deficient in rjs (runty, jerky, sterile) mice. Proc Natl Acad Sci USA 95:9436–9441
Myant NB, Fobes SA, Day INM, Gallagher J (1997) Estimation of the age of Ancestral Argenine3500 → Glutamine mutation in Human ApoB-100. Genomic 45:78–87
Novak EK, Reddington M, Zhen L, Stenberg PE, Jackson CW, McGarry MP, Swank RT (1995) Inherited thrombocytopenia caused by reduced platelet production in mice with the gunmetal pigment gene mutation. Blood 85:1781–1789
Posthuma D, Visscher PM, Willemsen G, Zhu G, Martin NG, Slagboom PE, de Geus EJ, Boomsma DI (2006). Replicated linkage for eye color on 15q using comparative ratings of sibling pairs. Behav Genet 36:12–17
Puri N, Gardner JM, Brilliant MH (2000). Aberrant pH of melanosomes in pink-eyed dilution (P) mutant melanocytes. J Invest Dermatol 115:607–613
Rebbeck TR, Kanetsky PA, Walker AH, Holmes R, Halpern AC, Schuchter LM, Elder DE, Guerry D (2002). P gene as an inherited biomarker of human eye color. Cancer Epidemiol Biomarkers Prev 11:782–784
Remenyi A, Scholer HR, Wilmanns M (2004). Combinatorial control of gene expression. Nat Struct Mol Biol 11:812–815
Russell LB, Montgomery CS, Casheiro NLA, Johnaso DK (1995) Complementation analysis of 45 mutations encompassing the pink-eyed dilution locus of the mouse. Genetics 141:1547–1562
Schäffer AA, Gupta SK, Shriram K, Cottingham RW Jr (1994). Recomputation in linkage analysis. Hum Hered 44:225–237
Spritz RA, Bailin T, Nicholls RD, Lee ST, Park SK, Mascari MJ, Butler MG (1997). Hypopigmentation in the Prader-Willi syndrome correlates with P gene deletion but not with haplotype of the hemizygous P allele. Am J Med Genet 71:57–62
Sturm RA, Teasdale RD, Box NF (2001) Human pigmentation genes; identification, structure and consequences of polymorphic variation. Gene 277:49–62
Toyofuku K, Valencia JC, Kushimoto T, Costin GE, Virador VM, Vieira WD, Ferrans VJ, Hearing VJ (2002). The etiology of oculocutaneous albinism (OCA) type II: the pink protein modulates the processing and transport of tyrosinase. Pigment Cell Res 5:217–224
Troelsen JT, Mitchelmore C, Olsen J (2003a) An enhancer activates the pig lactase phlorizin hydrolase promoter in intestinal cells. Gene 305:101–111
Troelsen JT, Olsen J, Møller J, Sjöström H (2003b). An upstream polymorphism associated with lactase persistence has increased enhancer activity. Gastroenterology 125:1686–1694
Yonggang J, Rebert NA, Joslin JM, Higgins J, Schultz RA, Nicholls RD (2000). Structure of the highly conserved HERC2 gene and of multiple partially duplicated paralogs in Human. Genome Res 10:319–329
Zhu G, Evans DM, Duffy DL, Montgomery GW, Medland SE, Gillespie NA, Ewen KR, Jewell M, Liew YW, Hayward NK, et al (2004). A genome scan for eye color in 502 twin families: most variation is due to a QTL on chromosome 15q. Twin Res 7:197–210
We would like to thank Karin U. Hansen for technical assistance. The project was financially supported by the Danish Research Foundation (JN 22-02-0208). Wilhelm Johannsen Centre is established by the National Danish Research Center.
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Eiberg, H., Troelsen, J., Nielsen, M. et al. Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression. Hum Genet 123, 177–187 (2008). https://doi.org/10.1007/s00439-007-0460-x
- Caco2 Cell
- Hair Color
- Blond Hair
- Oculocutaneous Albinism
- Danish Family