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Eiberg H, Troelsen J, Nielsen M, Mikkelsen A, Mengel-From J, Kjaer KW 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

Department of Cellular and Molecular Medicine, Section IV Build. 24.4, Panum Institute, University of Copenhagen, Blegdamsvej 3b, 2200, Copenhagen, Denmark.
Human Genetics (Impact Factor: 4.82). 04/2008; 123(2):177-87. DOI: 10.1007/s00439-007-0460-x
Source: PubMed

ABSTRACT

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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    • "For example, SNP rs12916300 at 15q13 (Figure S2) lies within intron 68 of HERC2, which encodes a ubiquitin-protein ligase recruited to sites of DNA damage from ionizing radiation, and which has been associated with BCC (Han et al., 2011) and pigmentation phenotypes (Han et al., 2011;Eiberg et al., 2008). This SNP is in high linkage disequilibrium (LD) (R 2 = 0.85) with rs12913832, another intronic SNP in HERC2 that M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 5 has been associated with pigmentation phenotypes (Sturm et al., 2008;Han et al., 2008;Eiberg et al., 2008;Branicki et al., 2009;Nan et al., 2009b) and that modifies expression of OCA2, a nearby gene encoding a melanosomal enzyme needed for melanin synthesis (Visser et al., 2012). However SNP rs12916300 remained associated with SCC risk with genome-wide significance after adjustment for rs12913832, suggesting that its effects are not merely due to its correlation with rs12913832. "
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    • "" red, " " blond, " " brown " ), particularly in large-scale GWAS studies (Sulem et al., 2007; Nan et al., 2009; Branicki et al., 2011; Walsh et al., 2013). As direct assessment of iris pigmentation using tristimulus colorimetry or narrow-band reflectometry is not possible, iris pigmentation has also been commonly described in descriptive terms (e.g., " blue, " " green, " brown " ) (Frudakis et al., 2003; Eiberg et al., 2008; Kayser et al., 2008; Sturm et al., 2008). However, recent efforts to quantitatively characterize iris pigmentation (e.g. using CIELab values) from high-resolution photographs (Liu et al., 2010; Walsh et al., 2011a; Edwards et al., 2012; Walsh et al., 2013; Beleza et al., 2013) have provided a more nuanced picture of iris pigmentation. "
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