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


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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    • "Genotypic profiling based on Single Nucleotide Polymorphisms (SNPs) has been successfully implemented to predict a person's amount of freckling, presence of moles, hair texture and skin color [2] [3] [4] [5] [6] [7] [8]. In forensic science genotyping has been used to predict an individual's eye color, hair color, sex and ancestry with high accuracy [9] [10]. "
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    ABSTRACT: Research into the importance of the human genome in the context of facial appearance is receiving increasing attention and has led to the detection of several Single Nucleotide Polymorphisms (SNPs) of importance. In this work we attempt a holistic approach predicting facial characteristics from genetic principal components across a population of 1266 individuals. For this we perform a genome-wide association analysis to select a large number of SNPs linked to specific facial traits, recode these to genetic principal components and then use these principal components as predictors for facial traits in a linear regression. We show in this proof-of-concept study for facial trait prediction from genome-wide SNP data that some facial characteristics can be modeled by genetic information: facial width, eyebrow width, distance between eyes, and features involving mouth shape are predicted with statistical significance (p<0.03).
    Forensic Science International: Genetics 09/2015; 19:263-268. DOI:10.1016/j.fsigen.2015.08.004
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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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    ABSTRACT: Objectives The main goals of this study are to 1) quantitatively measure skin, hair, and iris pigmentation in a diverse sample of individuals, 2) describe variation within and between these samples, and 3) demonstrate how quantitative measures can facilitate genotype-phenotype association tests.Materials and Methods We quantitatively characterize skin, hair, and iris pigmentation using the Melanin (M) Index (skin) and CIELab values (hair) in 1,450 individuals who self-identify as African American, East Asian, European, Hispanic, or South Asian. We also quantify iris pigmentation in a subset of these individuals using CIELab values from high-resolution iris photographs. We compare mean skin M index and hair and iris CIELab values among populations using ANOVA and MANOVA respectively and test for genotype-phenotype associations in the European sample.ResultsAll five populations are significantly different for skin (P <2 × 10−16) and hair color (P <2 × 10−16). Our quantitative analysis of iris and hair pigmentation reinforces the continuous, rather than discrete, nature of these traits. We confirm the association of three loci (rs16891982, rs12203592, and rs12913832) with skin pigmentation and four loci (rs12913832, rs12203592, rs12896399, and rs16891982) with hair pigmentation. Interestingly, the derived rs12203592 T allele located within the IRF4 gene is associated with lighter skin but darker hair color.DiscussionThe quantitative methods used here provide a fine-scale assessment of pigmentation phenotype and facilitate genotype-phenotype associations, even with relatively small sample sizes. This represents an important expansion of current investigations into pigmentation phenotype and associated genetic variation by including non-European and admixed populations. Am J Phys Anthropol, 2015. © 2015 Wiley Periodicals, Inc.
    American Journal of Physical Anthropology 09/2015; DOI:10.1002/ajpa.22861
    • "S/A [50] rs10777129 KITLG 12 88961713 H [45] rs11636232 HERC2 15 28386626 E/H [45] [51] rs12203592 IRF4 6 396321 E/H [36,47,48,52,53] rs12592730 HERC2 15 28530359 E [54] rs12896399 SLC24A4 14 92773663 E/H [11] [13] [47] [48] [55] rs12913832 HERC2 15 28365618 E/H [52] [54] [56] rs13289 SLC45A2 5 33986409 H/S [41] [46] [51] rs1426654 SLC24A5 15 48426484 H/S [5] [10] [12] [16] [48] rs1667394 HERC2 15 28530182 E/H [15] [34] [55] rs16891982 SLC45A2 5 33951693 E/H/S [10] [12] [42] [48] [52] rs1805008 MC1R 16 89986144 H [45] [47] [55] rs26722 SLC45A2 5 33963870 E/H/S [41] [47] rs3782974 DCT 13 95092896 S/A [57] rs4778138 OCA2 15 28335820 E/H [34] [47] [51] rs4778241 OCA2 15 28338713 E/H [47] [51] rs7495174 OCA2 15 28344238 E/H [45] [51] rs916977 HERC2 15 28513364 E/H [45] [47] [51] "
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    ABSTRACT: There is growing interest in skin colour prediction in the forensic field. However, a lack of consensus approaches for recording skin colour phenotype plus the complicating factors of epistatic effects, environmental influences such as exposure to the sun and unidentified genetic variants, present difficulties for the development of a forensic skin colour predictive test centred on the most strongly associated SNPs. Previous studies have analysed skin colour variation in single unadmixed population groups, including South Asians (Stokowski et al., 2007, Am. J. Hum. Genet, 81: 1119-32) and Europeans (Jacobs et al., 2013, Hum Genet. 132: 147-58). Nevertheless, a major challenge lies in the analysis of skin colour in admixed individuals, where co-ancestry proportions do not necessarily dictate any one person's skin colour. Our study sought to analyse genetic differences between African, European and admixed African-European subjects where direct spectrometric measurements and photographs of skin colour were made in parallel. We identified strong associations to skin colour variation in the subjects studied from a pigmentation SNP discovery panel of 59 markers and developed a forensic online classifier based on naïve Bayes analysis of the SNP profiles made. A skin colour predictive test is described using the ten most strongly associated SNPs in 8 genes linked to skin pigmentation variation.
    Forensic Science International: Genetics 11/2014; 13. DOI:10.1016/j.fsigen.2014.06.017
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