Eiberg H, Mohr JAssignment of genes coding for brown eye colour (BEY2) and brown hair colour (HCL3) on chromosome 15q. Eur J Hum Genet 4:237-241

University Institute of Medical Biochemistry and Genetics, Department of Medical Genetics, Danish Centre for Genome Research, Copenhagen, Denmark.
European Journal of HumanGenetics (Impact Factor: 4.35). 02/1996; 4(4):237-41.
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ABSTRACT Brown eye colour (BEY), or total brown iris pigmentation is one of the most common phenotypes of iris colour. Data of eye colour as well as hair colour were obtained for linkage analysis through an enquiry in our family material of 832 families from Copenhagen area. By exclusion mapping with 80 markers in 120 segregating families and 290 markers in 5 segregating families, we obtained some indication of a locus BEY2 for brown eye colour on chromosome 15. For possible confirmation, we selected a total of 45 families from our DNA bank segregating for BEY. All these were tested for chromosome 15 markers in the area between D15S11 and CYP19. We found a strong indication of tight linkage with the DNA polymorphism D15S165 (Z = 24.25; theta M = F = 0.010) and with the flanking markers D15S156 (Z = 14.04; theta M = F = 0.0.029) and D15S144 (Z = 12.99; theta M = F = 0.060). BEY2 is assigned to the region 15q11-15q21 by physically localized markers. A new locus for brown hair colour (HCL3) was localized by indication of linkage to BEY2 in our 45 families segregating for BEY (Z = 9.93; theta M = F = 0.10). The gene (DN10 or P) homologous to the pink-eye-dilution gene (p) in mice could be a candidate gene for BEY2 or for HCL3.

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    • "The function of the gene product is not unequivocally established, but it is related to a transporter protein family which has 12 transmembrane domains and is localised to the melanosome [25]. Associations of OCA2 and HERC2 SNPs with hair and eye colour were found in this study, in accordance with previous reports of linkage or association [3],[4],[5],[6],[7]. The major contribution to eye colour was conveyed by two HERC2 SNPs, rs1129038 and rs129138332, which lie about 20 kb upstream of the OCA2 gene, and which were almost in perfect linkage disequilibrium [5,6]. "
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    ABSTRACT: Eye and hair colour is highly variable in the European population, and is largely genetically determined. Both linkage and association studies have previously been used to identify candidate genes underlying this variation. Many of the genes found were previously known as underlying mutant mouse phenotypes or human genetic disease, but others, previously unsuspected as pigmentation genes, have also been discovered. We assayed the hair of a population of individuals of Scottish origin using tristimulus colorimetry, in order to produce a quantitative measure of hair colour. Cluster analysis of this data defined two groups, with overlapping borders, which corresponded to visually assessed dark versus red/light hair colour. The Danish population was assigned into categorical hair colour groups. Both cohorts were also assessed for eye colour. DNA from the Scottish group was genotyped at SNPs in 33 candidate genes, using 384 SNPs identified by HapMap as representatives of each gene. Associations found between SNPs and colorimetric hair data and eye colour categories were replicated in a cohort of the Danish population. The Danish population was also genotyped with SNPs in 4 previously described pigmentation genes. We found replicable associations of hair colour with the KITLG and OCA2 genes. MC1R variation correlated, as expected, with the red dimension of colorimetric hair colour in Scots. The Danish analysis excluded those with red hair, and no associations were found with MC1R in this group, emphasising that MC1R regulates the colour rather than the intensity of pigmentation. A previously unreported association with the HPS3 gene was seen in the Scottish population. However, although this replicated in the smaller cohort of the Danish population, no association was seen when the whole study population was analysed. We have found novel associations with SNPs in known pigmentation genes and colorimetrically assessed hair colour in a Scottish and a Danish population.
    BMC Genetics 12/2009; 10(1):88. DOI:10.1186/1471-2156-10-88 · 2.40 Impact Factor
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    • "Another phenotype, green eye color (GEY) was mapped to chromosome 19 by linkage to Secretor and Lutheran blood groups (Eiberg and Mohr, 1987). Later work testing for segregation of DNA markers in Danish families suggested linkage of brown hair and brown eye colour (BEY2) to an interval on chromosome 15q11–15q21 containing the OCA2 and MYO5A genes (Eiberg and Mohr, 1996), with the OCA2 gene homologous to the mouse p-gene being a candidate locus responsible for the phenotype. A complete genome microsatellite scan at the 5– 10 cM resolution level in a collection of adolescent twins in which eye colour phenotype was recorded on a three-point scale found a peak LOD score of 19.2 for blue-brown eye colour in a region that was over the OCA2 locus (Zhu et al., 2004), but with a long tail towards the telomere that may implicate other genes contributing to the phenotype. "
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    ABSTRACT: The presence of melanin pigment within the iris is responsible for the visual impression of human eye colouration with complex patterns also evident in this tissue, including Fuchs' crypts, nevi, Wolfflin nodules and contraction furrows. The genetic basis underlying the determination and inheritance of these traits has been the subject of debate and research from the very beginning of quantitative trait studies in humans. Although segregation of blue-brown eye colour has been described using a simple Mendelian dominant-recessive gene model this is too simplistic, and a new molecular genetic perspective is needed to fully understand the biological complexities of this process as a polygenic trait. Nevertheless, it has been estimated that 74% of the variance in human eye colour can be explained by one interval on chromosome 15 that contains the OCA2 gene. Fine mapping of this region has identified a single base change rs12913832 T/C within intron 86 of the upstream HERC2 locus that explains almost all of this association with blue-brown eye colour. A model is presented whereby this SNP, serving as a target site for the SWI/SNF family member HLTF, acts as part of a highly evolutionary conserved regulatory element required for OCA2 gene activation through chromatin remodelling. Major candidate genes possibly effecting iris patterns are also discussed, including MITF and PAX6.
    Pigment Cell & Melanoma Research 08/2009; 22(5):544-62. DOI:10.1111/j.1755-148X.2009.00606.x · 4.62 Impact Factor
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    • "The conventional methods based on reflectometry or biochemical analysis cannot be applied to evaluate iris pigmentation in anthropological or genetic studies. Traditionally, studies of iris color have been based on classification of iris pigmentation in broad categories (e.g., blue, gray, green, hazel, light brown, dark brown) by trained observers (Eiberg and Mohr, 1996; Rebbeck et al., 2002; Zhu et al., 2004; Duffy et al., 2007). However, this qualitative approach fails to capture the quantitative nature of iris pigmentation variation. "
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    ABSTRACT: Pigmentation, which is primarily determined by the amount, the type, and the distribution of melanin, shows a remarkable diversity in human populations, and in this sense, it is an atypical trait. Numerous genetic studies have indicated that the average proportion of genetic variation due to differences among major continental groups is just 10-15% of the total genetic variation. In contrast, skin pigmentation shows large differences among continental populations. The reasons for this discrepancy can be traced back primarily to the strong influence of natural selection, which has shaped the distribution of pigmentation according to a latitudinal gradient. Research during the last 5 years has substantially increased our understanding of the genes involved in normal pigmentation variation in human populations. At least six genes have been identified using genotype/phenotype association studies and/or direct functional assays, and there is evidence indicating that several additional genes may be playing a role in skin, hair, and iris pigmentation. The information that is emerging from recent studies points to a complex picture where positive selection has been acting at different genomic locations, and for some genes only in certain population groups. There are several reasons why elucidating the genetics and evolutionary history of pigmentation is important. 1) Pigmentation is a trait that should be used as an example of how misleading simplistic interpretations of human variation can be. It is erroneous to extrapolate the patterns of variation observed in superficial traits such as pigmentation to the rest of the genome. It is similarly misleading to suggest, based on the "average" genomic picture, that variation among human populations is irrelevant. The study of the genes underlying human pigmentation diversity brings to the forefront the mosaic nature of human genetic variation: our genome is composed of a myriad of segments with different patterns of variation and evolutionary histories. 2) Pigmentation can be very useful to understand the genetic architecture of complex traits. The pigmentation of unexposed areas of the skin (constitutive pigmentation) is relatively unaffected by environmental influences during an individual's lifetime when compared with other complex traits such as diabetes or blood pressure, and this provides a unique opportunity to study gene-gene interactions without the effect of environmental confounders. 3) Pigmentation is of relevance from a public health perspective, because of its critical role in photoprotection and vitamin D synthesis. Fair-skinned individuals are at higher risk of several types of skin cancer, particularly in regions with high UVR incidence, and dark-skinned individuals living in high latitude regions are at higher risk for diseases caused by deficient or insufficient vitamin D levels.
    American Journal of Physical Anthropology 01/2007; Suppl 45(S45):85-105. DOI:10.1002/ajpa.20727 · 2.38 Impact Factor
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