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

  title={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},
  author={Hans Eiberg and Jesper Thorvald Troelsen and Mette Nielsen and Annemette Mikkelsen and Jonas Mengel-From and Klaus Wilbrandt Kjaer and Lars Kai Hansen},
  journal={Human Genetics},
The human eye color is a quantitative trait displaying multifactorial inheritance. [] Key Method 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…

Genotyping of five single nucleotide polymorphisms in the OCA2 and HERC2 genes associated with blue‐brown eye color in the Japanese population

The present study is the first to examine in detail the genotype and haplotype frequencies for these five SNPs in an Asian (Japanese) population comprising solely brown‐eyed individuals and revealed significant differences between Japanese and other populations.

Further insight into the global variability of the OCA2-HERC2 locus for human pigmentation from multiallelic markers

This study provides an example on the informativeness of multiallelic markers that, despite their current limited potential contribution to forensic eye color prediction, supports the use of microsatellites for identifying causing variants showing similar genetic features and history.

Genotype–phenotype associations and human eye color

Further research and observation has indicated that eye color does not follow the classical paths of inheritance, and single-nucleotide polymorphisms in either of these two genes have a large role in the eye color of an individual.

Molecular genetics of human pigmentation diversity.

  • R. Sturm
  • Biology
    Human molecular genetics
  • 2009
From a culmination of genetic and functional studies, it is apparent that a number of genes impacting melanosome biogenesis or the melanin biosynthetic pathway are candidates to explain the diversity seen in human pigmentation.

Genetics of Eye Colour

The large effect sizes make this an excellent model for the investigation of the architecture of gene action, especially gene-by-gene interactions (epistasis), as well as multi-trait action (pleiotropy).

Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up

A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations.

Inheritance of a novel mutated allele of the OCA2 gene associated with high incidence of oculocutaneous albinism in a Polynesian community

A novel missense substitution in the OCA2 gene (Gly775Asp) is identified responsible for OCA 2 in individuals of Polynesian heritage from Tuvalu and it is hypothesized that this mutation may bePolynesian specific and that it originated from a common founder.

Gene–gene interactions contribute to eye colour variation in humans

This research indicates interactive effects of a synergistic character between HERC2 and OCA2, and provides evidence for a novel strong synergistic interaction between Herc2 and TYRP1, both affecting determination of green eye colour.

Genetics of human iris colour and patterns

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.

Association of the SLC45A2 gene with physiological human hair colour variation

It is indicated that the rare allele L374 significantly increases the possibility of having black hair colour (OR = 7.05) and thus may be considered as a future marker forblack hair colour prediction.



A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation.

The minor population impact of the nonsynonymous coding-region polymorphisms Arg305Trp and Arg419Gln associated with nonblue eyes and the tight linkage of the major TGT haplotype within the intron 1 of OCA2 with blue eye color and lighter hair and skin tones suggest that differences within the 5' proximal regulatory control region of the OCA1 gene alter expression or messenger RNA-transcript levels and may be responsible for these associations.

A genome scan for eye color in 502 twin families: most variation is due to a QTL on chromosome 15q.

It is concluded that most variation in eye color in Europeans is due to polymorphism in OCA2 but that there may be modifiers at several other loci, including additive x additive epistasis.

Sequences associated with human iris pigmentation.

The results suggest that cryptic population structure might serve as a leverage tool for complex trait gene mapping if genomes are screened with the appropriate ancestry informative markers.

Structure of the highly conserved HERC2 gene and of multiple partially duplicated paralogs in human.

The results establish that some genes not only have a protein coding function but can also play a structural role in the genome and provide significant insights into the structure of complex duplicons and into the evolutionary pathways of formation, dispersal, and genomic instability of duplicons.

Complementation analyses for 45 mutations encompassing the pink-eyed dilution (p) locus of the mouse.

The homozygous and heterozygous phenotypes are described and characterized for 45 new pink-eyed dilution (p) locus mutations, most of them radiation-induced, that affect survival at various stages of

Hypopigmentation in the Prader-Willi syndrome correlates with P gene deletion but not with haplotype of the hemizygous P allele.

The results indicate that hypopigmentation is likely the result of deletion of the P gene in the context of Prader-Willi syndrome but do not support the linked hypothesis that hypipigmentation results from hemizygosity for variant P alleles with reduced function.

Assignment of Genes Coding for Brown Eye Colour (BEY2) and Brown Hair Colour (HCL3) on Chromosome 15q

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, which is assigned to the region 15q11-15q21 by physically localized markers.

A very large protein with diverse functional motifs is deficient in rjs (runty, jerky, sterile) mice.

On the basis of sequence homology and conserved synteny, the rjs gene is the single mouse homolog of a previously described five- or six-member human gene family, represented by at least two genes from human chromosome 15q11-q13.

Estimation of the age of the ancestral arginine3500-->glutamine mutation in human apoB-100.

The amount of recombination between the apoB gene and markers on chromosome 2 in 34 FDB (R3500Q) probands in whom the mutation is on a 194 haplotype is estimated, estimating that the ancestral mutation occurred about 270 generations ago.