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

Eiberg, Hans; Troelsen, Jesper T.; Nielsen, Mette Ødegaard; Mikkelsen, Annemette; Mengel‐From, Jonas; Kjaer, Klaus; Hansen, Lars

doi:10.1007/s00439-007-0460-x

Cited by 313 publications

(334 citation statements)

References 26 publications

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“…This was in concordance with previous studies in which HERC2 rs12913832 was described to be the main predictor of qualitative [14,15,16] and quantitative eye colour [17]. To assess possible confounding effects of HERC2 rs12913832 on the gender effect, association tests of gender with the PIE-score were carried out using the non-parametric Wilcoxon-rank-sum test based on the SNP-types of HERC2 rs12913832 (Table 2 and Figure 1).…”

Section: Association Between Gender the Irisplex Snps And Eye Coloursupporting

confidence: 84%

The effect of gender on eye colour variation in European populations and an evaluation of the IrisPlex prediction model

Pietroni

Andersen

Johansen

et al. 2014

Forensic Science International: Genetics

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In this study, we investigate the role of gender as a factor that contributes to eye colour variation and suggest that the gender effect on eye colour is population specific.A total of 230 Italian individuals were typed for the six IrisPlex SNPs (rs12913832, rs1800407, rs12896399, rs1393350, rs16891982 and rs12203592). A quantitative eye colour score (Pixel Index of the Eye: PIE-score) was calculated based on digital eye images using the custom made DIAT software. The results were compared with those of Danish and Swedish population samples.As expected, we found HERC2 rs12913832 as the main predictor of human eye colour independently of ancestry. Furthermore, we found gender to be significantly associated with quantitative eye colour measurements in the Italian population sample. We found that the association was statistically significant only among Italian individuals typed as heterozygote GA for HERC2 rs12913832. Interestingly, we did not observe the same association in the Danish and Swedish population. This indicated that the gender effect on eye colour is population specific. We estimated the effect of gender on quantitative eye colour in the Italian population sample to be 4.9%. Among gender and the IrisPlex SNPs, gender ranked as the second most important predictor of human eye colour variation in Italians after HERC2 rs12913832. We, furthermore, tested the five lower ranked IrisPlex predictors, and evaluated all possible 3 6 (729) genotype combinations of the IrisPlex assay and their corresponding predictive values using the IrisPlex prediction model [4]. The results suggested that maximum three (rs12913832, rs1800407, rs16891982) of the six IrisPlex SNPs are useful in practical forensic genetic casework.

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Section: Association Between Gender the Irisplex Snps And Eye Coloursupporting

confidence: 84%

The effect of gender on eye colour variation in European populations and an evaluation of the IrisPlex prediction model

Pietroni

Andersen

Johansen

et al. 2014

Forensic Science International: Genetics

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“…All those heterozygous for the Polynesian OCA2 mutation p.Gly775Asp with green or blue eyes had known Caucasian ancestors, suggesting possible interaction with other pigmentation-influencing variants. 16,22,23 There was a predominance for gray hair in heterozygous carriers; however, the majority of participants expressed black hair irrespective of carrier status and age-related hair graying must be taken into account.…”

Section: Oca2 Gene Mutation Detectionmentioning

confidence: 99%

“…20 Polymorphism within the OCA2 gene is significantly associated with eye color 21 and also underlies the previous assignment of the brown eye (BEY2/EYCL3, MIM227220) and brown hair (HCL3, MIM601800) phenotypes. A single single-nucleotide polymorphism in the neighboring gene, HERC2, was recently found to be a common founder polymorphism affecting an OCA2 regulatory element, which in turn results in blue eye color 22,23 and reduced melanin content in cultured human melanocytes. 24 MC1R is associated with red hair in the European population and has been found to modify the OCA2 phenotype to also express red hair.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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Oculocutaneous albinism type 2 (OCA2) is a human autosomal-recessive hypopigmentation disorder associated with pathological mutations of the OCA2 gene. In this study, we investigated a form of OCA in a Polynesian population with an observed phenotype characterized by fair skin, some brown nevi present in the sun-exposed areas and green or blue eyes. Hair presented with a unique red coloration since birth, with tones ranging across individuals from Yellow-Red to Brown-Red, or Auburn. We genetically screened for mutations in the OCA2 and MC1R genes as their products have previously been shown to be associated with red hair/fair skin and OCA2. The SLC45A2 gene was also screened to identify any possible relation to skin color variation. We have identified a novel missense substitution in the OCA2 gene (Gly775Asp) responsible for OCA2 in individuals of Polynesian heritage from Tuvalu. The estimated incidence of this form of OCA2 in the primary study community is believed to occur at one of the highest recorded rates of albinism at approximately 1 per 669 individuals. In addition, we have analyzed four unrelated individuals with albinism who have Polynesian heritage from three other separate communities and found they carry the same OCA2 mutation. We also analyzed an out-group comprising three unrelated individuals with albinism of Melanesian ancestries from two separate communities, one Australian Aboriginal and three Australian Caucasians, and did not detect this mutation. We hypothesize that this mutation may be Polynesian specific and that it originated from a common founder.

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“…Further studies of this region and its sequence revealed that a change in one nucleotide, single-nucleotide polymorphism (SNP), regulates the binding site for the transcription of the OCA2 gene, altering its expression. 9 The base changes from a thymine to a cytosine. The SNP, rs12913832, causes a phenotype change from brown to blue eyes, respectively.…”

Section: Genotype-phenotype Interactionsmentioning

confidence: 99%

“…These genes are of the greatest importance for eye color. [9][10][11] Numerous ubiquitin ligases are coded for throughout the body. Chromosome 15 contains HERC1 and HERC2.…”

Section: Introductionmentioning

confidence: 99%

Genotype–phenotype associations and human eye color

White

Rabago-Smith

2010

J Hum Genet

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Although eye color is usually modeled as a simple, Mendelian trait, further research and observation has indicated that eye color does not follow the classical paths of inheritance. Eye color phenotypes demonstrate both epistasis and incomplete dominance. Although there are about 16 different genes responsible for eye color, it is mostly attributed to two adjacent genes on chromosome 15, hect domain and RCC1-like domain-containing protein 2 (HERC2) and ocular albinism (that is, oculocutaneous albinism II (OCA2)). An intron in HERC2 contains the promoter region for OCA2, affecting its expression. Therefore, singlenucleotide polymorphisms in either of these two genes have a large role in the eye color of an individual. Furthermore, with all genetic expression, aberration also occurs. Some individuals may express two phenotypes-one in each eye-or a complete lack of pigmentation, ocular albinism. In addition, the evolutionary and population roles of the different expressions are significant.

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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

Cited by 313 publications

References 26 publications

The effect of gender on eye colour variation in European populations and an evaluation of the IrisPlex prediction model

The effect of gender on eye colour variation in European populations and an evaluation of the IrisPlex prediction model

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

Genotype–phenotype associations and human eye color

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