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A global view of the OCA2-HERC2 region and pigmentation.

ABSTRACT: Mutations in the gene OCA2 are responsible for oculocutaneous albinism type 2, but polymorphisms in and around OCA2 have also been associated with normal pigment variation. In Europeans, three haplotypes in the region have been shown to be associated with eye pigmentation and a missense SNP (rs1800407) has been associated with green/hazel eyes (Branicki et al. in Ann Hum Genet 73:160-170, 2009). In addition, a missense mutation (rs1800414) is a candidate for light skin pigmentation in East Asia (Yuasa et al. in Biochem Genet 45:535-542, 2007; Anno et al. in Int J Biol Sci 4, 2008). We have genotyped 3,432 individuals from 72 populations for 21 SNPs in the OCA2-HERC2 region including those previously associated with eye or skin pigmentation. We report that the blue-eye associated alleles at all three haplotypes were found at high frequencies in Europe; however, one is restricted to Europe and surrounding regions, while the other two are found at moderate to high frequencies throughout the world. We also observed that the derived allele of rs1800414 is essentially limited to East Asia where it is found at high frequencies. Long-range haplotype tests provide evidence of selection for the blue-eye allele at the three haplotyped systems but not for the green/hazel eye SNP allele. We also saw evidence of selection at the derived allele of rs1800414 in East Asia. Our data suggest that the haplotype restricted to Europe is the strongest marker for blue eyes globally and add further inferential evidence that the derived allele of rs1800414 is an East Asian skin pigmentation allele.

SUBMITTER: Donnelly MP

PROVIDER: S-EPMC3325407 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description:The OCA2-HERC2 locus is responsible for the greatest proportion of eye color variation in humans. Numerous studies extensively described both functional SNPs and associated patterns of variation over this region. The goal of our study is to examine how these haplotype structures and allelic associations vary when highly variable markers such as microsatellites are used. Eleven microsatellites spanning 357 Kb of OCA2-HERC2 genes are analyzed in 3029 individuals from worldwide populations. We found that several markers display large differences in allele frequency (10% to 35% difference) among Europeans, East Asians and Africans. In Europe, the alleles showing increased frequency can also discriminate individuals with (IrisPlex) predicted blue and brown eyes. Distinct haplotypes are identified around the variants C and T of the functional SNP rs12913832 (associated to blue eyes), with linkage disequilibrium r2 values significant up to 237 Kb. The haplotype carrying the allele rs12913832 C has high frequency (76%) in blue eye predicted individuals (30% in brown eye predicted individuals), while the haplotype associated to the allele rs12913832 T is restricted to brown eye predicted individuals. Finally, homozygosity values reach levels of 91% near rs12913832. Odds ratios show values of 4.2, 7.4 and 10.4 for four markers around rs12913832 and 7.1 for their core haplotype. Hence, 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.

| S-EPMC8602267 | biostudies-literature

HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter.

Project description:Pigmentation of skin, eye, and hair reflects some of the most evident common phenotypes in humans. Several candidate genes for human pigmentation are identified. The SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species. However, the exact functional role of HERC2 rs12913832 in human pigmentation is unknown. Here we demonstrate that the HERC2 rs12913832 region functions as an enhancer regulating OCA2 transcription. In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression. In contrast, in lightly pigmented melanocytes carrying the rs12913832 C-allele, chromatin-loop formation, transcription factor recruitment, and OCA2 expression are all reduced. Hence, we demonstrate that allelic variation of a common noncoding SNP located in a distal regulatory element not only disrupts the regulatory potential of this element but also affects its interaction with the relevant promoter. We provide the key mechanistic insight that allele-dependent differences in chromatin-loop formation (i.e., structural differences in the folding of gene loci) result in differences in allelic gene expression that affects common phenotypic traits. This concept is highly relevant for future studies aiming to unveil the functional basis of genetically determined phenotypes, including diseases.

| S-EPMC3290780 | biostudies-literature

Association between Variants in the <i>OCA2-HERC2</i> Region and Blue Eye Colour in <i>HERC2</i> rs12913832 AA and AG Individuals.

Project description:The OCA2-HERC2 region is strongly associated with human pigmentation, especially eye colour. The HERC2 SNP rs12913832 is currently the best-known predictor for blue and brown eye colour. However, in a previous study we found that 43 of 166 Norwegians with the brown eye colour genotype rs12913832:AA or AG, did not have the expected brown eye colour. In this study, we carried out massively parallel sequencing of a ~500 kbp HERC2-OCA2 region in 94 rs12913832:AA and AG Norwegians (43 blue-eyed and 51 brown-eyed) to search for novel blue eye colour variants. The new candidate variants were subsequently typed in a Norwegian biobank population (total n = 519) for population specific association analysis. We identified five new variants, rs74409036:A, rs78544415:T, rs72714116:T, rs191109490:C and rs551217952:C, to be the most promising candidates for explaining blue eye colour in individuals with the rs12913832:AA and AG genotype. Additionally, we confirmed the association of the missense variants rs74653330:T and rs121918166:T with blue eye colour, and observed lighter skin colour in rs74653330:T individuals. In total, 37 (86%) of the 43 blue-eyed rs12913832:AA and AG Norwegians could potentially be explained by these seven variants, and we suggest including them in future prediction models.

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Distribution of two OCA2 polymorphisms associated with pigmentation in East-Asian populations.

Project description:Two OCA2 polymorphisms (rs1800414 and rs74653330) have been associated with pigmentation in East Asians. We explored the distribution of these markers in a panel of samples from populations around the world. The derived allele of rs1800414 has high frequencies in a broad East-Asian region, whereas the derived allele of rs74653330 is primarily restricted to northern East Asia. Our data suggest that these polymorphisms may have been selected independently in different regions of East Asia.

| S-EPMC4785538 | biostudies-literature

The distinctive geographic patterns of common pigmentation variants at the OCA2 gene.

Project description:Oculocutaneous Albinism type 2 (OCA2) is a gene of great interest because of genetic variation affecting normal pigmentation variation in humans. The diverse geographic patterns for variant frequencies at OCA2 have been evident but have not been systematically investigated, especially outside of Europe. Here we examine population genetic variation in and near the OCA2 gene from a worldwide perspective. The very different patterns of genetic variation found across world regions suggest strong selection effects may have been at work over time. For example, analyses involving the variants that affect pigmentation of the iris argue that the derived allele of the rs1800407 single nucleotide polymorphism, which produces a hypomorphic protein, may have contributed to the previously demonstrated positive selection in Europe for the enhancer variant responsible for light eye color. More study is needed on the relationships of the genetic variation at OCA2 to variation in pigmentation in areas beyond Europe.

| S-EPMC7508881 | biostudies-literature

Variants at the OCA2/HERC2 locus affect time to first cutaneous squamous cell carcinoma in solid organ transplant recipients collected using two different study designs.

Project description:BackgroundVariants at the oculocutaneous albinism 2 (OCA2)/HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2) locus have been associated with pigmentation phenotypes and risk of developing several types of skin cancer.ObjectivesTo evaluate OCA2/HERC2 locus variants for their impact on time to develop cutaneous squamous cell carcinoma (cSCC) in organ transplant recipients (OTRs) who are at elevated risk of developing cSCC.MethodsParticipants were solid OTRs ascertained from two centres (n = 125 and 261) with an average of 13·1 years of follow-up post-transplant. DNA was available for genotyping for all participants, in addition to medical records and questionnaire data. The Ohio State University study had a case-control design with prospective follow-up, and the University of California San Francisco study was a national cross-sectional survey with retrospective chart review.ResultsOCA2 variants rs12913832 and rs916977 were significantly associated with time to first cSCC post-transplant. OTRs homozygous for the brown-eye alleles of rs916977 (GG) and rs12913832 (AA) had significant delays of time to first cSCC post-transplant compared with individuals homozygous for the blue-eye alleles (hazard ratio 0·34, P < 0·001 and hazard ratio 0·54, P = 0·012, respectively). Both variants were highly associated with eye colour in the combined studies (P < 0·001).ConclusionsThis study is the first to show an association between OCA2/HERC2 variants and time to first cSCC post-transplant. This may impact dermatological screening recommendations for high-risk populations.

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Hepatocellular carcinoma: A global view.

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Functional interactions between OCA2 and the protein complexes BLOC-1, BLOC-2, and AP-3 inferred from epistatic analyses of mouse coat pigmentation.

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