Dataset Information

Association between brown eye colour in rs12913832:GG individuals and SNPs in TYR, TYRP1, and SLC24A4.

ABSTRACT: The genotype of a single SNP, rs12913832, is the primary predictor of blue and brown eye colours. The genotypes rs12913832:AA and rs12913832:GA are most often observed in individuals with brown eye colours, whereas rs12913832:GG is most often observed in individuals with blue eye colours. However, approximately 3% of Europeans with the rs12913832:GG genotype have brown eye colours. The purpose of the study presented here was to identify variants that explain brown eye colour formation in individuals with the rs12913832:GG genotype. Genes and regulatory regions surrounding SLC24A4, TYRP1, SLC24A5, IRF4, TYR, and SLC45A2, as well as the upstream region of OCA2 within the HERC2 gene were sequenced in a study comprising 40 individuals with the rs12913832:GG genotype. Of these, 24 individuals were considered to have blue eye colours and 16 individuals were considered to have brown eye colours. We identified 211 variants within the SLC24A4, TYRP1, IRF4, and TYR target regions associated with eye colour. Based on in silico analyses of predicted variant effects we recognized four variants, TYRP1 rs35866166:C, TYRP1 rs62538956:C, SLC24A4 rs1289469:C, and TYR rs1126809:G, to be the most promising candidates for explanation of brown eye colour in individuals with the rs12913832:GG genotype. Of the 16 individuals with brown eye colours, 14 individuals had four alleles, whereas the alleles were rare in the blue eyed individuals. rs35866166, rs62538956, and rs1289469 were for the first time found to be associated with pigmentary traits, whilst rs1126809 was previously found to be associated with pigmentary variation. To improve prediction of eye colours we suggest that future eye colour prediction models should include rs35866166, rs62538956, rs1289469, and rs1126809.

SUBMITTER: Meyer OS

PROVIDER: S-EPMC7485777 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Association between brown eye colour in rs12913832:GG individuals and SNPs in TYR, TYRP1, and SLC24A4.

Meyer Olivia S OS Lunn Maja M B MMB Garcia Sara L SL Kjærbye Anne B AB Morling Niels N Børsting Claus C Andersen Jeppe D JD

PloS one 20200911 9

The genotype of a single SNP, rs12913832, is the primary predictor of blue and brown eye colours. The genotypes rs12913832:AA and rs12913832:GA are most often observed in individuals with brown eye colours, whereas rs12913832:GG is most often observed in individuals with blue eye colours. However, approximately 3% of Europeans with the rs12913832:GG genotype have brown eye colours. The purpose of the study presented here was to identify variants that explain brown eye colour formation in individ ...[more]

PMID: 32915910

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Project description:BackgroundThe observed correlation between ultraviolet light incidence and skin color, together with the geographical apportionment of skin reflectance among human populations, suggests an adaptive value for the pigmentation of the human skin. We have used Affymetrix U133a v2.0 gene expression microarrays to investigate the expression profiles of a total of 9 melanocyte cell lines (5 from lightly pigmented donors and 4 from darkly pigmented donors) plus their respective unirradiated controls. In order to reveal signatures of selection in loci with a bearing on skin pigmentation in humans, we have resequenced between 4 to 5 kb of the proximal regulatory regions of three of the most differently expressed genes, in the expectation that variation at regulatory regions might account for intraespecific morphological diversity, as suggested elsewhere.ResultsContrary to our expectations, expression profiles did not cluster the cells into unirradiated versus irradiated melanocytes, or into lightly pigmented versus darkly pigmented melanocytes. Instead, expression profiles correlated with the presence of Bovine Pituitary Extract (known to contain alpha-MSH) in the media. This allowed us to differentiate between melanocytes that are synthesizing melanin and those that are not. TYR, TYRP1 and DCT were among the five most differently expressed genes between these two groups. Population genetic analyses of sequence haplotypes of the proximal regulatory flanking-regions included Tajima's D, HEW and DHEW neutrality tests analysis. These were complemented with EHH tests (among others) in which the significance was obtained by a novel approach using extensive simulations under the coalescent model with recombination. We observe strong evidence for positive selection for TYRP1 alleles in Africans and for DCT and TYRP1 in Asians. However, the overall picture reflects a complex pattern of selection, which might include overdominance for DCT in Europeans.ConclusionDiversity patterns clearly evidence adaptive selection in pigmentation genes in Africans and Asians. In Europeans, the evidence is more complex, and both directional and balancing selection may be involved in light skin. As a result, different non-African populations may have acquired light skin by alternative ways, and so light skin, and perhaps dark skin too, may be the result of convergent evolution.

Project description:We previously demonstrated an inverse correlation between tyrosinase-related protein 1 (TYRP1) mRNA expression in melanoma metastases and patient survival. However, TYRP1 protein was not detected in half of tissues expressing mRNA and did not correlate with survival. Based on a study reporting that 3' untranslated region (UTR) of TYRP1 mRNA contains two miR-155-5p (named miR-155) binding sites exhibiting single-nucleotide polymorphisms (SNPs) that promote (matched miRNA-mRNA interaction) mRNA decay or not (mismatched), we aimed to investigate the role of miR-155 in the regulation of TYRP1 mRNA expression and protein translation accounting for these SNPs.The effect of miR-155 on TYRP1 mRNA/protein expression was evaluated in two melanoma cell lines harbouring matched or mismatched miR-155-TYRP1 mRNA interaction after transfection with pre-miR-155. In parallel, 192 skin and lymph node melanoma metastases were examined for TYRP1 mRNA/protein, miR-155 and SNPs and correlated with patient survival. TYRP1 mRNA, SNPs at its 3'UTR and miR-155 were analysed by RT-qPCR, whereas TYRP1 protein was evaluated by western blot in cell lines and by immunohistochemistry in metastatic tissues.The miR-155 induced a dose-dependent TYRP1 mRNA decay and hampered its translation into protein in the line with the 'match' genotype. In melanoma metastases, TYRP1 mRNA inversely correlated with miR-155 expression but not with TYRP1 protein in the 'match' group, whereas it positively correlated with protein but not with miR-155 in the 'mismatch' group. Consequently, in the latter group, TYRP1 protein inversely correlated with survival.Polymorphisms in 3'UTR of TYRP1 mRNA can affect TYRP1 mRNA regulation by miR-155 and its subsequent translation into protein. These SNPs can render TYRP1 mRNA and protein expression nonsusceptible to miR-155 activity and disclose a prognostic value for TYRP1 protein in a subgroup of melanoma patients. These data support the interest in the prognostic value of melanogenic markers and propose TYRP1 to refine prognosis in patients with advanced disease.

Project description:This study aims to explore biomarkers associated with vitiligo and analyze the pathological role of immune cell infiltration in the disease. We used the robust rank aggregation (RRA) method to integrate three vitiligo data sets downloaded from gene expression omnibus database, identify the differentially expressed genes (DEGs) and analyze the functional correlation. Then, the comprehensive strategy of combined weighted gene coexpression network analysis (WGCNA) and logical regression of the selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE), and random forest (RF) machine learning algorithm are employed to screen and biomarkers associated with vitiligo. Finally, the immune cell infiltration of vitiligo was evaluated by CIBERSORT, and the correlation between biomarkers and infiltrating immune cells was analyzed. Herein, we identified 131 robust DEGs, and enrichment analysis results showed that robust DEGs and melanogenesis were closely associated with vitiligo development and progression. TYR, TYRP1, DCT and LARP7 were identified as vitiligo-related biomarkers. Immune infiltration analysis demonstrated that CD4 T Cell, CD8 T Cell, Tregs, NK cells, dendritic cells, and macrophages were involved in vitiligo's pathogenesis. In summary, we adopted a comprehensive strategy to screen biomarkers related to vitiligo and explore the critical role of immune cell infiltration in vitiligo.Abbreviations: TYR, Tyrosinase; TYRP1, Tyrosinase-related protein-1; DCT, dopachrome tautomerase; LARP7, La ribonucleoprotein domain family, member-7; RRA, robust rank aggregation; DEGs, differentially expressed genes; WGCNA, weighted gene coexpression network analysis; LASSO, logical regression of the selection operator; SVM-RFE, support vector machine recursive feature elimination; RF, random forest; GWAS, Genome-wide association study; FasL, Fas-Fas ligand; Tregs, T-regulatory cells; NK, natural killer; GEPCs, gene expression profiling chips; GO, gene ontology; GSEA, gene set enrichment analysis; FDR, false discovery rate; AUC, area under the curve; ROC, receiver-operating characteristic; BP, biological process; CC, cellular component; MF, molecular function.

Dataset Information

Association between brown eye colour in rs12913832:GG individuals and SNPs in TYR, TYRP1, and SLC24A4.

Publications

Association between brown eye colour in rs12913832:GG individuals and SNPs in TYR, TYRP1, and SLC24A4.

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