HERC2 rs12913832 C allele causes blue eyes in Europeans by reducing OCA2 expression.
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rs12913832 C/C genotype yields 99% non-brown eyes in Europeans. T/T genotype yields 80-92% brown eyes. C-TGT haplotype frequency 91% in blue-eyed vs 37% in brown-eyed Europeans. Variant absent from non-European populations. Positive genetic selection in Europeans for blue-eye allele. Conserved HERC2 intron 86 region contains enhancer controlling OCA2 expression. Blue-eye C allele abolishes HLTF transcription factor binding site. OCA2 R419Q variant independently modifies eye color penetrance. R419Q increases melanoma risk independently. Strong LD across HERC2-OCA2 region limits fine mapping. European allele frequencies match segregation models for blue eyes. Mouse Herc2 deletions confirm regulatory role without affecting HERC2 protein. MITF and LEF1 sites in enhancer disrupted by minor alleles. 42% of tested HERC2 SNPs monomorphic in Anglo-Celtic sample. Single SNP explains most eye color variation in fair-skinned Europeans.

Genetics Science Europe and the EU White people Skin color and pigmentation Evolution

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