Human skin color is influenced by an intergenic DNA polymorphism regulating transcription of the nearby BNC2 pigmentation gene.

Single nucleotide polymorphisms (SNPs) found to be statistically significant when associated with human diseases, and other phenotypes are most often located in non-coding regions of the genome. One example is rs10765819 located in the first intron of the BNC2 gene previously associated with (saturation of) human skin color. Here, we demonstrate that a nearby intergenic SNP (rs12350739) in high linkage disequilibrium with rs10756819 is likely the causal DNA variant for the observed BNC2 skin color association. The highly conserved region surrounding rs12350739 functions as an enhancer element regulating BNC2 transcription in human melanocytes, while the activity of this enhancer element depends on the allelic status of rs12350739. When the rs12350739-AA allele is present, the chromatin at the region surrounding rs12350739 is inaccessible and the enhancer element is only slightly active, resulting in low expression of BNC2, corresponding with light skin pigmentation. When the rs12350739-GG allele is present however, the chromatin at the region surrounding rs12350739 is more accessible and the enhancer is active, resulting in a higher expression of BNC2, corresponding with dark skin pigmentation. Overall, we demonstrate the identification of the functional DNA variant that explains the BNC2 skin color association signal, providing another important step towards further understanding human pigmentation genetics beyond statistical association. We thus deliver a clear example of how an intergenic non-coding DNA variant modulates the regulatory potential of the enhancer element it is located within, which in turn results in allele-dependent differential gene expression affecting variation in common human traits.