HERC2, Don’t It Make My Brown Eyes Blue
And the even bigger question that some of you may have-especially if you are young and not a fan of 70's country music- is who the heck is Crystal Gayle? You can Google that one on your own time, and as you probably guessed, losing your man or wo-man is not the cause of blue eyes.
Human eye color is a multifactorial and complex hereditary trait. The variation in eye color from brown to green is a result of varying amounts of melanin in the iris, and blue eye color is the result of iris-specific melanin production being turned way down.
Recently it has been found that blue eye color in European descendents probably resulted from a founder mutation that originated six to ten thousand years ago in the northwest part of the Black Sea region1. The mutation has been discovered to be a single nucleotide polymorphism (SNP) fine-mapped to a short highly conserved sequence in intron 86 of the HERC2 (hect domain and RLD2) gene1,2. This SNP, rs1291382, is part of a consensus binding site for the helicase-like transcription factor (HLTF) also known as SMARCA3. Before this more definitive association of HERC2 to the blue-eye phenotype, the OCA2 (oculotaneous albinism 2) gene was primarily associated with the variation of eye color. As it turns out, OCA2 is critical in eye color determination, but it is the regulation of OCA2 by sequences mapped to rs1291382 in the neighboring HERC2 gene that are the main determiner of blue eye color. Eiberg et al have performed experiments in cell culture that have shown that the regulatory element containing the rs1291382 blue allele has inhibitory effects on OCA2 promoter activity.
The study of regulatory elements and the factors that bind them will be a next step in understanding the complexity of eye color. Does SMARCA3 have a role? And what other factors might bind these sequences? The interesting subject of eye color also brings up the question of what are the exact cellular functions of the HERC2 and OCA2 gene products which remain uncharacterized, and why can't I get that song out of my head?
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