Thursday, January 31, 2008

HERC2 and eye color variation

OCA2 has been the one of the main genes thought to be responsible for eye color variation (see here). Now, two papers in AJHG (open access, here, here) show that SNPs in HERC2 may represent the strongest association with eye color. Dienekes and Razib have also covered these papers, including some maps of HERC2 SNP frequencies across Europe. Razib did some further digging and found a paper where they used cell culture to determine that a HERC2 SNP causes changes to OCA2 promoter activity... now we're getting somewhere! By the way, HERC2 is very close to OCA2 on chr. 15, and that region has been under recent selection in Europeans.
from the first abstract:
Testing markers in the HERC2-OCA2 region may be useful in forensic applications to predict eye color phenotypes of unknown persons of European genetic origin.
from the second abstract:
We conclude that the conserved region around rs12913832 (of HERC2) represents a regulatory region controlling constitutive expression of OCA2 and that the C allele at rs12913832 leads to decreased expression of OCA2, particularly within iris melanocytes, which we postulate to be the ultimate cause of blue eye color.
Interestingly in the Kayser paper, none of the other candidate genes (MATP, ASIP, CYP1A2, TYRP1, CYP2C8, and CYP2C9 showed any association.
These studies makes you wonder about similar confounding (eg. hitchhiking) in other phenotype-genotype associations. Resolving this seems to require a combination of large independently replicated WGA studies, functional assays, as well as looking for what other genes lie in the regions of strong selection signals.
One also wonders if the effects of these loci are independent of variation in other pigmentation related traits.
I also wondered if they examined if there was the potential for confounding due to population stratification (which can happen in Europeans). It looks like they did in the Kayser paper, although I'm unclear about exactly how they did it, and in the Sturm paper, they say that 95% of subjects are of N. European origin. Related to this, Kayser et al. warn at the very end of their paper:
However, until more data become available, such a DNA-based iris color prediction test shall only be considered in individuals of whom a European genetic origin has been verified with appropriate ancestry-informative genetic markers.

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