In a few recent posts I've referred to the fact that variation on the OCA2 locus can predict about 3/4 of the eye color variation in the European population. Specifically, OCA2 is probably the quasi-Mendelian locus which is the culprit behind the classical dominant/recessive pedigree inheritance patterns which geneticists have long noted. The genomic region has also been subjected to a recent selection event. Why?

One model posits that the selection is directly for blue eyes. For example, some sort of sexual selection where blue eyes are strongly preferred. There's a problem with any model which posits selection for blue eyes: at very low frequencies selection on recessive traits is weak. That is, if you have alleles responsible for blue eyes extant at a frequency of 10%, only 1% of the population will express blue eyes (assumes random mating and a tighter correlation between the alleles and the phenotype as well as perfect dominance/recessiveness, all violated, but gets the logic across). So only 1 out of 10 blue eye causing alleles can be subject to selection. A way to get around this issue is population substructure, imagine that you have small demes drifting in all directions. A deme which drifts to a high or fixed frequency of blue eyes can then allow selection to operate strongly upon the allele responsible for this trait. This also requires specific meta-population dynamics so as to prevent these high frequency demes from being swamped out by gene flow from low frequency demes. Frankly, I'm really skeptical that a continent wide Shifting Balance process can really explain the third longest haplotype in the European genome.

But there's another model, a bit simpler: the gene responsible for blue eyes is being selected for a another reason. Blue eyes are simply a byproduct, and that other reason is additive in its phenotypic expression so that even single copy variants are subject to the power of selection. I would hazard to guess that the most boring explanation here would be skin color. I've offered below that OCA2 does track skin color variation, but I've been pretty vague about this. The data isn't always easy to find, so I've repackaged Table 5 from A Three-Single-Nucleotide Polymorphism Haplotype in Intron 1 of OCA2 Explains Most Human Eye-Color Variation. Please note that there is a typo in the table in the paper, they have the correct data in the text, so I went by that.

	Fair skin	Medium skin	Olive skin
Blue/Blue	46.5	46.1	7.4
Blue/Brown	31.3	52.2	16.6
Brown/Brown	25.6	37.9	37.0
I've pooled the genetic variants associated with blue and brown eyes into the three combinations, two of them homozygote and one of them heterozygote. As you can see, there is a phenotypic effect in the heterozygote state for skin color. This makes sense as skin color genes seem to be easily characterized as additive and independent in the way that they contribute to genetic variation.

Obviously there are other genes at work in regards to skin color, there's some population substructure which is probably lurking in the data, and the association of the variants themselves with an eye color aren't perfect either. That being said, this isn't the only study which does note that OCA2 has not only localized affects, but some global affects as well.

Labels: Genetics, Pigmentation