Eye and skin pigmentation genetics: Cape Verdeans as informative population

01 Apr
Cape Verde from space
Still getting updated with the backlog. Here there is an interesting study on human pigmentation using the heavily admixed Cape Verdean (essentially West African + West Iberian) population as reference.
Sandra Beleza et al., Genetic Architecture of Skin and Eye Color in an African-European Admixed Population. PLoS Genetics 2013. Open accessLINK [doi:10.1371/journal.pgen.1003372]


Variation in human skin and eye color is substantial and especially apparent in admixed populations, yet the underlying genetic architecture is poorly understood because most genome-wide studies are based on individuals of European ancestry. We study pigmentary variation in 699 individuals from Cape Verde, where extensive West African/European admixture has given rise to a broad range in trait values and genomic ancestry proportions. We develop and apply a new approach for measuring eye color, and identify two major loci (HERC2[OCA2] P = 2.3×10−62, SLC24A5 P = 9.6×10−9) that account for both blue versus brown eye color and varying intensities of brown eye color. We identify four major loci (SLC24A5 P = 5.4×10−27, TYR P = 1.1×10−9, APBA2[OCA2] P = 1.5×10−8, SLC45A2 P = 6×10−9) for skin color that together account for 35% of the total variance, but the genetic component with the largest effect (~44%) is average genomic ancestry. Our results suggest that adjacent cis-acting regulatory loci for OCA2 explain the relationship between skin and eye color, and point to an underlying genetic architecture in which several genes of moderate effect act together with many genes of small effect to explain ~70% of the estimated heritability.

Children of Praia
(CC by Otimarte)
Most interestingly maybe the authors conclude that KITLG, a gene which displays large differences in allele frequency between Africa and Eurasia and has been therefore suggested to be a cause of pigmentation differences, does not actually play any obvious role in this matter.
HERC2 (OCA2) is confirmed to be very important in eye color (semi-recessive inheritance for blue color), the only other gene known to affect eye color is SLC24A5, which is mostly involved in skin pigmentation however.  
SLC24A5 and SLC45A2 are confirmed as important pigmentation genes. However two otherwise unsuspecting genes, APBA2 (near OCA2) and GRM5TYR, are found to have also important impact in skin pigmentation.
Still most (~3/5) of the inherited pigmentation traits remain unexplained and are probably caused by some sort of complex interactions. Eye and skin pigmentation have no strong genetic correlation apparently.
Some interesting images from the paper:

Figure 1. Relationship of geography and ancestry to skin and eye color.
Individual ancestry proportions for Cape Verdeans displayed on all four panels were obtained from a supervised analysis in frappe
with K = 2 and HapMap’s CEU and YRI fixed as European and African
parental populations. (a) Bar plots of individual ancestry proportions
for Cape Verdeans across the islands. The width of the plots is
proportional to sample size (Santiago, n = 172; Fogo, n = 129; NW
cluster, n = 192; Boa Vista, n = 27). The proportion of African vs.
European ancestry of the individuals is indicated by the proportion of
blue vs. red color in each plot. (b) Individual African ancestry
distribution in the total cohort of 685 Cape Verdeans (histogram) and in
802 African Americans (kernel density curve) from the Family Blood
Pressure Program (FBPP) [21].
(c) Scatter-plot of skin color vs. Individual African ancestry
proportions. Skin color is measured by the MM index described in
Material and Methods. (d) Scatter-plot of eye color vs. Individual
African ancestry proportions. Eye color is measured by the T-index,
described in Figure 2 and Material and Methods. Points in scatter-plots are color coded according to the island of origin of the individuals.
Figure 3. GWAS results for skin and eye color in the total Cape Verdean cohort.
Results are shown as −log10(P
value) for the genotyped SNPs. Plots are ordered by chromosomal
position. (a,c) Genotype and admixture association scan results for skin
color. (b,d) Genotype and admixture association scan results for eye
color. (a,b) show the P values obtained in the initial scans and (c,d) the P values of the following scans adjusting for the strongest associated SNP (in SLC24A5 for skin color and in HERC2 for eye color). Dashed red lines correspond to the genome-wide significance threshold (P<5×10−8 in the genotype scan; P<7×10−6
in the ancestry scan [see Material and Methods]). The location and
identity of candidate genes are colored to correspond with chromosomal
location; individual SNPs are given in Table 1.
Figure 7. Genetic architecture of skin color variation.
Effect sizes of the loci associated with skin color. Effect values
represent the beta values obtained from a regression model containing
the four associated loci plus ancestry. (b) The pie chart represents the
proportion of phenotypic variation accounted for by the different
components, including non-heritable factors (~20%), the four major loci
(~35%, color-coded as in [a]), and average genomic ancestry (44%). The
heritable contributions were estimated by regression and variance
decomposition as described in Material and Methods, and are also
represented below the pie chart separately as grey (genomic ancestry) or
open (four major loci) areas. However, because of admixture
stratification, the heritable contributions overlap as described in the


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