Human pigmentation: painting by numbers or ancestry?

Our human ancestors who migrated out of Africa some 60 to 80 000 yrs ago and radiated across the globe were likely to have had a dark complexion, eye and hair colour, characteristics of African people today. As they encountered different climatic environments and selective pressures, novel gene variants in small founder groups increased in frequency when they conferred a selective advantage. Notably, many of the genes under selection were involved in human pigmentation (Sturm and Duffy, 2012), with some specific alleles reaching geographical or population-specific fixation, for example as discovered for the SLC45A2 Leu374Phe and SLC24A5 Ala111Thr gene polymorphisms in Europeans (Lamason et al., 2005). Using molecular techniques, the timing of these selective sweeps is proposed to have occurred some 11 to 19 000 yrs ago (Beleza et al., 2013), consistent with glacial melting and the movement of people into Northern Europe. Single-nucleotide changes (SNPs) with such high-frequency differences between population groups are often used as indicators of geographical ancestry, that is as ancestry informative markers (AIMs). The diversity of pigmentation is much greater between than within ancestral human populations, and identifying the genes responsible for these biological differences has long been of scientific interest. The most obvious contrast in phenotypes exists between black-white skin colour and brown-blue eye colour. The appearance of intermediate colours for these traits is especially apparent in offspring of parents from different biogeographical ancestries, providing an opportunity to understand the genes responsible, their inheritance and their mode of action. A unique population in which to address some of these issues is presented in the report by Beleza et al. The study population is located at Cape Verde, a group of 10 islands off the coast of West Africa first colonized by the Portuguese. Founder populations there have been established over several centuries, drawing from extensive admixture between African and European ancestral populations. These populations provide a wide spectrum of skin and eye colours and represent a resource to address two questions: to identify the contribution of specific gene polymorphisms to the range of colours seen in individuals, and to study the effect of genome-wide ancestry, an issue not suitable for genetic association studies conducted within homogeneous populations. There were 699 individuals included in the study whose genotypes were determined using a high-density array of over 1 9 10 SNPs. Skin phenotype was quantified by reflectance spectroscopy giving a measure of melanin content (MM, square root of the M-index), and eye colour was classified using a new algorithm based on digital photographs and RGB colour scale reflectance (T-index). This combination of genotypic and phenotypic information was analysed to detect and quantify the contribution of four loci to the range of human skin colours, SLC45A2, SLC24A5, TYR and OCA2[APBA2], and two to eye colour variation, OCA2[HERC2] and SLC24A5. Although these genes and even the population-specific polymorphisms were sometimes already known to contribute to the differences between African and European skin colour, estimates of the relative contributions of these genes and the polygenic background generally are of considerable interest. Surprisingly, other loci known to contribute to variation within European (MC1R) or between European and African (KITLG) skin colour were not detected. Blonde and red hair colours are reportedly rare in Cape Verde, consistent with the population founders from Europe being non-carriers of the alleles responsible for these traits (MC1R RHC alleles), which also overlap with skin colour. Why KITLG effects were not detected is less obvious, although one possibility is that its contribution may have simply been too small to detect in this population sample. The mean M-index value for Europeans was 5.38 (SD 0.27), while Cape Verdeans had a mean of 7.39 (SD 0.85). On this scale, the effect sizes of the alleles were SLC24A5 0.34, SLC45A2 and OCA2[APBA2] each 0.18, and TYR 0.2, with the sum of the effect sizes shifting only about 1/3 of the total range of skin colour observed. The population-attributable variance (PAV) is a novel index these authors present, which attempts to capture the extent of both intragametic and extragametic association between a given locus and a phenotype for a given admixed population. Like population-attributable fraction in epidemiology, it is non-additive. So, although the proportion of variance in skin colour within the Cape Verdean population explained by overall genomic ancestry was 44%, and approximately half of this was explainable by the SLC24A5, SLC45A2, OCA2[APBA2] and TYR gene, the PAVs were 18, 7, 9 and 7%, respectively, reflecting a combination of direct effect and the different efficiencies of these markers as proxies for overall ancestry. Their conclusion points to an underlying genetic architecture in this admixed population in which several genes of moderate effect, in this case four for skin and two for eye, act together with many other genes of small effect to explain around 70% of the estimated heritability of colour variation measured. A possible lesson for the forensic applications of this work in the prediction of pigmentation phenotype Coverage on: Beleza S, Johnson NA, Candille SI, Absher DM, Coram MA, Lopes J, Campos J, Ara ujo II, Anderson TM, Vilhj almsson BJ, Nordborg M, Correia E Silva A, Shriver MD, Rocha J, Barsh GS, Tang H. (2013). Genetic architecture of skin and eye colour in an African-European admixed population. PLoS Genet. 9(3):e1003372.