Abstract
We aimed to study the selective pressures interacting on SLC45A2 to investigate the interplay between selection and susceptibility to disease. Thus, we enrolled 500 volunteers from a geographically limited population (Basques from the North of Spain) and by resequencing the whole coding region and intron 5 of the 34 most and the 34 least pigmented individuals according to the reflectance distribution, we observed that the polymorphism Leu374Phe (L374F, rs16891982) was statistically associated with skin color variability within this sample. In particular, allele 374F was significantly more frequent among the individuals with lighter skin. Further genotyping an independent set of 558 individuals of a geographically wider population with known ancestry in the Spanish population also revealed that the frequency of L374F was significantly correlated with the incident UV radiation intensity. Selection tests suggest that allele 374F is being positively selected in South Europeans, thus indicating that depigmentation is an adaptive process. Interestingly, by genotyping 119 melanoma samples, we show that this variant is also associated with an increased susceptibility to melanoma in our populations. The ultimate driving force for this adaptation is unknown, but it is compatible with the vitamin D hypothesis. This shows that molecular evolution analysis can be used as a useful technology to predict phenotypic and biomedical consequences in humans.
Highlights
Adaptation to new environments is key to species survival
The adaptive nature of pigmentation in humans was already suggested by Relethford [1], who observed that 88% of total variation in skin color is due to differences among major geographic groups, contrary to other neutral genetic markers and DNA polymorphisms which show most of their diversity, instead, within local populations
Graf et al [14] were the first to reveal an association between SLC45A2 alleles and intrapopulation pigmentation variation based on E272K and L374F allele frequency differences, showing that alleles 374L and 272K were significantly associated with dark hair, skin, and eye color in North Europeans
Summary
Adaptation to new environments is key to species survival. The adaptive nature of pigmentation in humans was already suggested by Relethford [1], who observed that 88% of total variation in skin color is due to differences among major geographic groups, contrary to other neutral genetic markers and DNA polymorphisms which show most of their diversity, instead, within local populations. It has been long assumed that the settlement of human populations in regions of higher latitudes, where the intensity of incident UV radiation was lower, brought along the depigmentation of the human skin. In such scenario, it still remains a source of debate whether the depigmentation process would reflect a relaxation of functional constraints, or if it conferred a selective advantage, presumably as a mechanism to enable the synthesis of the appropriate levels of vitamin D [4],[5],[6]
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