Abstract
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.
Highlights
Differences in human skin color have been shaped principally and dramatically by selection [1,2], and the underlying genetic architecture may inform disease-related traits such as obesity or hypertension, for which common susceptibility alleles may have been advantageous to early humans that came to inhabit different environments [3]
We have studied a unique population in Cape Verde, an archipelago located off the West African coast, in which extensive mixing between individuals of Portuguese and West African ancestry has given rise to a broad range of phenotypes and ancestral genome proportions
Our results indicate that Cape Verdean pigmentary variation is the result of variation in a different set of genes from those determining variation within Europe, suggest that longrange regulatory effects help to explain the relationship between skin and eye color, and highlight the potential and the pitfalls of using allele distribution patterns and signatures of selection as indicators of phenotypic differences
Summary
Differences in human skin color have been shaped principally and dramatically by selection [1,2], and the underlying genetic architecture may inform disease-related traits such as obesity or hypertension, for which common susceptibility alleles may have been advantageous to early humans that came to inhabit different environments [3]. Our knowledge of skin and eye color genetics is incomplete, based mostly on the limited range of phenotypic diversity represented by individuals of European ancestry [4,5,6,7,8,9,10], or on candidate gene studies in African Americans [11,12,13,14,15]. The previously uninhabited islands were discovered and colonized by the Portuguese in the 15th Century, and subsequently prospered during the transatlantic slave trade. In this population, extensive genetic admixture between the African and European ancestral populations during the last several centuries [16,17] has facilitated assortment of pigmentary alleles. Blond or red hair color is very rare in Cape Verde, but there is a wide spectrum of variation in both eye and skin color, and individuals with dark skin and blue eyes are not infrequent
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