An Unexpectedly Complex Architecture for Skin Pigmentation in Africans

Abstract

Fewer than 15 genes have been directly associated with skin pigmentation variation in humans, leading to its characterization as a relatively simple trait. However, by assembling a global survey of quantitative skin pigmentation phenotypes, we demonstrate that pigmentation is more complex than previously assumed with genetic architecture varying by latitude. We investigate polygenicity in the Khoe and the San, populations indigenous to southern Africa, who have considerably lighter skin than equatorial Africans. We demonstrate that skin pigmentation is highly heritable, but that known pigmentation loci explain only a small fraction of the variance. Rather, baseline skin pigmentation is a complex, polygenic trait in the KhoeSan. Despite this, we identify canonical and non-canonical skin pigmentation loci, including near SLC24A5, TYRP1, SMARCA2/VLDLR, and SNX13 using a genome-wide association approach complemented by targeted resequencing. By considering diverse, under-studied African populations, we show how the architecture of skin pigmentation can vary across humans subject to different local evolutionary pressures.

Existence and implications of population variance structure

“…Unlike existing variance models, ADGLM accounts for continuous and discrete definitions of ancestry, arbitrary covariates, and binary or continuous phenotypes. We used ADGLM to discover many ancestry-variance associations in a British-ancestry and admixed human populations for a wide range of binary and continuous traits, including diseases and methylation, many of which have been subject to natural selection 42,56,57,59,60 .…”

“…Of the 14 phenotypes tested in three populations, 4 associations in 3 phenotypes are significant at a Bonferroni-corrected level of 0.05 (which is conservative because the phenotypes are highly correlated): asthma and @ in Puerto Ricans, and @ and 2 in African-Americans. In addition, six of the phenotypes have previously-documented ancestry-mean associations which are also detected as mean effects with ADGLM ( 7 ¹0): FEV and FEV1 in Puerto Ricans 54 , asthma in Mexicans and Puerto Ricans 55 , baseline melanin 56,57 , @ , and 2 in African-Americans 58 .…”

XGMix: Local-Ancestry Inference with Stacked XGBoost

“…By using patternmatching algorithms along the genome, local ancestry inference can annotate each region of the genome with an ancestry label. This permits association studies to be run using an indicator label (ancestry at each genomic position) to de-convolve the effects of ancestry on the correlation structure of neighboring genomic variants [7]. It also allows accurate personalized genetic predictions (polygenic risk scores) to be based on the ancestry of the genomic region in which an associated variant is located.…”

SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation

“…Sequence variation at the loci for some of these genes has been linked to variability in skin, hair and eye color among humans (Adhikari, Mendoza-Revilla et al, 2019, Branicki, Brudnik et al, 2008, Crawford, Kelly et al, 2017, Han, Kraft et al, 2008, Lamason, Mohideen et al, 2005, Liu, Visser et al, 2015, Martin, Lin et al, 2017, Stokowski, Pant et al, 2007. Nevertheless, the molecular function of the majority of the OCA genes has not yet been fully characterized.…”