An Unexpectedly Complex Architecture for Skin Pigmentation in Africans

Abstract

Summary Approximately 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 KhoeSan, populations indigenous to southern Africa, who have considerably lighter skin than equatorial Africans. We demonstrate that skin pigmentation is highly heritable, but 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.

Clinical and Biological Characterization of Skin Pigmentation Diversity and Its Consequences on UV Impact

“…Recently, two studies have shed light on the architecture of skin pigmentation in African skin and on regions of the genome not previously associated with skin color [ 37 , 38 ]. Four regions of the human genome associated with skin color in African populations living in Ethiopia, Tanzania and Botswana have been identified in or near SLC24A5 , MFSD12 (Major facilitator superfamily domain containing 12), DDB1 (Damage specific DNA binding protein 1)/ TMEM38 (Transmembrane protein 38) and OCA2 / HERC2 (HECT And RLD domain containing E3 ubiquitin protein ligase 2) [ 37 ].…”

“…In contrast to the lack of variation at MC1R in Africans [ 60 ], both light and dark alleles at MFSD2 , DDB1 , OCA2 and HERC2 arose in hominid and continued to evolve. In southern African populations with considerably lighter skin than equatorial Africans, novel variants associated with skin pigmentation have been identified in canonical SLC24A5 , TYRP1 and non-canonical pigmentation genes, including near SMARCA2 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 2)/ VLDLR (Very low density lipoprotein receptor) and SNX13 (Sorting nexin 13) [ 38 ]. VLDLR and SMARCA2 have been implicated in pigmentation in model organisms and in vitro studies.…”

<p>Melanogenic Difference Consideration in Ethnic Skin Type: A Balance Approach Between Skin Brightening Applications and Beneficial Sun Exposure</p>

“…The proportion of the affected genes is predominant in Caucasian skin. This number is 54 30 UQCC (ubiquinol-cytochrome c reductase complex); transmembrane protein involved in FGF regulated growth control 40 31 VLDLR (very-low-density-lipoprotein receptor); transmembrane receptor involved in endocytosis 55 32 PROCR (protein C receptor); cell survival and proliferation 56 33 ADAM17 (ADAM metallopeptidase domain 17); involved in cell adhesion and migration 57 significantly decreased in Oriental skin, with evident further reduction in darker skin types of Indian and African origin (Table 2 and Figure 1). The individual genes altered by polymorphism can be further identified as predominant within each skin type and organized in the functional categories based on the role within the melanogenic pathway.…”

“…Polymorphic genes in African skin are the biomarkers of melanocyte biogenesis and survival SMARCA2 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 2) 55 and VLDLR (verylow-density-lipoprotein receptor) 55 as well as melanosome biogenesis and trafficking SNX13 (sorting nexin 13), 55 TMEM38 (trans-membrane protein 38) 51 and MFSD12 (major facilitator superfamily domain containing 12). 51 Genes altered by polymorphism in African skin also represent biomarkers of melanosome biogenesis and maturation including SLC45A2/MATP, 78 OCA2 51,84 and SLC24A5 51,78,87 but the SNPs are also present across all other skin types (Table 2).…”

Localization of adaptive variants in human genomes using averaged one-dependence estimation

“…http://dx.doi.org/10.1101/229070 doi: bioRxiv preprint first posted online Dec. 4, 2017; To test SWIF(r)'s robustness to misspecification of recent population growth, we implemented a set of 440 simulations using a demographic model from Gravel et al 29 per generation, and the recombination rate at 10 8 . Note that for testing the robustness of SWIF(r), we only 457 considered sites from these simulations that landed in exons or UTRs.…”