Loci associated with skin pigmentation identified in African populations

African genomics and skin color Skin color varies among human populations and is thought to be under selection, with light skin maximizing vitamin D production at higher latitudes and dark skin providing UV protection in equatorial zones. To identify the genes that give rise to the palette of human skin tones, Crawford et al. applied genome-wide analyses across diverse African populations (see the Perspective by Tang and Barsh). Genetic variants were identified with likely function in skin phenotypes. Comparison to model organisms verified a conserved function of MFSD12 in pigmentation. A global genetic panel was used to trace how alleles associated with skin color likely moved across the globe as humans migrated, both within and out of Africa. Science, this issue p. eaan8433; see also p. 867 Genome-wide analysis of 2000 Africans identifies and functionally characterizes pigmentation loci. INTRODUCTION Variation in pigmentation among human populations may reflect local adaptation to regional light environments, because dark skin is more photoprotective, whereas pale skin aids the production of vitamin D. Although genes associated with skin pigmentation have been identified in European populations, little is known about the genetic basis of skin pigmentation in Africans. RATIONALE Genetically and phenotypically diverse African populations are informative for mapping genetic variants associated with skin pigmentation. Analysis of the genetics of skin pigmentation in Africans informs upon melanocyte biology and the evolution of skin pigmentation in humans. RESULTS We observe extensive variation in skin pigmentation in Africa, with lowest melanin levels observed in southern African San hunter-gatherers and highest levels in East African Nilo-Saharan pastoralists. A genome-wide association study (GWAS) of 1570 Africans identified variants significantly associated with skin pigmentation, which clustered in four genomic regions that together account for almost 30% of the phenotypic variation. The most significantly associated single-nucleotide polymorphisms were at SLC24A5, a gene associated with pigmentation in Europeans. We show that SLC24A5 was introduced into East Africa >5 thousand years ago (ka) and has risen to high frequency. The second most significantly associated region is near the gene MFSD12. Using in vitro and in vivo analyses, we show that MFSD12 codes for a lysosomal protein that modifies pigmentation in human melanocytes, with decreased MFSD12 expression associated with darker pigmentation. We also show that genetic knockout of Mfsd12 affects pigmentation in mice. A third highly associated region encompasses a cluster of genes that play a role in ultraviolet (UV) response and DNA damage repair. We find the strongest associations in a regulatory region upstream of DDB1, the gene encoding damage-specific DNA binding protein 1, and that these variants are associated with increased expression of DDB1. The alleles associated with light pigmentation swept to near fixation outside of Africa due to positive selection, and we show that these lineages coalesce ~60 ka, corresponding with the time of migration of modern humans out of Africa. The fourth significantly associated region encompasses the OCA2 and HERC2 loci. We identify previously uncharacterized variants at HERC2 associated with the expression of OCA2. These variants arose independently from eye and skin pigmentation–associated variants in non-Africans. We also identify variants at OCA2 that are correlated with alternative splicing; alleles associated with light pigmentation are correlated with a shorter transcript, which lacks a transmembrane domain. CONCLUSION We identify previously uncharacterized genes and variants associated with skin pigmentation in ethnically diverse Africans. These genes have diverse functions, from repairing UV damage to playing important roles in melanocyte biology. We show that both dark and light pigmentation alleles arose before the origin of modern humans and that both light and dark pigmented skin has continued to evolve throughout hominid history. We show that variants associated with dark pigmentation in Africans are identical by descent in South Asian and Australo-Melanesian populations. This study sheds light on the evolutionary history, and adaptive significance, of skin pigmentation in humans. GWAS and functional assays illuminate the genetic basis of pigmentation in Africa. A GWAS identified four genomic regions associated with skin pigmentation in Africa. Functional assays in melanocytes and mice characterized their impact on skin pigmentation. Evolutionary genetic analyses revealed that most derived variants evolved before the origin of modern humans. Ma, million years ago. Despite the wide range of skin pigmentation in humans, little is known about its genetic basis in global populations. Examining ethnically diverse African genomes, we identify variants in or near SLC24A5, MFSD12, DDB1, TMEM138, OCA2, and HERC2 that are significantly associated with skin pigmentation. Genetic evidence indicates that the light pigmentation variant at SLC24A5 was introduced into East Africa by gene flow from non-Africans. At all other loci, variants associated with dark pigmentation in Africans are identical by descent in South Asian and Australo-Melanesian populations. Functional analyses indicate that MFSD12 encodes a lysosomal protein that affects melanogenesis in mice, and that mutations in melanocyte-specific regulatory regions near DDB1/TMEM138 correlate with expression of ultraviolet response genes under selection in Eurasians.