Loci associated with skin pigmentation identified in African populations

Abstract

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 southern Asian and Australo-Melanesian populations. Functional analyses indicate that MFSD12 encodes a lysosomal protein that affects melanogenesis in zebrafish and mice, and that mutations in melanocyte-specific regulatory regions near DDB1/TMEM138 correlate with expression of UV response genes under selection in Eurasians.

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“…Also, the gene variants associated with dark and light skin color are found in every major human population (Crawford et al, 2017). This means that the alleles associated with "light skin" are found in "dark-skinned" populations and vice versa (Crawford et al, 2017). The variants associated with dark or light skin are simply more prevalent in certain populations (Crawford et al, 2017).…”

SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation

“…This is analogous to other proteins on the melanosome membrane, such as the chloride channel OCA2 and the cation channel TPC2, which also directly regulate melanosome pH through ion transport (Ambrosio et al, 2016, Bellono et al, 2014, Bellono et al, 2016, Sitaram et al, 2009, and contrasts with ion transporters/channels that may indirectly regulate melanosome pH through effects on other organelles. For example, the putative solute transporter MFSD12 negatively regulates pigmentation from lysosomes (Crawford et al, 2017) and NCKX5 encoded by SLC24A5, the gene deficient in OCA6, appears to positively regulate pigmentation from the trans Golgi network (Ginger, Askew et al, 2008, Rogasevskaia, Szerencsei et al, 2019. Together, these observations suggest that melanosome pH is regulated both directly and indirectly via a complex network of putative channels/transporters.…”

“…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.…”

“…Consistent with a function in proton export and neutralization of acidic organelles, pigmentation of a zebrafish Slc45a2 mutant was rescued upon inhibition of endolysosomal and melanosomal acidification by treatment with bafilomycin A1 or by knockdown of the atp6v1 subunit of the vacuolar ATPase (Dooley et al, 2013), and knockdown of SLC45A2 in a pigmented melanoma cell line resulted in increased acidification of early stage melanosomes (Bin et al, 2015). However, despite limited evidence for SLC45A2 on melanosomes (Bin et al, 2015), the localization of SLC45A2 within melanocytes has not yet been firmly established and it is not clear whether the effects of SLC45A2 mutants reflect a direct effect of SLC45A2 function on the lumenal environment of melanosomes or an indirect effect due to impaired function of other organelles during melanosome maturation, as appears to be the case for the endolysosomal transporter MFSD12 (Crawford et al, 2017). Moreover, if SLC45A2 indeed functions to neutralize melanosome pH, its function must be coordinated with that of OCA2, a major regulator of melanosomal pH (Bellono et al, 2014).…”

Membrane transport proteins in melanosomes: Regulation of ions for pigmentation

“…Most importantly, although it is not easy to dissect transport functions of organellar transport proteins, the transport function of the ion transporters can be revealed by using a classical biochemical method, the cell-free transport assay with proteoliposomes, purified protein-reconstituted liposomes as shown by Moriyama or others [141,142]. Recently, MFSD12 (major facilitator superfamily domain containing protein 12) was identified as an associated gene in pigmentation in African population by GWAS [143,144]. In addition to the ion transport proteins we described above, MFSD12 requires characterization of its function and role in melanocytes.…”