SLC24A5, a Putative Cation Exchanger, Affects Pigmentation in Zebrafish and Humans

TLDR

Lighter pigmentation in humans is linked to reduced melanosome number, size, and density, and the ancestral allele of a conserved SLC24A5 coding polymorphism is common in African and East Asian populations. The zebrafish golden mutant, carrying a slc24a5 cation exchanger that localizes to melanosomes, shows the same melanosomal defects as lighter human skin, and the human SLC24A5 variant allele fixed in Europeans reduces heterozygosity and correlates with lighter pigmentation.

Abstract

Lighter variations of pigmentation in humans are associated with diminished number, size, and density of melanosomes, the pigmented organelles of melanocytes. Here we show that zebrafish golden mutants share these melanosomal changes and that golden encodes a putative cation exchanger slc24a5 (nckx5) that localizes to an intracellular membrane, likely the melanosome or its precursor. The human ortholog is highly similar in sequence and functional in zebrafish. The evolutionarily conserved ancestral allele of a human coding polymorphism predominates in African and East Asian populations. In contrast, the variant allele is nearly fixed in European populations, is associated with a substantial reduction in regional heterozygosity, and correlates with lighter skin pigmentation in admixed populations, suggesting a key role for the SLC24A5 gene in human pigmentation.