SLC24A5

Sodium/potassium/calcium exchanger 5 (NCKX5), also known as solute carrier family 24 member 5 (SLC24A5), is a is_associated_with::protein that in humans is encoded by the SLC24A5 is_associated_with::gene that has a major influence on natural skin colour variation. The NCKX5 protein is a member of the potassium-dependent sodium/calcium exchanger family. Sequence variation in the SLC24A5 gene, particularly a non-synonymous SNP changing the is_associated_with::amino acid at position 111 in NCKX5 from is_associated_with::alanine to is_associated_with::threonine, has been associated with differences in skin pigmentation.

The SLC24A5 gene's derived threonine or Ala111Thr allele (rs1426654 ) has been shown to be a major factor in the light skin tone of is_associated_with::Europeans compared to is_associated_with::Africans, and is believed to represent as much as 25–40% of the average skin tone difference between Europeans and is_associated_with::West Africans. It has been the subject of recent selection in is_associated_with::Western Eurasia, and is fixed in European populations.

Gene
The SLC24A5 gene, in humans, is located on the long (q) arm of chromosome 15 on position 21.1, from is_associated_with::base pair 46,200,461 to base pair 46,221,881.

Protein
NCKX5 is 43 kDa protein that is partially localized to the trans-Golgi network in is_associated_with::melanocytes. Removal of the NCKX5 protein disrupts melanogenesis in human and mouse melanocytes, causing a significant reduction in is_associated_with::melanin pigment production. is_associated_with::Site-directed mutagenesis corresponding to a non-synonymous single nucleotide polymorphism in SLC24A5 alters a residue in NCKX5 (A111T) that is important for NCKX5 sodium-calcium exchanger activity.

Effect on skin color
SLC24A5 appears to have played a key role in the evolution of light skin in humans of European ancestry. The gene's function in pigmentation was discovered in zebrafish as a result of the positional cloning of the gene responsible for the "golden" variety of this common pet store fish. Evidence in the is_associated_with::International HapMap Project database of genetic variation in human populations showed that Europeans, represented by the "CEU" population, had two primary is_associated_with::alleles differing by only one is_associated_with::nucleotide, changing the 111th is_associated_with::amino acid from is_associated_with::alanine to is_associated_with::threonine, abbreviated "A111T".

The derived threonine allele (Ala111Thr; also known as A111T or Thr111) represented 98.7 to 100% of the alleles in European samples, while the ancestral or alanine form was found in 93 to 100% of samples of Sub-Saharan Africans, East Asians and Indigenous Americans. The variation is a SNP polymorphism rs1426654, which had been previously shown to be second among 3011 tabulated SNPs ranked as is_associated_with::ancestry-informative markers. This single change in SLC24A5 explains between 25 and 38% of the difference in skin is_associated_with::melanin index between peoples of West African vs. European Ancestry. Furthermore, the European mutation is associated with the largest region of diminished genetic variation in the CEU HapMap population, suggesting the possibility that the A111T mutation may be the subject of the single largest degree of selection in human populations of European ancestry. It is theorised that selection for the derived allele is based on the need for sunlight to produce the essential nutrient is_associated_with::vitamin D. In northerly latitudes, where there is less sun, greater requirement for body coverage due to colder climate, and frequently, diets poor in vitamin D, making lighter skin more suitable for survival. Tests for this variation have obvious application to forensic science.

It has been estimated that the threonine allele became predominant among Europeans 11,000 to 19,000 years ago.