Sodium/potassium/calcium exchanger 5 (NCKX5), also known as solute carrier family 24 member 5 (SLC24A5), is a
protein that in humans is encoded by the SLC24A5gene that has a major influence on natural skin colour variation.[5] 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
amino acid at position 111 in NCKX5 from
alanine to
threonine, has been associated with differences in
skin pigmentation.[6]
The SLC24A5 gene's derived threonine or Ala111Thr allele (rs1426654[7]) has been shown to be a major factor in the light skin tone of
Europeans compared to
Sub-SaharanAfricans, and is believed to represent as much as 25–40% of the average skin tone difference between Europeans and
West Africans.[5][8] Possibly originating as long as 19,000 years ago, it has been the subject of selection in the ancestors of
Europeans as recently as within the last 5,000 years,[9] and is fixed in modern European populations.[10][11][12] It was introduced into
Khoisan people via "back-to-Africa" migration around 2,000 years ago is partly responsible for their differing skin tone to most other African populations.[13]
Gene
The SLC24A5 gene, in humans, is located on the long (q) arm of
chromosome 15 on position 21.1, from
base pair 46,200,461 to base pair 46,221,881.[5]
Protein
NCKX5 is 43 k
Da protein that is partially localized to the
trans-Golgi network in
melanocytes. Removal of the NCKX5 protein disrupts
melanogenesis in human and mouse melanocytes, causing a significant reduction in
melanin pigment production.
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.[6]
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
International HapMap Project database of genetic variation in human populations showed that Europeans, represented by the "CEU" population, had two primary
alleles differing by only one
nucleotide, changing the 111th
amino acid from
alanine to
threonine, abbreviated "A111T".[5][14][15]
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
ancestry-informative markers. This single change in SLC24A5 explains between 25 and 38% of the difference in skin
melanin index between peoples of sub-Saharan African and European ancestry.[5]
The SNP rs2470102 independently affects skin pigmentation variation among the South Asian population.[16]
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.[5] It is hypothesized that selection for the derived allele is based on the need for sunlight to produce the essential nutrient
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.[17]
The earliest known sample of the threonine allele is 13,000 years old from
Satsurblia Cave in Georgia.[18] The allele was widespread from Anatolia to Ukraine and Iran at the beginning of the Neolithic.[19][20][21]
This allele forms part of the
HIrisplex DNA test system used to estimate pigmentation in forensic investigations.[22][23]
^Soejima M, Koda Y (January 2007). "Population differences of two coding SNPs in pigmentation-related genes SLC24A5 and SLC45A2". International Journal of Legal Medicine. 121 (1): 36–9.
doi:
10.1007/s00414-006-0112-z.
PMID16847698.
S2CID11192076.
^Mathieson I, Lazaridis I, Rohland N, Mallick S, Patterson N, Roodenberg SA, Harney E, Stewardson K, Fernandes D, Novak M, Sirak K (2015-10-10). "Eight thousand years of natural selection in Europe".
bioRxiv10.1101/016477.
^Chaitanya L, Breslin K, Zuñiga S, Wirken L, Pośpiech E, Kukla-Bartoszek M, et al. (July 2018). "The HIrisPlex-S system for eye, hair and skin colour prediction from DNA: Introduction and forensic developmental validation". Forensic Science International. Genetics. 35: 123–135.
doi:
10.1016/j.fsigen.2018.04.004.
hdl:1805/15921.
PMID29753263.
S2CID21673970.
Soejima M, Koda Y (January 2007). "Population differences of two coding SNPs in pigmentation-related genes SLC24A5 and SLC45A2". International Journal of Legal Medicine. 121 (1): 36–9.
doi:
10.1007/s00414-006-0112-z.
PMID16847698.
S2CID11192076.