|Solute carrier family 24, member 5|
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 SLC24A5 gene that has a major influence on natural skin colour variation.1 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.2
The SLC24A5 gene's derived threonine or Ala111Thr allele (rs14266543) has been shown to be a major factor in the light skin tone of Europeans compared to African-Americans, and is believed to represent as much as 25–40% of the average skin tone difference between Europeans and West Africans.41 It has been the subject of recent selection in Western Eurasia, and is fixed in European populations.567
NCKX5 is 43 kDa 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.2
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. In this work, cancer geneticist Keith Cheng used electron microscopy to probe the cellular mechanism underlying the lighter color of golden zebrafish, and noted a striking similarity between the changes of melanocytes (pigment cells) in those lighter-skinned fish and lighter-skinned humans (in particular, Europeans). This led Cheng to hypothesize that a "coding" mutation (one that changes an amino acid) in this same gene or the involved pathway might contribute in a major way towards lighter skin in one of the lighter-skinned branches of humanity. In a search for scientists who had human DNA linked to skin color measurements, he found that his Pennsylvania State University colleague, anthropologist Mark D. Shriver, had such DNA. Shriver, who collaborates internationally to study the basis of variation in human skin color and other features in human populations, pointed to the then-new International HapMap Project database of genetic variation in human populations. In fact, 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".189
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. Collaborator Victor Canfield, also of Penn State, plotted the human data to estimate that this single change in SLC24A5 explains between 25 and 38% of the difference in skin melanin index between peoples of West African vs. European Ancestry.
The discovery of this gene has interesting social implications because the derived European allele was created by mutation from the ancestral gene sequence. Based on the belief that Africa is the birthplace of all modern humans, and that amino acids important to gene function are frequently conserved in evolution, Cheng and Canfield hypothesized that the alanine allele would be conserved in vertebrates. Indeed, this amino acid was conserved all vertebrates sequenced to date, mutant only in the European allele, and only rarely in West African or East Asian populations (presumably by admixture).citation needed
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.1 It is theorised 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.10 Tests for this variation has obvious application to forensic science.
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- Reference SNP(refSNP) Cluster Report: rs1426654 **clinically associated**. Ncbi.nlm.nih.gov (2008-12-30). Retrieved on 2011-02-27.
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