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I know Razib and I are both interested in how skin color is determined. Many different genetic loci have been identified as factors in the skin pigmentation biochemical pathway. It can be a mysterious task, but often all it takes is homology in sequences to clue investigators into considering a new loci as a possible skin color gene. But sequence homology doesn’t tell us the exact function. To really confirm the function of a gene in a pathway, a knock-down or knock-out mutational analysis maybe necessary to correlate a genotype to a phenotype.

In a new announcement issued by the American Society for Biochemistry and Molecular Biology, the protein (NCKX5) of a gene previously identified as an ion exchanger (SLC24A5); one that exchanges sodium for calcium across a membrane, regulated by potassium has been shown to have a role in regulating melanosome production. Here’s a synopsis of the press release,

“…[the researchers] found that NCKX5 is not present on the cell surface, but internally in a compartment known as the trans-Golgi network. This compartment is where new proteins and vesicles are processed, modified and sorted.

When the researchers knocked out NCKX5 in melanocytes (the skin cells that manufacture the melanin pigment), melanin production decreased dramatically. They also demonstrated that changing the ancestral amino acid (alanine) at position 111 to the European form associated with lighter skintone (threonine) reduced NCKX5’s exchanger activity.

While they plan on teasing out the exact biological mechanism, Ginger and colleagues propose that NCKX5 could play a direct role in the trafficking decisions that influence the assembly of melanosomes, the specialized cell vesicles where melanin is produced. Alterations that increase or decrease NCKX5 effectiveness would be expected to influence total skin pigment production.”

I’ve done a quick literature search to see where NCKX5 has been published about before. A recent open access PLoS One paper, “A Practical Genome Scan for Population-Specific Strong Selective Sweeps That Have Reached Fixation,” identified SLC24A5/NCKX5 as one of the strongest signatures of European-specific selective sweeps. So what does this all mean? Well, the European allele, mentioned in the excerpt above, reduces NCKX5’s ability to function and yields a similar phenotype as if it was completely knocked out (low melanin production). This allele has been fixed really fast within European populations.

These sets of studies are one of the first, in my knowledge, to actually correlate a function of a gene, a phenotype, and the frequency the allele is found within a population.

    Kimura, R., Fujimoto, A., Tokunaga, K., Ohashi, J., Harpending, H. (2007). A Practical Genome Scan for Population-Specific Strong Selective Sweeps That Have Reached Fixation. PLoS ONE, 2(3), e286. DOI: 10.1371/journal.pone.0000286
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