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Earlier this year, I wrote a massive summary on the genetics of pigmentation for one of my graduate courses. I wasn’t particularly keen on the topic before but it has since grown on me and I’m now a big fan. So to read from Yann, Dienekes, and Razib that one of the key pigmentation genes, SLC45A2 is involved in hair color among Polish people, I was both excited and, well, frankly not very surprised.

Before I drag you into a review of the paper let me first introduce the gene and its function. SLC45A2 stands for solute carrier family 45, member 2. It is found on the short arm of chromosome 5. Not very informational, but the protein it ultimately encodes for is known as membrane-associated transporter protein (MATP). As the name implies, this protein is thought to regulate traffic melanosomal proteins into melanosomes, organelles within pigmentation cells (melanocytes) where melanin is produced. Melanin functions as a protective agent. It is dark in color and accumulates in cells in reaction to sunlight, absorbing light and protecting the nuclear genome from mutations caused by the ionizing radiation from UV rays. Thus, making MATP and the genetics of SLC45A2 an important part of the skin pigmentation pathway.

Recent studies have shown that certain variants of MATP affect pigmentation, such as Cook et al., 2008 and Graf et al., 2007. In the latest piece that everyone is buzzing about, “Association of the SLC45A2 gene with physiological human hair colour variation,” the authors were able to make an significant association between one of two non-synonymous polymorphisms in SLC45A2 and the hair color phenotype of a Polish population.

Don't blame me, blame Razib for linking up Marzena Cieslik, Miss Poland 2006

Inspired by Razib's example: Marzena Cieslik, Miss Poland 2006

The two SNPs are rs26722 and rs16891982. Both are missense mutations that encode for a different amino acids. The first SNP, rs26722, is a change from a guanine base to an adenine at position 907 of the mRNA transcript. This swap to an adenine affects the resultant the codon, creating a lysine on position 272 of the amino acid sequence instead of a glutamic acid residue (annotated as E373K). Similarly, rs16891982, is also a switch of a guanine but for a cytosine base on a different position of the transcript, 1214. The leucine residue on position 374 is thus changed to a phenylalanine (annotated as L374F).

Biochemistry aside, these two end products, MATP-E272K and MATP-L374F, have distinct population frequency distributions, especially MATP-L374F. Among the Polish sample of 392 individuals of varying skin, hair, and eye color, the rare allele is L374… Found in only 2.3% of the population. The MATP-374F allele is represented in 97.7% of the Polish sample. Curiously, all people who carried the rare allele had dark hair. The authors calculated the odds the L374 genotype increased the likelihood a person would have dark hair by 7 times.

Razib linked up an awesome resource, called ALFRED, the allele frequency database which shows the distribution of rs16891982 world wide. You can see that in northern Europe, 374F is the prevalent allele. Only when you get to Italy, Spain, Turkey, do you begin to see more of the L374 allele (the dark hair allele).

Worldwide Distirbution of the rs16891982 SLC45A2 Allele

Worldwide Distribution of the rs16891982 SLC45A2 Allele

This all makes sense, people who carry a cytosine on position 1214 of the SLC45A2 mRNA have lighter color hair than those who carry a guanine (L374). A similar distribution frequency was observed a German and Japanese sample by Nakayama et al., 2002 & Yuasa et al., 2004 & Yuasa et al., 2006. 96.5% of Germans had the lighter 374F allele. 100% of Japanese had the darker L374.

But why?

I returned to one of the previous studies I mentioned earlier, the Cook et al. paper, “Analysis of Cultured Human Melanocytes Based on Polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P Loci.” The authors of this paper grew primary melanocytic cells with specific mutations and tried to see the effects they had on melanin content and tyrosinase activity. In their array, one of their comparisons included the impacts of the MATP-L374 variant to the MATP-374F variant. They found that MATP-L374 cells expressed significantly lower MATP transcript levels compared to MATP-374F ones.

I’ve spent a lot of time thinking about this and quite frankly, I’m very confused. Correct me if I’m wrong, but lower levels of MATP transcript means less transport proteins translated and available to bring melanosomal proteins into the cells. Less building blocks equals less melanin. And less melanin should equal lighter pigmentation. So why do people who have dark hair have the less productive allele?

Come to think of it, there could be many different reasons, actually. Biochemical pathways are hardly ever a 1:1 mechanism. There’s lots of redundancy and sometimes one component isn’t the point man. For example, other parts of the pathway, such as tyrosinase, an enzyme that catalyzes the production of melanin, is higher in darker skin. Other transport proteins, such as SLC24A5/NCKX5 are also part of the melanin and melanosome production network and could have a different impact.

Either way, there are a few curious things to come out of all of this… We now know a definitive allele that affects hair color. Albeit, how is still up in the air, ’cause darker haired people come with less membrane-associated transporter proteins on their melanocytes. But still, there is a distinct structure to the distributions of these haplotypes.

    Wojciech Branicki, Urszula Brudnik, Jolanta Draus-Barini, Tomasz Kupiec, Anna Wojas-Pelc (2008). Association of the SLC45A2 gene with physiological human hair colour variation Journal of Human Genetics DOI: 10.1007/s10038-008-0338-3