Genes and Proteins
Some genes expressed in the production of melanin are associated with 1) biosynthesis or 2) regulation of biosynthesis. Different alleles for these genes affect either the kind or amount of melanin.
Many Genes, Many Proteins
The expression of a multitude of genes is required for the characteristic known as skin color. This expression results in a continuous palette of skin color. The skin pigments, eumelanin and pheomelanin are synthesized in melanosomes, which form in melanocytes. Melanosomes subsequently are transported to keratinocytes where they protect those cells. The most completely studied genes related to human skin pigmentation are key to pigment synthesis and regulation of that synthesis.
Initiation of melanin synthesis: MC1R and ASIP
The hormone alpha-melanocyte stimulating hormone (α-MSH) interacts with the melanocortin 1 receptor, MC1R, on the outside membrane of melanocytes. cAMP levels increase. A cascade of reactions converts the amino acid tyrosine to the pigment eumelanin.
A single change in an amino acid lowers MC1R’s affinity for α-MSH. The result is the synthesis of the pigment pheomelanin instead of eumelanin and lighter skin. There are many alleles of the MC1R gene. Agouti Signaling Protein (ASIP, coded by the ASIP gene) is an antagonist to MC1R, shutting down the pathway of eumelanin synthesis. Thus, the production of pheomelanin is favored. Variations of this gene, alleles, are found in some people with lighter skin.
Synthesis of melanins: TYR, TRP1 and DCT (TRP2).
Tyrosinase, (coded by the TYR gene) is the primary enzyme involved in the conversion of tyrosine to melanin. Nucleotide differences in the TYR gene correlate with skin pigmentation variation in humans. There are two tyrosine related proteins that that work with tyrosinase to produce melanins. One is TRP1; the other is dopachrome tautomerase , DCT, which is also known as TRP2. These proteins are associated with regulating pigment synthesis, although the mechanisms are unclear. There are known alternative alleles for the corresponding genes, which appear to correlate with the kind and amount of melanin made.
Regulation of melanin synthesis: OCA2, SLC24A5, and SLC45A2 (=MATP)
The internal environment of the melanosome regulates the amount of melanin synthesized. Thus, genes and proteins that influence this environment are key in determining skin color. The SLC24A5 gene codes for a potassium dependent (K+) sodium/calcium (Na+/Ca++) exchange transporter. The amount of calcium in the melanosome affects the entry of tyrosine, which determines the amount of melanin made. A specific allele of this gene is common in light skin populations (Western Europe).
SLC45A2 (=MATP) regulates the melanosomal pH. pH levels affect tyrosinase activity and subsequently the amount of eumelanin or pheomelanin synthesized. There are many variations (alleles) in the SLC45A2 gene.
OCA2 (gene is OCA2) resembles anion transporters in bacteria and also regulates melanosomal pH. OCA2 is thought to serve as a control point at which ethnic skin color variation is determined. Thus, the internal environment determines the amount of either pigment made, regulated by transporters (p-protein, MATP, SLC24A5)