Skin Color (the Mutation Lead to White, and Pigment Genes)

Human skin color is a “polygenic” trait, meaning multiple genetic loci are involved. As last counted by the International Federation of Pigment Cell Society on October 2, 2011, there are total of 378 genetic loci were implicated in skin color determination in human and/or mouse. Among them, only 171 have been cloned. The rest of 207 loci are mapped but the true gene identities are still yet to be determined.

From those cloned “color genes”, a sub-group belongs to the components of melanosomes and their precursors. Melanosomes are the granules within the melanocytes where melanin is synthesized. In humans, melanin is the primary determinant of skin color. It is also found in hair and the pigmented tissue underlying the iris of the eye. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms. Most eumelanins are derived from the amino acid tyrosine. The following diagram summarizes the biogenesis pathway of melanin in human melanocyte and its transportation to adjacent keratinocyte. Not surprisingly, many genes depicted in this figure are the so-called “color genes”.

Wasmeier et al., December 15, 2008 J Cell Sci121, 3995-3999

For example, the gene MC1R is located at the cellular membrane of melanocyte. MC1R stands for melanocortin 1 receptor. It is also known as melanocyte-stimulating hormone receptor (MSHR), melanin-activating peptide receptor, or melanotropin receptor. When activated by α-MSH, MC1R initiates a complex signaling cascade that turns on TYRP1 gene with the help of MITF, the master regulator of melanocyte lineage. TYRP1 and TYP (tyrosinase) are both needed to augment the production of the brown or black pigment eumelanin. Mutations, or SNPs (single nucleotide polymorphism) of MC1R, such as Arg151Sys (rs1805007), Arg160Trp (rs1805008), Asp294Sys (rs1805009), Val60Leu (rs1805005) and Val92Met (rs2228479) have been shown to cause red hair and pale skin that does not tan in a small percentage of the human population.

Another gene called SLC24A5 (Solute carrier family 24 member 5) regulates calcium in melanocytes. Its exact role in melanogenesis has yet to be revealed (therefore, not shown in the diagram above). Evidences suggested that the Thr111Ala allele (SNP type rs1426654) is a major factor in the light skin tone of Europeans. All Asian and African populations keep the original version of the allele, while the mutant one is found in about 99.9% of Europeans. This single base pair substitution is believed to represent some 25–40% of the difference in skin tone between Europeans and Africans, and appears to have arisen as recently as within the last 10,000 years. It became predominant amongst Europeans only around 5,300 to 6,000 years ago.

The rapid rise to dominance of the mutant SLC24A5 allele in European population suggests a strong selective pressure for human skin color. Selection favoring low levels of melanin pigmentation, or white skin, in geographic regions where there are low levels of UV radiation (such as European regions in the high latitudes) may also involve the following factors:

The regulation of Vitamin D synthesis
Frost bite sensitivity and cold tolerance

The biologically-active form of vitamin D, called calcitriol, circulates as a hormone, regulating the concentration of calcium and phosphate in the bloodstream and promoting the healthy growth and remodeling of bone. The prohormone, or previtamin D, is synthesized in skin by the action of UV-B in the sunlight. UV-B exposure causes a photochemical (non-enzymatic) conversion of 7-DHC (or 7-dehydrocholesterol ) into previtamin D. High melanin content in skin reduces UV-B exposure and cuts photochemical conversion, therefore as the theory goes, early Europeans acquired that mutation in SLC24A5 of light skin and benefited from it.

However, extended exposure to ultraviolet light in the sun causes DNA damage of the skin cells, which leads to many skin ailments including skin cancers. High melanin content in dark-skinned persons can neutralize sunlight exposure. Furthermore, UV-A rays from sunlight can also cause folic acid deficiency in light skinned people. Lack of folic acid will cause problem for cell division and growth, which is especially important in infancy and pregnancy. For children as well as adults, folic acid is required to produce healthy red blood cells and prevent anemia. Therefore, as the theory goes, Asian and African population keeps the original form of in SLC24A5 of dark skin and benefited from it. A glance at the map of indigenous skin color distribution in the world based on Von Luschan's chromatic scale seems to support that theory.

When the mutant allele of SLC24A5 was first described in the journal of Science in 2005, it was dubbed as the “white gene”. Scientifically, this is a wrong designation, because skin color is a multi-gene trait, as we mentioned before. People with the original SLC24A5 allele (the “black allele”, as it’s called sometimes) can still develop albinism. Mutation in many of the mentioned “color genes”, can cause albinism.

Although the genetic basis for skin color is complicated and so as the social and economical implication of skin color is controversial, one thing is clear that those genetic variations contributing to our skin color is also affecting our heath in different ways. When interviewed by Scientific American magazine in 2005, Dr. Mark Shriver of the Pennsylvania State University, the co-discoverer of SLC24A5 mutant allele, said:

"We know so little about the genetic and evolutionary architecture of human traits. We cannot expect to use human genetics to understand complex diseases most effectively without first working out how fundamental characteristics, such as eye, hair and skin color, are determined."

And therefore, the search continues…