Human OCA2 Gene Is Responsible for Eye Color and Skin Color

 
Oculocutaneous albinism Type II [OMIN 203200] is a common type of albinism (especially in Africans). It characterized by loss of pigment-containing melanocytes in the skin. The genetic locus of this phenotype was localized to a single region on chromosome 15 and the gene was named OCA2 (oculocutaneous albinism Type II). See Beull's Blog; a blog written by a young man suffering from oculocutaneous albinism Type II.

The gene maps to 15q11-2-q12 and it has 24 small exons spread out over more than 350 kb (350,000 base pairs) [EntrezGene 4948]. The 836 aa coding region produces a protein called P protein, which has been localized to the membranes surrounding melanocytes.

The function of P protein is not well understood. It seems to play a role in the processing and trafficking of proteins that are localized to melanocytes. There is data to suggest an interaction with the melanocortin-1 receptor (MC1R OMIN 155555), a gene involved in the tanning response in fair skinned individuals. Whatever the exact role of P protein, it is clear that severe disruptions of OCA2 result in reduced numbers of melanocytes and low levels of melanin pigment in the skin.

The association between mutations in OCA2 and eye color has been known for some time. The human gene is the ortholog of the mouse pink-eyed (p) dilute gene. A gene scan for eye color variants in a Caucasian population from Brisbane, Australia revealed that 74% of eye color variablity localized to OCA2 (Zhu et al. 2004).

Duffy et al. (2007) examined the known variants of this gene. There are three dozen different alleles segregating in humans. Most of these have no effect on the amino acid sequence of the protein. Substitutions at amino acid 419 effect eye color: the present of glutamine 419Gln is strongly associated with green or hazel eyes. All other variants this position product brown eyes [OMIN 227220].

Blue eye color is associated with neutral mutations that map to the 5ʹ end of the gene suggesting that the actual change that gives rise to blue eyes is in the regulatory sequences that control expression of OCA2. The idea is that down regulation of P protein leads to reduced levels of melanin and this is what gives eyes a blue appearance (Strum and Frudakis, 2004).

The standard explanation for human eye color is based on a two-factor model (see The Genetics of Eye Color). We now know that this model is too simple. The main eye color gene (OCA2) has blue, green, and brown alleles but the expression of the corresponding phenotype is modified by a number of other genes.

Zhu, G., Evans, D.M., Duffy, D.L., Montgomery, G.W., Medland, S.E., Gillespie, N.A., Ewen, K.R., Jewell, M., Liew, Y.W., Hayward, N.K., Sturm, R.A., Trent, J.M., and Martin, N.G. (2004) A genome scan for eye color in 502 twin families: most variation is due to a QTL on chromosome 15q. Twin Res. 7:197-210. [free reprint]

Sturm, R.A. and Frudakis, T.N. (2004) Eye colour: portals into pigmentation genes and ancestry. Trends in Genetics 20: 327-332. [free reprint]

Duffy, D.L., Montgomery, G.W., Chen, W., Zhao, Z,Z,, Le, L., James, M.R., Hayward, N.K., Martin, N.G. and Sturm, R.A. (2007) A Three-Single-Nucleotide Polymorphism Haplotype in Intron 1 of OCA2 Explains Most Human Eye-Color Variation. The American Journal of Human Genetics 80: 241-252. [PubMed]