Sandwalk: Human OCA2 Gene Is Responsible for Eye Color and Skin Color

Friday, March 09, 2007

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]

1 comment :

Anonymous said...: This might be a really dumb question (indeed I am certain it is), but hopefully you'll indulge me.

Say a particular trait, blue eyes for example, is "controlled" by a mutation in a single gene and is advantageous, presumably natural selection finds this easy to grab hold of.

However, what about traits which are controlled by more than one gene? What if brown eyes requires a mutation in genes a, b and c. How does natural selection preserve a mutation in a, whilst waiting for b and c to mutate and produce the trait that is beneficial and will be selected? How does natural selection deal with genes that are operating together?

Thanks!; Friday, March 09, 2007 4:54:00 PM

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The old argument of design in nature, as given by Paley, which formerly seemed to me to be so conclusive, fails, now that the law of natural selection has been discovered. We can no longer argue that, for instance, the beautiful hinge of a bivalve shell must have been made by an intelligent being, like the hinge of a door by man. There seems to be no more design in the variability of organic beings and in the action of natural selection, than in the course which the wind blows.Charles Darwin (c1880)

Although I am fully convinced of the truth of the views given in this volume, I by no means expect to convince experienced naturalists whose minds are stocked with a multitude of facts all viewed, during a long course of years, from a point of view directly opposite to mine. It is so easy to hide our ignorance under such expressions as "plan of creation," "unity of design," etc., and to think that we give an explanation when we only restate a fact. Any one whose disposition leads him to attach more weight to unexplained difficulties than to the explanation of a certain number of facts will certainly reject the theory.

Charles Darwin (1859)

Science reveals where religion conceals. Where religion purports to explain, it actually resorts to tautology. To assert that "God did it" is no more than an admission of ignorance dressed deceitfully as an explanation...

Peter Atkins

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The world is not inhabited exclusively by fools, and when a subject arouses intense interest, as this one has, something other than semantics is usually at stake. Stephen Jay Gould (1982)
I have championed contingency, and will continue to do so, because its large realm and legitimate claims have been so poorly attended by evolutionary scientists who cannot discern the beat of this different drummer while their brains and ears remain tuned to only the sounds of general theory. Stephen Jay Gould (2002) p.1339
The essence of Darwinism lies in its claim that natural selection creates the fit. Variation is ubiquitous and random in direction. It supplies raw material only. Natural selection directs the course of evolutionary change. Stephen Jay Gould (1977)
Rudyard Kipling asked how the leopard got its spots, the rhino its wrinkled skin. He called his answers "just-so stories." When evolutionists try to explain form and behavior, they also tell just-so stories—and the agent is natural selection. Virtuosity in invention replaces testability as the criterion for acceptance. Stephen Jay Gould (1980)
Since 'change of gene frequencies in populations' is the 'official' definition of evolution, randomness has transgressed Darwin's border and asserted itself as an agent of evolutionary change. Stephen Jay Gould (1983) p.335
The first commandment for all versions of NOMA might be summarized by stating: "Thou shalt not mix the magisteria by claiming that God directly ordains important events in the history of nature by special interference knowable only through revelation and not accessible to science." In common parlance, we refer to such special interference as "miracle"—operationally defined as a unique and temporary suspension of natural law to reorder the facts of nature by divine fiat. Stephen Jay Gould (1999) p.84

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My own view is that conclusions about the evolution of human behavior should be based on research at least as rigorous as that used in studying nonhuman animals. And if you read the animal behavior journals, you'll see that this requirement sets the bar pretty high, so that many assertions about evolutionary psychology sink without a trace.

Jerry Coyne
Why Evolution Is True

I once made the remark that two things disappeared in 1990: one was communism, the other was biochemistry and that only one of them should be allowed to come back.

Sydney Brenner
TIBS Dec. 2000

It is naïve to think that if a species' environment changes the species must adapt or else become extinct.... Just as a changed environment need not set in motion selection for new adaptations, new adaptations may evolve in an unchanging environment if new mutations arise that are superior to any pre-existing variations

Douglas Futuyma

One of the most frightening things in the Western world, and in this country in particular, is the number of people who believe in things that are scientifically false. If someone tells me that the earth is less than 10,000 years old, in my opinion he should see a psychiatrist.

Francis Crick

There will be no difficulty in computers being adapted to biology. There will be luddites. But they will be buried.

Sydney Brenner

An atheist before Darwin could have said, following Hume: 'I have no explanation for complex biological design. All I know is that God isn't a good explanation, so we must wait and hope that somebody comes up with a better one.' I can't help feeling that such a position, though logically sound, would have left one feeling pretty unsatisfied, and that although atheism might have been logically tenable before Darwin, Darwin made it possible to be an intellectually fulfilled atheist

Richard Dawkins

Another curious aspect of the theory of evolution is that everybody thinks he understand it. I mean philosophers, social scientists, and so on. While in fact very few people understand it, actually as it stands, even as it stood when Darwin expressed it, and even less as we now may be able to understand it in biology.

Jacques Monod

The false view of evolution as a process of global optimizing has been applied literally by engineers who, taken in by a mistaken metaphor, have attempted to find globally optimal solutions to design problems by writing programs that model evolution by natural selection.

Richard Lewontin

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Friday, March 09, 2007

Human OCA2 Gene Is Responsible for Eye Color and Skin Color

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