From 16 December 2005 issue of Science:

News of the Week

GENETICS:
Zebrafish Researchers Hook Gene for Human Skin Color

Michael Balter

People come in many different hues, from black to brown to white and shades in between. The chief determinant of skin color is the pigment melanin, which protects against ultraviolet rays and is found in cellular organelles called melanosomes. But the genetics behind this spectrum of skin colors have remained enigmatic. Now, on page 1782 of this week's issue of Science, an international team reports the identification of a zebrafish pigmentation gene and its human counterpart, which apparently accounts for a significant part of the difference between African and European skin tones. One variant of the gene seems to have undergone strong natural selection for lighter skin in Europeans.

The new work is raising goose bumps among skin-color researchers. "Entirely original and groundbreaking," says molecular biologist Richard Sturm of the University of Queensland in Brisbane, Australia. Anthropologist Nina Jablonski of the California Academy of Sciences in San Francisco, California, notes that the paper "provides very strong support for positive selection" of light skin in Europeans. Researchers have not been sure whether European pale skin is the result of some selective advantage or due to a relaxation of selection for dark skin, after the ancestors of modern Europeans migrated out of Africa into less sunny climes.

Yet the authors agree that the new gene, SLC24A5, is far from the whole story: Although at least 93% of Africans and East Asians share the same allele, East Asians are usually light skinned too. This means that variation in other genes, a handful of which have been previously identified, also affects skin color.

The Science paper is the culmination of a decade of work, says team leader Keith Cheng, a geneticist at Pennsylvania State University College of Medicine in Hershey. He and his colleagues were using the zebrafish as a model organism to search for cancer genes and became curious about a zebrafish mutation called golden, which lightens the fish's normally dark, melanin-rich stripes. Cheng's team identified the mutated gene and found that the zebrafish version shared about 69% of its sequence with the human gene SLC24A5, which is thought to be involved in ion exchange across cellular membranes--an important process in melanosome formation. And when Cheng and his co-workers injected human SLC24A5 messenger RNA (an intermediary molecule in protein synthesis) into golden zebrafish embryos, wild-type pigmentation pattern was restored.

Researchers say the ability of human SLC24A5 to "rescue" the mutant zebrafish is strong evidence that the gene has a similar function in fish and humans. "The zebrafish data are extremely compelling," says human geneticist Neil Risch of the University of California, San Francisco.

The team then searched for genetic variants among humans. Data from the HapMap database of human genetic diversity (Science, 28 October, p. 601) showed that SLC24A5 has two primary alleles, which vary by one amino acid. Nearly all Africans and East Asians have an allele with alanine in a key locus, whereas 98% of Europeans have threonine at that locus. These marked frequency differences combined with the pattern of variation in nearby genes suggest that the threonine variant has been the target of a recent selective sweep among the ancestors of modern Europeans, Cheng's team concluded.

Finally, the team measured the pigmentation levels of 203 African Americans and 105 African Caribbeans--groups that represent an admixture of African and European ancestry--and compared their SLC24A5 genotypes. Subjects homozygous for the threonine allele tended to be lightest skinned, those homozygous for the alanine allele were darkest, and heterozygotes were in between, as shown by the degree of reflectance of their skin. The team concludes that between 25% and 38% of the skin-color difference between Europeans and Africans can be attributed to SLC24A5 variants. The experiments provide "a beautiful example of the critical role that model organism genetics continues to play for understanding human gene function," says geneticist Gregory Barsh of Stanford University in California.

The new work doesn't solve the question of why fair skin might have been favored among Europeans. However, it is consistent with a long-standing but unproven hypothesis that light skin allows more absorption of sunshine and so produces more vitamin D, a trait that would be favored at less sunny European latitudes.

Barsh adds that the paper "indicates how the genetics of skin-color variation is quite different from, and should not be confused with, the concept of race." Rather, he says, "one of the most obvious characteristics that distinguishes among different humans is nothing more than a simple change in activity of a protein expressed in pigment cells." Jablonski agrees: "Skin color does not equal race, period."