A single letter of genetic code can determine hair color, while leaving other aspects of pigmentation unaffected. The finding sheds light on how blond hair evolved, and also on its future in a world where genetic populations are much less isolated.

In one of those wonderful examples of how good research can prove useful in totally unexpected places, Stanford's Professor David Kingsley started off studying three-spined sticklebacks, a species of previously marine fish that seized the chance to take over lakes and rivers freed from glaciation at the end of the last Ice Age.

The rapid diversification of this fish into a wide range of habitats provides a great chance to study the molecular side of evolution. Kingsley found that the stickleback's color was determined by the KIT ligand gene, but that a range of regulatory genes located in very different parts of the genome act on the KIT ligand gene, creating complex variation in the stickleback's colors.

The KIT ligand gene is not restricted to fish. "The very same gene that we found controlling skin color in fish showed one of the strongest signatures of selection in different human populations around the world," says Kinglsey. "It looked like regulatory mutations in both fish and humans were changing pigment." 

However, working out which regulatory genes are at play is much harder than finding the gene that codes for a specific protein. "We have to be kind of choosy about which regulatory elements we decide to zoom in on," Kingsley says. "We thought human hair color was at least as interesting as stickleback skin color."

The quest is important as well as interesting. Kingsley has found that 85% of the changes in stickleback traits are caused by changes in the regulatory genes, and the effects in humans are starting to get more recognition as well.

KIT ligand influences the body in ways that extend far beyond hair. Blood stem cells, skin color and sperm and egg precursors are all altered by KIT ligand, with different regulatory genes responsible. Dr Catherine Guenther, a researcher in Kingsley's lab attached genes that change color when switched on to candidate stretches of regulatory DNA and put them into mice. Kingsley and Guenther report in Nature that one of these proved to be the answer, lightening the mice's fur. 

This gene alters the amount of KIT ligand expressed in hair follicles, but not anywhere else in the body. Moreover, the difference between the version that produced dark hair and light turned out to be just one DNA letter, adenine for dark hair, guanine for light. While we are taught at high school to think of genes as on or off (dominant or recessive) in this case the choice of letter affects the amount of KIT ligand expressed by just 20%. The same a/g nucleotide change has been marked as a possible determinant of hair color in northern Europeans from genome-wide association studies.

“What we’re seeing is that this regulatory region exercises exquisite control over where, and how much, KIT LG expression occurs,” says Kingsley. “In this case, it controls hair color. In another situation — perhaps under the influence of a different regulatory region — it probably controls stem cell division. Dialing up and down the expression of an essential growth factor in this manner could be a common mechanism that underlies many different traits.”

“Because this nucleotide switch only effects the KITLG expression by about 20% or so, it would have been difficult to believe it would have such an effect on hair color,” says Kingsley. However, the mouse results make Kingsley confident the team have found their gene.

Knowing the identity of the hair color gene might only be useful to those with a desperate desire to determine their children's coloring, but the principle could be significant for far more significant traits. As just one potential lead, KIT ligand has been found to fight skin cancer under certain circumstances.

“What we’re seeing is that this regulatory region exercises exquisite control over where, and how much, KIT LG expression occurs,” says Kingsley. “In this case, it controls hair color. In another situation — perhaps under the influence of a different regulatory region — it probably controls stem cell division. Dialing up and down the expression of an essential growth factor in this manner could be a common mechanism that underlies many different traits.”

It shouldn't be necessary to say it, but perhaps it is, “This isn’t something that also affects other traits, like intelligence or personality,” says Kingsley. “The change that causes blond hair is, literally, only skin deep.”