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A single DNA tweak leads to blond hair

Howard Hughes Medical Institute


"This particular genetic variation in humans is associated with blond hair, but it isn't associated with eye color or other pigmentation traits," says David Kingsley, an HHMI investigator at Stanford University who led the study. "The specificity of the switch shows exactly how independent color changes can be encoded to produce specific traits in humans." Kingsley and his colleagues published their findings in the June 1, 2014, issue of the journal Nature Genetics.



Genomic surveys by other groups had revealed that the gene - Kit ligand - is indeed evolutionarily significant among humans. "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," Kingsley says. His team went on to show that in humans, different versions of Kit ligand were associated with differences in skin color.

Furthermore, in both fish and humans, the genetic changes associated with pigmentation differences were distant from the DNA that encodes the Kit ligand protein, in regions of the genome where regulatory elements lie. "It looked like regulatory mutations in both fish and humans were changing pigment," Kingsley says. Kingsley's subsequent stickleback studies have shown that when new traits evolve in different fish populations, changes in regulatory DNA are responsible about 85 percent of the time. Genome-wide association studies have linked many human traits to changes in regulatory DNA, as well. Tracking down specific regulatory elements in the vast expanse of the genome can be challenging, however. "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." So his team focused its efforts on a human pigmentation trait that has long attracted attention in history, art, and popular culture.


Catherine Guenther, an HHMI research specialist in Kingsley's lab, began experiments to search for regulatory switches that might specifically control hair color. She snipped out segments of human DNA from the region implicated in previous blond genetic association studies, and linked each piece to a reporter gene that produces a telltale blue color when it is switched on. When she introduced these into mice, she found that one piece of DNA switched on gene activity only in developing hair follicles. "When we found the hair follicle switch, we could then ask what's different between blonds and brunettes in northern Europe," Kingsley said. Examining the DNA in that regulatory segment, they found a single letter of genetic code that differed between individuals with different hair colors.

Their next step was to test each version's effect on the activity of the Kit ligand gene. Their preliminary experiments, conducted in cultured cells, indicated that placing the gene under the control of the "blond" switch reduced its activity by about 20 percent, as compared to the "brunette" version of the switch. The change seemed slight, but Kingsley and Guenther suspected they had identified the critical point in the DNA sequence.


"Sure enough, when you look at them, that one base pair is enough to lighten the hair color of the animals, even though it is only a 20 percent difference in gene expression," Kingsley says. "This is a good example of how fine-tuned regulatory differences may be to produce different traits. The genetic mechanism that controls blond hair doesn't alter the biology of any other part of the body. It's a good example of a trait that's skin deep--and only skin deep."

Given Kit ligand's range of activities throughout the body, Kingsley says many such regulatory elements are likely scattered throughout the DNA that surrounds the gene. "We think the genome is littered with switches," he says. And like the hair color switch, many of the regulatory elements that control Kit ligand and other genes may subtly adjust activity. "A little up or a little down next to key genes-rather than on or off-is enough to produce significant differences. The trick is, which switches have changed to produce which traits?


