If you’re like me, you get your blond hair from the salon. But now a new study in Nature Genetics shows how some get this hair color for free with as little as a single base pair change in their DNA (1).
David Kingsley, a Howard Hughes Medical Investigator at Stanford University in Palo Alto, California and lead author of the study, didn’t set out to study blond hair color per se. Motivated by how complex traits arise in natural populations, he investigates how three-spined stickleback fish evolve new skin colors in different environments. But his studies repeatedly turned up a variant in a genomic region upstream of the human Kit-ligand gene, which was associated with hair color.
From in vitro experiments, Kingsley’s group learned that this genetic variant appeared in an enhancer region, meaning it turned expression of the Kit ligand gene up or down, rather than on or off. In fact, the “blond” variation of the enhancer dials down the gene’s expression by only 20% compared with the ancestral or brunette version, the group found.
To look at causality, the group moved their studies into new mouse models—one expressing the blond enhancer and the other expressing the ancestral sequence—using a method previously developed by co-author Liqun Luo at Stanford to insert a single-copy transgene into a specific place on a chromosome (2). (Conventional transgenic mouse lines, which incorporate DNA into the genome with potential variations in copy number, position, and orientation, would not have been precise enough, Kingsley said.) Indeed, the mice with the blond enhancer were blond.
"The study was beautifully and rigorously performed with an elegant use of mouse models, shedding new light on an important human regulatory variant," said Pardis Sabeti, a systems biologist at the Broad Institute of Harvard and MIT, who was not involved with the work.
Kingsley’s group plans to unpack more of the regulatory regions surrounding Kit ligand, which is also involved in the development of skin cells, blood cells, and germ cells, and has been linked to cancer.
1. Guenther CA et al. A molecular basis for classic blond hair color in Europeans. Nat Genet. 2014 Jun 1. doi: 10.1038/ng.2991. [Epub ahead of print]
2. Tasic B et al. Site-specific integrase-mediated transgenesis in mice via pronuclear injection. Proc. Natl. Acad. Sci. 2011. 108, 7902–7907.