While hair color is among the most outwardly varying traits, the underlying genetic mechanisms that determine it have been poorly understood.  Even with new, data-rich, and far-reaching approaches such as the genome-wide association study, or GWAS, that have pointed to several spots on the human genome involved in pigmentation, how variation in these genetic regions connects with different hair color has until now been a complete mystery. However, a team of Stanford University researchers cracked the code for blonde hair color, and their findings were published this week in the journal Nature Genetics.

The groundbreaking work under senior author David Kingsley’s direction is important because in addition to discovering what makes a person have blonde hair, the discovery illustrates the importance of regulatory segments of the genetic code in how an organism looks. Changes, or mutations in genes have been known to cause changes in appearance, but this discovery involves a change in a DNA “switch” for a gene and not the gene itself.

The genetic determinants of hair color have been a research topic for geneticists for a long time, but answers have been slow in coming. Recent GWAS studies have identified about eight chromosomal regions associated with blonde hair color. These studies found certain single-nuleotide polymorphisms, or SNPs, were more common in fair-haired individuals. However, causal links have to date not yet been established.

Kingsley and colleagues had for years studied a gene called KITLG in stickleback fish. Changes in the regulation of this gene led to changes in the fish skin color. The regulatory change was caused by a SNP in the regulatory DNA for KITLG. The researchers decided to examine KITLG regulation in mice and found that making changes to the regulatory DNA for this gene in mice caused the coat to be much lighter and in some cases, even white.

The researchers then engineered mice with two versions of human KITLG, one with the blonde-producing SNP and the other version that produces darker hair. The mice with the blonde-producing SNP were lighter. Interestingly, KITLG is not a gene for pigmentation but for determining cell fate in developing organisms. The blonde-producing SNP causes the transcription of the gene to drop by about 20 percent.

“This isn’t a ‘turn the switch off,’ ” Kingsley says. “It’s a ‘turn the switch down.’ ”

The etymology and spelling of the words blond and blonde form an interesting side note. The adjective “blond” has predominantly been used for males, whereas “blonde” is most often used for females.