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The blonde gene mutation found by Stanford scientists

A molecule critical to stem cell function plays a major role in determining human hair color, according to a study from the Stanford University School of Medicine. The study describes for the first time the molecular basis for one of our most noticeable traits. It also outlines how tiny DNA changes can reverberate through our genome in ways that may affect evolution, migration and even human history.

The blonde gene mutation found by Stanford scientists.
The blonde gene mutation found by Stanford scientists.Anne Hart, photography.

If you're wondering where natural blonde hair originated, you might want to check out the June 1, 2014 Stanford School of Medicine news release, by Krista Konger, "Subtle change in DNA, protein levels determines blond or brunette tresses." A molecule critical to stem cell function plays a major role in determining human hair color, according to a recent study from the Stanford University School of Medicine.

The research, "A molecular basis for classic blond hair color in Europeans," describes for the first time the molecular basis for one of our most noticeable traits. It also outlines how tiny DNA changes can reverberate through our genome in ways that may affect evolution, migration and even human history. The research appears online June 1, 2014 in the journal Nature Genetics.

“We’ve been trying to track down the genetic and molecular basis of naturally occurring traits — such as hair and skin pigmentation — in fish and humans to get insight into the general principles by which traits evolve,” said David Kingsley, PhD, according to the news release, "Subtle change in DNA, protein levels determines blond or brunette tresses." Kingsley is a professor of developmental biology. “Now we find that one of the most crucial signaling molecules in mammalian development also affects hair color.”

Kingsley, who is also a Howard Hughes Medical Institute investigator, is the senior author of the study, published online June 1, 2014 in Nature Genetics. Research specialist Catherine Guenther, PhD, is the lead author.

The researchers found that the blond hair commonly seen in Northern Europeans is caused by a single change in the DNA that regulates the expression of a gene that encodes a protein called KITLG, also known as stem cell factor. This change affects how much KITLG is expressed in the hair follicles without changing how it’s expressed in the rest of the body. Introducing the change into normally brown-haired laboratory mice yields an animal with a decidedly lighter coat — not quite Norma Jeane to Marilyn Monroe, but significant nonetheless.

Tiny changes, noticeable effects

The study shows that even small, tissue-specific changes in the expression of genes can have noticeable morphological effects. It also emphasizes how difficult it can be to clearly connect specific DNA changes with particular clinical or phenotypic outcomes. In this case, the change is subtle: A single nucleotide called an adenine is replaced by another called a guanine on human chromosome 12. The change occurs over 350,000 nucleotides away from the KITLG gene and only alters the amount of gene expression about 20 percent — a relatively tiny blip on a biological scale more often assessed in terms of gene expression being 100 percent “on” or “off.”

“What we’re seeing is that this regulatory region exercises exquisite control over where, and how much, KITLG expression occurs,” said Kingsley, according to the news release. “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.”

Kingsley is known for his studies of the evolution of a tiny fish called the threespine stickleback. The stickleback adapts quickly to changes in its environment. It becomes darker in murky lakes, and develops modified spine, fin and armor structures in response to different types of predators. Kingsley’s research has shown that these adaptive changes are often driven by changes in the regulatory regions that surround and control gene expression, rather than within the coding regions of the genes themselves.

In the current study, the researchers had a couple of clues as to which regulatory regions might be important in hair color

One was the fact that the adenine-to-guanine nucleotide change had been previously associated with blond hair color in Northern Europeans in genome-wide association studies. The second was the existence in laboratory mice of a large mutation called an inversion that affects several million nucleotides near the KITLG gene. Mice with two copies of this mutation (one on each chromosome) are white; those with just one copy are significantly lighter than wild-type mice. But it wasn’t known exactly how either of these changes affects hair pigment.

The researchers began by confirming that the mouse mutation occurs in a region that is similar, or homologous, to where the single nucleotide change occurs in humans. They also showed that the skin of mice with one copy of the mutation expressed about 60 percent the amount of KITLG as the skin of mice without the mutation.

Further study showed that the region of human DNA that contained the single nucleotide change associated with blondness specifically affected the expression of KITLG only in hair follicles.

Finally, the researchers replaced the mouse mutation with human sequences with and without the blond-associated nucleotide change. Those with the guanine tied to blond hair in humans did in fact have significantly lighter hair.

“Because this nucleotide switch only effects the KITLG expression by about 20 percent or so, it would have been difficult to believe it would have such an effect on hair color,” Kingsley said, according to the news release. “For that we needed these very carefully constructed, well-controlled animal models. They clearly showed us that this small difference in expression is enough to switch hair color in these animals.”

He added, according to the news release, “It’s clear that this hair color change is occurring through a regulatory mechanism that operates only in the hair. This isn’t something that also affects other traits, like intelligence or personality. The change that causes blond hair is, literally, only skin deep.” Other Stanford authors of the study are former postdoctoral scholar Bosiljka Tasic, PhD, and professor of biology Liqun Luo, PhD. The research was funded by the National Institutes of Health (grant 5P50HG2568) and the Howard Hughes Medical Institute. Information about Stanford’s Department of Developmental Biology, which also supported the work, is available at the Stanford University website.

As of June 1, 2014, research on the blonde gene mutation is all over the news. For example, the NBC article, "Scientists Discover 'Blonde Gene'." The mutation from an A to a G in the DNA, what scientists used to call the "junk DNA" is enough to produce a blonde person.

The recent Stanford University study. Another Stanford University study found the "blonde gene" in Melanesians. You may wish to see the article, " Naturally blond hair in Solomon Islanders rooted in native gene, study finds." The common occurrence of blond hair among the dark-skinned indigenous people of the Solomon Islands is due to a homegrown genetic variant distinct from the gene that leads to blond hair in Europeans, according to a 2012 study from the Stanford University School of Medicine. Ironically, news of finding the gene markers for the Melanesian blondes didn't make the news quite as prolifically as the study announced on June 1, 2014 of researchers locating the marker that leads to blonde hair in Europeans and in some Middle Eastern peoples. You also may wish to check out the June 1, 2014 TODAY.com article, "Scientists discover 'blonde gene'.

David Kingsley, a Howard Hughes Medical Institute investigator at Stanford University led the 2014 study. The gene that’s being changed is called the KITLG gene and it’s essential for many different cell types, including melanocytes — involved in skin color — blood cells and basic cells called germ cells. Mutations can kill mice or make them anemic or sterile, says the article, "Scientists Discover 'Blonde Gene'."

The mutation that makes people blonde, however, isn’t in the gene itself

It’s in a different region of the DNA that controls how the gene actually works. The single-letter change, from an “A” to a “G” in the four-letter DNA code, makes the difference between being a blonde or a brunette. That mutation only affects hair color, not skin or eye color.

Blonde hair may be more common to people whose ancestors came from Scandinavia, but with so many admixtures over so many hundreds or thousands of years, blonde hair could show up in places where most people don't have blonde hair. Humans have many different genes that affect hair color, and some affect overall coloring.

This particular blonde type that was being studied at Stanford is common among people living in Iceland and in Scandinavia and is more of a light blonde rather than a dark blonde/light brown hue found in many other geographic areas. Have you ever seen those tow-haired kids with natural blonde hair that's almost silvery white? That's the gene scientists are talking about, that natural nearly platinum blonde that's found in some people and/or the light blonde you see on those who don't have to choose "lightest ash blonde" from the hair tint shelf. Then again, there are so many shades of blonde from golden and ash blonde to dark blonde and strawberry.

The term 'blonde' used to be used to describe blonde women and the word 'blond' without the 'e' to refer to blond men. In some blondes, kids with white-blonde tresses could still grow up to have light brown hair streaked with blonde from the sun.

And understanding these changes has more importance than merely understanding why humans are so varied in eye, skin and hair coloring. These little changes in little-understood regions of the genome may affect disease and other traits

What may be happening is that a person's genome has various switches. The Stanford research team discovered this particular blonde mutation while studying stickleback fish, which change their coloring depending on how murky the water is where they live. How the scientists found the mutation was to take the mutation out of the DNA and breed mice with the same genetic mutation.

The result gave the mice a DNA “A” letter at that point in the DNA, and the mice have brown fur. But when the researchers gave the mice a “G” mutation in their DNA, the mice turned out with light brown fur, which is similar to being blonde in a human

That brings readers to one of the reasons why blondes can be found in many geographic areas along routes linking the Baltic regions to Asia. It seems there was this medieval slave trade where blondes were preferred, according to the April 16, 2014 news release, "Medieval slave trade routes in Eastern Europe extended from Finland and the Baltic Countries to Asia." Researchers from the University of Eastern Finland studied this blondes preferred during the era of the medieval slave trade routes in Eastern Europe, which extended from Finland and the Baltic Countries to Asia, says a recent study. Have you ever wondered how blondes reached the Middle East? The routes of slave trade in Eastern Europe in the medieval and pre-modern period extended all the way to the Caspian Sea and Central Asia.

The medieval Baltic slave trade

You may wish to check out the study, "The Baltic Finnic People in the Medieval and Pre-Modern Eastern European Slave Trade." Raids and the kidnapping of humans in East Europe together with a late medieval and pre-modern Black Sea slave trade are well known in the scholarly literature, says the study's abstract.

This kind of slave trade also extended via the Volga to the Caspian Sea area and to Central Asia. Besides young male slaves, there was a market for small blond boys and girls in both regions, where they were expensive luxury items. Gangs from the Volga, at least, launched raids towards the north, and it is possible that the northern kidnapping raids and the transportation of prisoners from the northern forests to Novgorod were also connected with the southern slave trade, explains the study's abstract.

The study completed at the University of Eastern Finland suggests that persons captured during raids into areas which today constitute parts of Finland, the Russian Karelia and the Baltic Countries ended up being sold on these remote trade routes. There was a particular demand for blonde girls and boys who were seen as exotic luxury items, and it was financially beneficial to transport them to the far-away markets. Interestingly, another recent studies found a blonde gene outside of Europe.

The study by Professor Jukka Korpela was published as a General Article in Russian History (1/2014), which is a leading journal addressing the history of Russia. The journal publishes only four peer-reviewed General Articles per year. The numbers of northern people who finally reached the southern markets were not large.

The study indicates that out of the thousands of persons kidnapped in the north, only a few hundred – at most – ended up in the Caspian Sea region and Central Asia via the Volgan and Crimean slave markets. Otherwise, slave trade in the Crimea and Volga regions was extensive, and tens of thousands of people were sold into slavery every year. However, the existence of the trade route shows that it was possible, even under primitive conditions, to distribute information about the demand for blonde girls in the far-away markets. The network of those involved in slave trade included men who participated in raids, slave traders and customers representing the leading class of society.

Raids into the north were launched especially from Novgorod, which was well connected to the Crimea and, from there on, to the Caspian Sea and the slave markets of Central Asia. Raids were done by private warlords and princely troops, and they extended all the way to the coasts of the Gulf of Bothnia and Lapland

The material used in the study consists of chronicles, travelogues and various administrative documents such as tax and land registers, as well as diplomatic reports. Slave trade in Eastern Europe gradually faded, as the control exercised by the emerging structure of European states became stronger. The spreading of Christianity also caused a decline in slave trade during the medieval period. Slave trade within Europe declined already in the early medieval period, but in regions bordering on Islamic countries, slave trade continued up until the pre-modern period.

Blonde hair shows up in not only in Europeans and in some people also in the Middle East, but also blonde hair also shows up in Melanesia, says another recent study, "Melanesian Blond Hair Is Caused by an Amino Acid Change in TYRP1." Melanesian blond hair is caused by an amino acid change in TYRP1," published online in Science, May 4, 2012. That study was funded by the MRC and a Wenner-Gren Foundation for Anthropological Research grant. Blonde hair also is found in some East and South Asians. See the Youtube video, "Blonde Mongolians 3."