Stanford Scientists Solve Small Part of Genetic Mystery Behind Blonde Hair

From a first pass, hair color is a pretty simple trait. Basically, the more pigment you have in your hair follicle, the darker it is.

Given how simple hair color is, it is surprising how complicated its genetics are. It turns out no one gene plays a dominant role in determining how much pigment you make. Lots of genes are involved in giving you that perfect shade of brown or blonde or auburn or whatever.

In a new study out in Nature Genetics, a group of scientists at Stanford has figured out how a certain version of one small bit of DNA that goes by the name of rs12821526 makes it more likely for some Europeans to have blonde hair. Basically the “blonde” version of this DNA can’t bend as easily. The end result is that hair follicle cells can’t read the kit ligand gene (KITLG) as well which means less pigment gets made.

Given hair color’s complicated genetics, it shouldn’t be surprising that this DNA variant is not the whole story behind blonde hair. In other words, not everyone with the blonde version of rs12821526 has blonde hair.

Think about it this way. Let’s say you have the variant they studied that tells your hair follicles to make a bit less pigment. On its own this won’t be enough because there are other genes telling your hair follicles how much pigment to make as well.

If the other genes all tell your hair follicles to make lots of pigment, you probably won’t have blonde hair even if you have the newly identified DNA variant. Your hair may be a lighter shade than someone else’s, but it probably won’t be blonde.

So this DNA variant is really just one of many you need to have blonde hair which means we can’t use it alone to predict someone’s hair color. You need to know more information about many other genes to have a shot at it.

The best hair color predictor out there right now looks at 24 different DNA variants and is right about 70-90% of the time, depending on the particular hair color. This is pretty good but it obviously isn’t perfect. There are undoubtedly more DNA variants involved in hair color that we haven’t discovered yet. As we find and add more of these, predicting hair color should get better and better.

Being able to do this will turn out to be a boon for all sorts of people. For example, it could help the police if the DNA found at a crime scene isn’t already in a database or it could help archeologists better understand what a population looked like thousands of years ago.
Unfortunately the DNA variant the Stanford scientists studied won’t make hair color predictions any better. This is because the hair color predictor is already using it.

The exciting part of this study is that they were able figure out why this DNA difference causes a hair follicle to make less pigment. Turns out that it controls how well the kit ligand gene (the KITLG) works from over 350,000 base pairs away.

Less Kinked DNA Leads to Blonde Hair 

The instructions in DNA are written with four chemical bases that are abbreviated to A, G, C, and T. People with the DNA variant of rs12821526 that are more likely to be blonde have a G at this position while darker haired people tend to have an A. As usual, I am blown away by the fact that one small change can make such a big difference.

This small difference isn’t in any gene though—there aren’t any nearby. DNA variants that affect traits that happen outside of genes usually do so by affecting how a gene in a separate part of the DNA works. And this is just what the Stanford researchers found.

From previous work, they were able to home in on a stretch of DNA that was 17,000 or so bases long. There is probably a whole lot going on in such a big piece of DNA and so they wanted to find some part that would only work in hair follicles.

To do this, they chopped this DNA up into three parts and had each control a gene that makes a blue color. They put each of these into mice and asked what parts of the mouse turned blue.

One of the pieces of DNA turned the mouse’s kidneys and hair follicles blue. They had found a 6,700 base pair fragment of DNA that specifically turned genes on in the kidney and hair follicle.

The next step was to chop this DNA up into smaller and smaller pieces to find one that just turned the hair follicles blue. They settled in on an 894 base pair piece that they named the hair follicle enhancer or HFE.

Previous experiments in mice had suggested that this region of the DNA controlled the kit ligand gene (KITLG) that is located 350,000 base pairs away. Since KITLG is involved in making pigment in hair follicles, this seemed like a reasonable target for the DNA they had found.

The authors created mice where either the dark haired or the blond version of this enhancer controlled how much KITLG was made. And lo and behold the mouse with the blonde version had a slightly lighter hair color. This is just what we’d expect from one of the many human variants that contribute to hair color.

To affect a gene hundreds of thousands of base pairs away, an enhancer needs to somehow get close to the gene. This is often accomplished in the cell by DNA looping. The enhancer loops around and interacts directly with the gene it affects. Very often this sort of looping is helped by proteins that bind directly to and bend the DNA.

A close look at the DNA change that can lead to blonde hair showed that it messed with the binding of one of these proteins, LEF-1. The researchers hypothesize that the enhancer can’t loop as well in people with the blonde DNA variant leading to less KITLG expression which ultimately leads to less pigment in the hair follicle. This makes sense given how important KITLG is to the cells that make pigment.

So there you have it. People with a DNA change that makes a part of the DNA less bendy are more likely to have blonde hair.

This was not easy to figure out. It wasn’t something relatively simple where a DNA change kills a gene causing some sort of trait. These are much easier mysteries to solve.

Instead we have a change that slightly decreases how well a cell reads the KITLG which is over 300,000 base pairs away. Figuring out what our DNA is doing will not be simple. But it sure will be fun!