A Single DNA Difference in the HERC2 Gene Explains Blue Eyes

Changes in the Non-Coding Region of HERC2 Are Responsible for Eye Colors other than Brown

February 14, 2008

A DNA difference in a gene not involved in eye color may help explain blue eyes.

A new study published in Human Genetics by Eiberg et. al. shows that a DNA change in the HERC2 gene causes blue eyes. Two other studies, a study by Kaser et. al. and a study by Sturm et. al. used different approaches to find the same thing. HERC2 is a surprise since it doesn't seem to be involved in eye color.

But the nearby OCA2 gene is. The researchers think that the DNA difference in HERC2 results in the shutting off of the OCA2 gene. And that a non-working OCA2 gene is one of the steps needed for blue eyes.

This is different than the results published last February that pointed to three DNA differences in the OCA2 gene itself that led to blue eyes. However, these three differences are very near the new difference and only explained about 2/3 of the cases of blue eyes. Most likely these differences are linked to blue eyes but don't cause them.

The researchers also found that all the blue-eyed people they looked at had the exact same DNA difference. This suggests that all of these folks came from the same blue-eyed ancestor. More analysis suggested that this blue-eyed ancestor migrated to Europe 6000-10,000 years ago where the gene spread like wildfire.

Close only Counts in Horseshoes, Hand Grenades, and Blue Eyes

Eye color happens because of the amount of the pigment melanin found in the front part of the iris. Little or no melanin there gives blue eyes. Lots of melanin in the iris gives brown eyes.

Within the last few years, scientists have identified the OCA2 gene as a major player in determining eye color. OCA2 is a key gene that's involved in determining how much melanin is made.

Some versions of OCA2 cause lots of pigment to be made and lead to brown eyes. Other versions that cause little or no pigment to get made lead to eye colors other than brown*. These other versions don't necessarily give blue eyes, though, because there are other eye color genes besides OCA2.

So how would a single mutation in a gene account for eye color? Well, there are lots of ways that this could happen. For instance, since OCA2 controls pigmentation, if it were broken, cells wouldn't have pigment. This is actually what happens in some types of albinism.

But most people with blue eyes do not have albinism. They just lack pigment in the eyes. To understand how a gene could work in one place but not in another, we need to go into a little more detail about genes.

Gene Structure

Genes are really just instructions for making proteins. The OCA2 gene, for example, has the instructions for making the P protein. The P protein helps make the pigment melanin.

A gene is made up of coding and non-coding sections. The coding part has the instructions for making the protein. The non-coding part has the instructions for when and where to make the protein. And how much of the protein to make.

Since people with blue eyes have pigment in other places in their body, it makes sense that the difference would be in a non-coding region. The difference wouldn't change the protein itself, it would only change where the protein is made.

In fact, the three previously identified DNA differences were in the non-coding region of OCA2. Which made sense.

What is a little weird with the new finding is that the change is actually in a non-coding region of another gene, HERC2. Basically, the researchers think that the non-coding region of HERC2 acts as a switch to tell the OCA2 gene to be on or off. To understand what might be going on, we need to go a bit into how non-coding regions can influence whether genes are turned on or off.

Genes and Transcription Factors

Whether or not a gene is on is controlled by special proteins called transcription factors (TFs). These TFs recognize certain pieces of DNA and bind to them. Some TFs turn on nearby genes and others turn them off.

The researchers suggest that the DNA difference in HERC2 causes a TF to bind where one didn't bind before. And when that TF binds, it shuts off the nearby OCA2 gene.

This is all theory at this point. The researchers were able to show that a protein binds HERC2 when it had the DNA difference. But they weren't able to identify the protein. Or show that it actually shuts off the OCA2 gene.

But why would this DNA difference cause OCA2 to get shut off in only the eyes? The reason is that different kinds of cells have different kinds of TFs.

Remember, most of our cells have the exact same DNA. But not all cells are alike. For example, a brain cell is very different from a skin cell.

These differences come about because different kinds of cells use different genes. And this comes about because different cells have different TFs.

So brain cells have different TFs than skin cells. Which means that different genes get turned on and off. That is how brain and skin cells are made. Or any other kind of cell as well.

The idea is that eye cells have a TF that binds the new DNA site and that skin and hair cells don't have that TF. So only the eyes end up without pigment and are blue.

It works like a switch. If you have a blue-eye version of the non-coding HERC2 region, then the switch is off, so you don't make the P protein and you have blue eyes. If you have a brown-eye version of the non-coding part of HERC2, then the switch is on so you make the P protein and you have brown eyes.

* This helps explain why blue eyes are recessive too. Remember that we have two copies of each of our genes—one from our mom and one from our dad. If you get the brown version of OCA2 (OCA2 is turned on) from one of your parents and you get the blue version of OCA2 from the other parent (OCA2 is turned off), you'll have brown eyes.

This is because the brown-eye version of OCA2 will over-ride the blue-eye version. Even if the blue-eye version from one parent is off, the brown-eyed version from the other parent will be on. The "on" version of OCA2 will still make pigment, even if the blue-eyed version does not, and you'll have brown eyes.

More Information

Genes have the instructions for how, when, and where to make a certain protein.










TFs like Lac Repressor bind DNA and turn genes on or off.

Only a Few Blue-Eyed People Migrated to Europe Around 6000 Years Ago

In the Eiberg study, 155 people with blue eyes from Denmark had the same version of HERC2. Only three people in the study had different versions. But their versions were not very different which means that most likely they arose from more recent mutations.

The authors looked at 7 other blue-eyed people from other parts of the world--5 from Turkey and 2 from Jordan. All seven people had the same version as the major group of people from Denmark.

In the two other studies that looked at where blue eyes come from, the authors looked at even more people. One study looked at 1406 people and the other looked at 384 people. All three studies found that the same DNA difference in the HERC2 gene was found in everyone with blue eyes.

Because so many unrelated individuals with blue eyes had the same HERC2 DNA difference, blue eyes might have come from one person with the mutation—--a common ancestor. Of course it is important to mention that in only one of the studies did the authors look at anyone outside of Europe. And in that study, only seven people outside of Denmark were studied--—a very small sample size. Checking more people from other places might find different ways to end up with blue eyes.

It could still be that having blue eyes can come from more than one version the OCA2 gene. This is the case for having red hair, another recessive trait. There are at least four versions of the red hair gene MC1R that lead to red hair. Having two of any of these red hair versions of MC1R will give you red hair. And some versions are more common in different parts of the world.

The authors estimate that this blue-eye mutation probably migrated from the Black Sea region to Europe somewhere between 6000-10,000 years ago. Because blue eyes are so common, if they really all came from one person then they may have been selected for.

Perhaps blue-eyed individuals had an advantage over darker-eyed individuals in this part of the world. What that advantage might be is still a bit of a mystery though.

It's possible that it had something to do with vitamin D. We used to get most of our vitamin D from sunlight. The cloudy skies of Northern Europe make it hard for dark-skinned people to make enough vitamin D. So light-skinned people had an advantage over dark-skinned people living there. If there were a link between blue eyes and light skin, then this might be the reason.

Maybe for some reason our ancestors thought blue eyes were sexier. This sort of thing is called sexual selection. This type of selection favors traits that have no real advantage other than making someone attractive to the opposite sex (think peacock feathers or antlers). In this scenario, blue-eyed people would have more kids leading to more blue-eyed people.

Another possibility is that the ancestors of people with blue eyes founded a population in Northern Europe and their descendants did very well. Blue-eyed people will almost always have blue-eyed kids (because blue eyes are recessive). So if a population started out with all blue eyes, then as long as there wasn't any outside source of eye color, there would mostly be blue-eyed kids.

Of course, it can be hard to wrap your head around the idea of one long lost blue-eyed relative being responsible for all 300 million blue eyed people around today. So hard in fact that this website has even said that most likely blue eyes arose multiple times. But could all blue eyes have come from a single ancestor?

Mathematically it is possible for the ~300 million blue-eyed people who live today to have come from the same ancestor. If we say that a generation is around 25 years, then 10,000 years would be about 400 generations. This could easily account for all 300 million people today that have blue eyes. But until we do more research and look at more blue-eyed folks, we won't know for sure if it happened this way. We only know that it could be possible.

By Katie Cunningham, Stanford University

Did all blue-eyes people come from one common ancestor?