Don't it make your brown eyes blue?

Blue eyes are caused by changes in the OCA2 gene
For something as interesting to the average person as eye color, very little is actually known about its genetics. Until now that is. Scientists have identified three different changes in the OCA2 gene that lead to blue eyes. These three changes probably aren't the whole story. But they do nail down OCA2 as the critical eye color gene that distinguishes brown eyes from blue. Now anyone who has looked over eye color genetics over the past few years (including our Ask a Geneticist section) may be a bit confused. You may never have heard of OCA2 before. In the past, this brown-blue gene has been called bey2 or EYCL3. These were the names of theoretical genes on chromosome 15. At the time of their naming, no one knew what or where the actual gene was. In the last few years though, a number of papers have come out that showed that OCA2 was probably the main eye color gene. The new paper that identifies these three changes strengthens this argument even more. So most likely, OCA2=bey2, EYCL3.
Location, location, location
Eye color happens because of the amount of the pigment melanin found in the eye. Not anywhere in the eye but in a very special place, the stroma of the iris. Lots of melanin here gives brown eyes and less melanin gives green. Little or no melanin in the stroma of the iris gives blue eyes. In terms of eye color, OCA2 comes in two versions—brown (B) and blue (b). The brown version works in the stroma, the blue version does not. Since the blue version doesn't work there, no melanin builds up. So these folks have blue eyes. Now OCA2 isn't just involved in eye color. When it is completely broken, we end up with something called P-gene related oculocutaneous albinism. This is a form of albinism more common in Africans than in Caucasians. So to have blue eyes without albinism, OCA2 has to work everywhere except the stroma. The new paper identifies DNA changes that presumably do this to the OCA2 gene. But how can a DNA change cause a gene to work in some places but not in others? By affecting whether a cell can read the gene or not. A gene really is just a recipe for making a protein. Just like a real recipe, if no one reads it and follows the directions, nothing gets made. So cells need to read a gene for it to have any effect. The first step in reading a gene is finding it. This might seem silly until we remember that only 2-3% of our DNA is genes. The cell can't waste its precious energy reading all of this DNA. So it has devised a way to find the start of genes. The start of a gene is marked in a certain way, sort of like sentences are when we write. In English, we know where a sentence starts because it starts with a capital letter and comes after a period (or exclamation point or question mark). The same sort of thing is true in cells. Not punctuation and capital letters, of course. But the start of a gene is marked. One way a cell marks a gene is to plop some proteins on the DNA nearby. These proteins tell the cell where the start of a new gene is. And different kinds of cells have different sets of proteins. That is what makes a lung cell different from a muscle cell. Or the stroma different from the rest of the eye. One type of protein that can vary from cell to cell is the kind that marks the start of a gene. So the stroma might have a different marker protein for OCA2 than the rest of the cells of the body. This is sort of like the different ways different languages have to mark the start of a sentence. In English, the start of a question is a capital letter. In Spanish, it is an upside down question mark and a capital letter. But why do changes in the DNA affect these marker proteins? Because the marker proteins know where to sit based on the DNA. Let's say there is a gene X. At the start of gene X is a series of DNA letters that looks like this: AAGTCCTGACTGA Now there is a protein found in the stroma that likes to sit on AGTC. There is one of these in front of gene X so the protein sits there. This protein tells the cell that this is a gene and to start reading. Now imagine that someone has this DNA in front of gene X: AATTCCTGACTGA Now our protein has nowhere to sit and so is not in front of gene X. The result is that the cell doesn't recognize the start of gene X anymore so gene X is not turned on in this cell. But this change would not affect another protein that likes GACTG. It can still sit on the DNA and mark the gene for the cell. So any cell that has this protein could still turn gene X on. This is presumably what is happening with OCA2 and blue eyes. The 3 identified changes are outside of the part of the gene that is read. So the changes may cause a protein in the stroma to no longer sit on the DNA. Now the machinery in the stroma cells doesn't see the gene and you have blue eyes. This is at least the theory. The next step will be to show how the gene isn't being read in the stroma. Stay tuned.

More Information

Blue eyes happen when
a part of the eye lacks
the pigment melanin.
Proteins on the DNA
can affect whether a gene
is on or off.
What about green, hazel, etc. eyes?
In all of this discussion, we've ignored green eyes. And all the colors in between. Do these results tell us anything about green eyes? A bit. There are lots of possible theories we can come up with to explain green eyes. One idea is that OCA2 explains all eye color. The data in this paper (and all of the inheritance studies that have been done) do not support this model. Why would people even consider this model? How could you get green eyes with just OCA2? By having it only partially on. Remember, lots of melanin in the stroma of the iris gives brown eyes and little or no melanin here gives blue ones. Green eyes are thought to happen when there is an intermediate amount of melanin. And genes aren't only on or off. They are more like a dimmer switch on a light. So green eyes might happen when OCA2 isn't going at full strength. The findings from some early, smaller studies suggested that this might be the case. But this bigger study doesn't really support this idea. So green eyes (and presumably all the other colors) probably come from other genes. The best models for eye color out there right now say that there are at least two genes involved in eye color (click here to learn more). One gene is OCA2. The other has been given the name gey. But what gey is precisely hasn't been nailed down yet. It is sort of the way OCA2 used to be when it was bey2 or EYCL3. So what might gey be doing? Here are some possibilities (these are by no means exhaustive): 1) Gey might be a weaker form of OCA2. It tells the stroma to make some melanin but not as much as the stronger OCA2 gene. The end result is green eyes. This would predict that people with green eyes would have a blue eye OCA2 gene. 2) Gey might be a gene whose job is to make OCA2 not work so hard. Now you would have less melanin in the stroma and have green or hazel eyes. This would predict that green eyed folks would have a working OCA2 gene. 3) Gey might be able to turn on a shut off OCA2 gene. Maybe it makes a protein that can sit in front of the OCA2 gene and turn it on. This protein isn't as good at directing the cell's machinery and so OCA2 wouldn't be on as high as it is for brown eyed people. This would predict that green eyed people would have blue eye OCA 2 genes. As you can see, there is plenty left to do! We are definitely getting a good handle on brown and blue eyes. All of the colors in between are our next challenge.
We don't yet know what
DNA is responsible for
green eyes.