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“Thought of you as my mountain top,
Thought of you as my peak.
Thought of you as everything,
I’ve had but couldn’t keep.
Linger on, your pale blue eyes.”

-The Velvet Underground - “Pale Blue Eyes”

The instant that my blue-eyed son Zach was born - to a green-eyed mother and brown-eyed father - I became interested in the genetics of human eye color. I now know, of course, that most Caucasian babies are born with blue eyes and that most of them change color before their first birthday. Nonetheless, an upcoming paper about the isolation of the mutation responsible for blue eye color in humans in Human Genetics caught my eye this week.

Variation in eye color is correlated with variation in melanin pigment levels in the iris. Blue versus blue eye color is a classic example of a simple single gene inheritance with brown being dominant to blue. This one gene model doesn’t cover all the variation seen in eye color - greens, grays, blue with brown flecks, blacks, and so on - indicating that there are more genes involved. While the gene responsible for brown or blue eye color -
OCA2 - has been known for over a decade, the particular mutation responsible for blue eyes was just isolated this week by a Danish research team. Their results are interesting for two reasons - first, the mutation responsible is not in the OCA2 gene but a nearby regulatory region and their interpretation of their results suggest that all blue-eyed people share a single common ancestor.

The Danish group, led by Hans Eiberg of the University of Copenhagen, used a three generation Danish family to genetically map the blue eye color mutation. Mapping a mutation involves establishing the location of a genetic locus responsible for a mutant phenotype relative to some known genetic markers. Eiberg and his colleague found that the blue eye color mutation maps to a region that encompasses the OCA2 gene and HERC2 - a gene of unknown function. Finer mapping and DNA sequencing revealed two DNA changes that are correlated with the blue eye color mutation. One of these was located in the promoter of the OCA2 gene and the second in an intron of HERC2. It seems that typically (in people with brown eyes) the latter sequence acts to repress activity of the OCA2 promoter and thus expression of that gene. When the blue eye color associated mutations are present, this repression is slightly relieved allowing a different pattern of OCA2 expression.

Eiberg’s team then analyzed the sequence of the relevant regulatory regions of a further 155 people from Denmark as well as seven blue-eyed people from Turkey or Jordan. Over 97% of people with blue eyes analyzed carried the mutation that Eiberg and his colleagues identified and the remainder had variations that could be explained by slight rearrangements of this mutation. The authors hypothesize that the variation they found represents a founder mutation that arose 6 - 10,000 years ago - in other words all humans with blue-eyes are descended from a single common ancestor. They further postulate that the high-frequency of blue-eyed people of northern European origin indicates a positive selection for eye color.

This paper doesn’t shed any light on the biological phenomenon that got me interested in how eye color is inherited in humans. Zach’s eyes are changing - probably to brown, although I’m hoping for green - I’m guessing this has something to do with a slow accumulation of melanin pigments in the eyes. However, Eiberg’s group does seem to have isolated the genetic mutation responsible for blue eyes. I’m not sure about their founder mutation hypothesis - the population size that they are using is extremely small and geographically biased. I would be hesitant to draw the conclusions that they have about a common ancestor and their timing is not based on their data. It’s an interesting study anyway and I think the best science is that which elicits discussion.

Image Credits:

Sky in his eyes

Veil and blue eyes

 

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