Eye color phenotypes  (from Eiburg et al. 2008)

Perhaps the main lesson we eventually learn in school is how little we actually know. In elementary genetics, we were taught that there are two alleles for eye color, blue and brown, with brown dominant, allowing simple assessment of whether we were more likely fathered by dad or the mailman. In these simple Mendelian days, eye color was not considered to be a focus for natural selection, except perhaps in the context of an associated trait, pale skin, being favored to help accrue vitamin D in the high, dark latitudes of northern Europe. Only over the past few months has a series of publications begun to reveal the true complexities of human eye-color genetics, genomics, selection and evolution. In the context of tantalizing data linking eye color to social behavior, rather than just skin and hair color, these studies show that the metaphor of eyes as windows to souls may be more than poetic.

The story begins with the discovery that a gene for human albinism resides on chromosome 15, in the region that is typically deleted in Prader-Willi and Angelman syndromes, both of which commonly involve reduced eye and skin pigmentation (Rinchik et al. 1993). Loss of function mutations of this so-called OCA2 gene (for Oculocutaneous Albinism Type 2) cause a loss of melanin pigmentation in the iris, leading to pink eyes in both mice and man. Other allelic variants of the OCA2 gene (and the adjacent HERC2 gene) have recently been found to be tightly associated with blue versus brown eye color (Frudakis et al. 2007; Sulem et al. 2007; Eiberg et al. 2008; Sturm et al. 2008). All ancestral humans, like chimps and gorillas, had brown eyes and dark skin, with the mutation for blue eyes arising just 6,000-10,000 years ago, in a single individual – call her Ayla – who apparently lived near the Black Sea, and whose descendents moved north into Europe during the great agricultural migration of the Neolithic (Eiberg et al. 2008). Ayla’s OCA2 allele was an astonishing evolutionary success, showing a strong signature of positive Darwinian selection (McEvoy et al. 2006), but for causal reasons that have remained unknown. Hypotheses have ranged from vitamin D deficiency, to skin cancer and to sexual selection – Ayla may also have been the first blonde.

But one hypothesis, linking blue eyes to social behavior, has been overlooked. Starting with Rosenberg and Kagan (1987), a series of studies has demonstrated associations between blue eyes and timid, inhibited behavior (e. g., Coplan et al. 1998). The physiological and developmental functions of the OCA2 gene remain unknown, but directly adjacent to OCA2, in our vast genome, resides a cluster of three brain-receptor genes, GABRA5, GABRB3 and GABRG3. Allelic variants of the latter two genes have been associated with risk of autism (Shao et al. 2003; Kim et al. 2006; DeLong et al. 2007) and with psychosis in Prader-Willi syndrome (Webb et al. 2008), and GABRB3-deficient mice exhibit reduced social and exploratory behavior (DeLorey et al. 2008) – in less-technical terms, these mice are shy.

Contiguous genes are commonly regulated and expressed together – are blue eye and behavior genes so controlled? Did Ayla’s extended haplotype – her large allele across a set of genes – in the GABRB3-GABRA5-GABRG3-OCA2 genic region involve not just blue eyes and blonde hair, but an alluringly-diffident nature? How commonly does adaptive or chance contiguity of genes influence phenotypes and disease? At least in this case, looking behind blue eyes should illuminate not just the genetics of eye color, but also the curious joint workings of brain, behavior and genome, and how they have jointly come to be.


Illustration from Eiburg et al. 2008

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