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.

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Illustration from Eiburg et al. 2008

Coplan RJ, Coleman B, Rubin KH (1998) Shyness and little boy blue: iris pigmentation, gender, and social wariness in preschoolers. Developmental Psychobiology 1998 32:37-44.

Delong R (2007) GABA(A) receptor alpha5 subunit as a candidate gene for autism and bipolar disorder: a proposed endophenotype with parent-of-origin and gain-of-function features, with or without oculocutaneous albinism. Autism 2007 11:135-47.

DeLorey TM, Sahbaie P, Hashemi E, Homanics GE, Clark JD (2008) Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder. Behavioral and Brain Research 2008 187:207-20.

Eiberg H, Troelsen J, Nielsen M, Mikkelsen A, Mengel-From J, Kjaer KW, Hansen L (2008) Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression. Human Genetics 2008 123:177-87.

Frudakis T, Terravainen T, Thomas M (2007) Multilocus OCA2 genotypes specify human iris colors. Human Genetics 2007 122:311-26.

Kim SA, Kim JH, Park M, Cho IH, Yoo HJ (2006) Association of GABRB3 polymorphisms with autism spectrum disorders in Korean trios. Neuropsychobiology. 2006 54:160-5.

McEvoy B, Beleza S, Shriver MD (2006) The genetic architecture of normal variation in human pigmentation: an evolutionary perspective and model. Human Molecular Genetics 2006 15 Spec No 2:R176-81.

Rinchik EM, Bultman SJ, Horsthemke B, Lee ST, Strunk KM, Spritz RA, Avidano KM, Jong MT, Nicholls RD (1993) A gene for the mouse pink-eyed dilution locus and for human type II oculocutaneous albinism. Nature 1993 361:72-6.

Rosenberg A, Kagan J (1987) Iris pigmentation and behavioral inhibition. Developmental Psychobiology 1987 20:377-92.

Shao Y, Cuccaro ML, Hauser ER, Raiford KL, Menold MM, Wolpert CM, Ravan SA, Elston L, Decena K, Donnelly SL, Abramson RK, Wright HH, DeLong GR, Gilbert JR, Pericak-Vance MA (2003) Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes. American Journal of Human Genetics 2003 72:539-48.

Sturm RA, Duffy DL, Zhao ZZ, Leite FP, Stark MS, Hayward NK, Martin NG, Montgomery GW (2008) A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color. American Journal of Human Genetics 2008 82:424-31.

Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T, Magnusson KP, Manolescu A, Karason A, Palsson A, Thorleifsson G, Jakobsdottir M, Steinberg S, Pálsson S, Jonasson F, Sigurgeirsson B, Thorisdottir K, Ragnarsson R, Benediktsdottir KR, Aben KK, Kiemeney LA, Olafsson JH, Gulcher J, Kong A, Thorsteinsdottir U, Stefansson K (2007) Genetic determinants of hair, eye and skin pigmentation in Europeans. Nature Genetics 2007 39:1443-52.

Webb T, Maina EN, Soni S, Whittington J, Boer H, Clarke D, Holland A (2008) In search of the psychosis gene in people with Prader-Willi syndrome. American Journal of Medical Genetics A 2008 146:843-53.




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