In literature, television and film, the eyes are often imbued special meaning; the idea that you can tell something about a person, or what they are thinking or feeling, by gazing into their eyes. Eye colour is often considered a very straight-forward trait, with eyes being either brown, blue or green. But it is easily apparent that there is far more variation in human eye colour than that allows for, and that its inheritance is not always what one might expect. There are even some people out there who will try to convince you that your eye colour is controlled by diet. What really controls the appearance of our eyes? What are our eyes saying about us?
Eye colour is determined primarily by the concentration and distribution of melanin in the iris. Higher concentrations of melanin produce a darker eye colour (and the same is true for melanin in the skin). Melanin is stored in the iris pigment epithelium, at the back of the iris. The concentration of melanin here is responsible for the large differences between brown, blue and green eye colours. The subtle differences in hue, which produce the a full and continuous spectrum of eye colours from black to pale blue, are influenced by the melanin content and structural density of the iris stroma (located at the front of the iris). These attributes of the stroma result in Rayleigh scattering of light, much like what happens when light travels through the atmosphere producing a blue sky, and are responsible for subtle variations in hue from person to person. Eye colour is an example of structural colour, and therefore will vary depending on the lighting conditions. This is especially true for paler coloured eyes.
Melanin is manufactured in the iris throughout our lives by melanocytes in the antereal layer of the iris stroma, and stored in specialised organelles called melanosomes. Melanin is inert and very resistant to chemical degradation, remaining in the melanosome for long periods of time. Because of this continual accumulation of melanin, eye colour can change during a person’s life. Most change occurs during the first year of life, with pale-eyes darkening with age. Paler eye colours (blue and green) produce less melanin but also have fewer melanosomes; both of which contribute to a lighter eye colour.
Melanin production involves a lengthy biochemical chain of reactions inside the melanosome, beginning with the raw materials tyrosine, dopa and cysteine. The pathway can lead either to the production of eumelanin (black / brown) or pheomelanin pigments (red / yellow). As with many human traits, melanin production is influenced by a number of different genes. Each step of synthesis is catalysed by an enzyme, controlled by a gene. A mutation affecting any one of these enzymes will likely influence the resulting pigment, or may even prevent it’s production altogether. Combine this with the genes involved in determining the stromal characteristics, and it is no surprise that eye colour is a polygenic trait: influenced by mutations in many different genes.
Patterns of Inheritance
It is for this reason that eye colour inheritance does not always follow the simple patterns of mendelian genetics that the text book suggests. Broadly speaking, brown eyes are dominant over green, which are in-turn dominant over blue. But in reality it is far more complex than this. Nevertheless, eye colour is highly heritable (98%), indicating that it is almost entirely genetically controlled, and environmental influences have little effect. Three genes have been identified which together account for the majority of variation in human eye colour; OCA2, HERC2 and MATP.
OCA2, also known as the Bey locus, on chromosome 15, is believed to be the main determinant of brown-blue eye colour variation. One mutation in this gene has been found to explain around 75% of the variation in human-eye colour. OCA2 encodes a melanosome membrane protein, believed to be integral to melanin production. Mutations in OCA2, and in its regulatory region, can result in paler eye-colour, by reducing the production of melanin in the melanocytes. Mutations in OCA2 are also associated with variation in freckles, mole counts, hair and skin tone; not surprisingly since these traits too are influenced by melanin production.
Although OCA2 had previously been thought to be the most influential gene controlling eye colour, a neighbouring gene, HERC2, is now increasingly believed to be key. HERC2 encodes a regulatory protein which interacts with the promoter region of OCA2, and mutations in HERC2 result in reduced OCA2 expression. A recent study showed that one single nucleotide change in HERC2 explains 78% of brown-blue eye colour variation. Additionally, other mutations in HERC2 are strongly influential in brown-blue-green variation. One variant, composed of two closely linked nucleotide changes, is found in two main alleles; a dominant (G) brown allele and a recessive (A) blue-green allele. In one study, all brown-eyed participants were found to carry the G allele, and 98% of blue-eyed participants carried two copies of the A allele. Green colouration was not as well explained by variation at this locus, but still 85% of green-eyed people carried the recessive AA genotype.
Mutations in HERC2 have a down-regulatory effect on the expression of OCA2, but they do not prevent its production entirely. Thus, some melanin is still produced, resulting in a paler eye colour, rather than a complete absence of melanin which causes albinism.
Although OCA2 production appears to be key in controlling the majority of eye colour variation in humans, as many as 16 different genes may be involved in producing the full spectrum of eye colours that exist. One gene, LYST, which has been previously identified as a pigmentation gene in mice and cattle, appears to be important in influencing the subtler eye-colour variation. LYST is found on chromosome 1 and encodes the lysosomal trafficking regulator. Melanosomes are specialised lysosomes, and therefore LYST may influence eye colour through its effect on the transport of molecules through the melanosome membranes. Pigment rings, which distinguish different shades of green and hazel eyes, have recently been linked to a mutation near the membrane protein SLC24A4, on chromosome 14. Another gene, MATP is also believed to be involved in influencing the darkness of eye colour, and variants in SLC24A4, TYR and TYRP1 may also be involved. We still do not fully understand how these genes interact to produce eye colour.
The Global Distribution of Eye Colour
Paler eye colours, particularly blue eyes, are primarily found in Europe – being most common in Northern and Eastern Europe. Pale skin and eyes are believed to have originated in Europe, and the origin of one mutation in HERC2 has been dated to between 6,000 and 10,000 years ago in Romania. Eye colour diversity declines rapidly away from Europe. Green eyes are first known in Bronze age Siberia, and are the least common eye-colour, although interestingly they have been found to be more common in women than men.
A huge diversity of eye colour has emerged in humans over a very short space of time. Some researchers believe that evolution this rapid could only have been caused by one thing: sex. This diversity evolved in cooler climates, where early humans would have been living a hunter-gather existence in tundra, conditions which may have lead to a shortage of men. With too much choice around, males would have been selected to find finer ways to distinguish good mates, and eye and hair-colour diversity may have resulted from this. Sexual selection can often be frequency-dependent, meaning that it pays to be rare. New mutations causing changes in eye or hair colour may have provided attractive new variation to choosy males, and lead to the rapid evolution of the huge diversity seen today.
Variations in pigmentation levels would have been hugely disadvantageous in tropical conditions, but may have provided an adaptation to cooler climates; increasing vitamin D production by maximising the amount of UV absorbed from sunlight. Relaxation of the selection imposed by the cancerous effects of overexposure to sunlight during the move from tropical to temperate climates may have opened this variation up for sexual selection to act.
As well as being potentially dangerous or beneficial because of their effect on skin cancer susceptibility and vitamin D production, pale eyes are also associated with a higher incidence of age-related mascular degeneration (ARMD), a loss of vision due to damage to the retina. It’s not all good news for the dark-eyed, though, one study found an increased risk of cataracts associated with brown eyes.
A Window into the Soul
Finally, the finer details of iris appearance, in particular the crypts (lines radiating out from the pupil, and contraction furrows (lines curving round the outer edge of the iris), may tell us something about personality. Both crypts and furrows are producted by the dilation of the pupil. One recent study showed a relationship between the density of crypts and furrows and a number of personality traits including warmheartedness, neurosis, empathy and impulsivity.
The genetics controlling iris variation are even less well understood than those responsible for colour variation. However, some studies have begun to elucidate genes that may be involved. A single nucleotide change in the promoter region of the SEMA3A gene is associated with the present of crypts. SEMA3A encodes a protein that is involved in cell movement in both the iris and the brain. Mutations in this gene have previously been linked to schizoprenia and Alzheimer’s disease. Furrows have been found to be influenced by another mutation, known only as rs3739070, located near to the TRAF3IP1 gene on chromosome 2.
Eye colour is a complex trait, influenced by several genes involved in melanin production in the iris. Genes influencing the production of one gene, OCA2, explain the majority of eye-colour variation, however many genes act together to produce the huge diversity of human eye colours. Eye colour diversity increased rapidly in Europe around 10,000 years ago, a change which may have been motivated by sexual selection. However, eye-colour is strongly linked to pigmentation in general, and variation in eye-colour can influence health in a number of ways, largely depending upon where you live. Whether the eyes truly are a window into the soul remains unclear, but our eyes may be giving away more than we think.
Want to Know More?
- Larsson et al (2011) GWAS Findings for Human Iris Patterns: Associations with Variants in Genes that Inﬂuence Normal Neuronal Pattern Development The American Journal of Human Genetics 89, 334–343
- SNPWatch (2011) Genetic Variation is in the Eye of the Beholder
- Liu et al (2010) target=”_blank”>Digital Quantification of Human Eye Color Highlights Genetic Association of Three New Loci PLoS Genetics 6 (5)
- Mengel-From et al (2010) Human eye colour and HERC2, OCA2 and MATP Forensic Science International: Genetics 4: 323 – 328
- The Chicken or the Egg (2010) The Complicated Genetics of Human Eye Colour Inheritance
- Sturm (2009) Molecular genetics of human pigmentation diversity Human Molecular Genetics (18) R9 – R17
- Eiberg et al (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 (123) 177 – 187
- Kayser et al (2008) Three Genome-Wide association studies and a Linkage Analysis Identify HERC2 as a Human Iris Color Gene The American Journal of Human Genetics 82: 411 – 423
- Sturm et al (2008) A Single SNP in an Evolutionary Conserved Region within Intron 86 of the HERC2 Gene Determins Human Blue-Brown Eye Color The American Journal of Human Genetics 82: 424 – 431
- Larsson, Pedersen and Stattin (2007) Associations between iris characteristics and personality in adulthood Biological Psychology 75(2): 165 – 175
- Duffy (2007) A Three-Single-Nucleotide Polymorphism Haplotype in Intron 1 of OCA2 Explains Most Human Eye-Color Variation The American Journal of Human Genetics 80: 241 – 252
- BBC Science and Nature (2006) Genetics of Eye Colour Unlocked
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- Sturm, Box and Ramsay (1998) Human pigmentation genetics: the difference is only skin deep BioEssays 20: 712 – 721