Untangling the mystery behind blue eyes in brown-eye world

By Ayokunle Afolabi Toye

Most sub-Saharan Africans never give a thought to eye colour, which is reasonable and not surprising, given that almost all sub-Saharan Africans have brown eyes of subtly varying shades, with little other variation.

The awareness that eye colour can and does differ from the ubiquitous brown, arises from exposure to people of other geographic origins including North Africa, the Middle East, Asia, northern and southern Europe and the Americas (North and South).

Such exposure might be through physical encounters/contact or print/telecommunication media (movies, magazines, books, photos etc) informal (educational/classroom) or other settings.

The second precipitant of awareness of variation in eye colour is exposure to individuals whose eye colour is altered by temporary or permanent changes in eye health (cataracts etc), which may or may not affect eye function/vision.

As such, many sub-Saharan Africans subconsciously activate an algorithm based shortcut of thinking when they encounter a person with an eye colour other than brown. Typically, one would ask oneself if they are of sub-Saharan African origin?

If they’re not, one would presume likely that their eye colour is associated with their “other” historic origin. If they are, then one would assume that the eye colour was due to health problems.

Typically, a person would arrive at one of the alternative answers in this algorithm within a fraction of seconds of the encounter, aiding a modulation of our behaviour in interacting with the person with non-brown eyes. Beyond Brown, the most common alternative eye colours are Blue, Grey, Green and Calico.

These colours of the eye may more specifically be described as colours of the iris, a disc-shaped component of the eye, which rests between the cornea (anterior) and lens (posterior) components at the front of the eye.

The colour of the iris is in turn determined by the extent of deposition of a natural pigment known as melanin. Most readers will already be familiar with melanin, from their knowledge that its deposition in skin determines skin colour and complexion.

The greater the amount of melanin deposited in the iris, the darker the eye colour. Brown eyes are associated with the highest levels of iris melanin deposition. Lighter eye colour arises from the inheritance of a natural propensity for lower iris melanin content in the general order Brown > Blue > Grey.

The density of cells and connective tissue/collagen network in the iris also contribute to eye colour; through effects on the scattering of the component colours/frequencies of light. As a result, eye colour will often differ to varying extents depending on the light conditions in which it is assessed.

The widely-held construct of the likely basis of observed eye colour outlined above has led to the belief that lighter eye colour often seen more frequently in the extreme southern and northern borders of Nigeria are due to recent introduction of genes into the local population by interbreeding with expatriates/migrants from other populations/origins.

The trans-Saharan trade route dating back over a thousand years is attributed to the introduction of lighter skin and eye colour into northern sub-Saharan Africa and indeed northern Nigeria. Similarly, the encounter with Northern Europeans who travelled by sea to the coastal regions of sub-Saharan African territories likely led to cases of interbreeding and is often invoked as a basis for examples of lighter skin and eye colour in the region.

Further, it has been suggested that the return of former slaves (admixed offspring of sub-Saharan Africans) to Africa contributed to the introduction of skin and eye colour determinants not typically found in sub-Saharan Africa.

All three explanations are indeed plausible, it however remains the case that a fourth mechanism is in play. Spontaneous changes can occur in the biological material that determines heritable eye colour which can give rise to individuals that present with unusual colour even among sub-Saharan Africans.

The likelihood of this occurring is exceedingly rare, and when it does, it can be extremely unsettling for the bearer (and or their relatives) and/or the perceiver/observer (people in their physical or virtual community); What we don’t know or expect can sometimes be a cause for anxiety and/or misinterpretation, particularly in a society in which the frequency and impact of people with scientific knowledge and training are low.

Beyond mere physical observation, we now have the tools to determine why heritable eye colour differs between people within and between populations, and also why certain eye colours predominate within some environments and not others.

These insights on the causal basis of heritable variation in eye colour extend to detailed information at the level of a material known as DNA (deoxyribonucleic acid) within our cells, which is the fundamental determinant of traits.  The material known as DNA is made up of 4 unique building blocks differentiated by the letters A, C, T and G.

These building blocks (nucleotides) are arranged end-to-end in a specific/non-random pattern to form long chains (polymers) that when placed end to end are three billion building blocks long. The entire set of three billion nucleotides contains all the information required to specify the human form and function and is called the genome.

One single misplaced block at any of the three billion positions in the genome can lead to profoundly different appearance, behaviour or function of the bearer of the altered genome.

An analogy would be that, in the English language which has 26 unique building blocks or letters of the alphabet, strings of building blocks called words to have unique meanings. One single misplaced block/letter at any of the positions along the chain of letters that specify a word could lead to a change in meaning or no meaning at all (nonsense).

For example in the chain of a specific sequence of 10 building blocks in the English language “complement”, a misassignment of any alphabet other than “e” at position 6 (numbered from left to right) will change the meaning of the word, rendering it unintelligible (nonsense), or if fortuitously the letter “i” is the one mis-assigned to position 6, it will yield the spelling “compliment” which, though intelligible, would simply change the meaning of the word.

These misplacements of building blocks in DNA occur accidentally (mutation) at the rate of 0.5 x 10-9 base pair per year in humans. Rare as these may seem, over hundreds of thousands of years of human history and in billions of humans across that span of history, such mutations accumulate in the genome, contributing to the variation we see in modern-day humans.

Some of the mutations affect the way we look or are, including mutations affecting eye/iris colour in some but not all humans. When such mutations have no beneficial outcome, their chances of survival in the population are slim, but when they are beneficial, they may confer an indirect advantage on the ability of the bearer to contribute offspring to the next generation, therefore increasing the frequency of such a variant in the population in the next generation through its larger than the usual number of offspring.

Over several generations, what was originally a rare variant is then enriched within such a population to a point where it becomes common.

All modern humans are believed to have originated out of Africa. Some mutations that confer an advantage in some but not all environments include those that are located in the portions of the genome (gene) responsible for making brown pigment (melanin) in the skin.

The partial or total loss of ability to deposit large amounts of melanin in skin results in light/pale skin as seen in people of middle eastern, Northern Asian and  European ancestry, particularly above latitude 35 °N.

Gene variants conferring this partial or total loss of ability to produce melanin in the skin are enriched in those populations because they confer the advantage of aiding the absorption of UV rays from what little year-round sun there is in those regions to facilitate the production of Vitamin D which is essential for bone deposition as well as development and function of the immune system. Conversely, there is a strong selective pressure to preserve the ability to produce high levels of melanin in the skin in areas below latitude 35 °N towards the equator and further towards latitude 35 °S because of the earth’s obliquity (tilt in the axis of rotation) relative to its orbital plane.

This is because such areas receive significantly more sunlight including component UV radiation all year round. So intense is this UV radiation from the sun in these regions that it can burn pale skin and promote skin cancer.

High melanin in the skin, which results in brown skin blocks the penetration of body tissue by UV radiation and thus protects against their damaging effects including cancer.

Thus, opposite sides of the same coin (light versus dark skin) are determined by the same pieces of DNA (genes), with variation from one type to the other produced by simple substitution of one type of building block (A, C, T or G) for another somewhere along the length of the gene(s). Genes including SLC24A5, MFSD12, OCA2, HERC2 and DDB1 determine skin colour and tone/complexion.

The eye is susceptible to damage by UV radiation from the sun, and further susceptible to cancers resulting from such damage. Melanin deposition in the iris which produces brown eye/iris colour and can limit damage due to UV exposure is therefore protective in the tropics.

Conversely, while a low level of iris melanin which results in lighter eye colour (including blue, grey, green and calico) may confer an increased risk of eye cancer if eyes are unprotected by sunglasses in the tropics, they actually confer an advantage of greater efficiency of light utilisation for vision in the temperate regions, which by their nature receive less daylight on average over the entire year.

This benefit extends to conferment of superior night vision in people that have light eye colour relative to people with brown eyes/irises. Subtler effects of eye colour and its effects on light sensitivity may relate to effects on the pineal gland which regulates melatonin production and its effects on sleep pattern and a myriad of other central nervous system and pituitary gland regulated biological functions. Gene determinants of eye colour include OCA2, HERC2, SLC4A4 and TYR.

Blue eyes in a Nigerian woman with no known familial history of blue eyes

In general, blue eyes are associated with non- sub-Saharan African origin and pale skin colour. In admixed populations, however, the independent assortment of traits yields examples of people with dark skin and blue eyes.

It is generally believed that all people on the planet that have blue eyes do so because they share a variant of the eye colour determining gene OCA2 which arose in one single individual as a genetic accident/mutation around 6000 – 10,000 years ago.

There seems to have been strong positive selection for blue eyes in Northern Europeans, although quite why is not as clear. Some believe that it may have conferred an advantage of sexual attractiveness; Studies have shown that eye colour rarity appears to increase sexual attractivity within a population.

Others believe that it is associated with parental imprinting; Studies have shown that people are more likely to be attracted to a partner that has an eye colour similar to their parent of the opposite sex (imprinting of parental eye colour).

By these constructs, blue eye colour which was originally rare within a population would rise in frequency with successive generations until its frequency was so high that it was no longer rare and therefore no longer advantageous in mate selection (marriage partner selection).

Recently, a social media report of Risiqot a blue-eyed woman of Yoruba ancestry (North Central Nigerian, West African, sub-Saharan African) spread like wildfire through the print and electronic media to the consciousness of Nigeria and the world.

While the rarity of her blue eyes drew attention to her, it was her social (rejection by her husband for her unusual eyes and production of two children with the same) and financial (inability to pay for her children’s education) plight that was speedily addressed by charitable well-wishers and benefactors across high and low strata of the social class ladder.

Seemingly, the question everyone was asking was “why should someone suffer such social injustice through no fault of theirs, after all, she didn’t choose her eye colour, it was gifted to her by the genes she inherited at birth! An empathetic response to Risiqot’s plight was helped by the masterstroke of public relations in the YouTube video reporting her story; perfectly lit medium to high-density video showed her brilliant blue eyes in contrast with her dark brown skin.

I can’t help wondering if her story would have reached and moved the world if she had a less attractive rare inherited trait. The same video showed Risiqot’s two daughters, both of whom had also inherited the rare trait.

To a geneticist, one who studies why we are the way we are, and why we as humans vary from person to person in the way we do, the discovery of Risiqot and her family is a dream come true.

The study of why she has blue eyes at the level of DNA will allow us to know how exactly it arose, whether it is unique or caused by the same mutation in other blue-eyed people across the world, what the current frequency of the causal gene variant in the population is, and whether it is likely to be associated with other appearance, health, and performance traits.

Such a study will also contribute to the knowledge of the mechanisms underlying human diversity at the molecular/DNA level.

What we know so far suggests that blue eyes in Risiqot and her daughters are the result of a DNA mutation inherited from either her father or mother. Because she claims to know of no history of blue eyes in her family or locale, it seems likely that the mutation responsible for her blue eyes is novel, and this makes her the Index or first case in which the blue-eyed trait was recorded/occurred in the local population.

The fact that she has two children, both of whom have blue eyes suggests that the eye color determinant is dominant, producing blue-eyed in an inheritor irrespective of the contribution by the other parent.

In the absence of a large number of offspring from Risiqot, some of whom are male, it may be difficult to arrive at a more precise definition of the mode of inheritance, including attribution of autosomal or sex-linked mechanisms of inheritance of the gene variant responsible for her blue eyes.

A quicker and more certain approach to deconvoluting the puzzle presented by the sudden appearance of her blue eyes within the family and region, is to derive the sequence of her genome and those of her closest relations and to compare such sequences with a vast array of human genome sequences archived electronically in some of the leading genome archives worldwide.

Such an approach would have been impossible till the turn of the century, and prohibitively expensive until quite recently.

The first human genome sequence took about 13 years to complete, required the activity of 20 institutions across 6 countries and cost $2.7 billion. Today, an entire human genome can be sequenced commercially at a cost of a mere $500.  By the whole genome sequencing approach, the specific mutation responsible for the blue-eyed trait in Risiqot can be identified.

Will it be unique or identical to the mutation in other blue-eyed people across the world? The results will tell. Through studies of the causal basis of unique trait variations in people like Risiqot we are learning that a small handful of mutations can change a black curly-haired, brown-eyed, dark-skinned person to a straight-haired, light hair coloured, light/pale-skinned, blue-eyed person.

We are also learning why particular appearance traits have historical benefit in the environments in which they are mostly found.

The outcome of studies of Risiqot’s genome can point to specific gene mutations that may guide clinical advice to Risiqott on how to preserve and maintain good health in the context of her unique genetics (Personalised Medicine).

Beyond understanding the basis of differences in hair, skin and eye colour, Genetics now offers us the possibility of producing so-called designer babies by selectively switching on or off a small selection of Genes through CRISPR/CAS9 gene-editing technology. Is this ethical?

Currently, the world thinks it is not, which suggests that the technology is ahead of its time. Perhaps in future, the world will be a little more at ease with the application of such technology in producing so-called designer babies.

Ayokunle Afolabi Toye is a specialist in the molecular and cellular functional biology of health, production and disease.

Vanguard

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