Human eye color

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(CC) Image: Laitr Keiows
Image of a human eye.

Eye color is a polygenic phenotypic character, determined mainly by the amount and type of pigments in the eye's iris.[1][2] Humans and other animals have many phenotypic variations in eye color, as blue, brown, gray, green and others.

Many different genes are involved in determining eye color; they include EYCL1 (a green/blue eye-color gene on chromosome 19), EYCL2 (a brown eye-color gene) and EYCL3 (a brown/blue eye-color gene on chromosome 15). The old view that blue eye color is a simple recessive trait is wrong.

Human eyes differ in color mainly because of different ratios of eumelanin produced by melanocytes in the iris.[2] The brightly colored eyes of many birds are largely determined by other pigments, such as pteridines, purines, and carotenoids.[3]

Three main elements within the iris contribute to its color: the melanin content of the iris pigment epithelium, the melanin content within the iris stroma, and the cellular density of the stroma.[4] In eyes of all colors, the iris pigment epithelium contains the black pigment, eumelanin.[2][4] Color variations among different irides are typically attributed to the melanin content within the iris stroma. The density of cells within the stroma affects how much light is absorbed by the underlying pigment epithelium.[4] OCA2 gene polymorphism, close to proximal 5′ regulatory region, explains most human eye-color variation.[5]

Genes for eye color

In humans, the most common eye color is brown, and the least common is green. Eye color is an inherited trait influenced by more than one gene.[6][7] Individuals differ in eye color mainly because of very slight differences in the genes that determine eye color; these genetic differences in individual genes are single nucleotide polymorphisms (SNP)s. The number of genes that contribute to eye color is currently unknown, but it is possible to predict the color of eyes with more than 90% accuracy for brown and blue, using just six SNPs (from six genes). [8]

One variant of the gene OCA2 causes the pink eye color and hypopigmentation common in human albinism. (The name of the gene is derived from the disorder it causes, oculocutaneous albinism type II.) Different SNPs within OCA2 are strongly associated with blue and green eyes as well as variations in freckling, mole counts, hair and skin tone. The polymorphisms may be in an OCA2 regulatory sequence, where they may influence the expression of the gene product, which in turn affects pigmentation.[5] A specific mutation within the HERC2 gene, a gene that regulates OCA2 expression, is partly responsible for blue eyes.[9] Other genes implicated in eye color variation are: SLC24A4 [10] and TYR.[10]

Blue eyes with a brown spot, green eyes and gray eyes are caused by an entirely different part of the genome. The SNP rs12913832 [of the Herc2 gene] is associated with the brown and blue eye color, but this single variation does not explain all the brown eye color variation.

Classification of color

Iris color can provide a large amount of information about an individual, and a classification of various colors may be useful in documenting pathological changes or determining how a person may respond to various ocular pharmaceuticals.[11] Various classification systems have ranged from a basic light or dark description to detailed gradings employing photographic standards for comparison.[11] Others have attempted to set objective standards of color comparison.[12]

Eye colors range from dark brown to light blue.[6] Seddon et al. developed a graded system based on the predominant iris color and the amount of brown or yellow pigment present.[13] Three pigment colors (brown, yellow, and blue) determine the appearance of the iris: . Green irides, for example, have blue and some yellow. Eye color in animals other than Homo sapiens is differently regulated. For example, autosomal recessive eye color in the skink species: Corucia zebrata is black, and the autosomal dominant color is yellow-green.[14]

Changes in eye color throughout life

Children are usually born with unpigmented eyes. As they develop, melanocytes within the iris slowly begin to produce melanin. Because melanocytes continually produce pigment, eye color can change. Most changes happen when the infant is about one year old, but it can happen up to three years of age. Observing the iris of an infant from the side using only transmitted light with no reflection from the back of the iris, it is possible to detect the presence or absence of low levels of melanin. An iris that appears blue by this method is more likely to remain blue as the infant ages. An iris that appears golden contains some melanin, and is likely to turn green or brown with age.

Lightening or darkening of eye color can occur during puberty, early childhood, pregnancy, and sometimes after serious trauma (like heterochromia).

Studies on twins have shown that eye color can change over time, and major demelanization of the iris may also be genetically determined. Most changes have been observed or reported in the Caucasian population with hazel eyes.[15]

Amber

Amber eyes are of a solid color and have a strong yellowish/golden and russet/coppery tint. This might be due to the yellow pigment called lipochrome in the iris (which is also found in green eyes). Amber eyes should not be confused with hazel eyes; hazel eyes usually comprise many other colors, including green, brown and orange and consist of flecks and ripples, while amber eyes are of a solid gold hue.

The eyes of some pigeons contain yellow fluorescing pigments known as pteridines.[16] The bright yellow eyes of the Great Horned Owl are thought to be due to the presence of the pteridine pigment xanthopterin within certain chromatophores (called xanthophores) in the iris stroma.[17] In humans, yellowish specks or patches are thought to be due to the pigment lipofuscin, also known as lipochrome.[18] In dogs, domestic cats, owls, eagles, pigeons and fish, amber eyes are common, whereas in humans this color occurs less frequently, more in places like Brazil and Asia.

Blue

Blue eyes contain low amounts of melanin within the iris stroma; longer wavelengths of light tend to be absorbed by the underlying iris pigment epithelium, and shorter wavelengths are reflected and undergo Rayleigh scattering.[4] The type of melanin present is eumelanin.[19] The inheritance pattern followed by blue eyes is considered similar to that of a recessive trait (in general, eye color inheritance is considered a polygenic trait, meaning that it is controlled by the interactions of several genes, not just one).[7] In 2008, new research revealed that people with blue eyes have a single common ancestor. Scientists tracked down a genetic mutation that leads to blue eyes. "Originally, we all had brown eyes," said Hans Eiberg from the University of Copenhagen.[20] Eiberg and colleagues showed in a study published in Human Genetics that a mutation in the 86th intron of the HERC2 gene, which is hypothesized to interact with the OCA2 gene promoter, reduced expression of OCA2 with subsequent reduction in melanin production.[21] The authors concluded that the mutation may have arisen in a single individual in the Near East or around the Black Sea region 6,000–10,000 years ago during the Neolithic revolution.[20][21][22] Eiberg stated, "A genetic mutation affecting the OCA2 gene in our chromosomes resulted in the creation of a 'switch,' which literally 'turned off' the ability to produce brown eyes."

"The genetic switch is located in the gene adjacent to OCA2 and rather than completely turning off the gene, the switch limits its action, which reduces the production of melanin in the iris. In effect, the turned-down switch diluted brown eyes to blue. If the OCA2 gene had been completely shut down, our hair, eyes and skin would be melanin-less, a condition known as albinism".[20]

Blue eyes are most common in Northern and Central Europe.[23] They are also found in parts of North Africa,[24] West Asia, and South Asia,[25] in particular the northern areas of India, largely Kashmir. Pakistan and Iran also have a considerable population of blue-eyed people.

A 2002 study found that the prevalence of blue eyes among Caucasians in the U.S.A. to be 33.8 percent for those born between 1936 and 1951 compared with 57.4 percent for those born between 1899 and 1905.[7] Blue eyes have become increasingly rare among American children, with only one out of every six or 16.6%, which is 49.8 million out of 300 million (22.4% of white Americans) of the total U.S. population with blue eyes.[26][27] The plunge in the past few decades has taken place at a remarkable rate. A century ago, 80 percent of people married within their ethnic group. Blue eyes were routinely passed down, especially among people of Western and Northern European ancestry.[26][27][28]

The outer surface of the iris of a blue-eyed person is clear, lacking the outer layer of pigmentation that is found in brown eyes. Their color is caused by the inner layer of pigmentation and the semi-opaque fibrous tissues that lie between the two layers.[29]

Brown

Brown eyes are dominant in humans[30] and, in many parts of the world, it is nearly the only eye color. It is least common in countries around the Baltic Sea and in Scandinavia. Brown eyes contain large amounts of melanin within the iris stroma, which absorbs light at both short and long wavelengths.

Gray

Gray eyes are most common in Northern and Eastern Europe. Under magnification, gray eyes exhibit small amounts of yellow and brown color in the iris. There are at least two things that determine gray eye color. The first is the amount of melanin made, and the second is the density of the proteins in the stroma. [31]

A gray iris can indicate the presence of an uveitis, but other visual signs make a uveitis obvious. People with gray eyes, like those with blue eyes, are at increased risk of uveal melanoma.[32]

Green

Green eyes are the product of low to moderate amounts of melanin and probably represent the interaction of multiple variants of OCA2 and other genes. Green eyes are most common in Northern and Central Europe. In Iceland, 89% of women and 87% of men have either blue or green eyes.[33] A study of Icelandic and Dutch adults found green eyes to be much more prevalent in women than in men. Among European Americans, green eyes are most common among those of Celtic and Germanic ancestry, about 16%.[34]

Hazel

Hazel eyes are due to a combination of Rayleigh scattering and a moderate amount of melanin in the iris's anterior border layer.[4][18] They often appear to shift in color from a light brown to a golden-green. Hazel mostly consists of brown and green. The dominant color in the eye can either be green or light brown/gold. This is how many people mistake hazel eyes to be amber and vice versa.[35][36][37] This can sometimes produce a multicolored iris, i.e., an eye that is light brown/amber near the pupil and charcoal or dark green on the outer part of the iris (and vice versa) when observed in sunlight.

Red

The eyes of people with severe forms of albinism may appear red under certain lighting conditions owing to the extremely low quantities of melanin,[38] allowing the blood vessels to show through. In addition, flash photography can sometimes cause a "red-eye effect", in which the very bright light from a flash reflects off the back of the eyeball, which is abundantly vascular, causing the pupil to appear red in the photograph.

Medical implications

Those with lighter iris color have been found to have a higher prevalence of age-related macular degeneration (ARMD) than those with darker iris color; lighter eye color is also associated with an increased risk of ARMD progression.[39] An increased risk of uveal melanoma has been found in those with blue, green or gray iris color.[32][33] However, a study in 2000 suggests that people with dark brown eyes are at increased risk of developing cataracts and therefore should protect their eyes from direct exposure to sunlight.[40]

Eye color may also be symptomatic of disease. Aside from the iris, yellowing of the whites of the eyes is associated with jaundice and symptomatic of liver disease, including cirrhosis, hepatitis and malaria. Yellowing of the whites of the eyes in people with darker pigmented skin is often due to melanin being present in the whites of the eyes. However, any sudden changes in the color of the whites of the eyes should be addressed by a medical professional.

Wilson's disease

Wilson's disease involves a mutation of the gene coding for the enzyme ATPase7B, which prevents copper from entering the Golgi apparatus in cells. Instead, the copper accumulates in the liver and in other tissues, including the iris . This results in dark Kayser-Fleischer rings, which encircle the iris. [41]

Anomalous conditions

Aniridia

Aniridia is a congenital condition characterized by an extremely underdeveloped iris, which appears absent on superficial examination.

Ocular albinism and eye color

Normally, there is a thick layer of melanin on the back of the iris. Even people with the lightest blue eyes, with no melanin on the front of the iris at all, have dark brown coloration on the back of it, to prevent light from scattering around inside the eye. In those with milder forms of albinism, the irides are typically blue but can vary from blue to brown. In severe forms of albinism, there is no pigment on the back of the iris, and light from inside the eye can pass through the iris to the front. In these cases, the only color seen is the red from the hemoglobin of the blood in the capillaries of the iris. Such albinos have pink eyes, as do albino rabbits, mice, or any other animal with a total lack of melanin. Transillumination defects can almost always be observed during an eye examination due to lack of iridial pigmentation. The ocular albino also lacks normal amounts of melanin in the retina, which allows more light than normal to reflect off the retina and out of the eye. Because of this, the pupillary reflex is much stronger in the albino, and this can increase the red eye effect in photographs.

Heterochromia

Heterochromia (also known as a heterochromia iridis or heterochromia iridium) is an ocular condition in which one iris is a different color from the other iris (complete heterochromia), or where the part of one iris is a different color from the remainder (partial heterochromia or sectoral heterochromia). It is a result of the relative excess or lack of pigment within an iris or part of an iris, which may be inherited or acquired by disease or injury.[42] This uncommon condition usually results due to uneven melanin content. A number of causes are responsible, including genetic causes, such as chimerism, Horners Syndrome and Waardenburg syndrome.

A chimera can have two different colored eyes just like any two siblings can—because each cell has different eye color genes. A mosaic can have two different colored eyes if the DNA difference happens to be in an eye color gene.

There are many other possible reasons for having two different colored eyes. For example, David Bowie different eye colors due to an injury that caused one pupil to be permanently dilated. Another idea about how this can happen is if an early viral infection while in the womb turns an eye color gene on or off in just one eye. Occasionally it can be a sign of a serious disease.

A common cause in females with heterochromia is X-inactivation, such as in calico cats. Trauma and certain medications can also cause increased pigmentation in one eye.[43] On occasion, the condition of having two different-colored eyes is caused by blood staining the iris after an injury.

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