Two brown-eyed parents can have a child with non-brown eyes due to recessive genetics.
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Peer-reviewed literature notes that eye color is a complex polygenic trait involving multiple genes, moving beyond simple Mendelian inheritance models.
Eye colour and colour perception are excellent examples to use when teaching genetics as they encompass not simply the basic Mendelian genetics of dominant, recessive and X-linked disorders, but also many of the new concepts such as non-allelic diseases, polygenic disease, phenocopies, genome-wide association study (GWAS), founder effects, gene-environment interaction, evolutionary drivers for variations, copy number variation, insertions deletions, methylation and gene inactivation. Beyond genetics, colour perception touches on concepts involving optics, physics, physiology and psychology and can capture the imagination of the population, as we saw with social media trend of "#the dress". Television shows such as Game of Thrones focused attention on the eye colour of characters, as well as their Dire-wolves and Dragons. These themes in popular culture can be leveraged as tools to teach and engage everyone in genetics, which is now a key component in all eye diseases. As the explosion of data from genomics, big data and artificial intelligence transforms medicine, ophthalmologists need to be genetically literate. Genetics is relevant, not just for Inherited Retinal Diseases and congenital abnormalities but also for the leading causes of blindness: age-related macular degeneration, glaucoma, myopia, diabetic retinopathy and cataract. Genetics should be part of the armamentarium of every practicing ophthalmologist. We need to ask every patient about their family history. In the near future, patients will attend eye clinics with genetic results showing they are at high risk of certain eye diseases and ophthalmologists will need to know how to screen, follow and treat these patients.
Colour blindness “Daltonism”, which affects 8% of the male population, is a leading example for teaching X-linked recessive disease (Fig. 1 ). This simple model works well most of the time, with the main blue eye gene OCA2 . We can draw pedigrees showing homozygote blue- and homozygote brown-eyed parents having heterozygote brown-eyed children and then grandchildren who may be homozygote or hererozygote blue- or brown-eyed depending on their other parent (Fig. 2 ). Fig. 1 Basic Mendelian Genetics of Eye Colour and Colour Perception. Upper row: Brown, Hazel/Green, Blue and Albino eyes as seen by most of the tritanopic “normal” population.
Geneticist Victor McKusick stated, “The early view that blue is a simple recessive has been repeatedly shown to be wrong by observation of brown-eyed offspring of two blue-eyed parents” [ 1 ]. This may have inspired his own interest in genetics, as he and his identical twin brother had brown eyes and their parents had blue! We now know that eye colour is actually a complex genetic trait, involving interaction of some major genes and many minor genes. This Mendelian-Complex genetic explanation for eye colour also crosses over into the genetics of many other eye diseases such as age-related macular degeneration and glaucoma.
Light is scattered by particles in the atmosphere (or by the opaque layers in the iris) with blue scattered more than red. Blue iris is an example of a structural colour rather than a pigment colour. Brown irises have the same layer with more melanin and appear brown while complete absence of melanin (Albinism), the iris appears red from the red of the retina. Moving beyond the simple Mendelian model Whilst two parents with blue-green eyes may ponder the genetics of their dark-eyed offspring (Fig. 6 ), the best example of this apparent breach of Mendelian rules was published in 1952 where two parents with oculo-cutaneous albinism had three normally pigmented offspring.
Another clinical example is Leber Congenital Amaurosis, a monogenic disease for which at least 27 different genes are implicated [ 16 ]. If two people with different genetic types of recessive LCA had offspring, then the children would be unaffected carriers (although for two different LCA genes). Fig. 6 Iris photos of a family. Parents above with blue-green eyes have two children below with dark brown eyes. Fig. 7 A multi-step pathway for pigment shows that the production of pigment can be blocked at different steps in its production and distribution to the tissues. One parent may be recessive at the first step, while the other parent may be recessive at the second step.
Thus, for each step, one of the parents does provide a “normal” copy of the gene needed and thus pigment is produced (although it may be reduced in amount). Eye colour in twins, heritability and linkage analysis Research with twins is a powerful tool in determining heritability. Heritability is the proportion of phenotypic variation in a population that is attributable to genetic
LOD or log of the odds is a statistic used in genetic linkage analysis and the usual cut-off when using several hundred markers in a linkage study (similar to a P value of 0.5) was 10 to the power minus 3 or 1/1000. Fig. 8 Iris photos from 4 sets of twins; two sets of identical twins on the left and two sets of non-identical twins on the right. Note the increased similarity of eye colour in the identical twins. A subsequent study looked at this region in more detail using single nucleotide polymorphisms (SNPs) markers in 3839 adolescent twins, their siblings and their parents [ 19 ].
Environmental factors influencing eye colour Eye colour change with age (but this could still be genetic) The twin studies showed that some environmental factors are associated with eye colour [ 18 ]. There is surprisingly little published data on change in eye colour with age. Parents are aware that babies’ eyes can darken in the first years of life. The Newborn Eye Screening Test study in California [ 25 ] enrolled 202 newborns, of whom 148 were followed up (73% of parents responded at the 2-year follow-up). Brown was the most common iris colour (52.0%) and was less likely to change over time compared to non-brown iris colours (brown to brown, 94%, 73/77).