Mysterious Genetic Origins of Blue Eyes in Ancient Humans

Contrary to most reports, Neanderthals did have some variation in genes related to pigmentation. What's more, some of that variation has been inherited by modern humans, and different variants are more or less common in different populations. One gene associated with blue eye color arose 250,000 years ago, give or take 100,000 years. Meanwhile, other genes associated with variation in eye pigmentation arose around 600,000 years ago and 900,000 years ago in the last common ancestor of Neanderthals and modern humans. It is true that many of the DNA variants that make a difference to pigmentation arose recently, and some of those were positively selected. But as it turns out, genes involved in pigmentation have more variants than previously believed, and indeed some of these variants did come into modern human populations from Neanderthals. As we will discuss, these gene variants are found in several places in chromosome 9 and chromosome 15. Considering that our species, Homo sapiens, did not evolve until around 300,000 years ago, the discovery suggests that the genes responsible for lighter pigmentation were present in the genetic material of our hominin ancestors, hundreds of thousands of years before the first modern humans walked the earth. The most interesting observation is that some ancestral light pigmentation genes are shared between early modern humans and archaic hominins such as Neanderthals and Denisovans, which suggests a shared common ancestry for this trait before the split of these three hominin lineages. People of European descent show the greatest variety in eye color of any population worldwide. The evolutionary reason for blue eyes is not understood, but it could have been sexually selected as many people who see blue eyes for the first time find them to be mesmerizing. Blue-eyed black lemurs and spider monkeys are the only two primates other than humans that have true blue eyes, which suggests that blue eyes could have been present in extinct human populations as well. Blue eyes should therefore not be considered a recent or modern trait. Through the analysis of ancient DNA, a study published in the journal Experimental Dermatology suggested that the specific genes for blue eye color likely originated in the Near East 42,000 years ago and arrived in Europe around 20,000 years ago, but different variations of this gene have existed for hundreds of thousands of years. Surprisingly, there is evidence that as many as 16 different genes could be responsible for eye color in modern humans. However, the main two genes associated with eye color variation are OCA2 and HERK2, and both are localized in chromosome 15. A specific mutation within the HERK2 gene, a gene that regulates OCA2 expression, is partly responsible for blue eyes. Other genes implicated in eye color variation are SLC24A4 and TYR. Incredibly, recent tests indicate that both light and dark pigmentation genes at OCA2 and HERK2 have been segregating in the hominin lineage for hundreds of thousands of years. The northernmost Neanderthals in Central Asia and Europe probably had less melanin, resulting in lighter pigmentation, than the ancient people who lived closer to the equator. It stands to reason that lighter pigmentation would be adaptive for them, for the same reason it is in recent people. In fact, it is estimated that light skin only evolved 30,000 years ago, and Neanderthals lived in the cold, dark north for 300,000 years. We also need to remember that Neanderthals did not only live in Europe, they also lived in the Nonetheless, only three Neanderthals have had their complete genomes analyzed, with one of them being from southeastern Europe, one from the Black Sea region, and one from eastern Russia. So far, no western or northern European Neanderthals have had their complete genomes retrieved. But we should not constrain ourselves to associating light-colored eyes, blonde hair, and light pigmentation only with Europeans. For example, many Melanesians often have blonde hair, many South Eurasian populations have green eyes, and lighter pigmentation is found in East Asian and even some African populations such as the Bushmen. Today we know of more than a hundred variants associated with pigmentation variation in living humans. Fewer than ten of these are known for Neanderthals, and this current knowledge may not be representative of the wider picture of Neanderthals. Nonetheless, two Neanderthal introgressed haplotypes involved in pigmentation are today very common in modern human populations, suggesting a history of selection. One of these haplotypes includes the gene OCA2, which is well known to have several variants in living humans and is associated with eye pigmentation. It is most commonly mentioned as a genetic association with blue versus brown eyes. In fact, one haplotype spanning the OCA2 gene that is common today came from Neanderthals. The introgressed haplotype has its highest frequencies, more than 60% in East Asian populations. This haplotype occurs in other populations also, with Melanesian and South Asian population samples around 35% and Europeans around 30%. That percentage is way higher than the 2-3% average Neanderthal genetic ancestry, which suggests that natural selection increased these haplotypes in past populations. According to scientists, this Neanderthal haplotype that spans OCA2 is a great example for how challenging it can be to work out the functional importance of introgressed haplotypes. This haplotype has no coding variants, so if there are functional differences between this haplotype and others, they must involve gene regulation rather than gene structure. The haplotype has dozens of gene variants, but only one had been flagged in previous studies of pigmentation. This one has an association with eye colour and hair colour in European ancestry samples, which is statistically significant, but its effect may be small. Because this gene does not strongly predict eye pigmentation, it is uncertain whether some other linked variant may be the cause of the association with eye colour. According to one often cited report, blue eye colour in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HARC2 gene, inhibiting OCA2 expression. HARC2 is adjacent to OCA2, but even with whole genomes, scientists can't say very precisely what pattern of pigmentation was in ancient populations like the Neanderthals. The simplified explanation for blue eyes is that the OCA2 gene controls pigment in the stroma, the tissue and blood vessels of the iris, the coloured part of the eye around the pupil, and the HARC2 gene is needed to help turn on the OCA2 gene to cause it to produce this pigment, resulting in brown eyes. If a person has a non-functioning OCA2 gene, they will always have blue eyes, because the HARC2 gene can't make the broken OCA2 gene work. Likewise, if a person has a HARC2 gene which doesn't work, the OCA2 gene will underachieve, failing to produce enough pigment to make brown eyes, resulting in blue eyes. In several recent studies, HARC2 was identified for pigmentation traits. The terminal part of the HARC2 gene contains a switch which regulates OCA2 expression. Another region of significantly associated genes encompasses the OCA2 and HARC2 gene on chromosome 15. The gene variant with highest probability of being causal for blue eyes in region 3 of chromosome 15 is RS4932620, which is located very close to HARC2. What's more, RS4932620 is also very close to RS916977, a gene associated with blue eye colour in Europeans. The most recent common ancestor of haplotypes containing the RS4932620 gene variant lived approximately 247,000 years ago, give or take 100,000 years. Meanwhile, another gene associated with pigmentation in region 1 of chromosome 15 dates to around 629,000 years ago, and another gene in region 2 dates to 921,000 years ago. Interestingly, the time period around 250,000 years ago corresponds to a major interbreeding event between Neanderthals and archaic Homo sapiens, where Neanderthals inherited about 10% of the ancient Homo sapiens genome and their X chromosome was replaced. Additionally, the variant RS916977 is part of the HARC2 haplotype on chromosome 15, found in 97% of all Caucasians with blue eyes. Furthermore, this haplotype showed a distribution across 23 European populations, which was significantly correlated to iris colour variation. As a result, researchers suggest that genetic variants regulating expression of the OCA2 gene exist in the HARC2 gene, or, alternatively, within the sequence between OCA2 and HARC2, and that most iris colour variation in Europeans is explained by those two genes. Thus, these data are consistent with the hypothesis of recurrent positive selection acting on multiple variants of OCA2, some of which arose in modern humans, and some that were inherited through hybridization with Neanderthals. Notably, the highest frequency introgressed haplotype encompasses a small region of the OCA2 gene and is found at appreciable frequencies in Europeans, 20%, and Melanesians, 35%. Both of these populations are known for blonde hair and blue eyes. In another study, an introgressed Neanderthal haplotype was found to contain an average of 10.6 differences with Neanderthals, which is a high number. According to the study, the introgressed haplotype does not overlap with variants that have previously been inferred to be targets of positive selection or are most strongly associated with pigmentation traits. However, it does contain a variant of the gene TYRP1, which is associated with blue versus brown eyes in Europeans. Furthermore, DNA analysis has shown that Western hunter-gatherers were blue-eyed. The blue eyes were the result of a variation in their OCA2 gene, which caused iris depigmentation. This mutation for light-coloured eyes most likely arose in the Caucasus region as much as 42,000 years ago. For the genes associated with light eye colour, Western hunter-gatherer groups show high frequencies of the gene which is responsible for the green or blue eyes. This gene was common in the Caucasus region at the time and spread west into Europe. So, the primary genes responsible for blue eyes are called OCA2 and HERK2. The simplified explanation is that the OCA2 gene controls pigment in the stroma, the tissue and blood vessels of the iris, the coloured part of the eye around the pupil, and the HERK2 gene is needed to help turn on the OCA2 gene to cause it to produce this pigment, resulting in brown eyes. If a person has a non-functioning OCA2 gene, they will always have blue eyes, because the HERK2 gene can't make the broken OCA2 gene work. Lastly, whole-genome Neanderthal admixture mapping identified several Neanderthal haplotypes that persist at higher frequencies than can be explained by genetic drift. Strikingly, two studies identified three genes in the small set of putative, adaptively-introgressed genes that play important roles in pigmentation. Although the specific selective pressure underlying the adaptive introgression at these gene location is unknown, it is interesting to note that one of these genes, BNC2, has recently been shown to influence pigmentation levels in Europeans. In another study, researchers discovered the most significant is a region on chromosome 9, where the highest Neanderthal ancestry in ancient individuals is 64%, and in present-day individuals is 67%. This region contains 12 genes, including BNC2, a gene that plays a role in pigmentation that is at 25% frequency in early out-of-Africa humans, and 65% in present-day individuals, indicating that variants may have been immediately beneficial and increased over time in modern humans, unlike previous reports. This solves one genetic mystery, but it also highlights the dangers of assuming that only one gene variant is responsible for eye color, and that it was impossible for ancient humans to have blue eyes. Regarding Neanderthal man, French anthropologist Ludovic Slimac has said that we are the puppet masters of these creatures from the past, which we have pieced together to create a sort of Frankenstein. Indeed, we may have converted the Neanderthal into a lifeless doll, which we have dressed up to fit our own imaginations. And with that tantalizing statement, we leave you to ponder the mysteries of our shared human history. Until next time, stay curious and stay questioning. Please subscribe, share and explore our channel's other videos. Thank you and take care.