I recently finished reading Armand Leroi's Mutants, where I learned about some of the polymorphisms (small changes in DNA sequence) linked to variations in human skin and hair color, particularly red hair. With two different types of redheads in the house, I have always been curious about the genetic basis of this relatively rare trait.
The ancestral form of the MC1R allele produces eumelanin; variant alleles are less functional, decreasing eumelanin production or increasing the amount of yellow/red melanin. Variations in MC1R contribute to a spectrum of phenotypes, including freckling, red hair color, and sun sensitivity. MC1R alleles that disrupt function are present in ~80% of individuals with red hair and ~20% with brown-black hair. More than 80 MC1R allele variations have been identified in European populations. Association studies have shown that certain MC1R variants (p.D84E, p.R151C, p.R160W, p.D294H, p.R142H, and p.I155T) are linked with the red hair color phenotype.
One unanswered question is why these polymorphisms are more prevalent in Eurasians than in Africans. The current hypothesis is that paler skin permits better synthesis of Vitamin D in environments with less sunlight. A recent study using data from the 1000 Genomes Project revealed that the polymorphisms are also more common in Northern Europe than Southern Europe, which supports the Vitamin D hypothesis. Interestingly, a MC1R variant has been observed in Neanderthals, indicating that red hair and pale skin were also present in this population. A recent paper has shown that the Neanderthal MC1R variant is rare in Europeans, but can be found in East Asian populations. This result suggests that mutation of MC1R was a common mechanism to adapt to changes in sunlight intensity.
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Hair and skin color are determined by the relative proportions of the two types of melanin pigment: eumelanin (dark brown) and pheomelanin (red/yellow). Large amounts eumelanin result in darker hair and very little produces blond hair. People with more pheomelanin have red hair. Red hair phenotypes can range from pale red to bright red or reddish brown, which is due to a balance of the two melanin types. Polymorphisms in the melanocortin 1 receptor gene (MC1R) are associated with variations in hair and skin color in mammals. The MC1R protein is a membrane receptor found only in melanin-producing cells (melanocytes). In response to melanocyte-stimulating hormones (MSHs), MC1R initiates a cascade of cellular events that turns on the production of pigment synthesizing genes, including pheomelanin or eumelanin. Essentially, MC1R determines pigmentation by regulating the relative proportion of eumelanin and pheomelanin.
One unanswered question is why these polymorphisms are more prevalent in Eurasians than in Africans. The current hypothesis is that paler skin permits better synthesis of Vitamin D in environments with less sunlight. A recent study using data from the 1000 Genomes Project revealed that the polymorphisms are also more common in Northern Europe than Southern Europe, which supports the Vitamin D hypothesis. Interestingly, a MC1R variant has been observed in Neanderthals, indicating that red hair and pale skin were also present in this population. A recent paper has shown that the Neanderthal MC1R variant is rare in Europeans, but can be found in East Asian populations. This result suggests that mutation of MC1R was a common mechanism to adapt to changes in sunlight intensity.
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| from David Fisher's lab |
Some MC1R variants are associated with an increased risk of melanoma. Due to increased sun sensitivity and freckling of people with pale skin, this relationship seems obvious. However, darkly pigmented Caucasians with certain MC1R variants also show an increased incidence of melanoma. This result suggests that the MC1R pathway may have another role in the development of melanoma beyond differences in the ability to filter UV rays in light and dark skin. In fact, scientists think that MC1R may play a pigment-dependent and a pigment-independent role in skin carcinogenesis. There are a few hypotheses to explain the link between MC1R and melanoma. First, after UV exposure, cells with more pheomelanin show increases in DNA damage, which is correlated with increases in abnormal cell growth and proliferation, a hallmark of cancer. Second, a recent paper in Molecular Cell suggested that UV light triggers the interaction of a tumor suppressor called PTEN with MC1R. The tumor suppressor can interact with wild type MC1R, but not the red hair alleles of MC1R. The PTEN-MC1R interaction protects PTEN from degradation, which suppresses an oncogenic signaling pathway (PI3K/Akt). In contrast, MC1R variants do not interact with PTEN, allowing increased levels of oncogenic signaling pathways after UV irradiation. Unfortunately for redheads, sun exposure alone is not the sole mechanism for skin cancer. A Nature paper from David Fisher’s lab used a red-head mouse model with inactive MC1R to investigate a possible UV-independent pathway. They found that in the presence of the most common melanoma oncoprotein (BRAF 600E), ginger mice developed melanoma without UV exposure, while MC1R wild-type mice did not. Thus, shielding easily freckled skin from the sun may not be enough to protect from skin cancer for people with certain MC1R variants.
The association between red hair and melanoma suggested that there may be a scientific basis for the headline from 2014 that climate change was putting the red hair gene in danger of extinction. The story was exposed as alarmist and scientifically inaccurate. One of the many problems with the article is that they label the red hair gene as recessive. Because hair color is a complex phenotype, it is not surprising that the genetics of red hair are also complex. Red hair is usually inherited in a recessive manner, but it can also be dominant. A 2000 study showed that the inheritance pattern depends on the MC1R allele that is present: most alleles are recessive, but some alleles can be dominant. Individuals that are heterozygous for a mutant MC1R allele show variations in red hair color, beard color, or freckling. Thus, there is a dosage effect of MC1R variants on hair and skin color, which explains why some men have red beards and brown hair. These results also explain how two red-haired parents can (on rare occasions) have children that don't have red hair. Thankfully, the many variations in MC1R and the complex inheritance patterns mean that red hair isn't likely to die out any time soon.
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For more information, I recommend the following links:
Red heads feel pain differently
A blog post from 23andme about the population genetics of red hair.
