Genetic interactions determine hair and skin colour

Y-chromosome DNA markers suggest that the first truly modern human beings emerged from Africa to colonise the planet some 72,000 years ago, at a time of an abrupt climate change due to the Toba supervolcano eruption in Sumatra.

The African emigres almost certainly had dark, highly reflective skin and jet black hair. As they moved northwards into the game-rich temperate grasslands of the central Asian steppes, then into Europe, eastern Asia and the polar north, their dark skin became a liability.

At higher latitudes, the lower angle of the sun, the longer and darker winters and the need to wear warm clothing, would have made them deficient in vitamin D, produced by the action of UV radiation on cholesterol in the skin.

Vitamin D is essential for normal calcium metabolism and immunosurveillance to detect incipient cancers. Chronic deficiency causes rickets, with its symptoms of bone pain, osteoporosis and bowing of the long limb bones.

Professor Rick Sturm, a principal research fellow at the University of Queensland's Institute of Molecular Bioscience and an NHMRC senior research fellow, told the Lorne Genome Conference that natural selection would have favoured mutations that enhanced vitamin D synthesis at lower radiation intensities by reducing production of melanin, the dark pigment that attenuates and reflects UV radiation in sunlight.

Since melanin is also the primary pigment in hair, variations in skin colour went hand-in-hand with lighter hair colours: brown, Celtic auburn and Nordic blond.

Sturm is investigating the inheritance of hair colour in Australians of European descent. He told the conference that Australians of European and British descent exhibit a diversity of lighter hair and skin hues.

Not coincidentally, they also have the highest rates of skin cancer in the world, as a result of their light skin colour and a lifestyle that results in frequent exposure to high levels of UV radiation.

The alleles, which occur as variants of half a dozen genes involved in melanin synthesis, arose as mutations in local populations across Europe some 30-40,000 years ago. They became fixed in various regional populations across Europe, then coalesced and mixed in Australians of European descent.

Sturm is trying to determine how these alleles interact to influence individual hair and skin colour. He has access to a large database on skin characteristics in more than 2000 identical and non-identical twins from south-east Queensland, compiled over the past two decades by skin-cancer researcher Professor Nick Martin, and Professor Adele Green, of the Queensland Institute of Medical Research.

Martin's database links traits such as eye colour, skin pigmentation, skin reflectance, freckling and mole counts, to susceptibility to skin cancers - squamous-cell and basal-cell carcinomas, and melanomas.

"It's a unique resource, and it has been wonderful collaborating with a team that has collected human phenotypes," Sturm said. "The genes that influence hair colour have been identified through a combination of human mutations involved in disease and mouse coat-colour genetics.

"The alleles we are talking about are specific to those of European descent, with some variants occurring in the Asian community. There is very little variation in Africans. We're talking about population-specific changes.

Skin colour does distinguish ethnic groups, against the view of some geneticists that all alleles are present in all populations."

Melanin synthesis

Sturm prefers to talk about the proteins involved in melanin synthesis, rather than the genes. They include:

- Tyrosinase, the catalyst for the first step in melanogenesis

- OCA2 (Oculocutaneous albinism type II), a mutation of which occurs at the pinkeye-dilute coat colour locus in mice, with variant alleles associated with blue eyes in humans

- TRYP1, a tyrosinase-like enzyme, from the mouse brown locus

- OCA4, which causes another form of albinism in mouse

- MC1R, the melanocortin receptor protein

- NCKX5, from the zebra fish golden locus.

Sturm has done most work on MC1R and OCA2. Earlier studies identified nine common variants of MCR1.

"It's most unusual to find that level of polymorphism at a locus and I'm interested in working out what they do. The research literature indicates the MCR1 alleles are strongly associated with red hair."

Sturm says around 25 per cent of the south-east Queensland twin population carry red-hair alleles, or are homozygous, so around five per cent are red-haired.

"MCR1 is a very important pigmentation gene in humans. It turns out that people with red hair have inactive or partially active alleles. Either the melanocortin receptor fails to reach the cell surface, or fails to activate the secondary messenger, cyclic AMP."

Individuals homozygous for the various 'redhead' alleles of MCR1 typically have freckles and do not tan.

"The [OCA2] eye-colour gene is one of those genes we were all introduced to in human genetics - brown-eyed parents like to know how they can have both brown-eyed and blue-eyed children.

"Superficially, it's simple. But whenever the talk is about pigmentation, it's a complex, multigenic trait. OCA2 is the major gene for blue eyes, but we can get different hues of blue, depending on what other alleles it is interacting with - OCA2 accounts for around 74 per cent of the effect.

"OCA4 and NCAX5 turn out to have major population-based differences in allele frequencies. They appear to be major genes associated with skin colour.

"MC1R has nine common alleles, but a single allele of OCA4 dominates across Europe - it has a leucine-phenylalanine change at position 374 in the protein sequence."

Sturm said the ancestral 374-leucine dominates in Africa, but the phenylalanine variant has reached almost fixation, approaching a frequency of 100 per cent in Europeans, with very low or variable frequencies of this allele in Asian populations.

Similarly, the golden gene has an alanine-threonine mutation at position 111 - the mutation dominates in European populations, and is virtually absent in Africa.

The low level of variation within the European haplotypes harbouring the OCA4 and NCKX5 alleles points to strong selection pressure for lighter skin colour - and increased vitamin D synthesis - in European populations around 30,000 years ago.

Sturm now plans to investigate the effect of the various alleles on cellular biology, by comparing gene-expression profiles from cultured melanoma tumour melanocytes and primary melanocytes from normal skin.