SANDRA LAING has brown skin and curly black hair. Her appearance is typical of the coloured people of South Africa, descendants of European settlers, Malay slaves and local peoples such as the Khoikhoi. What’s unusual is that Laing’s parents were “white” Afrikaaners, as were her grandparents and great-grandparents. That she turned out to resemble a more distant ancestor should have been a mere curiosity – except that Laing had the misfortune to be born in apartheid South Africa back in 1955.
People like Laing, whose story is being turned into a film, illustrate the complexity of the genes that determine our skin, hair and eye colour. Her case, like those of twins where one has light skin and the other dark, has attracted much media attention. But they come as no surprise to geneticists.
“When you look at people of different pigmentation who have had children, it’s quite clear there are discrete categories. One parent is fair, one is dark, but the children are not all in the middle,” says Greg Barsh, a pigmentation geneticist at Stanford University School of Medicine in Palo Alto, California. “What that indicates is that while there are not one or two genes, there are not 10 or 20. There are probably 5 to 10 genes.” We are now rapidly uncovering these genes – and the findings are throwing up some surprises about how skin colours evolved.
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For many of those involved in the work, simply understanding the basis of colour differences is worthwhile in itself. “So much world history is ascribed to ‘These people look different from me’,” says Barsh. “I see providing answers as something that will remove some of the mystique and prejudice.”
Meanwhile, law enforcement agencies hope for more practical benefits: they want to be able to generate a description of a person from a DNA sample found at a crime scene. Perhaps the most intriguing prospect is that as we work out exactly out what determines our colour, we may be able to develop ways to tweak it that are far more effective than anything that exists today.
The key to our colour is a dark pigment called melanin. The more melanin there is in skin cells, hair or the iris of the eye, the darker they are. It sounds simple, but there’s more to it. For starters, melanin is not a single substance – its basic building blocks join to form various complicated chains. Rather than floating free within cells, these molecules are made inside little granules called melanosomes, whose size, number and distribution in the cells can vary. What’s more, the melanosomes are not even made in the skin cells and hair they end up in; instead, specialised cells called melanocytes produce the melanosomes and dole them out to other cells via tentacle-like extrusions. How dark a person looks depends on variations in each step in the triggering, making, packing and distribution of melanin.
Sometimes one of these steps breaks down completely, causing abnormalities such as albinism. Studies of pigmentation disorders in animals and people have led to the discovery of more than 120 associated genes. Yet only a few gene variants have been found that contribute to the differences in normal human skin colour, and one of the most important was stumbled across only recently.
“He had stumbled on a key gene for skin colour”
Keith Cheng, a cancer researcher at Pennsylvania State University in Hershey, was working with golden zebrafish, a strain whose stripes are paler than the typical black. This mutant was first found in an Oregon pet shop in the 1970s. Curious about its lighter colour, Cheng’s team took a closer look and found that its skin cells have fewer, smaller and less dense melanosomes – just like those of lighter-skinned people.
As part of his work, Cheng needed to identify the mutation responsible for the fish’s golden colour. It turned out to involve a gene now called SLC24A5, which codes for an ion-exchange protein that probably sits in the membrane of melanosomes.
Cheng’s colleague Mark Shriver then suggested looking for variations in the human version, SLC24A5, in sequences collected as part of the International HapMap, a project to chart genetic variation in humans. The team found two variants, one of which was present in everybody of European descent.
To prove these variants affect skin colour, the researchers looked at which were present in people of mixed African and European descent. They found that those with one copy of the “golden variant” tend to have much paler skin. If both copies of the gene have the golden mutation, the skin is lighter still. They concluded that the golden variant is responsible for between 25 and 38 per cent of the difference in skin colour between Africans and Europeans. Cheng had stumbled upon one of the key genes determining skin colour (Science, vol 310, p 1782).
“One of the questions I get asked is, ‘Does this mutation alone make you white?'” Cheng says. “The answer is no.” That is, you can have light skin without the golden variant: Japanese and Chinese people have the same form of this gene as the Yoruba of Nigeria. You can also have dark skin with the golden variant: up to three-quarters of Sri Lankans have the golden mutation, recent studies have shown.
Clearly there is far more to skin colour than SLC24A5. A variation in a gene called MATP (also known as SLC45A2, which probably makes another melanosomal transport protein, also contributes to the light skin of Europeans. And variations in the gene for tyrosinase, the enzyme that produces the building blocks of melanin, may also play a role, according to a genetic survey published in December by a team including Shriver (Molecular Biology and Evolution, DOI: 10.1093/molbev/msl203).
To the researchers’ surprise, their findings show that the light skins of east Asians and Europeans evolved separately: the dark forms of SLC24A5 and MATP are the ancestral forms, and only after modern humans migrated out of Africa did SLC24A5 mutate in one individual, giving rise to the golden variant. The MATP variant appeared in a separate individual, either earlier or later. Both variants spread rapidly among the ancestors of modern Europeans.
“We expect there will be other genes that will fit the bill for east Asians,” says lead author Heather Norton of the University of Arizona in Tucson. While the study identified variants in two pigment genes that are common in Asian populations, it is still unclear if these variants affect skin colour.
It could turn out that every distinct human population has unique skin-colour gene variants, but there are also some that we all share. In two genes that influence skin colour, Norton found variants that were common to all the groups her team looked at, suggesting these arose before modern humans dispersed.
So why did different populations evolve different skin tones? The leading theory, proposed by Nina Jablonski, also at Penn State, is that our colour reflects a balance between conflicting needs. Not only can sunlight damage our skin, it also breaks down folic acid (also known as folate), an essential B vitamin. On the other hand, we need ultraviolet light to make vitamin D.
Jablonski and colleagues have shown that skin colour around the planet correlates more closely with winter UV levels than with summer levels (New Scientist, 12 October 2002, p 34). This suggests that our skin colour has evolved to optimise folic acid and vitamin D levels during winter, with tanning allowing us to adapt to higher UV levels in summer.
If the folic acid hypothesis is correct, the diet of our ancestors was as important as UV levels in influencing colour. It has been suggested that early European farmers ate little vitamin D, making very light skin an advantage, whereas peoples like the Inuit got so much vitamin D from their fish-rich diet that they have retained relatively dark skin despite living in the far north.
There are other possibilities. Mutations that make skin lighter could simply have persisted in regions where this feature is not a disadvantage. However, the fact that the same variants spread among almost all Europeans shows there was strong selection for them. And while sexual selection could have played a role in this most visible of characteristics, the latest evidence fits well with Jablonski’s ideas. “Natural selection should leave a stronger signature, and that’s what we see,” says Shriver.
Indeed, while most researchers had assumed that light skin evolved only once, Jablonski predicted that similar skin colours evolved separately in different populations as modern humans dispersed into regions with different UV levels. “I am now eager to see genetic evidence that darkly pigmented skin evolved more than once: for instance, in the ancestors of modern equatorial Africans, southern Indians and Sri Lankans, and indigenous Austronesians,” she says.
Despite the rapid progress, there is much left to discover. “There are some major parts of the world where we don’t know what to expect,” Shriver says. Only a few groups in Africa have been studied, for instance, despite the large variation in skin pigmentation across the continent.
What we do know, though, could soon be put to use. Murray Brilliant of the University of Arizona College of Medicine in Tucson has shown that variations in just six genes accounted for 50 to 80 per cent of the differences in eye, skin and hair colour among 800 individuals he studied. Those genes included SLC24A5 and MATP. The work was funded by the US National Institute of Justice, which is interested in building up a picture of suspects when DNA samples draw a blank against police databases.
In fact, a cruder form of DNA testing is already being used for this purpose. DNAPrint Genomics of Sarasota, Florida, sells police forces a test that reveals people’s ancestral origins, thus giving some idea of what a suspect might look like. The company says its test has been used in around 150 cases in the US and UK. Looking directly at the gene variants that affect appearance will be more accurate, however, and DNAPrint has already developed such a test for predicting eye colour. Brilliant’s work could lead to tests for skin and hair colour as well.
For others, the goal is to change skin colour by manipulating melanin levels. There is a huge market for products that claim to do this. “People generally do it for cosmetic purposes alone,” Cheng says. Others wish to treat dark or light patches, from age spots to more serious pigmentation disorders.
Most existing products leave a lot to be desired. Take skin lighteners. Hydroquinone, long the key ingredient in many of these creams, was thought to work by inhibiting tyrosinase, the enzyme that helps make melanin. Now it seems that it works by killing melanocytes and may be carcinogenic, leading many countries to ban it.
What’s more, most products are not very effective. “It’s very difficult to distinguish treated skin versus untreated skin,” says Genji Imokawa of the Tokyo University of Technology in Japan, who worked on skin products for 35 years at Kao Corporation. You can measure the difference, he says, but it’s not easy to see just by looking. The exception is monobenzylether of hydroquinone, which completely and permanently depigments the skin, apparently by destroying melanocytes. It’s drastic, but can give people with severe pigmentation disorders an even skin tone.
Darkening the skin is also tricky. Most attempts to boost melanin levels have focused on synthetic versions of MSH, the hormone that causes tanning after sun exposure (New Scientist, 7 May 2005, p 40). The trouble is, such products may do least for those who need them most – fair-skinned people who tan poorly have mutations in the receptor for MSH, called MC1R. Hence the interest in forskolin, a compound recently found to activate a later step in the tanning pathway. It darkens the skin of mice even if they have mutations in the MC1R gene (Nature, vol 443, p 340).
While efforts to develop conventional drugs continue, genetic discoveries could lead to a whole new approach based on RNA interference – using small bits of RNA to switch off specific genes. The trick will be getting these “siRNAs” into the melanocytes. “The skin is a formidable barrier,” says David Fisher of Harvard University. But if it can be done, RNA interference could open the way to the creation of lotions that gradually produce dramatic changes in skin colour and would only need to be applied once a week or less.
Already, cosmetics company Avon has filed a patent for lightening skin by using siRNAs to switch off the tyrosinase gene (patent number WO2005060536). The patent says the method has been tested on isolated mouse melanocytes and outlines ways of delivering siRNAs to melanocytes in situ. Avon would not discuss details with New Scientist but says that the research is continuing.
If this kind of approach proves successful, our skin colour might one day become almost as easy to change as hair colour is today, freeing us from the constraints of our genes.
It would, after all, make a lot of sense to adjust our skin colour to suit the local climate. And being able to choose our colour would make life far harder for those who still insist on judging people on the basis of a handful of gene variants.
The eyes have it
The textbooks are wrong. Eye colour is often described as a single-gene trait, with brown eyes dominating over blue, but there is more to it than that.
Brown irises have more melanin and absorb most of the light that hits them. When there’s less melanin, it can scatter light, creating a blue colour. Green and hazel eyes are usually a mixture of blue and brown.
The main gene involved, called OCA2, appears to affect melanin production by altering the pH of cells in the iris, but it is now clear that other, as yet unidentified genes also play a role. For instance, Richard Sturm of the University of Queensland in Brisbane, Australia, has shown that variations in the OCA2 gene can explain only 74 per cent of the differences in human eye colour. So blue-eyed parents can have a brown-eyed child – there’s no need to blame the postman.
Eye colour is alterable – the latest glaucoma drugs have the unexpected side effect of darkening the iris, especially in those with hazel eyes. The drugs can also lengthen and darken eyelashes, sparking hopes that similar drugs could help reverse baldness.
Keeping grey at bay
Hair colour depends on the pigment-producing melanocytes in the base of hair follicles, which dole out melanin to the cells whose corpses make up each hair strand. As you would expect, blonde hair contains less melanin than light brown or black hair.
Red hair is due to various mutations in a gene called MC1R. Their effect is to block production of black-brown melanin – the most common form. Redheads produce only a red-yellow type.
The particular gene variants that make our hair black, brown or blonde remain elusive, but we do at least have a better handle on a most vexing aspect of hair colour – its tendency to go away. David Fisher’s team at Harvard Medical School has recently shown that melanocyte stem cells near the top of the hair follicle disappear just before a hair turns white. This means the mature melanocytes at the base of the follicle are not replaced when the hair falls out and a new one begins to form (Science, vol 307, p 720).
Greyness could be reversible. In fact, an existing cancer drug seems to occasionally restore pigmentation, and more reliable, safer methods are on the horizon. For instance, AntiCancer of San Diego, California, has developed ways of delivering drugs or genes to hair follicles in fatty sacs. The payload could include genes that restore melanin production, says company president Robert Hoffman. The problem is getting high enough gene expression in all the cells, he says, to avoid producing streaky, partially pigmented hair.
Once we fully understand the genetics, it might be possible to use siRNAs (see below) to alter the colour of growing hairs. The effects of a single treatment could last for weeks, making dark roots a thing of the past for those who prefer it blonde. The first siRNA hair treatment likely to go on sale, though, will neither change nor preserve colour. Sirna Therapeutics of San Francisco is developing an siRNA method for long-lasting hair removal.
