With the imminent arrival of a next-generation sequencing capability at the University of Birmingham (sequences 100x faster and cheaper than before), many new previously undreamt of research opportunities are opening up. I spent last Friday morning rushing around editing, printing and delivering a proposal for a medical school studentship with the head of cancer studies to use deep sequencing to follow the evolution of a cancer gene in chronic lymphocytic leukaemia. Such deep sequencing in cancer, whether of single genes or whole cancers, is now all the rage.
What has cancer got to do with evolution? Well, lots! In recent years, it has become clear that Darwin’s theory of evolution by natural selection applies at the cellular level, with natural selection clearly driving the evolution of cancer cells. In a cellular struggle for existence, cancer cells compete for space and resources, evade predation by the immune system and evolve to disperse and colonise new organs. In addition, cancer cells evolve in response to treatment, often becoming resistant to anti-cancer drugs. Here are a couple of recent references:
Merlo LM, et al. (2006) Cancer as an evolutionary and ecological process. Nat Rev Cancer. 6(12):924-35.
Goymer P. (2008) Natural selection: The evolution of cancer. Nature. 454(7208):1046-8.
And our view of cancer grows ever more sophisticated. Although for many years, it has been accepted that cancer is usually a clonal phenomenon, i.e. any given cancer arises from a single cell, it is now clear that the cancer cell population in fact represents a diverse and dynamic cellular ecosystem, with many sub-clones bearing adaptive (driver) mutations and neutral (passenger) mutations emerging, persisting and/or undergoing extinction
And as proof that roaming the blogosphere can take you places you don't usually stumble upon in the peer-reviewed literature, I recently came across these two blog postings, which discuss the terrifying idea of transmissible cancers:
Fortunately, evolutionary theory does not just provide us with better explanations of cancer, but also provides new cures--a few months ago, I heard Cambridge molecular biologist Greg Winter describe how he had used a Darwinian approach to select for modified antibodies active against cancer.
On Friday my attention was drawn to this short film on the advantages and disadvantages of being ginger, made by Helen Cooper (one of my colleagues at the University of Birmingham) and Nick Rutter.
My reactions to the film are mixed. It certainly kept one’s attention and was entertaining throughout. I worry that in re-hashing prejudices against redheads, it might help fuel them—but in that case English comedian Katherine Tate could be held guilty of the same crime:
The film certainly stimulated my interest in the question “why ginger hair?” And in broad terms the science seems OK, pointing out a paradox (why do the ginger genes survive in the face of social stigma and an increased susceptibility to skin cancer) and sketching out three kinds of potential evolutionary explanation: sexual selection, genetic drift and natural selection. The film leaves out any detailed consideration of the other kind of answer to the “why ginger hair question?”, i.e. a mechanistic genetic explanation of the phenomenon—but one can only go so far in a six-minute film!
In fact, the explanation has been clear for over a decade. Ginger or red hair appears in people who have two copies of a recessive gene that encodes a mutant form of the melanocortin 1 receptor (MC1R) protein, a protein which regulates the production of various forms of the skin and hair pigment melanin. Over sixty different mutations that affect the function of MC1R can cause variously grades of red-ginger hair, usually accompanied by pale skin, freckles and a tendency for skin to burn rather than tan after exposure to sunlight—for an excellent introduction to the genetics of MC1R, see the relevant article from OMIM (Online Mendelian Inheritance in Man). Interestingly, a study published in May this year showed that red-headedness is what geneticists call the null phenotype in human, i.e. is what you get when you have no functioning MC1R at all.
The ginger complexion is very rare in humans, found in less than 1% of the world population. It is common in the North West of Europe, with the highest rates in Scotland and Ireland. As a result of Scots and Irish migration to the New World, the largest number of ginger-haired people occurs in North America; there are also many in Australia. A few years ago, during a trip to the Northern-Irish city of Derry/Londonderry, I visited a million-pound high-tech exhibition called “The Fifth Province” which is housed within the city’s Calgach centre. The exhibition focuses on the Irish Diaspora and features a series of Irish, North American and Australian ginger-haired freckled children as proof of a common Irish heritage. In fact, in Irish step dancing competitions, according to a friend from Northern Ireland, marks are awarded for how “Irish” girls look and the ginger complexion is considered so authentically Irish that girls often wear ginger-haired wigs.
Curiously, in Jamaica, native-born white people are usually termed “red men” by the rest of the population— a fact brought home to me earlier in year when Karen Nelson, a Jamaican-American expert on bacterial genomes, was introduced via e-mail and photo to my collaborator on the Origin of Species in Dub, Jamaican geneticist Dominic White (who has a Northern-Irish mother and Jamaican father). Her first comment was how “red” he looked!
But even more curiously, in Jamaica there are people from the self-identified black community, who have reddish hair, freckles, and a rusty complexion (they are sometimes called “red Ibos”). A study from the University of the West Indies has confirmed that this complexion is linked to mutations in MC1R.
Let’s now examine the claims in the film in more detail.
First of all, the idea that the genes for ginger hair and the ginger phenotype are destined to die out soon appears to be an urban myth/persistent meme that has little or no basis in reality. This topic has been explored repeatedly in the blogosphere:
Working through the film’s explanations for ginger hair in reverse order…
What about the claim that ginger hair and pale skin provide a selective advantage by facilitating the synthesis of vitamin D in the skin? The idea that the pale skins seen in Europeans are the result of selection for increased vitamin D production (a process driven by UV radiation from the sun and masked by melanin) has been around for several decades, but is still the subject of some controversy. However, I can find no evidence in the scientific literature that specifically links increased vitamin D production to the ginger-haired phenotype rather than simply to European-style pale skin in general.
In addition, there is no evidence from molecular genetic studies to suggest that natural selection has been acting on the MC1R mutations associated with red-headedness. In fact, the opposite appears to be the case: in Africa at least natural selection seems to be acting to preserve the original dark-skinned dark-haired version of the gene. However, as an interesting aside, Darwin reported in The Descent of Man a claim that redheads were the best suited of all Europeans to working in an African environment!!
The second explanation discussed in the film, a relaxation in the selective pressure to maintain the original genotype in high latitudes, appears to be most likely according to genetic studies. In other words, what is not forbidden by natural selection is allowed.
What of the first explanation: sexual selection? As pointed out in the film, this was the explanation favoured by Darwin in the Descent of Man for differences in human skin colour and in this context has recently been re-visited in a review article by Aoki (which I have not been able to obtain: can anyone e-mail me a PDF?). The folk wisdom is that redheadedness is attractive in a woman, but unattractive in a man. But I can find no papers that attempt to document or quantify the attractiveness of ginger hair colour or that describe any mathematical model that would explain current gene frequencies through an interplay between the negative effects of natural selection and female-specific positive effects of sexual selection Perhaps, someone out there can start a collaboration between psychologists, geneticists and mathematical modellers that would deliver the ultimate truth on this tricky question!
And before closing, let me throw in two final pertinent points.
Firstly, ancient DNA studies on Neanderthals have shown that provided evidence that at least some Neanderthals had MC1R mutations that although not seen in modern humans, probably resulted in red hair.
Secondly, our close relatives the orangutans have ginger-red hair, provoking the two “why” questions:
Why in genetic terms? These apes have been shown to have a functional MC1R, suggesting that the mechanism of red hair generation in orangs is different from the prevalent mechanism in European human populations. One hopes that the orang genome sequence will soon deliver the answer.
Why in evolutionary terms? Sexual selection again? Or genetic drift? But as they live in the Tropics, one might argue that the selection would favour a darker complexion?
Clearly, the evolution and genetics of red hair will keep scientists busy for a few more years yet!
