WHAT is the greatest force driving human evolution? Some say it is our environment, others argue it might be sex. But intriguing new evidence is pointing to a third, more unexpected player – pathogens. It seems that the bacteria, viruses and other freeloaders that try to make a living in our bodies have fashioned our genome to a greater extent than we ever imagined, and may still be doing so.
By killing off people who have little resistance, pathogens have ensured mutations that protect their owners against infection are preserved in the human genome. But there is a price to pay. Inherited genetic diseases, such as sickle-cell anaemia, thalassaemia and perhaps even cystic fibrosis result when a person inherits a double dose of these otherwise beneficial mutations.
These findings are more than evolutionary curiosities. Studying the molecular structure of disease genes is giving us new insights into our ancestors’ environments. Finding out how extensively pathogens have moulded our genes will be vital if we are to design and test new drugs and vaccines effectively. And they will open up new avenues of attack for fighting diseases such as AIDS and malaria. Some researchers speculate that studying our evolutionary past will help us understand the roots of killers such as heart disease and cancer, although this has yet to be proved.
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We have known for centuries that people can differ remarkably in how they react to infection. But it was not until the late 1940s that the great polymath J. B. S. Haldane came up with an explanation for why some people seem to be naturally more resistant to a particular disease than others. It was his suggestion that first hinted at the possibility that our pathogens could shape our genes.
At the International Congress of Genetics in Stockholm in 1948, American scientists James Neel and William Valentine were puzzling over an inherited form of deadly anaemia called thalassaemia that they had observed in some of the Mediterranean immigrant populations of the US. They were trying to explain the high frequency of the disease in these immigrants and suggested that it might reflect an extremely high mutation rate in the gene or genes involved.
Haldane was unhappy with this suggestion – he thought the proposed mutation rates were too high. He knew that thalassaemia is a “recessive” disorder. This means that a child must inherit two faulty copies of the gene, one from each parent, to develop the condition. People with only one defective copy are symptomless carriers.
Children with thalassaemia cannot make enough haemoglobin, the protein in red blood cells that transports oxygen to the body’s tissues. But Haldane knew that carriers, although symptomless, have smaller red blood cells than “normal” people. He was also aware that malaria, caused by single-celled parasites that attack red blood cells, had been a major killer in the Mediterranean region until the second world war. So he suggested that the small red blood cells might be more resistant to infection by malaria parasites and so protect carriers from the disease. Children who inherited two faulty genes were the unfortunate casualties in an arms race between parasite and human host.
So the concept of “balanced polymorphisms” was born. These are genetic conditions where people carrying a single copy of a defective gene have a survival advantage, such as disease resistance. The frequency of the defective gene increases in the population until balanced by the premature death of people carrying two copies.
Haldane’s idea is elegant and appealing, but finding out whether it holds true for many of our genetic diseases is no easy task. It was only in 1997, after decades of painstaking research that we were able to say for sure that he was right about thalassaemia. And we don’t yet fully understand how it offers protection against malaria. But the lessons we have learned from thalassaemia should help us understand more about how pathogens are driving the evolution of our genes, and what it means for us.
The first clue that Haldane was right came in 1953, when geneticist Anthony Allison showed that carriers of a similar genetic disease, sickle-cell anaemia, were partly protected against malaria infection. More recently, in 1991, Oxford geneticist Adrian Hill showed that sickle-cell carriers enjoy up to 80 per cent protection from severe malaria symptoms.
But while the principle that carriers of a genetic disease might have a survival advantage had been demonstrated for one condition, the mystery surrounding thalassaemia was deepening. In the 1960s and 70s, researchers discovered that the disease was far more widespread than originally thought and is in fact the commonest single-gene disorder affecting humankind. It occurs widely throughout regions of Africa, the Mediterranean, the Middle East, the Indian subcontinent and in many parts of South-east Asia (see Map). But how on earth had it become so widely distributed, where did it originate and did its high frequency reflect an advantage for carriers?
At first, guessing the origin of thalassaemia became a major sport. Some even suggested that it arose in the Mediterranean and was spread eastwards by Alexander the Great’s armies sowing their wild oats. Its relationship with malaria was equally baffling; in some malarious areas there was no thalassaemia, and where the two existed together, it was not always possible to demonstrate any relationship between them. The first major development came in the 1970s, when the new science of molecular biology helped uncover a big surprise: thalassaemia could be caused by not just one or two mutations, but hundreds, all affecting the genes that code for haemoglobin.
Human haemoglobin consists of two different pairs of protein chains, α and β. Researchers found that there are two major forms of thalassaemia, α and β, which result from the defective synthesis of the α or β-globin chains respectively. Remarkably, it turned out that there are well over a hundred different mutations that can cause β-thalassaemia. Even more surprising, populations suffering from a high frequency of the disease each had mutations peculiar to themselves, usually two or three common ones together with many rare forms (see Map). α-thalassaemia is equally varied and even more common; in some parts of the world up to 80 per cent of the population are carriers.
Armed with this new information, our team at the University of Oxford decided to re-examine the question of the relationship between thalassaemia and malaria.
The first clue came in 1986, when Jonathan Flint and Adrian Hill demonstrated a remarkable decline in the frequency of α-thalassaemia across an area from the north coast of Papua New Guinea, where it affects close on 70 per cent of the population, to the Solomon Islands, where the disease is rare. Remarkably, the incidence of malaria almost exactly mirrored that of α-thalassaemia in this region. Of course this could have simply reflected the introduction of α-thalassaemia from the Asian mainland by the founding populations and its gradual dilution as they moved south and east across the region.
To find out more, our team compared the α-globin genes of thalassaemia sufferers in the islands with those on the Asian mainland. The disease-causing mutations in the α-globin genes were entirely different, suggesting that they had arisen independently. Furthermore, the DNA sequences in the regions surrounding the affected α-globin genes were also different in the two populations. This showed that the original mutations had arisen in two different people, confirming that they had happened independently. This strongly suggested that whenever mutations like these arose, there was pressure from natural selection to hang on to them, in spite of their terrible effects when inherited in double dose. The most likely source of that pressure was malaria.
Although this was powerful evidence, it was only in 1997 that we were able to uncover the final piece. Two other members of the Oxford group, Steve and Angela Allen, studied populations in northern Papua New Guinea. They found that the milder forms of α-thalassaemia offer more than 60 per cent protection against the severe complications of malaria. Intriguingly, they also discovered that there was a similar degree of protection against other childhood infections, particularly those of the respiratory tract. This may be telling us that protection against malaria, which in endemic areas causes severe chronic ill-health in children, may improve the quality of their lives in that they are less prone to other infectious killers. This work provides, at last, vindication of Haldane’s ideas about the reasons for the high frequency of thalassaemia in some populations and undoubtedly puts the balanced polymorphism idea on a firm observational footing.
We still don’t understand how thalassaemia protects against malaria. Haldane’s idea that the small red blood cells in this condition offer a miserable environment for malarial parasites is not the answer. But another husband-and-wife team in our group, Tom and Kath Williams, uncovered an interesting clue while studying people in Vanuatu, a group of islands in the south-west Pacific.
In many regions malaria is caused by at least two different parasites: Plasmodium falciparum, which causes the severe form of malaria, and Plasmodium vivax, which results in a much milder condition. Surprisingly, in Vanuatu, infection rates for both types tend to be higher in infants with α-thalassaemia, at a time when they are protected against severe disease by other factors, such as antibodies in their mothers’ breast milk. Infection with P. vivax usually precedes that with P. falciparum, raising the possibility that early immunisation with P. vivax renders them more resistant to the serious complications of P. falciparum in later life, although this remains to be proved.
Thalassaemia and sickle-cell anaemia are the best understood examples of harmful mutations that protect their carriers against disease. But these are just the tip of the iceberg. There is growing evidence that many of our genes and organs have been, and are still being, moulded by our parasites.
Malaria alone is responsible for forcing changes to at least 14 human genes, and the list is growing. Almost every part of the red blood cell has been singled out for alteration. For example, a protein found on the surface of red blood cells, the Duffy blood group antigen, is a vital part of the pathway whereby P. vivax enters the red cell, and is missing from certain African and Papua New Guinean populations. In Melanesia there is a genetic disorder characterised by strange, oval-shaped red cells. It turns out that carriers for this condition, although they are affected by malaria in much the same way as normal people, rarely develop cerebral malaria. And a key red blood cell enzyme, glucose-6-phosphate dehydrogenase, is deficient in millions of people worldwide. The result is that they are prone to severe anaemia after consuming certain drugs or foods, including fava (broad) beans. It turns out that the very high frequency of this condition, termed favism, is also the result of protection against malaria.
Genetic variability in response to malaria extends far beyond the proteins of the red blood cell. For example, a cluster of immune system genes called the human major histocompatibility complex – the most variable region of the human genome analysed to date – appears to have come under strong selective pressure by infectious disease. In parts of Africa, for example, a particular version of one of these genes offers considerable resistance against the severe manifestations of malaria. Other immune system genes have been affected too. Certain white blood cells make a chemical signal called TNF-α, which plays a key role in coordinating the immune response. There is now evidence that variation in the sequence of DNA that controls the activity of the TNF-α gene is related to the severity of symptoms suffered by a malaria patient.
But the malaria story is by no means unique. In recent years researchers have discovered clues that many other infectious diseases have had a hand in fashioning our genome. Various genes have been identified as major players in conferring different degrees of susceptibility to a wide range of bacterial and viral infections, including tuberculosis, leprosy, HIV/AIDS, and hepatitis.
For example, there is a strong association between susceptibility to tuberculosis and variation of the gene for the vitamin D receptor. Vitamin D, best known for its role in building up strong bones, is also involved in marshalling immune responses.
Another association is between resistance to HIV and a variant form of a cell-surface protein called chemokine receptor 5, one of the molecules HIV uses to get into immune cells. People carrying two copies of the variant gene have almost complete protection against HIV infection. Other genetic variants have also been found to interfere with HIV infection or the speed with which it progresses to AIDS.
The catalogue of genetic variability promoted by malaria and other diseases is growing by the month. Many of these gene mutations are apparently harmless in double dose, which is why no one has discovered them before. But thanks to the increasing application of genome-searching technology, the discoveries are likely to continue unabated. So what is all this new information really telling us?
Studying the global distribution of conditions such as thalassaemia can give us useful insights into human history. For example, malaria may have begun to plague humanity only relatively recently, as analysis of the thalassaemia mutations indicates they first arose some 5000 years ago. This coincides with the beginning of agriculture, when conditions for the dissemination of the parasite would have been more favourable.
Similar studies can tell us something about ancient migration patterns too. The absence of thalassaemia and sickle-cell anaemia in the native populations of South America may reflect the fact that malaria was not established on the Asian mainland at the time when humans crossed the Bering Straits to populate the Americas. And John Clegg and his team at the Institute for Molecular Medicine in Oxford made a surprising discovery while trying to find out why some Polynesian islanders carry α-thalassaemia mutations, despite the fact that malaria has never been encountered there. The team found that the forms of thalassaemia in these regions are identical to those that occur in the Vanuatuan Islands and quite different to those of the Asian mainland populations. Thus it appears that the settlers of these islands had originated from the Vanuatuan region and left α-thalassaemia mutations like visiting cards as they populated different islands in their travels.
History aside, findings like these are vitally important for biomedical research. When malaria vaccines are developed it will be essential to know which members of the population in which the vaccine is being tested have a very high degree of innate resistance to the parasite. But even more tantalisingly, a better understanding of the protective mechanisms involved in innate genetic resistance to infection may offer valuable clues to developing new treatments – why not try to utilise approaches based on these remarkable experiments of nature?
Clearly therefore, our genetic make-up has been moulded extensively in our long struggle against infective agents, and must still be changing. Diseases such as sickle-cell anaemia and thalassaemia are the scars we bear for our evolutionary progress. But apart from genetic diseases, are there any other downsides to the changes in our genes that have resulted from our long exposure to infection? Is it possible that these changes might be deleterious in the completely new environments that we have created for ourselves? The answer will only become apparent as we explore the genetic basis for our varying susceptibility to the wide range of environmental agents that appear to be responsible for the common killers in developed countries, such as diabetes, obesity and heart disease.
Recently, some researchers have attempted to interpret many, if not all, human diseases in evolutionary terms, and the new field of “evolutionary medicine” has appeared. Its proponents would have it that everything from morning sickness to some forms of cancer and psychiatric disease can be viewed as evolutionary adaptations. This is highly speculative and based on little or no evidence at present. Nevertheless, the evidence from studies of infectious disease leaves little doubt that viewing disease from its evolutionary aspect promises extremely valuable insights into both the cause and distribution of many of our current killers.