Matt Ridley

the latter being the most susceptible type. It is a world of strangely fluctuating fortunes. The very combination that is most beneficial in your generation guarantees you some susceptible children.

D I S E A S E 1 4 1

Now imagine what happens if everybody in one town is A A , but a newcomer arrives who is B B . If she can fend off the cholera long enough to breed, she will have AB children, who will be resistant.

In other words, the advantage will always lie with the rare version of the gene, so neither version can become extinct because if it becomes rare, it comes back into fashion. This is known, in the trade, as frequency-dependent selection, and it seems to be one of the commonest reasons that we are all so genetically diverse.

This explains the balance between A and B. But if O blood makes you more susceptible to cholera, then why has natural selection not driven the O mutation extinct? The answer probably lies with a different disease, malaria. People with type O blood seem to be slightly more resistant to malaria than people of other blood groups.

They also seem to be slightly less likely to get cancers of various kinds. This enhanced survival was probably enough to keep the O

version of the gene from disappearing, despite its association with susceptibility to cholera. A rough balance was struck between the three variations on the blood group gene.

The link between disease and mutations was first noticed in the late 1940s by an Oxford graduate student with a Kenyan background, Anthony Allison. He suspected that the frequency of a disease called sickle-cell anaemia in Africa might be connected with the prevalence of malaria. The sickle-cell mutation, which causes blood cells to collapse in the absence of oxygen, is frequently fatal to those with two copies of it, but only mildly harmful to those with just one copy. But those with one copy are largely resistant to malaria. Allison tested the blood of Africans living in malarial areas and found that those with the mutation were far less likely to have the malaria parasite as well. The sickle-cell mutation is especially common in parts of west Africa where malaria has long been endemic, and is common also in African-Americans, some of whose ancestors came from west Africa in the slave ships. Sickle-cell disease is a high price paid today for malaria resistance in the past. Other forms of anaemia, such as the thalassaemia common in various parts of the Mediterranean and south-east Asia, appear to have a similar protective effect 1 4 2 G E N O M E

against malaria, accounting for its presence in regions once infested with the disease.

The haemoglobin gene, where the sickle-cell mutation occurs as just a single-letter change, is not alone in this respect. According to one scientist, it is the tip of an iceberg of genetic resistance to malaria. Up to twelve different genes may vary in their ability to confer resistance to malaria. Nor is malaria alone. At least two genes vary in their ability to confer resistance to tuberculosis, including the gene for the vitamin D receptor, which is also associated with a variability in susceptibility to osteoporosis. 'Naturally', writes Adrian Hill of Oxford University,4 'We can't resist suggesting that natural selection for TB resistance in the recent past may have increased the prevalence of susceptibility genes for osteoporosis.'

Meanwhile, a newly discovered but similar connection links the genetic disease cystic fibrosis with the infectious disease typhoid.

The version of the C F T R gene on chromosome 7 that causes cystic fibrosis — a dangerous disease of the lungs and intestines — protects the body against typhoid, an intestinal disease caused by a Salmonella bacterium. People with just one such version do not get cystic fibrosis, but they are almost immune to the debilitating dysentery and fever caused by typhoid. Typhoid needs the usual version of the C F T R gene to get into the cells it infects; the altered version, missing three D N A letters, is no good to it. By killing those with other versions of the gene, typhoid put natural pressure on the altered version to spread. But because people inheriting two copies of the altered version were lucky to survive at all, the gene could never be very common. Once again, a rare and nasty version of a gene was maintained by disease.5

Approximately one in five people are genetically unable to release the water-soluble form of the A B O blood group proteins into their saliva and other body fluids. These 'non-secretors' are more likely to suffer from various forms of disease, including meningitis, yeast infection and recurrent urinary tract infection. But they are less likely to suffer from influenza or respiratory syncitial virus. Wherever you D I S E A S E 143

look, the reasons behind genetic variability seem to have something to do with infectious disease.6

We have barely scratched the surface of this subject. As they scourged our ancestors, the great epidemic diseases of the past -

plague, measles, smallpox, typhus, influenza, syphilis, typhoid, chicken pox, and others - left behind their imprint on our genes.

Mutations which granted resistance thrived, but that resistance often came at a price, the price varying from severe (sickle-cell anaemia) to theoretical (the inability to receive transfusions of the wrong type of blood).

Indeed, until recently, doctors were in the habit of underestimating the importance of infectious disease. Many diseases that are generally thought to be due to environmental conditions, occupation, diet or pure chance are now beginning to be recognised as the side-effects of chronic infections with little known viruses or bacteria. The most spectacular case is stomach ulcers. Several drug companies grew rich on new drugs intended to fight the symptoms of ulcers, when all that were needed all along were antibiotics. Ulcers are caused by Helicobacter pylori, a bacterium usually acquired in childhood, rather than by rich food, anxiety or misfortune. Likewise, there are strong suggestive links between heart disease and infection with chlamydia or herpes virus, between various forms of arthritis and various viruses, even between depression or schizophrenia and a rare brain virus called Borna disease virus that usually infects horses and cats.

Some of these correlations may prove misleading and in other cases the disease may attract the microbe rather than the other way round.

But it is a proven fact that people vary in their genetic resistance to things like heart disease. Perhaps these genetic variants, too, relate to resistance to infection.7

In a sense the genome is a written record of our pathological past, a medical scripture for each people and race. The prevalence of O blood groups in native Americans may reflect the fact that cholera and other forms of diarrhoea, which are diseases associated with crowded and insanitary conditions, never established themselves in the newly populated continents of the western hemisphere 1 4 4 G E N O M E

before relatively modern times. But then cholera was a rare disease probably confined to the Ganges delta before the 1830s, when it suddenly spread to Europe, the Americas and Africa. We need a better explanation of the puzzling prevalence of the O version of the gene in native Americans, especially given the fact that the blood of ancient pre-Columbian mummies from North America seems quite often to be of the A or B type. It is almost as if the A and B genes were rapidly driven extinct by a different selection pressure unique to the western hemisphere. There are hints that the cause might be syphilis, a disease that seems to be indigenous to the Americas (this is still hotly disputed in medical-history circles, but the fact remains that syphilitic lesions are known in North American