Selected to survive. Many people in Southeast Asia--including the Karen--have a mutation that offers some protection against Plasmodium vivax.


Asian Mutation Protects Against Malaria

A mutation common in Southeast Asia that causes anemia also provides some protection against malaria, according to a new study. The mutation doesn't shield carriers from the best-known and most severe cause of the disease, but from a more benign parasite that has been studied far less.

Scientists already know that humans' long battle with malaria has shaped our genome. One-third of sub-Saharan Africans, for example, carry a mutation that causes sickle cell anemia but that also protects against malaria: The deformed red blood cells prevent the malaria parasite from entering. Researchers have identified other mutations as well, but almost all protect against Plasmodium falciparum, a parasite transmitted by Anopheles mosquitoes that kills more than a million people annually.

In the current study, geneticist Anavaj Sakuntabhai of the Pasteur Institute in Paris and colleagues examined a mutation in the gene-encoding glucose-6-phosphate dehydrogenase (G6PD), an enzyme that helps protect cells from damage by oxidizing molecules. Mutations in G6PD can cause jaundice in newborns, anemia after infection with certain pathogens, and other problems. Some of these mutations are very common in certain areas, including parts of Asia and Africa. So researchers have long suspected that they must have an upside as well--perhaps protection against malaria, given that G6PD is important in red blood cells. But studies on P. falciparum in Africa have not found a solid link.

Sakuntabhai's group instead turned its attention to Thailand, where P. falciparum and its lesser-known cousin, P. vivax, cause malaria. The team zoomed in on one G6PD mutation dubbed Mahidol--after the father of the current king of Thailand, a famed physician and public health advocate--which occurs throughout Southeast Asia and is most common in Myanmar. Sakuntabhai and colleagues first undertook a genetic study among 384 people--most of them belonging to an ethnic group called the Karen--in Thailand's Suan Phung district, where malaria is prevalent. The frequency of the Mahidol mutation was 24%, and using a so-called long-range haplotype test--a technique that helps sniff out recent natural selection in the genome--the team found that natural selection has indeed strongly favored the mutation, starting about 1500 years ago. Scientists think that malaria spread along with human agriculture, which creates small pools of stagnant water that mosquitoes like. As it happens, researchers think the Karen moved out of Tibet and started rice farming some 1500 years ago, says Sakuntabhai.

In clinical studies, the team showed that the Mahidol mutation actually makes a difference. Over a 7-year period, people with the mutation had about the same number of episodes of malaria as noncarriers, the authors report in today's issue of Science, but the mutation did decrease the number of P. vivax parasites in their blood. Women who had one copy of the gene had 30% fewer parasites; those with two copies had 61% fewer. Because G6PD is on the X chromosome, men can have one copy at most; those who did had 40% fewer parasites than did controls. "The parasite isn't happy at all; it can't grow as well," says Sakuntabhai. But Mahidol had no effect on P. falciparum numbers.

P. vivax "is usually dismissed as an insignificant player" that didn't shape the human genome like P. falciparum did, says Richard Carter, a malaria geneticist at the University of Edinburgh in the United Kingdom. The new study shows that's probably wrong. P. vivax isn't a fast killer like P. falciparum, and today most people can buy drugs to treat it. But in the past, people may have suffered from repeated and long bouts with P. vivax, Carter says, which "would slowly grind them down." The reductions in parasite density seen in Mahidol carriers may have lengthened carriers' lives considerably and allowed them to have more children.

Sakuntabhai adds that even today, P. vivax may be a bigger health problem than people assume. A study published last year in PloS Medicine showed that P. vivax killed children in Papua New Guinea, and as-yet unpublished work by another group that Sakuntabhai has seen shows that the parasite can cause anemia more than a month after the infection is over. "The bottom line is, we shouldn't underestimate P. vivax," he says--"and we should study it more."