Malaria as diverse as us?

Gene screen suggests one drug won't beat parasite.
18 July 2002

TOM CLARKE

The malaria parasite: we go back a long way. © SPL

The parasite that causes malaria is much older and more genetically diverse than some researchers had thought, a new analysis has revealed. The discovery could mean that it will be difficult to make drugs and vaccines to combat the disease worldwide³.

Each year malaria kills up to 2.7 million people and makes over 200 million sick. Many scientists had suspected that the Plasmodium falciparum parasite that causes the disease is as diverse as the humans that it infects.

But four years ago Francisco Ayala of the University of California, Irvine, suggested that the majority of parasites died out 3,000-5,000 years ago, leaving just a small population¹. This seed population, being genetically quite homogenous, would, he reasoned, be poorly equipped to develop resistance to drugs or vaccines.

Dubbed the 'Malaria's Eve' hypothesis, this appealing but controversial idea raised hopes that a vaccine or drug developed against P. falciparum from Thailand, say, would stand a good chance of working against one from Africa.

The latest analysis "lays that idea to rest", says Austin Hughes, who works on the molecular biology of evolution of the University of South Carolina in Columbia. Carried out by Xin-zhuan Su, of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and colleagues, it is the largest survey of a section the P. falciparum genome carried out so far.

Su's team concludes that malaria parasites have been evolving separately for between 100,000 and 180,000 years. "This is around the time when the human population exploded," says Su. As humans began to migrate around the globe, it looks like the malaria parasite went with them.

Site specific

The researchers scanned the third chromosome of P. falciparum from five continents. They looked for one-letter differences in the DNA code known as single-nucleotide polymorphisms, or SNPs². These are a measure of the number of random mutations that an organism has undergone, and therefore how closely related it is to others of the same species.

Previous studies, Su suggests, may not have sampled a sufficiently diverse array of malaria parasites from around the globe.

Ayala is not convinced. "The analysis has major flaws," he says, arguing that the genome sites chosen for study are too unstable to estimate the age of a population. "They leave the issue of Malaria's Eve completely open," he concludes.

Others are more sanguine. These flaws are real, concedes Andrew Clark, a population geneticist at Cornell University in Ithaca, New York. Nevertheless, he says, Su's study "is far larger than its predecessors, and provides strong evidence that P. falciparum is diverse enough to raise a greater challenge for publc-health measures."

What is clear is that the argument must be settled soon. Having a good idea of the genetic background of P. falciparum "could tell us something about how to design strategies to combat the disease", says malaria geneticist Karen Day of the University of Oxford, UK. If malaria proves to be more recalcitrant than drug designers had thought, they need to know sooner rather than later.

In a simultaneous study, Su's team scanned the entire parasite genome for a gene known to cause resistance to chloroquine - a common anti-malaria drug. It was thought that chloroquine resistance evolved twice, once in South America and once in Southeast Asia. Su's team conclude that it must have evolved separately in at least four places: South East Asia, Papua New Guinea and twice in South America. In addition, they find that once chloroquine resistance evolved in South East Asia it spread to Africa in a matter of decades.

Chloroquine resistance is still rare, but the new finding lends weight to the argument that P. falciparum is worryingly adaptable.

1. Rich, S. M., Licht, M. C., Hudson, R. R. & Ayala, F. J. Malaria's Eve: evidence of a recent population bottleneck throughout the world populations of Plasmodium falciparum. Proc. Natl Acad. Sci. USA, 95, 4425 - 4430, (1998).
2. Mu, J. et al. Chromosome-wide SNPs reveal an ancient origin for Plasmodium falciparum. Nature, 418, 323 - 326, (2002).
3. Wootton, J. C. et al. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature, 418, 320 - 322, (2002).