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Although more than 160 species of the Plasmodium parasite have been found, only four species infect humans. And these species differ remarkably – not only between species but also within each species.
"Even the species that infect humans have different evolutionary histories," says Professor Karen Day. "Plasmodium falciparum is more closely related to chimpanzee malaria and to bird malaria than to P. vivax, which is more like monkey malaria infecting macaques. Chimpanzee malaria and falciparum diverged about 5-7 million years ago – the same time as the divergence of humans and chimps – so something falciparum-like has been with our hominid ancestors for a long time. How does the falciparum we see today relate to something that has been evolving for possibly 7 million years?"
At the University of Oxford, Professor Day is examining the diversity and evolution of the parasite, research that has been galvanised by the availability of the Plasmodium falciparum genome sequence. "It's a revolution," she says. "We have lots of DNA sequences and information to examine. We can look at the sequences and see which are diverse or conserved, inferring certain things about the evolution of the parasite."
The high levels of diversity seen in some regions of the parasite's genome – in particular the genes producing proteins attacked by the human immune system – could suggest that it is old and has evolved from an ancient common ancestor. Alternatively, regions with little variation suggest that there may have been many lineages existing with our hominid ancestors but at some point there was a bottleneck – where only one line survived – and then subsequent expansion and diversification.
The latter, 'malaria's Eve', hypothesis was first proposed in 1998 by Rich and Ayala, when the falciparum genome was found to lack 'synonymous polymorphisms'. Such DNA variations, which do not lead to changes in the amino-acid sequences of proteins, accumulate by chance over time and are found in abundance in old organisms (the bacteria Escherichia coli, for example).
To test the idea that falciparum might be a relatively young organism, Professor Day and colleagues from Harvard, Professors Dyann Wirth and Dan Hartl, examined the DNA sequences in the introns of 'housekeeping genes' (the non-coding DNA of genes that keep the parasite running, without being involved in infection). "We found polymorphisms in these introns to be rare," says Professor Day, "but lots of polymorphisms in genes under selection".
Their results indicate that the falciparum parasite we see today arose about 3200–7000 years ago: an era that coincides with the dawn of agriculture in Africa. This was a time of massive ecological change, when humans began living in large communities and the rainforest was being cut down for slash-and-burn agriculture. Other findings also support the timeframe for the birth of the modern falciparum: there was also a major change in the mosquito vector at that time, when it began biting humans instead of animals; and a human red blood cell polymorphism that protects against falciparum dates to less than 10 000 years ago. "It all fits together to about 6000 years ago," says Professor Day. "So the diversity we see today has happened in a relatively short period of time. Further sequencing of additional regions of the parasite genome will be required to confirm this view of malaria evolution."
While the lack of diversity in certain regions of the falciparum genome provide clues to the parasite's age, studies of highly diverse regions – microsatellites, which evolve rapidly – show how it has changed over the last few 5–6000 years. "We've looked at the diversity of the parasite in different parts of the world," says Professor Day; "we find a lot of diversity in Africa, some in Thailand and the Pacific, and not much at all in South America".
These findings can be tied – albeit in general terms – to human migrations of thousands of years ago. Humans started migrating out of Africa about 100 000 years ago, moving into Melanesia first about 60 000 years ago and then again about 4000 years ago – falciparum probably travelling with the humans of the second migration. Conversely, the arrival of falciparum in South America is likely to be a very recent event: "It's unlikely that falciparum travelled over the ice bridge from Asia into the Americas about 16 000 years ago; with so little diversity, the South American pattern is more consistent with falciparum going with the slave trade about 500 years ago," explains Professor Day.
Understanding the population structure of the malaria parasite, and how it is genetically distinct in different regions, may open up new avenues to area-specific control measures. "From Ronald Ross's discovery that malaria is transmitted by mosquitoes came the idea that we could control malaria by impacting the life span of the mosquito," says Professor Day. "If we can understand the evolution and diversity of malaria, we may find an Achilles heel in the parasite or new ways to thinking about control."
Page of 3; 2/9/04
[WTD023858] The evolution of malaria parasites.doc