The origin of malaria: mixed messages from genetic diversity

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Abstract
The past 35 years have seen an upsurge in the prevalence of malaria, caused by a number of mutually reinforcing factors, including the spread of drug-resistant Plasmodium falciparum parasites and insecticide-resistant mosquitoes, increased population density, global warming and poverty in affected countries. There is evidence to indicate that a similar rapid expansion of the P. falciparum population took place about 10,000 years ago. Understanding the population history of P. falciparum is important for determining the most effective ways to combat the present malaria epidemic, as the level of genetic diversity present in the parasite genome has important implications for the evolution of parasite resistance to drugs. Studies of the levels of synonymous polymorphism in P. falciparum protein-coding sequences generally support an expansion of the parasite population 10,000 years ago. However, differences in the sets of genes analysed, and errors in some sequence database entries, have led to discrepancies in the conclusions that have been drawn from these studies. Analysis of non-coding parasite sequences should provide a more accurate picture of levels of genetic variation, as they are subject to a lower levels of selective constraints than are coding sequences. However, high levels of mutation in microsatellite sequences have led to difficulties in interpreting the results of such studies, as have discrepancies in the results obtained for different genomic regions, which are likely to result from the effects of recombination. Mitochondrial DNA has been used to clarify the results obtained using other methods, as it is not subject to recombination. Analysis of the P. falciparum mitochondrial genome generally supports the theory that the parasite population expanded rapidly 10,000 years ago. Altogether, these studies indicate that the level of genetic variation is much lower in P. falciparum than in many other microorganisms. This has important implications for strategies to combat malaria, as it suggests that the parasite is likely to require new mutations to occur in order to develop resistance to drugs, a theory that is borne out by the fact that resistance to chloroquine has been slow to evolve.