Plasmodium falciparum

Malaria has been a affliction of humans throughout historical times, and despite the past century of research and our ever-increasing understanding of the parasite's biology, it remains an elusive target of strategies aimed to intervene in its transmission. Many of these efforts have been thwarted, and it is clear that future successes are contingent upon understanding the broad adaptive-potentiality as manifest in the genomic variation comprising the material basis of evolution. In my view, it is imperative that we look to the pastæwhich is chronicled in the genomic information of the parasites to understand the future potential that the parasite may acquire.

Population structure and evolution of Plasmodium falciparum

Until quite recently, a common view of falciparum-malaria was that it comprises an ancient lineage of parasites, with some antigenic variants dating back 35 million years ago. However, my colleagues and I have demonstrated that among the global populations of P. falciparum there is an extraordinary paucity of synonymous nucleotide polymorphism (i.e. those sites that ARE NOT involved in amino acid change), suggesting that the current, global distribution has a much more recent origin. The discrepancy is due to the earlier inferences drawn from the observation of extensive differentiation of P. falciparum populations at nonsynonymous nucleotide sites (i.e. those sites that ARE involved in amino acid change) particularly in antigenic loci. Strong selection for immune invasion causes rapid rates of evolution among nonsynonymous sites, while the synonymous sites are effectively neutral and therefore evolve in a more "clock-like" fashion. These clock-like sites provide much more reliable estimates of species age. Our conclusions (1998) were originally met with no small degree of debate, however several groups have now independently confirmed our results (as recently highlighted in two articles in Science; 21 June 2001 and 20 July 2001).

Based on the current best estimates of all available data, it appears that all extant P. falciparum parasites have arisen from a very small propagule, or population bottleneck, dating back no more than 8,000 years. At first, the extensive polymorphism evident among the protein sequences comprising important drug and vaccine targets seems paradoxical to this conclusion. However, we have demonstrated that much of this variation is due to extremely rapid mutational processes resembling those of mini- and microsatellite loci. Therefore, the extensive differentiation in these encoded proteins accumulates in short time periods. Our ongoing research interests are to determine the true molecular basis of these mutations and to estimate the rates at which they occur. At the center of this work, we study the genes encoding proteins that have been put forth as candidates for vaccine development. It is obvious that the long-term efficacy of these vaccines will depend on the mutability of their targets.

In addition to identifying mutational mechanisms and quantifying their rates, we seek to determine the role that meiotic recombinationæas associated with the sexual phase of the parasiteæplays in generating new alleles and distributing existing variants among individuals in populations. Recent work suggests that the extent sexual recombination varies among sites as function of certain site-specific epidemiological factors. In short, parasites appear to be randomly mating at some endemic sites, while other sites manifest little or no sexual recombination whatsoever. Despite the differences in mating strategies, all of these parasite populations appear to maintain high levels of phenotypic variability, suggesting that sex is not a necessary component for parasite success.