A population genetic analysis of antifolate resistance in Plasmodium falciparum in Southeast Africa

This thesis is a description of the effects of Sulphadoxine/Pyrimethamine (SP) selection on the genome of Plasmodium Jalciparum. Antimalarial resistance in P. Jalciparum to the antifolate combination of SP is conferred by a series of substitutions that alter the active sites of the target enzymes dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS).

Different combinations of substitutions result in differing levels of drug insensitivity as shown by both in vitro studies and association with treatment failure. In southeast Africa, where the samples taken for this study originate, the two most highly resistant dhfr and dhps alleles are the triple mutant (N51I+C59R+Sl08N) and the double mutant (A437G+K540E) ,respectively. A molecular population genetic analytic approach is applied to examine the emergence and spread of SP resistant mutations in Africa. We observe that differences in the frequencies of the resistance alleles between southeast African populations broadly reflect heterogeneity in drug selection history across the region. We find that this exists despite strongly homogenising gene flow.

Selection for a favourable allele can have effects on neutral loci flanking the selected site. A selective sweep occurs when neutral flanking loci hitchhike with the selected allele as it increases in frequency, reducing genetic diversity along the chromosome in the population. The hitchhiking alleles indicate the ancestry of the selected allele and has shown that alleles at dhfr and dhps comprised of multiples of mutations have emerged rarely in east African parasite populations (Roper et al. 2003).

The thesis is the first description of the full extent of the selective sweeps around three dhfr and dhps resistance alleles in southeast Africa. The thesis contains analysis of the changes that occur to a selective sweep over time and in populations with contrasting recombination rates and selection histories. Through use of a deterministic model we identify that gene flow plays an important role in establishing the frequency of the resistance allele at values greater than l/Ne, the frequency of a de novo mutation.