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Title: The origin, genetics and dispersal of drug-resistant Plasmodium falciparum in Kenya
Author: Mwangi, Jonathan Maina
ISNI:       0000 0001 3438 4899
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2006
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Three sets of molecular markes were used to investigate the population genetics of three populations of Plasmodium falciparum from Kenya; Mwea (low transmission), Tiwi (moderate transmission) and Bondo (high transmission). One set of markers codes for polymorphic antigens while the other two are microsatellite markers; one set located in non coding regions of the genome while the other set is located in the regions flanking two genes whose products are targets of the antimalarial drug sulphadoxine/pyrimethamine (SP). A comparison of the effectiveness of antigen-coding and the unlinked microsatellite loci in differentiating recrudescence from reinfection revealed that both sets of markers are equally effective. The microsatellite loci however, revealed more alleles per population than the antigen-coding loci possibly due to their different mutation rates. An analysis of the three populations using the neutral microsatellite loci revealed high levels of diversity, lack of linkage disequilibrium and virtually no population substructuring (FST < 0.008) in the Kenyan P. falciparum populations even with the geographical areas being as much as 800 km apart. This indicates a lot of gene flow among these populations a factor that can only be explained by movement of people between the areas studied. An analysis of the same samples from the three areas at the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) gene loci that code for targets of the antimalarial drug SP revealed high prevalence of the multiply substituted alleles associated with SP resistance in the three regions. An analysis of ~17 kb regions flanking both sides dhfr reveal a strong selective sweep of the 108N/51I/59R triple mutation alleles associated with pyrimethamine resistance. The work presented also demonstrates that alleles of the dhfr gene, especially the triple mutant allele, isolated from the three different areas are closely related to one another and probably share a common and very recent ancestor. Most notable is the finding that dhfr triple mutants seem to be imported into the country through immigration from elsewhere. An equivalent region flanking the dhps gene also revealed a strong selective sweep of the 437G/540E double mutation allele associated with sulphadoxine resistance in two of the three sites. However, double mutation dhps alleles from Mwea revealed no selection at all. While the three populations reveal no geographic substructuring using the results of the unlinked microsatellite loci, they seem to be highly structured in their drug resistance patterns. While it would be expected that these populations would have the same prevalence of drug resistance mutations (due to the apparent panmixia), the Mwea population appears quite different in regard to selection for drug resistance-associted alleles. This is possibly due to the diet, other drug interactions or the hosts' genetics in this area. A simplistic model on the rate of spread of drug resistance in the three populations reveals that the selection for drug resistance alleles is faster in the lower transmission area of Mwea (selection coefficient, s = 0.26) and slowest in Bondo (s = 0.10) indicating selection for drug resistant alleles is favoured by low transmission. These observations have implications for malaria drug resistance surveillance programs due to the fact that if treatment failure spreads faster in low transmission areas where almost all the population has low immunity, malaria epidemics are bound to occur resulting in huge morbidity and mortality.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QR Microbiology