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Title: A molecular and genetic approach to an investigation of pyrimethamine resistance in malaria parasites
Author: Culleton, Richard
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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The work presented in this thesis describes the development of, and investigation into a novel genetic method. Linkage Group Selection (LGS), which achieves rapid de novo location of genes encoding selectable phenotypes of malaria parasites. A phenotype-specific selection pressure is applied to the uncloned progeny of a genetic cross between two malaria parasites that differ in the phenotype under investigation. Selected and unselected progeny are analyzed using genome-wide quantitative genetic markers. Markers of the “sensitive” parent, which are reduced after selection, are sequenced and located in genomic databases. They are expected to be closely linked to gene(s) determining the phenotype under selection. The validation of LGS presented in this work was carried out with the rodent malaria parasite Plasmodium chabaudi chabaudi using a phenotype, pyrimethamine resistance, whose controlling gene, that encoding dihydrofolate reductase (dhfr), is known. The results show that molecular markers closely linked to dhfr, and only those linked to this gene, were reduced or removed by pyrimethamine treatment in accordance with the expectations of LGS. In addition, experiments investigating the “fitness cost” of pyrimethamine resistance are described. The recombinant progeny of a cross between drug-sensitive and drug-resistant parasites were grown in infections in mice, and the proportions of the sensitive and resistance alleles of dhfr were measured throughout the infection. It was found that parasites carrying the pyrimethamine resistance mutation at dhfr grew, more slowly than those carrying the sensitive allele, indicating this specific mutation for drug resistance carried a fitness cost to the parasite. This result may have important implications for the design of effective drug policies in malaria endemic areas.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available