MAPPING DRUG RESISTANCE GENES IN PLASMODIUM FALCIPARUM

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The malaria parasite, Plasmodium falciparum, has developed resistance to most of the major classes of antimalarial drugs currently in use, which severly hampers our ability to control this disease. Knowledge of the genetic basis of resistance would provide insights into mode of action of antimalarial drugs, as well as providing a basis for development of novel compounds and redesign of existing drugs. We propose to exploit the dense microsatellite map and the emerging genome sequence data frm P. falciparum together with recent advances in statistical genetics to locate genes underlying drug resistance. Our approach will involve both phenotypic and genotypic characterization of field collected parasites. We will measure in vitro susceptibility to 4 important antimalarial compounds-mefloquine, quinine, artemisinin and chloroquine in malaria parasites obtained from a site on the Thai-Burmese border. We will then genotype these parasites for 200 microsatellite markers distributed at 5-10 cM intervals across the parasite genome. To locate genomic regions containing quantitative trait loci for drug resistance we will use two-stage strategy. First we will use variance component linkage methods in which we use genetic marker data to infer kinship relationships between parasites. We will then fine-scale map regions of the genome containing quantitative trait loci for drug resistance, by inspecting linkage disequilibrium between marker loci and genes underlying resistance. Candidate genes will be identified using sequence data emerging from the malaria genome project.