Microarray- based alleelic variation scanning of Plasmodium vivax

Scripps Research Institute, The, La Jolla CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The spread of resistance to anti-malarial drugs is a major problem in combating malaria. Plasmodium vivax is the most widespread of the malaria agents, severely impacting human quality of life and economic growth in endemic regions. In Plasmodium falciparum, drug resistance has been associated with specific mutations in resistance genes and gene duplication events. Additionally, patterns of linkage disequilibrium have indicated regions of chromosomes under selection in drug resistant strains. To test the hypothesis that similar genetic differences are responsible for drug resistance in P. vivax, we will use micoarray-based comparative genome hybridization to identify duplicated genomic regions and regions of linkage disequilibrium. Specific aim 1 involves creation and testing of a whole-genome tiling array for detecting genomic differences in P. vivax. In specific aim 2, genomic DNA from Peruvian isolates of P. vivax amplified from collected blood samples of infected individuals will be hybridized to this array to create a high- resolution genetic map of allelic variation in P. vivax. This will establish levels of population genetic variation throughout the entire genome of Peruvian P. vivax strains. Currently there are no known chloroquine resistance genes in P. vivax. Mutations in genes known to influence chloroquine resistance in P. falciparum do not correlate with drug resistance in P. vivax. Therefore, by rapidly scanning the entire genome of resistant strains for variation, and comparison to our population samples, we are likely to discover new drug resistance genes. Comparison of drug-resistant versus drug-sensitive strains will allow variable loci to be correlated with drug-resistance phenotypes. For specific aim 3 we will map genomic duplication events and identify regions of linkage disequilibrium in resistant isolates to identify drug resistance loci. This will lead to the production of genetic tools to examine isolates from different geographical regions to determine the spread of drug resistance. This project aims to identify genes linked to drug resistance in Plasmodium vivax and highly variable parasite antigens. The high-resolution genetic map created through this project will vastly expand the number of variable loci for genotyping P. vivax strains. This knowledge will .provide basic population genetic information and indicate the underlying genetic mechanisms of drug resistance of this devastating parasite. [unreadable] [unreadable] [unreadable]