Genomic/Genetic Approach To Malaria Parasite Development

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The Malaria Genomic Unit uses the malaria parasite genome databases and develops new resources to study the mechanism of drug resistance, gene regulation during parasite sexual development, and parasite population diversity and dynamics. One project in this direction is the genotyping of Plasmodium falciparum field isolates with hundreds of microsatellite markers to identify chromosome loci associated with drug resistance. A worldwide collection of 90 parasite isolates have been typed with 342 markers and have revealed, in addition to candidate loci for drug resistance, important information on parasite genome structure, diversity, drug selective sweeps, and evolutionary relationships. Another project is the collection of single nucleotide polymorphisms (SNP) from the parasite transporter genes and the association of the SNP to drug responses. Various candidate genes have been identified. We are also developing resources for larger scale studies to include: 1) A genome-wide SNP database with at least one SNP per gene, integrated with MS markers; 2) A worldwide collection of parasite isolates; 3). Statistical and computer programs for association analysis specific for the haploid genome of P. falciparum. About 400 genes on chromoosme 2 and 3 have been sequenced from four parasite isolates and hundreds of SNP have been identified. With these resources, we can concentrate on phenotype evaluation and measurement, including parasite responses to various antimalarials and nutrient changes. These tools will also be used to study parasite population genetics and transmission dynamics in endemic areas. Another research interest of our lab is the study of gene function and gene interactions by expressional analysis using microarray and proteomic methods. We are using these techniques to study protein expression in the parasite food vacuole as well as stages of early sexual development. Various proteins from the food vacuole and stages of gametocyte development have been identified using 2-D gels and mass spectrometry. We have also printed microarray slides using 6300 oligonucleotides derived from the parasite genome and have done some preliminary hybridization experiments. Detailed biochemical and genetic characterization will follow after identification of candidate genes.