Genome Surveillance for drug resistant malaria

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Plasmodium falciparum, the major causative agent of human malaria, has remained a major health threat in part through the evolution of drug resistant organisms, such that the cheapest antimalarial drugs are no longer effective and resistance is emerging to newer drugs. Genetic diversity in the parasite is likely to be a major determinant for many of the adaptive changes in parasite populations. Understanding the frequency and distribution of polymorphisms in the extant parasite population is essential for the development of genetic mapping tools that can provide a powerful approach to identify genetic loci responsible for important phenotypes such as drug resistance. The human haplotype map (HapMap) project has pioneered the way for systematic, genome-wide scans for the detection of chromosomal regions associated with virtually any kind of complex trait, including the identification of genes likely evolving under positive or balancing selection. As the human HapMap was in its final stages, we began working with collaborators at the Broad Institute to ascertain SNPs (single-nucleotide polymorphisms) across the genome of P. falciparum, using similar intense efforts to monitor and establish high quality data as those employed in the human HapMap. The rationale was to produce community resources that could be used for genetic association studies in P. falciparum, encouraged by the great utility of smaller scale studies by others that identified the genes responsible for chloroquine and pyrimethamine resistance. The SNP discovery phase has recently been completed and a robust genotyping tool has been developed. We are here requesting support to use the SNP database to genotype world-wide isolates of P. falciparum in order to perform a proof-of-principle validation of association studies to identify genetic determinants of drug resistance. This approach represents a confluence of the availability of the P. falciparum genomic sequence, a database of common SNPs (Broad Institute), the availability of 83 isolates of Plasmodium falciparum derived from the world-wide population, the technology for in vitro testing to determine accurate drug sensitivity phenotypes, and the development of inexpensive, accurate technologies for highthroughput SNP genotyping.