Evolutionary Adaptation and Antimalarial Resistance in Plasmodium falciparum

The malaria parasite, Plasmodium falciparum, has a demonstrated history of adaptation to antimalarials and host immune pressure. This ability unraveled global eradication programs fifty years ago and seriously threatens renewed efforts today. Despite the magnitude of the global health problem, little is known about the genetic mechanisms by which the parasite evades control efforts. Population genomic methods provide a new way to identify the mutations and genes responsible for drug resistance and other clinically important traits.;In this thesis, I set out to develop and apply novel approaches to studying parasite adaptation in three parts. First, I carry out a global, genomic survey of P. falciparum diversity and perform a genome-wide association study (GWAS) to identify a number of candidate markers of drug resistance. Subsequent validation shows a causal relationship between one of these candidates and parasite drug response.;Second, I further pursue the GWAS approach by sampling a single population more deeply and moving from array-based genotypes to whole-genome sequence data. I demonstrate the deficiences of array-based GWAS in low linkage disequilibrium (LD) populations and argue for a complete transition to sequence-based GWAS for small, low-LD genomes like P. falciparum. I additionally develop the use of a long-haplotype natural selection test to detect associations with adaptive traits.;Finally, I exploit the parasite's short generation time to detect temporal signatures of selection in progress from samples collected over several years. I develop and evaluate new genome-wide statistics for this test and find that it identifies coding variants, often in surface proteins subject to balancing selection. This approach is complementary to existing selection tests and is a timely addition to the genomic toolkit available to malaria eradication efforts.;This research contributes numerous novel approaches to the problem of the rapidly evolving P. falciparum parasite and significantly advances the field's ability to provide the tools and knowledge required for current global eradication campaigns.