Myanmar, the Southeast Asian country with the heaviest malaria burden, has been a historical gateway for the dissemination of drug-resistant malaria to India and the rest of the world. The emergence of artemisinin resistant falciparum malaria in western Cambodia and its subsequent appearance in Vietnam, Laos, China and Myanmar has raised the specter of losing the efficacy of first-line malaria treatments in the region and worldwide and poses a serious threat to renewed hopes for malaria eradication. Averting this grim scenario requires aggressive measures to eliminate malaria in areas where resistance is present and in areas at high risk of acquiring resistance through spreading or de novo mutations, and tools to identify such areas. The previous failed attempt to eradicate malaria in the 1950s and 1960s taught us that ongoing research and evidence-based, locally tailored public health interventions are essential for successful malaria elimination. Tools that can help distinguish locally transmitted versus imported malaria and identify sources and sinks of malaria transmission will also help National Malaria Control Programs target malaria elimination interventions effectively. Using samples collected as part of Project 1 from sites within Myanmar and bordering regions of China and Bangladesh, we propose to identify patterns of malaria parasite population structure and migration to facilitate malaria elimination efforts and track the emergence and spread of drug-resistant parasites. The work will be accomplished in two aims. In the first aim, we will estimate P. falciparum and P. vivax genetic diversity and population structure over time in sites within Myanmar and bordering regions of China and Bangladesh. This will be done by generating whole genome sequence data from both species and estimating genetic diversity, multiplicity of infection, and population structure over multiple years. Using these data, we will identify a minimum set of markers needed to detect population structure and to differentiate parasites from different geographic areas at an increasingly fine scale, and we will develop an assay that can be used in- country to track parasites in time and space. In the second aim, we will use the whole genome sequence data from Aim 1 to estimate parasite migration rates using coalescent-based methods and methods based on shared haplotypes that are identical-by-descent. Molecular markers of antimalarial drug resistance and flanking loci in linkage disequilibrium with drug resistance genes will be called from whole genome sequences to determine the prevalence and origins of drug resistance mutations. Rates of parasite migration will be compared to estimates of human mobility determined in Project 3 and between regions with evidence of spreading drug resistance. If successful, this project will generate actionable evidence about the structure and movement of parasite populations that can be used to guide targeted elimination interventions and deter the spread of drug resistance.
