Plasmodium falciparum malaria in the Greater Mekong Sub-region: Elucidating parasite migration and genomic signatures of selection

Abstract

Current estimates place over one third of the world's population at risk of contracting malaria, with approximately 300-500 million cases of clinical illness each year. Among these cases it is estimated more than 600k end in death, mostly among children less than 5 years of age in Africa, making malaria one of the leading causes of infectious disease death in the world. There is currently widespread drug resistance in Plasmodium falciparum to most anti-malaria medications, with some areas harboring multidrug resistant parasites, including those resistant to the current first line treatment artemisinin. Single nucleotide polymorphisms (SNPs) were typed from over 2000 field samples by DNA microarray and whole-genome sequencing. Genotypes were used to group parasites into putative subpopulations and bidirectional migration rates between geographic locations were estimated using model-based ADMIXTURE and LAMARC. We detected thirteen subpopulations within Southeast Asian samples including a core of six sub-populations within West Cambodia, the region with the highest prevalence of artemisinin resistance. We find evidence of parasite gene flow across Southeast Asia and between proximal and distant populations. Analysis investigating genes under positive selection using long-haplotype methods (iHS and XP-EHH) as well as population differentiation found multiple shared loci across populations including drug resistance genes, vaccine antigens, and genes possibly involved in local natural adaptation. Our study highlights the complex genetic structure within Southeast Asia and patterns of parasite migration that identify areas most susceptible to the import of resistant parasites, as well as genes under selection that could be future drug targets or vaccine antigens.