Whole Genome Sequencing of Field Isolates Reveals Extensive Genetic Diversity in Plasmodium vivax from Colombia

Abstract

Plasmodium vivax is the most prevalent malarial species in South America and exerts a substantial burden on the populations it affects. The control and eventual elimination of P. vivax are global health priorities. Genomic research contributes to this objective by improving our understanding of the biology of P. vivax and through the development of new genetic markers that can be used to monitor efforts to reduce malaria transmission. Here we analyze whole-genome data from eight field samples from a region in Cordóba, Colombia where malaria is endemic. We find considerable genetic diversity within this population, a result that contrasts with earlier studies suggesting that P. vivax had limited diversity in the Americas. We also identify a selective sweep around a substitution known to confer resistance to sulphadoxine-pyrimethamine (SP). This is the first observation of a selective sweep for SP resistance in this species. These results indicate that P. vivax has been exposed to SP pressure even when the drug is not in use as a first line treatment for patients afflicted by this parasite. We identify multiple non-synonymous substitutions in three other genes known to be involved with drug resistance in Plasmodium species. Finally, we found extensive microsatellite polymorphisms. Using this information we developed 18 polymorphic and easy to score microsatellite loci that can be used in epidemiological investigations in South America.

Genomic variation in Plasmodium vivax malaria reveals regions under selective pressure

“…There was little difference across the chromosomes with mean 11.1x10 -4 (range 6.0 x 10 −4 to 19.0x10 -4 ), which is consistent with other studies with similar sample size [14] as well as larger datasets when restricted to high quality SNPs (1.5x10 -3 ) [6, 7]. LD decays rapidly for non-rare polymorphism (minor allele frequency ≥ 5%) within a few hundred base pairs, and reaches a baseline within 500bp in South American and Thai nuclear genomes ( Fig 1C ).…”

Molecular variation of Plasmodium vivax dehydrofolate reductase in Mexico and Nicaragua contrasts with that occurring in South America

“…A dhfr gene fragment comprising codons 16 -198 Information concerning Pvdhfr gene polymorphism was obtained from French Guiana, 35 Colombia, [28][29][30][31][32] Peru, 28 Brazil, 28,33,34 Honduras 44 and Mexico 28 (tables I-III). In those previous studies, P. vivax-infected blood samples were collected between 2001 and 2013.…”

“…47 On the other hand, those observations contrast with records from previous studies carried out in South America. Mutations at pvdhfr conferring pyrimethamine resistance, such as those found in residues 58R/N and 117N and haplotypes having both substitutions, have been very frequently detected in Colombia, [28][29][30][31][32] Peru, 28 French Guiana 35 and Brazil. 28,33,34 However, the distribution of parasites carrying other important mutations varies among regions of the same country.…”

“…26,27 In South America, Pvdhfr mutations at codons S58R and I117N were reported. [28][29][30][31][32][33][34][35] Resistance has also been documented in areas not exposed to SP, probably due to the introduction of resistant parasites through human migrations. 36,37 Mexico and Central America have not officially used SP to treat malaria, 15,38,39 and the molecular susceptibility status of local P. vivax to SP is unknown.…”

Malaria Epidemiology at the Clone Level

“…Across almost all genotyping studies, P. falciparum and P. vivax were found to be highly diverse [11, 19–21]. For instance, using a panel of a few microsatellites, or sequencing a parasite antigen such as AMA-1 [22, 23], in most populations nearly every parasite sampled was different.…”