A genome-wide map of diversity in Plasmodium falciparum

Abstract

Genetic variation allows the malaria parasite Plasmodium falciparum to overcome chemotherapeutic agents, vaccines and vector control strategies and remain a leading cause of global morbidity and mortality. Here we describe an initial survey of genetic variation across the P. falciparum genome. We performed extensive sequencing of 16 geographically diverse parasites and identified 46,937 SNPs, demonstrating rich diversity among P. falciparum parasites (pi = 1.16 x 10(-3)) and strong correlation with gene function. We identified multiple regions with signatures of selective sweeps in drug-resistant parasites, including a previously unidentified 160-kb region with extremely low polymorphism in pyrimethamine-resistant parasites. We further characterized 54 worldwide isolates by genotyping SNPs across 20 genomic regions. These data begin to define population structure among African, Asian and American groups and illustrate the degree of linkage disequilibrium, which extends over relatively short distances in African parasites but over longer distances in Asian parasites. We provide an initial map of genetic diversity in P. falciparum and demonstrate its potential utility in identifying genes subject to recent natural selection and in understanding the population genetics of this parasite.

Whole-genome sequencing and microarray analysis of ex vivo Plasmodium vivax reveal selective pressure on putative drug resistance genes

“…Although one mutation may help the parasite evade a drug, a compensatory mutation at an unrelated site in the same protein may also be needed to help to stabilize the protein's structure or improve its catalytic efficiency. This pattern has been observed by sequencing field isolates as well (36,37). There are more SNPs (12 nonsynonymous and 0 synonymous) in the chloroquine resistance transporter (pfcrt) in assorted P. falciparum isolates relative to what would be expected by chance without considering the resistance or sensitivity phenotype (36,37).…”

Stepwise acquisition of pyrimethamine resistance in the malaria parasite

“…Elsewhere in the genome, a selective sweep associated with pyrimethamine resistance has been reported across a region of chromosome 13 (39). It is an interesting, testable hypothesis that this region of chromosome 13 may include 1 or more mutations that also alleviate the deleterious fitness effects of DHFR resistance alleles.…”

Transcriptional variation in the malaria parasitePlasmodium falciparum

“…The degree of genetic diversity between isolates in these gene families provides insights into the physiological role of transcriptional variability. Gene families specifically amplified in the P. falciparum lineage can be roughly divided into those that show hypervariability between parasite isolates, such as var, rif, stevor, and pfmc-2tm, and those that are conserved between isolates, including the majority of other amplified families (e.g., phist, dnaj, fikk, etramp, acs, lysophospholipases, and many others) (Jeffares et al 2007;Mu et al 2007;Volkman et al 2007;Templeton 2009). Amplification of these two types of gene families was probably driven by immune evasion and functional diversification, respectively (Templeton 2009).…”

“…While genetic variation in P. falciparum has been extensively characterized (Jeffares et al 2007;Mu et al 2007;Volkman et al 2007;Van Tyne et al 2011), the genome-wide extent of clonally variant gene expression remains unknown. Some studies have compared global blood stages transcription between different P. falciparum lines, but their sample size and experimental design resulted in the identification of only a small number of variantly expressed genes: One study compared two isogenic lines selected to display different antigenic and adhesive properties (Mok et al 2007), whereas another study compared the transcriptome of three genetically different parasite lines, focusing on the comparison of patterns of expression along the life cycle rather than comparing transcript levels (Llinas et al 2006).…”