Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs

Abstract

Antimalarial drugs impose strong pressure on Plasmodium falciparum parasites and leave signatures of selection in the parasite genome 1,2. Search for signals of selection may lead to genes encoding drug or immune targets 3. The lack of high-throughput genotyping methods, inadequate knowledge of parasite population history, and time-consuming adaptations of parasites to in vitro culture have hampered genome-wide association studies (GWAS) of parasite traits. Here we report genotyping of DNA from 189 culture-adapted P. falciparum parasites using a custom-built array with thousands of single nucleotide polymorphisms (SNPs). Population structure, variation in recombination rate, and loci under recent positive selection were detected. Parasite half maximum inhibitory concentrations (IC50) to seven antimalarial drugs were obtained and used in GWAS to identify genes associated with drug responses. The SNP array and genome-wide parameters provide valuable tools and information for new advances in P. falciparum genetics.

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

“…Similar to previous studies of directional selection in P. falciparum, we identified drug-resistance genes (e.g., pfcrt and kelch K13) with evidence of strong directional selection (Table 3) (26)(27)(28)(29). Allele frequencies for all polymorphisms in known drugresistance genes are summarized in Table S6.…”

Malaria Genomics in the Era of Eradication

“…Following the generation of reference genome assemblies, malaria investigators followed the path of other organisms in the postgenomic era and characterized genomic diversity through sequencing surveys (Jeffares et al 2007;Mu et al 2007;Volkman et al 2007;Tan et al 2011;Neafsey et al 2012) and later genome-wide single nucleotide polymorphism (SNP) arrays (Neafsey et al , 2010Mu et al 2010;Tan et al 2011;Van Tyne et al 2011). Such work illuminated the recent demographic history of multiple parasite and vector species, defined sometimes complex gene flow boundaries, and revealed the impact of immune, drug, or insecticide selection on the genomes of malaria parasites and vectors.…”

Discovery of new antimalarial chemotypes through chemical methodology and library development

“…Once prepared, these libraries can be examined in a host of biological processes, here exemplified with a neglected disease of the third world for discovery of probes and future drugs. In our collaborative effort, the CMLD-BU compound collection was assayed for antimalarial activity against five lines of P. falciparum with distinct geographic origins, representing genotypic variation in part resulting from acquired antimalarial drug resistance (16). Overall, the CMLD-BU compound collection provided an effective source of chemotypes in the antimalaria assays.…”

“…Detailed procedures for the synthesis of indoline alkadoids are outlined in previous publications (14,16). Characterization of biologically active indoline alkaloids are provided in the SI Appendix.…”

“…We selected these five lines to include two sets of parents of two genetic crosses (Dd2xHB3, and 7G8xGB4) for which we have progeny available to permit genetic mapping of the chromosomal locus controlling the differential activity (10). The CP250 line from Cambodia was included to identify compounds active on a multidrug resistant strain (16).…”