Early identification of causal genetic variants underlying antimalarial drug resistance could provide robust epidemiological tools for timely public health interventions. Using a novel natural genetics strategy for mapping novel candidate genes we analyzed >75,000 high quality single nucleotide polymorphisms selected from high-resolution whole-genome sequencing data in 27 isolates of Plasmodium falciparum. We identified genetic variants associated with susceptibility to dihydroartemisinin that implicate one region on chromosome 13, a candidate gene on chromosome 1 (PFA0220w, a UBP1 ortholog) and others (PFB0560w, PFB0630c, PFF0445w) with putative roles in protein homeostasis and stress response. There was a strong signal for positive selection on PFA0220w, but not the other candidate loci. Our results demonstrate the power of full-genome sequencing-based association studies for uncovering candidate genes that determine parasite sensitivity to artemisinins. Our study provides a unique reference for the interpretation of results from resistant infections.

Original publication

DOI

10.1038/srep03318

Type

Journal article

Journal

Sci Rep

Publication Date

25/11/2013

Volume

3

Keywords

Antimalarials, Artemisinins, Base Sequence, DNA, Protozoan, Drug Resistance, Genome, Protozoan, High-Throughput Nucleotide Sequencing, Humans, Kenya, Malaria, Falciparum, Parasitic Sensitivity Tests, Plasmodium falciparum, Polymorphism, Single Nucleotide, Sequence Analysis, DNA