Whole Genome Sequence of Plasmodium chabaudi clone AS-ATNMF

The possible evolution of resistance to Artemisinin Combination Treatments (ACTs) by malaria parasites, will severely undermine our ability to control this devastating disease. Here, we have used whole genome re-sequencing to characterize the genetic variation in Plasmodium chabaudi parasites resistant to the artesunate + mefloquine version of ACTs. Five novel single nucleotide polymorphisms (SNPs) and a large duplication (80kbp) were detected in the resistant parasite AS-ATNMF1 and/or in its progenitor, AS-ATN. The large 80kb duplication contained an estimated twenty-two genes, including mdr1. Furthermore, we observed that a previously undescribed E738K mutation in a 26S proteasome subunit was selected for under artesunate pressure (in AS-ATN) and retained in AS-ATNMF-1. Molecular modelling simulations of the 26S proteasome subunit P. falciparum homologue suggested that the E738K mutation could change the PC domain toroidal organization and consequently alter the recognition of ubiquitylated proteins or the mediation process of interaction with neighboring subunits or auxiliary factors. The mutation in the 26S proteasome subunit may therefore contribute to reducing oxidation-dependent ubiquitination of MDR1 or of other proteins that may targeted by artesunate, resulting in an increase in protein turnover.