A common DNA deletion altering the 3’UTR of mdr1 is associated with reduced mefloquine susceptibility in P. vivax parasites from Cambodian patients

Artemisinin-combination therapies (ACTs) are now recommended for the treatment of uncomplicated malaria caused by Plasmodium vivax, the parasite responsible for the majority of malaria infections outside of Africa. We sequence the genomes of 206 P. vivax parasites collected from Cambodian malaria patients and show that more than 80% of them carry a DNA deletion located immediately downstream of the multidrug resistance 1 gene (mdr1) protein-coding sequence. This 837 bp deletion overlaps with a different deletion present at low frequency in South American isolates, suggesting a functional role despite not altering the coding sequence of mdr1. Using RNA sequencing, we show that these deletions alter the transcripts expressed from mdr1 and result in mRNAs with different 3' untranslated regions. In Cambodian isolates, the deletion was significantly associated with a higher level of mdr1 mRNA, a lower ex vivo susceptibility to mefloquine, and increased in frequency in Cambodia since the introduction of mefloquine as ACT partner drug. Overall, these findings indicate that a common deletion of a non-coding sequence affects the transcription, stability, or translation of mdr1 in P. vivax parasites and could mediate reduced susceptibility to antimalarial drug(s) currently used for the treatment of uncomplicated vivax malaria.