Peeling the onion: how complex is the artemisinin resistance genetic trait of malaria parasites?

The genetics of Plasmodium as an intracellular, mostly haploid, sexually reproducing, eukaryotic organism with a complex life cycle, presents unprecedented challenges in studying drug resistance. This article summarizes current knowledge on the genetic basis of artemisinin resistance (AR) - a main component of current drug therapies for falciparum malaria. Although centered on nonsynonymous single-nucleotide polymorphisms (nsSNPs), we describe multifaceted resistance mechanisms as part of a complex, cumulative genetic trait that involves regulation of expression by a wide array of polymorphisms in noncoding regions. These genetic variations alter transcriptome profiles linked to Plasmodium's development and population dynamics, ultimately influencing the emergence and spread of the resistance.