FIGURE 8.

A model of ecDNA generation and maintenance inPlasmodium falciparum. Part 1 summarizes the paths to generate few to many tandemdhodhamplicons on chromosome 6 (blue boxes) under drug selection.Dhodhamplicons do not contain known centromere sequences (red circle) but they do potentially harbor a short, AT‐rich sequence in the center of the amplicon that is expanded in ecDNA molecules (yellow region). Note: the physiological relevance of this sequence has not yet been demonstrated. Part 2 depicts the generation of circular ecDNA by loop formation and recombination. Individual ecDNA molecules likely contain a range of amplicon numbers (although higher numbers may facilitate segregation) and some amplicon copies remain stable on chromosome 6. Part 3 highlights proposed mechanisms of replication that may contribute to maintenance of ecDNA. We speculate that the expansion of the short, AT‐rich sequence (yellow region, >5,000‐fold enrichment over other sequences, termed “super‐peak”) may occur during replication and contribute to ecDNA stability. Part 4. The presence of ecDNA dictates the level of resistance achieved by the parasites (H, high level resistance; M, moderate resistance; L, low level resistance). Unequal segregation of ecDNA into daughter parasites, even in a clonal parasite line, likely contributes to the growth phenotype observed in highly resistant parasites (Guler et al.,2013)