Asexual populations of the malaria parasite, P.falcip, use a 2-step genomic strategy to acquire beneficial DNA amplifications
Guler JL, Freeman DL, Ahyong V, Patrapuvich R, White J, Gujjar R, Phillips MA, DeRisi J, Rathod PKPLoS Pathog., 2013Abstract:
Malaria drug resistance contributes to up to a million annual deaths. Judicious
deployment of new antimalarials and vaccines could benefit from an understanding
of early molecular events that promote the evolution of parasites. Continuous in
vitro challenge of Plasmodium falciparum parasites with a novel dihydroorotate
dehydrogenase (DHODH) inhibitor reproducibly selected for resistant parasites.
Genome-wide analysis of independently-derived resistant clones revealed a
two-step strategy to evolutionary success. Some haploid blood-stage parasites
first survive antimalarial pressure through fortuitous DNA duplications that
always included the DHODH gene. Independently-selected parasites had different
sized amplification units but they were always flanked by distant A/T tracks.
Higher level amplification and resistance was attained using a second, more
efficient and more accurate, mechanism for head-to-tail expansion of the founder
unit. This second homology-based process could faithfully tune DNA copy numbers
in either direction, always retaining the unique DNA amplification sequence from
the original A/T-mediated duplication for that parasite line. Pseudo-polyploidy
at relevant genomic loci sets the stage for gaining additional mutations at the
locus of interest. Overall, we reveal a population-based genomic strategy for
mutagenesis that operates in human stages of P. falciparum to efficiently yield
resistance-causing genetic changes at the correct locus in a successful parasite.
Importantly, these founding events arise with precision; no other new
amplifications are seen in the resistant haploid blood stage parasite. This
minimizes the need for meiotic genetic cleansing that can only occur in sexual
stage development of the parasite in mosquitoes.