Tuning Haploid Happenstance

See allHide authors and affiliations

Science  21 Jun 2013:
Vol. 340, Issue 6139, pp. 1379
DOI: 10.1126/science.340.6139.1379-a

How can the malarial parasite Plasmodium falciparum evolve drug resistance when it is haploid and does not have recourse to meiosis? Guler et al. challenged P. falciparum with a drug nicknamed DSM1, which inhibits the parasite's flavonoid enzyme, dihydroorotate dehydrogenase (DHODH), required for the biosynthesis of pyrimidine and nucleic acids. Resistant clones arose that had multiple copies of DHODH and no point mutations. Deep sequencing revealed that an initial duplication arose stochastically by mitotic rearrangements between scattered tracks of polyadenine or polythymine (A/T). The rigidity of A/T tracks is known to trigger recombination and so could promote mitotic DNA rearrangements. Hence, the first step is luck, and eventually a beneficial mutation is selected out of the millions of failures in the replicating parasite population. Subsequently, copies of DHODH are precisely ramped up and down depending on drug pressure. The amplicon responsible for resistance was the only new amplicon seen in DSM1-resistant parasites, so there is a further mechanism for restraining the collateral damage arising from unlimited amplification of bits of haploid genome. In the A/T-rich genome of P. falciparum, this two-step mechanism may be the primary driver for evolution, not just drug resistance.

PLoS Pathogens 9, 10.1371/journal.ppat.1003375 (2013).

Navigate This Article