The topic of the evolvability of chloroquine (CQ) resistance in the Plasmodium falciparum parasite has been discussed at length by Behe and his critics, but one paper I haven’t seen mentioned in all of this is Gabryszewski et al. (2016):
The abstract:
The emergence of drug resistance continuously threatens global control of infectious diseases, including malaria caused by the protozoan parasite Plasmodium falciparum. A critical parasite determinant is the P. falciparum chloroquine resistance transporter (PfCRT), the primary mediator of chloroquine (CQ) resistance (CQR), and a pleiotropic modulator of susceptibility to several first-line artemisinin-based combination therapy partner drugs. Aside from the validated CQR molecular marker K76T, P. falciparum parasites have acquired at least three additional pfcrt mutations, whose contributions to resistance and fitness have been heretofore unclear. Focusing on the quadruple-mutant Ecuadorian PfCRT haplotype Ecu1110 (K76T/A220S/N326D/I356L), we genetically modified the pfcrt locus of isogenic, asexual blood stage P. falciparum parasites using zinc-finger nucleases, producing all possible combinations of intermediate pfcrt alleles. Our analysis included the related quintuple-mutant PfCRT haplotype 7G8 (Ecu1110 + C72S) that is widespread throughout South America and the Western Pacific. Drug susceptibilities and in vitro growth profiles of our combinatorial pfcrt-modified parasites were used to simulate the mutational trajectories accessible to parasites as they evolved CQR. Our results uncover unique contributions to parasite drug resistance and growth for mutations beyond K76T and predict critical roles for the CQ metabolite monodesethyl-CQ and the related quinoline-type drug amodiaquine in driving mutant pfcrt evolution. Modeling outputs further highlight the influence of parasite proliferation rates alongside gains in drug resistance in dictating successful trajectories. Our findings suggest that P. falciparum parasites have navigated constrained pfcrt adaptive landscapes by means of probabilistically rare mutational bursts that led to the infrequent emergence of pfcrt alleles in the field.
Their results show that some single mutations can result in increased resistance to CQ and its metabolite md-CQ (e.g. N326D), and that under some scenarios (e.g. when there is quite a high selection pressure on CQ resistance over growth rates), there exist evolutionary trajectories from no CQ resistance to high CQ resistance involving 4 mutations that increase fitness in a stepwise manner.
While these single-mutation stepwise trajectories existed and were viable, far more viable were the evolutionary trajectories that involved bursts of multiple mutations occurring near-simultaneously. Basically these trajectories had steeper fitness gains, as you might expect.
What are people’s thoughts on this paper?
@swamidass @NLENTS @Art (tagging some people I’ve seen talk about this subject before.)