Abstract
Predicting evolutionary paths to antibiotic resistance is key for understanding and controlling drug resistance. When considering a single final resistant genotype, epistatic contingencies among mutations restrict evolution to a small number of adaptive paths. Less attention has been given to multi-peak landscapes, and while specific peaks can be favoured, it is unknown whether and how early a commitment to final fate is made. Here we characterize a multi-peaked adaptive landscape for trimethoprim resistance by constructing all combinatorial alleles of seven resistance-conferring mutations in dihydrofolate reductase. We observe that epistatic interactions increase rather than decrease the accessibility of each peak; while they restrict the number of direct paths, they generate more indirect paths, where mutations are adaptively gained and later adaptively lost or changed. This enhanced accessibility allows evolution to proceed through many adaptive steps while delaying commitment to genotypic fate, hindering our ability to predict or control evolutionary outcomes.
Highlights
Predicting evolutionary paths to antibiotic resistance is key for understanding and controlling drug resistance
We studied the evolutionary paths to trimethoprim resistance using a set of resistance-conferring mutations identified by laboratory evolution experiments, where five initially isogenic and drug-susceptible Escherichia coli populations were evolved in parallel under dynamically sustained trimethoprim selection, yielding several different drug-resistant genotypes[8]
We find that genetic interactions limit the number of direct evolutionary paths to adaptive genotypes, where mutations are only gained, they greatly expand the number of indirect paths, where mutations can be adaptively lost or replaced by a different mutation at the same locus
Summary
Predicting evolutionary paths to antibiotic resistance is key for understanding and controlling drug resistance. We observe that epistatic interactions increase rather than decrease the accessibility of each peak; while they restrict the number of direct paths, they generate more indirect paths, where mutations are adaptively gained and later adaptively lost or changed This enhanced accessibility allows evolution to proceed through many adaptive steps while delaying commitment to genotypic fate, hindering our ability to predict or control evolutionary outcomes. We find that genetic interactions limit the number of direct evolutionary paths to adaptive genotypes, where mutations are only gained, they greatly expand the number of indirect paths, where mutations can be adaptively lost or replaced by a different mutation at the same locus This allows intermediate genotypes in the evolutionary process to trace feasible paths to many adaptive peaks, preventing early commitment to a genotypic fate. We find from simulations that this behaviour arises as a general property of multi-peak adaptive landscapes rich in high-order genetic interactions
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
