title: Delayed commitment to evolutionary fate in antibiotic resistance fitness landscapes.
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.
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.|School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Palmer
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: Erdal
authors.initials: E
authors.lastname: Toprak
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Baym
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Seungsoo
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Veres
authors.affiliation: Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Shimon
authors.initials: S
authors.lastname: Bershtein
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Biology and Department of Computer Science, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Roy
authors.initials: R
authors.lastname: Kishony
mesh_terms: D005075:Biological Evolution; D004352:Drug Resistance, Microbial / Q000235:genetics*; D004843:Epistasis, Genetic