title: Environmental changes bridge evolutionary valleys.
abstract: In the basic fitness landscape metaphor for molecular evolution, evolutionary pathways are presumed to follow uphill steps of increasing fitness. How evolution can cross fitness valleys is an open question. One possibility is that environmental changes alter the fitness landscape such that low-fitness sequences reside on a hill in alternate environments. We experimentally test this hypothesis on the antibiotic resistance gene TEM-15 β-lactamase by comparing four evolutionary strategies shaped by environmental changes. The strategy that included initial steps of selecting for low antibiotic resistance (negative selection) produced superior alleles compared with the other three strategies. We comprehensively examined possible evolutionary pathways leading to one such high-fitness allele and found that an initially deleterious mutation is key to the allele's evolutionary history. This mutation is an initial gateway to an otherwise relatively inaccessible area of sequence space and participates in higher-order, positive epistasis with a number of neutral to slightly beneficial mutations. The ability of negative selection and environmental changes to provide access to novel fitness peaks has important implications for natural evolutionary mechanisms and applied directed evolution.
authors: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA.
authors: Barrett
authors: 0000-0003-2036-1164
authors: B
authors: Steinberg
authors: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA.
authors: Marc
authors: M
authors: Ostermeier
mesh_terms: D000483:Alleles; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D004352:Drug Resistance, Microbial / Q000187:drug effects / Q000235:genetics*; D004777:Environment; D004843:Epistasis, Genetic / Q000187:drug effects / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D019143:Evolution, Molecular; D056084:Genetic Fitness / Q000187:drug effects / Q000235:genetics*; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D012641:Selection, Genetic / Q000187:drug effects / Q000235:genetics*; D001618:beta-Lactamases / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; C106857:TEM-15 beta-lactamase; D001618:beta-Lactamases
keywords: beta-lactamase; directed evolution; environmental changes; epistasis; fitness landscape; molecular evolution