Genomic evolution of antibiotic resistance is contingent on genetic background following a long-term experiment withEscherichia coli

Abstract

Antibiotic resistance is a growing health concern. Efforts to control resistance would benefit from an improved ability to forecast when and how it will evolve. Epistatic interactions between mutations can promote divergent evolutionary trajectories, which complicates our ability to predict evolution. We recently showed that differences between genetic backgrounds can lead to idiosyncratic responses in the evolvability of phenotypic resistance, even among closely related Escherichia coli strains. In this study, we examined whether a strain's genetic background also influences the genotypic evolution of resistance. Do lineages founded by different genotypes take parallel or divergent mutational paths to achieve their evolved resistance states? We addressed this question by sequencing the complete genomes of antibiotic-resistant clones that evolved from several different genetic starting points during our earlier experiments. We first validated our statistical approach by quantifying the specificity of genomic evolution with respect to antibiotic treatment. As expected, mutations in particular genes were strongly associated with each drug. Then, we determined that replicate lines evolved from the same founding genotypes had more parallel mutations at the gene level than lines evolved from different founding genotypes, although these effects were more subtle than those showing antibiotic specificity. Taken together with our previous work, we conclude that historical contingency can alter both genotypic and phenotypic pathways to antibiotic resistance.

Idiosyncratic variation in the fitness costs of tetracycline‐resistance mutations in Escherichia coli

“…We previously sequenced the complete genomes of the 16 resistant lines, and we compared them to their parental strains to identify the mutations responsible for their resistance (Card et al. 2021a). Two lines had no identifiable mutations (Ara−5‐1 and Ara+5‐1), even though they had increased phenotypic resistance relative to their respective parent strains (Card et al.…”

“…Ara+4‐3 has mutations in hns , which encodes a histone‐like global regulator, and lpcA , which encodes a phosphoheptose isomerase; Ara+5‐2 has a single mutation in ompF , which encodes an outer‐membrane porin (Card et al. 2021a). We asked whether these two extreme cases are solely responsible for the heterogeneity in fitness costs by performing an ANOVA that excludes them.…”

The Population Genetics of Collateral Resistance and Sensitivity

“…Full JDFEs could differ substantially from the koJDFEs that we examined here. Finally, the availability and the type of resistance mutations depend on drug concentrations, other environmental conditions and on the bacterial species and strain (Lindsey et al, 2013;Das et al, 2020;Pinheiro et al, 2020;Card et al, 2020). All these factors could significantly affect the JDFE shape.…”

“…Some of the inconsistencies can be attributed to the fact that resistance mutations vary between bacterial strains, drug dosages, etc. (Mira et al, 2015;Das et al, 2020;Pinheiro et al, 2020;Card et al, 2020). However, these factors cannot explain the wide variation in the pleiotropic outcomes of adaptation that are observed in replicate populations in the same experiment (Oz et al, 2014;Nichol et al, 2019).…”

“…These adaptive mutations affect a variety of genetic targets (Lang et al, 2013;Tenaillon et al, 2012;Kryazhimskiy et al, 2014;Venkataram et al, 2016;Good et al, 2017;Blundell et al, 2019) and provide fitness benefits of various magnitudes (Rees and Bataillon, 2006;MacLean and Buckling, 2009;Khan et al, 2011;Chou et al, 2011;Levy et al, 2015;Venkataram et al, 2016) via diverse physiological mechanisms (Travisano and Lenski, 1996;Jerison et al, 2020;Pinheiro et al, 2020;Kinsler et al, 2020). As a consequence, different mutations also have diverse pleiotropic effects on fitness in non-home environments (Lenski, 1988;Ostrowski et al, 2005;Qian et al, 2012;Hietpas et al, 2013;Rodríguez-Verdugo et al, 2014;Jerison et al, 2020;Kinsler et al, 2020;Card et al, 2020). Recent evidence suggests that even when adaptive mutations are concentrated in relatively few genetic targets, they still exhibit a large variety of pleiotropic effects (Kinsler et al, 2020).…”