Opposing effects of population density and stress on <i>Escherichia coli</i> mutation rate

Krašovec, Rok; Richards, Huw; Gifford, Danna R.; Belavkin, Roman V.; Channon, Alastair; Aston, Elizabeth; McBain, Andrew J.; Knight, Christopher G.

doi:10.1101/256305

Cited by 2 publications

(1 citation statement)

References 35 publications

(43 reference statements)

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“…This 3 was enhanced by the activity of the promoter and orientation of the gene, leading to the suggestion that stalled RNA polymerase can allow deamidation of nucleotides on template strands. Such specific mutagenic processes can interact with regional mutational biases, such as genomic strandedness and location, to enhance mutation rates (Horton, Flanagan, Jackson, Priest, & Taylor, 2021;Shepherd, Horton, & Taylor, 2022), but also any process that biases the spectrum of mutations in the genome (Gifford et al, 2024;Krasovec et al, 2018;Sane, Diwan, Bhat, Wahl, & Agashe, 2023). The multitude of mechanistic causes of hotspots has a singular consequence: they increase the production of variants presented to selection (McCandlish & Stoltzfus, 2014), often explaining instances of parallel evolution (Lind, Libby, Herzog, & Rainey, 2019).…”

Section: Introductionmentioning

confidence: 99%

An extreme mutational hotspot innlpDdepends on transcriptional induction ofrpoS

Farr,

Vasileiou,

Lind

et al. 2024

Preprint

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Mutation rate varies within and between genomes. Within genomes, tracts of nucleotides, including short sequence repeats and palindromes, can cause localised elevation of mutation rate. Additional mechanisms remain poorly understood. Here we report an instance of extreme mutational bias inPseudomonas fluorescensSBW25 associated with a single base-pair change innlpD.These mutants frequently evolve in static microcosms, and have a cell-chaining (CC) phenotype. Analysis of 153 replicate populations revealed 137 independent instances of a C565T loss-of-function mutation at codon 189 (CAG to TAG (Q189*)). Fitness measures of alternativenlpDmutants showed molecular parallelism to be unconnected to selective advantage. Recognising that transcription can be mutagenic, and that codon 189 overlaps with a predicted promoter (rpoSp) for the adjacent stationary phase sigma factor,rpoS, transcription across this promoter region was measured. This confirmedrpoSpis induced in stationary phase and that C565T mutation caused significant elevation of transcription. The latter provided opportunity to determine the C565T mutation rate using a reporter-gene fused torpoSp. Fluctuation assays demonstrate the C565T mutation rate to be 5,700-fold higher than expected. InPseudomonas, transcription ofrpoSrequires the positive activator PsrA, which we show also holds for SBW25. Fluctuation assays performed in a ΔpsrAbackground showed a 60-fold reduction in mutation rate confirming that the elevated rate of mutation at C565T mutation rate is dependent on induction of transcription. This hotspot suggests a generalisable phenomenon where the induction of transcription causes elevated mutation rates within defining regions of promoters.

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Section: Introductionmentioning

confidence: 99%

An extreme mutational hotspot innlpDdepends on transcriptional induction ofrpoS

Farr,

Vasileiou,

Lind

et al. 2024

Preprint

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Mutators drive evolution of multi-resistance to antibiotics

Gifford¹,

Berríos-Caro

Joerres³

et al. 2019

Preprint

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Combination therapy aims to prevent growth of organisms not resistant to all component drugs, making it an obvious strategy for countering the global rise of multi-drug resistance. However, success relies on preventing resistance from arising to all component drugs before full inhibition is reached during treatment. Here, we investigated whether bacterial populations can overcome combination therapy by evolving 'multi-resistance', i.e. independent resistance mutations to multiple drugs, during single-drug and combination antibiotic treatment. Using both experimental evolution and in silico stochastic simulations, we studied resistance evolution in a common laboratory strain of bacteria (Escherichia coli K-12 BW25113). Populations were exposed to either single-drug or combination treatments involving rifampicin and nalidixic acid, with concentrations increasing through time. For wild-type populations, multi-resistance was not detected in any of the experimental populations, and simulations predict its evolution should be rare.However, populations comprising mixtures of wild-type and 'mutator' strains were readily capable of evolving multi-resistance. Increasing the initial frequency of mutators resulted in a higher proportion of populations evolving multi-resistance. Experiments and simulations produced the same qualitative-and in many cases, quantitative-insights about the association between resistance, mutators and antibiotic treatment. In particular, both approaches demonstrated that multi-resistance can arise through sequential acquisition of independent resistance mutations, without a need to invoke multi-drug resistance mechanisms. Crucially, we found multi-resistance evolved even when not directly favoured by natural selection, i.e. under single-drug treatments. Simulations revealed this resulted from elevated mutation supply caused by genetic hitch-hiking of the mutator allele on single-drug resistant backgrounds. Our results suggest that combination therapy does not necessarily prevent sequential acquisition of multiple drug resistances via spontaneous mutation when mutators are present. Indeed both combination and single-drug treatments actively promoted multi-resistance, meaning that combination therapy will not be a panacea for the antibiotic resistance crisis. inference, stochastic simulations, individual-based model, Markov chains W , K. B., 2016 Pairwise interactions and the battle against combinatorics in multidrug therapies.

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Opposing effects of population density and stress on Escherichia coli mutation rate

Cited by 2 publications

References 35 publications

An extreme mutational hotspot innlpDdepends on transcriptional induction ofrpoS

An extreme mutational hotspot innlpDdepends on transcriptional induction ofrpoS

Mutators drive evolution of multi-resistance to antibiotics

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