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Impact of transient acquired hypermutability on the inter- and intra-species competitiveness of Pseudomonas aeruginosa.

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Figueroa, Wendy 
Fan, Catherine 
Bényei, Éva Bernadett 


Once acquired, hypermutation is unrelenting, and in the long-term, leads to impaired fitness due to its cumulative impact on the genome. This raises the question of why hypermutators arise so frequently in microbial ecosystems. In this work, we explore this problem by examining how the transient acquisition of hypermutability affects inter- and intra-species competitiveness, and the response to environmental insults such as antibiotic challenge. We do this by engineering Pseudomonas aeruginosa to allow the expression of an important mismatch repair gene, mutS, to be experimentally controlled over a wide dynamic range. We show that high levels of mutS expression induce genomic stasis (hypomutation), whereas lower levels of induction lead to progressively higher rates of mutation. Whole-genome sequence analyses confirmed that the mutational spectrum of the inducible hypermutator is similar to the distinctive profile associated with mutS mutants obtained from the airways of people with cystic fibrosis (CF). The acquisition of hypermutability conferred a distinct temporal fitness advantage over the wild-type P. aeruginosa progenitor strain, in both the presence and the absence of an antibiotic selection pressure. However, over a similar time-scale, acquisition of hypermutability had little impact on the population dynamics of P. aeruginosa when grown in the presence of a competing species (Staphylococcus aureus). These data indicate that in the short term, acquired hypermutability primarily confers a competitive intra-species fitness advantage.



3107 Microbiology, 31 Biological Sciences, 3105 Genetics, Human Genome, Lung, Rare Diseases, Genetics, Cystic Fibrosis, Infection

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Springer Science and Business Media LLC
Cystic Fibrosis Trust (SRC-017)
Wellcome Trust (107032/B/15/Z)
YYO was supported by the Government of Malaysia under a King’s Scholarship [BYDPA 2018]. Elements of the work described in this research article were also supported by funding from the UK Cystic Fibrosis Trust [SRC017]. WFC was supported by CONAcYT and the Cambridge Trusts. EBB is supported by a studentship from the Oliver Gatty Trust (Cambridge). RAF, AW, and CR are supported by the Wellcome Trust (107032AIA), the Botnar Foundation (6063), and the UK Cystic Fibrosis Trust (Innovation Hub grant 001). RAF is supported by the NIHR Cambridge Biomedical Research Centre, and Health Enterprise East.