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Measuring Microbial Mutation Rates with the Fluctuation Assay
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Estimating mutation rates under heterogeneous stress responses.

Lucy Lansch-Justen1, Meriem El Karoui2,3,4, Helen K Alexander1,3

  • 1Institute of Ecology and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, Scotland, United Kingdom.

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Summary

Environmental stressors like antibiotics can increase bacterial mutation rates, accelerating resistance. This study introduces a new model to accurately estimate stress-induced mutation increases, even with heterogeneous responses in bacterial populations.

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Area of Science:

  • Microbiology
  • Evolutionary Biology
  • Genetics

Background:

  • Environmental stressors, including antibiotics, trigger bacterial stress responses.
  • Some stress responses elevate mutation rates, potentially accelerating bacterial resistance evolution.
  • Existing methods for estimating mutation rates under stress do not account for heterogeneous stress response expression in bacterial populations.

Purpose of the Study:

  • To develop a population dynamic model addressing heterogeneous stress responses and their impact on mutation and division rates.
  • To derive a method for estimating mutation-rate increases specifically linked to stress response expression.
  • To differentiate between mutation rate heterogeneity and mutant fitness costs in fluctuation assay data.

Main Methods:

  • Developed a population dynamic model incorporating heterogeneous stress responses (on/off subpopulations).
  • Modeled impacts of stress responses on both mutation and cell division rates, inspired by E. coli's SOS response.
  • Derived mutant count distribution for fluctuation assays and implemented maximum likelihood estimation.

Main Results:

  • The new inference method accurately estimates mutation-rate increases under stress, especially when the increase is substantial and division rate is reduced.
  • The study highlights that both heterogeneous stress responses and mutant fitness costs can yield similar fluctuation assay patterns, necessitating further investigation.
  • Current methods accurately estimate the population mean mutation rate increase, but the novel method can infer distinct stress-induced mutation rates.

Conclusions:

  • A novel population dynamic model and inference method accurately quantify stress-induced mutation rate increases in bacteria, even with heterogeneous responses.
  • Distinguishing between heterogeneous stress responses and mutant fitness costs is crucial for understanding bacterial evolution.
  • The developed method offers a way to parameterize evolutionary models with distinct stress-induced mutation rates.