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The Population Genetics of Collateral Resistance and Sensitivity

Sarah M. Ardell, View ORCID ProfileSergey Kryazhimskiy
doi: https://doi.org/10.1101/2020.08.25.267484
Sarah M. Ardell
1Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093
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Sergey Kryazhimskiy
1Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093
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  • ORCID record for Sergey Kryazhimskiy
  • For correspondence: skryazhi@ucsd.edu
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Abstract

Resistance mutations against one drug can elicit collateral sensitivity against other drugs. Multi-drug treatments exploiting such trade-offs can help slow down the evolution of resistance. However, if mutations with diverse collateral effects are available, a treated population may evolve either collateral sensitivity or collateral resistance. How to design treatments robust to such uncertainty is unclear. We show that many resistance mutations in Escherichia coli against various antibiotics indeed have diverse collateral effects. We propose to characterize such diversity with a joint distribution of fitness effects (JDFE) and develop a theory for describing and predicting collateral evolution based on simple statistics of the JDFE. We show how to robustly rank drug pairs to minimize the risk of collateral resistance and how to estimate JDFEs. In addition to practical applications, these results have implications for our understanding of evolution in variable environments.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • This revision addresses the criticisms raised by reviewers. Specifically: * We now extend the theory to the concurrent mutations regime * We use existing data from E. coli knock-out collection and from deep mutational scanning to show that resistance mutations have diverse collateral effects. * Refocused paper on collateral sensitivity/resistance * Added a section on ranking drug pairs and a section on estimating JDFEs.

  • https://github.com/ardellsarah/JDFE-project

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted August 22, 2021.
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The Population Genetics of Collateral Resistance and Sensitivity
Sarah M. Ardell, Sergey Kryazhimskiy
bioRxiv 2020.08.25.267484; doi: https://doi.org/10.1101/2020.08.25.267484
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The Population Genetics of Collateral Resistance and Sensitivity
Sarah M. Ardell, Sergey Kryazhimskiy
bioRxiv 2020.08.25.267484; doi: https://doi.org/10.1101/2020.08.25.267484

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