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Competing evolutionary paths in growing populations with applications to multidrug resistance

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  • Michael D Nicholson
  • Tibor Antal

Abstract

Investigating the emergence of a particular cell type is a recurring theme in models of growing cellular populations. The evolution of resistance to therapy is a classic example. Common questions are: when does the cell type first occur, and via which sequence of steps is it most likely to emerge? For growing populations, these questions can be formulated in a general framework of branching processes spreading through a graph from a root to a target vertex. Cells have a particular fitness value on each vertex and can transition along edges at specific rates. Vertices represent cell states, say genotypes or physical locations, while possible transitions are acquiring a mutation or cell migration. We focus on the setting where cells at the root vertex have the highest fitness and transition rates are small. Simple formulas are derived for the time to reach the target vertex and for the probability that it is reached along a given path in the graph. We demonstrate our results on several scenarios relevant to the emergence of drug resistance, including: the orderings of resistance-conferring mutations in bacteria and the impact of imperfect drug penetration in cancer.Author summary: How long does it take for a treatment naive, growing bacterial colony to be able to survive exposure to a cocktail of antibiotics? En route to multidrug resistance, what order did the drugs become impotent in? Questions such as these that pertain to the emergence of a significant cell type in a growing population arise frequently. They are often investigated via mathematical modelling but biologically insightful results are challenging to obtain. Here we outline a general framework of a stochastically growing population spreading through a graph to study such questions and provide simple formulas as answers. The significant cell type appears upon the population reaching a target vertex. Due to their simplicity, the derived formulas are widely accessible and can be used to guide and develop intuition on a range of biological scenarios. We demonstrate this on several settings including: how a region where drugs cannot penetrate affects the emergence of resistance, and, the ordering of mutations that leads to drugs being ineffective.

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  • Michael D Nicholson & Tibor Antal, 2019. "Competing evolutionary paths in growing populations with applications to multidrug resistance," PLOS Computational Biology, Public Library of Science, vol. 15(4), pages 1-25, April.
    • Handle: RePEc:plo:pcbi00:1006866
    DOI: 10.1371/journal.pcbi.1006866
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