title: Stochasticity in the Genotype-Phenotype Map: Implications for the Robustness and Persistence of Bet-Hedging.
abstract: Nongenetic variation in phenotypes, or bet-hedging, has been observed as a driver of drug resistance in both bacterial infections and cancers. Here, we study how bet-hedging emerges in genotype-phenotype (GP) mapping through a simple interaction model: a molecular switch. We use simple chemical reaction networks to implement stochastic switches that map gene products to phenotypes, and investigate the impact of structurally distinct mappings on the evolution of phenotypic heterogeneity. Bet-hedging naturally emerges within this model, and is robust to evolutionary loss through mutations to both the expression of individual genes, and to the network itself. This robustness explains an apparent paradox of bet-hedging-why does it persist in environments where natural selection necessarily acts to remove it? The structure of the underlying molecular mechanism, itself subject to selection, can slow the evolutionary loss of bet-hedging to ensure a survival mechanism against environmental catastrophes even when they are rare. Critically, these properties, taken together, have profound implications for the use of treatment-holidays to combat bet-hedging-driven resistant disease, as the efficacy of breaks from treatment will ultimately be determined by the structure of the GP mapping.
authors: Department of Computer Science, University of Oxford, OX1 3QD, United Kingdom daniel.nichol@cs.ox.ac.uk Alexander.Anderson@Moffitt.org.|Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612.
authors: Daniel
authors: D
authors: Nichol
authors: Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612.
authors: Mark
authors: M
authors: Robertson-Tessi
authors: Department of Computer Science, University of Oxford, OX1 3QD, United Kingdom.
authors: Peter
authors: P
authors: Jeavons
authors: Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612 daniel.nichol@cs.ox.ac.uk Alexander.Anderson@Moffitt.org.
authors: Alexander R A
authors: AR
authors: Anderson
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D018740:Genetic Heterogeneity; D005838:Genotype; D008957:Models, Genetic; D010641:Phenotype; D013269:Stochastic Processes
keywords: bacterial persistence; bet-hedging; drug resistance; evolution; genotype–phenotype map