Tuning Spatial Profiles of Selection Pressure to Modulate the Evolution of Drug Resistance

摘要

238102.1-238102.6%Spatial heterogeneity plays an important role in the evolution of drug resistance. While recent studies have indicated that spatial gradients of selection pressure can accelerate resistance evolution, much less is known about evolution in more complex spatial profiles. Here we use a stochastic toy model of drug resistance to investigate how different spatial profiles of selection pressure impact the time to fixation of a resistant allele. Using mean first passage time calculations, we show that spatial heterogeneity accelerates resistance evolution when the rate of spatial migration is sufficiently large relative to mutation but slows fixation for small migration rates. Interestingly, there exists an intermediate regime-characterized by comparable rates of migration and mutation-in which the rate of fixation can be either accelerated or decelerated depending on the spatial profile, even when spatially averaged selection pressure remains constant. Finally, we demonstrate that optimal tuning of the spatial profile can dramatically slow the spread and fixation of resistant subpopulations, even in the absence of a fitness cost for resistance. Our results may lay the groundwork for optimized, spatially resolved drug dosing strategies for mitigating the effects of drug resistance.