Population persistence under high mutation rate: From evolutionary rescue to lethal mutagenesis

Abstract

Populations may genetically adapt to severe stress that would otherwise cause their extirpation. Recent theoretical work, combining stochastic demography with Fisher's geometric model of adaptation, has shown how evolutionary rescue becomes unlikely beyond some critical intensity of stress. Increasing mutation rates may however allow adaptation to more intense stress, raising concerns about the effectiveness of treatments against pathogens. This previous work assumes that populations are rescued by the rise of a single resistance mutation. However, even in asexual organisms, rescue can also stem from the accumulation of multiple mutations in a single genome. Here, we extend previous work to study the rescue process in an asexual population where the mutation rate is sufficiently high so that such events may be common. We predict both the ultimate extinction probability of the population and the distribution of extinction times. We compare the accuracy of different approximations covering a large range of mutation rates. Moderate increase in mutation rates favors evolutionary rescue. However, larger increase leads to extinction by the accumulation of a large mutation load, a process called lethal mutagenesis. We discuss how these results could help design “evolution‐proof” antipathogen treatments that even highly mutable strains could not overcome.

Ecological limits to evolutionary rescue

“…Once fitness becomes sufficiently negative, the population size plummets. The situation is then more akin to an abrupt environmental change, where a large amount of theory has explored the probability of persistence (reviewed in [43] and [1]; for quantitative traits see, for example, [44][45][46][47][48]). Novel mathematical techniques such as rate-dependent bifurcation theory [49] may be useful tools royalsocietypublishing.org/journal/rstb Phil.…”

The emergence of a birth-dependent mutation rate in asexuals: causes and consequences

“…It is well-known that increasing the mutation rate has antagonistic effects on adaptation in the FGM (and other models with both deleterious and beneficial mutations) as it generates fitness variance to fuel and speed-up adaptation but lowers the mean fitness by creating a larger mutation load (e.g. Anciaux et al, 2019). Here, these two effects shape the trajectories of adaptation.…”

“…Regarding theoretical work, since the first studies on the accumulation of mutation load (Haldane, 1937;Kimura and Maruyama, 1966), several modelling approaches have investigated the effect of the mutation rate on various aspects of the adaptation of asexuals. This includes lethal mutagenesis theory (Bull et al, 2007;Bull and Wilke, 2008), where too high mutation rates may lead to extinction, evolutionary rescue (Anciaux et al, 2019) or the invasion of a sink . The evolution of the mutation rate per se is also the subject of several models (André and Godelle, 2006;Lynch, 2010).…”

“…In this last case, we expect that the consequences of the trade-off on the dynamics of adaptation strongly depend on the existence of a positive correlation between the birth rate and the mutation rate. High mutation rates tend to promote adaptation when the population is far from equilibrium (Sniegowski et al, 2000) but eventually have a detrimental effect due to a higher mutation load when it approaches a mutation-selection equilibrium (Anciaux et al, 2019). This ambivalent effect of mutation may therefore lead to complex trajectories of adaptation when the birth and mutation rates are correlated.…”

Evolutionary Rescue of an Environmental Pseudomonas otitidis in Response to Anthropogenic Perturbation

“…Given the difficulties of in situ studies (Bell, 2017), evolutionary rescue in bacteria has only been studied in silico through mathematical models and simulations (Gomulkiewicz and Holt, 1995;Unckless, 2008, 2014;Uecker and Hermisson, 2016;Vogwill et al, 2016;Van Den Elzen et al, 2017;Anciaux et al, 2018Anciaux et al, , 2019Carja and Plotkin, 2019) and in few laboratory experiments (Bell and Gonzalez, 2009;Agashe et al, 2011;Ramsayer et al, 2013). Long-term consequences of evolutionary rescue are is still under debate; for instance, does the resulting erosion in genetic diversity leaves populations vulnerable to extinction after evolutionary rescue (Carlson et al, 2014;Bell, 2017)?…”