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