Evolutionary rescue from mutational meltdown

Mutagenic drugs are promising candidates for the treatment of various RNA virus infections. By increasing the mutation rate of the virus they lead to rapid accumulation of deleterious mutation load, which is proposed to ultimately result in extinction as described by the theoretical concepts of mutational meltdown and lethal mutagenesis. However, the conditions and potential mechanisms of viral escape from the effects of mutagenic drugs have not been systematically explored. Here we investigate the population dynamics and genetics of a population under high mutation rates and discuss the probabilities of evolutionary rescue by means of three mechanisms: (1) “traditional” beneficial mutations increasing growth/fitness, (2) a mutation rate modifier (i.e., evolution of resistance), and (3) a modifier of the distribution of fitness effects, which either dampens or increases deleterious effects (i.e., evolution of tolerance). We investigate extinction times and we find that successful rescue mutations have to appear early to compensate the increasing mutational load. However, the observed stochasticity of rescue, especially by means of tolerance, highlights potential dangers of the use of mutagenic treatments that are almost impossible to capture in experimental trials. Supervisor: Claudia Bank Co-author: Mark Schmitz