Evolutionary models predict potential mechanisms of escape from mutational meltdown

Abstract

Mutagenic drugs are promising candidates for the treatment of various RNA virus infections. Increasing the mutation rate of the virus leads 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 conceptually explored. Here we apply a computational approach to quantify the population dynamics and genetics of a population under high mutation rates and discuss the likelihood of adaptation to a mutagenic drug by means of three proposed mechanisms: (1) a proportion of “traditional” beneficial mutations that increase growth/fitness, (2) a mutation rate modifier (i.e., evolution of resistance to the mutagenic drug) that reduces the mutation rate, and (3) a modifier of the distribution of fitness effects, which either decreases or increases deleterious effects of mutations (i.e., evolution of tolerance to the mutagenic drug). We track the population dynamics and genetics of evolving populations and find that successful adaptations have to appear early to override the increasing mutational load and rescue the population from its imminent extinction. We highlight that the observed stochasticity of adaptation, especially by means of modifiers of the distribution of fitness effects, is difficult to capture in experimental trials, which may leave potential dangers of the use of mutagenic treatments unexposed.

The extinction time under mutational meltdown driven by high mutation rates

“…This is because as the virus survives under the mutagenic pressure, it may accumulate not only deleterious mutations but also beneficial ones. Such mutations could help it survive in the presence of the drug (i.e., evolution of drug resistance or tolerance; Bank et al (2022)), or they might be more general adaptations that make the virus more dangerous when it is transmitted to other hosts. Because of this danger that is specific to mutagenic drug treatments, it is important to theoretically know/predict and empirically minimize the expected time to population extinction under mutagenic treatment.…”

Transient evolutionary epidemiology of viral adaptation and lethal mutagenesis

“…First, it is important to realise that mutation is a double-edged sword: even if most mutations are deleterious, some may be beneficial and could speed up within-host evolution. Some concern has emerged regarding the potential risk of "sublethal mutagenesis" that may result in immune escape or higher transmission [20][21][22][23]. Experimental evolution of bacteriophage T7 under high mutation rates showed that the exposition to a mutagen may boost adaptation and increase the mean fitness of the viral population [12,24].…”