Two sides of the same coin: A population genetics perspective on lethal mutagenesis and mutational meltdown

Abstract

The extinction of RNA virus populations upon application of a mutagenic drug is frequently referred to as evidence for the existence of an error threshold, above which the population cannot sustain the mutational load. To explain the extinction process after reaching this threshold, models of lethal mutagenesis have been proposed, in which extinction is described as a deterministic (and thus population size-independent) process. As a separate body of literature, the population genetics community has developed models of mutational meltdown, which focus on the stochastic (and thus population-size dependent) processes governing extinction. However, recent extensions of both models have blurred these boundaries. Here, we first clarify definitions in terms of assumptions, expectations, and relevant parameter spaces, and then assess similarities and differences. As concepts from both fields converge, we argue for a unified theoretical framework that is focused on the evolutionary processes at play, rather than dispute over terminology.

Domestication reprogrammed the budding yeast life cycle

“…Recombination also occurs under yeast mitosis but at vastly lower rates 64,65 . Thus, domestication near abolished or impaired the yeast capacity to combine beneficial variants into one genotype, to cleanse otherwise healthy genomes from deleterious mutations 66,67 , to prevent their catastrophic accumulation through a ratchet mechanism 68 and to generate a sufficiently broad diversity of genotypes to fully exploit and adapt to multi-faceted wild niches 69 . Sexual recombination accelerates yeast adaptation 70 and the loss of sexual recombination is likely to be particularly costly in constantly changing wild niches where fast adaptation is key.…”

Considering mutational meltdown as a potential SARS-CoV-2 treatment strategy

“…Under this model, if the input of deleterious mutations is sufficiently high, the number of reproducing individuals will decline. Though the model of lethal mutagenesis is also commonly noted in this regard (e.g., Bull et al 2007), the mutational meltdown framework is in fact more general, and critically incorporates the stochastic effects inherent to natural populations (see Matuszewski et al 2017).…”

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

“…In these models, mean fitness dynamics and extinction stem from the deterministic effects of selection and mutation. Alternatively, Matuszewski et al (2017) discuss the continuity between these models and models of mutational meltdown, where extinction is driven by the interaction of genetic drift and deleterious mutation. Lethal mutagenesis has been investigated empirically for treatment against viruses (Springman et al 2010;Arias et al 2014), bacteria (Bull and Wilke 2008), or cancer cells (Liu et al 2015).…”