Dynamics and Fate of Beneficial Mutations Under Lineage Contamination by Linked Deleterious Mutations

Abstract

Beneficial mutations drive adaptive evolution, yet their selective advantage does not ensure their fixation. Haldane's application of single-type branching process theory showed that genetic drift alone could cause the extinction of newly arising beneficial mutations with high probability. With linkage, deleterious mutations will affect the dynamics of beneficial mutations and might further increase their extinction probability. Here, we model the lineage dynamics of a newly arising beneficial mutation as a multitype branching process. Our approach accounts for the combined effects of drift and the stochastic accumulation of linked deleterious mutations, which we call lineage contamination. We first study the lineage-contamination phenomenon in isolation, deriving dynamics and survival probabilities (the complement of extinction probabilities) of beneficial lineages. We find that survival probability is zero when U * s b ; where U is deleterious mutation rate and s b is the selective advantage of the beneficial mutation in question, and is otherwise depressed below classical predictions by a factor bounded from below by $ 1 2 U=s b : We then put the lineage contamination phenomenon into the context of an evolving population by incorporating the effects of background selection. We find that, under the combined effects of lineage contamination and background selection, ensemble survival probability is never zero but is depressed below classical predictions by a factor bounded from below by e 2eU= s b ; where s b is mean selective advantage of beneficial mutations, and e ¼ 1 2 e 21 % 0:63: This factor, and other bounds derived from it, are independent of the fitness effects of deleterious mutations. At high enough mutation rates, lineage contamination can depress fixation probabilities to values that approach zero. This fact suggests that high mutation rates can, perhaps paradoxically, (1) alleviate competition among beneficial mutations, or (2) potentially even shut down the adaptive process. We derive critical mutation rates above which these two events become likely.

Imposed mutational meltdown as an antiviral strategy

“…study observed no mutational escape, consistent with the idea that even in the presence of newly arising beneficial resistance mutations, the linked deleterious load under strong mutation pressure can be simply too great to enable significant net adaptation (Pénnison et al. 2017), again emphasizing the potential advantage of such a genome‐wide target size.…”

“…One cluster of mutations in the polymerase subunit PA was associated with the subcellular localization of viral RdRp components, and two of these RdRp mutations conferred resistance to favipiravir in IAV-infected cells (Goldhill et al 2018). Nonetheless, under high concentrations of favipiravir, the Bank et al study observed no mutational escape, consistent with the idea that even in the presence of newly arising beneficial resistance mutations, the linked deleterious load under strong mutation pressure can be simply too great to enable significant net adaptation (Pénnison et al 2017), again emphasizing the potential advantage of such a genome-wide target size.…”

Spike protein mutational landscape in India: Could Muller’s ratchet be a future game-changer for COVID-19?

“…Therefore, keeping in mind the observed correlation between the S-R complex stability and fatality rate across Indian states, here we pose an open question for future research: Does the phylodynamics of SARS-CoV-2 in India indicate any nascent action of Muller’s ratchet where the otherwise deleterious mutations tend to get fixed in the population as natural selection remains unable to purge them due to excessive mutational pressures? If so, there lies an immense potential of using therapeutics that could facilitate such a process of mutational meltdown, as was demonstrated earlier for influenza A virus [48, 49]. Therefore, future large-scale population genomics analysis supported by epidemiological information is of high importance to explore this question for India as well as for other countries across the globe to develop efficient analytical methods, thereby guiding better surveillance programs, prevention and treatment management of COVID-19.…”

Spike protein mutational landscape in India during the complete lockdown phase: Could Muller's ratchet be a future game-changer for COVID-19?

“…Combining all this information, here we pose an open question for future research: Does the phylodynamics of SARS-CoV-2 in India indicate any nascent action of Muller's ratchet where the otherwise deleterious mutations tend to get fixed in the population as natural selection remains unable to purge them due to excessive mutational pressures? If so, there lies an immense potential of using therapeutics that could facilitate such a process of mutational meltdown, as was demonstrated earlier for influenza A virus ( Ormond et al, 2017 ; Penisson et al, 2017 ). Altogether, future large-scale population genomics analyses supported by reliable epidemiological metadata are highly important to explore this question for India as well as for other countries across the globe to develop efficient analytical methods, thereby guiding better surveillance programs, prevention and treatment management of COVID-19.…”