Genetic consequences of effective and suboptimal dosing with mutagenic drugs in a hamster model of SARS-CoV-2 infection
Christopher J R Illingworth, Jose A Guerra-Assuncao, Samuel Gregg, Oscar Charles, Juanita Pang, Sunando Roy, Rana Abdelnabi, Johan Neyts, Judith Breuer
doi:10.1093/ve/veae001/7511244
Mutagenic antiviral drugs have shown promise against multiple viruses, but concerns have been raised about whether their use might promote the emergence of new and harmful viral variants. Recently, genetic signatures associated with molnupiravir use have been identified in the global SARS-COV-2 population. Here, we examine the consequences of using favipiravir and molnupiravir to treat SARS-CoV-2 infection in a hamster model, comparing viral genome sequence data collected from (i) untreated hamsters, and (ii) from hamsters receiving effective
is expected to tend, under mutation-selection balance, to an equilibrium frequency of x=/s, where is the mutation rate and s is the magnitude of selection against the allele 53 , according to the equation Furthermore, assuming mutation rates from one allele to the other are equal, the frequency of a neutral allele is expected to tend to a frequency of one half, according to the equation In both of these formulas, the change in the frequency x is proportional to when x is small. Although positive selection and linkage disequilibrium will affect the evolution of the viral population, we nevertheless sought to fit a linear model to our data.
Analysis of variant composition The proportion of low-frequency variation of distinct mutational classes was measured using variants at frequencies of 1% or below. Briefly, the calculation of q was repeated, considering exclusively low-frequency variants, following which the proportion of this sum that is comprised of each of the 12 mutational classes was calculated. In order to explore the potential adaptive evolution of the viral populations, we identified variants which had reached a frequency of 5% or more. To analyse the composition of these variants we calculated πN/πS, defined as
Non-synonymous and synonymous variation Where cN and cS were the genome-wide counts of non-synonymous and synonymous variants reaching a frequency of 5% or more, and oN and oS are the number of potential nonsynonymous and synonymous variants that..
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