Lethal Mutagenesis in Viruses and Bacteria

TL;DR

This study models how mutations affecting protein stability influence virus and bacteria survival, revealing lethal mutagenesis thresholds and correlating stability with mutation rates, aligning with experimental data.

Contribution

It introduces a genotype-phenotype model linking protein stability changes to cell viability and predicts mutation rate thresholds for lethal mutagenesis.

Findings

Lethal mutagenesis occurs near 7 mutations/genome for RNA viruses.

DNA organisms tolerate about half that mutation rate.

Model reproduces natural protein stability distributions accurately.

Abstract

Here we study how mutations which change physical properties of cell proteins (stability) impact population survival and growth. In our model the genotype is presented as a set of N numbers, folding free energies of cells N proteins. Mutations occur upon replications so that stabilities of some proteins in daughter cells differ from those in parent cell by random amounts drawn from experimental distribution of mutational effects on protein stability. The genotype-phenotype relationship posits that unstable proteins confer lethal phenotype to a cell and in addition the cells fitness (duplication rate) is proportional to the concentration of its folded proteins. Simulations reveal that lethal mutagenesis occurs at mutation rates close to 7 mutations per genome per replications for RNA viruses and about half of that for DNA based organisms, in accord with earlier predictions from analytical theory and experiment. This number appears somewhat dependent on the number of genes in the organisms and natural death rate. Further, our model reproduces the distribution of stabilities of natural proteins in excellent agreement with experiment. Our model predicts that species with high mutation rates, tend to have less stable proteins compared to species with low mutation rate.