Originally published as Genetics Published Articles Ahead of Print on July 20, 2009.

Genetics, Vol. 183, 639-650, October 2009, Copyright © 2009
doi:10.1534/genetics.109.106492

Lethal Mutagenesis in Viruses and Bacteria

Peiqiu Chen*,{dagger} and Eugene I. Shakhnovich*,1

* Department of Chemistry and Chemical Biology and {dagger} Department of Physics, Harvard University, Cambridge, Massachusetts 02138

1 Corresponding author: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, MA 02138.
E-mail: eugene{at}belok.harvard.edu

In this work we study how mutations that change physical properties of cell proteins (stability) affect population survival and growth. We present a model in which the genotype is presented as a set folding free energies of cell proteins. Mutations occur upon replication, so stabilities of some proteins in daughter cells differ from those in the parent cell by amounts deduced from the distribution of mutational effects on protein stability. The genotype–phenotype relationship posits that the cell's fitness (replication rate) is proportional to the concentration of its folded proteins and that unstable essential proteins result in lethality. Simulations reveal that lethal mutagenesis occurs at a mutation rate close to seven mutations in each replication of the genome for RNA viruses and at about half that rate for DNA-based organisms, in accord with earlier predictions from analytical theory and experimental results. This number appears somewhat dependent on the number of genes in the organisms and the organism's natural death rate. Further, our model reproduces the distribution of stabilities of natural proteins, in excellent agreement with experiments. We find that species with high mutation rates tend to have less stable proteins compared to species with low mutation rates.