The relationship between the number of randomly accumulated mutations in a genome and fitness is a key parameter in evolutionary biology1,2,3,4,5. Mutations may interact such that their combined effect on fitness is additive (no epistasis), reinforced (synergistic epistasis) or mitigated (antagonistic epistasis). We measured the decrease in fitness caused by increasing mutation number in the bacterium Salmonella typhimurium using a regulated, error-prone DNA polymerase (polymerase IV, DinB). As mutations accumulated, fitness costs increased at a diminishing rate. This suggests that random mutations interact such that their combined effect on fitness is mitigated and that the genome is buffered against the fitness reduction caused by accumulated mutations. Levels of the heat shock chaperones DnaK and GroEL increased in lineages that had accumulated many mutations, and experimental overproduction of GroEL further increased the fitness of lineages containing deleterious mutations. These findings suggest that overexpression of chaperones contributes to antagonistic epistasis.
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We thank P. Geli for help with statistics and B. Albiger, C. Kyriakopoulou, K. Maisnier-Patin and A. Poplawski for sharing their expertise in protein purification and immunological methods. This work was supported by grants from the Swedish Research Council and Uppsala University to D.I.A.
The authors declare no competing financial interests.
Chromosomal distribution and size of the random DNA fragments sequenced. (PDF 157 kb)
Negative logarithmic of fitness as a function of the logarithmic number of mutations, selective reduction factor. (PDF 80 kb)
Location and type of mutations identified in the evolved lineages. (PDF 48 kb)
Lineages with altered mutation rates. (PDF 42 kb)
Fitness and number of mutations. (PDF 45 kb)
List of bacterial strains and plasmids. (PDF 53 kb)
Calculation of the number of mutations and impact of potential biases on the observed results. (PDF 177 kb)
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Maisnier-Patin, S., Roth, J., Fredriksson, Å. et al. Genomic buffering mitigates the effects of deleterious mutations in bacteria. Nat Genet 37, 1376–1379 (2005). https://doi.org/10.1038/ng1676
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