Abstract:
Linking the molecular effects of mutations to fitness is central to understanding evolutionary dynamics. Here, we establish a quantitative relation between the
global effect of mutations on the
E. coli proteome and bacterial fitness. We created
E. coli strains with specific destabilizing mutations in the
chromosomal folA gene encoding
dihydrofolate reductase(DHFR) and quantified the ensuing changes in the abundances of 2,000+
E. coli proteins in mutant strains using
tandem mass tags with subsequent LC-MS/MS. mRNA abundances in the same
E. coli strains were also quantified. The
proteomic effects of mutations in
DHFRare quantitatively linked to
phenotype: the SDs of the distributions of logarithms of relative (to WT) protein abundances anticorrelate with bacterial growth rates. Proteomes hierarchically cluster first by media conditions, and within each condition, by the severity of the perturbation to DHFR function. These results highlight the importance of a systems-level layer in the genotype-phenotype relationship.
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