Mutation rate dynamics in a bacterial population reflect tension between adaptation and genetic load

Abstract

Mutations are the ultimate source of heritable variation for evolution. Understanding how mutation rates themselves evolve is thus essential for quantitatively understanding many evolutionary processes. According to theory, mutation rates should be minimized for well-adapted populations living in stable environments, whereas hypermutators may evolve if conditions change. However, the long-term fate of hypermutators is unknown. Using a phylogenomic approach, we found that an adapting Escherichia coli population that first evolved a mutT hypermutator phenotype was later invaded by two independent lineages with mutY mutations that reduced genome-wide mutation rates. Applying neutral theory to synonymous substitutions, we dated the emergence of these mutations and inferred that the mutT mutation increased the point-mutation rate by ∼150-fold, whereas the mutY mutations reduced the rate by ∼40-60%, with a corresponding decrease in the genetic load. Thus, the long-term fate of the hypermutators was governed by the selective advantage arising from a reduced mutation rate as the potential for further adaptation declined.

Fig. 1.

Mutation rate dynamics in an experimental population of E. coli. (A) Phylogenomic tree reconstructed from point mutations in individual clones (designated by letters A to D) isolated at the indicated time points (e.g., 20,000 generations shown as 20K) and rooted at the ancestor. Branches are colored by the presence of ancestral (wild type) or evolved alleles in the mutT and mutY genes and scaled by the number of substitutions. Note the change in scale (bars of length 2 and 50) when the mutT genotype arose after 20,000 generations. (B) Trajectory of mean fitness measured in competition against the ancestral strain is shown in green; the trajectory was fit using log-transformed values of fitness and time (Materials and Methods). Other colored symbols show the total number of point mutations relative to the ancestor in sequenced genomes, with line segments indicating rates of mutation accumulation in each background. Dashed lines indicate apparent extinctions of the ancestral and mutT-only types at unknown times. (C) Rates of mutations conferring rifampicin resistance (Rif^R) in clones estimated from fluctuation tests. Mutation rates were highest in mutT genotypes and decreased in later clones with secondary mutY mutations. Error bars show 95% confidence intervals.

Fig. 2.

Maximum likelihood model of mutation rate dynamics fit to synonymous mutations. (A) Point mutation rate estimates, expressed on a genome-wide basis. The ancestral rate was derived from a previous analysis of nonmutator clones from eight experimental populations (31). Error bars are 95% confidence intervals. (B) Relative mutation rates for two mutY compensatory mutations inferred from the maximum likelihood model and expressed relative to the mutT-only rate. Box plots show the probability distribution of this parameter, where the box shows the upper and lower quartiles, the black line the median, and the whiskers the 95% confidence interval. (C) Timing of changes in mutation rates and phylogenetic branch points. Each box plot shows the probability distribution, in time, for a branch point or change in mutation rate (with quartiles, median, and confidence limits as above). The phylogeny is overlaid on the box plots.