SUMMARYMutations are critical for evolutionary change. Although mutation spectra (mutational biases) vary greatly across organisms, we lack direct evidence of their evolutionary consequences. Here, we show experimentally that a biased spectrum alters the distribution of fitness effects in a bacterium, and should facilitate adaptation by increasing beneficial mutations and reducing genetic load. Adaptive walk simulations show that this advantage arises via better sampling of mutational classes that were poorly explored by the ancestor. Hence, reversing the spectrum of a biased ancestor is generally advantageous, while introducing bias in an unbiased ancestor is selectively neutral. Indeed, across bacterial lineages, evolutionary transitions in DNA repair enzymes – which shape spectra – typically reverse ancestral bias. These broad consequences of mutation spectra imply a major role in shaping evolutionary dynamics.
Contrary to previous understanding, recent evidence indicates that synonymous codon changes may sometimes face strong selection. However, it remains difficult to generalize the nature, strength, and mechanism(s) of such selection. Previously, we showed that synonymous variants of a key enzyme-coding gene (fae) of Methylobacterium extorquens AM1 decreased enzyme production and reduced fitness dramatically. We now show that during laboratory evolution, these variants rapidly regained fitness via parallel yet variant-specific, highly beneficial point mutations in the N-terminal region of fae. These mutations (including four synonymous mutations) had weak but consistently positive impacts on transcript levels, enzyme production, or enzyme activity. However, none of the proposed mechanisms (including internal ribosome pause sites or mRNA structure) predicted the fitness impact of evolved or additional, engineered point mutations. This study shows that synonymous mutations can be fixed through strong positive selection, but the mechanism for their benefit varies depending on the local sequence context.
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