Abstract
When examining bacterial genomes for evidence of past selection, the results obtained depend heavily on the mutational distance between chosen genomes. Even within a bacterial species, genomes separated by larger mutational distances exhibit stronger evidence of purifying selection as assessed by dN/dS, the normalized ratio of nonsynonymous to synonymous mutations. Here, we show that the classical interpretation of this scale-dependence, weak purifying selection, leads to problematic mutation accumulation when applied to available gut microbiome data. We propose an alternative, adaptive reversion model with exactly opposite implications for dynamical intuition and applications of dN/dS. Reversions that occur and sweep within-host populations are nearly guaranteed in microbiomes due to large population sizes, short generation times, and variable environments. Using analytical and simulation approaches, we show that adaptive reversion can explain the dN/dS decay given only dozens of locally-fluctuating selective pressures, which is realistic in the context of Bacteroides genomes. The success of the adaptive reversion model argues for interpreting low values of dN/dS obtained from long-time scales with caution, as they may emerge even when adaptive sweeps are frequent. Our work thus inverts the interpretation of an old observation in bacterial evolution, illustrates the potential of mutational reversions to shape genomic landscapes over time, and highlights the importance of studying bacterial genomic evolution on short time scales.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
In response to the reviewer comments, we have significantly revised our manuscript. We have added three new analyses covering recombination in the purifying model, compensatory mutations in the reversion model, and genomic evidence of reversion. Together, these changes have resulted in a new main figure panel, 6 new SI Figures, and 2 new SI tables, alongside numerous enhancements to the text. We have also edited the text substantially to better highlight the novelty and significance of the work. Referenced page numbers may differ due to differences in formatting.
