Abstract
ABSTRACTThe causes and consequences of spatiotemporal variation in mutation rates remain to be explored in nearly all organisms. Here we examine relationships between local mutation rates and replication timing in three bacterial species whose genomes have multiple chromosomes: Vibrio fischeri, Vibrio cholerae, and Burkholderia cenocepacia. Following five mutation accumulation experiments with these bacteria conducted in the near absence of natural selection, the genomes of clones from each lineage were sequenced and analyzed to identify variation in mutation rates and spectra. In lineages lacking mismatch repair, base substitution mutation rates vary in a mirrored wave-like pattern on opposing replichores of the large chromosomes of V. fischeri and V. cholerae, where concurrently replicated regions experience similar base substitution mutation rates. The base substitution mutation rates on the small chromosome are less variable in both species but occur at similar rates to those in the concurrently replicated regions of the large chromosome. Neither nucleotide composition nor frequency of nucleotide motifs differed among regions experiencing high and low base substitution rates, which along with the inferred ~800-kb wave period suggests that the source of the periodicity is not sequence specific but rather a systematic process related to the cell cycle. These results support the notion that base substitution mutation rates are likely to vary systematically across many bacterial genomes, which exposes certain genes to elevated deleterious mutational load.
Highlights
The causes and consequences of spatiotemporal variation in mutation rates remain to be explored in most organisms
Effects of genomic position on bpsm rates can be studied in much greater detail in the mutator lineages, where adequate numbers of bpsms are distributed across the genome at intervals as short as 10 kb (Table 1), the approximate length of bacterial microdomains [7]
This enables direct comparisons between concurrently replicated intervals on both chromosomes. To illustrate how this analysis works, we plotted the patterns of bpsm rates from a recent E. coli mutator mutation accumulation (MA) experiment in which mutation rates were demonstrated to vary in a wave-like pattern that is mirrored on the two replichores of its singular circular chromosome [20, 22] (Fig. S1B)
Summary
The causes and consequences of spatiotemporal variation in mutation rates remain to be explored in most organisms. Neither nucleotide composition nor frequency of nucleotide motifs differed among regions experiencing high and low base substitution rates, which along with the inferred ~800-kb wave period suggests that the source of the periodicity is not sequence specific but rather a systematic process related to the cell cycle These results support the notion that base substitution mutation rates are likely to vary systematically across many bacterial genomes, which exposes certain genes to elevated deleterious mutational load. This study captured thousands of mutations and revealed wave-like rate variation that is synchronized with replication timing and not explained by sequence context The scale of this rate variation over hundreds of kilobases of DNA strongly suggests that a temporally regulated cellular process may generate wave-like variation in mutation risk. MA studies of MMR-deficient bacteria, including Escherichia coli, Pseudomonas fluorescens, Pseudomonas aeruginosa, and Bacillus subtilis, have revealed significant nonlinear or periodic variation in mutation rates among genome regions [19, 22,23,24,25]
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