Genome - wide biases in the rate and molecular spectrum of spontaneous 1 mutations in Vibrio cholerae and

38. CC-BY-NC 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not. ABSTRACT 39 The vast diversity in nucleotide composition and architecture among bacterial 40 genomes may be partly explained by inherent biases in the rates and spectra of 41 spontaneous mutations. Bacterial genomes with multiple chromosomes are relatively 42 unusual but some are relevant to human health, none more so than the causative agent 43 of cholera, Vibrio cholerae. Here, we present the genome-wide mutation spectra in wild-44 type and mismatch repair (MMR) defective backgrounds of two Vibrio species, the low-45 GC% squid symbiont V. fischeri and the pathogen V. cholerae, collected under 46 conditions that greatly minimize the efficiency of natural selection. In apparent contrast 47 to their high diversity in nature, both wild-type V. fischeri and V. cholerae have among 48 the lowest rates for base-substitution mutations (bpsms) and insertion-deletion 49 mutations (indels) that have been measured, below 10-3 /genome/generation. V. fischeri 50 and V. cholerae have distinct mutation spectra, but both are AT-biased and produce a 51 surprising number of multi-nucleotide indels. Furthermore, the loss of a functional MMR 52 system caused the mutation spectra of these species to converge, implying that the 53 MMR system itself contributes to species-specific mutation patterns. Bpsm and indel 54 rates varied among genome regions, but do not explain the more rapid evolutionary 55 rates of genes on chromosome 2, which likely result from weaker purifying selection. 56 More generally, the very low mutation rates of Vibrio species correlate inversely with 57 their immense population sizes and suggest that selection may not only have 58 maximized replication fidelity but also optimized other polygenic traits relative to the 59 constraints of genetic drift. 60. CC-BY-NC 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not .