Mutation landscape of base substitutions, duplications, and deletions in the representative current cholera pandemic strain

Abstract

Pandemic cholera is a major concern for public health because of its high mortality and morbidity. Mutation accumulation (MA) experiments were performed on a representative strain of the current cholera pandemic. Although the base-pair substitution mutation rates in Vibrio cholerae (1.24×1010 per site per generation for wild-Type lines and 3.29×10-8 for mismatch repair deficient lines) are lower than that previously reported in other bacteria using MA analysis, we discovered specific high rates (8.31×10-8 site/generation forwild-Type lines and 1.82×10-6 formismatch repair deficient lines) of base duplication or deletion driven by large-scale copy number variations (CNVs). These duplication-deletions are located in two pathogenic islands, IMEX and the large integron island. Each element of these islands has discrepant rate in rapid integration and excision,which provides clues to the pandemicity evolution of V. cholerae. These results also suggest that large-scale structural variants such asCNVs can accumulate rapidly during short-Term evolution. Mismatch repair deficient lines exhibit a significantly increased mutation rate in the larger chromosome (Chr1) at specific regions, and this pattern is not observed in wild-Type lines. We propose that the high frequency of GATC sites in Chr1 improves the efficiency ofMMR, resulting in similar rates of mutation in the wild-Type condition. In addition, differentmutation rates and spectrawere observed in theMA lines under distinct growth conditions, including minimalmedia, rich media and antibiotic treatments.