PT  - JOURNAL ARTICLE
AU  - Oleksandra Silayeva
AU  - Jan Engelstaedter
AU  - Andrew C Barnes
TI  - Mutators as drivers of adaptation in pathogenic bacteria and a risk factor for host jumps and vaccine escape: insights into evolutionary epidemiology of the global aquatic pathogen <em>Streptococcus iniae</em>
AID  - 10.1101/355412
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 355412
4099  - http://biorxiv.org/content/early/2018/07/12/355412.short
4100  - http://biorxiv.org/content/early/2018/07/12/355412.full
AB  - Hypermutable strains (mutators) occur via mutations in DNA repair genes and facilitate microbial adaptation as they may rapidly generate stress-resistance mutations. Bacterial mutators deficient in mismatch repair (MMR) and oxidised guanine repair (OG) are abundant in clinical settings, however their role in epidemiology and evolution of virulence remains poorly understood. Here we determine phylogenetic relationship among 80 strains of Streptococcus iniae isolated globally over 40 years using non-recombinant core genome single nucleotide polymorphisms (SNPs), estimate their mutation rate by fluctuation analysis, and identify variation in major MMR (mutS, mutL, dnaN, recD2, rnhC) and OG (mutY, mutM, mutT) genes. We find that S. iniae mutation rate phenotype and genotype are strongly associated with phylogenetic diversification and variation in major streptococcal virulence determinants (capsular polysaccharide, hemolysin, cell chain length, resistance to oxidation, and biofilm formation). Furthermore, profound changes in virulence determinants observed in mammalian isolates (atypical host) and vaccine-escape isolates found in bone (atypical tissue) of vaccinated barramundi are linked to multiple MMR and OG variants and unique mutation rates. This implies that adaptation to new host taxa, to new host tissue, and to immunity of a vaccinated host is facilitated by mutator strains. Our findings highlight the importance of mutators and mutation rate dynamics in evolution of pathogenic bacteria, in particular adaptation to a drastically different immunological setting that occurs during host jump and vaccine escape events.