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Abstract
Phase-variation of Type I restriction-modification systems can rapidly alter the sequence motifs they target, diversifying both the epigenetic patterns and endonuclease activity within clonally descended populations. Here, we characterize the Streptococcus pneumoniae SpnIV phase-variable Type I RMS, encoded by the translocating variable restriction (tvr) locus, to identify its target motifs, mechanism and regulation of phase variation, and effects on exchange of sequence through transformation. The specificity-determining hsdS genes were shuffled through a recombinase-mediated excision-reintegration mechanism involving circular intermediate molecules, guided by two types of direct repeat. The rate of rearrangements was limited by an attenuator and toxin-antitoxin system homologs that inhibited recombinase gene transcription. Target motifs for both the SpnIV, and multiple Type II, MTases were identified through methylation-sensitive sequencing of a panel of recombinase-null mutants. This demonstrated the species-wide diversity observed at the tvr locus can likely specify nine different methylation patterns. This will reduce sequence exchange in this diverse species, as the native form of the SpnIV RMS was demonstrated to inhibit the acquisition of genomic islands by transformation. Hence the tvr locus can drive variation in genome methylation both within and between strains, and limits the genomic plasticity of S. pneumoniae.
Highlights
Streptococcus pneumoniae is both a major bacterial respiratory pathogen [1] and an important model for studying the evolution of bacterial diversity in traits including antibiotic resistance, antigenic profile and virulence [2,3,4]
This work expands the characterized repertoire of pneumococcal restriction modification systems (RMSs) beyond the Dpn and SpnIII systems, which respectively target GATC and one of a fixed set of six sequences in almost all pneumococci, to the genomic islands (GIs)-encoded Type II RMS and Type I SpnIV RMSs, which exhibit greater population-wide diversity
The motifs recognized by the SpnIV system were somewhat limited compared to the previously hypothesized range of specificities [7]: two of the N-terminal target recognition domains (TRDs) suspected of being functionally distinct recognized the same motif; the C-terminal TRD iv was not found to facilitate targeting of particular sequences, and in loci with a 2+2 arrangement, only the upstream hsdS gene was active
Summary
Streptococcus pneumoniae (the pneumococcus) is both a major bacterial respiratory pathogen [1] and an important model for studying the evolution of bacterial diversity in traits including antibiotic resistance, antigenic profile and virulence [2,3,4]. This variation often represents the distribution of genomic islands (GIs), loci present in only a subset of the species [5,6,7,8]. Likely to be contributing to these evolutionary patterns are the diverse repertoire of restriction modification systems (RMSs) found in the pneumococcal population
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