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Meningococcal core and accessory phasomes vary by clonal complex
Joseph J Wanford1, Jonathan C Holmes1, Christopher D Bayliss1
1Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.
Abstract:
Neisseria meningitidis is a Gram-negative human commensal pathogen, with extensive phenotypic plasticity afforded by phase-variable (PV) gene expression. Phase variation is a stochastic switch in gene expression from an ON to an OFF state, mediated by localized hypermutation of simple sequence repeats (SSRs). Circulating N. meningitidis clones vary in propensity to cause disease, with some clonal complexes (ccs) classified as hypervirulent and others as carriage-associated. We examined the PV gene repertoires, or phasome, of these lineages in order to determine whether phase variation contributes to disease propensity. We analysed 3328 genomes representative of nine circulating meningococcal ccs with PhasomeIt, a tool that identifies PV genes by the presence of SSRs and homologous gene clusters. The presence, absence and functions of all identified PV gene clusters were confirmed by annotation or blast searches within the Neisseria PubMLST database. While no significant differences were detected in the number of PV genes or the core, conserved phasome content between hypervirulent and carriage lineages, individual ccs exhibited major variations in PV gene numbers. Phylogenetic clusters produced by phasome or core genome analyses were similar, indicating co-evolution of PV genes with the core genome. While conservation of PV clusters is high, with 76 % present in all meningococcal isolates, maintenance of an SSR is variable, ranging from conserved in all isolates to present only in a single cc, indicating differing evolutionary trajectories for each lineage. Diverse functional groups of PV genes were present across the meningococcal lineages; however, the majority directly or indirectly influence bacterial surface antigens and could impact on future vaccine development. Finally, we observe that meningococci have open pan phasomes, indicating ongoing evolution of PV gene content and a significant potential for adaptive changes in this clinically relevant genus.
Insights
Neisseria meningitidis phase variation influences disease potential. Analysis of 3328 genomes reveals that while the number of phase-variable genes varies, their presence co-evolves with the core genome, impacting surface antigens and vaccine development.
Area of Science:
- Microbiology
- Genomics
- Evolutionary Biology
Background:
- Neisseria meningitidis exhibits phenotypic plasticity through phase-variable (PV) gene expression, a process mediated by simple sequence repeats (SSRs).
- Different circulating N. meningitidis lineages (clonal complexes, ccs) display varying disease propensities, ranging from hypervirulent to carriage-associated.
Purpose of the Study:
- To investigate the role of phase variation in N. meningitidis disease propensity by analyzing the phase-variable gene repertoires (phasomes) of different lineages.
- To determine if differences in phasome content correlate with hypervirulence or carriage association in N. meningitidis.
Main Methods:
- Analysis of 3328 N. meningitidis genomes from nine circulating clonal complexes using PhasomeIt to identify PV genes based on SSRs and homologous gene clusters.
- Confirmation of PV gene presence, absence, and function through annotation and BLAST searches in the Neisseria PubMLST database.
- Comparison of phasome content and core genome phylogeny between hypervirulent and carriage-associated lineages.
Main Results:
- No significant differences in the total number of PV genes or core phasome content were found between hypervirulent and carriage lineages.
- Individual clonal complexes showed substantial variation in PV gene numbers, with phylogenetic clustering aligning between phasome and core genome analyses, suggesting co-evolution.
- While PV gene clusters are highly conserved (76%), SSR maintenance varies, indicating distinct evolutionary paths. Most PV genes influence surface antigens, relevant for vaccine development.
Conclusions:
- Phase variation contributes to N. meningitidis phenotypic diversity, but differences in phasome content do not directly distinguish hypervirulent from carriage lineages.
- Co-evolution of PV genes with the core genome is evident, with ongoing evolution of PV gene content (open pan phasomes) suggesting significant adaptive potential.
- The influence of PV genes on surface antigens highlights their importance for understanding meningococcal pathogenesis and potential targets for future vaccine strategies.
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