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.

中文翻译：

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脑膜炎球菌核心和辅助相体因克隆复合体而异。


脑膜炎奈瑟菌是一种革兰氏阴性人类共生病原体，具有由相变（PV）基因表达提供的广泛表型可塑性。相位变异是基因表达从 ON 状态到 OFF 状态的随机转换，由简单序列重复 (SSR) 的局部超突变介导。循环中的脑膜炎奈瑟氏球菌克隆引起疾病的倾向各不相同，一些克隆复合体（ccs）被归类为高毒力，而另一些则被归类为与携带相关。我们检查了这些谱系的 PV 基因库或相体，以确定相变是否会导致疾病倾向。我们使用 PhasomeIt 分析了代表 9 种循环脑膜炎球菌 cc 的 3328 个基因组，PhasomeIt 是一种通过 SSR 和同源基因簇来识别 PV 基因的工具。所有已识别的 PV 基因簇的存在、缺失和功能均通过 Neisseria PubMLST 数据库中的注释或 Blast 搜索得到确认。虽然高毒力谱系和携带谱系之间的 PV 基因数量或核心、保守相体含量没有检测到显着差异，但各个 ccs 在 PV 基因数量上表现出重大差异。相体或核心基因组分析产生的系统发育簇相似，表明 PV 基因与核心基因组共同进化。虽然PV簇的保守性很高，在所有脑膜炎球菌分离株中存在76%，但SSR的维持是可变的，从在所有分离株中保守到仅存在于单个cc中，这表明每个谱系有不同的进化轨迹。 PV 基因的不同功能群存在于脑膜炎球菌谱系中；然而，大多数直接或间接影响细菌表面抗原，并可能影响未来的疫苗开发。 最后，我们观察到脑膜炎球菌具有开放的泛相体，表明 PV 基因内容的持续进化以及该临床相关属的适应性变化的巨大潜力。