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The CC17 lineage of the important multi-host pathogen group B Streptococcus has emerged as a hypervirulent clone in human neonates, the molecular basis for which remains elusive. In this study we identify a novel type II restriction modification system that is uniquely associated with the CC17 clade. Using in vitro and in vivo techniques, we show that this system acts as a barrier to genetic exchange, which drives the genetic recalcitrance and low levels of homologous recombination associated with the CC17 clade. Strikingly, the restriction modification system also directly regulates expression of the transcriptional activator NanR and promotes murine vaginal colonization and ascension to the uterus, implicating a role for DNA methylation in promoting persistence at polymicrobial mucosal surfaces. Together, these findings reveal for the first time the importance of restriction modification system activity in defining the lineage structure and virulence potential of group B Streptococcus, uncovering a novel mechanism that underpins the global success of the CC17 clade as a major neonatal pathogen.<\/jats:p>","DOI":"10.1093\/nar\/gkag683","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T09:50:25Z","timestamp":1783504225000},"source":"Crossref","is-referenced-by-count":0,"title":["Acquisition of a novel restriction modification system regulates genetic flux and gene expression in the hypervirulent and globally disseminated CC17 lineage of group B\n                    <i>Streptococcus<\/i>"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3131-9834","authenticated-orcid":false,"given":"Joana","family":"Alves","sequence":"first","affiliation":[{"name":"The Roslin Institute, University of Edinburgh , Easter Bush 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, Dundee, Scotland DD1 5EH ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4232-6837","authenticated-orcid":false,"given":"Kelly S","family":"Doran","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus , Aurora, CO 80045 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1164-8000","authenticated-orcid":false,"given":"Ruth N","family":"Zadoks","sequence":"additional","affiliation":[{"name":"Sydney School of Veterinary Science, Faculty of Science, University of Sydney , Camden, NSW 2570 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1599-4330","authenticated-orcid":false,"given":"Nicola N","family":"Lynskey","sequence":"additional","affiliation":[{"name":"The Roslin Institute, 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