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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><italic>Streptococcus agalactiae</italic> clones infecting humans were selected and fixed through the extensive use of tetracycline</title><author><name sortKey="Da Cunha, Violette" sort="Da Cunha, Violette" uniqKey="Da Cunha V" first="Violette" last="Da Cunha">Violette Da Cunha</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A2">CNRS UMR3525, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Institut Pasteur, Bioinformatics platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Davies, Mark R" sort="Davies, Mark R" uniqKey="Davies M" first="Mark R." last="Davies">Mark R. Davies</name><affiliation><nlm:aff id="A4">The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 15A, UK.</nlm:aff></affiliation><affiliation><nlm:aff id="A5">Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, 4072 Queensland, Australia.</nlm:aff></affiliation></author><author><name sortKey="Douarre, Pierre Emmanuel" sort="Douarre, Pierre Emmanuel" uniqKey="Douarre P" first="Pierre-Emmanuel" last="Douarre">Pierre-Emmanuel Douarre</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A2">CNRS UMR3525, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Rosinski Chupin, Isabelle" sort="Rosinski Chupin, Isabelle" uniqKey="Rosinski Chupin I" first="Isabelle" last="Rosinski-Chupin">Isabelle Rosinski-Chupin</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A2">CNRS UMR3525, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Margarit, Immaculada" sort="Margarit, Immaculada" uniqKey="Margarit I" first="Immaculada" last="Margarit">Immaculada Margarit</name><affiliation><nlm:aff id="A6">Novartis Vaccines and Diagnostics, Siena 53100, Italy.</nlm:aff></affiliation></author><author><name sortKey="Spinali, Sebastien" sort="Spinali, Sebastien" uniqKey="Spinali S" first="Sebastien" last="Spinali">Sebastien Spinali</name><affiliation><nlm:aff id="A7">Centre National de Référence des Streptocoques, Hôpitaux Universitaires, Paris Centre Cochin–Hôtel Dieu-Broca, Paris 75014, France.</nlm:aff></affiliation></author><author><name sortKey="Perkins, Tim" sort="Perkins, Tim" uniqKey="Perkins T" first="Tim" last="Perkins">Tim Perkins</name><affiliation><nlm:aff id="A6">Novartis Vaccines and Diagnostics, Siena 53100, Italy.</nlm:aff></affiliation></author><author><name sortKey="Lechat, Pierre" sort="Lechat, Pierre" uniqKey="Lechat P" first="Pierre" last="Lechat">Pierre Lechat</name><affiliation><nlm:aff id="A3">Institut Pasteur, Bioinformatics platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Dmytruk, Nicolas" sort="Dmytruk, Nicolas" uniqKey="Dmytruk N" first="Nicolas" last="Dmytruk">Nicolas Dmytruk</name><affiliation><nlm:aff id="A7">Centre National de Référence des Streptocoques, Hôpitaux Universitaires, Paris Centre Cochin–Hôtel Dieu-Broca, Paris 75014, France.</nlm:aff></affiliation></author><author><name sortKey="Sauvage, Elisabeth" sort="Sauvage, Elisabeth" uniqKey="Sauvage E" first="Elisabeth" last="Sauvage">Elisabeth Sauvage</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A2">CNRS UMR3525, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Ma, Laurence" sort="Ma, Laurence" uniqKey="Ma L" first="Laurence" last="Ma">Laurence Ma</name><affiliation><nlm:aff id="A8">Institut Pasteur Genomic platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Romi, Benedetta" sort="Romi, Benedetta" uniqKey="Romi B" first="Benedetta" last="Romi">Benedetta Romi</name><affiliation><nlm:aff id="A6">Novartis Vaccines and Diagnostics, Siena 53100, Italy.</nlm:aff></affiliation></author><author><name sortKey="Tichit, Magali" sort="Tichit, Magali" uniqKey="Tichit M" first="Magali" last="Tichit">Magali Tichit</name><affiliation><nlm:aff id="A8">Institut Pasteur Genomic platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Lopez Sanchez, Maria Jose" sort="Lopez Sanchez, Maria Jose" uniqKey="Lopez Sanchez M" first="Maria-José" last="Lopez-Sanchez">Maria-José Lopez-Sanchez</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A2">CNRS UMR3525, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Descorps Declere, Stephane" sort="Descorps Declere, Stephane" uniqKey="Descorps Declere S" first="Stéphane" last="Descorps-Declere">Stéphane Descorps-Declere</name><affiliation><nlm:aff id="A3">Institut Pasteur, Bioinformatics platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Souche, Erika" sort="Souche, Erika" uniqKey="Souche E" first="Erika" last="Souche">Erika Souche</name><affiliation><nlm:aff id="A3">Institut Pasteur, Bioinformatics platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Buchrieser, Carmen" sort="Buchrieser, Carmen" uniqKey="Buchrieser C" first="Carmen" last="Buchrieser">Carmen Buchrieser</name><affiliation><nlm:aff id="A2">CNRS UMR3525, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A9">Institut Pasteur, Biologie des Bactéries Intracellulaires, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Trieu Cuot, Patrick" sort="Trieu Cuot, Patrick" uniqKey="Trieu Cuot P" first="Patrick" last="Trieu-Cuot">Patrick Trieu-Cuot</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A10">CNRS ERL3526, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Moszer, Ivan" sort="Moszer, Ivan" uniqKey="Moszer I" first="Ivan" last="Moszer">Ivan Moszer</name><affiliation><nlm:aff id="A3">Institut Pasteur, Bioinformatics platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Clermont, Dominique" sort="Clermont, Dominique" uniqKey="Clermont D" first="Dominique" last="Clermont">Dominique Clermont</name><affiliation><nlm:aff id="A11">Institut Pasteur, Collection de l’Institut Pasteur (CIP), Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Maione, Domenico" sort="Maione, Domenico" uniqKey="Maione D" first="Domenico" last="Maione">Domenico Maione</name><affiliation><nlm:aff id="A6">Novartis Vaccines and Diagnostics, Siena 53100, Italy.</nlm:aff></affiliation></author><author><name sortKey="Bouchier, Christiane" sort="Bouchier, Christiane" uniqKey="Bouchier C" first="Christiane" last="Bouchier">Christiane Bouchier</name><affiliation><nlm:aff id="A8">Institut Pasteur Genomic platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Mcmillan, David J" sort="Mcmillan, David J" uniqKey="Mcmillan D" first="David J." last="Mcmillan">David J. Mcmillan</name><affiliation><nlm:aff id="A12">QIMR Berghofer Medical Research Institute, Brisbane, 7006 Queensland, Australia.</nlm:aff></affiliation><affiliation><nlm:aff id="A13">Inflammation and Healing Research Cluster, University of the Sunshine Coast, Sippy Downs, 4556 Queensland, Australia.</nlm:aff></affiliation></author><author><name sortKey="Parkhill, Julian" sort="Parkhill, Julian" uniqKey="Parkhill J" first="Julian" last="Parkhill">Julian Parkhill</name><affiliation><nlm:aff id="A4">The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 15A, UK.</nlm:aff></affiliation></author><author><name sortKey="Telford, John L" sort="Telford, John L" uniqKey="Telford J" first="John L." last="Telford">John L. Telford</name><affiliation><nlm:aff id="A6">Novartis Vaccines and Diagnostics, Siena 53100, Italy.</nlm:aff></affiliation></author><author><name sortKey="Dougan, Gordan" sort="Dougan, Gordan" uniqKey="Dougan G" first="Gordan" last="Dougan">Gordan Dougan</name><affiliation><nlm:aff id="A4">The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 15A, UK.</nlm:aff></affiliation></author><author><name sortKey="Walker, Mark J" sort="Walker, Mark J" uniqKey="Walker M" first="Mark J." last="Walker">Mark J. Walker</name><affiliation><nlm:aff id="A5">Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, 4072 Queensland, Australia.</nlm:aff></affiliation></author><author><name sortKey="Holden, Matthew T G" sort="Holden, Matthew T G" uniqKey="Holden M" first="Matthew T. G." last="Holden">Matthew T. G. Holden</name><affiliation><nlm:aff id="A4">The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 15A, UK.</nlm:aff></affiliation></author><author><name sortKey="Poyart, Claire" sort="Poyart, Claire" uniqKey="Poyart C" first="Claire" last="Poyart">Claire Poyart</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A7">Centre National de Référence des Streptocoques, Hôpitaux Universitaires, Paris Centre Cochin–Hôtel Dieu-Broca, Paris 75014, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A14">Institut Cochin, Université Sorbonne Paris Descartes, Paris 75014, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A15">INSERM, U1016, Paris 75014, France.</nlm:aff></affiliation></author><author><name sortKey="Glaser, Philippe" sort="Glaser, Philippe" uniqKey="Glaser P" first="Philippe" last="Glaser">Philippe Glaser</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A2">CNRS UMR3525, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Institut Pasteur, Bioinformatics platform, Paris 75015, France.</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25088811</idno><idno type="pmc">4538795</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538795</idno><idno type="RBID">PMC:4538795</idno><idno type="doi">10.1038/ncomms5544</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">002D87</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002D87</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>Streptococcus agalactiae</italic> clones infecting humans were selected and fixed through the extensive use of tetracycline</title><author><name sortKey="Da Cunha, Violette" sort="Da Cunha, Violette" uniqKey="Da Cunha V" first="Violette" last="Da Cunha">Violette Da Cunha</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A2">CNRS UMR3525, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Institut Pasteur, Bioinformatics platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Davies, Mark R" sort="Davies, Mark R" uniqKey="Davies M" first="Mark R." last="Davies">Mark R. Davies</name><affiliation><nlm:aff id="A4">The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 15A, UK.</nlm:aff></affiliation><affiliation><nlm:aff id="A5">Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, 4072 Queensland, Australia.</nlm:aff></affiliation></author><author><name sortKey="Douarre, Pierre Emmanuel" sort="Douarre, Pierre Emmanuel" uniqKey="Douarre P" first="Pierre-Emmanuel" last="Douarre">Pierre-Emmanuel Douarre</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A2">CNRS UMR3525, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Rosinski Chupin, Isabelle" sort="Rosinski Chupin, Isabelle" uniqKey="Rosinski Chupin I" first="Isabelle" last="Rosinski-Chupin">Isabelle Rosinski-Chupin</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A2">CNRS UMR3525, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Margarit, Immaculada" sort="Margarit, Immaculada" uniqKey="Margarit I" first="Immaculada" last="Margarit">Immaculada Margarit</name><affiliation><nlm:aff id="A6">Novartis Vaccines and Diagnostics, Siena 53100, Italy.</nlm:aff></affiliation></author><author><name sortKey="Spinali, Sebastien" sort="Spinali, Sebastien" uniqKey="Spinali S" first="Sebastien" last="Spinali">Sebastien Spinali</name><affiliation><nlm:aff id="A7">Centre National de Référence des Streptocoques, Hôpitaux Universitaires, Paris Centre Cochin–Hôtel Dieu-Broca, Paris 75014, France.</nlm:aff></affiliation></author><author><name sortKey="Perkins, Tim" sort="Perkins, Tim" uniqKey="Perkins T" first="Tim" last="Perkins">Tim Perkins</name><affiliation><nlm:aff id="A6">Novartis Vaccines and Diagnostics, Siena 53100, Italy.</nlm:aff></affiliation></author><author><name sortKey="Lechat, Pierre" sort="Lechat, Pierre" uniqKey="Lechat P" first="Pierre" last="Lechat">Pierre Lechat</name><affiliation><nlm:aff id="A3">Institut Pasteur, Bioinformatics platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Dmytruk, Nicolas" sort="Dmytruk, Nicolas" uniqKey="Dmytruk N" first="Nicolas" last="Dmytruk">Nicolas Dmytruk</name><affiliation><nlm:aff id="A7">Centre National de Référence des Streptocoques, Hôpitaux Universitaires, Paris Centre Cochin–Hôtel Dieu-Broca, Paris 75014, France.</nlm:aff></affiliation></author><author><name sortKey="Sauvage, Elisabeth" sort="Sauvage, Elisabeth" uniqKey="Sauvage E" first="Elisabeth" last="Sauvage">Elisabeth Sauvage</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A2">CNRS UMR3525, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Ma, Laurence" sort="Ma, Laurence" uniqKey="Ma L" first="Laurence" last="Ma">Laurence Ma</name><affiliation><nlm:aff id="A8">Institut Pasteur Genomic platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Romi, Benedetta" sort="Romi, Benedetta" uniqKey="Romi B" first="Benedetta" last="Romi">Benedetta Romi</name><affiliation><nlm:aff id="A6">Novartis Vaccines and Diagnostics, Siena 53100, Italy.</nlm:aff></affiliation></author><author><name sortKey="Tichit, Magali" sort="Tichit, Magali" uniqKey="Tichit M" first="Magali" last="Tichit">Magali Tichit</name><affiliation><nlm:aff id="A8">Institut Pasteur Genomic platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Lopez Sanchez, Maria Jose" sort="Lopez Sanchez, Maria Jose" uniqKey="Lopez Sanchez M" first="Maria-José" last="Lopez-Sanchez">Maria-José Lopez-Sanchez</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A2">CNRS UMR3525, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Descorps Declere, Stephane" sort="Descorps Declere, Stephane" uniqKey="Descorps Declere S" first="Stéphane" last="Descorps-Declere">Stéphane Descorps-Declere</name><affiliation><nlm:aff id="A3">Institut Pasteur, Bioinformatics platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Souche, Erika" sort="Souche, Erika" uniqKey="Souche E" first="Erika" last="Souche">Erika Souche</name><affiliation><nlm:aff id="A3">Institut Pasteur, Bioinformatics platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Buchrieser, Carmen" sort="Buchrieser, Carmen" uniqKey="Buchrieser C" first="Carmen" last="Buchrieser">Carmen Buchrieser</name><affiliation><nlm:aff id="A2">CNRS UMR3525, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A9">Institut Pasteur, Biologie des Bactéries Intracellulaires, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Trieu Cuot, Patrick" sort="Trieu Cuot, Patrick" uniqKey="Trieu Cuot P" first="Patrick" last="Trieu-Cuot">Patrick Trieu-Cuot</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A10">CNRS ERL3526, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Moszer, Ivan" sort="Moszer, Ivan" uniqKey="Moszer I" first="Ivan" last="Moszer">Ivan Moszer</name><affiliation><nlm:aff id="A3">Institut Pasteur, Bioinformatics platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Clermont, Dominique" sort="Clermont, Dominique" uniqKey="Clermont D" first="Dominique" last="Clermont">Dominique Clermont</name><affiliation><nlm:aff id="A11">Institut Pasteur, Collection de l’Institut Pasteur (CIP), Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Maione, Domenico" sort="Maione, Domenico" uniqKey="Maione D" first="Domenico" last="Maione">Domenico Maione</name><affiliation><nlm:aff id="A6">Novartis Vaccines and Diagnostics, Siena 53100, Italy.</nlm:aff></affiliation></author><author><name sortKey="Bouchier, Christiane" sort="Bouchier, Christiane" uniqKey="Bouchier C" first="Christiane" last="Bouchier">Christiane Bouchier</name><affiliation><nlm:aff id="A8">Institut Pasteur Genomic platform, Paris 75015, France.</nlm:aff></affiliation></author><author><name sortKey="Mcmillan, David J" sort="Mcmillan, David J" uniqKey="Mcmillan D" first="David J." last="Mcmillan">David J. Mcmillan</name><affiliation><nlm:aff id="A12">QIMR Berghofer Medical Research Institute, Brisbane, 7006 Queensland, Australia.</nlm:aff></affiliation><affiliation><nlm:aff id="A13">Inflammation and Healing Research Cluster, University of the Sunshine Coast, Sippy Downs, 4556 Queensland, Australia.</nlm:aff></affiliation></author><author><name sortKey="Parkhill, Julian" sort="Parkhill, Julian" uniqKey="Parkhill J" first="Julian" last="Parkhill">Julian Parkhill</name><affiliation><nlm:aff id="A4">The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 15A, UK.</nlm:aff></affiliation></author><author><name sortKey="Telford, John L" sort="Telford, John L" uniqKey="Telford J" first="John L." last="Telford">John L. Telford</name><affiliation><nlm:aff id="A6">Novartis Vaccines and Diagnostics, Siena 53100, Italy.</nlm:aff></affiliation></author><author><name sortKey="Dougan, Gordan" sort="Dougan, Gordan" uniqKey="Dougan G" first="Gordan" last="Dougan">Gordan Dougan</name><affiliation><nlm:aff id="A4">The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 15A, UK.</nlm:aff></affiliation></author><author><name sortKey="Walker, Mark J" sort="Walker, Mark J" uniqKey="Walker M" first="Mark J." last="Walker">Mark J. Walker</name><affiliation><nlm:aff id="A5">Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, 4072 Queensland, Australia.</nlm:aff></affiliation></author><author><name sortKey="Holden, Matthew T G" sort="Holden, Matthew T G" uniqKey="Holden M" first="Matthew T. G." last="Holden">Matthew T. G. Holden</name><affiliation><nlm:aff id="A4">The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 15A, UK.</nlm:aff></affiliation></author><author><name sortKey="Poyart, Claire" sort="Poyart, Claire" uniqKey="Poyart C" first="Claire" last="Poyart">Claire Poyart</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A7">Centre National de Référence des Streptocoques, Hôpitaux Universitaires, Paris Centre Cochin–Hôtel Dieu-Broca, Paris 75014, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A14">Institut Cochin, Université Sorbonne Paris Descartes, Paris 75014, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A15">INSERM, U1016, Paris 75014, France.</nlm:aff></affiliation></author><author><name sortKey="Glaser, Philippe" sort="Glaser, Philippe" uniqKey="Glaser P" first="Philippe" last="Glaser">Philippe Glaser</name><affiliation><nlm:aff id="A1">Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A2">CNRS UMR3525, Paris 75015, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Institut Pasteur, Bioinformatics platform, Paris 75015, France.</nlm:aff></affiliation></author></analytic><series><title level="j">Nature communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P6"><italic>Streptococcus agalactiae</italic> (Group B <italic>Streptococcus</italic>, GBS) is a commensal of the digestive and genitourinary tracts of humans that emerged as the leading cause of bacterial neonatal infections in Europe and North America during the 1960s. Due to the lack of epidemiological and genomic data, the reasons for this emergence are unknown. Here we show by comparative genome analysis and phylogenetic reconstruction of 229 isolates that the rise of human GBS infections corresponds to the selection and worldwide dissemination of only a few clones. The parallel expansion of the clones is preceded by the insertion of integrative and conjugative elements conferring tetracycline resistance (TcR). Thus, we propose that the use of tetracycline from 1948 onwards led in humans to the complete replacement of a diverse GBS population by only few TcR clones particularly well adapted to their host, causing the observed emergence of GBS diseases in neonates.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Edwards, Ms" uniqKey="Edwards M">MS Edwards</name></author><author><name sortKey="Baker, Cj" uniqKey="Baker C">CJ Baker</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Edmond, Km" uniqKey="Edmond K">KM Edmond</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Eickhoff, Tc" uniqKey="Eickhoff T">TC Eickhoff</name></author><author><name sortKey="Klein, Jo" uniqKey="Klein J">JO Klein</name></author><author><name sortKey="Daly, Ak" uniqKey="Daly A">AK Daly</name></author><author><name sortKey="Ingall, D" uniqKey="Ingall D">D Ingall</name></author><author><name sortKey="Finland, M" uniqKey="Finland M">M Finland</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kexel, G" uniqKey="Kexel G">G Kexel</name></author><author><name sortKey="Schoenbohm, S" uniqKey="Schoenbohm S">S Schoenbohm</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jones, N" uniqKey="Jones N">N Jones</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tazi, A" uniqKey="Tazi A">A Tazi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brochet, M" uniqKey="Brochet M">M Brochet</name></author><author><name sortKey="Couve, E" uniqKey="Couve E">E Couve</name></author><author><name sortKey="Bercion, R" uniqKey="Bercion R">R Bercion</name></author><author><name sortKey="Sire, Jm" uniqKey="Sire J">JM Sire</name></author><author><name sortKey="Glaser, P" uniqKey="Glaser P">P 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<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101528555</journal-id><journal-id journal-id-type="pubmed-jr-id">37539</journal-id><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn></journal-meta><article-meta><article-id pub-id-type="pmid">25088811</article-id><article-id pub-id-type="pmc">4538795</article-id><article-id pub-id-type="doi">10.1038/ncomms5544</article-id><article-id pub-id-type="manuscript">EMS64295</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title><italic>Streptococcus agalactiae</italic> clones infecting humans were selected and fixed through the extensive use of tetracycline</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Da Cunha</surname><given-names>Violette</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Davies</surname><given-names>Mark R.</given-names></name><xref ref-type="aff" rid="A4">4</xref><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Douarre</surname><given-names>Pierre-Emmanuel</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Rosinski-Chupin</surname><given-names>Isabelle</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Margarit</surname><given-names>Immaculada</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Spinali</surname><given-names>Sebastien</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Perkins</surname><given-names>Tim</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Lechat</surname><given-names>Pierre</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Dmytruk</surname><given-names>Nicolas</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Sauvage</surname><given-names>Elisabeth</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Ma</surname><given-names>Laurence</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Romi</surname><given-names>Benedetta</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Tichit</surname><given-names>Magali</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Lopez-Sanchez</surname><given-names>Maria-José</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Descorps-Declere</surname><given-names>Stéphane</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Souche</surname><given-names>Erika</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Buchrieser</surname><given-names>Carmen</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Trieu-Cuot</surname><given-names>Patrick</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Moszer</surname><given-names>Ivan</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Clermont</surname><given-names>Dominique</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Maione</surname><given-names>Domenico</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Bouchier</surname><given-names>Christiane</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>McMillan</surname><given-names>David J.</given-names></name><xref ref-type="aff" rid="A12">12</xref><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Parkhill</surname><given-names>Julian</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Telford</surname><given-names>John L.</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Dougan</surname><given-names>Gordan</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Walker</surname><given-names>Mark J.</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><collab>The DEVANI Consortium</collab><xref ref-type="author-notes" rid="FN2">‡</xref></contrib><contrib contrib-type="author"><name><surname>Holden</surname><given-names>Matthew T. G.</given-names></name><xref ref-type="aff" rid="A4">4</xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Poyart</surname><given-names>Claire</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A7">7</xref><xref ref-type="aff" rid="A14">14</xref><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><name><surname>Glaser</surname><given-names>Philippe</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref></contrib></contrib-group><aff id="A1"><label>1</label>Institut Pasteur, Unité de Biologie des Bacteries Pathogènes à Gram-positif, Paris 75015, France.</aff><aff id="A2"><label>2</label>CNRS UMR3525, Paris 75015, France.</aff><aff id="A3"><label>3</label>Institut Pasteur, Bioinformatics platform, Paris 75015, France.</aff><aff id="A4"><label>4</label>The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 15A, UK.</aff><aff id="A5"><label>5</label>Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, 4072 Queensland, Australia.</aff><aff id="A6"><label>6</label>Novartis Vaccines and Diagnostics, Siena 53100, Italy.</aff><aff id="A7"><label>7</label>Centre National de Référence des Streptocoques, Hôpitaux Universitaires, Paris Centre Cochin–Hôtel Dieu-Broca, Paris 75014, France.</aff><aff id="A8"><label>8</label>Institut Pasteur Genomic platform, Paris 75015, France.</aff><aff id="A9"><label>9</label>Institut Pasteur, Biologie des Bactéries Intracellulaires, Paris 75015, France.</aff><aff id="A10"><label>10</label>CNRS ERL3526, Paris 75015, France.</aff><aff id="A11"><label>11</label>Institut Pasteur, Collection de l’Institut Pasteur (CIP), Paris 75015, France.</aff><aff id="A12"><label>12</label>QIMR Berghofer Medical Research Institute, Brisbane, 7006 Queensland, Australia.</aff><aff id="A13"><label>13</label>Inflammation and Healing Research Cluster, University of the Sunshine Coast, Sippy Downs, 4556 Queensland, Australia.</aff><aff id="A14"><label>14</label>Institut Cochin, Université Sorbonne Paris Descartes, Paris 75014, France.</aff><aff id="A15"><label>15</label>INSERM, U1016, Paris 75014, France.</aff><author-notes><corresp id="CR1">Correspondence and requests for materials should be addressed to P.G. (<email>pglaser@pasteur.fr</email>)</corresp><fn fn-type="present-address" id="FN1"><label>†</label><p id="P3">Present address: School of Medicine, University of St Andrews, St Andrews KY16 9TF, Scotland, UK</p></fn><fn id="FN2"><label>‡</label><p id="P4">Pierette Melin<sup>16</sup>, Antoaneta Decheva<sup>17</sup>, Bogdan Petrunov<sup>17</sup>, Paula Kriz<sup>18</sup>, Reinhard Berner<sup>19</sup>, Anna Büchele<sup>19</sup>, Markus Hufnagel<sup>19</sup>, Mirjam Kunze<sup>19</sup>, Roberta Creti<sup>20</sup>, Lucilla Baldassarri<sup>20</sup>, Graziella Orefici<sup>20</sup>, Alberto Berardi<sup>21</sup>, Javier Rodriguez Granger<sup>22</sup>, Manuel De La Rosa Fraile<sup>22</sup>, Baharak Afshar<sup>23</sup> & Androulla Efstratiou<sup>23</sup></p><p id="P5"><sup>16</sup> National Reference Centre for Group B Streptococci, University Hospital of Liege 4000, Belgium. <sup>17</sup> National Center of Infectious and Parasitic Diseases, Sofia 1504, Bulgaria. <sup>18</sup> National Institute of Public Health, Prague 10042, Czech Republic. <sup>19</sup> University Hospital Freiburg, Freiburg 79106, Germany. <sup>20</sup> Istituto Superiore di Sanità, Rome 00161, Italy. <sup>21</sup> Azienda Ospedaliero-Universitaria Policlinico, Modena 41124, Italy. <sup>22</sup> Hospital Universitario Virgen de las Nieves, Granada 18014, Spain. <sup>23</sup> Health Protection Agency Centre for Infections, London NW9 5EQ, UK</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>27</day><month>7</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>04</day><month>8</month><year>2014</year></pub-date><pub-date pub-type="collection"><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>17</day><month>8</month><year>2015</year></pub-date><volume>5</volume><fpage>4544</fpage><lpage>4544</lpage><pmc-comment>elocation-id from pubmed: 10.1038/ncomms5544</pmc-comment>
<permissions><license license-type="permissions-link"><license-p><bold>Reprints and permission</bold> information is available online at <ext-link ext-link-type="uri" xlink:href="http://npg.nature.com/reprintsandpermissions/">http://npg.nature.com/reprintsandpermissions/</ext-link></license-p></license><license license-type="open-access"><license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p id="P6"><italic>Streptococcus agalactiae</italic> (Group B <italic>Streptococcus</italic>, GBS) is a commensal of the digestive and genitourinary tracts of humans that emerged as the leading cause of bacterial neonatal infections in Europe and North America during the 1960s. Due to the lack of epidemiological and genomic data, the reasons for this emergence are unknown. Here we show by comparative genome analysis and phylogenetic reconstruction of 229 isolates that the rise of human GBS infections corresponds to the selection and worldwide dissemination of only a few clones. The parallel expansion of the clones is preceded by the insertion of integrative and conjugative elements conferring tetracycline resistance (TcR). Thus, we propose that the use of tetracycline from 1948 onwards led in humans to the complete replacement of a diverse GBS population by only few TcR clones particularly well adapted to their host, causing the observed emergence of GBS diseases in neonates.</p></abstract></article-meta></front><body><p id="P7"><italic>Streptococcus agalactiae</italic>, or Group B streptococcus (GBS) generate considerable neonatal morbidity and mortality worldwide<sup><xref rid="R1" ref-type="bibr">1</xref>,<xref rid="R2" ref-type="bibr">2</xref></sup>. In the 1960s, it became the leading cause of neonatal infections in the US and in Europe. The first descriptions of the increase of GBS disease were reported in 1964 as between December 1961 to June 1963 GBS was described as the most frequent cause of neonatal sepsis at the Boston city hospital<sup><xref rid="R3" ref-type="bibr">3</xref></sup> and in 1965, when Kexel and Schönbohm<sup><xref rid="R4" ref-type="bibr">4</xref></sup> reported three independent cases of meningitis caused by GBS at the Children’s Clinic of the University of Bonn in Germany. However, in humans <italic>S. agalactiae</italic> is primarily a commensal of the digestive and urinary tracts, colonizing about 15–30% of healthy adults<sup><xref rid="R1" ref-type="bibr">1</xref></sup>. Surprisingly, multi-locus sequence typing (MLST) of GBS isolated from different countries showed that most human carriage and clinical isolates cluster into only five major clonal complexes (CC) (CC1, CC10, CC17, CC19 and CC23)<sup><xref rid="R5" ref-type="bibr">5</xref></sup> (<xref ref-type="table" rid="T1">Table 1</xref>). Among those, CC17 strains are considered ‘hypervirulent’ as they are responsible for the vast majority of the meningitis among neonates, and for more than 80% of the late-onset disease cases appearing after 7 days of life<sup><xref rid="R5" ref-type="bibr">5</xref>,<xref rid="R6" ref-type="bibr">6</xref></sup>. In contrast, strains responsible for early-onset disease, appearing before the 6th day of life, belong to all five major CCs. A sixth CC, CC26 is common in African countries<sup><xref rid="R7" ref-type="bibr">7</xref></sup>. In addition to causing disease in humans, GBS is also a veterinary pathogen, causing bovine mastitis<sup><xref rid="R8" ref-type="bibr">8</xref></sup>. Distinct from human isolates, the majority of bovine isolates belongs to the CC67, a CC for which no human strains have been described<sup><xref rid="R9" ref-type="bibr">9</xref></sup>. Phylogenetic analysis of 238 isolates of human and bovine origin based on the sequences of 15 genes revealed that CC17 strains represent a homogeneous group of strains of recent origin<sup><xref rid="R9" ref-type="bibr">9</xref></sup>. The expansion of CC17 strains was suggested to have contributed to the emergence of GBS infections. However, until now, the events responsible for this expansion and the emergence of GBS neonatal infections were unknown.</p><p id="P8">Here we set out to examine GBS evolution and the rise of neonatal GBS infections. We sequence the genomes of 229 strains isolated between 1953 and 2011 spanning four continents. By combining phylogenetic analyses and the analysis of antibiotic resistance markers, we show that all six human associated CCs have a recent origin and that the observed homogeneity of CC17 strains results from a low rate of recombination relative to the other CCs. Most importantly, we show that the emergence of GBS diseases is associated with the replacement of the bacterial population by a limited number of tetracycline resistant (TcR) clones.</p><sec sec-type="results" id="S1"><title>Results</title><sec id="S2"><title>Genome-based phylogeny reveals the expansion of a few clones</title><p id="P9">The sequence of 216 GBS genomes of carriage and invasive isolates selected to represent the known diversity of the human GBS population based on MLST studies and of 13 isolates of animal origin was determined. Single-nucleotide polymorphisms (SNPs) were identified by mapping the sequence reads against the genome sequence of a representative ST19 serotype III strain, RBH11. This strain belongs to the dominant CC19 clone that has been shown to display lower levels of polymorphism with strains from other CCs<sup><xref rid="R10" ref-type="bibr">10</xref></sup>. In total, we identified 40,898 SNPs sites among 1,384,073 interrogated bases unambiguously mapped in the 229 genomes. Using maximum likelihood phylogenetic methods on SNPs in the core chromosome, we determined that 97% of the 216 human isolates clustered into six well-resolved lineages that correspond to the six major human CCs (<xref ref-type="fig" rid="F1">Fig. 1a</xref>) as defined by MLST (<xref ref-type="table" rid="T1">Table 1</xref>). The average polymorphism between lineages is 0.52% (ranging from 0.36 to 0.65%). Strikingly, we observed that within each CC, one or two dominant clones showing limited polymorphisms are present, representing 83% of all isolates. Such a signature is indicative of an evolutionary bottleneck, which has resulted in a recent reduction in population size and expansion of positively selected clones.</p></sec><sec id="S3"><title>GBS CCs except for CC17 show a high rate of recombination</title><p id="P10">Based on the comparison of eight GBS genome sequences, we previously showed that the recombination of large chromosomal segments is a major contributor to the genomic diversification of GBS<sup><xref rid="R10" ref-type="bibr">10</xref></sup>. Indeed, based on the SNP distribution, here we identified evidence of recombination events encompassing all parts of the core genome (<xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 1</xref>), thus distorting the true phylogenetic relationships between GBS lineages. Recombination within each single CC was extensive involving 47% of the genome in CC1, 44% in CC10, 24% in CC19, 42% in CC23 and 19% in CC26 strains but was surprisingly low in CC17, with only 3% (<xref ref-type="fig" rid="F2">Fig. 2</xref> and <xref ref-type="table" rid="T2">Table 2</xref>). Most recombination events included genetic determinants for known surface antigens, such as genes encoding the capsular polysaccharide biosynthesis proteins, the major antigenic protein Rib/Alp, the R5 protein, the serine-rich protein and the pili (<xref ref-type="table" rid="T2">Table 2</xref>), which modulate host–cell interactions<sup><xref rid="R11" ref-type="bibr">11</xref></sup>. It is therefore likely that immune pressure is a major driving force in the genome diversification of human GBS.</p></sec><sec id="S4"><title>Specific GBS clones expanded in the mid-20th century</title><p id="P11">To non-ambiguously reconstruct the evolutionary history of the six GBS lineages, we performed evolutionary studies separately for each CC after mapping the sequencing reads against a representative strain of the CC and filtering out the recombined regions (<xref ref-type="fig" rid="F3">Figs 3</xref> and <xref ref-type="fig" rid="F4">4</xref>, <xref ref-type="supplementary-material" rid="SD1">Supplementary Figs 2</xref>–<xref ref-type="supplementary-material" rid="SD1">4</xref>, and <xref ref-type="table" rid="T2">Table 2</xref>). This showed that strains of each of the six CCs acquired only a very small number of SNPs, since their respective last common ancestor ranging from 74 to 174 SNPs per Mb. To date the last common ancestor of these clusters and of the nodes corresponding to the major sublineages, we performed temporal Bayesian analyses (BEAST)<sup><xref rid="R12" ref-type="bibr">12</xref></sup> of CC1, CC17, CC19 and CC23 for which the number of isolates and the timespan of isolations provided sufficient posterior support (<xref ref-type="fig" rid="F1">Fig. 1b–e</xref>). This analysis estimated that these CCs emerged from a common ancestor within the last 300 years, at a mutation rate of 0.56–0.93 SNP per Mb per year (<xref ref-type="fig" rid="F1">Fig. 1b–e</xref>; <xref ref-type="table" rid="T2">Table 2</xref>). These values are in-between the mutation rate predicted for the hypervirulent 027/BI/NAP1 <italic>Clostridium difficile</italic> variant (0.15–0.53 mutations per year per Mb)<sup><xref rid="R13" ref-type="bibr">13</xref></sup> and for the globally expanded multidrug-resistant PMEN1 pneumococcus (1.57 mutations per year per Mb)<sup><xref rid="R14" ref-type="bibr">14</xref></sup>. Nevertheless, the diversification of the six CCs predates by several decades the clinical emergence of GBS neonatal infections that took place in the 1960s<sup><xref rid="R3" ref-type="bibr">3</xref></sup>; therefore, the increased incidence of neonatal infections cannot be directly connected to the selection of these clones. Conversely, the majority of the predominant subclones within CC1, CC17, CC19 and CC23, were predicted to have emerged between 1917 and 1966 (<xref ref-type="fig" rid="F1">Fig. 1b–e</xref>), a time period corresponding to the observed emergence of neonatal GBS infections. Linear regression of maximum likelihood root-to-tip distances against the year of sampling showed a strong correlation with this data (<xref ref-type="fig" rid="F5">Fig. 5</xref>). This temporal analysis indicates that an evolutionary bottleneck has played a major role in altering the population structure of human GBS within the mid-20th century.</p></sec><sec id="S5"><title>Human GBS isolates belong mainly to a small number of TcR clones</title><p id="P12">A striking feature of human GBS strains is their high rate (>90%) of TcR, which is predominantly linked with the <italic>tet</italic>(M) gene encoding an elongation factor G-like protein. Among recent GBS studies, <italic>tet</italic>(M) was found in 95% of human isolates in Romania<sup><xref rid="R15" ref-type="bibr">15</xref></sup>, 85% in Kuwait<sup><xref rid="R16" ref-type="bibr">16</xref></sup> and 91% in Tunisia<sup><xref rid="R17" ref-type="bibr">17</xref></sup>. In contrast, <italic>tet</italic>(M)-associated TcR is much less frequent among strains of bovine origin. Specifically, 58% of animal GBS isolates from Portugal were TcR with only 22% expressing <italic>tet</italic>(M)<sup><xref rid="R18" ref-type="bibr">18</xref></sup>. Similar observations have been made in France where 39% are TcR and 21% express <italic>tet</italic>(M)<sup><xref rid="R19" ref-type="bibr">19</xref></sup>, Estonia, where 22% of strains exhibited varying levels of TcR<sup><xref rid="R20" ref-type="bibr">20</xref></sup> and in GBS strains isolated from milk in the state of New York where only 14.5% were TcR and 2.5% expressed <italic>tet</italic>(M)<sup><xref rid="R21" ref-type="bibr">21</xref></sup>. Furthermore, the <italic>tet</italic>(M) gene was detected in only 25% of the 51 bovine GBS genome sequences and 10% of the genome of 22 GBS strains isolated from fish that were available at the NCBI database as of 15 May, 2014. These values highlight a very high incidence of <italic>tet</italic>(M)-associated TcR within human isolates compared with animal GBS. It is known that the use of antibiotics results in a strong positive selection for antibiotic-resistant clones and an overall reduction in bacterial population diversity<sup><xref rid="R22" ref-type="bibr">22</xref></sup>. To identify a possible link between the population structure of human GBS and antibiotic resistance, we analysed the resistome of the 229 sequenced genomes (<xref ref-type="table" rid="T3">Table 3</xref>). In agreement with the epidemiological surveys, the most frequent determinants in the 216 human isolates were <italic>tet</italic>(M) (<italic>n</italic> = 183, 84%) and <italic>tet</italic>(O) (<italic>n</italic> = 10, 5%) both encoding ribosomal protection proteins, and <italic>erm</italic>(B) (<italic>n</italic> = 18, 9%) and <italic>erm</italic>(TR) (<italic>n</italic> = 12, 5.5%) encoding methylases conferring resistance to macrolides and lincosamides. Other resistance determinants were rare (<xref ref-type="table" rid="T3">Table 3</xref>). Except for one strain, <italic>tet</italic>(M) was carried by two related integrative and conjugative elements (ICEs): Tn<italic>916</italic> (<italic>n</italic> = 111) or Tn<italic>5801</italic> (<italic>n</italic> = 70) (<xref ref-type="fig" rid="F3">Fig. 3b</xref>). In the collection sequenced, Tn<italic>916</italic> and Tn<italic>5801</italic> were found in 23 and 2 different insertion sites, respectively (<xref ref-type="table" rid="T4">Table 4</xref> and <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>). Importantly, the expanded clones in all six CCs represent monophyletic lineages sharing the TcR-conferring ICE inserted at the same position (<xref ref-type="table" rid="T4">Table 4</xref>; <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>; <xref ref-type="fig" rid="F3">Figs 3a</xref> and <xref ref-type="fig" rid="F4">4a</xref> and <xref ref-type="supplementary-material" rid="SD1">Supplementary Figs 2</xref>–<xref ref-type="supplementary-material" rid="SD1">4</xref>). Moreover, for a given TcR lineage, each transposon shows a maximum of five SNPs supporting a single insertion event for each lineage. These data strongly suggest that the acquisition of ICE harbouring <italic>tet</italic>(M) has been a landmark event in the expansion of these lineages and in the emergence of the human pathogenic GBS population. Tetracycline was first used in 1948 therefore the subsequent expansion of TcR GBS clones is in agreement with our temporal analysis dating the origin of these clones in the mid-20th century (<xref ref-type="fig" rid="F1">Fig. 1b–e</xref>). Interestingly, the major clones include strains from different European and African countries and from Australia, indicating that following their selection, these clones spread globally.</p><p id="P13">GBS genomes contain a large number of ICEs and other integrative elements. To determine whether the acquisition of other genomic islands has also contributed to the expansion of these clones, we systematically searched for genes specifically acquired by the four major TcR lineages to which the reference genomes belong (CC1 lineage Tn<italic>916</italic>-1, CC17 Tn<italic>5801</italic>-11, CC19 Tn<italic>916</italic>-17 and CC23 Tn<italic>5801</italic>-23). However, we did not find evidence based on the sequenced genomes that such events have taken place.</p></sec><sec id="S6"><title>Macrolide resistance contributed to CC1 expansion</title><p id="P14">Tetracycline is not used to treat GBS infections; the most commonly employed antibiotics are ß-lactams, followed by macrolides<sup><xref rid="R23" ref-type="bibr">23</xref></sup>. Several epidemiological studies reported an increase in the incidence of macrolide resistance in GBS, in particular in strains belonging to the CC1 (<xref rid="R24" ref-type="bibr">ref. 24</xref>). Indeed, among the 32 isolates of our collection that contained an <italic>erm</italic> gene, 19 belonged to CC1 (50% of the sequenced CC1 collection) whereas the remaining 13 were sporadically distributed among the other CCs (<xref ref-type="table" rid="T3">Table 3</xref>). Among the 19 <italic>erm</italic>-positive CC1 isolates, 17 clustered into three lineages nested into TcR lineages (<xref ref-type="fig" rid="F4">Fig. 4a</xref>). In the largest of these three lineages (<italic>n</italic> = 11 isolates), the <italic>erm</italic>(B) gene is carried by Tn<italic>917</italic> inserted into Tn<italic>916</italic> leading to Tn<italic>3872</italic> first described in <italic>S. pneumoniae</italic><sup><xref rid="R25" ref-type="bibr">25</xref></sup>. A twelfth isolate, Bangui-IP-50, which belongs to another sub-lineage of the CC1 Tn<italic>916</italic>-1 lineage, also carries a Tn<italic>3872</italic> element. Comparison of the ancestral Tn<italic>916</italic> and the two versions of Tn<italic>3872</italic> showed that the majority of the SNPs (12 out of 15, strain DE-NI-001 and the 76 SNPs, strain Bangui-IP-50) clusters upstream of Tn<italic>917</italic> (<xref ref-type="fig" rid="F4">Fig. 4b</xref>). This observation suggests that Tn<italic>917</italic> was inserted in Tn<italic>916</italic> by recombination following the conjugative transfer of two versions of Tn<italic>3872</italic>; however, we cannot rule out an integration of Tn<italic>3872</italic> following the loss of Tn<italic>916</italic>. In <italic>S. agalactiae</italic>, Tn<italic>3872</italic> was first identified in four serotype V isolates and one serotype Ia isolate showing similar macro restriction patterns<sup><xref rid="R26" ref-type="bibr">26</xref></sup>. The <italic>erm</italic>(B) sequences in these strains are identical to the one present in the major macrolide resistance sub-lineage we have identified, but shows three SNPs over 738 bp in comparison with the Bangui-IP-50 <italic>erm</italic>(B) gene. Furthermore, the insertion site reported for Tn<italic>3872</italic> is the same as the insertion site of Tn<italic>916</italic>-1. It is therefore likely that the four serotype V isolates carrying Tn<italic>3872</italic> previously described belong to this sub-lineage. These findings show that the <italic>erm</italic> genes were gained after the acquisition of Tn<italic>916</italic>. Therefore, acquisition of macrolide and lincosamide resistance genes occurred after the selection of the TcR clones, and in the case of the ST1 Tn<italic>916</italic>-1 lineage, has contributed to its clonal expansion.</p></sec></sec><sec sec-type="discussion" id="S7"><title>Discussion</title><p id="P15">Our analyses indicate that the observed emergence of GBS infections in the 1960s was not due to past under-diagnosis and case reporting of the disease<sup><xref rid="R27" ref-type="bibr">27</xref></sup> but that it corresponds to a dramatic modification of the human GBS population. Indeed, we show that the human disease-causing and carriage GBS population is dominated be few TcR clones that have spread globally. Tetracycline is a broad-spectrum antibiotic, which was first used clinically in 1948. Subsequently it became widely used, with the first reported case of TcR described in <italic>Shigella dysenteriae</italic> in Japan in 1953 (<xref rid="R28" ref-type="bibr">ref. 28</xref>). This timeframe is compatible with the Bayesian estimates that predicted the origin of the GBS TcR clones in four CCs in the mid-20th century (<xref ref-type="fig" rid="F1">Fig. 1b–e</xref>) and the identification of three TcR isolates dating back to 1955 within the CC17 clone carrying Tn<italic>916</italic>-12. These three isolates represent the oldest known strains carrying Tn<italic>916</italic> (<xref rid="R29" ref-type="bibr">ref. 29</xref>). Strikingly, unlike non-CC17 isolates, and despite the larger number of sequenced isolates (<italic>n</italic> = 79), all CC17 strains belong to clones that have acquired Tn<italic>916</italic> or Tn<italic>5801</italic> (<xref ref-type="fig" rid="F3">Fig. 3a</xref> and <xref ref-type="table" rid="T4">Table 4</xref>). The absence of a CC17 population naive for these ICEs suggests that CC17 strains were rare before the evolutionary bottleneck exerted by the widespread use of tetracycline. Thus, our data allow us to propose that the acquisition of TcR led to the expansion of hypervirulent CC17 clones that then contributed to the increase of neonatal infections.</p><p id="P16">Due to the broad distribution of resistance in many bacterial species, the use of tetracycline in human health has declined<sup><xref rid="R30" ref-type="bibr">30</xref></sup>. However, in contrast to what is usually observed for other bacterial species when antibiotic selection pressure decreases, TcR among human GBS remains remarkably stable at the same very high level (>90%). These observations suggest that once inserted in the GBS genome, Tn<italic>916</italic> and Tn<italic>5801</italic> are maintained, as they seem to impose a limited fitness cost to GBS. Indeed, it has been suggested that due to the intricate mechanism of Tn<italic>916</italic> regulation, Tn<italic>916</italic> gene expression likely results in minimizing the biological cost to the host<sup><xref rid="R31" ref-type="bibr">31</xref>,<xref rid="R32" ref-type="bibr">32</xref></sup>. It should be noted that the dominance of the <italic>tet</italic>(M) gene carried by these ICEs is not specific to GBS<sup><xref rid="R31" ref-type="bibr">31</xref></sup>. Indeed, 133 of 271 <italic>Enterococcus faecalis</italic> genome sequences available in GenBank as of 15 May, 2014 contain a <italic>tet</italic>(M) gene, while only 11 contain <italic>tet</italic>(S) and one <italic>tet</italic>(O). Furthermore, TcR genes remain the most abundant antibiotic resistance genes identified in human gut microbiota as recently reported<sup><xref rid="R33" ref-type="bibr">33</xref></sup>. Therefore, the strong selective pressure that tetracycline usage has exerted is more widely observed, but in the case of GBS it has led to the emergence of pathogenic clones.</p><p id="P17">Recombination through the conjugative transfer of large genomic regions has a major role in the diversification of GBS lineages (<xref ref-type="fig" rid="F2">Fig. 2</xref>). In particular, serotype switching due to recombination of the chromosomal region encompassing the capsular biosynthesis locus is the event the most frequently observed. This is also supported by overlaying the capsular serotype distribution onto the Bayesian phylogeny (<xref ref-type="fig" rid="F1">Fig. 1b–e</xref>). Indeed, the majority of strains within CC1, CC17, CC19 and CC23 cluster into a dominant capsular serotype (<italic>cps</italic>): CC1/<italic>cps</italic>V, CC17/<italic>cps</italic>III, CC19/<italic>cps</italic>III and CC23/<italic>cps</italic>Ia. However, there is a still substantial heterogeneity within CCs relating to capsular serotype. In the case of CC19 and CC23, capsular switching is evident within the major TcR clone. Like the other major CCs examined in this study, isolates belonging to CC17 share a recent origin, however, they differ from the other CCs by a low rate of recombination. Indeed, in this CC, we detected only two recombination events in the early branch leading to the serotype IV ST256 sub-lineage (<xref ref-type="table" rid="T2">Table 2</xref>). No recombination was identified among CC17 strains, although we have previously shown that, under laboratory conditions, these strains are as permissive to conjugative transfers and recombination as non-CC17 strains<sup><xref rid="R10" ref-type="bibr">10</xref></sup>. Furthermore, all CC17 strains encode a specific repertoire of surface proteins shown to contribute to increased adherence to intestinal, choroid plexus and microvascular endothelial cells<sup><xref rid="R6" ref-type="bibr">6</xref></sup>. These observations suggest that CC17 strains colonize a specific habitat leading to genetic isolation.</p><p id="P18">In GBS, the vast majority of Tn<italic>916</italic> and Tn<italic>5801</italic> are inserted in the core genome (<xref ref-type="table" rid="T4">Table 4</xref>). Therefore, these ICE were acquired by conjugation and <italic>tet</italic>(M) is likely the major adaptive function not directly associated with genes encoding virulence factors as it has been described in enterococci<sup><xref rid="R34" ref-type="bibr">34</xref></sup>. However, the expansion of these TcR clones does not explain the concurrent emergence of neonatal infections. We propose as a model that among the selected TcR clones, those with a higher potency to colonize and to disseminate have been selected and have spread across continents replacing less virulent clones. The higher rate of TcR strains and more particularly of the <italic>tet</italic>(M) gene in human compared with bovine isolates is in support of this hypothesis. A link between antibiotic resistance and increased virulence or transmissibility has been observed for different lineages of opportunistic pathogens leading to the concept of ‘superbugs’<sup><xref rid="R35" ref-type="bibr">35</xref></sup>. Examples are the <italic>C. difficile</italic> clone 027/BI/NAP1, among which two highly virulent lineages expanded following the independent acquisition of resistance to fluoroquinolones<sup><xref rid="R13" ref-type="bibr">13</xref></sup>, and the epidemic community-acquired methicillin-resistant <italic>Staphylococcus aureus</italic> clone USA300, which is more virulent than hospital acquired MRSAs, and which emerged from CC8 <italic>S. aureus</italic> following the acquisition of the methicillin resistance-encoding staphylococcal cassette chromosome <italic>mec</italic> (SCC<italic>mec</italic>) type IV element, and the arginine catabolite mobile element<sup><xref rid="R36" ref-type="bibr">36</xref></sup>. In USA300, the type I arginine catabolite mobile element is integrated proximal to the SCC<italic>mec</italic> element, and carries a <italic>speG</italic> gene which encodes a spermidine acetyl transferase that has been shown to contribute to the dissemination and to the virulence of these strains<sup><xref rid="R37" ref-type="bibr">37</xref></sup>. Another striking example is the <italic>Enterococcus faecium</italic> hospital-associated lineages ST17, ST18 and ST78 that are all virulent and resistant to multiple antibiotics including vancomycin<sup><xref rid="R38" ref-type="bibr">38</xref>,<xref rid="R39" ref-type="bibr">39</xref></sup>. <italic>E. faecium</italic> hospital-adapted lineages show a distinct genetic repertoire compared with carriage strains and phylogenomic analysis indicated that they are unrelated to human carrier isolates but they originate from animal strains<sup><xref rid="R39" ref-type="bibr">39</xref></sup>. However, unique to GBS, the recent evolutionary bottleneck due to the use of tetracycline led to the global replacement of the GBS population colonizing humans. In particular, this bottleneck led to the fixation of the CC17 lineage, which shows a higher virulence in neonates<sup><xref rid="R6" ref-type="bibr">6</xref></sup>. Therefore, our data strongly suggest that the widespread use of tetracycline has helped drive the emergence of GBS neonatal infections, and created pandemic drug-resistant clones which pose a continued threat to human health.</p></sec><sec sec-type="methods" id="S8"><title>Methods</title><sec id="S9"><title><italic>Streptococcus agalactiae</italic> (GBS) isolates</title><p id="P19">GBS strains isolated between 1953 and 2011 are listed in <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>. Their geographical origin, the epidemiological status (early-onset disease; late-onset disease; adult invasive disease, AInv; neonatal invasive disease, NInv; carriage or of animal origin), the year of isolation, the capsular serotype (<italic>cps</italic>) and the sequence type are indicated. Strains were predominantly isolated from Europe (nine countries), Africa (three countries) and Australia. Carriage and invasive strains were selected to reflect the distribution of isolates according to MLST studies (<xref ref-type="table" rid="T1">Table 1</xref>). CC17 strains were over represented in the collection in an attempt to help characterize the specificity of this hypervirulent lineage. The 12 strains isolated between 1953 and 1961 from the Institut Pasteur bacterial strain collection (CRBIP) belong to CC17, CC19 and CC23. The earliest isolates from the CC1 lineage are from 1997, therefore contributing to lower confidence in dating the origin of this particular lineage (<xref ref-type="fig" rid="F1">Fig. 1e</xref>). Thirteen strains are of animal origin.</p></sec><sec id="S10"><title>Sequencing, mapping and SNP detection</title><p id="P20">Genomes were sequenced using the Illumina GAIIX or HiSeq2000 sequencing platforms. The read length for each genome is specified in <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>. The minimal coverage was 75-fold. The sequencing reads were filtered to exclude reads with a quality score of <25 in 10% of the reads and aligned to the reference sequence by using Burrows-Wheeler Aligner<sup><xref rid="R40" ref-type="bibr">40</xref></sup>. SNP calling was done using SAMtools MPILEUP and varFilter<sup><xref rid="R41" ref-type="bibr">41</xref></sup>. We excluded SNPs identified in repeated regions, within 100 bp of the contig boundaries from draft reference genome assemblies, or in regions with coverage lower than 40% of the strain’s mean coverage. Reference genomes selected as belonging to the dominant clone of each CC are described in <xref ref-type="table" rid="T2">Table 2</xref>. The genome of strain COH1 was completely finished by closing the gaps of the previously determined draft genome sequence<sup><xref rid="R42" ref-type="bibr">42</xref></sup>. Finishing was performed by Sanger sequencing of PCR products corresponding to gaps and to low-quality regions. The COH1 genome was annotated as previously described<sup><xref rid="R43" ref-type="bibr">43</xref></sup>. Briefly, coding sequences were defined by combining Genmark predictions with visual inspection of each open-reading frame for the presence of a start codon with an upstream ribosome-binding site and BLASTp similarity searches on Uniref 90, Trembl and Swissprot databases. Function predictions were based on blastp similarity searches and on the analysis of motifs using the Pfam databases (<ext-link ext-link-type="uri" xlink:href="http://pfam.xfam.org/">http://pfam.xfam.org/</ext-link>). The five other reference genomes were obtained after ordering the Velvet assembled contigs by using the MAUVE software<sup><xref rid="R44" ref-type="bibr">44</xref></sup> and the genome of 2603V/R as reference<sup><xref rid="R45" ref-type="bibr">45</xref></sup>. They were automatically annotated by using the RAST server<sup><xref rid="R46" ref-type="bibr">46</xref></sup>.</p></sec><sec id="S11"><title><italic>De novo</italic> assembly and sequence analysis</title><p id="P21">Genome sequences were assembled using the Velvet software<sup><xref rid="R47" ref-type="bibr">47</xref></sup> with an optimized <italic>k</italic>-value and a minimal coverage of 10. MLST types were determined by extracting the sequences of the seven genes of the GBS MLST system<sup><xref rid="R5" ref-type="bibr">5</xref></sup> and comparing them with the known STs from the GBS MLST web server (<ext-link ext-link-type="uri" xlink:href="http://pubmlst.org/sagalactiae/">http://pubmlst.org/sagalactiae/</ext-link>). Serotypes were determined by BLASTn similarity search using as query the nucleotide sequences of the ten <italic>cps</italic> loci corresponding to the 10 known GBS serotypes. Antibiotic resistance genes were searched by BLASTx search with the protein sequences of 38 resistance genes from Gram-positive bacteria for tetracycline, macrolides, streptomycin, kanamycin, spectinomycin, streptothrycin, lincosamides and chloramphenicol. Genomic islands encoding antibiotic resistance genes were analysed by extracting the sequences surrounding the antibiotic resistance genes. Tn<italic>916</italic> and Tn<italic>5801</italic> insertion sites were determined by analysing the chromosome–transposon junctions (<xref ref-type="table" rid="T4">Table 4</xref>).</p></sec><sec id="S12"><title>Phylogenetic analysis</title><p id="P22">A phylogeny of the 229 GBS isolates sequenced here and the fish isolate SS1219 (<xref rid="R48" ref-type="bibr">ref. 48</xref>) was constructed by considering nucleotides corresponding to all variable positions located in the core genome for example, in regions present in all isolates. Individual phylogenies of the six CCs were performed after removal of the genomic islands not shared by all isolates, and recombined regions. Automatic detection of recombined regions using the Gubbins software<sup><xref rid="R14" ref-type="bibr">14</xref></sup> was used to predict genome variation that had arisen by homologous recombination. The ability of this method to robustly predict recombination across the whole population was limited due to the observed genetic diversity of the population, and the corresponding deep branches of the phylogeny. We therefore combined this automatic detection with the visual inspection of variation in each of individual CCs in SyntView<sup><xref rid="R49" ref-type="bibr">49</xref></sup> viewer (<ext-link ext-link-type="uri" xlink:href="http://genopole.pasteur.fr/SynTView/flash/Streptococcus_agalactiae">http://genopole.pasteur.fr/SynTView/flash/Streptococcus_agalactiae</ext-link>), to identify clusters of SNPs likely to have arisen by recombination. Phylogenetic relationships were inferred using the Maximum Likelihood (ML) method in MEGA5 version 5.10 (<xref rid="R50" ref-type="bibr">ref. 50</xref>) and the BEAST software v1.7.5 (<xref rid="R51" ref-type="bibr">ref. 51</xref>). The confidence of the ML tree was estimated using the bootstrap method with 200 bootstrap replications. The trees of the six individual CCs were rooted by using the sequence of an isolate belonging to another CC. The species tree is unrooted. The Bayesian phylogenetic software of BEAST v1.7.5 (<xref rid="R12" ref-type="bibr">ref. 12</xref>) was used to investigate the temporal evolution of CC1, CC17, CC19 and CC23. The non-recombined variable sites as defined above for each CC was used as markers of ancestral polymorphisms and the year of isolation for each isolate (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>) was used to calibrate the clock rate. We used the GTR model of nucleotide substitution with four discrete gamma-distributed rate categories and a default gamma prior distribution of 1. To identify the most suitable models, we compared the strict, lognormal relaxed and exponential-relaxed molecular clock models and coalescent constant, exponential growth, expansion growth and Bayesian skyline tree models, using stepping-stone sampling and comparison of log marginal likelihoods<sup><xref rid="R52" ref-type="bibr">52</xref>–<xref rid="R54" ref-type="bibr">54</xref></sup>. Model analyses were conducted in triplicate for 50 million Markov Chain Monte Carlo generations with samples taken every 1,000 generations. Replicate analyses were combined with 10% removed as burn-in using LogCombiner<sup><xref rid="R12" ref-type="bibr">12</xref></sup>. The Bayesian skyline tree model along with the uncorrelated lognormal relaxed molecular clock to accommodate for rate variation among lineages was preferred. Therefore, final phylogenetic analyses were run in triplicate for 100 million Markov Chain Monte Carlo generations with 10% burn-in using the above parameters. Overall congruency of Bayesian models were observed for all four CCs analysed by BEAST; however, the lack of a wide temporal sampling of strains for CC1 resulted in the lack of an accurate root to accurately define a clock rate, hence the broad confidence values observed in <xref ref-type="fig" rid="F1">Fig. 1e</xref>. Path-O-Gen (<ext-link ext-link-type="uri" xlink:href="http://tree.bio.ed.ac.uk/software/pathogen/">http://tree.bio.ed.ac.uk/software/pathogen/</ext-link>) was used to identify a ‘molecular clock’ evolutionary signal as defined by a linear association between the ML root-to-tip branch lengths and year of strain isolation for the five major TcR sub-lineages. This also enabled an alternative method to the Bayesian approach of BEAST to date the expansion event of the five major TcR sub-lineages. ML trees were generated in the sub-lineages: CC1 Tn<italic>916</italic>-1 (<italic>n</italic> = 26); CC19 Tn<italic>916</italic>-17 (<italic>n</italic> = 20); CC17 Tn<italic>5801</italic>-11 (<italic>n</italic> = 41); CC17 Tn<italic>916</italic>-12 (<italic>n</italic> = 23) and CC23 Tn<italic>5801</italic>-2 (<italic>n</italic> = 18) from the same recombination-removed SNP alignments used for BEAST analyses.</p></sec></sec><sec sec-type="supplementary-material" id="SM"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="SD1"><label>Supplementary data</label><media xlink:href="NIHMS64295-supplement-Supplementary_data.pdf" orientation="portrait" xlink:type="simple" id="d36e1365" position="anchor"></media></supplementary-material></sec></body><back><ack id="S13"><title>Acknowledgements</title><p>This work was supported by the French National Research Agency (Grant ANR-08-GENM-027-001 and 2010-PATH-004-02) and by the Labex IBEID. The Institut Pasteur Genopole is a member of France Génomique (ANR10-IBNS-09-08). M.R.D. is supported by the National Health and Medical Research Council of Australia (565526 and 635250). M.T.G.H. and J.P. were supported by Wellcome Trust grant 098051. This study was in part supported by the European Commission Seventh Framework (grant agreement number 200481) as part of the DEVANI program. We would like to acknowledge Dr Sri Sriprakash and Ms Karen Taylor for their involvement with the Australian GBS strain collection and Alexandre Almeida for critical reading of the manuscript.</p></ack><fn-group><fn id="FN4"><p id="P23"><bold>Accession codes:</bold> The finished genome of GBS strain COH1 has been deposited in the DDBJ/GenBank/EMBL nucleotide databases with accession code HG939456. The sequence reads of the 228 GBS Illumina-sequenced genomes have been deposited in the European Nucleotide Archive (ENA) with accession codes ERS039613 to ERS039707, ERS046905 to ERS046932, and ERS337437 to ERS337549 (as specified in <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>).</p></fn><fn id="FN5"><p id="P24"><bold><xref ref-type="supplementary-material" rid="SM">Supplementary Information</xref></bold> accompanies this paper at <ext-link ext-link-type="uri" xlink:href="http://www.nature.com/naturecommunications">http://www.nature.com/naturecommunications</ext-link></p></fn><fn id="FN6"><p id="P25"><bold>Competing financial interests:</bold> J.L.T., I.M. and D.M. are full-time employees of Novartis Vaccines and Diagnostics srl. The remaining of authors declare no conflict of interest.</p></fn></fn-group><app-group><app id="APP1"><title>Author contributions</title><p id="P2">V.D.C., M.R.D. and M.T.G.H. analysed data and wrote the manuscript; P.-E.D. and I.R.-C. performed experiments and analysed data; I.Ma., T.P., E.S., L.M., B.R., M.T., M.-J.L.-S., P.T.-C., D.M., C.Bo. and J.P. performed experiments; S.S. and N.D. provided GBS isolates; P.L., S.D.-D., E.S. and I.Mo. provided software and bioinformatics expertise; C.Bu. and M.J.W. wrote the manuscript; J.L.T., G.D. and M.J.W. designed the experiments, The DEVANI members, D.C. and D.J.M. selected and provided GBS isolates; C.P. selected and provided GBS isolates and wrote the manuscript, P.G. conceived the experiments, selected isolates, analysed data and wrote the manuscript.</p></app></app-group><ref-list><title>References</title><ref id="R1"><label>1</label><element-citation publication-type="book"><person-group person-group-type="author"><name><surname>Edwards</surname><given-names>MS</given-names></name><name><surname>Baker</surname><given-names>CJ</given-names></name></person-group><person-group person-group-type="editor"><name><surname>Klein</surname><given-names>JO</given-names></name><name><surname>Remington</surname><given-names>JS</given-names></name></person-group><article-title>Group B streptococcal infections</article-title><source>Infectious Diseases of the Fetus and Newborn Infant</source><year>2005</year><publisher-name>Saunders</publisher-name></element-citation></ref><ref id="R2"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Edmond</surname><given-names>KM</given-names></name><etal></etal></person-group><article-title>Group B streptococcal disease in infants aged younger than 3 months: systematic review and meta-analysis</article-title><source>Lancet</source><year>2012</year><volume>379</volume><fpage>547</fpage><lpage>556</lpage><pub-id pub-id-type="pmid">22226047</pub-id></element-citation></ref><ref id="R3"><label>3</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Eickhoff</surname><given-names>TC</given-names></name><name><surname>Klein</surname><given-names>JO</given-names></name><name><surname>Daly</surname><given-names>AK</given-names></name><name><surname>Ingall</surname><given-names>D</given-names></name><name><surname>Finland</surname><given-names>M</given-names></name></person-group><article-title>Neonatal sepsis and other infections due to group B beta-hemolytic streptococci</article-title><source>N. 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Chemother</source><year>2010</year><volume>65</volume><fpage>1907</fpage><lpage>1914</lpage><pub-id pub-id-type="pmid">20584746</pub-id></element-citation></ref><ref id="R59"><label>59</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Huber</surname><given-names>CA</given-names></name><name><surname>McOdimba</surname><given-names>F</given-names></name><name><surname>Pflueger</surname><given-names>V</given-names></name><name><surname>Daubenberger</surname><given-names>CA</given-names></name><name><surname>Revathi</surname><given-names>G</given-names></name></person-group><article-title>Characterization of invasive and colonizing isolates of <italic>Streptococcus agalactiae</italic> in East African adults</article-title><source>J. Clin. Microbiol</source><year>2011</year><volume>49</volume><fpage>3652</fpage><lpage>3655</lpage><pub-id pub-id-type="pmid">21865428</pub-id></element-citation></ref></ref-list></back><floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><title>Population structure of human GBS is driven by tetracycline resistance acquisition</title><p>(<bold>a</bold>) Whole-genome-based phylogeny of 229 sequenced GBS isolates and strain SS1219 isolated from fish<sup><xref rid="R48" ref-type="bibr">48</xref></sup>. Maximum Likelihood (ML) using MEGA was used to infer phylogenetic relationships. The major clonal complexes (CC) 1, 10, 17, 19, 23 and 26 as defined on the GBS MLST web site (<ext-link ext-link-type="uri" xlink:href="http://pubmlst.org/sagalactiae/">http://pubmlst.org/sagalactiae/</ext-link>) correspond to well-defined branches. Isolates are indicated by dots coloured according to their geographical origin. Flanking the whole-genome phylogeny, are four Bayesian maximum clade credibility phylogenies (<bold>b–e</bold>) based on the non-recombinogenic genome for the GBS CC17 (<bold>b</bold>), CC23 (<bold>c</bold>), CC19 (<bold>d</bold>) and CC1 strains (<bold>e</bold>). Divergence dates (median estimates with 95% highest posterior density dates in brackets) are provided in blue for the major nodes. Coloured branches relate to the major tetracycline-resistant clones. Arrows indicate the predicted time of insertion of the ICE carrying the <italic>tet</italic>(M) resistance determinant within the major clones. Capsular serotypes are indicated on the right of each tree according to the indicated colour code.</p></caption><graphic xlink:href="emss-64295-f0001"></graphic></fig><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><title>Distribution of SNPs and recombination across all GBS isolates from the six major CCs</title><p>The maps were generated by using the SyntView software. Isolates were ordered according to the distance from the reference genome depicted at the inner circle. CC numbers are indicated in the centre. Recombined regions compared with the reference genome correspond to regions with a higher density of SNPs indicated by short lines on each circle corresponding to one strain. Around the outside circle are the relative positions of selected antigenic loci. The reference genomes were BG-NI-011 for CC1, DK-NI-008 for CC10, COH1 for CC17, RBH11 for CC19, CCH210801006 for CC23 and Bangui-IP-105 for CC26.</p></caption><graphic xlink:href="emss-64295-f0002"></graphic></fig><fig id="F3" orientation="portrait" position="float"><label>Figure 3</label><caption><title>Phylogeny of the ‘hypervirulent’ CC17 lineage</title><p>(<bold>a</bold>) ML phylogeny based on the alignment of 3,922 polymorphic positions. Six independent ICE insertions (indicated on the right and by blue arrows) corresponding to six different lineages (indicated by different colours) were identified and are numbered from 11 to 16 (<xref ref-type="table" rid="T4">Table 4</xref>). A star indicates that Tn<italic>5801</italic> has been lost by this isolate. Following the loss of Tn<italic>5801</italic>, strains CCH210160764 and CCH207800974 have acquired unrelated ICE expressing <italic>tet</italic>(M) and <italic>erm</italic>(B), and <italic>tet</italic>(O) and <italic>erm</italic>(B), respectively. Nodes with >90% bootstrap support are indicated by black dots. (<bold>b</bold>) Genetic maps and alignment of Tn<italic>916</italic> and Tn<italic>5801</italic>. Comparisons were performed by BLASTn. The <italic>tet</italic>(M) gene is coloured in yellow, genes encoding type 4 secretion system components are in blue and the integrase and excisionase genes which are not conserved between the two transposons in red. Percentages of identities are shown in blue scale and range between 68 and 98% for the <italic>tet</italic>(M) region.</p></caption><graphic xlink:href="emss-64295-f0003"></graphic></fig><fig id="F4" orientation="portrait" position="float"><label>Figure 4</label><caption><title>Phylogeny of clonal complex CC1</title><p>(<bold>a</bold>) ML phylogeny from the alignment of pseudosequences of the 1,244 polymorphic positions in 914 interrogated kbases. The five independent Tn<italic>916</italic> or Tn<italic>5801</italic> insertions are indicated in blue and numbers from 1 to 5 refer to their description in <xref ref-type="table" rid="T4">Table 4</xref>. The two TcR lineages with more than one isolate are coloured in blue and red. Three sub-lineages have acquired an <italic>erm</italic> resistance gene. Within lineage Tn<italic>916</italic>-1, 40% of the isolates (12) carry Tn<italic>3872</italic> (dark-blue branch and strain Bangui-IP-30). The four observed serotypes (<italic>cps</italic>) II, IV, V and VI are indicated in violet. A star indicates that Tn<italic>916</italic> has been lost by the isolate. Antibiotic resistance genes other than <italic>tet</italic>(M) are indicated in red. Nodes with >90% bootstrap support are indicated by black dots. (<bold>b</bold>) Genetic map of Tn<italic>3872</italic>. Tn<italic>917</italic> carrying the <italic>erm</italic>(B) gene is in grey the <italic>erm</italic>(B) gene being in orange, Tn<italic>916</italic> genes are coloured as in <xref ref-type="fig" rid="F3">Fig. 3</xref>. The location of 13 out of the 15 SNPs between strain CZ-NI-006 Tn<italic>916</italic> and strain DE-NI-001 Tn<italic>3872</italic>, indicated by black bars are located between positions 10,407 and 13,659 (Tn<italic>916</italic> coordinates) and the 76 SNPs between strain Bangui-IP-50 and strain CZ-NI-006, all located between position 10,407 and 13,497 are in blue.</p></caption><graphic xlink:href="emss-64295-f0004"></graphic></fig><fig id="F5" orientation="portrait" position="float"><label>Figure 5</label><caption><title>Correlation of isolation date with maximum likelihood root-to-tip branch length for the five major TcR lineages calculated with Path-O-Gen</title><p>These analyses predict the origin of these clones in agreement with the BEAST analysis except for the CC23 lineage where there was a lack of temporal sampling to support tree root estimates. <italic>X</italic> axis, time in years; <italic>Y</italic> axis root-to-tip branch length in SNP per Mb. (<bold>a</bold>) CC1 lineage Tn<italic>916</italic>-1; (<bold>b</bold>) CC19 lineage Tn<italic>916</italic>-17; (<bold>c</bold>) CC17 lineage Tn<italic>5801</italic>-11; (<bold>d</bold>) CC17 lineage Tn<italic>916</italic>-12; (<bold>e</bold>) CC23 lineage Tn<italic>5801</italic>-23.</p></caption><graphic xlink:href="emss-64295-f0005"></graphic></fig><table-wrap id="T1" position="float" orientation="landscape"><label>Table 1</label><caption><title>Summary of global multi-locus sequence typing studies<xref ref-type="table-fn" rid="TFN2">*</xref>.</title></caption><table frame="below" rules="groups"><thead><tr><th align="left" valign="middle" rowspan="1" colspan="1">Study<xref ref-type="table-fn" rid="TFN3">†</xref></th><th align="left" valign="middle" rowspan="1" colspan="1">Origin<xref ref-type="table-fn" rid="TFN4">‡</xref></th><th align="left" valign="middle" rowspan="1" colspan="1">Clinical origin<xref ref-type="table-fn" rid="TFN5">§</xref></th><th align="right" valign="middle" rowspan="1" colspan="1">Number of<break></break>isolates</th><th align="center" valign="middle" rowspan="1" colspan="1">CC1 (ST1)<xref ref-type="table-fn" rid="TFN6">∥</xref></th><th align="center" valign="middle" rowspan="1" colspan="1">CC10<xref ref-type="table-fn" rid="TFN7">¶</xref></th><th align="center" valign="middle" rowspan="1" colspan="1">CC17</th><th align="center" valign="middle" rowspan="1" colspan="1">CC19 (ST19, 28)<xref ref-type="table-fn" rid="TFN6">∥</xref></th><th align="center" valign="middle" rowspan="1" colspan="1">CC23</th><th align="center" valign="middle" rowspan="1" colspan="1">CC26</th><th align="center" valign="middle" rowspan="1" colspan="1">Other</th></tr></thead><tbody><tr><td align="left" valign="middle" rowspan="1" colspan="1">Jones<sup><xref rid="R5" ref-type="bibr">5</xref></sup></td><td align="left" valign="middle" rowspan="1" colspan="1">World</td><td align="left" valign="middle" rowspan="1" colspan="1">Ca, Ninv, Ainv</td><td align="right" valign="middle" rowspan="1" colspan="1">152</td><td align="center" valign="middle" rowspan="1" colspan="1">16% (14%)</td><td align="center" valign="middle" rowspan="1" colspan="1">18%</td><td align="center" valign="middle" rowspan="1" colspan="1">30%</td><td align="center" valign="middle" rowspan="1" colspan="1">17% (13%–2%)</td><td align="center" valign="middle" rowspan="1" colspan="1">12%</td><td align="center" valign="middle" rowspan="1" colspan="1">2%</td><td align="center" valign="middle" rowspan="1" colspan="1">5%</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Luan<sup><xref rid="R55" ref-type="bibr">55</xref></sup></td><td align="left" valign="middle" rowspan="1" colspan="1">Sweden (1988–1997)</td><td align="left" valign="middle" rowspan="1" colspan="1">Ninv, Ainv</td><td align="right" valign="middle" rowspan="1" colspan="1">158</td><td align="center" valign="middle" rowspan="1" colspan="1">15% (9%)</td><td align="center" valign="middle" rowspan="1" colspan="1">13%</td><td align="center" valign="middle" rowspan="1" colspan="1">24%</td><td align="center" valign="middle" rowspan="1" colspan="1">29% (16%–1%)</td><td align="center" valign="middle" rowspan="1" colspan="1">14%</td><td align="center" valign="middle" rowspan="1" colspan="1">0</td><td align="center" valign="middle" rowspan="1" colspan="1">4%</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Manning<sup><xref rid="R56" ref-type="bibr">56</xref></sup></td><td align="left" valign="middle" rowspan="1" colspan="1">Canada Alberta (1993–2002)</td><td align="left" valign="middle" rowspan="1" colspan="1">Ca, Ninv</td><td align="right" valign="middle" rowspan="1" colspan="1">413</td><td align="center" valign="middle" rowspan="1" colspan="1">23% (19%)</td><td align="center" valign="middle" rowspan="1" colspan="1">14%</td><td align="center" valign="middle" rowspan="1" colspan="1">16%</td><td align="center" valign="middle" rowspan="1" colspan="1">20% (19%–NA)</td><td align="center" valign="middle" rowspan="1" colspan="1">22%</td><td align="center" valign="middle" rowspan="1" colspan="1">NA</td><td align="center" valign="middle" rowspan="1" colspan="1">5%</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Bohnsack<sup><xref rid="R57" ref-type="bibr">57</xref></sup></td><td align="left" valign="middle" rowspan="1" colspan="1">USA (1995–1999)</td><td align="left" valign="middle" rowspan="1" colspan="1">Ca, Ninv</td><td align="right" valign="middle" rowspan="1" colspan="1">899</td><td align="center" valign="middle" rowspan="1" colspan="1">16% (15%)</td><td align="center" valign="middle" rowspan="1" colspan="1">9%</td><td align="center" valign="middle" rowspan="1" colspan="1">13%</td><td align="center" valign="middle" rowspan="1" colspan="1">17% (12%–2%)</td><td align="center" valign="middle" rowspan="1" colspan="1">40%</td><td align="center" valign="middle" rowspan="1" colspan="1">0</td><td align="center" valign="middle" rowspan="1" colspan="1">5%</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Sadowi<sup><xref rid="R58" ref-type="bibr">58</xref></sup></td><td align="left" valign="middle" rowspan="1" colspan="1">Poland (1996–2005)</td><td align="left" valign="middle" rowspan="1" colspan="1">Ca, Ninv, Ainv</td><td align="right" valign="middle" rowspan="1" colspan="1">114</td><td align="center" valign="middle" rowspan="1" colspan="1">17% (13%)</td><td align="center" valign="middle" rowspan="1" colspan="1">18%</td><td align="center" valign="middle" rowspan="1" colspan="1">14%</td><td align="center" valign="middle" rowspan="1" colspan="1">12% (9–2%)</td><td align="center" valign="middle" rowspan="1" colspan="1">37%</td><td align="center" valign="middle" rowspan="1" colspan="1">1%</td><td align="center" valign="middle" rowspan="1" colspan="1">1%</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Huber<sup><xref rid="R59" ref-type="bibr">59</xref></sup></td><td align="left" valign="middle" rowspan="1" colspan="1">Kenya (2007–2010)</td><td align="left" valign="middle" rowspan="1" colspan="1">Ca, Ainv</td><td align="right" valign="middle" rowspan="1" colspan="1">169</td><td align="center" valign="middle" rowspan="1" colspan="1">12% (9%)</td><td align="center" valign="middle" rowspan="1" colspan="1">17%</td><td align="center" valign="middle" rowspan="1" colspan="1">21%</td><td align="center" valign="middle" rowspan="1" colspan="1">14% (5%–4%)</td><td align="center" valign="middle" rowspan="1" colspan="1">27%</td><td align="center" valign="middle" rowspan="1" colspan="1">2%</td><td align="center" valign="middle" rowspan="1" colspan="1">7%</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Brochet<sup><xref rid="R7" ref-type="bibr">7</xref></sup></td><td align="left" valign="middle" rowspan="1" colspan="1">Dakar Bangui (2006–2007)</td><td align="left" valign="middle" rowspan="1" colspan="1">Ca</td><td align="right" valign="middle" rowspan="1" colspan="1">163</td><td align="center" valign="middle" rowspan="1" colspan="1">20% (9%)</td><td align="center" valign="middle" rowspan="1" colspan="1">6%</td><td align="center" valign="middle" rowspan="1" colspan="1">12%</td><td align="center" valign="middle" rowspan="1" colspan="1">28% (4%–15%)</td><td align="center" valign="middle" rowspan="1" colspan="1">17%</td><td align="center" valign="middle" rowspan="1" colspan="1">15%</td><td align="center" valign="middle" rowspan="1" colspan="1">2%</td></tr></tbody></table><table-wrap-foot><fn id="TFN1"><p id="P26">NA, Not available.</p></fn><fn id="TFN2"><label>*</label><p id="P27">As percentage in each clonal complex.</p></fn><fn id="TFN3"><label>†</label><p id="P28">First author of the publication and reference.</p></fn><fn id="TFN4"><label>‡</label><p id="P29">In parenthesis the years of isolation if known.</p></fn><fn id="TFN5"><label>§</label><p id="P30">The epidemiological origin: Ca, carriage, Ninv, neonatal invasive disease, Ainv, adults invasive disease.</p></fn><fn id="TFN6"><label>∥</label><p id="P31">In parenthesis, the percentage corresponding to the indicated sequence types (STs).</p></fn><fn id="TFN7"><label>¶</label><p id="P32">Corresponds to strains from the closely related clonal complexes (CC) CC6, CC8 and CC10.</p></fn></table-wrap-foot></table-wrap><table-wrap id="T2" position="float" orientation="portrait"><label>Table 2</label><caption><title>Diversity within the six clonal complexes.</title></caption><table frame="below" rules="groups"><thead><tr><th align="left" valign="top" rowspan="1" colspan="1"></th><th align="center" valign="top" rowspan="1" colspan="1">CC1</th><th align="center" valign="top" rowspan="1" colspan="1">CC10</th><th align="center" valign="top" rowspan="1" colspan="1">CC17</th><th align="center" valign="top" rowspan="1" colspan="1">CC19</th><th align="center" valign="top" rowspan="1" colspan="1">CC23</th><th align="center" valign="top" rowspan="1" colspan="1">CC26</th></tr></thead><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">Strain name</td><td align="center" valign="top" rowspan="1" colspan="1">BG-NI-011</td><td align="center" valign="top" rowspan="1" colspan="1">DK-NI-008</td><td align="center" valign="top" rowspan="1" colspan="1">COH1</td><td align="center" valign="top" rowspan="1" colspan="1">RBH11</td><td align="center" valign="top" rowspan="1" colspan="1">CCH210801006</td><td align="center" valign="top" rowspan="1" colspan="1">Bangui-IP-105</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Genome size<xref ref-type="table-fn" rid="TFN8">*</xref></td><td align="center" valign="top" rowspan="1" colspan="1">2,078 (25)</td><td align="center" valign="top" rowspan="1" colspan="1">2,080 (34)</td><td align="center" valign="top" rowspan="1" colspan="1">2,065 (1)</td><td align="center" valign="top" rowspan="1" colspan="1">2,180 (34)</td><td align="center" valign="top" rowspan="1" colspan="1">2,055 (17)</td><td align="center" valign="top" rowspan="1" colspan="1">2,054 (45)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">No. of isolates</td><td align="center" valign="top" rowspan="1" colspan="1">39</td><td align="center" valign="top" rowspan="1" colspan="1">18</td><td align="center" valign="top" rowspan="1" colspan="1">79</td><td align="center" valign="top" rowspan="1" colspan="1">39</td><td align="center" valign="top" rowspan="1" colspan="1">36</td><td align="center" valign="top" rowspan="1" colspan="1">6</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Interrogated regions<xref ref-type="table-fn" rid="TFN9">†</xref></td><td align="center" valign="top" rowspan="1" colspan="1">914 kb</td><td align="center" valign="top" rowspan="1" colspan="1">1,069 kb</td><td align="center" valign="top" rowspan="1" colspan="1">1,860 kb</td><td align="center" valign="top" rowspan="1" colspan="1">1,427 kb</td><td align="center" valign="top" rowspan="1" colspan="1">980 kb</td><td align="center" valign="top" rowspan="1" colspan="1">1,582 kb</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Polymorphic positions</td><td align="center" valign="top" rowspan="1" colspan="1">1,244</td><td align="center" valign="top" rowspan="1" colspan="1">971</td><td align="center" valign="top" rowspan="1" colspan="1">3,922</td><td align="center" valign="top" rowspan="1" colspan="1">2,016</td><td align="center" valign="top" rowspan="1" colspan="1">1,329</td><td align="center" valign="top" rowspan="1" colspan="1">263</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Recombination<xref ref-type="table-fn" rid="TFN10">‡</xref></td><td align="center" valign="top" rowspan="1" colspan="1">987 kb<break></break><italic>pil1, pil2, cps</italic>, R5,<break></break><italic>alp, srr</italic></td><td align="center" valign="top" rowspan="1" colspan="1">914 kb<break></break><italic>pil1, pil2, cps</italic>, R5,<break></break><italic>alp, srr</italic></td><td align="center" valign="top" rowspan="1" colspan="1">68 kb<break></break><italic>cps</italic>, R5</td><td align="center" valign="top" rowspan="1" colspan="1">532 kb<break></break><italic>cps</italic>, R5, <italic>pil2,</italic><break></break><italic>srr, alp</italic></td><td align="center" valign="top" rowspan="1" colspan="1">875 kb<break></break><italic>pil1, pil2, cps</italic>, R5,<break></break><italic>alp, srr</italic></td><td align="center" valign="top" rowspan="1" colspan="1">398 kb<break></break>Tn<italic>916</italic>/CRISPR,<break></break>R5, <italic>alp</italic></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Depth<xref ref-type="table-fn" rid="TFN11">§</xref></td><td align="center" valign="top" rowspan="1" colspan="1">174±23</td><td align="center" valign="top" rowspan="1" colspan="1">126±7</td><td align="center" valign="top" rowspan="1" colspan="1">129±16</td><td align="center" valign="top" rowspan="1" colspan="1">97±21</td><td align="center" valign="top" rowspan="1" colspan="1">169±16</td><td align="center" valign="top" rowspan="1" colspan="1">74±34</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Mutation rate<xref ref-type="table-fn" rid="TFN12">∥</xref></td><td align="center" valign="top" rowspan="1" colspan="1">0.64</td><td align="center" valign="top" rowspan="1" colspan="1">—
</td><td align="center" valign="top" rowspan="1" colspan="1">0.56</td><td align="center" valign="top" rowspan="1" colspan="1">0.93</td><td align="center" valign="top" rowspan="1" colspan="1">0.75</td><td align="center" valign="top" rowspan="1" colspan="1">—
</td></tr></tbody></table><table-wrap-foot><fn id="TFN8"><label>*</label><p id="P33">Total contig size in kb, in parenthesis, the number of contigs.</p></fn><fn id="TFN9"><label>†</label><p id="P34">Cumulative size in kb of regions not predicted to have recombined.</p></fn><fn id="TFN10"><label>‡</label><p id="P35">Cumulative size in kb of the recombined regions and the exchanged antigenic loci.</p></fn><fn id="TFN11"><label>§</label><p id="P36">Expressed as the average number of single-nucleotide polymorphism (SNP) per Mb from the root to the tips of the tree for strains isolated after 2005.</p></fn><fn id="TFN12"><label>∥</label><p id="P37">As estimated by dividing the depth of each lineage by its age predicted by the BEAST analysis, in SNPs per Mb per year (<xref ref-type="fig" rid="F1">Fig. 1b–e</xref>).</p></fn></table-wrap-foot></table-wrap><table-wrap id="T3" position="float" orientation="portrait"><label>Table 3</label><caption><title>Distribution of antibiotic resistance genes among the 229 sequenced isolates.</title></caption><table frame="below" rules="groups"><thead><tr><th align="left" valign="middle" rowspan="1" colspan="1">Antibiotic resistance</th><th align="center" valign="middle" rowspan="1" colspan="1">Gene</th><th colspan="7" align="right" valign="middle" rowspan="1">Number of isolates<hr></hr></th><th align="right" valign="middle" rowspan="1" colspan="1">Total</th></tr><tr><th align="left" valign="middle" rowspan="1" colspan="1"></th><th align="center" valign="middle" rowspan="1" colspan="1"></th><th align="right" valign="middle" rowspan="1" colspan="1">CC1</th><th align="right" valign="middle" rowspan="1" colspan="1">CC10</th><th align="right" valign="middle" rowspan="1" colspan="1">CC17</th><th align="right" valign="middle" rowspan="1" colspan="1">CC19</th><th align="right" valign="middle" rowspan="1" colspan="1">CC23</th><th align="right" valign="middle" rowspan="1" colspan="1">CC26</th><th align="right" valign="middle" rowspan="1" colspan="1">Other</th><th align="right" valign="middle" rowspan="1" colspan="1"></th></tr></thead><tbody><tr><td align="left" valign="middle" rowspan="1" colspan="1">Tetracycline</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>tet</italic>(M)</td><td align="right" valign="middle" rowspan="1" colspan="1">34</td><td align="right" valign="middle" rowspan="1" colspan="1">13</td><td align="right" valign="middle" rowspan="1" colspan="1">77</td><td align="right" valign="middle" rowspan="1" colspan="1">27</td><td align="right" valign="middle" rowspan="1" colspan="1">27</td><td align="right" valign="middle" rowspan="1" colspan="1">5</td><td align="right" valign="middle" rowspan="1" colspan="1">7</td><td align="right" valign="middle" rowspan="1" colspan="1">190</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>tet</italic>(O)</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">2</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">6</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">11</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>tet</italic>(L)</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">2</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Erythromycin</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>erm</italic>(B)</td><td align="right" valign="middle" rowspan="1" colspan="1">13</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">2</td><td align="right" valign="middle" rowspan="1" colspan="1">4</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">19</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>erm</italic>(TR)</td><td align="right" valign="middle" rowspan="1" colspan="1">6</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">2</td><td align="right" valign="middle" rowspan="1" colspan="1">2</td><td align="right" valign="middle" rowspan="1" colspan="1">2</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">12</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>erm</italic>(T)</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>mefE</italic></td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Streptomycin</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>aadE</italic></td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">4</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">6</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Kanamycin</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>aph3’</italic>-III</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">3</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Streptothrycin</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>sta</italic></td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">3</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Chloramphenicol</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>cat</italic></td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">2</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">2</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Lincosamides</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>lnuB</italic></td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Lincosamide—streptogramin</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>lsa</italic>(C)</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">2</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">6</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Spectinomycin</td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>spcR</italic></td><td align="right" valign="middle" rowspan="1" colspan="1">3</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">2</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">2</td><td align="right" valign="middle" rowspan="1" colspan="1">0</td><td align="right" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Total number of isolates</td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">39</td><td align="right" valign="middle" rowspan="1" colspan="1">19</td><td align="right" valign="middle" rowspan="1" colspan="1">78</td><td align="right" valign="middle" rowspan="1" colspan="1">39</td><td align="right" valign="middle" rowspan="1" colspan="1">36</td><td align="right" valign="middle" rowspan="1" colspan="1">6</td><td align="right" valign="middle" rowspan="1" colspan="1">12</td><td align="right" valign="middle" rowspan="1" colspan="1">229</td></tr></tbody></table></table-wrap><table-wrap id="T4" position="float" orientation="portrait"><label>Table 4</label><caption><title>Characteristics of clones deriving from Tn<italic>916</italic> and Tn<italic>5801</italic> insertions.</title></caption><table frame="below" rules="groups"><thead><tr><th colspan="4" align="left" valign="middle" rowspan="1">Clone<hr></hr></th><th align="center" valign="middle" rowspan="1" colspan="1">No. of isolates per clone</th><th align="center" valign="middle" rowspan="1" colspan="1">Integrative and conjugative element<break></break>and site<xref ref-type="table-fn" rid="TFN14">*</xref> of insertion</th><th align="center" valign="middle" rowspan="1" colspan="1">Recombination events<break></break>within the clone<xref ref-type="table-fn" rid="TFN15">†</xref></th></tr><tr><th align="left" valign="middle" rowspan="1" colspan="1"><italic>N</italic></th><th align="right" valign="middle" rowspan="1" colspan="1">CC</th><th align="right" valign="middle" rowspan="1" colspan="1">Sequence type</th><th align="center" valign="middle" rowspan="1" colspan="1"><italic>cps</italic></th><th align="center" valign="middle" rowspan="1" colspan="1"></th><th align="center" valign="middle" rowspan="1" colspan="1"></th><th align="center" valign="middle" rowspan="1" colspan="1"></th></tr></thead><tbody><tr><td align="left" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="right" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">V</td><td align="center" valign="middle" rowspan="1" colspan="1">27 (2)<xref ref-type="table-fn" rid="TFN16">‡</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> GI 624 kb<xref ref-type="table-fn" rid="TFN17">§</xref>,,<xref ref-type="table-fn" rid="TFN18">∥</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">92 kb <italic>alp</italic>; 100 kb</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">2</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">196, 459</td><td align="center" valign="middle" rowspan="1" colspan="1">IV</td><td align="center" valign="middle" rowspan="1" colspan="1">6</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> GI 624 kb<xref ref-type="table-fn" rid="TFN17">§</xref>,,<xref ref-type="table-fn" rid="TFN18">∥</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">80 kb <italic>alp</italic>: 35kb</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">3</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">2</td><td align="center" valign="middle" rowspan="1" colspan="1">IV</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>5801</italic> 972 kb<xref ref-type="table-fn" rid="TFN19">¶</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">—
<xref ref-type="table-fn" rid="TFN20">#</xref></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">4</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">2</td><td align="center" valign="middle" rowspan="1" colspan="1">IV</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>5801</italic> 972 kb<xref ref-type="table-fn" rid="TFN19">¶</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">5</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">2</td><td align="center" valign="middle" rowspan="1" colspan="1">II</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 726 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">3<xref ref-type="table-fn" rid="TFN21">**</xref></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">6</td><td align="right" valign="middle" rowspan="1" colspan="1">10</td><td align="right" valign="middle" rowspan="1" colspan="1">10</td><td align="center" valign="middle" rowspan="1" colspan="1">V-II</td><td align="center" valign="middle" rowspan="1" colspan="1">5</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>5801</italic> 972 kb<xref ref-type="table-fn" rid="TFN19">¶</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">347 kb <italic>cps</italic> operon</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">7</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">Ib</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 846 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">—
</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">8</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">12</td><td align="center" valign="middle" rowspan="1" colspan="1">II</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 260 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">9</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">10</td><td align="center" valign="middle" rowspan="1" colspan="1">Ib</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 626 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">10</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">10</td><td align="center" valign="middle" rowspan="1" colspan="1">II</td><td align="center" valign="middle" rowspan="1" colspan="1">2</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 1,255 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">—
</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">5<xref ref-type="table-fn" rid="TFN21">**</xref></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">11</td><td align="right" valign="middle" rowspan="1" colspan="1">17</td><td align="right" valign="middle" rowspan="1" colspan="1">17</td><td align="center" valign="middle" rowspan="1" colspan="1">III</td><td align="center" valign="middle" rowspan="1" colspan="1">42 (3)<xref ref-type="table-fn" rid="TFN16">‡</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>5801</italic> 972 kb<xref ref-type="table-fn" rid="TFN19">¶</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">—
</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">12</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">17</td><td align="center" valign="middle" rowspan="1" colspan="1">III</td><td align="center" valign="middle" rowspan="1" colspan="1">23</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 241 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">—
</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">13</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">17</td><td align="center" valign="middle" rowspan="1" colspan="1">III</td><td align="center" valign="middle" rowspan="1" colspan="1">6</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 950 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">—
</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">14</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">17</td><td align="center" valign="middle" rowspan="1" colspan="1">III</td><td align="center" valign="middle" rowspan="1" colspan="1">2</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 1,928 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">—
</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">15</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">17</td><td align="center" valign="middle" rowspan="1" colspan="1">III</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 1,928 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">16</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">291</td><td align="center" valign="middle" rowspan="1" colspan="1">IV</td><td align="center" valign="middle" rowspan="1" colspan="1">5</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>5801</italic> 52 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">—
</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">17</td><td align="right" valign="middle" rowspan="1" colspan="1">19</td><td align="right" valign="middle" rowspan="1" colspan="1">19</td><td align="center" valign="middle" rowspan="1" colspan="1">III V</td><td align="center" valign="middle" rowspan="1" colspan="1">20 (3)<xref ref-type="table-fn" rid="TFN16">‡</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 923 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">253 kb <italic>cps</italic> operon 36 kb R5 protein</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">18</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">19</td><td align="center" valign="middle" rowspan="1" colspan="1">III</td><td align="center" valign="middle" rowspan="1" colspan="1">4 (1)<xref ref-type="table-fn" rid="TFN16">‡</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> GI 557 kb<xref ref-type="table-fn" rid="TFN18">∥</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">—
</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">19</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">19</td><td align="center" valign="middle" rowspan="1" colspan="1">III</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 2,005 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">20</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">28</td><td align="center" valign="middle" rowspan="1" colspan="1">II</td><td align="center" valign="middle" rowspan="1" colspan="1">2</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 395 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">—
</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">21</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">28</td><td align="center" valign="middle" rowspan="1" colspan="1">II</td><td align="center" valign="middle" rowspan="1" colspan="1">3</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 1,445 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">—
</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">22</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">28</td><td align="center" valign="middle" rowspan="1" colspan="1">II</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 2,005 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">8<xref ref-type="table-fn" rid="TFN21">**</xref></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">23</td><td align="right" valign="middle" rowspan="1" colspan="1">23</td><td align="right" valign="middle" rowspan="1" colspan="1">23</td><td align="center" valign="middle" rowspan="1" colspan="1">Ia</td><td align="center" valign="middle" rowspan="1" colspan="1">18 (1)<xref ref-type="table-fn" rid="TFN16">‡</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>5801</italic> 972 kb<xref ref-type="table-fn" rid="TFN19">¶</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">107 kb <italic>alp</italic>; 56 kb R5 protein; 93 kb</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">24</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">23, 144</td><td align="center" valign="middle" rowspan="1" colspan="1">Ia–V</td><td align="center" valign="middle" rowspan="1" colspan="1">8 (1)<xref ref-type="table-fn" rid="TFN16">‡</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 1,928 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">91 kb <italic>alp</italic>; 193 kb <italic>cps</italic></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">25</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">23</td><td align="center" valign="middle" rowspan="1" colspan="1">III</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>5801</italic> 972 kb<xref ref-type="table-fn" rid="TFN19">¶</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">26</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">23</td><td align="center" valign="middle" rowspan="1" colspan="1">Ia</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>5801</italic> 972 kb<xref ref-type="table-fn" rid="TFN19">¶</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">8<xref ref-type="table-fn" rid="TFN21">**</xref></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">27</td><td align="right" valign="middle" rowspan="1" colspan="1">26</td><td align="right" valign="middle" rowspan="1" colspan="1">26</td><td align="center" valign="middle" rowspan="1" colspan="1">V</td><td align="center" valign="middle" rowspan="1" colspan="1">3</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> GI 1,023 kb<xref ref-type="table-fn" rid="TFN18">∥</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">—
</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">28</td><td align="right" valign="middle" rowspan="1" colspan="1"></td><td align="right" valign="middle" rowspan="1" colspan="1">26</td><td align="center" valign="middle" rowspan="1" colspan="1">V</td><td align="center" valign="middle" rowspan="1" colspan="1">2</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 923 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">77 kb R5 protein</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">29</td><td align="right" valign="middle" rowspan="1" colspan="1">22</td><td align="right" valign="middle" rowspan="1" colspan="1">22</td><td align="center" valign="middle" rowspan="1" colspan="1">II</td><td align="center" valign="middle" rowspan="1" colspan="1">2</td><td align="center" valign="middle" rowspan="1" colspan="1">Tn<italic>916</italic> 1787 kb</td><td align="center" valign="middle" rowspan="1" colspan="1">—
</td></tr></tbody></table><table-wrap-foot><fn id="TFN13"><p id="P38">n.a., Not applicable.</p></fn><fn id="TFN14"><label>*</label><p id="P39">Position relative to the completely sequenced 2603 V/R genome<sup><xref rid="R45" ref-type="bibr">45</xref></sup>.</p></fn><fn id="TFN15"><label>†</label><p id="P40">Size of the recombined regions and antigenic loci.</p></fn><fn id="TFN16"><label>‡</label><p id="P41">In parenthesis are indicated the number of strains predicted to have lost Tn<italic>916</italic> or Tn<italic>5801</italic>.</p></fn><fn id="TFN17"><label>§</label><p id="P42">Tn<italic>916</italic> is inserted in the opposite orientation at the same site.</p></fn><fn id="TFN18"><label>∥</label><p id="P43">Tn<italic>916</italic> is inserted within genomic islands inserted at the reported locations relative to the 2603 V/R genome.</p></fn><fn id="TFN19"><label>¶</label><p id="P44">972 kb correspond to a hot spot of insertion of Tn<italic>5801</italic> at the 5′ end of the <italic>guaA</italic> gene.</p></fn><fn id="TFN20"><label>#</label><p id="P45">A dash indicates no recombination event.</p></fn><fn id="TFN21"><label>**</label><p id="P46">Number of isolates in clonal complex (CC)1, 10, 19 and 23 predicted not to have acquired Tn<italic>916</italic> or Tn<italic>5801</italic>.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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