Links to Exploration step
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Genome analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of the etiologic agent of tuberculosis</title><author><name sortKey="Supply, Philip" sort="Supply, Philip" uniqKey="Supply P" first="Philip" last="Supply">Philip Supply</name><affiliation><nlm:aff id="A1">Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Marceau, Michael" sort="Marceau, Michael" uniqKey="Marceau M" first="Michael" last="Marceau">Michael Marceau</name><affiliation><nlm:aff id="A1">Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Mangenot, Sophie" sort="Mangenot, Sophie" uniqKey="Mangenot S" first="Sophie" last="Mangenot">Sophie Mangenot</name><affiliation><nlm:aff id="A5">CNRS-UMR 8030 , Evry, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Commissariat à l’Energie Atomique et aux Energies Alternatives CEA/DSV/IG/Genoscope, LABGeM, Evry, France</nlm:aff></affiliation></author><author><name sortKey="Roche, David" sort="Roche, David" uniqKey="Roche D" first="David" last="Roche">David Roche</name><affiliation><nlm:aff id="A5">CNRS-UMR 8030 , Evry, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Commissariat à l’Energie Atomique et aux Energies Alternatives CEA/DSV/IG/Genoscope, LABGeM, Evry, France</nlm:aff></affiliation></author><author><name sortKey="Rouanet, Carine" sort="Rouanet, Carine" uniqKey="Rouanet C" first="Carine" last="Rouanet">Carine Rouanet</name><affiliation><nlm:aff id="A1">Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Khanna, Varun" sort="Khanna, Varun" uniqKey="Khanna V" first="Varun" last="Khanna">Varun Khanna</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Majlessi, Laleh" sort="Majlessi, Laleh" uniqKey="Majlessi L" first="Laleh" last="Majlessi">Laleh Majlessi</name><affiliation><nlm:aff id="A8">Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="A9">INSERM U1041, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Criscuolo, Alexis" sort="Criscuolo, Alexis" uniqKey="Criscuolo A" first="Alexis" last="Criscuolo">Alexis Criscuolo</name><affiliation><nlm:aff id="A10">Institut Pasteur, Genotyping of Pathogens and Public Health (PF8), Paris, France</nlm:aff></affiliation></author><author><name sortKey="Tap, Julien" sort="Tap, Julien" uniqKey="Tap J" first="Julien" last="Tap">Julien Tap</name><affiliation><nlm:aff id="A10">Institut Pasteur, Genotyping of Pathogens and Public Health (PF8), Paris, France</nlm:aff></affiliation></author><author><name sortKey="Pawlik, Alexandre" sort="Pawlik, Alexandre" uniqKey="Pawlik A" first="Alexandre" last="Pawlik">Alexandre Pawlik</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Fiette, Laurence" sort="Fiette, Laurence" uniqKey="Fiette L" first="Laurence" last="Fiette">Laurence Fiette</name><affiliation><nlm:aff id="A11">Institut Pasteur, Unité d’Histopathologie Humaine et Modèles Animaux, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="A12">Université Versailles-Saint Quentin en Yvelines, Faculté de Médecine, DER Histologie, Versailles, France</nlm:aff></affiliation></author><author><name sortKey="Orgeur, Mickael" sort="Orgeur, Mickael" uniqKey="Orgeur M" first="Mickael" last="Orgeur">Mickael Orgeur</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Fabre, Michel" sort="Fabre, Michel" uniqKey="Fabre M" first="Michel" last="Fabre">Michel Fabre</name><affiliation><nlm:aff id="A13">Laboratoire de Biologie Clinique, HIA Percy, Clamart, France</nlm:aff></affiliation></author><author><name sortKey="Parmentier, Cecile" sort="Parmentier, Cecile" uniqKey="Parmentier C" first="Cécile" last="Parmentier">Cécile Parmentier</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Frigui, Wafa" sort="Frigui, Wafa" uniqKey="Frigui W" first="Wafa" last="Frigui">Wafa Frigui</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Simeone, Roxane" sort="Simeone, Roxane" uniqKey="Simeone R" first="Roxane" last="Simeone">Roxane Simeone</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Boritsch, Eva C" sort="Boritsch, Eva C" uniqKey="Boritsch E" first="Eva C." last="Boritsch">Eva C. Boritsch</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Debrie, Anne Sophie" sort="Debrie, Anne Sophie" uniqKey="Debrie A" first="Anne-Sophie" last="Debrie">Anne-Sophie Debrie</name><affiliation><nlm:aff id="A1">Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Willery, Eve" sort="Willery, Eve" uniqKey="Willery E" first="Eve" last="Willery">Eve Willery</name><affiliation><nlm:aff id="A1">Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Walker, Danielle" sort="Walker, Danielle" uniqKey="Walker D" first="Danielle" last="Walker">Danielle Walker</name><affiliation><nlm:aff id="A14">Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Quail, Michael A" sort="Quail, Michael A" uniqKey="Quail M" first="Michael A." last="Quail">Michael A. Quail</name><affiliation><nlm:aff id="A14">Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK</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="A15">Institut Pasteur, Genopole, Platform Genomics PF1, Paris, France</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="A15">Institut Pasteur, Genopole, Platform Genomics PF1, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Salvignol, Gregory" sort="Salvignol, Gregory" uniqKey="Salvignol G" first="Grégory" last="Salvignol">Grégory Salvignol</name><affiliation><nlm:aff id="A5">CNRS-UMR 8030 , Evry, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Commissariat à l’Energie Atomique et aux Energies Alternatives CEA/DSV/IG/Genoscope, LABGeM, Evry, France</nlm:aff></affiliation></author><author><name sortKey="Sayes, Fadel" sort="Sayes, Fadel" uniqKey="Sayes F" first="Fadel" last="Sayes">Fadel Sayes</name><affiliation><nlm:aff id="A8">Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="A9">INSERM U1041, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Cascioferro, Alessandro" sort="Cascioferro, Alessandro" uniqKey="Cascioferro A" first="Alessandro" last="Cascioferro">Alessandro Cascioferro</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Seemann, Torsten" sort="Seemann, Torsten" uniqKey="Seemann T" first="Torsten" last="Seemann">Torsten Seemann</name><affiliation><nlm:aff id="A16">Victorian Bioinformatics Consortium, Monash University, Clayton, Australia</nlm:aff></affiliation></author><author><name sortKey="Barbe, Valerie" sort="Barbe, Valerie" uniqKey="Barbe V" first="Valérie" last="Barbe">Valérie Barbe</name><affiliation><nlm:aff id="A5">CNRS-UMR 8030 , Evry, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Commissariat à l’Energie Atomique et aux Energies Alternatives CEA/DSV/IG/Genoscope, LABGeM, Evry, France</nlm:aff></affiliation></author><author><name sortKey="Locht, Camille" sort="Locht, Camille" uniqKey="Locht C" first="Camille" last="Locht">Camille Locht</name><affiliation><nlm:aff id="A1">Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Gutierrez, Maria Cristina" sort="Gutierrez, Maria Cristina" uniqKey="Gutierrez M" first="Maria-Cristina" last="Gutierrez">Maria-Cristina Gutierrez</name><affiliation><nlm:aff id="A1">Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A17">Institut Pasteur, Department d’Infection et d’Epidemiologie, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Leclerc, Claude" sort="Leclerc, Claude" uniqKey="Leclerc C" first="Claude" last="Leclerc">Claude Leclerc</name><affiliation><nlm:aff id="A8">Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="A9">INSERM U1041, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Bentley, Stephen" sort="Bentley, Stephen" uniqKey="Bentley S" first="Stephen" last="Bentley">Stephen Bentley</name><affiliation><nlm:aff id="A14">Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Stinear, Timothy P" sort="Stinear, Timothy P" uniqKey="Stinear T" first="Timothy P." last="Stinear">Timothy P. Stinear</name><affiliation><nlm:aff id="A18">Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia</nlm:aff></affiliation></author><author><name sortKey="Brisse, Sylvain" sort="Brisse, Sylvain" uniqKey="Brisse S" first="Sylvain" last="Brisse">Sylvain Brisse</name><affiliation><nlm:aff id="A10">Institut Pasteur, Genotyping of Pathogens and Public Health (PF8), Paris, France</nlm:aff></affiliation></author><author><name sortKey="Medigue, Claudine" sort="Medigue, Claudine" uniqKey="Medigue C" first="Claudine" last="Médigue">Claudine Médigue</name><affiliation><nlm:aff id="A5">CNRS-UMR 8030 , Evry, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Commissariat à l’Energie Atomique et aux Energies Alternatives CEA/DSV/IG/Genoscope, LABGeM, Evry, France</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="A14">Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Cruveiller, Stephane" sort="Cruveiller, Stephane" uniqKey="Cruveiller S" first="Stéphane" last="Cruveiller">Stéphane Cruveiller</name><affiliation><nlm:aff id="A5">CNRS-UMR 8030 , Evry, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Commissariat à l’Energie Atomique et aux Energies Alternatives CEA/DSV/IG/Genoscope, LABGeM, Evry, France</nlm:aff></affiliation></author><author><name sortKey="Brosch, Roland" sort="Brosch, Roland" uniqKey="Brosch R" first="Roland" last="Brosch">Roland Brosch</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23291586</idno><idno type="pmc">3856870</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856870</idno><idno type="RBID">PMC:3856870</idno><idno type="doi">10.1038/ng.2517</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">002E21</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002E21</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genome analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of the etiologic agent of tuberculosis</title><author><name sortKey="Supply, Philip" sort="Supply, Philip" uniqKey="Supply P" first="Philip" last="Supply">Philip Supply</name><affiliation><nlm:aff id="A1">Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Marceau, Michael" sort="Marceau, Michael" uniqKey="Marceau M" first="Michael" last="Marceau">Michael Marceau</name><affiliation><nlm:aff id="A1">Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Mangenot, Sophie" sort="Mangenot, Sophie" uniqKey="Mangenot S" first="Sophie" last="Mangenot">Sophie Mangenot</name><affiliation><nlm:aff id="A5">CNRS-UMR 8030 , Evry, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Commissariat à l’Energie Atomique et aux Energies Alternatives CEA/DSV/IG/Genoscope, LABGeM, Evry, France</nlm:aff></affiliation></author><author><name sortKey="Roche, David" sort="Roche, David" uniqKey="Roche D" first="David" last="Roche">David Roche</name><affiliation><nlm:aff id="A5">CNRS-UMR 8030 , Evry, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Commissariat à l’Energie Atomique et aux Energies Alternatives CEA/DSV/IG/Genoscope, LABGeM, Evry, France</nlm:aff></affiliation></author><author><name sortKey="Rouanet, Carine" sort="Rouanet, Carine" uniqKey="Rouanet C" first="Carine" last="Rouanet">Carine Rouanet</name><affiliation><nlm:aff id="A1">Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Khanna, Varun" sort="Khanna, Varun" uniqKey="Khanna V" first="Varun" last="Khanna">Varun Khanna</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Majlessi, Laleh" sort="Majlessi, Laleh" uniqKey="Majlessi L" first="Laleh" last="Majlessi">Laleh Majlessi</name><affiliation><nlm:aff id="A8">Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="A9">INSERM U1041, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Criscuolo, Alexis" sort="Criscuolo, Alexis" uniqKey="Criscuolo A" first="Alexis" last="Criscuolo">Alexis Criscuolo</name><affiliation><nlm:aff id="A10">Institut Pasteur, Genotyping of Pathogens and Public Health (PF8), Paris, France</nlm:aff></affiliation></author><author><name sortKey="Tap, Julien" sort="Tap, Julien" uniqKey="Tap J" first="Julien" last="Tap">Julien Tap</name><affiliation><nlm:aff id="A10">Institut Pasteur, Genotyping of Pathogens and Public Health (PF8), Paris, France</nlm:aff></affiliation></author><author><name sortKey="Pawlik, Alexandre" sort="Pawlik, Alexandre" uniqKey="Pawlik A" first="Alexandre" last="Pawlik">Alexandre Pawlik</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Fiette, Laurence" sort="Fiette, Laurence" uniqKey="Fiette L" first="Laurence" last="Fiette">Laurence Fiette</name><affiliation><nlm:aff id="A11">Institut Pasteur, Unité d’Histopathologie Humaine et Modèles Animaux, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="A12">Université Versailles-Saint Quentin en Yvelines, Faculté de Médecine, DER Histologie, Versailles, France</nlm:aff></affiliation></author><author><name sortKey="Orgeur, Mickael" sort="Orgeur, Mickael" uniqKey="Orgeur M" first="Mickael" last="Orgeur">Mickael Orgeur</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Fabre, Michel" sort="Fabre, Michel" uniqKey="Fabre M" first="Michel" last="Fabre">Michel Fabre</name><affiliation><nlm:aff id="A13">Laboratoire de Biologie Clinique, HIA Percy, Clamart, France</nlm:aff></affiliation></author><author><name sortKey="Parmentier, Cecile" sort="Parmentier, Cecile" uniqKey="Parmentier C" first="Cécile" last="Parmentier">Cécile Parmentier</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Frigui, Wafa" sort="Frigui, Wafa" uniqKey="Frigui W" first="Wafa" last="Frigui">Wafa Frigui</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Simeone, Roxane" sort="Simeone, Roxane" uniqKey="Simeone R" first="Roxane" last="Simeone">Roxane Simeone</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Boritsch, Eva C" sort="Boritsch, Eva C" uniqKey="Boritsch E" first="Eva C." last="Boritsch">Eva C. Boritsch</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Debrie, Anne Sophie" sort="Debrie, Anne Sophie" uniqKey="Debrie A" first="Anne-Sophie" last="Debrie">Anne-Sophie Debrie</name><affiliation><nlm:aff id="A1">Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Willery, Eve" sort="Willery, Eve" uniqKey="Willery E" first="Eve" last="Willery">Eve Willery</name><affiliation><nlm:aff id="A1">Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Walker, Danielle" sort="Walker, Danielle" uniqKey="Walker D" first="Danielle" last="Walker">Danielle Walker</name><affiliation><nlm:aff id="A14">Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Quail, Michael A" sort="Quail, Michael A" uniqKey="Quail M" first="Michael A." last="Quail">Michael A. Quail</name><affiliation><nlm:aff id="A14">Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK</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="A15">Institut Pasteur, Genopole, Platform Genomics PF1, Paris, France</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="A15">Institut Pasteur, Genopole, Platform Genomics PF1, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Salvignol, Gregory" sort="Salvignol, Gregory" uniqKey="Salvignol G" first="Grégory" last="Salvignol">Grégory Salvignol</name><affiliation><nlm:aff id="A5">CNRS-UMR 8030 , Evry, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Commissariat à l’Energie Atomique et aux Energies Alternatives CEA/DSV/IG/Genoscope, LABGeM, Evry, France</nlm:aff></affiliation></author><author><name sortKey="Sayes, Fadel" sort="Sayes, Fadel" uniqKey="Sayes F" first="Fadel" last="Sayes">Fadel Sayes</name><affiliation><nlm:aff id="A8">Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="A9">INSERM U1041, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Cascioferro, Alessandro" sort="Cascioferro, Alessandro" uniqKey="Cascioferro A" first="Alessandro" last="Cascioferro">Alessandro Cascioferro</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Seemann, Torsten" sort="Seemann, Torsten" uniqKey="Seemann T" first="Torsten" last="Seemann">Torsten Seemann</name><affiliation><nlm:aff id="A16">Victorian Bioinformatics Consortium, Monash University, Clayton, Australia</nlm:aff></affiliation></author><author><name sortKey="Barbe, Valerie" sort="Barbe, Valerie" uniqKey="Barbe V" first="Valérie" last="Barbe">Valérie Barbe</name><affiliation><nlm:aff id="A5">CNRS-UMR 8030 , Evry, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Commissariat à l’Energie Atomique et aux Energies Alternatives CEA/DSV/IG/Genoscope, LABGeM, Evry, France</nlm:aff></affiliation></author><author><name sortKey="Locht, Camille" sort="Locht, Camille" uniqKey="Locht C" first="Camille" last="Locht">Camille Locht</name><affiliation><nlm:aff id="A1">Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation></author><author><name sortKey="Gutierrez, Maria Cristina" sort="Gutierrez, Maria Cristina" uniqKey="Gutierrez M" first="Maria-Cristina" last="Gutierrez">Maria-Cristina Gutierrez</name><affiliation><nlm:aff id="A1">Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A17">Institut Pasteur, Department d’Infection et d’Epidemiologie, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Leclerc, Claude" sort="Leclerc, Claude" uniqKey="Leclerc C" first="Claude" last="Leclerc">Claude Leclerc</name><affiliation><nlm:aff id="A8">Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="A9">INSERM U1041, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Bentley, Stephen" sort="Bentley, Stephen" uniqKey="Bentley S" first="Stephen" last="Bentley">Stephen Bentley</name><affiliation><nlm:aff id="A14">Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Stinear, Timothy P" sort="Stinear, Timothy P" uniqKey="Stinear T" first="Timothy P." last="Stinear">Timothy P. Stinear</name><affiliation><nlm:aff id="A18">Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia</nlm:aff></affiliation></author><author><name sortKey="Brisse, Sylvain" sort="Brisse, Sylvain" uniqKey="Brisse S" first="Sylvain" last="Brisse">Sylvain Brisse</name><affiliation><nlm:aff id="A10">Institut Pasteur, Genotyping of Pathogens and Public Health (PF8), Paris, France</nlm:aff></affiliation></author><author><name sortKey="Medigue, Claudine" sort="Medigue, Claudine" uniqKey="Medigue C" first="Claudine" last="Médigue">Claudine Médigue</name><affiliation><nlm:aff id="A5">CNRS-UMR 8030 , Evry, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Commissariat à l’Energie Atomique et aux Energies Alternatives CEA/DSV/IG/Genoscope, LABGeM, Evry, France</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="A14">Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Cruveiller, Stephane" sort="Cruveiller, Stephane" uniqKey="Cruveiller S" first="Stéphane" last="Cruveiller">Stéphane Cruveiller</name><affiliation><nlm:aff id="A5">CNRS-UMR 8030 , Evry, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Commissariat à l’Energie Atomique et aux Energies Alternatives CEA/DSV/IG/Genoscope, LABGeM, Evry, France</nlm:aff></affiliation></author><author><name sortKey="Brosch, Roland" sort="Brosch, Roland" uniqKey="Brosch R" first="Roland" last="Brosch">Roland Brosch</name><affiliation><nlm:aff id="A7">Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</nlm:aff></affiliation></author></analytic><series><title level="j">Nature genetics</title><idno type="ISSN">1061-4036</idno><idno type="eISSN">1546-1718</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P2">Global spread and genetic monomorphism are hallmarks of <italic>Mycobacterium tuberculosis</italic>, the agent of human tuberculosis. In contrast, <italic>Mycobacterium canettii</italic>, and related tubercle bacilli that also cause human tuberculosis and exhibit unusual smooth colony morphology, are restricted to East-Africa. Here, we sequenced and analyzed the genomes of five representative strains of smooth tubercle bacilli (STB) using Sanger (4-5x coverage), 454/Roche (13-18x coverage) and/or Illumina DNA sequencing (45-105x coverage). We show that STB are highly recombinogenic and evolutionary early-branching, with larger genome sizes, 25-fold more SNPs, fewer molecular scars and distinct CRISPR-Cas systems relative to <italic>M. tuberculosis</italic>. Despite the differences, all tuberculosis-causing mycobacteria share a highly conserved core genome. Mouse-infection experiments revealed that STB are less persistent and virulent than <italic>M. tuberculosis.</italic> We conclude that <italic>M. tuberculosis</italic> emerged from an ancestral, STB-like pool of mycobacteria by gain of persistence and virulence mechanisms and we provide genome-wide insights into the molecular events involved.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Dye, C" uniqKey="Dye C">C Dye</name></author><author><name sortKey="Williams, Bg" uniqKey="Williams B">BG Williams</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sreevatsan, S" uniqKey="Sreevatsan S">S Sreevatsan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wirth, T" uniqKey="Wirth T">T Wirth</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brosch, R" uniqKey="Brosch R">R Brosch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Supply, P" uniqKey="Supply P">P Supply</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hirsh, Ae" uniqKey="Hirsh A">AE Hirsh</name></author><author><name sortKey="Tsolaki, Ag" uniqKey="Tsolaki A">AG Tsolaki</name></author><author><name sortKey="Deriemer, K" uniqKey="Deriemer K">K DeRiemer</name></author><author><name sortKey="Feldman, Mw" uniqKey="Feldman M">MW Feldman</name></author><author><name sortKey="Small, Pm" uniqKey="Small P">PM Small</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Soolingen, D" uniqKey="Van Soolingen D">D van Soolingen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fabre, M" uniqKey="Fabre M">M Fabre</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gutierrez, Mc" uniqKey="Gutierrez M">MC Gutierrez</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fabre, M" uniqKey="Fabre M">M Fabre</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Koeck, Jl" uniqKey="Koeck J">JL Koeck</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cole, St" uniqKey="Cole S">ST Cole</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Garnier, T" uniqKey="Garnier T">T Garnier</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Springer, B" uniqKey="Springer B">B Springer</name></author><author><name sortKey="Stockman, L" uniqKey="Stockman L">L Stockman</name></author><author><name sortKey="Teschner, K" uniqKey="Teschner K">K Teschner</name></author><author><name sortKey="Roberts, Gd" uniqKey="Roberts G">GD Roberts</name></author><author><name sortKey="Bottger, Ec" uniqKey="Bottger E">EC Bottger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goris, J" uniqKey="Goris J">J Goris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stinear, Tp" uniqKey="Stinear T">TP Stinear</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Veyrier, Fj" uniqKey="Veyrier F">FJ Veyrier</name></author><author><name sortKey="Dufort, A" uniqKey="Dufort A">A Dufort</name></author><author><name sortKey="Behr, Ma" uniqKey="Behr M">MA Behr</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sassetti, Cm" uniqKey="Sassetti C">CM Sassetti</name></author><author><name sortKey="Boyd, Dh" uniqKey="Boyd D">DH Boyd</name></author><author><name sortKey="Rubin, Ej" uniqKey="Rubin E">EJ Rubin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sassetti, Cm" uniqKey="Sassetti C">CM Sassetti</name></author><author><name sortKey="Rubin, Ej" uniqKey="Rubin E">EJ Rubin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Griffin, Je" uniqKey="Griffin J">JE Griffin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Becq, J" uniqKey="Becq J">J Becq</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Makarova, Ks" uniqKey="Makarova K">KS Makarova</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hendrix, Rw" uniqKey="Hendrix R">RW Hendrix</name></author><author><name sortKey="Smith, Mc" uniqKey="Smith M">MC Smith</name></author><author><name sortKey="Burns, Rn" uniqKey="Burns R">RN Burns</name></author><author><name sortKey="Ford, Me" uniqKey="Ford M">ME Ford</name></author><author><name sortKey="Hatfull, Gf" uniqKey="Hatfull G">GF Hatfull</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gordon, Sv" uniqKey="Gordon S">SV Gordon</name></author><author><name sortKey="Bottai, D" uniqKey="Bottai D">D Bottai</name></author><author><name sortKey="Simeone, R" uniqKey="Simeone R">R Simeone</name></author><author><name sortKey="Stinear, Tp" uniqKey="Stinear T">TP Stinear</name></author><author><name sortKey="Brosch, R" uniqKey="Brosch R">R Brosch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Deshayes, C" uniqKey="Deshayes C">C Deshayes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smith, Nh" uniqKey="Smith N">NH Smith</name></author><author><name sortKey="Hewinson, Rg" uniqKey="Hewinson R">RG Hewinson</name></author><author><name sortKey="Kremer, K" uniqKey="Kremer K">K Kremer</name></author><author><name sortKey="Brosch, R" uniqKey="Brosch R">R Brosch</name></author><author><name sortKey="Gordon, Sv" uniqKey="Gordon S">SV Gordon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reed, Mb" uniqKey="Reed M">MB Reed</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bentley, Sd" uniqKey="Bentley S">SD Bentley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brosch, R" uniqKey="Brosch R">R Brosch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Comas, I" uniqKey="Comas I">I Comas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hershberg, R" uniqKey="Hershberg R">R Hershberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rocha, Ep" uniqKey="Rocha E">EP Rocha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Castillo Ramirez, S" uniqKey="Castillo Ramirez S">S Castillo-Ramirez</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Croucher, Nj" uniqKey="Croucher N">NJ Croucher</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Korber, B" uniqKey="Korber B">B Korber</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goldman, N" uniqKey="Goldman N">N Goldman</name></author><author><name sortKey="Yang, Z" uniqKey="Yang Z">Z Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Simeone, R" uniqKey="Simeone R">R Simeone</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kalscheuer, R" uniqKey="Kalscheuer R">R Kalscheuer</name></author><author><name sortKey="Weinrick, B" uniqKey="Weinrick B">B Weinrick</name></author><author><name sortKey="Veeraraghavan, U" uniqKey="Veeraraghavan U">U Veeraraghavan</name></author><author><name sortKey="Besra, Gs" uniqKey="Besra G">GS Besra</name></author><author><name sortKey="Jacobs, Wr" uniqKey="Jacobs W">WR Jacobs</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Felsenstein, J" uniqKey="Felsenstein J">J Felsenstein</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Achtman, M" uniqKey="Achtman M">M Achtman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Namouchi, A" uniqKey="Namouchi A">A Namouchi</name></author><author><name sortKey="Didelot, X" uniqKey="Didelot X">X Didelot</name></author><author><name sortKey="Schock, U" uniqKey="Schock U">U Schock</name></author><author><name sortKey="Gicquel, B" uniqKey="Gicquel B">B Gicquel</name></author><author><name sortKey="Rocha, Ep" uniqKey="Rocha E">EP Rocha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mba Medie, F" uniqKey="Mba Medie F">F Mba Medie</name></author><author><name sortKey="Ben Salah, I" uniqKey="Ben Salah I">I Ben Salah</name></author><author><name sortKey="Henrissat, B" uniqKey="Henrissat B">B Henrissat</name></author><author><name sortKey="Raoult, D" uniqKey="Raoult D">D Raoult</name></author><author><name sortKey="Drancourt, M" uniqKey="Drancourt M">M Drancourt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nguyen, Kt" uniqKey="Nguyen K">KT Nguyen</name></author><author><name sortKey="Piastro, K" uniqKey="Piastro K">K Piastro</name></author><author><name sortKey="Gray, Ta" uniqKey="Gray T">TA Gray</name></author><author><name sortKey="Derbyshire, Km" uniqKey="Derbyshire K">KM Derbyshire</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Medzhitov, R" uniqKey="Medzhitov R">R Medzhitov</name></author><author><name sortKey="Janeway, Ca" uniqKey="Janeway C">CA Janeway</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Aagaard, C" uniqKey="Aagaard C">C Aagaard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cadieux, N" uniqKey="Cadieux N">N Cadieux</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Maiden, Mc" uniqKey="Maiden M">MC Maiden</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Huson, Dh" uniqKey="Huson D">DH Huson</name></author><author><name sortKey="Bryant, D" uniqKey="Bryant D">D Bryant</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Batzoglou, S" uniqKey="Batzoglou S">S Batzoglou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brosch, R" uniqKey="Brosch R">R Brosch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zerbino, Dr" uniqKey="Zerbino D">DR Zerbino</name></author><author><name sortKey="Birney, E" uniqKey="Birney E">E Birney</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vallenet, D" uniqKey="Vallenet D">D Vallenet</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carver, T" uniqKey="Carver T">T Carver</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Richter, M" uniqKey="Richter M">M Richter</name></author><author><name sortKey="Rossello Mora, R" uniqKey="Rossello Mora R">R Rossello-Mora</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ning, Z" uniqKey="Ning Z">Z Ning</name></author><author><name sortKey="Cox, Aj" uniqKey="Cox A">AJ Cox</name></author><author><name sortKey="Mullikin, Jc" uniqKey="Mullikin J">JC Mullikin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Niemann, S" uniqKey="Niemann S">S Niemann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Delcher, Al" uniqKey="Delcher A">AL Delcher</name></author><author><name sortKey="Phillippy, A" uniqKey="Phillippy A">A Phillippy</name></author><author><name sortKey="Carlton, J" uniqKey="Carlton J">J Carlton</name></author><author><name sortKey="Salzberg, Sl" uniqKey="Salzberg S">SL Salzberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Suyama, M" uniqKey="Suyama M">M Suyama</name></author><author><name sortKey="Torrents, D" uniqKey="Torrents D">D Torrents</name></author><author><name sortKey="Bork, P" uniqKey="Bork P">P Bork</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Edgar, Rc" uniqKey="Edgar R">RC Edgar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Darling, Ae" uniqKey="Darling A">AE Darling</name></author><author><name sortKey="Mau, B" uniqKey="Mau B">B Mau</name></author><author><name sortKey="Perna, Nt" uniqKey="Perna N">NT Perna</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Saitou, N" uniqKey="Saitou N">N Saitou</name></author><author><name sortKey="Nei, M" uniqKey="Nei M">M Nei</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bruen, Tc" uniqKey="Bruen T">TC Bruen</name></author><author><name sortKey="Philippe, H" uniqKey="Philippe H">H Philippe</name></author><author><name sortKey="Bryant, D" uniqKey="Bryant D">D Bryant</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smith, Jm" uniqKey="Smith J">JM Smith</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jakobsen, Ib" uniqKey="Jakobsen I">IB Jakobsen</name></author><author><name sortKey="Easteal, S" uniqKey="Easteal S">S Easteal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pethe, K" uniqKey="Pethe K">K Pethe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Majlessi, L" uniqKey="Majlessi L">L Majlessi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bottai, D" uniqKey="Bottai D">D Bottai</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9216904</journal-id><journal-id journal-id-type="pubmed-jr-id">2419</journal-id><journal-id journal-id-type="nlm-ta">Nat Genet</journal-id><journal-id journal-id-type="iso-abbrev">Nat. Genet.</journal-id><journal-title-group><journal-title>Nature genetics</journal-title></journal-title-group><issn pub-type="ppub">1061-4036</issn><issn pub-type="epub">1546-1718</issn></journal-meta><article-meta><article-id pub-id-type="pmid">23291586</article-id><article-id pub-id-type="pmc">3856870</article-id><article-id pub-id-type="doi">10.1038/ng.2517</article-id><article-id pub-id-type="manuscript">EMS53121</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Genome analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of the etiologic agent of tuberculosis</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Supply</surname><given-names>Philip</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><xref ref-type="aff" rid="A4">4</xref><xref ref-type="corresp" rid="CR1">*</xref></contrib><contrib contrib-type="author"><name><surname>Marceau</surname><given-names>Michael</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><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Mangenot</surname><given-names>Sophie</given-names></name><xref ref-type="aff" rid="A5">5</xref><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Roche</surname><given-names>David</given-names></name><xref ref-type="aff" rid="A5">5</xref><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Rouanet</surname><given-names>Carine</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><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Khanna</surname><given-names>Varun</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Majlessi</surname><given-names>Laleh</given-names></name><xref ref-type="aff" rid="A8">8</xref><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Criscuolo</surname><given-names>Alexis</given-names></name><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Tap</surname><given-names>Julien</given-names></name><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Pawlik</surname><given-names>Alexandre</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Fiette</surname><given-names>Laurence</given-names></name><xref ref-type="aff" rid="A11">11</xref><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Orgeur</surname><given-names>Mickael</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Fabre</surname><given-names>Michel</given-names></name><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Parmentier</surname><given-names>Cécile</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Frigui</surname><given-names>Wafa</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Simeone</surname><given-names>Roxane</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Boritsch</surname><given-names>Eva C.</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Debrie</surname><given-names>Anne-Sophie</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><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Willery</surname><given-names>Eve</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><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Walker</surname><given-names>Danielle</given-names></name><xref ref-type="aff" rid="A14">14</xref></contrib><contrib contrib-type="author"><name><surname>Quail</surname><given-names>Michael A.</given-names></name><xref ref-type="aff" rid="A14">14</xref></contrib><contrib contrib-type="author"><name><surname>Ma</surname><given-names>Laurence</given-names></name><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><name><surname>Bouchier</surname><given-names>Christiane</given-names></name><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><name><surname>Salvignol</surname><given-names>Grégory</given-names></name><xref ref-type="aff" rid="A5">5</xref><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Sayes</surname><given-names>Fadel</given-names></name><xref ref-type="aff" rid="A8">8</xref><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Cascioferro</surname><given-names>Alessandro</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Seemann</surname><given-names>Torsten</given-names></name><xref ref-type="aff" rid="A16">16</xref></contrib><contrib contrib-type="author"><name><surname>Barbe</surname><given-names>Valérie</given-names></name><xref ref-type="aff" rid="A5">5</xref><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Locht</surname><given-names>Camille</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><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Gutierrez</surname><given-names>Maria-Cristina</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><xref ref-type="aff" rid="A4">4</xref><xref ref-type="aff" rid="A17">17</xref></contrib><contrib contrib-type="author"><name><surname>Leclerc</surname><given-names>Claude</given-names></name><xref ref-type="aff" rid="A8">8</xref><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Bentley</surname><given-names>Stephen</given-names></name><xref ref-type="aff" rid="A14">14</xref></contrib><contrib contrib-type="author"><name><surname>Stinear</surname><given-names>Timothy P.</given-names></name><xref ref-type="aff" rid="A18">18</xref></contrib><contrib contrib-type="author"><name><surname>Brisse</surname><given-names>Sylvain</given-names></name><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Médigue</surname><given-names>Claudine</given-names></name><xref ref-type="aff" rid="A5">5</xref><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Parkhill</surname><given-names>Julian</given-names></name><xref ref-type="aff" rid="A14">14</xref></contrib><contrib contrib-type="author"><name><surname>Cruveiller</surname><given-names>Stéphane</given-names></name><xref ref-type="aff" rid="A5">5</xref><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Brosch</surname><given-names>Roland</given-names></name><xref ref-type="aff" rid="A7">7</xref><xref ref-type="corresp" rid="CR1">*</xref></contrib></contrib-group><aff id="A1"><label>1</label>Institut National de la Santé et de la Recherche Médicale (INSERM), U1019, Center for Infection and Immunity of Lille, Lille, France</aff><aff id="A2"><label>2</label>Centre National de la Recherche Scientifique (CNRS), Unite mixte de recherche (UMR) 8204, Center for Infection and Immunity of Lille, Lille, France</aff><aff id="A3"><label>3</label>Univ Lille Nord de France, Center for Infection and Immunity of Lille, Lille, France</aff><aff id="A4"><label>4</label>Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France</aff><aff id="A5"><label>5</label>CNRS-UMR 8030 , Evry, France</aff><aff id="A6"><label>6</label>Commissariat à l’Energie Atomique et aux Energies Alternatives CEA/DSV/IG/Genoscope, LABGeM, Evry, France</aff><aff id="A7"><label>7</label>Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France</aff><aff id="A8"><label>8</label>Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris, France</aff><aff id="A9"><label>9</label>INSERM U1041, Paris, France</aff><aff id="A10"><label>10</label>Institut Pasteur, Genotyping of Pathogens and Public Health (PF8), Paris, France</aff><aff id="A11"><label>11</label>Institut Pasteur, Unité d’Histopathologie Humaine et Modèles Animaux, Paris, France</aff><aff id="A12"><label>12</label>Université Versailles-Saint Quentin en Yvelines, Faculté de Médecine, DER Histologie, Versailles, France</aff><aff id="A13"><label>13</label>Laboratoire de Biologie Clinique, HIA Percy, Clamart, France</aff><aff id="A14"><label>14</label>Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK</aff><aff id="A15"><label>15</label>Institut Pasteur, Genopole, Platform Genomics PF1, Paris, France</aff><aff id="A16"><label>16</label>Victorian Bioinformatics Consortium, Monash University, Clayton, Australia</aff><aff id="A17"><label>17</label>Institut Pasteur, Department d’Infection et d’Epidemiologie, Paris, France</aff><aff id="A18"><label>18</label>Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia</aff><author-notes><corresp id="CR1"><label>*</label>To whom correspondence should be addressed: <email>philip.supply@ibl.fr</email> and <email>roland.brosch@pasteur.fr</email></corresp><fn id="FN1"><p id="P1"><bold>Author contributions</bold> P.S., M.-C.G. and R.B. designed the study; P.S. and R.B. analyzed data and wrote the paper with comments from all authors; M.M., D.W., J.P., C.M. and S.Be. annotated the genomes; S.M., E.C.B., M.A.Q. L.Ma, C.B. and V.B. performed and/or verified the finishing and assembly of sequences; D.R. and S.C. performed SNP analyses and database management with support of G.S.; C.R., A.P., W.F., R.S., A.-S.D., E.W., A.Ca. and M.-C.G. performed mouse infection experiments, in vivo data analyses and/or mycobacterial growth assays; L.Maj., F.S., C.Lo. and C.Le. conducted and/or analyzed immune assays; J.T., A.Cr. and S.Br. conducted MLST, recombination and/or phylogenetic analyses; L.F. conducted histopathological analyses; V.K, M.O. and C.P. created bioinformatics tools and analyzed data; M.F. isolated STB strains; T.S. and T.P.S conducted core genome and NeighborNet analyses.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>30</day><month>11</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>06</day><month>1</month><year>2013</year></pub-date><pub-date pub-type="ppub"><month>2</month><year>2013</year></pub-date><pub-date pub-type="pmc-release"><day>09</day><month>12</month><year>2013</year></pub-date><volume>45</volume><issue>2</issue><elocation-id>10.1038/ng.2517</elocation-id><permissions><license><license-p>Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
<uri xlink:type="simple" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</uri></license-p></license></permissions><abstract><p id="P2">Global spread and genetic monomorphism are hallmarks of <italic>Mycobacterium tuberculosis</italic>, the agent of human tuberculosis. In contrast, <italic>Mycobacterium canettii</italic>, and related tubercle bacilli that also cause human tuberculosis and exhibit unusual smooth colony morphology, are restricted to East-Africa. Here, we sequenced and analyzed the genomes of five representative strains of smooth tubercle bacilli (STB) using Sanger (4-5x coverage), 454/Roche (13-18x coverage) and/or Illumina DNA sequencing (45-105x coverage). We show that STB are highly recombinogenic and evolutionary early-branching, with larger genome sizes, 25-fold more SNPs, fewer molecular scars and distinct CRISPR-Cas systems relative to <italic>M. tuberculosis</italic>. Despite the differences, all tuberculosis-causing mycobacteria share a highly conserved core genome. Mouse-infection experiments revealed that STB are less persistent and virulent than <italic>M. tuberculosis.</italic> We conclude that <italic>M. tuberculosis</italic> emerged from an ancestral, STB-like pool of mycobacteria by gain of persistence and virulence mechanisms and we provide genome-wide insights into the molecular events involved.</p></abstract><funding-group><award-group><funding-source country="United Kingdom">Wellcome Trust : </funding-source><award-id>098051 || WT</award-id></award-group></funding-group></article-meta></front><body><p id="P3"><italic>Mycobacterium tuberculosis</italic> is a pervasive human pathogen, currently estimated to infect two billion people throughout the world<sup><xref ref-type="bibr" rid="R1">1</xref></sup>. The bacterial population size resulting from this massive spread is very large, yet the genetic diversity within the classical members of the <italic>M. tuberculosis</italic> complex (MTBC), comprising <italic>Mycobacterium africanum</italic>, <italic>Mycobacterium bovis</italic>, <italic>Mycobacterium microti</italic>, <italic>Mycobacterium pinnipedii</italic>, and <italic>M. tuberculosis</italic> is very limited. Tuberculosis is therefore assumed to be a recent human disease<sup><xref ref-type="bibr" rid="R2">2</xref>,<xref ref-type="bibr" rid="R3">3</xref></sup> linked to clonal expansion of its causative organism<sup><xref ref-type="bibr" rid="R4">4</xref>-<xref ref-type="bibr" rid="R6">6</xref></sup>.</p><p id="P4">In contrast to MTBC, smooth tubercle bacilli (STB), defined as clinical isolates displaying a distinctive smooth colony phenotype on culture media, named <italic>Mycobacterium canettii</italic> and/or <italic>Mycobacterium prototuberculosis</italic><sup><xref ref-type="bibr" rid="R7">7</xref>-<xref ref-type="bibr" rid="R10">10</xref></sup>, are less genetically restricted. Initial genotyping analysis suggested that these isolates possess a higher diversity with traces of intraspecies horizontal gene transfer (HGT) and might therefore represent early-branching lineages of tuberculosis-causing mycobacteria. Since their first isolation by Georges Canetti in 1969, less than one hundred strains of STB have been identified. All STB have been obtained from human tuberculosis patients, mostly from (or with connection to) East-Africa<sup><xref ref-type="bibr" rid="R8">8</xref>,<xref ref-type="bibr" rid="R11">11</xref></sup>. Thus, a collection of a few tens of STB strains from a geographically restricted region appears to contain greater genetic diversity than the worldwide population of MTBC strains. This observation raises intriguing questions about the origin of tuberculosis and provided an opportunity to examine the molecular and evolutionary events involved in the emergence of <italic>M. tuberculosis</italic>. Herein, we describe and compare complete genome sequences of five diverse STB isolates and the physiopathological properties of these mycobacteria relative to <italic>M. tuberculosis</italic> as well as whole genome shotgun (WGS) sequences of four additional STB strains for secondary screening and confirmation purposes.</p><sec id="S1"><title>Ancestral features of STB genomes</title><p id="P5">We applied multilocus sequence typing (MLST) based on 12 house-keeping genes to a panel of 55 available STB isolates and identified a total of 13 sequence types among them (<xref ref-type="fig" rid="F1">Fig. 1</xref> and <xref ref-type="supplementary-material" rid="SD1">Supplementary Tables 1</xref> and <xref ref-type="supplementary-material" rid="SD1">2</xref>). From analyses of the concatenated sequences we inferred a highly reticulated phylogeny, suggestive of conflicting phylogenetic signals and possible HGT among the target genes. We then selected five representative isolates for the principal comprehensive genomic analysis. This selection included the original strain isolated by George Canetti, of sequence type A and an isolate from the most prevalent group of sequence type D (both belonging to the <italic>M. canettii</italic> cluster), as well as strains from the most distant sequence types L, J and K (<xref ref-type="fig" rid="F1">Fig. 1</xref> and <xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 1</xref>)<sup><xref ref-type="bibr" rid="R9">9</xref></sup>.</p><p id="P6">Comparison of these five STB genomes with those of <italic>M. tuberculosis</italic> H37Rv<sup><xref ref-type="bibr" rid="R12">12</xref></sup> and other MTBC members<sup><xref ref-type="bibr" rid="R13">13</xref></sup> revealed a very similar overall organization between STB and MTBC, with a high percentage of syntenic genes (from 96% for strain A and 93% for strain K, compared to only 77% between <italic>M. tuberculosis</italic> H37Rv and <italic>Mycobacterium marinum</italic>, one of the phylogenetically closest non-tuberculous mycobacterial species<sup><xref ref-type="bibr" rid="R14">14</xref></sup>). No major chromosomal rearrangements or plasmids were detected (<xref ref-type="fig" rid="F1">Fig. 1</xref>). Pairwise analyses between the conserved STB and MTBC genome sequences showed that all combinations had average nucleotide identities of at least 97.3%, above the 95% threshold proposed for classification into the same species<sup><xref ref-type="bibr" rid="R15">15</xref></sup>. However, the genomes of STB are 10-115 kb larger than those of the MTBC members and thus represent the largest genomes known for tubercle bacilli, although they are still much smaller than those of <italic>M. marinum</italic> (6.6 Mb)<sup><xref ref-type="bibr" rid="R16">16</xref></sup> and the other most closely related, non-tuberculous species <italic>M. kansasii</italic> (6.4 Mb)<sup><xref ref-type="bibr" rid="R17">17</xref></sup>. Excluding repetitive sequences such as PE_PGRS- and PPE_MPTR-encoding regions, which account for ~ 8% of the coding capacity of <italic>M. tuberculosis</italic><sup><xref ref-type="bibr" rid="R12">12</xref></sup>, STB and MTBC share > 89.3% of their genomes, representing a core genome for tubercle bacilli of > 3.938 Mb. This core comprises 96.3% of the 774 <italic>M. tuberculosis</italic> H37Rv genes predicted as being essential for <italic>in vitro</italic> growth, and all 194 genes required for mycobacterial survival during mouse infection<sup><xref ref-type="bibr" rid="R18">18</xref>-<xref ref-type="bibr" rid="R20">20</xref></sup>, further reflecting the close affiliations of STB and <italic>M. tuberculosis</italic>. The accessory genomes of individual STB strains harbor from 124 (strain A) to 366 genes (strains K and J) not present in MTBC members that enlarge the known pan-genome of tubercle bacilli by 890 predicted coding sequences (CDS), representing a supplement of more than 20% relative to the gene pool of <italic>M. tuberculosis</italic> (<xref ref-type="supplementary-material" rid="SD2">Supplementary Table 3</xref> and <xref ref-type="supplementary-material" rid="SD1">Supplementary Figs 2a, b</xref>). Interestingly, only nine of these CDS were common to all five STB genomes analyzed (<xref ref-type="supplementary-material" rid="SD2">Supplementary Table 3</xref> and <xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 2c</xref>). Conversely, 51 genes partially overlapping with genomic islands<sup><xref ref-type="bibr" rid="R21">21</xref></sup> present in MTBC were not found in any of the STB strains (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 4</xref>). These genes encode derivatives of mobile elements, such as the phiRv1 and phiRv2 prophage-like regions (24 CDS), 3 transposases, 5 unique members of a glycine-rich protein family (e.g. PE_PGRS33; <xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 3a</xref>) and 19 other hypothetical proteins (<xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 3b</xref>). It is noteworthy that Rv1989c-Rv1990c from one such MTBC specific region showed around 90% identity with proteins encoded on a plasmid from <italic>Mycobacterium gilvum</italic> and <italic>Mycobacterium</italic> sp. KMS, raising intriguing questions about possible transmission routes of the corresponding genes into the MTBC. Several other MTBC-specific hypothetical proteins had no or only weak amino-acid similarity with other mycobacterial proteins (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 4</xref>), suggesting HGT into MTBC from distant donors after the separation from the STB lineages.</p><p id="P7">We also identified prominent, HGT-related differences in clustered regularly interspaced short palindromic repeats-CRISPR-associated proteins (CRISPR-Cas) systems between STB and MTBC. These systems may confer adaptive immunity against phages and plasmids in bacteria and archea via repeat/spacer-derived short RNAs<sup><xref ref-type="bibr" rid="R22">22</xref></sup>. The genomes of STB strains A and D contain a single CRISPR-Cas locus encoding a system of major type III-A that is similar to that of MTBC genomes, but with a few <italic>crispr</italic> spacers in common<sup><xref ref-type="bibr" rid="R7">7</xref>,<xref ref-type="bibr" rid="R10">10</xref></sup> and substantially lower sequence similarities of their Cas proteins (down to 75%) than those of the core proteins (98%-100 %) (<xref ref-type="fig" rid="F2">Fig. 2</xref>.). The same genomic region in the more distant K, L and J strains is occupied by a completely different CRISPR-Cas system of a rare type-Ic variant (<xref ref-type="fig" rid="F2">Fig. 2</xref>), most closely related to those of environmental actinobacteria such as <italic>Gordonia amarae</italic> or purple sulfur bacteria <italic>Thioalkalivibrio sp.</italic>. Furthermore, in strain K, the presence of a second CRISPR-Cas module of a different type Ic was identified 260 kb upstream of the other locus (<xref ref-type="fig" rid="F2">Fig. 2</xref>), whose Cas proteins were most similar to those of <italic>Moorella sp.</italic> or <italic>Thiorhodovibrio sp</italic>. Finally, screening of WGS-derived sequences from STB strains E, G, H, and I, located at well-distributed intermediate positions of the STB MLST-based network (<xref ref-type="fig" rid="F1">Fig. 1</xref>), revealed the existence of yet another type I-E module in strains G and I that was most closely related to those of environmental actinobacteria such as <italic>Saccharomonospora sp.</italic>, while in the two remaining E and H strains, a type Ic variant similar to those of STB-J, -K and -L was found (<xref ref-type="fig" rid="F2">Fig. 2a</xref>). As CRISPR-Cas systems have not been identified in non-tuberculous mycobacterial species, these different systems were most likely acquired by independent HGT events that occurred after the divergence of STB and MTBC. While it is not known whether the CRISPR systems in tubercle bacilli are functional, their disparate origins suggest that the distinct, respective <italic>crispr</italic> spacer sets might not necessarily reflect genetic records of recent encounters of tubercle bacilli with distinct phage transgressors but, instead, older traces of interaction of the respective CRISPR-Cas donor organisms with non-mycobacterial phages. The identification of a 55 kb prophage region in the WGS-derived sequence of STB-I that is large enough to encode a potentially complete virion<sup><xref ref-type="bibr" rid="R23">23</xref></sup> (<xref ref-type="fig" rid="F2">Fig. 2</xref>), which to our knowledge represents the first such finding in tubercle bacilli, provides a promising future model for testing the functionality of mycobacterial CRISPR-Cas systems on adaptive immunity against phages.</p><p id="P8">Progressive genome downsizing is a hallmark of mycobacterial pathogen evolution<sup><xref ref-type="bibr" rid="R17">17</xref>,<xref ref-type="bibr" rid="R24">24</xref></sup>. Therefore, the larger genome sizes of STB compared with MTBC argue for their ancestral status. Further evidence for ancestrality of STB genome structures comes from inspection of interrupted coding sequence (ICDS) orthologs, thought to reflect molecular scars inherited during pseudogenization of the MTBC genomes<sup><xref ref-type="bibr" rid="R25">25</xref>,<xref ref-type="bibr" rid="R26">26</xref></sup>. Among the 81 reported ICDS in MTBC, most were found to be also interrupted both in STB and more distantly related mycobacteria, suggesting evolutionary ancient mycobacterial scars (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 5</xref>). However, we identified four ICDS, e.g. <italic>pks8</italic> belonging to the <italic>pks</italic> multi-gene family encoding polyketide synthases that are involved in the biosynthesis of important cell envelope lipids<sup><xref ref-type="bibr" rid="R16">16</xref>,<xref ref-type="bibr" rid="R27">27</xref></sup>, which were intact in the genomes of STB (in one case - <italic>rv3741/42</italic>, the region was absent from STB-J) and from the <italic>M. marinum</italic> and/or <italic>M. kansasii</italic> outgroup genomes (<xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 4</xref>). Thus, these scars occurred in the most recent common ancestor of the MTBC after divergence from STB-like progenitors. The opposite situation, <italic>i.e.</italic> ICDS shared by the STB genomes corresponding to intact CDS in MTBC, was never observed, further supporting the ancestral status of the STB genome structure. In addition, we detected four independent loci (<italic>narX, pks5, pknH, lppV</italic>), where a likely ancestral gene organization present both in the mycobacterial outgroups <italic>M. marinum</italic> and/or <italic>M. kansasii</italic> and in STB, was rearranged to result in a single hybrid gene and loss of intervening gene(s) in MTBC genomes (<xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 5</xref>), similar to what has been observed for <italic>pknH</italic> in <italic>M. africanum</italic><sup><xref ref-type="bibr" rid="R28">28</xref></sup>.</p><p id="P9">Ancient branching of STB lineages is also consistent with the much higher numbers of single nucleotide polymorphisms (SNPs) detected among STB genomes compared to MTBC. Pairwise comparisons of the STB-D, -A, -L, -J, and -K genome sequences with the <italic>M. tuberculosis</italic> H37Rv reference uncovered 16,168 - 61,228 SNPs (<xref ref-type="fig" rid="F1">Fig. 1</xref>). This amount is within the 9,525-65,744 SNP range observed among the group of STB strains alone, and up to 25-fold higher than the 741-2437 SNPs previously observed among members of the MTBC<sup><xref ref-type="bibr" rid="R13">13</xref>,<xref ref-type="bibr" rid="R29">29</xref>,<xref ref-type="bibr" rid="R30">30</xref></sup>. Consistent with MLST data (here and ref. <xref ref-type="bibr" rid="R9">9</xref>), a NeighborNet analysis based on pairwise comparisons of the genome-wide SNP data showed that MTBC forms a single compact group within a much larger, reticulated network of the STB genotypes (<xref ref-type="fig" rid="F1">Fig. 1</xref>). Consistently, this reticulation was even increased when WGS-derived sequence data from four additional STB strains were included (<xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 6</xref>), further confirming the MLST-derived phylogeny at the genome level. The Phi test for recombination was highly significant (<italic>p</italic>=10<sup>−6</sup>). Importantly, the relative compactness of the MTBC branch is additionally confirmed by the structure of the phylogenetic tree, obtained after exclusion of the genome portions affected by recombination/HGT (see further and <xref ref-type="fig" rid="F3">Fig. 3a</xref>). These results thus firmly demonstrate that the worldwide MTBC population only represents a genetically homogeneous subset branching from the larger diversity of recombinogenic STB isolates. Taken together with independent lines of evidence pointing to an earlier branching, they suggest that STB lineages diverged from the common ancestor of all tubercle bacilli well before the successful clonal radiation of MTBC began.</p></sec><sec id="S2"><title>Impact of selection and recombination</title><p id="P10">In order to compare the impact of selection on the evolution of the STB and MTBC genomes, we calculated global ratios of non-synonymous <italic>vs</italic> synonymous SNPs (dN/dS). The genome-wide dN/dS ratio is unusually high in MTBC, which has been suggested to reflect relaxed purifying selection against non-synonymous changes that are in general slightly deleterious<sup><xref ref-type="bibr" rid="R31">31</xref></sup>. The dN/dS ratios in the different gene categories among the STB strains were only about a third of those found in the MTBC (<xref ref-type="table" rid="T1">Table 1</xref>), and are thus compatible with a much longer time of exposure of STB to purifying selection, given the time dependence of dN/dS for closely related bacteria<sup><xref ref-type="bibr" rid="R32">32</xref>-<xref ref-type="bibr" rid="R34">34</xref></sup> and assuming that purifying selection pressures were the same for STB as for MTBC.</p><p id="P11">As an important exception, protective human CD4+ and CD8+ T-cell antigens and epitopes of <italic>M. tuberculosis</italic> have been described to be under purifying selection, suggesting that MTBC members do not use T-cell antigen variation to escape human immune responses but, instead, might benefit from recognition by T-cells<sup><xref ref-type="bibr" rid="R30">30</xref></sup>. Similarly, we found that the dN/dS ratios based on pairwise, concatenated codon alignments<sup><xref ref-type="bibr" rid="R35">35</xref>,<xref ref-type="bibr" rid="R36">36</xref></sup> of the 65 T-cell antigen-encoding STB genes conserved across all STB genomes were on average lower than those of the 2,300 genes classified as non essential and similar to slightly lower than the 710 essential genes<sup><xref ref-type="bibr" rid="R18">18</xref></sup> conserved among all STB (<xref ref-type="table" rid="T1">Table 1</xref>). Overall similar results were also obtained when only the epitope regions of the T-cell antigens were considered. Thus, like the subset of essential proteins, human T-cell antigens tend to be more conserved in STB relative to the rest of the proteome. Following the argument of Comas and colleagues<sup><xref ref-type="bibr" rid="R30">30</xref></sup>, this sequence conservation suggests that STB and MTBC might have inherited a common strategy of immune subversion of the human host that predates the clonal emergence of the MTBC. However, there may be alternative explanations, as most of these low dN/dS antigens are also highly conserved in the environmental, facultative pathogens <italic>M. marinum</italic> and/or <italic>M. kansasii</italic> and/or other mycobacteria. For example, the 6-kD early secreted antigenic target (ESAT-6, Rv3875) and the 34.6-kD secreted antigen 85B (Ag85B; Rv1886c), that both show 100% amino-acid conservation in MTBC and STB, have orthologues in <italic>M. marinum</italic> that show 91% (ESAT-6) and 89% (Ag85B) amino-acid identity, which is above the average overall pairwise identity of 85.2%<sup><xref ref-type="bibr" rid="R16">16</xref></sup>. The conservation of these proteins might thus also be explained by their role in host-pathogen interaction such as phagosomal rupture<sup><xref ref-type="bibr" rid="R37">37</xref></sup>, cell envelope stability<sup><xref ref-type="bibr" rid="R38">38</xref></sup> or other functions that are not necessarily linked to interactions with human T-cells.</p><p id="P12">Extensive recombination among STB, revealed by our comparative genome analysis, might also have played a role in the discrepancy in dN/dS between the MTBC and STB groups, as it could more efficiently oppose fixation of slightly deleterious mutations than in the more clonal MTBC population<sup><xref ref-type="bibr" rid="R39">39</xref></sup>. Consistent with this contention, strong variations in the local distribution of SNPs were observed throughout the aligned STB and MTBC genomes, suggestive of numerous recombination events. Approximately one-third of the core genome alignment consists of zones with significantly lower or higher SNP density compared to expectations for predicted recombination-free nucleotide differences between each pair of genomes. A stringent selection of informative regions among the predicted recombination-free blocks led to a minimal clonal backbone of 1,794,643 characters (~33% of the core genome), which was used to infer a phylogenetic tree (<xref ref-type="fig" rid="F3">Fig. 3a</xref>). Inspection of the genomic regions with unexpected SNP densities allowed us to identify > 110 blocks, of up to 14 kb and including each from 1 to 5 complete genes (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 6</xref>), with homoplasic SNP distributions (relative to the tree), indicative of likely inter-strain recombination events among STB and/or between STB and MTBC strains (<xref ref-type="fig" rid="F3">Fig. 3b</xref> and <xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 7a, b</xref>). The extensive impact of recombination was independently confirmed by the finding that ~8% to ~15% of the protein coding sequence alignments from the core genome has mosaic structures indicative of inter-strain intragenic recombination events. In contrast, the influence of exogenous importation from more distant mycobacterial species on the core genome sequence diversity is apparently minimal, as inferred by the detection of only few regions with unexpectedly high SNP densities in STB strains, yielding BLAST best hits closer to non-tuberculous mycobacteria than to STB and MTBC (<xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 7c</xref>).</p><p id="P13">Remarkably, the gene blocks in <italic>M. tuberculosis</italic> whose sequences perfectly match those of one or more STB strains, showed SNPs in the orthologous region in <italic>M. bovis</italic> and/or other MTBC strains (<xref ref-type="fig" rid="F3">Fig. 3b</xref>), suggesting that gene fluxes between <italic>M. tuberculosis</italic> and the STB strain pool existed even well after the divergence of the MTBC, and perhaps still exist. We also found intermediate situations, where the SNP distribution clearly suggests recombination events that were more ancient and likely followed by accumulation of a few mutations in the recipient or the donor strains (<xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 7a</xref>). These data provide new, solid evidence to the question of inter-strain gene flux in <italic>M. tuberculosis</italic><sup><xref ref-type="bibr" rid="R40">40</xref>,<xref ref-type="bibr" rid="R41">41</xref></sup>. Our findings also raise puzzling questions on the (micro-) environments and mechanisms favoring or having favored such extensive DNA exchanges. The high number of apparently recent recombination episodes, as suggested by numerous perfect large sequence matches detected among sequences from different STB lineages together with the almost exclusive isolation of STB strains from patients around the Horn of Africa strongly suggests a common local source. Aquatic environments rich in mycobacteria, potentially residing in protozoan hosts<sup><xref ref-type="bibr" rid="R24">24</xref>,<xref ref-type="bibr" rid="R42">42</xref></sup>, are one possible opportunity for genetic exchange to occur, as suggested by a recent report on detection of MTBC DNA in rural water sources in Ethiopia (E. Wellington, personal communication, Abstract, 16th International Symposium on the Biology of Actinomycetes). The presence of a 55 kb genomic segment corresponding to a putative complete phage-encoding region inserted into the Lys tRNA gene of strain STB-I (<xref ref-type="fig" rid="F2">Fig. 2</xref>) suggests a possible mediation by phages, although alternative mechanisms such as DNA transfer by conjugation, reported for <italic>Mycobacterium smegmatis</italic> under biofilm conditions<sup><xref ref-type="bibr" rid="R43">43</xref></sup>, could also be involved.</p></sec><sec id="S3"><title>STB persist less during infection than <italic>M. tuberculosis</italic></title><p id="P14">To determine whether the genome differences between the STB and MTBC strains impact on host-pathogen interactions, we first measured their growth in <italic>in vitro</italic> cultures. Most STB grew 2 to 3 times faster than <italic>M. tuberculosis</italic> both in liquid (<xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 8</xref>) and on solid media (data not shown) at 30°c and 37°c, in line with previous observations<sup><xref ref-type="bibr" rid="R10">10</xref>,<xref ref-type="bibr" rid="R11">11</xref></sup>. Upon infection of BALB/c mice (<xref ref-type="fig" rid="F4">Fig. 4</xref>) and C57BL6 mice (<xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 9</xref>) by aerosol, the STB strains effectively multiplied in lungs and disseminated to the spleens during the acute infection phase, but consistently persisted less well during the chronic infection phase compared to <italic>M. tuberculosis</italic>. While the latter was able to persist in the lungs for up to 30 weeks at levels close to those of the acute phase (peaking at 3 weeks with around 10<sup>7.7</sup> colony-forming units (CFUs)), the infection levels of all STB strains dropped by at least 1 log at all (and by 2 to 3 logs at most) later time points in these organs (p=0.05 by Mann-Whitney test, except for day 130 for strains D, L and K). The strongest difference with <italic>M. tuberculosis</italic> was observed for strain K, the strain phylogenomically most distant from MTBC and for which bacterial counts were undetectable after 30 weeks in BALB/c mice (<xref ref-type="fig" rid="F4">Fig. 4c, d</xref>). Similar trends were observed in spleens, with strain K also almost completely cleared at day 210. In parallel, histopathological analyses revealed less intense lung lesions and inflammation 128 days after infection with the STB strains compared to <italic>M. tuberculosis</italic> infection, with strain K showing the least damages (<xref ref-type="fig" rid="F4">Fig. 4</xref> and <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 7</xref>). Furthermore, C57BL/6 mice intravenously infected with high doses of STB survived in contrast to controls infected with <italic>M. tuberculosis</italic> strains of different lineages (data not shown), confirming decreased virulence of STB.</p><p id="P15">Finally, we determined whether these variations could be correlated to differences in innate or adaptive immune responses elicited by infection. The STB and <italic>M. tuberculosis</italic> strains were similarly able to induce maturation of innate immunity cells <italic>in vitro</italic>, such as dentritic cells derived from C57BL/6, <italic>tlr2<sup>°/°</sup></italic>, <italic>tlr4<sup>°/°</sup></italic>, or double KO mice (data not shown), suggesting shared major Pathogen-Associated Molecular Patterns (PAMPs)<sup><xref ref-type="bibr" rid="R44">44</xref></sup>. Consistently, substantial recruitment of activated innate immune cells, i.e., CD11b<sup>+</sup> BST-2<sup>+</sup> (Bone Marrow Stromal Cell Antigen-2)<sup>+</sup> and CD11c<sup>+</sup> MHC-II<sup>hi</sup>, was observed <italic>in vivo</italic> in the lung parenchyma of SCID mice after 3 weeks of infection by STB, but to a lower extent as compared to <italic>M. tuberculosis</italic> infection (data not shown). Concerning adaptive responses, massive recruitment of activated CD4<sup>+</sup> and CD8<sup>+</sup> T-cells, displaying CD44 modulation and CD45RB, CD27, CD62L downregulation, was detected in the lungs of C57BL/6 mice after 13 weeks of infection by smooth strains. Again, the responses were overall quantitatively lower for STB compared to <italic>M. tuberculosis</italic> strains, especially for STB-K (<xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 10</xref>), in line with the lower virulence and persistence of STB.</p></sec><sec id="S4"><title>Concluding remarks</title><p id="P16">With the larger pan genome reflecting the ancestral, wider gene pool of tubercle bacilli, their, lower virulence and faster growth especially at temperatures below 37°C, plausibly reflecting broader environmental adaptability, STB strains might thus come nearer to the as yet unknown missing link between the obligate pathogen <italic>M. tuberculosis</italic> and environmental mycobacteria. We propose that <italic>M. tuberculosis</italic> has evolved its so successful widespread, pathogenic lifestyle starting from a pool of STB-like mycobacteria by gaining additional virulence and persistence mechanisms through a potential combination of i) loss of gene function, ii) acquisition of novel genes via HGT, iii) inter-strain recombination of gene clusters and (iv) fixation of SNPs. From the data presented here, a rational experimental design to elucidate which of these genetic events were involved can now be undertaken. Primary candidates are MTBC-specific genes (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 4</xref>), including prophage-like phiRv1 / phiRv2 encoding regions reported to be important for late infection<sup><xref ref-type="bibr" rid="R45">45</xref></sup>, genes encoding PE_PGRS33 or other MTBC-acquired PE/PPE proteins known to enhance cellular toxicity<sup><xref ref-type="bibr" rid="R46">46</xref></sup>, polyketide synthase Pks8/17, the large prophage region in STB-I and/or CRISPR-cas systems. The insights gained through our analysis thus open novel perspectives to identify new targets to combat tuberculosis infection and disease.</p></sec><sec sec-type="methods" id="S5" specific-use="web-only"><title>Online-Methods</title><sec id="S6"><title>Bacterial strains and multi-locus sequence typing</title><p id="P17">The 55 STB and 10 reference MTBC isolates are described in <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>. Twelve house-keeping genes were selected for MLST<sup><xref ref-type="bibr" rid="R47">47</xref></sup> (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 2</xref>). Phylogenetic groupings were identified by split decomposition analysis<sup><xref ref-type="bibr" rid="R48">48</xref></sup> on the concatenated target sequences .</p></sec><sec id="S7"><title>Genome sequencing</title><p id="P18">Genomic DNA was extracted from cultured single bacterial colonies<sup><xref ref-type="bibr" rid="R12">12</xref></sup>. For genome sequencing of STB-D, -J, -K and -L, Sanger reads from 10-kb fragment shotgun libraries at 4- 4.9 fold coverages were assembled with contigs obtained from Newbler assemblies of 454/Roche reads at 13-18.1 fold coverages, using Arachne<sup><xref ref-type="bibr" rid="R49">49</xref></sup>. Scaffolds were validated using Mekano interface (Genoscope). Primer walking, PCRs and in-vitro transposition were used for finishing. The assembled consensus sequences were validated using Illumina reads at 45-105 fold coverages and consed functionalities, and by mapping of termini-sequences from bacterial artificial chromosome libraries<sup><xref ref-type="bibr" rid="R50">50</xref></sup>. High quality, contiguous genome sequences of 4420 kb (STB-L, 9 contigs), 4432 kb (STB-D, 12 contigs), 4524 kb (STB-J, 11 contigs), and 4525 kb (STB-K, 9 contigs) were generated. Remaining gaps estimated not to exceed 2 kb correspond to GC-rich and repetitive regions coding for PE_PGRS proteins, and/or the <italic>pks5</italic> region (STB-J). For STB-A, a fully finished, contiguous sequence of 4,482,059 bp was obtained by using ~ 80,000 shotgun Sanger reads, Illumina-generated reads and finishing<sup><xref ref-type="bibr" rid="R12">12</xref>,<xref ref-type="bibr" rid="R28">28</xref></sup>. WGS data from STB strains E, G, H, and I were generated using Illumina HiSseq technology and single lanes. Resulting reads that covered the genomes of these STB up to 900x were assembled using the Velvet software<sup><xref ref-type="bibr" rid="R51">51</xref></sup> and contigs were ordered using <italic>M. canettii</italic> CIPT 140010059 (STB-A) and <italic>M. tuberculosis</italic> H37Rv as reference genomes.</p></sec><sec id="S8"><title>Annotation and comparative genomics</title><p id="P19">Annotation and genome comparisons were performed with the Microscope platform<sup><xref ref-type="bibr" rid="R52">52</xref></sup>, Artemis and Artemis comparison tool (ACT)<sup><xref ref-type="bibr" rid="R53">53</xref></sup>. When applicable, annotations were transferred from those of <italic>M. tuberculosis</italic> orthologs in the TubercuList/Mycobrowser database, using BLAST matches of > 90% protein sequence identity, an alignable region of > 80% of the shortest protein length in pairwise comparisons and visual inspection of the gene synteny. Pairwise average nucleotide identities were calculated using JSpecies<sup><xref ref-type="bibr" rid="R54">54</xref></sup>. The core/accessory genomes of STB and <italic>M. tuberculosis</italic> were determined as described<sup><xref ref-type="bibr" rid="R16">16</xref></sup>.</p></sec><sec id="S9"><title>SNP and indel analysis</title><p id="P20">SNiPer pipeline (Genoscope) based on the SSAHA2 package<sup><xref ref-type="bibr" rid="R55">55</xref></sup> was used to map Illumina reads and detect SNPs and indels of STB strains against a corrected version<sup><xref ref-type="bibr" rid="R56">56</xref></sup> of the <italic>M. tuberculosis</italic> H37Rv reference sequence (NC_000962)<sup><xref ref-type="bibr" rid="R12">12</xref></sup>. After exclusion of ambiguous maps on repeat regions, an average of 4.7 million split paired-end reads of 36 bp (STB-A, -D, -L, - J) or trimmed at 50 bp (STB-K) were mapped at a resulting genome coverage > 40x. SNPs with base coverage < 10, base quality < 25, or heterozygosity > 0.2 were removed. ACT<sup><xref ref-type="bibr" rid="R53">53</xref></sup> comparison files were created by using MUMmer and NUCmer softwares<sup><xref ref-type="bibr" rid="R57">57</xref></sup> to visualize the SNP distribution in local genome regions.</p></sec><sec id="S10"><title>Calculation of dN/dS</title><p id="P21">dN/dS ratios were calculated on orthologs conserved in all STB and <italic>M. tuberculosis</italic> H37Rv, as identified by bidirectional best hits, alignable region of >80% and sequence identity >=30%. Pairwise, concatenated codon alignments between <italic>M. tuberculosis</italic> H37Rv and each STB strain were generated using PAL2NAL<sup><xref ref-type="bibr" rid="R58">58</xref></sup>, after respective protein alignments obtained with MUSCLE<sup><xref ref-type="bibr" rid="R59">59</xref></sup>. Synonymous and non-synonymous substitutions were defined using Nei-Gojobori method-based SNAP<sup><xref ref-type="bibr" rid="R35">35</xref></sup> or maximum likelihood-based PAML<sup><xref ref-type="bibr" rid="R36">36</xref></sup>. STB T-cell antigen, essential and non-essential gene categories, as well as T-cell epitope codon concatenates were constructed as described<sup><xref ref-type="bibr" rid="R30">30</xref></sup>.</p></sec><sec id="S11"><title>Recombination</title><p id="P22">The genomes of <italic>M. tuberculosis</italic> H37Rv, <italic>M. bovis</italic> AF2122/97 and the five STB strains were aligned using progressive Mauve<sup><xref ref-type="bibr" rid="R60">60</xref></sup>. Given a pair <italic>ij</italic> of aligned genomes, the number of SNPs <italic>x<sub>ij</sub></italic> observed between <italic>i</italic> and <italic>j</italic> within a region of length <italic>l</italic> follows a binomial distribution <italic>B</italic>(<italic>l</italic>, <italic>p<sub>ij</sub></italic>), where <italic>p<sub>ij</sub></italic> is the expected proportion of recombination-free nucleotide differences between taxa <italic>i</italic> and <italic>j</italic>. Regions containing at least one pair of sequences <italic>ij</italic> with an unexpectedly large or low number <italic>x<sub>ij</sub></italic> of SNPs, i.e. min [Pr (<italic>X</italic> ≥ <italic>x<sub>ij</sub></italic> ), Pr (<italic>X</italic> ≤ <italic>x<sub>ij</sub></italic> )] < 0.05 where <italic>X</italic> ~ <italic>B</italic>(<italic>l</italic>, <italic>p<sub>ij</sub></italic>), were identified by using a 200 character-long sliding window along the conserved (core) portions of the multiple genome alignment. The value <italic>p<sub>ij</sub></italic> inside each window was estimated as the proportion of SNPs between <italic>i</italic> and <italic>j</italic> within the 10000 aligned characters flanking the sliding window on both sides. To obtain a reference phylogeny, all regions of length ≥ 500 characters (excluding gaps) that did not contain an unexpected number of SNPs were concatenated. The derived supermatrix was used to infer a phylogenetic tree by using the Neighbor-Joining algorithm on the pairwise nucleotide <italic>p</italic>-distances<sup><xref ref-type="bibr" rid="R61">61</xref></sup>. All regions of length ≥ 500 characters with a significantly high or low number of SNPs were inspected visually for detection of concentration of homoplasic characters using ACT<sup><xref ref-type="bibr" rid="R53">53</xref></sup>, leading to similarities between strains incongruent with the phylogenetic tree. The proportion of protein coding sequences within the core genome likely affected by inter-strain recombination was assessed with the Pairwise Homoplasy Index<sup><xref ref-type="bibr" rid="R62">62</xref></sup>, the Maximum <italic>x<sup>2</sup></italic> test<sup><xref ref-type="bibr" rid="R63">63</xref></sup>, and the Neighbour Similarity Score<sup><xref ref-type="bibr" rid="R64">64</xref></sup>.</p></sec><sec id="S12"><title>Bacterial growth assays</title><p id="P23">Growth rates of STB and reference MTBC strains in liquid media were measured by using a BACTEC 460 system (Beckton-Dickinson) as recommended by the manufacturer.</p></sec><sec id="S13"><title>Mouse infection experiments , histopathological and cell analyses</title><p id="P24">Mice were maintained according to the Institut Pasteur de Lille and Paris guidelines for laboratory animal husbandry. Animal experiments were approved by the Nord-Pas-De-Calais ethical committee (CEEA 15/2009) and the Institut Pasteur Hygiene Committee (authorization number 75-1469), in accordance with European and French guidelines (Directive 86/609/CEE and Decree 87–848). Eight-week-old female BALB/c mice were infected by the intranasal route with 10<sup>3</sup> CFUs of either STB or <italic>M. tuberculosis</italic> H37Rv strains, respectively. At indicated times, 4 mice per group were sacrificed, and colony counting was performed from homogenized individual lungs and spleens as described<sup><xref ref-type="bibr" rid="R65">65</xref></sup>. For histopathological evaluation, whole lungs were harvested from 3 BALB/c mice per group 128 days post-infection, fixed in 4% formalin, and embedded in paraffin. Four mm-thick sections were stained with hematoxylin-eosin. Virulence and cell-analysis-based immunological assays using C57BL/6 and/or SCID mice were performed as described<sup><xref ref-type="bibr" rid="R66">66</xref>,<xref ref-type="bibr" rid="R67">67</xref></sup>. Adaptive immune cells from infected mice were prepared, incubated with conjugated mAbs (Beckton-Dickinson), fixed, and analyzed using a CyAn system and Summit (Beckman Coulter) and FlowJo (Treestar) softwares.</p></sec></sec><sec sec-type="supplementary-material" id="SM"><title>Supplementary Material</title><supplementary-material content-type="loca-data" id="SD1"><label>1</label><media xlink:href="NIHMS53121-supplement-1.pdf" mimetype="application" mime-subtype="pdf" orientation="portrait" xlink:type="simple" id="d36e1514" position="anchor"></media></supplementary-material><supplementary-material content-type="loca-data" id="SD2"><label>2</label><media xlink:href="NIHMS53121-supplement-2.xls" mimetype="application" mime-subtype="vnd.ms-excel" orientation="portrait" xlink:type="simple" id="d36e1518" position="anchor"></media></supplementary-material></sec></body><back><ack id="S14"><title>Acknowledgements</title><p>We are grateful to Stewart Cole for help in initiating the <italic>M. canettii</italic> CIPT 140010059 genome sequencing project and advice, to Thierry Garnier and Adamandia Kapopoulou for help in data management and to Zoe Rouy for help with sequence deposal. The work was supported in part by the Institut Pasteur (PTR 314, PTR 383), the European Community’s FP7 program Grant no. 260872, the Wellcome trust grant 098051, and a Genoscope collaborative grant no. 114.</p></ack><fn-group><fn id="FN2"><p id="P25"><bold>URLs</bold> Magnifying Genome (MaGe) server, <ext-link ext-link-type="uri" xlink:href="https://www.genoscope.cns.fr/agc/microscope/about/collabprojects.php?P_id=44#ancreLogin">https://www.genoscope.cns.fr/agc/microscope/about/collabprojects.php?P_id=44#ancreLogin</ext-link>; MycoBrowser database, <ext-link ext-link-type="uri" xlink:href="http://mycobrowser.epfl.ch/">http://mycobrowser.epfl.ch/</ext-link>; The Mycobacteriophage database, <ext-link ext-link-type="uri" xlink:href="http://phagesdb.org/">http://phagesdb.org/</ext-link>.</p></fn><fn id="FN3"><p id="P26"><bold>Accession Codes</bold> The complete genome sequence for strain STB-A (CIPT 140010059) was deposited under Accession No. HE572590. Genome sequences of strains STB-D (CIPT 140060008), STB-J (CIPT 140070017), STB-K (CIPT 140070010), and STB-L (CIPT 140070008) were deposited in the EMBL database under accession numbers PRJEB94 - BN44 - FO203507, PRJEB93 - BN43 - FO203508, PRJEB92 - BN42 - FO203509, and PRJEB95 - BN45 - FO203510, respectively. Illumina-derived WGS sequences for strains STB-E (CIPT 140070002), STB-G (CIPT 140070005), STB-H (CIPT 140070013), and STB-I (CIPT 140070007) were deposited in the EMBL WGS repository under project numbers PRJEB584, PRJEB585, PRJEB586, and PRJEB587, respectively.</p></fn></fn-group><ref-list><title>References</title><ref id="R1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dye</surname><given-names>C</given-names></name><name><surname>Williams</surname><given-names>BG</given-names></name></person-group><article-title>The population dynamics and control of tuberculosis</article-title><source>Science</source><year>2010</year><volume>328</volume><fpage>856</fpage><lpage>861</lpage><pub-id pub-id-type="pmid">20466923</pub-id></element-citation></ref><ref id="R2"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sreevatsan</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Restricted structural gene polymorphism in the <italic>Mycobacterium tuberculosis</italic> complex indicates evolutionarily recent global dissemination</article-title><source>Proc Natl Acad Sci U S A</source><year>1997</year><volume>94</volume><fpage>9869</fpage><lpage>9874</lpage><pub-id pub-id-type="pmid">9275218</pub-id></element-citation></ref><ref id="R3"><label>3</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wirth</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>Origin, spread and demography of the <italic>Mycobacterium tuberculosis</italic> complex</article-title><source>PLoS Pathog</source><year>2008</year><volume>4</volume><fpage>e1000160</fpage><pub-id pub-id-type="pmid">18802459</pub-id></element-citation></ref><ref id="R4"><label>4</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Brosch</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>A new evolutionary scenario for the <italic>Mycobacterium tuberculosis</italic> complex</article-title><source>Proc Natl Acad Sci U S A</source><year>2002</year><volume>99</volume><fpage>3684</fpage><lpage>3689</lpage><pub-id pub-id-type="pmid">11891304</pub-id></element-citation></ref><ref id="R5"><label>5</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Supply</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>Linkage disequilibrium between minisatellite loci supports clonal evolution of <italic>Mycobacterium tuberculosis</italic> in a high tuberculosis incidence area</article-title><source>Mol Microbiol</source><year>2003</year><volume>47</volume><fpage>529</fpage><lpage>538</lpage><pub-id pub-id-type="pmid">12519202</pub-id></element-citation></ref><ref id="R6"><label>6</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hirsh</surname><given-names>AE</given-names></name><name><surname>Tsolaki</surname><given-names>AG</given-names></name><name><surname>DeRiemer</surname><given-names>K</given-names></name><name><surname>Feldman</surname><given-names>MW</given-names></name><name><surname>Small</surname><given-names>PM</given-names></name></person-group><article-title>Stable association between strains of <italic>Mycobacterium tuberculosis</italic> and their human host populations</article-title><source>Proc Natl Acad Sci U S A</source><year>2004</year><volume>101</volume><fpage>4871</fpage><lpage>4876</lpage><pub-id pub-id-type="pmid">15041743</pub-id></element-citation></ref><ref id="R7"><label>7</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>van Soolingen</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>A novel pathogenic taxon of the <italic>Mycobacterium tuberculosis</italic> complex, Canetti: characterization of an exceptional isolate from Africa</article-title><source>Int J Syst Bacteriol</source><year>1997</year><volume>47</volume><fpage>1236</fpage><lpage>1245</lpage><pub-id pub-id-type="pmid">9336935</pub-id></element-citation></ref><ref id="R8"><label>8</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fabre</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>High genetic diversity revealed by variable-number tandem repeat genotyping and analysis of hsp65 gene polymorphism in a large collection of “Mycobacterium canettii” strains indicates that the <italic>M. tuberculosis</italic> complex is a recently emerged clone of “M. canettii”</article-title><source>J Clin Microbiol</source><year>2004</year><volume>42</volume><fpage>3248</fpage><lpage>3255</lpage><pub-id pub-id-type="pmid">15243089</pub-id></element-citation></ref><ref id="R9"><label>9</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gutierrez</surname><given-names>MC</given-names></name><etal></etal></person-group><article-title>Ancient origin and gene mosaicism of the progenitor of <italic>Mycobacterium tuberculosis</italic></article-title><source>PLoS Pathog</source><year>2005</year><volume>1</volume><fpage>e5</fpage><pub-id pub-id-type="pmid">16201017</pub-id></element-citation></ref><ref id="R10"><label>10</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fabre</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Molecular characteristics of “Mycobacterium canettii” the smooth <italic>Mycobacterium tuberculosis</italic> bacilli</article-title><source>Infect Genet Evol</source><year>2010</year><volume>10</volume><fpage>1165</fpage><lpage>1173</lpage><pub-id pub-id-type="pmid">20692377</pub-id></element-citation></ref><ref id="R11"><label>11</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Koeck</surname><given-names>JL</given-names></name><etal></etal></person-group><article-title>Clinical characteristics of the smooth tubercle bacilli ‘Mycobacterium canettii’ infection suggest the existence of an environmental reservoir</article-title><source>Clin Microbiol Infect</source><year>2011</year><volume>17</volume><fpage>1013</fpage><lpage>1019</lpage><pub-id pub-id-type="pmid">20831613</pub-id></element-citation></ref><ref id="R12"><label>12</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cole</surname><given-names>ST</given-names></name><etal></etal></person-group><article-title>Deciphering the biology of <italic>Mycobacterium tuberculosis</italic> from the complete genome sequence</article-title><source>Nature</source><year>1998</year><volume>393</volume><fpage>537</fpage><lpage>544</lpage><pub-id pub-id-type="pmid">9634230</pub-id></element-citation></ref><ref id="R13"><label>13</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Garnier</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>The complete genome sequence of <italic>Mycobacterium bovis</italic></article-title><source>Proc Natl Acad Sci U S A</source><year>2003</year><volume>100</volume><fpage>7877</fpage><lpage>7882</lpage><pub-id pub-id-type="pmid">12788972</pub-id></element-citation></ref><ref id="R14"><label>14</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Springer</surname><given-names>B</given-names></name><name><surname>Stockman</surname><given-names>L</given-names></name><name><surname>Teschner</surname><given-names>K</given-names></name><name><surname>Roberts</surname><given-names>GD</given-names></name><name><surname>Bottger</surname><given-names>EC</given-names></name></person-group><article-title>Two-laboratory collaborative study on identification of mycobacteria: molecular versus phenotypic methods</article-title><source>J. Clin. Microbiol</source><year>1996</year><volume>34</volume><fpage>296</fpage><lpage>303</lpage><pub-id pub-id-type="pmid">8789004</pub-id></element-citation></ref><ref id="R15"><label>15</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goris</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>DNA-DNA hybridization values and their relationship to whole-genome sequence similarities</article-title><source>Int J Syst Evol Microbiol</source><year>2007</year><volume>57</volume><fpage>81</fpage><lpage>91</lpage><pub-id pub-id-type="pmid">17220447</pub-id></element-citation></ref><ref id="R16"><label>16</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stinear</surname><given-names>TP</given-names></name><etal></etal></person-group><article-title>Insights from the complete genome sequence of <italic>Mycobacterium marinum</italic> on the evolution of <italic>Mycobacterium tuberculosis</italic></article-title><source>Genome Res</source><year>2008</year><volume>18</volume><fpage>729</fpage><lpage>741</lpage><pub-id pub-id-type="pmid">18403782</pub-id></element-citation></ref><ref id="R17"><label>17</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Veyrier</surname><given-names>FJ</given-names></name><name><surname>Dufort</surname><given-names>A</given-names></name><name><surname>Behr</surname><given-names>MA</given-names></name></person-group><article-title>The rise and fall of the <italic>Mycobacterium tuberculosis</italic> genome</article-title><source>Trends Microbiol</source><year>2011</year><volume>19</volume><fpage>156</fpage><lpage>161</lpage><pub-id pub-id-type="pmid">21277778</pub-id></element-citation></ref><ref id="R18"><label>18</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sassetti</surname><given-names>CM</given-names></name><name><surname>Boyd</surname><given-names>DH</given-names></name><name><surname>Rubin</surname><given-names>EJ</given-names></name></person-group><article-title>Genes required for mycobacterial growth defined by high density mutagenesis</article-title><source>Mol Microbiol</source><year>2003</year><volume>48</volume><fpage>77</fpage><lpage>84</lpage><pub-id pub-id-type="pmid">12657046</pub-id></element-citation></ref><ref id="R19"><label>19</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sassetti</surname><given-names>CM</given-names></name><name><surname>Rubin</surname><given-names>EJ</given-names></name></person-group><article-title>Genetic requirements for mycobacterial survival during infection</article-title><source>Proc Natl Acad Sci U S A</source><year>2003</year><volume>100</volume><fpage>12989</fpage><lpage>12994</lpage><pub-id pub-id-type="pmid">14569030</pub-id></element-citation></ref><ref id="R20"><label>20</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Griffin</surname><given-names>JE</given-names></name><etal></etal></person-group><article-title>High-resolution phenotypic profiling defines genes essential for mycobacterial growth and cholesterol catabolism</article-title><source>PLoS Pathog</source><year>2011</year><volume>7</volume><fpage>e1002251</fpage><pub-id pub-id-type="pmid">21980284</pub-id></element-citation></ref><ref id="R21"><label>21</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Becq</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Contribution of horizontally acquired genomic islands to the evolution of the tubercle bacilli</article-title><source>Mol Biol Evol</source><year>2007</year><volume>24</volume><fpage>1861</fpage><lpage>1871</lpage><pub-id pub-id-type="pmid">17545187</pub-id></element-citation></ref><ref id="R22"><label>22</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Makarova</surname><given-names>KS</given-names></name><etal></etal></person-group><article-title>Evolution and classification of the CRISPR-Cas systems</article-title><source>Nat Rev Microbiol</source><year>2011</year><volume>9</volume><fpage>467</fpage><lpage>477</lpage><pub-id pub-id-type="pmid">21552286</pub-id></element-citation></ref><ref id="R23"><label>23</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hendrix</surname><given-names>RW</given-names></name><name><surname>Smith</surname><given-names>MC</given-names></name><name><surname>Burns</surname><given-names>RN</given-names></name><name><surname>Ford</surname><given-names>ME</given-names></name><name><surname>Hatfull</surname><given-names>GF</given-names></name></person-group><article-title>Evolutionary relationships among diverse bacteriophages and prophages: all the world’s a phage</article-title><source>Proc Natl Acad Sci U S A</source><year>1999</year><volume>96</volume><fpage>2192</fpage><lpage>2197</lpage><pub-id pub-id-type="pmid">10051617</pub-id></element-citation></ref><ref id="R24"><label>24</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gordon</surname><given-names>SV</given-names></name><name><surname>Bottai</surname><given-names>D</given-names></name><name><surname>Simeone</surname><given-names>R</given-names></name><name><surname>Stinear</surname><given-names>TP</given-names></name><name><surname>Brosch</surname><given-names>R</given-names></name></person-group><article-title>Pathogenicity in the tubercle bacillus: molecular and evolutionary determinants</article-title><source>Bioessays</source><year>2009</year><volume>31</volume><fpage>378</fpage><lpage>388</lpage><pub-id pub-id-type="pmid">19274661</pub-id></element-citation></ref><ref id="R25"><label>25</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Deshayes</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Detecting the molecular scars of evolution in the Mycobacterium tuberculosis complex by analyzing interrupted coding sequences</article-title><source>BMC Evol Biol</source><year>2008</year><volume>8</volume><fpage>78</fpage><pub-id pub-id-type="pmid">18325090</pub-id></element-citation></ref><ref id="R26"><label>26</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Smith</surname><given-names>NH</given-names></name><name><surname>Hewinson</surname><given-names>RG</given-names></name><name><surname>Kremer</surname><given-names>K</given-names></name><name><surname>Brosch</surname><given-names>R</given-names></name><name><surname>Gordon</surname><given-names>SV</given-names></name></person-group><article-title>Myths and misconceptions: the origin and evolution of <italic>Mycobacterium tuberculosis</italic></article-title><source>Nat Rev Microbiol</source><year>2009</year><volume>7</volume><fpage>537</fpage><lpage>544</lpage><pub-id pub-id-type="pmid">19483712</pub-id></element-citation></ref><ref id="R27"><label>27</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Reed</surname><given-names>MB</given-names></name><etal></etal></person-group><article-title>A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response</article-title><source>Nature</source><year>2004</year><volume>431</volume><fpage>84</fpage><lpage>87</lpage><pub-id pub-id-type="pmid">15343336</pub-id></element-citation></ref><ref id="R28"><label>28</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bentley</surname><given-names>SD</given-names></name><etal></etal></person-group><article-title>The genome of <italic>Mycobacterium africanum</italic> West African 2 reveals a lineage-specific locus and genome erosion common to the <italic>M. tuberculosis</italic> complex</article-title><source>PLoS Negl Trop Dis</source><year>2012</year><volume>6</volume><fpage>e1552</fpage><pub-id pub-id-type="pmid">22389744</pub-id></element-citation></ref><ref id="R29"><label>29</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Brosch</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Genome plasticity of BCG and impact on vaccine efficacy</article-title><source>Proc Natl Acad Sci U S A</source><year>2007</year><volume>104</volume><fpage>5596</fpage><lpage>5601</lpage><pub-id pub-id-type="pmid">17372194</pub-id></element-citation></ref><ref id="R30"><label>30</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Comas</surname><given-names>I</given-names></name><etal></etal></person-group><article-title>Human T cell epitopes of <italic>Mycobacterium tuberculosis</italic> are evolutionarily hyperconserved</article-title><source>Nat Genet</source><year>2010</year><volume>42</volume><fpage>498</fpage><lpage>503</lpage><pub-id pub-id-type="pmid">20495566</pub-id></element-citation></ref><ref id="R31"><label>31</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hershberg</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>High functional diversity in <italic>M. tuberculosis</italic> driven by genetic drift and human demography</article-title><source>PLoS Biol</source><year>2008</year><volume>6</volume><fpage>e311</fpage><pub-id pub-id-type="pmid">19090620</pub-id></element-citation></ref><ref id="R32"><label>32</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rocha</surname><given-names>EP</given-names></name><etal></etal></person-group><article-title>Comparisons of dN/dS are time dependent for closely related bacterial genomes</article-title><source>J Theor Biol</source><year>2006</year><volume>239</volume><fpage>226</fpage><lpage>235</lpage><pub-id pub-id-type="pmid">16239014</pub-id></element-citation></ref><ref id="R33"><label>33</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Castillo-Ramirez</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>The impact of recombination on dN/dS within recently emerged bacterial clones</article-title><source>PLoS Pathog</source><year>2011</year><volume>7</volume><fpage>e1002129</fpage><pub-id pub-id-type="pmid">21779170</pub-id></element-citation></ref><ref id="R34"><label>34</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Croucher</surname><given-names>NJ</given-names></name><etal></etal></person-group><article-title>Rapid pneumococcal evolution in response to clinical interventions</article-title><source>Science</source><year>2011</year><volume>331</volume><fpage>430</fpage><lpage>434</lpage><pub-id pub-id-type="pmid">21273480</pub-id></element-citation></ref><ref id="R35"><label>35</label><element-citation publication-type="book"><person-group person-group-type="author"><name><surname>Korber</surname><given-names>B</given-names></name></person-group><person-group person-group-type="editor"><name><surname>Rodrigo</surname><given-names>AG</given-names></name><name><surname>Learn</surname><given-names>GH</given-names></name></person-group><source>Computational Analysis of HIV Molecular Sequences</source><year>2000</year><fpage>55</fpage><lpage>72</lpage><publisher-name>Kluwer Academic Publishers</publisher-name><comment>Ch. 4</comment></element-citation></ref><ref id="R36"><label>36</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goldman</surname><given-names>N</given-names></name><name><surname>Yang</surname><given-names>Z</given-names></name></person-group><article-title>A codon-based model of nucleotide substitution for protein-coding DNA sequences</article-title><source>Mol Biol Evol</source><year>1994</year><volume>11</volume><fpage>725</fpage><lpage>736</lpage><pub-id pub-id-type="pmid">7968486</pub-id></element-citation></ref><ref id="R37"><label>37</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Simeone</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Phagosomal rupture by <italic>Mycobacterium tuberculosis</italic> results in toxicity and host cell death</article-title><source>PLoS Pathog</source><year>2012</year><volume>8</volume><fpage>e1002507</fpage><pub-id pub-id-type="pmid">22319448</pub-id></element-citation></ref><ref id="R38"><label>38</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kalscheuer</surname><given-names>R</given-names></name><name><surname>Weinrick</surname><given-names>B</given-names></name><name><surname>Veeraraghavan</surname><given-names>U</given-names></name><name><surname>Besra</surname><given-names>GS</given-names></name><name><surname>Jacobs</surname><given-names>WR</given-names><suffix>Jr.</suffix></name></person-group><article-title>Trehalose-recycling ABC transporter LpqY-SugA-SugB-SugC is essential for virulence of <italic>Mycobacterium tuberculosis</italic></article-title><source>Proc Natl Acad Sci U S A</source><year>2010</year><volume>107</volume><fpage>21761</fpage><lpage>21766</lpage><pub-id pub-id-type="pmid">21118978</pub-id></element-citation></ref><ref id="R39"><label>39</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Felsenstein</surname><given-names>J</given-names></name></person-group><article-title>The evolutionary advantage of recombination</article-title><source>Genetics</source><year>1974</year><volume>78</volume><fpage>737</fpage><lpage>756</lpage><pub-id pub-id-type="pmid">4448362</pub-id></element-citation></ref><ref id="R40"><label>40</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Achtman</surname><given-names>M</given-names></name></person-group><article-title>Insights from genomic comparisons of genetically monomorphic bacterial pathogens</article-title><source>Philos Trans R Soc Lond B Biol Sci</source><year>2012</year><volume>367</volume><fpage>860</fpage><lpage>867</lpage><pub-id pub-id-type="pmid">22312053</pub-id></element-citation></ref><ref id="R41"><label>41</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Namouchi</surname><given-names>A</given-names></name><name><surname>Didelot</surname><given-names>X</given-names></name><name><surname>Schock</surname><given-names>U</given-names></name><name><surname>Gicquel</surname><given-names>B</given-names></name><name><surname>Rocha</surname><given-names>EP</given-names></name></person-group><article-title>After the bottleneck: Genome-wide diversification of the <italic>Mycobacterium tuberculosis</italic> complex by mutation, recombination, and natural selection</article-title><source>Genome Res</source><year>2012</year><volume>22</volume><fpage>721</fpage><lpage>734</lpage><pub-id pub-id-type="pmid">22377718</pub-id></element-citation></ref><ref id="R42"><label>42</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mba Medie</surname><given-names>F</given-names></name><name><surname>Ben Salah</surname><given-names>I</given-names></name><name><surname>Henrissat</surname><given-names>B</given-names></name><name><surname>Raoult</surname><given-names>D</given-names></name><name><surname>Drancourt</surname><given-names>M</given-names></name></person-group><article-title><italic>Mycobacterium tuberculosis</italic> complex mycobacteria as amoeba-resistant organisms</article-title><source>PLoS One</source><year>2011</year><volume>6</volume><fpage>e20499</fpage><pub-id pub-id-type="pmid">21673985</pub-id></element-citation></ref><ref id="R43"><label>43</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nguyen</surname><given-names>KT</given-names></name><name><surname>Piastro</surname><given-names>K</given-names></name><name><surname>Gray</surname><given-names>TA</given-names></name><name><surname>Derbyshire</surname><given-names>KM</given-names></name></person-group><article-title>Mycobacterial biofilms facilitate horizontal DNA transfer between strains of <italic>Mycobacterium smegmatis</italic></article-title><source>J Bacteriol</source><year>2010</year><volume>192</volume><fpage>5134</fpage><lpage>5142</lpage><pub-id pub-id-type="pmid">20675473</pub-id></element-citation></ref><ref id="R44"><label>44</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Medzhitov</surname><given-names>R</given-names></name><name><surname>Janeway</surname><given-names>CA</given-names></name></person-group><article-title>Innate Immunity cecognition and control of adaptive immune responses</article-title><source>Semin Immunol</source><year>1998</year><volume>10</volume><fpage>351</fpage><lpage>353</lpage><pub-id pub-id-type="pmid">9799709</pub-id></element-citation></ref><ref id="R45"><label>45</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Aagaard</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>A multistage tuberculosis vaccine that confers efficient protection before and after exposure</article-title><source>Nat Med</source><year>2011</year><volume>17</volume><fpage>189</fpage><lpage>194</lpage><pub-id pub-id-type="pmid">21258338</pub-id></element-citation></ref><ref id="R46"><label>46</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cadieux</surname><given-names>N</given-names></name><etal></etal></person-group><article-title>Induction of cell death after localization to the host cell mitochondria by the <italic>Mycobacterium tuberculosis</italic> PE_PGRS33 protein</article-title><source>Microbiology</source><year>2011</year><volume>157</volume><fpage>793</fpage><lpage>804</lpage><pub-id pub-id-type="pmid">21081760</pub-id></element-citation></ref><ref id="R47"><label>47</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Maiden</surname><given-names>MC</given-names></name><etal></etal></person-group><article-title>Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms</article-title><source>Proc Natl Acad Sci U S A</source><year>1998</year><volume>95</volume><fpage>3140</fpage><lpage>3145</lpage><pub-id pub-id-type="pmid">9501229</pub-id></element-citation></ref><ref id="R48"><label>48</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Huson</surname><given-names>DH</given-names></name><name><surname>Bryant</surname><given-names>D</given-names></name></person-group><article-title>Application of phylogenetic networks in evolutionary studies</article-title><source>Mol Biol Evol</source><year>2006</year><volume>23</volume><fpage>254</fpage><lpage>267</lpage><pub-id pub-id-type="pmid">16221896</pub-id></element-citation></ref><ref id="R49"><label>49</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Batzoglou</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>ARACHNE: a whole-genome shotgun assembler</article-title><source>Genome Res</source><year>2002</year><volume>12</volume><fpage>177</fpage><lpage>189</lpage><pub-id pub-id-type="pmid">11779843</pub-id></element-citation></ref><ref id="R50"><label>50</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Brosch</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Use of a <italic>Mycobacterium tuberculosis</italic> H37Rv bacterial artificial chromosome library for genome mapping, sequencing, and comparative genomics</article-title><source>Infect Immun</source><year>1998</year><volume>66</volume><fpage>2221</fpage><lpage>2229</lpage><pub-id pub-id-type="pmid">9573111</pub-id></element-citation></ref><ref id="R51"><label>51</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zerbino</surname><given-names>DR</given-names></name><name><surname>Birney</surname><given-names>E</given-names></name></person-group><article-title>Velvet: algorithms for de novo short read assembly using de Bruijn graphs</article-title><source>Genome Res</source><year>2008</year><volume>18</volume><fpage>821</fpage><lpage>829</lpage><pub-id pub-id-type="pmid">18349386</pub-id></element-citation></ref><ref id="R52"><label>52</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vallenet</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>MicroScope: a platform for microbial genome annotation and comparative genomics</article-title><source>Database (Oxford)</source><year>2009</year></element-citation></ref><ref id="R53"><label>53</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Carver</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>Artemis and ACT: viewing, annotating and comparing sequences stored in a relational database</article-title><source>Bioinformatics</source><year>2008</year><volume>24</volume><fpage>2672</fpage><lpage>2676</lpage><pub-id pub-id-type="pmid">18845581</pub-id></element-citation></ref><ref id="R54"><label>54</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Richter</surname><given-names>M</given-names></name><name><surname>Rossello-Mora</surname><given-names>R</given-names></name></person-group><article-title>Shifting the genomic gold standard for the prokaryotic species definition</article-title><source>Proc Natl Acad Sci U S A</source><year>2009</year><volume>106</volume><fpage>19126</fpage><lpage>19131</lpage><pub-id pub-id-type="pmid">19855009</pub-id></element-citation></ref><ref id="R55"><label>55</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ning</surname><given-names>Z</given-names></name><name><surname>Cox</surname><given-names>AJ</given-names></name><name><surname>Mullikin</surname><given-names>JC</given-names></name></person-group><article-title>SSAHA: a fast search method for large DNA databases</article-title><source>Genome Res</source><year>2001</year><volume>11</volume><fpage>1725</fpage><lpage>1729</lpage><pub-id pub-id-type="pmid">11591649</pub-id></element-citation></ref><ref id="R56"><label>56</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Niemann</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Genomic diversity among drug sensitive and multidrug resistant isolates of <italic>Mycobacterium tuberculosis</italic> with identical DNA fingerprints</article-title><source>PLoS One</source><year>2009</year><volume>4</volume><fpage>e7407</fpage><pub-id pub-id-type="pmid">19823582</pub-id></element-citation></ref><ref id="R57"><label>57</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Delcher</surname><given-names>AL</given-names></name><name><surname>Phillippy</surname><given-names>A</given-names></name><name><surname>Carlton</surname><given-names>J</given-names></name><name><surname>Salzberg</surname><given-names>SL</given-names></name></person-group><article-title>Fast algorithms for large-scale genome alignment and comparison</article-title><source>Nucleic Acids Res</source><year>2002</year><volume>30</volume><fpage>2478</fpage><lpage>2483</lpage><pub-id pub-id-type="pmid">12034836</pub-id></element-citation></ref><ref id="R58"><label>58</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Suyama</surname><given-names>M</given-names></name><name><surname>Torrents</surname><given-names>D</given-names></name><name><surname>Bork</surname><given-names>P</given-names></name></person-group><article-title>PAL2NAL: robust conversion of protein sequence alignments into the corresponding codon alignments</article-title><source>Nucleic Acids Res</source><year>2006</year><volume>34</volume><fpage>W609</fpage><lpage>612</lpage><pub-id pub-id-type="pmid">16845082</pub-id></element-citation></ref><ref id="R59"><label>59</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Edgar</surname><given-names>RC</given-names></name></person-group><article-title>MUSCLE: multiple sequence alignment with high accuracy and high throughput</article-title><source>Nucleic Acids Res</source><year>2004</year><volume>32</volume><fpage>1792</fpage><lpage>1797</lpage><pub-id pub-id-type="pmid">15034147</pub-id></element-citation></ref><ref id="R60"><label>60</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Darling</surname><given-names>AE</given-names></name><name><surname>Mau</surname><given-names>B</given-names></name><name><surname>Perna</surname><given-names>NT</given-names></name></person-group><article-title>progressiveMauve: multiple genome alignment with gene gain, loss and rearrangement</article-title><source>PLoS One</source><year>2010</year><volume>5</volume><fpage>e11147</fpage><pub-id pub-id-type="pmid">20593022</pub-id></element-citation></ref><ref id="R61"><label>61</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Saitou</surname><given-names>N</given-names></name><name><surname>Nei</surname><given-names>M</given-names></name></person-group><article-title>The neighbor-joining method: a new method for reconstructing phylogenetic trees</article-title><source>Mol Biol Evol</source><year>1987</year><volume>4</volume><fpage>406</fpage><lpage>425</lpage><pub-id pub-id-type="pmid">3447015</pub-id></element-citation></ref><ref id="R62"><label>62</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bruen</surname><given-names>TC</given-names></name><name><surname>Philippe</surname><given-names>H</given-names></name><name><surname>Bryant</surname><given-names>D</given-names></name></person-group><article-title>A simple and robust statistical test for detecting the presence of recombination</article-title><source>Genetics</source><year>2006</year><volume>172</volume><fpage>2665</fpage><lpage>2681</lpage><pub-id pub-id-type="pmid">16489234</pub-id></element-citation></ref><ref id="R63"><label>63</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Smith</surname><given-names>JM</given-names></name></person-group><article-title>Analyzing the mosaic structure of genes</article-title><source>J Mol Evol</source><year>1992</year><volume>34</volume><fpage>126</fpage><lpage>129</lpage><pub-id pub-id-type="pmid">1556748</pub-id></element-citation></ref><ref id="R64"><label>64</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jakobsen</surname><given-names>IB</given-names></name><name><surname>Easteal</surname><given-names>S</given-names></name></person-group><article-title>A program for calculating and displaying compatibility matrices as an aid in determining reticulate evolution in molecular sequences</article-title><source>Comput Appl Biosci</source><year>1996</year><volume>12</volume><fpage>291</fpage><lpage>295</lpage><pub-id pub-id-type="pmid">8902355</pub-id></element-citation></ref><ref id="R65"><label>65</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pethe</surname><given-names>K</given-names></name><etal></etal></person-group><article-title>The heparin-binding haemagglutinin of <italic>M. tuberculosis</italic> is required for extrapulmonary dissemination</article-title><source>Nature</source><year>2001</year><volume>412</volume><fpage>190</fpage><lpage>194</lpage><pub-id pub-id-type="pmid">11449276</pub-id></element-citation></ref><ref id="R66"><label>66</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Majlessi</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Influence of ESAT-6 secretion system 1 (RD1) of <italic>Mycobacterium tuberculosis</italic> on the interaction between mycobacteria and the host immune system</article-title><source>J Immunol</source><year>2005</year><volume>174</volume><fpage>3570</fpage><lpage>3579</lpage><pub-id pub-id-type="pmid">15749894</pub-id></element-citation></ref><ref id="R67"><label>67</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bottai</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>ESAT-6 secretion-independent impact of ESX-1 genes <italic>espF</italic> and <italic>espG1</italic> on virulence of <italic>Mycobacterium tuberculosis</italic></article-title><source>J Infect Dis</source><year>2011</year><volume>203</volume><fpage>1155</fpage><lpage>1164</lpage><pub-id pub-id-type="pmid">21196469</pub-id></element-citation></ref></ref-list></back><floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><title>Selection and genome features of analyzed strains</title><p><bold>(a)</bold> multilocus sequence typing of 56 STB and 10 MTBC reference isolates. Phylogenetic positions based on split decomposition analysis of concatenated sequences of 12 house-keeping gene segments are represented. The scale bar represents Hamming distance. Numbers indicate the percent of bootstrap support of the splits obtained after 1,000 replicates. Arrows and stars indicate isolates selected for complete genome sequence and genome shotgun analyses, respectively. (<bold>b)</bold> pairwise, linear genomic comparisons of <italic>M. tuberculosis</italic> H37Rv, <italic>M. bovis</italic> AF2122/97, five selected STB strains, and two non-tuberculous mycobacterial species, <italic>M. marinum</italic> M and <italic>M. smegmatis mc<sup>2</sup>155</italic>. Red and blue lines indicate co-linear blocks of DNA:DNA similarity, and inverted matches, respectively. <italic>M. tub., M. tuberculosis</italic>; <italic>M. mar, M. marinum</italic>; <italic>M. smeg., M. smegmatis.</italic> (<bold>c)</bold> numbers of SNPs in pairwise comparisons between the indicated genomes. (<bold>d</bold>) Network phylogeny inferred among the five STB isolates subjected to complete genome sequence analysis and MTBC by NeighborNet analysis, based on pairwise alignments of whole genome SNP data. ‘*’ indicates 90% bootstrap support, while all other nodes had 100% support, 1000 iterations. (<bold>e</bold>) Histogram showing the respective numbers of SNPs between the aligned <italic>M. tuberculosis</italic> H37Rv and <italic>M. bovis</italic> or STB genomes (depicted in panel b).</p></caption><graphic xlink:href="emss-53121-f0001"></graphic></fig><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><title>CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated proteins) systems and prophages in STB and MTBC genomes</title><p>(<bold>a)</bold> Gene content of different CRISPR-Cas systems in MTBC and STB strains. Spacers are color-coded according to sequence similarities. Percentages of protein sequence identities are indicated between type III-A systems of <italic>M. tuberculosis</italic> H37Rv and STB A and D. The various combinations of identities between ubiquitous proteins (e.g. Cas2) of different CRISPR-Cas types are much lower (below 40%) and are not indicated. A star indicates a potential <italic>csb1</italic> pseudogene in the system of STB-H. A broken line denotes ends of DNA sequence contigs variably delimiting the identified repeat zones of type I-E systems of STB-F, -G and -I. Mut id, mutual protein sequence identities; rep, repeats; Tnp, transposon; <italic>cas</italic>, <italic>csm</italic>, <italic>csb</italic>, <italic>csx</italic>, <italic>cse,</italic> various Cas gene families. (<bold>b)</bold> Schematic representation of a 55 kb spanning genomic region that encodes a putative prophage in STB strain I. STB-I genomic positions are marked on horizontal scales in bp. Brackets indicate a portion homologous to a prophage region in the <italic>M. marinum</italic> genome. Predicted coding sequences are shown above or below scales, corresponding to rightward and leftward transcription, respectively. Color-coding define features of predicted encoded products as follows. Gray, phage protein without database match or homologous to non-mycobacteriophage proteins of unknown function; blue, phage protein homologous to other mycobacteriophage proteins of unknown function (names of homologs are written in blue text, except for the portion homologous to the <italic>M. marinum</italic> prophage region); black, STB-I coding sequences and tRNA genes (conserved in other STB strains and <italic>M. tuberculosis</italic> H37Rv) flanking the phage insertion site corresponding to the Lys tRNA gene; all other colors, phage proteins with a predicted function (indicated in black text). A gray box on the second horizontal scale indicates a sequence contig break. Functional annotations of the predicted genes were made based on comparisons of the encoded products via the Genbank database, detection of protein domain signatures, and expert annotation of 374 other mycobacteriophage genomes retrieved from the PhagesDB database.</p></caption><graphic xlink:href="emss-53121-f0002"></graphic></fig><fig id="F3" orientation="portrait" position="float"><label>Figure 3</label><caption><title>Inter-strain recombination segments between STB and MTBC genomes</title><p><bold>(a)</bold> phylogenetic tree inferred by using Neighbor-Joining algorithm on nucleotide p-distances, after concatenation of sequence alignments of 2,047 genes of the predicted clonal portion of the STB-MTBC core genome (i.e. after exclusion of the genes affected by recombination- see text- and of gapped regions). (<bold>b)</bold> SNP distribution among STB and MTBC aligned genome segments, showing probable recombination regions involving genes <italic>rv1936-rv1937</italic> between STB-J and <italic>M. tuberculosis</italic>. Each of the three panels shows a comparison of two STB or <italic>M. bovis</italic> strains (top, bottom) relative to <italic>M. tuberculosis</italic> H37Rv (middle). Red lines indicate individual SNPs identified between pairwise compared genomes. Thicker or uneven red lines result from multiple SNPs in close proximity or shifts due to small insertions/deletions. Note the SNP-free, identical genome segments between STB-J and H37Rv (boxed) conflict with their distant respective positions on the clonal core genome-based tree. <italic>M. tub.</italic> H37Rv, <italic>M. tuberculosis</italic> H37Rv.</p></caption><graphic xlink:href="emss-53121-f0003"></graphic></fig><fig id="F4" orientation="portrait" position="float"><label>Figure 4</label><caption><title>Virulence and persistence of smooth tubercle bacilli (STB) and <italic>M. tuberculosis</italic></title><p><bold>(a)</bold> colony forming units (CFUs) recovered from lungs (<bold>a, c</bold>) and spleens (<bold>b, d</bold>) of BALB/c mice after intranasal infection with 10<sup>3</sup> CFUs. Panels <bold>a/b</bold> and <bold>c/d</bold> depict two independent experiments. The results are the median and range of CFUs from four mice. <bold>e</bold>, <bold>f</bold>, histopathological sections of lungs of BALB/c infected mice, 128 days post-intranasal infection with 10<sup>3</sup> CFUs. Blue circles show bronchi, “A” indicates alveoli, and “V” indicates blood-vessels.</p></caption><graphic xlink:href="emss-53121-f0004"></graphic></fig><table-wrap id="T1" position="float" orientation="portrait"><label>Table 1</label><caption><p>Ratios of non-synonymous versus synonymous SNPs in gene categories</p></caption><table frame="void" rules="groups"><thead><tr><th align="center" valign="middle" rowspan="1" colspan="1"></th><th colspan="5" align="center" valign="middle" rowspan="1"><hr></hr></th></tr><tr><th align="center" valign="middle" rowspan="1" colspan="1"></th><th colspan="5" align="center" valign="middle" rowspan="1">dN/dS in gene category</th></tr><tr><th align="center" valign="middle" rowspan="1" colspan="1"></th><th colspan="5" align="center" valign="middle" rowspan="1"><hr></hr></th></tr><tr><th align="center" valign="middle" rowspan="1" colspan="1">Strain</th><th align="center" valign="middle" rowspan="1" colspan="1">All</th><th align="center" valign="middle" rowspan="1" colspan="1">essential</th><th align="center" valign="middle" rowspan="1" colspan="1">Nonessential</th><th align="center" valign="middle" rowspan="1" colspan="1">T-cell antigens</th><th align="center" valign="middle" rowspan="1" colspan="1">T-cell epitopes</th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">STB-A</td><td align="center" valign="middle" rowspan="1" colspan="1">0.19/0.15</td><td align="center" valign="middle" rowspan="1" colspan="1">0.14/0.11</td><td align="center" valign="middle" rowspan="1" colspan="1">0.21/0.17</td><td align="center" valign="middle" rowspan="1" colspan="1">0.14/0.12</td><td align="center" valign="middle" rowspan="1" colspan="1">0.18/0.14</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">STB-J</td><td align="center" valign="middle" rowspan="1" colspan="1">0.18/ 0.13</td><td align="center" valign="middle" rowspan="1" colspan="1">0.14/0.11</td><td align="center" valign="middle" rowspan="1" colspan="1">0.19/0.15</td><td align="center" valign="middle" rowspan="1" colspan="1">0.14/0.11</td><td align="center" valign="middle" rowspan="1" colspan="1">0.13/0.09</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">STB-D</td><td align="center" valign="middle" rowspan="1" colspan="1">0.20/0.16</td><td align="center" valign="middle" rowspan="1" colspan="1">0.16/0.12</td><td align="center" valign="middle" rowspan="1" colspan="1">0.22/0.17</td><td align="center" valign="middle" rowspan="1" colspan="1">0.15/0.12</td><td align="center" valign="middle" rowspan="1" colspan="1">0.10/0.08</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">STB-L</td><td align="center" valign="middle" rowspan="1" colspan="1">0.19/ 0.15</td><td align="center" valign="middle" rowspan="1" colspan="1">0.16/0.12</td><td align="center" valign="middle" rowspan="1" colspan="1">0.21/0.17</td><td align="center" valign="middle" rowspan="1" colspan="1">0.14/0.12</td><td align="center" valign="middle" rowspan="1" colspan="1">0.15/0.11</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">STB-K</td><td align="center" valign="middle" rowspan="1" colspan="1">0.17/0.13</td><td align="center" valign="middle" rowspan="1" colspan="1">0.14/ 0.10</td><td align="center" valign="middle" rowspan="1" colspan="1">0.19/0.15</td><td align="center" valign="middle" rowspan="1" colspan="1">0.15/0.12</td><td align="center" valign="middle" rowspan="1" colspan="1">0.13/0.09</td></tr><tr><td colspan="6" align="center" valign="middle" rowspan="1"><hr></hr></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">MTBC<xref ref-type="table-fn" rid="TFN2">a</xref></td><td align="center" valign="middle" rowspan="1" colspan="1">ND</td><td align="center" valign="middle" rowspan="1" colspan="1">0.53</td><td align="center" valign="middle" rowspan="1" colspan="1">0.66</td><td align="center" valign="middle" rowspan="1" colspan="1">0.50</td><td align="center" valign="middle" rowspan="1" colspan="1">0.53-0.25<xref ref-type="table-fn" rid="TFN3">b</xref></td></tr></tbody></table><table-wrap-foot><fn id="TFN1"><p id="P27">ND, not done. dN/dS ratios were calculated on orthologs conserved in the 5 STB strains subjected to complete genome sequence analysis and <italic>M. tuberculosis</italic> H37Rv, based on pairwise, concatenated codon alignments and using SNAP (value on the left)<sup><xref ref-type="bibr" rid="R35">35</xref></sup> and PAML maximum likelihood methods (value on the right)<sup><xref ref-type="bibr" rid="R36">36</xref></sup>. <italic>M. tuberculosis</italic> H37Rv T-cell antigen, essential and non-essential gene categories, as well as T cell epitope codon concatenates were constructed as in Comas et al.<sup><xref ref-type="bibr" rid="R30">30</xref></sup>.</p></fn><fn id="TFN2"><label>a</label><p id="P28">dN/dS ratios calculated by Comas et al.<sup><xref ref-type="bibr" rid="R30">30</xref></sup> from SNPs identified across 21 MTBC strains.</p></fn><fn id="TFN3"><label>b</label><p id="P29">Lower value obtained after exclusion of epitopes of three antigens considered as outliers.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Asie/explor/AustralieFrV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 002E210 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 002E210 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Asie
|area= AustralieFrV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé=
|texte=
}}
| This area was generated with Dilib version V0.6.33. |  |