title: Origin of modern syphilis and emergence of a pandemic Treponema pallidum cluster.
abstract: The abrupt onslaught of the syphilis pandemic that started in the late fifteenth century established this devastating infectious disease as one of the most feared in human history1. Surprisingly, despite the availability of effective antibiotic treatment since the mid-twentieth century, this bacterial infection, which is caused by Treponema pallidum subsp. pallidum (TPA), has been re-emerging globally in the last few decades with an estimated 10.6 million cases in 2008 (ref. 2). Although resistance to penicillin has not yet been identified, an increasing number of strains fail to respond to the second-line antibiotic azithromycin3. Little is known about the genetic patterns in current infections or the evolutionary origins of the disease due to the low quantities of treponemal DNA in clinical samples and difficulties in cultivating the pathogen4. Here, we used DNA capture and whole-genome sequencing to successfully interrogate genome-wide variation from syphilis patient specimens, combined with laboratory samples of TPA and two other subspecies. Phylogenetic comparisons based on the sequenced genomes indicate that the TPA strains examined share a common ancestor after the fifteenth century, within the early modern era. Moreover, most contemporary strains are azithromycin-resistant and are members of a globally dominant cluster, named here as SS14-Ω. The cluster diversified from a common ancestor in the mid-twentieth century subsequent to the discovery of antibiotics. Its recent phylogenetic divergence and global presence point to the emergence of a pandemic strain cluster.
authors.affiliation: Institute for Evolutionary Biology and Environmental Studies, University of Zurich, 8057 Zurich, Switzerland.|Zurich Institute of Forensic Medicine, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Natasha
authors.initials: N
authors.lastname: Arora
authors.affiliation: Institute for Archaeological Sciences, University of Tübingen, 72070 Tübingen, Germany.
authors.forename: Verena J
authors.initials: VJ
authors.lastname: Schuenemann
authors.affiliation: Center for Bioinformatics, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Jäger
authors.affiliation: Institute for Archaeological Sciences, University of Tübingen, 72070 Tübingen, Germany.|Center for Bioinformatics, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Peltzer
authors.affiliation: Center for Bioinformatics, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Seitz
authors.affiliation: Institute for Archaeological Sciences, University of Tübingen, 72070 Tübingen, Germany.|Center for Bioinformatics, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Herbig
authors.affiliation: Department of Biology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Strouhal
authors.affiliation: Department of Biology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic.
authors.forename: Linda
authors.initials: L
authors.lastname: Grillová
authors.affiliation: Unidad Mixta Infección y Salud Pública FISABIO/Universidad de Valencia; CIBER in Epidemiology and Public Health, 46020, Spain.|Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Leonor
authors.initials: L
authors.lastname: Sánchez-Busó
authors.affiliation: Institute of Integrative Biology, Department of Environmental Systems Science, ETH Zürich, 8092 Zurich, Switzerland.
authors.forename: Denise
authors.initials: D
authors.lastname: Kühnert
authors.affiliation: Institute for Archaeological Sciences, University of Tübingen, 72070 Tübingen, Germany.
authors.forename: Kirsten I
authors.initials: KI
authors.lastname: Bos
authors.affiliation: Institute for Evolutionary Biology and Environmental Studies, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Leyla Rivero
authors.initials: LR
authors.lastname: Davis
authors.affiliation: Department of Biology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Mikalová
authors.affiliation: Department of Infectious Diseases, Public Health Laboratory, GGD Amsterdam, 1018 WT Amsterdam, the Netherlands.
authors.forename: Sylvia
authors.identifier: http://orcid.org/0000-0003-4897-4261
authors.initials: S
authors.lastname: Bruisten
authors.affiliation: Department of Dermatology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Komericki
authors.affiliation: The Mortimer Market Centre CNWL, Camden Provider Services, London NW1 2PL, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: French
authors.affiliation: Department of Clinical Microbiology and Virology, University College London Hospitals NHS Foundation Trust, London W1T 4EU, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Grant
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, 1121 Buenos Aires, Argentina.
authors.forename: María A
authors.initials: MA
authors.lastname: Pando
authors.affiliation: Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Microbiología Clínica, Universidad de Buenos Aires, 1113 Buenos Aires, Argentina.
authors.forename: Lucía Gallo
authors.initials: LG
authors.lastname: Vaulet
authors.affiliation: Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Microbiología Clínica, Universidad de Buenos Aires, 1113 Buenos Aires, Argentina.
authors.forename: Marcelo Rodríguez
authors.identifier: http://orcid.org/0000-0003-2543-4262
authors.initials: MR
authors.lastname: Fermepin
authors.affiliation: Servicio de Dermatología, Hospital General Universitario de Valencia, 46014 Valencia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, and Department of Global Health, University of Washington, Seattle, Washington 98105, USA.
authors.forename: Arturo
authors.initials: A
authors.lastname: Centurion Lara
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, and Department of Global Health, University of Washington, Seattle, Washington 98105, USA.
authors.forename: Lorenzo
authors.identifier: http://orcid.org/0000-0003-3889-7274
authors.initials: L
authors.lastname: Giacani
authors.affiliation: Department of Pathology and Laboratory Medicine, UTHealth McGovern Medical School, Houston, Texas 77225, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Norris
authors.affiliation: Department of Biology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Šmajs
authors.affiliation: Department of Dermatology, University Hospital of Zurich, 8091 Zurich, Switzerland.
authors.forename: Philipp P
authors.initials: PP
authors.lastname: Bosshard
authors.affiliation: Unidad Mixta Infección y Salud Pública FISABIO/Universidad de Valencia; CIBER in Epidemiology and Public Health, 46020, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: González-Candelas
authors.affiliation: Center for Bioinformatics, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Nieselt
authors.affiliation: Institute for Archaeological Sciences, University of Tübingen, 72070 Tübingen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Krause
authors.affiliation: Institute for Evolutionary Biology and Environmental Studies, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Homayoun C
authors.initials: HC
authors.lastname: Bagheri
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017963:Azithromycin / Q000494:pharmacology; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D024881:Drug Resistance, Bacterial; D019143:Evolution, Molecular; D014644:Genetic Variation; D016680:Genome, Bacterial; D005838:Genotype; D014943:Global Health; D006801:Humans; D017720:Molecular Epidemiology; D058873:Pandemics; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D013587:Syphilis / Q000453:epidemiology* / Q000382:microbiology*; D014210:Treponema pallidum / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D017963:Azithromycin