title: Genetic variation in Mycobacterium tuberculosis isolates from a London outbreak associated with isoniazid resistance.
abstract: The largest outbreak of isoniazid-resistant (INH-R) Mycobacterium tuberculosis in Western Europe is centred in North London, with over 400 cases diagnosed since 1995. In the current study, we evaluated the genetic variation in a subset of clinical samples from the outbreak with the hypothesis that these isolates have unique biological characteristics that have served to prolong the outbreak.
  
  
  
  Fitness assays, mutation rate estimation, and whole-genome sequencing were performed to test for selective advantage and compensatory mutations.
  
  
  
  This detailed analysis of the genetic variation of these INH-R samples suggests that this outbreak consists of successful, closely related, circulating strains with heterogeneous resistance profiles and little or no associated fitness cost or impact on their mutation rate.
  
  
  
  Specific deletions and SNPs could be a peculiar feature of these INH-R M. tuberculosis isolates, and could potentially explain their persistence over the years.
authors.affiliation: Department of Infection, Centre for Clinical Microbiology, University College London, London, UK. Giovanni.satta@nhs.net.|Imperial College Healthcare NHS Trust, London, UK. Giovanni.satta@nhs.net.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Satta
authors.affiliation: Institute of Infection and Immunity, St George's, University of London, London, UK.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Witney
authors.affiliation: Department of Infection, Centre for Clinical Microbiology, University College London, London, UK.|Public Health Laboratory Manchester, Manchester Royal Infirmary, Manchester, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Shorten
authors.affiliation: Department of Infection, Centre for Clinical Microbiology, University College London, London, UK.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Karlikowska
authors.affiliation: Royal Free London NHS Foundation Trust, London, UK.|UCL Respiratory, Division of Medicine, University College London, London, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Lipman
authors.affiliation: Department of Infection, Centre for Clinical Microbiology, University College London, London, UK.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: McHugh
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use; D004196:Disease Outbreaks; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics; D005060:Europe / Q000453:epidemiology; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology / Q000627:therapeutic use*; D008131:London / Q000453:epidemiology; D008826:Microbial Sensitivity Tests / Q000379:methods; D009154:Mutation / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014376:Tuberculosis / Q000188:drug therapy / Q000453:epidemiology* / Q000235:genetics*; D018088:Tuberculosis, Multidrug-Resistant
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid
keywords: Fitness; Mutation rate; Mycobacterium tuberculosis; Whole-genome sequencing