title: Genomic epidemiology of Lineage 4 Mycobacterium tuberculosis subpopulations in New York City and New Jersey, 1999-2009.
abstract: Whole genome sequencing (WGS) has rapidly become an important research tool in tuberculosis epidemiology and is likely to replace many existing methods in public health microbiology in the near future. WGS-based methods may be particularly useful in areas with less diverse Mycobacterium tuberculosis populations, such as New York City, where conventional genotyping is often uninformative and field epidemiology often difficult. This study applies four candidate strategies for WGS-based identification of emerging M. tuberculosis subpopulations, employing both phylogenomic and population genetics methods.
  
  
  
  M. tuberculosis subpopulations in New York City and New Jersey can be distinguished via phylogenomic reconstruction, evidence of demographic expansion and subpopulation-specific signatures of selection, and by determination of subgroup-defining nucleotide substitutions. These methods identified known historical outbreak clusters and previously unidentified subpopulations within relatively monomorphic M. tuberculosis endemic clone groups. Neutrality statistics based on the site frequency spectrum were less useful for identifying M. tuberculosis subpopulations, likely due to the low levels of informative genetic variation in recently diverged isolate groups. In addition, we observed that isolates from New York City endemic clone groups have acquired multiple non-synonymous SNPs in virulence- and growth-associated pathways, and relatively few mutations in drug resistance-associated genes, suggesting that overall pathoadaptive fitness, rather than the acquisition of drug resistance mutations, has played a central role in the evolutionary history and epidemiology of M. tuberculosis subpopulations in New York City.
  
  
  
  Our results demonstrate that some but not all WGS-based methods are useful for detection of emerging M. tuberculosis clone groups, and support the use of phylogenomic reconstruction in routine tuberculosis laboratory surveillance, particularly in areas with relatively less diverse M. tuberculosis populations. Our study also supports the use of wider-reaching phylogenomic and population genomic methods in tuberculosis public health practice, which can support tuberculosis control activities by identifying genetic polymorphisms contributing to epidemiological success in local M. tuberculosis populations and possibly explain why certain isolate groups are apparently more successful in specific host populations.
authors.affiliation: Department of Medicine, Columbia University, New York, NY, USA.
authors.forename: Tyler S
authors.initials: TS
authors.lastname: Brown
authors.affiliation: Sackler Institute for Comparative Genomics, American Museum of Natural History, New York, NY, USA.
authors.forename: Apurva
authors.initials: A
authors.lastname: Narechania
authors.affiliation: The Genomic Institute of the Novartis Research Foundation, San Diego, CA, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Planet
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Bifani
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, SUNY Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Sergios-Orestis
authors.initials: SO
authors.lastname: Kolokotronis
authors.affiliation: Tuberculosis Center, Public Health Research Institute, Newark, NJ, USA.
authors.forename: Barry N
authors.initials: BN
authors.lastname: Kreiswirth
authors.affiliation: Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, USA. bm2055@columbia.edu.
authors.forename: Barun
authors.initials: B
authors.lastname: Mathema
mesh_terms: D002473:Cell Wall / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D016680:Genome, Bacterial; D023281:Genomics / Q000379:methods; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D050356:Lipid Metabolism; D017720:Molecular Epidemiology; D009169:Mycobacterium tuberculosis / Q000145:classification* / Q000235:genetics* / Q000378:metabolism; D009515:New Jersey / Q000453:epidemiology; D009519:New York City / Q000453:epidemiology; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D014376:Tuberculosis / Q000453:epidemiology* / Q000266:history / Q000382:microbiology*
keywords: Mycobacterium tuberculosis; Phylogenomics; Surveillance; Whole genome sequencing