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    Whole genome sequencing reveals genomic heterogeneity and antibiotic purification in Mycobacterium tuberculosis isolates

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    Type
    Article
    Authors
    Black, PA
    de Vos, M.
    Louw, GE
    van der Merwe, RG
    Dippenaar, A.
    Streicher, EM
    Abdallah, A. M.
    Sampson, SL
    Victor, TC
    Dolby, T.
    Simpson, JA
    van Helden, PD
    Warren, RM
    Pain, Arnab cc
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Pathogen Genomics Laboratory
    Date
    2015-10-24
    Online Publication Date
    2015-10-24
    Print Publication Date
    2015-12
    Permanent link to this record
    http://hdl.handle.net/10754/581783
    
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    Abstract
    Background Whole genome sequencing has revolutionised the interrogation of mycobacterial genomes. Recent studies have reported conflicting findings on the genomic stability of Mycobacterium tuberculosis during the evolution of drug resistance. In an age where whole genome sequencing is increasingly relied upon for defining the structure of bacterial genomes, it is important to investigate the reliability of next generation sequencing to identify clonal variants present in a minor percentage of the population. This study aimed to define a reliable cut-off for identification of low frequency sequence variants and to subsequently investigate genetic heterogeneity and the evolution of drug resistance in M. tuberculosis. Methods Genomic DNA was isolated from single colonies from 14 rifampicin mono-resistant M. tuberculosis isolates, as well as the primary cultures and follow up MDR cultures from two of these patients. The whole genomes of the M. tuberculosis isolates were sequenced using either the Illumina MiSeq or Illumina HiSeq platforms. Sequences were analysed with an in-house pipeline. Results Using next-generation sequencing in combination with Sanger sequencing and statistical analysis we defined a read frequency cut-off of 30 % to identify low frequency M. tuberculosis variants with high confidence. Using this cut-off we demonstrated a high rate of genetic diversity between single colonies isolated from one population, showing that by using the current sequencing technology, single colonies are not a true reflection of the genetic diversity within a whole population and vice versa. We further showed that numerous heterogeneous variants emerge and then disappear during the evolution of isoniazid resistance within individual patients. Our findings allowed us to formulate a model for the selective bottleneck which occurs during the course of infection, acting as a genomic purification event. Conclusions Our study demonstrated true levels of genetic diversity within an M. tuberculosis population and showed that genetic diversity may be re-defined when a selective pressure, such as drug exposure, is imposed on M. tuberculosis populations during the course of infection. This suggests that the genome of M. tuberculosis is more dynamic than previously thought, suggesting preparedness to respond to a changing environment.
    Citation
    Whole genome sequencing reveals genomic heterogeneity and antibiotic purification in Mycobacterium tuberculosis isolates 2015, 16 (1) BMC Genomics
    Publisher
    Springer Nature
    Journal
    BMC Genomics
    DOI
    10.1186/s12864-015-2067-2
    PubMed ID
    26496891
    Additional Links
    http://www.biomedcentral.com/1471-2164/16/857
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    • [Dataset]
      PA Black, M. De Vos, GE Louw, RG Van Der Merwe, A. Dippenaar, EM Streicher, … A. Pain. (2015). Whole genome sequencing reveals genomic heterogeneity and antibiotic purification in Mycobacterium tuberculosis isolates. Figshare. https://doi.org/10.6084/m9.figshare.c.3596495. DOI: 10.6084/m9.figshare.c.3596495 HANDLE: 10754/624126
    ae974a485f413a2113503eed53cd6c53
    10.1186/s12864-015-2067-2
    Scopus Count
    Collections
    Articles; Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program

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