1887

Abstract

Pathogens of the complex (MTBC) are considered to be monomorphic, with little gene content variation between strains. Nevertheless, several genotypic and phenotypic factors separate strains of the different MTBC lineages (L), especially L5 and L6 (traditionally termed ) strains, from each other. However, this genome variability and gene content, especially of L5 strains, has not been fully explored and may be important for pathobiology and current approaches for genomic analysis of MTBC strains, including transmission studies. By comparing the genomes of 355 L5 clinical strains (including 3 complete genomes and 352 Illumina whole-genome sequenced isolates) to each other and to H37Rv, we identified multiple genes that were differentially present or absent between H37Rv and L5 strains. Additionally, considerable gene content variability was found across L5 strains, including a split in the L5.3 sub-lineage into L5.3.1 and L5.3.2. These gene content differences had a small knock-on effect on transmission cluster estimation, with clustering rates influenced by the selected reference genome, and with potential overestimation of recent transmission when using H37Rv as the reference genome. We conclude that full capture of the gene diversity, especially high-resolution outbreak analysis, requires a variation of the single H37Rv-centric reference genome mapping approach currently used in most whole-genome sequencing data analysis pipelines. Moreover, the high within-lineage gene content variability suggests that the pan-genome of is at least several kilobases larger than previously thought, implying that a concatenated or reference-free genome assembly () approach may be needed for particular questions.

Funding
This study was supported by the:
  • H2020 European Research Council (Award 883582)
    • Principle Award Recipient: SebastienGagneux
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Award 310030_188888, IZRJZ3_164171, IZLSZ3_170834 and CRSII5_177163)
    • Principle Award Recipient: SebastienGagneux
  • Generalitat Valenciana (Award SEJI/2019/011)
    • Principle Award Recipient: MireiaCoscolla
  • Ministerio de Ciencia, Innovación y Universidades (ESCMID) (Award RYC-2015-18213 and RTI2018-094399-A-I00)
    • Principle Award Recipient: CoscollaMireia
  • H2020 European Research Council (Award 311725)
    • Principle Award Recipient: BoukeC. de Jong
  • Directorate General for Development (DGD), Belgium (Award FA4)
    • Principle Award Recipient: N'Dira SanoussiC.
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