Abstract
Mycobacteria have been classified into rapid and slow growing phenotypes, but the genetic factors that underlie these growth rate differences are not well understood. We compared the genomes of 157 mycobacterial species, representing all major branches of the mycobacterial phylogenetic tree to identify genes and operons enriched among rapid and slow growing mycobacteria. Overlaying growth phenotype on a phylogenetic tree based on 304 core genes suggested that ancestral mycobacteria had a rapid growth phenotype with a single major evolutionary separation into rapid and slow growing sub-genera. We identified 293 genes enriched among rapid growing sub-genera, including genes encoding for amino acid transport/metabolism (e.g., livFGMH operon) and transcription, as well as novel ABC transporters. Loss of the livFGMH and ABC transporter operons among slow growing species suggests that reduced cellular amino acid transport may be growth limiting. Comparative genomic analysis suggests that horizontal gene transfer, from non-mycobacterial genera, may have contributed to niche adaptation and pathogenicity, especially among slow growing species. Interestingly, the mammalian cell entry (mce) operon was found to be ubiquitous, irrespective of growth phenotype or pathogenicity, although protein sequence homology between rapid and slow growing species was low (<50%). This suggests that the mce operon was present in ancestral rapid growing species, but later adapted by slow growing species for use as a mechanism to establish an intra-cellular lifestyle.
Highlights
Mycobacteria are common environmental organisms, but some species are significant human pathogens
The phylogeny of Actinobacteria has confirmed that mycobacteria are evolutionary related to Rhodococcus and Nocardia species (Supplementary Figure S1)
Ancestral strains belonging to the Mycobacteroides and Mycolicibacterium sub-genera included almost all of the rapid growers, with a single evolutionary split separating the vast majority of species with a rapid or slow growing phenotype
Summary
Mycobacteria are common environmental organisms, but some species are significant human pathogens. Mycobacterium tuberculosis is responsible for tuberculosis in humans (World Health Organization, 2019), and M. leprae and M. lepromatosis, the cause of leprosy, has become dependent on the human host for survival and dispersal (Monot et al, 2009; Singh et al, 2015). Slow growing species typically require more than 7 days before colonies become visible on solid media, while rapid growing species form colonies on selective media within 2–5 days (Kim et al, 2013). The slow growing phenotype has been associated with an intra-cellular lifestyle and pathogenicity, while rapid growing species are mainly environmental and include only a limited number of opportunistic pathogens (Philley and Griffith, 2015). Studies using genetic markers suggested that slow growing species represent a genetically distinct group that evolved from rapid growing species (Wee et al, 2017), while the ancestral M. abscessus-chelonae clade is highly divergent from other rapid growing species and have developed unique colonization and disease causing mechanisms (Medjahed et al, 2010; Tortoli, 2012)
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