New insights into the transposition mechanisms of IS<i>6110</i> and its dynamic distribution between <i>Mycobacterium tuberculosis</i> Complex lineages

<div><p>The insertion Sequence IS<i>6110</i>, only present in the pathogens of the <i>Mycobacterium tuberculosis</i> Complex (MTBC), has been the gold-standard epidemiological marker for TB for more than 25 years, but biological implications of IS<i>6110</i> transposition during MTBC adaptation to humans remain elusive. By studying 2,236 clinical isolates typed by IS<i>6110</i>-RFLP and covering the MTBC, we remarked a lineage-specific content of IS<i>6110</i> being higher in modern globally distributed strains. Once observed the IS<i>6110</i> distribution in the MTBC, we selected representative isolates and found a correlation between the normalized expression of IS<i>6110</i> and its abundance in MTBC chromosomes. We also studied the molecular regulation of IS<i>6110</i> transposition and we found a synergistic action of two post-transcriptional mechanisms: a -1 ribosomal frameshift and a RNA pseudoknot which interferes translation. The construction of a transcriptionally active transposase resulted in 20-fold increase of the transposition frequency. Finally, we examined transposition in <i>M</i>. <i>bovis</i> and <i>M</i>. <i>tuberculosis</i> during laboratory starvation and in a mouse infection model of TB. Our results shown a higher transposition in <i>M</i>. <i>tuberculosis</i>, that preferably happens during TB infection in mice and after one year of laboratory culture, suggesting that IS<i>6110</i> transposition is dynamically adapted to the host and to adverse growth conditions.</p>