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Background  The IS 6110  insertion sequence, a member of the IS3 family of insertion sequences, was found to be specific to the  Mycobacterium tuberculosis  complex (MTBC). Although IS 6110  has been extensively characterized as a transposable genetic marker, the evolutionary history of its own transposase-encoding sequence has not, to the best of our knowledge, been investigated.    Methodology/Principal Findings  Here we explored the evolution of the IS 6110  sequence by analysing the genetic variability and the selective forces acting on its transposase-encoding open reading frames (ORFs) A and B ( orfA  and  orfB ). For this purpose, we used a strain collection consisting of smooth tubercle bacilli (STB), an early branching lineage of the MTBC, and present-day  M .  tuberculosis  strains representing the full breadth of genetic diversity in Tunisia. In each ORF, we found a major haplotype that dominated over a flat distribution of rare descendent haplotypes, consisting mainly of single- and double-nucleotide variant singletons. The predominant haplotypes consisted of both ancestral and present-day strains, suggesting that IS 6110  acquisition predated the emergence of the MTBC. There was no evidence of recombination and both ORFs were subjected to strict purifying selection, as demonstrated by their dN/dS ratios (0.29 and 0.51, respectively), as well as their significantly negative Tajima’s  D  statistics. Strikingly, the purifying selection acting on  orfA  proved much more stringent, suggesting its critical role in regulating the transpositional process. Maximum likelihood analyses further excluded any possibility of positive selection acting on single amino acid residues.    Conclusions/Significance  Taken together our data fit with an evolutionary scenario according to which the observed variability pattern of the IS 6110  transposase-encoding ORFs is generated mainly through random point mutations that accrued on a functionally optimal IS 6110  copy, whose acquisition predated the emergence of the MTBC complex. Background selection acting against deleterious mutations led to an excess of low-frequency variants.

Evolutionary Trends of the Transposase-Encoding Open Reading Frames A and B (orfA and orfB) of the Mycobacterial IS6110 Insertion Sequence