Abstract
Insertion sequence (IS) 6110 is found at multiple sites in the Mycobacterium tuberculosis genome and displays a high degree of polymorphism with respect to copy number and insertion sites. Therefore, IS6110 is considered to be a useful molecular marker for diagnosis and strain typing of M. tuberculosis. Generally IS6110 elements are identified using experimental methods, useful for analysis of a limited number of isolates. Since short read genome sequences generated using next-generation sequencing (NGS) platforms are available for a large number of isolates, a computational pipeline for identification of IS6110 elements from these datasets was developed. This study shows results from analysis of NGS data of 1377 M. tuberculosis isolates. These isolates represent all seven major global lineages of M. tuberculosis. Lineage specific copy number patterns and preferential insertion regions were observed. Intra-lineage differences were further analyzed for identifying spoligotype specific variations. Copy number distribution and preferential locations of IS6110 in different lineages imply independent evolution of IS6110, governed mainly through ancestral insertion, fitness (gene truncation, promoter activity) and recombinational loss of some copies. A phylogenetic tree based on IS6110 insertion data of different isolates was constructed in order to understand genome level variations of different markers across different lineages.
Highlights
Insertion sequence (IS) 6110 is found at multiple sites in the Mycobacterium tuberculosis genome and displays a high degree of polymorphism with respect to copy number and insertion sites
Other popular strain typing methods are based on variable number of tandem repeats (VNTR) and presence/absence of spacer oligonucleotide known as spoligotyping[6]
Mycobacterial drug resistance is shown to be associated with insertion events, for example, IS6110 insertions in the tlyA gene is observed in capreomycin resistant M. smegmatis and M. tuberculosis[28]; isoniazid, ethionamide and para-aminosalicylic acid resistance of M. bovis has been associated with insertion in katG, etaA and thyA genes respectively[29,30]
Summary
Insertion sequence (IS) 6110 is found at multiple sites in the Mycobacterium tuberculosis genome and displays a high degree of polymorphism with respect to copy number and insertion sites. IS6110 is specific to the M. tuberculosis complex and can be used for diagnosis, that is, the presence of M. tuberculosis cells in a biological sample Since these elements are mobile and are located at different sites, IS6110 based restriction fragment length polymorphism (RFLP) has become a popular tool for strain typing[13,14,15]. One limitation of this approach is that not all isolates display multiple copies of these elements and some lack even a single copy[16,17]. This study provides analysis of 1377 publicly available NGS datasets of M. tuberculosis isolates to generate a global picture of IS6110 distribution
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