Comparison of Mycobacterium tuberculosis genomes reveals frequent deletions in a 20 kb variable region in clinical isolates

The Mycobacterium tuberculosis complex is associated with a remarkably low level of structural gene polymorphism. As part of a search for alternative forms of genetic variation that may act as a source of biological diversity in M. tuberculosis, we have identified a region of the genome that is high ly variable amongst a panel of unrelated clinical isolates. Fifteen of 24 i solates examined contained one or more copies of the M. tuberculosis-specif ic IS6110 insertion element within this 20 kb variable region, In nine of t he isolates, including the laboratory-passaged strain H37Rv, genomic deleti ons were identified, resulting in loss of between two and 13 genes. In each case, deletions were associated with the presence of a copy of the IS6110 element. Absence of flanking tri- or tetra-nucleotide repeats identified ho mologous recombination between adjacent IS6110 elements as the most likely mechanism of the deletion events. IS6110 insertion into hotspots within the genome of M. tuberculosis provides a mechanism for generation of genetic d iversity involving a high frequency of insertions and deletions. Copyright (C) 2000 John Wiley & Sons, Ltd.