IS1096-mediated DNA rearrangements play a key role in genome evolution of Mycobacterium smegmatis

Wang, Xiaoming; Galamba, Alexandra; Warner, Digby F.; Soetaert, Karine; Merkel, Jane S.; Kalai, Michaël; Bifani, Pablo; Lefèvre, Philippe; Mizrahi, Valerie

doi:10.1016/j.tube.2008.02.003

Cited by 19 publications

(18 citation statements)

References 32 publications

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“…While chromosomal duplications have been reported for other nonpathogenic mycobacteria, each of these has clearly been selected for through continuous in vitro passage. In Mycobacterium smegmatis mc 2 155, a 56-kb duplication that is flanked by two copies of an IS1096 element has been identified (37). The ATCC 607 progenitor does not contain the 56-kb duplication.…”

Section: Discussionmentioning

confidence: 99%

Massive Gene Duplication Event among Clinical Isolates of the Mycobacterium tuberculosis W/Beijing Family

et al. 2010

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As part of our effort to uncover the molecular basis for the phenotypic variation among clinical Mycobacterium tuberculosis isolates, we have previously reported that isolates belonging to the W/Beijing lineage constitutively overexpress the DosR-regulated transcriptional program. While generating dosR knockouts in two independent W/Beijing sublineages, we were surprised to discover that they possess two copies of dosR. This dosR amplification is part of a massive genomic duplication spanning 350 kb and encompassing >300 genes. In total, this equates to 8% of the genome being present as two copies. The presence of IS6110 elements at both ends of the region of duplication, and in the novel junction region, suggests that it arose through unequal homologous recombination of sister chromatids at the IS6110 sequences. Analysis of isolates representing the major M. tuberculosis lineages has revealed that the 350-kb duplication is restricted to the most recently evolved sublineages of the W/Beijing family. Within these isolates, the duplication is partly responsible for the constitutive dosR overexpression phenotype. Although the nature of the selection event giving rise to the duplication remains unresolved, its evolution is almost certainly the result of specific selective pressure(s) encountered inside the host. A preliminary in vitro screen has failed to reveal a role of the duplication in conferring resistance to common antitubercular drugs, a trait frequently associated with W/Beijing isolates. Nevertheless, this first description of a genetic remodeling event of this nature for M. tuberculosis further highlights the potential for the evolution of diversity in this important global pathogen.Mycobacterium tuberculosis-the bacterium responsible for almost 2 million human deaths each year due to tuberculosis (TB)-exhibits a highly clonal population structure and, unlike many pathogenic bacteria, shows little evidence of having recently acquired exogenous DNA from unrelated organisms via horizontal gene transfer and recombination (30). Thus, it seems that the primary mechanism by which M. tuberculosis is able to modify existing phenotypes is through an alteration in the complement of genetic material that it already has available. To date, most of the phenotypic variation that has been reported for M. tuberculosis involves single nucleotide polymorphisms (SNPs) and deletions, although transposition of conserved insertion sequence elements (e.g., IS6110) represents another potential mode for generating variability (1,14,16,22). Recent SNP-and microarray-based whole-genome surveys have demonstrated that M. tuberculosis has evolved via clonal expansion into six major lineages that are referred to colloquially as Indo-Oceanic, East Asian, East African-Indian, Euro-American, West African-1, and West African-2. Aside from the widespread Euro-American lineage, each of these lineages tends to exhibit a strong degree of association with a particular geographic area (19,29,38).Of all the major lineages described to date, it is...

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Section: Discussionmentioning

confidence: 99%

Massive Gene Duplication Event among Clinical Isolates of the Mycobacterium tuberculosis W/Beijing Family

et al. 2010

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“…Relatively few examples of large chromosomal duplications have been reported in the genus Mycobacterium, including a 56-kb duplication flanked by two copies of IS1096 in M. smegmatis mc 2 155 (18,19). Among members of the M. tuberculosis complex, two independent tandem duplications are present in the vaccine strain M. bovis BCG: DU1, a 29-kb duplication that includes oriC and is present only in BCG Pasteur, and DU2, a 36-kb duplication that occurs in different forms and that initially arose through a 141-kb tandem duplication followed by subsequent internal deletions (20).…”

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Origins of a 350-Kilobase Genomic Duplication in Mycobacterium tuberculosis and Its Impact on Virulence

et al. 2014

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bIn the present study, we have investigated the evolution and impact on virulence of a 350-kb genomic duplication present in the most recently evolved members of the Mycobacterium tuberculosis East Asian lineage. In a mouse model of infection, comparing HN878 subclones HN878-27 (no duplication) and HN878-45 (with the 350-kb duplication) revealed that the latter is impaired for in vivo growth during the initial 3 weeks of infection. Furthermore, the median survival time of mice infected with isolate HN878-45 is significantly longer (77 days) than that of mice infected with HN878-27. Whole-genome sequencing of both isolates failed to reveal any mutational events other than the duplication that could account for such a substantial difference in virulence. Although we and others had previously speculated that the 350-kb duplication arose in response to some form of hostapplied selective pressure ( , here we show that this large chromosomal amplification event is very rapidly selected within standard in vitro broth cultures in a range of isolates. Indeed, subclones harboring the duplication were detectable after just five rounds of in vitro passage. In contrast, the duplication appears to be highly unstable in vivo and is negatively selected during the later stages of infection in mice. We believe that the rapid in vitro evolution of M. tuberculosis is an underappreciated aspect of its biology that is often ignored, despite the fact that it has the potential to confound the data and conclusions arising from comparative studies of isolates at both the genotypic and phenotypic levels.

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“…A pesar de la poca variación entre las especies del complejo M. tuberculosis, existe variabilidad representada por mutaciones puntuales, polimorfismos largos y eventos de inserción y transposición (1,8,17). Estas diferencias genotípicas, a su vez, pueden resultar en cambios fenotípicos grandes.…”

Section: Discussionunclassified

“…La genómica comparativa ha llevado a avances en los campos de la biología evolutiva (8,9), reconstrucción filogenética (1,10,11), programas de descubrimiento de medicamentos (12,13) y predicción de funciones en genes hipotéticos (14). A esto se le suma la identificación de regiones intrónicas (15), sitios de splicing y un mayor conocimiento de regiones no codificadoras (16,17).…”

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Análisis comparativo de seis genomas del complejo Mycobacterium tuberculosis

et al. 2010

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IS1096-mediated DNA rearrangements play a key role in genome evolution of Mycobacterium smegmatis

Cited by 19 publications

References 32 publications

Massive Gene Duplication Event among Clinical Isolates of the Mycobacterium tuberculosis W/Beijing Family

Massive Gene Duplication Event among Clinical Isolates of the Mycobacterium tuberculosis W/Beijing Family

Origins of a 350-Kilobase Genomic Duplication in Mycobacterium tuberculosis and Its Impact on Virulence

Análisis comparativo de seis genomas del complejo Mycobacterium tuberculosis

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