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Sequencing Study Provides Clues to Tuberculosis Pathogen Emergence

NEW YORK (GenomeWeb News) – A new Nature Genetics study suggests the widespread tuberculosis pathogen Mycobacterium tuberculosis likely emerged from an ancestral strain resembling a group of smooth colony-forming mycobacteria that currently cause human infections almost exclusively in East Africa.

An international team led by Roland Brosch, a researcher with the Pasteur Institute's integrated mycobacterial pathogenomics unit, did comprehensive whole-genome sequencing on five of the so-called "smooth tubercle bacilli," or STB, strains, along with shotgun sequencing on four more STB strains.

When they compared the STB isolates with the more common TB pathogen M. tuberculosis, the researchers found several telltale genetic differences that led them to believe that STB-like strains preceded the evolution of M. tuberculosis and tuberculosis-causing pathogens in the same complex.

In addition, their findings hint that the global distribution of M. tuberculosis is, in part, a consequence of genetic streamlining, coupled with the acquisition of factors that bumped up its infectiousness.

"We conclude that M. tuberculosis emerged from an ancestral [smooth tubercle bacilli]-like pool of mycobacteria by gain of persistence and virulence mechanisms," Brosch and his colleagues wrote, "and we provide insights into the molecular events involved."

The majority of human TB cases around the world are caused by mycobacteria in the so-called M. tuberculosis complex, or MTBC. That group includes M. tuberculosis itself, along with M. africanum, M. bovis, M. microti, and M. pinnipedii — species that can cause disease in humans and/or other animals.

In addition to their ability to cause TB, the MTBC species share a markedly low genetic diversity, the team pointed out, suggesting fairly recent divergence. Less is known about the genetics of STB strains such as M. canettii, though preliminary analyses indicate that they may sport substantially higher levels of genetic variation.

"Initial genotyping analysis suggested that these isolates possess higher diversity with traces of intra-species horizontal gene transfer," the researchers noted, "and might therefore represent early-branching lineages of tuberculosis-causing mycobacteria."

In an effort to explore that possibility, the team set out to interrogate as many STB strains as they could get their hands on.

Using multilocus sequence type information at a dozen sites in the mycobacterial genome, the researchers first classified the 55 available STB isolates into 13 distinct sequence types.

They then selected representatives from five of the sequence types — STB-A, STB-D, STB-L, STB-J, and STB-K — for whole-genome sequencing by Sanger, Roche 454, and/or Illumina HiSeq sequencing.

In contrast to low genetic diversity that characterizes MTBC strains, the newly sequenced genomes exhibited both extensive genetic variation and high recombination rates, the researchers reported. The STB genomes were also noticeably larger than those of bugs in the MTBC group and harbored somewhat different and diverse bacterial immune system components.

Still, study authors said, the core genome shared by the TB-causing STB strains and M. tuberculosis has remained largely conserved. That conservation encompasses stretches of sequence that encode most of the genes known to be crucial for the growth of a M. tuberculosis reference strain called H37Rv, both in the lab and in a mouse model.

Likewise, the STB and MTBC genomes were organized in a similar manner, the team noted, and showed extensive gene synteny.

Consistent with the high levels of diversity found in STB strains, though, investigators saw that just a fraction of protein-coding genes falling outside of the core STB-MTBC genome were shared between all five of the newly sequenced STB isolates.

Moreover, the STB isolates contained far more genetic variants than have been reported for MTBC pathogens.

Coupled with the propensity for mycobacterial pathogen genomes to shrink over the course of evolution, the researchers explained, both the levels of genetic variability in the STB strains and pseudogene patterns across the mycobacterial strains suggest that the smooth colony-forming lineage branched off earlier than that leading to MTBC strains such as M. tuberculosis.

Some sequence swapping seems to have taken place since that split. But the overall trend the team detected suggests MTBC genomes have diminished in size over the course of evolution, while taking on features that have made them more virulent and persistent than their STB-like precursors — a pattern supported by the team's experiments in mouse models infected with mycobacteria.

"With the larger pan-genome reflecting the ancestral, wider gene pool of tubercle bacilli, their lower virulence and faster growth … STB strains might thus come nearer to the as-yet-unknown missing link between the obligate pathogen M. tuberculosis and environmental mycobacteria," the study's authors concluded.