Whole Genome Sequencing Better at Tracing TB Outbreaks

A study revealed that a new form of genetic testing of the bacteria that cause tuberculosis (TB) provides better information on TB transmission and thus allows tracing of TB outbreaks more accurately than the current standard tests.

A team of experts from public-health institutions, research institutes, and universities in Germany and France led by Stefan Niemann from the Forschungszentrum Borstel (Borstel, Germany) compared the results of the two types of tests on 86 Mycobacterium tuberculosis isolates from a TB outbreak in the German states Hamburg and Schleswig-Holstein (overall 2301 TB cases have been investigated in the study period from 1997 to 2010).

They found that the new test, based on the sequencing of the respective whole genomes (i.e., whole genome sequencing, WGS) provided more accurate information on clustering and temporal spread of the pathogen than the standard tests, which are based on the analysis of small genome regions (classical genotyping). Importantly, while standard tests were not able to distinguish the strains involved, WGS-based analyses revealed that only a particular clone started spreading at the onset of the outbreak, suggesting that subtle differences in the genome might influence the success of pathogen transmission.

"Only genome based investigations allowed us to trace the spread of M. tuberculosis with the resolution needed to visualize transmission patterns correctly," said Dr. Andreas Rötzer, first author of the study.

Genotyping of M. tuberculosis strains is usually used to detect TB outbreaks and guide tracing contacts of TB cases. However, standard genotyping analyses only tiny parts of the genome, and may therefore not be able to distinguish between closely related strains spreading in distinct transmission chains. This was confirmed by this study: WGS-based typing discriminated better the different strain variants involved in the outbreak, was in better agreement with information on known contacts between the patients, and allowed the investigators to more precisely follow the spread of clones over space and time.

Based on the genome sequencing data, the authors were also able to estimate that the genome of M. tuberculosis evolves in its natural host population (infected individuals) at a slower mutation rate than other bacterial pathogens (0.4 mutations per genome per year). This measure of the bacterium’s mutation rate will be useful to trace future outbreaks and estimate when and via which individual they originated.

An additional advantage of WGS compared to standard genotyping is that WGS allows the identification of mutations of bacterial genes causing antibiotic resistance mutations and variations in virulence genes. This is especially important as M. tuberculosis strains that are resistant to the most potent drugs are increasingly emerging in several world regions and rapid detection of resistance is crucial for successful treatment.

The costs of whole genome analysis based on Next Generation Sequencing are declining; therefore, this test could soon become the standard method for identifying transmission patterns and rates of infectious disease outbreaks.

In addition, the authors state: “We envision that the progressive effective implementation of WGS for Public Health and medical diagnostics will also be accelerated by the broader distribution of more accessible and flexible sequencing machines, and upcoming bioinformatics developments to facilitate quick and relevant interpretation of the resulting data by the clinical and medical staff.”

The study was published in PLOS Medicine on February 12, 2013.

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