Although one-third of the world’s population is infected with Mycobacterium tuberculosis, the disease garners relatively little attention as it ispredominantly a disease of developing nations and disadvantaged populations.Significant advances against tuberculosis (TB) have been made in the pastcentury, in particular the development of the TB skin test and the discovery ofantibiotics, but without new tools for TB diagnosis and management, it will beimpossible to further reduce the burden of disease worldwide. One majorquestion that remains unanswered for TB is what role does genetic variation inthe bacterium play in clinical and epidemiological outcomes? In contrast toother bacteria, the challenge is that M. tuberculosis is highly conservedgenetically and without the use of ultra-high-throughput sequencing, it is notpossible to distinguish subtle, yet potentially clinically important, changesbetween many strains of the bacterium.

The British Columbia Centre for Disease Control (BCCDC) worked closely with the Vancouver Island Health Authority and First Nations representatives to manage an ongoing outbreak of tuberculosis centered in the Port Alberni region of Vancouver Island. Of the thousands of people who were screened since May 2006, 40 epidemiologically-linked cases of active disease were identified. Conventional genotyping methods were inadequate for explaining the observed temporal and spatial patterns of transmission of this large persistent outbreak. This project used ultra-high-throughput DNA sequencing for the whole genome characterization of all the M. tuberculosis isolates from this outbreak.

Of the common bacterial diseases, M. tuberculosis is the only pathogen so highly conserved that such an analysis is both necessary and informative. This project recognized a unique opportunity to understand the molecular epidemiology at the highestgenetic resolution, effectively observing the microevolution of a bacteriumduring an ongoing outbreak and correlating this with our detailed clinical andepidemiological data. Not only was this the first attempt to perform whole genome sequencing of a clonal and epidemiologically-linked group of bacteria, but this is also was performed during the course of an outbreak. There are few public health institutions in the world that can routinely conduct such a coordinated laboratory and epidemiological investigation of a large outbreaksuch as this. By characterizing the mutations and studying the microevolutionof this strain of M. tuberculosis, researchers were able to better understand why this strain was able to emerge and persist despite best efforts to contain the ongoing outbreak. Combining high resolution genetic data with detailed contact tracing and social network analysis, researchers were able to develop new tools to track disease emergence and new approaches to prevent outbreaks closer to the source.

This project was a collaboration that brought together a unique set of capabilities and skills, alllocated in BC, the laboratory and epidemiology resources of the BCCDC (www.bccdc.org), the state-of-the-art genome sequencing and assembly capabilities at the Genome Sciences Center (GSC) located at the British Columbia Cancer Agency (www.bcgsc.bc.ca), and the bioinformatics capabilities of Dr. Fiona Brinkman at Simon Fraser University (www.pathogenomics.sfu.ca/brinkman/). Additionally, this work complemented internationally-recognized population-based TB research in Canada such as the Respiratory Epidemiology and Clinical Research Unit at McGill and the mycobacteriology research performed at the National Microbiology Laboratory.