Retrospective cohort study of a dominating Danish genotype.

Since 1992, Denmark has experienced the largest sustained outbreak of tuberculosis (TB) in Scandinavia ascribed to a single genotype. Based on nationwide strain-typing of every Mycobacterium tuberculosis culture-positive case, the '1112-15' outbreak has been documented to progress at a surprisingly high rate, despite an overall declining trend in total Danish TB cases. As of Spring 2017, the International Reference Laboratory of Mycobacteriology (IRLM) in Copenhagen has collected and identified isolates from more than a thousand cases belonging to this outbreak via routine MIRU-VNTR typing. In 2015, we began a project of whole-genome sequencing every available '1112-15' isolate identified between 1992 – 2014 (n=989), which is currently ~80% complete. Here, we present our first retrospective analysis of the 1112-15 dataset, based on whole-genome data from a sparse time-series consisting of five randomly selected isolates from each of the 23 years. Even if these data are derived from only 12% of the isolates, we have been able to extract important key information, such as mutation rate, conserved single-nucleotide polymorphisms to identify discrete transmission chains, and finally, the possible historical origins of the outbreak. In addition to helping us to put the outbreak in a global context, these data therefor also provide us with relevant information for future classification of new cases and ongoing monitoring of discrete transmission chains.