Long-range dispersal moved Francisella tularensis into Western Europe from the East

For many infections transmitting to humans from reservoirs in nature, disease dispersal patterns over space and time are largely unknown. Here, a reversed genomics approach helped us understand disease dispersal and yielded insight into evolution and biological properties of Francisella tularensis, the bacterium causing tularemia. We whole-genome sequenced 67 strains and characterized by single-nucleotide polymorphism assays 138 strains, collected from individuals infected 1947-2012 across Western Europe. We used the data for phylogenetic, population genetic and geographical network analyses. All strains (n=205) belonged to a monophyletic population of recent ancestry not found outside Western Europe. Most strains (n=195) throughout the study area were assigned to a star-like phylogenetic pattern indicating that colonization of Western Europe occurred via clonal expansion. In the East of the study area, strains were more diverse, consistent with a founder population spreading from east to west. The relationship of genetic and geographic distance within the F. tularensis population was complex and indicated multiple long-distance dispersal events. Mutation rate estimates based on year of isolation indicated null rates; in outbreak hotspots only, there was a rate of 0.4 mutations/genome/year. Patterns of nucleotide substitution showed marked AT mutational bias suggestive of genetic drift. These results demonstrate that tularemia has moved from east to west in Europe and that F. tularensis has a biology characterized by long-range geographical dispersal events and mostly slow, but variable, replication rates. The results indicate that mutation-driven evolution, a resting survival phase, genetic drift and long-distance geographical dispersal events have interacted to generate genetic diversity within this species.This work was supported by the Swedish Civil Contingencies Agency [grant number TA 014-2010-01;] and the US Department of Homeland Security’s Science and Technology Directorate [award number HSHQDC-10-C-00139;] pursuant to the agreement between the Kingdom of Sweden and the US government on Cooperation in Science and Technology for Homeland Security Matters. The authors R.E. and P.A. were supported by the Ministerio de Economía y Competitividad, Spain [grant number CGL2015-66962-C2-2-R]. We thank Johanna Thelaus, Per Stenberg, Andreas Sjödin, and Petter Lindgren for comments that improved the manuscript. We are grateful to the researchers, physicians, and veterinarians who contributed F. tularensis samples for this study