Origin and dispersal of the Mycobacterium tuberculosis Haarlem genotype: Clues from its phylogeographic landscape and human migration.

The Haarlem family belongs to the Euro-American phylogenetic lineage of Mycobacterium tuberculosis and is one of the globally spread genotypes of this important human pathogen. In spite of the sporadic observations on drug resistance and peculiar virulence profile, Haarlem remains in the shade of other M. tuberculosis genotypes. I analyzed genotyping data of the Haarlem genotype in light of its pathogenic properties and relevant human migration, to gain insight into its origin, evolutionary history, and current spread. Central Europe is marked with a very high prevalence of both major Haarlem subclades ancestral H3/SIT50 and derived H1, jointly making 33-41 % in Czechia, Austria, and Hungary. There is a declining gradient of Haarlem beyond central Europe with 10-18 % in Italy, France, Belgium, 10-13 % in the Balkan countries and Turkey. Placing the available genetic diversity and ancient DNA data within the historical context, I hypothesize that M. tuberculosis Haarlem genotype likely originated in Central Europe and its primary long-term circulation occurred within the area of the former Austria/Austria-Hungary Empire in the 14th-19th centuries. The genotype is not highly transmissible and its spread was driven by long-term human migration. The European colonial expansion (when accompanied by a sufficient volume of migration) was a vehicle of its secondary dissemination. I conclude that human migration and its lack thereof (but not strain pathobiology) was a major driving force that shaped the population structure of this global lineage of M. tuberculosis. At the same time, Haarlem strains appear over-represented in some ethnic groups which warrants in-depth experimental research.