[Clade-specific ecological niches and transmission patterns of Francisella tularensis subsp. holarctica].

Objective: Quantitative analysis of the spatial distribution and ecological niche differentiation characteristics of the major evolutionary clades of Francisella tularensis subsp. holarctica (Fth), elucidate the mechanism of epidemiological heterogeneity. Methods: A systematic search of public databases was conducted to collect and curate whole-genome sequences and metadata of 415 Fth strains. A maximum-likelihood phylogenetic tree was constructed using core-genome single-nucleotide polymorphisms,and an additional 1 047 strains with complete metadata from public databases were integrated to perform geographic analysis by incorporating geographic information. A Bayesian molecular clock model was used to infer the divergence history of the major evolutionary clades. A 4×3 contingency table was constructed using 126 representative strains to determine niche preferences among evolutionary clades and isolation origins. Fisher's exact test was applied to examine general associations, and adjusted standardized residuals (ASR) were computed to determine the source-specific preference for each clade (|ASR| >1.96 implies a statistically significant difference). Results: The Phylogenetic analysis for the Fth strains indicated that there are subgenomic B.4, B.6, B.12, and B.16, which show evident geographic groups. Bayesian molecular clock analysis of the most recent common ancestor of Fth yielded an estimate of about 2276 years Before Common Era Fisher's exact test showed a powerful relationship between Fth clade types and sources of isolation (P<0.001). ASR analysis revealed that clade B.12 was significantly overrepresented in animal sources (ASR=4.95) and underrepresented in human sources (ASR=-4.77), and that clade B.6 was significantly overrepresented in human sources (ASR=2.88) and underrepresented in animal sources (ASR=-2.50). Conclusions: The two main Fth clades, B.6 and B.12, have distinct and opposite niche differentiation. Clade B.12 has a strong "zoonotic affinity", and clade B.6 has a significant "human affinity", indicating that B.6 is a zoonotic lineage that is more prone to infecting humans and poses a greater threat to public health. These will conclude the importance of the clade type in future disease monitoring and risk assessment for targeted disease prevention and control.