Complete genomes of Rickettsia typhi reveal a clonal population

Murine typhus, caused by infection with Rickettsia typhi, is a neglected disease contributing to infectious disease burden in south- and southeast Asia. Despite its importance, we have minimal knowledge of the genomics of R. typhi, with only four complete genomes being sequenced prior to this work. We sequenced a further 25 genomes including historical strains collected before 1976 from both human and rat hosts, and recent genomes isolated from patients at a single hospital in Laos. Whole genome SNP analysis reveals extremely low levels of genetic diversity across the 29 genomes, with overall nucleotide diversity ({pi}) of 1.27e-05 and evidence of purifying selection, and a minimal pan-genome. Phylogenetic analysis shows clustering of the genome by historic or modern origin, with the exception of one modern strain which is most closely related to historic strains from Thailand, and no clustering by host origin. The highly conserved genome of R. typhi suggests strong constraints on genome evolution in this obligate intracellular parasite, and has implications for the design of future murine typhus diagnostic tools and vaccines. Impact StatementRickettsia typhi is the causative agent of murine typhus, an infectious disease that causes morbidity and mortality in humans. This study has expanded the genomic dataset from a small number of genomes to a comprehensive collection of 29 complete genomes. The genome comparison includes historic and modern strains and reveals a clonal population structure with minimal genetic diversity across time. This shows the evolutionary stability of R. typhi, which is most likely due to strong purifying selection and an intracellular lifestyle. This extremely low genomic variation has significant impacts for the development of murine typhus vaccines and robust diagnostic assays.