Insights into Yersinia pestis evolution through rearrangement analysis of 242 complete genomes

Yersinia pestis, the bacterium that causes the plague, has a dynamic genome with highly conserved fragments prone to rearrangement, influencing gene function and evolution. However, understanding these patterns is limited by few complete genomes and analytical methods. We developed a dual-validation strategy to analyze 242 complete genomes of Y. pestis natural isolates from diverse phylogroups. We detected 459 rearrangements, which enhanced phylogenetic resolution and resolved the third pandemic’s polytomy. Rearrangements are primarily mediated by four common insertion sequences, with IS1661 and IS100 showing the highest activity. These rearrangements are under strong positive selection, evidenced by 43 hotspots and convergent evolution in the rpsO-pnp operon, whose disruptions and reconnections altered gene expressions and temperature stress responses. We also identified unique structural alterations in human avirulent phylogroups, inactivating three genes and reordering 17 intergenic regions, some affecting virulence-related genes. This study provides a fresh perspective on Y. pestis evolution, revealing experimental targets and establishing a methodology for microbes with frequent rearrangements. Analysis of synteny blocks and genomic rearrangement patterns of 178 newly sequenced and 64 publicly available complete genomes of Yersinia pestis highlights the impact of key variations on genes involved in adaptation and virulence.