Abstract
Yersinia pestis, the causative agent of plague, has triggered multiple pandemics throughout human history, yet its long-term evolutionary patterns and reservoir dynamics remain poorly understood. Here, we present a global phylogenomic analysis of ancient and modern Y. pestis strains spanning from the Neolithic and Bronze Age to the present day. We show that pandemic-causing lineages did not arise from a single ancestral strain but instead emerged independently along deep branches of the Y. pestis phylogeny. Pandemic-associated Y. pestis strains were recovered exclusively from human remains and display clear local temporal divergence, indicating evolution driven by human transmission during outbreaks. These findings support the hypothesis that plague emergence is driven by complex, regionally rooted reservoirs, with recurrent spillovers into human populations across millennia. Our work highlights the need to view plague not as a series of isolated outbreaks but as a long-standing zoonotic threat shaped by deep evolutionary history, host ecology, and human societal structures.