Plagued by a cryptic clock: insight and issues from the global phylogeny of Yersinia pestis

The emergence of the plague pathogen throughout history is investigated using molecular clock modelling and phylogenetic analyses. Plague has an enigmatic history as a zoonotic pathogen. This infectious disease will unexpectedly appear in human populations and disappear just as suddenly. As a result, a long-standing line of inquiry has been to estimate when and where plague appeared in the past. However, there have been significant disparities between phylogenetic studies of the causative bacterium, Yersinia pestis, regarding the timing and geographic origins of its reemergence. Here, we curate and contextualize an updated phylogeny of Y. pestis using 601 genome sequences sampled globally. Through a detailed Bayesian evaluation of temporal signal in subsets of these data we demonstrate that a Y. pestis-wide molecular clock is unstable. To resolve this, we developed a new approach in which each Y. pestis population was assessed independently, enabling us to recover substantial temporal signal in five populations, including the ancient pandemic lineages which we now estimate may have emerged decades, or even centuries, before a pandemic was historically documented from European sources. Despite this methodological advancement, we only obtain robust divergence dates from populations sampled over a period of at least 90 years, indicating that genetic evidence alone is insufficient for accurately reconstructing the timing and spread of short-term plague epidemics.

Automated summary

By using molecular clock modeling and phylogenetic analyses, the emergence of the plague pathogen throughout history is investigated. However, there have been significant disparities between phylogenetic studies of the causative bacterium, Yersinia pestis, regarding the timing and geographic origins of its reemergence. A new approach is developed to assess each Y. pestis population independently, enabling the recovery of substantial temporal signal in five populations, including ancient pandemic lineages that may have emerged before the documented pandemics from European sources.