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

Abstract

Plague has an enigmatic history as a zoonotic pathogen. This potentially devastating 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. We perform a detailed Bayesian evaluation of temporal signal in subsets of these data and demonstrate that a Y. pestis-wide molecular clock model is unstable. To resolve this, we devised a new approach in which each Y. pestis population was assessed independently. This enabled us to recover significant 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, 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. Finally, we identify key historical data sets that can be used in future research, which will complement the strengths and mitigate the weaknesses of genomic data.

Ancient Yersinia pestis genomes lack the virulence-associated Ypf Φ prophage present in modern pandemic strains

“…As the phage is only present in one modern phylogenetic sub-branch, it is possible to estimate the approximate time of its incorporation based on the molecular dating of the splits in the phylogeny. Molecular dating depends on various factors, such as the included strains and the methods used for the analysis, and thus there seems to be no consensus in the literature concerning the exact date of the 1.ORI branch split [35]. Although the 1.ORI branch could have emerged anytime between approximately 550 and 150 years ago [9,[35][36][37], it is likely that both the split and the genomic acquisition of YpfΦ occurred before the Modern plague pandemic.…”