Recurrent Emergence of Yersinia pestis: Ancient DNA and the Role of Eurasian Reservoirs

Yersinia pestis causes plague and has triggered multiple pandemics throughout history. Its exact origin and modes of transmission remain unclear. Paleogenomic research reveals that the pathogen has been present in Eurasia since the Neolithic, indicating a complex zoonotic and human history. The first pandemic (541-750 CE) marked the shift of plague from localized outbreaks to a global threat. Newly sequenced genomes from Jordan, Jerash, and regions near the historical epicenter close the critical gaps and highlight widespread early transmission. Phylogenomic analysis of both modern and ancient strains reveals that pandemics emerged from different geographical reservoirs. This emphasizes the ecological complexity of plague and reframing it as a chronic zoonotic disease shaped by human mobility and evolution.  

This research utilized both modern and ancient Y. pestis genomes to reconstruct the evolutionary history and phylogenetic relationships. A total of 258 modern genomes representing the main biovars (Pestoides, Antiqua, Medievalis, Orientalis), and 68 ancient genomes from various pandemic eras (33 from the Second Pandemic, 16 from the First Pandemic, and 19 from the Late Neolithic/Bronze Age) were collected from GenBank. Metadata included collection dates, strain origin, and geospatial coordinates derived from the literature sources. Geographic coordinates were calculated by using the OpenCage geocoding module. 

The Y. pestis CO92 genome (comprising plasmids pCD1, pMT1, pPCP1, and the chromosome) was used as a reference, while two Y. pseudotuberculosis genomes served as outgroups. The nf-core/eager pipeline was used to align ancient war reading to the reference. Snippy v.4.6.0 was used for modern assemblies, and core SNPs were extracted with Snippy-core and filtered at 50% alignment coverage, resulting in a 31,453 bp alignment with 3 singleton sites. IQ-TREE v.2.1.2, with the TVM+F+R9 model, was used for phylogenetic reconstruction, along with SH-aLRT (1000 replicates) and bootstrap. Divergence times were determined using LSD2 v.1.9.8, while spatiotemporal dynamics were analyzed through migration analysis in Treetime v.0.8.1. The final phylogenies were visualized with Nextstrain (Auspice, Augur) and hosted online. 

The results indicate that Y. pestis has deep Eurasian roots, and it spread widely across Central Asia and Europe before the reported pandemics. Ancient DNA from the Neolithic/Bronze Age reveals prehistoric outbreaks, and genomes from the First Pandemic indicate a highly supported clade originating from the Eurasian steppes. The Jerash genome from present-day Jordan provides the first evidence of plague in the Eastern Mediterranean, bridging a key gap in the genetic record. A rare Kyrgyzstan strain predating the First Pandemic highlights early divergent lineages. 

Phylogenetic analyses indicate that pandemic lineages did not originate from a single ancestor, but rather evolved independently from multiple branches. Modern lineages exhibit slow evolutionary rates likely due to the presence of continuous large zoonotic reservoirs. While ancient strains display stronger temporal displacement signals reflecting the human-driven transmission during the pandemics. The absence of a consistent molecular clock complicates long-term evolutionary monitoring.  

Host range analysis reveals that humans primarily drove prehistoric, First, and Second Pandemic strains. This suggests epidemic and human-centric transmission in contrast to modern strains. These results highlight the episodic, human-driven nature of historical outbreaks versus the modern persistence in complex ecological systems. 

Ancient DNA evidence suggests that Y. pestis originated in Eurasia during the Neolithic and Bronze Ages. Early strains permitted sporadic transmission, highlighting the non-linear evolutionary trajectory. Modern lineages appear static due to long periods of dormancy; however, human-driven transmission during pandemics has accelerated divergence. This highlights the importance of ecological reservoirs and human movement in shaping the evolution of plague. 

Overall, this study underscores the importance of integrating archaeological, genetic, and ecological data to gain a deeper understanding of disease emergence. However, limitations include uneven temporal and geographic sampling, specifically from Central or Western Asia and North Africa, as well as reliance on human remains and inadequate environmental and animal data. These gaps restrict a full understanding of plague transmission ecology. 

References: Dutta S, Upadhyay A, Adapa SR, O’Corry-Crowe G, Tripathy S, Jiang RHY. Ancient Origins and Global Diversity of Plague: Genomic Evidence for Deep Eurasian Reservoirs and Recurrent Emergence. Pathogens. 2025; 14(8):797. doi:10.3390/pathogens14080797