Ancient DNA finally solves the mystery of the world’s first pandemic

The landmark discovery, led by an interdisciplinary team at the University of South Florida and Florida Atlantic University, with collaborators in India and Australia, identified Yersinia pestis, the microbe that causes plague, in a mass grave at the ancient city of Jerash, Jordan, near the pandemic’s epicenter. The groundbreaking find definitively links the pathogen to the Justinian Plague marking the first pandemic (AD 541-750), resolving one of history’s long-standing mysteries.

For centuries, historians have deliberated on what caused the devastating outbreak that killed tens of millions, reshaped the Byzantine Empire and altered the course of Western civilization. Despite circumstantial evidence, direct proof of the responsible microbe had remained elusive — a missing link in the story of pandemics.

Two newly published papers led by USF and FAU provide these long-sought answers, offering new insight into one of the most consequential episodes in human history. The discovery also underscores plague’s ongoing relevance today: while rare, Y. pestis continues to circulate worldwide. In July, a resident of northern Arizona died from pneumonic plague, the most lethal form of Y. pestis infection, marking the first such fatality in the U.S. since 2007, and just last week another individual in California tested positive for the disease.

“This discovery provides the long-sought definitive proof of Y. pestis at the epicenter of the Plague of Justinian,” said Rays H. Y. Jiang, PhD, lead PI of the studies and associate professor with the USF College of Public Health. “For centuries, we’ve relied on written accounts describing a devastating disease, but lacked any hard biological evidence of plague’s presence. Our findings provide the missing piece of that puzzle, offering the first direct genetic window into how this pandemic unfolded at the heart of the empire.”

The Plague of Justinian first appeared in the historical record in Pelusium (present day Tell el-Farama) in Egypt before spreading throughout the Eastern Roman, or Byzantine, Empire. While traces of Y. pestis had previously been recovered thousands of miles away in small western European villages, no evidence had ever been found within the empire itself or near the heart of the pandemic.

“Using targeted ancient DNA techniques, we successfully recovered and sequenced genetic material from eight human teeth excavated from burial chambers beneath the former Roman hippodrome in Jerash, a city just 200 miles from ancient Pelusium” said Greg O’Corry-Crowe, PhD, co-author and a research professor at FAU Harbor Branch Oceanographic Institute and a National Geographic Explorer.

The arena had been repurposed as a mass grave during the mid-sixth to early seventh century, when written accounts describe a sudden wave of mortality.

Genomic analysis revealed that the plague victims carried nearly identical strains of Y. pestis, confirming for the first time that the bacterium was present within the Byzantine Empire between AD 550-660. That genetic uniformity suggests a rapid, devastating outbreak consistent with historical descriptions of a plague causing mass death.

“The Jerash site offers a rare glimpse of how ancient societies responded to public health disaster,” said Jiang. “Jerash was one of the key cities of the Eastern Roman Empire, a documented trade hub with magnificent structures. That a venue once built for entertainment and civic pride became a mass cemetery in a time of emergency shows how urban centers were very likely overwhelmed.”

A companion study, also led by USF and FAU, places the Jerash discovery into a wider evolutionary context. By analyzing hundreds of ancient and modern Y. pestis genomes — including those newly recovered from Jerash — the researchers showed that the bacteria had been circulating among human populations for millennia before the Justinian outbreak.

The team also found that later plague pandemics, from the Black Death of the 14^th century to cases still appearing today, did not descend from a single ancestral strain. Instead, they arose independently and repeatedly from longstanding animal reservoirs, erupting in multiple waves across different regions and eras. This repeated pattern stands in stark contrast to the SARS-CoV-2 pandemic (COVID-19), which originated from a single spillover event and evolved primarily through human-to-human transmission.

Together, the landmark findings reshape the understanding of how pandemics emerge, recur and spread, and why they remain a persistent feature of human civilization. The research underscores that pandemics are not singular historical catastrophes, but repeating biological events driven by human congregation, mobility and environmental change — themes that remain relevant today.

“This research was both scientifically compelling and personally resonant. It offered an extraordinary opportunity to delve into the study of human history through the lens of ancient DNA at a time when we ourselves were living through a global pandemic,” said O’Corry-Crowe. “Equally profound was the experience of working with ancient human remains — individuals who lived, suffered, and died centuries ago — and using modern science to help recover and share their stories. It’s a humbling reminder of our shared humanity across time and a moving testament to the power of science to give voice to those long silent.”

While very different from COVID-19, both diseases highlight the enduring link between connectivity and pandemic risk, as well as the reality that some pathogens can never be fully eradicated.

“We’ve been wrestling with plague for a few thousand years and people still die from it today,” Jiang said. “Like COVID, it continues to evolve, and containment measures evidently can’t get rid of it. We have to be careful, but the threat will never go away.”

Building on the Jerash breakthrough, the team is now expanding its research to Venice, Italy and the Lazaretto Vecchio, a dedicated quarantine island and one the world’s most significant plague burial sites. More than 1,200 samples from this Black Death-era mass grave are now housed at USF, offering an unprecedented opportunity to study how early public health measures intersected with pathogen evolution, urban vulnerability and cultural memory.