Livestock played a role in prehistoric plague infections

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Role of livestock in spreading the plague: Yersinia pestis has been identified in a 4,000-year-old sheep, indicating that livestock played a role in spreading an early form of plague that once circulated throughout Eurasia during the Late Neolithic and Bronze Age (LNBA) periods. Spillover from unknown reservoir: Genetic analysis reveals that humans and sheep were infected by nearly identical plague strains. The disease was contracted through spillover from an unknown wild animal reservoir, and sheep grazing over large pastures likely increased human exposure to the pathogen. Distinct plague evolution: The LNBA plague lineage, found in both sheep and humans, lacked the genetic machinery necessary for flea transmission. This lineage exhibited parallel genetic changes under strong evolutionary constraints, suggesting different disease dynamics compared to later historic plagues. Historical context: The increase in livestock herding during the Bronze Age may have led to greater contact between humans, animals, and wild reservoirs of the plague. This underscores the importance of animal domestication and husbandry in the emergence and spread of major zoonotic diseases. Around 5,000 years ago, a mysterious form of plague spread throughout Eurasia, only to disappear 2,000 years later. Known only from ancient DNA, this enigmatic ‘LNBA plague’ lineage has left scientists puzzled about its likely zoonotic origin and transmission. In a new study published in Cell, this ancient plague is identified in an animal for the first time - a 4,000-year-old domesticated sheep excavated at the pastoralist site Arkaim in the Western Eurasian Steppe. Different lines of evidence suggest that plague infections in both human and sheep stem from spillover of a still unknown wild reservoir, and that widespread sheep herding during the Bronze Age brought steppe pastoralist communities into closer contact with this reservoir. This study reveals the connections between domesticated animals and the spread of one of the world's most infamous bacteria, providing insight into how the pathogen was so successful in infecting people across thousands of kilometers over thousands of years.

Zoonotic origins of prehistoric plague infections The majority of human pathogens known today have a zoonotic origin, meaning they jumped from animals into humans - a process known as spillover. A growing body of evidence suggests that many of the infectious diseases they cause emerged within the last 10,000 years - overlapping with the domestication of livestock and pets and pointing to our increasingly close relationships with these animals as the source of these diseases in humans. The study of pathogens from ancient animals using ancient DNA methods offers a unique opportunity to investigate the emergence of human infectious disease, but remains largely unexplored to date.

Plague is among the most deadly zoonotic diseases known. Spread by fleas living on rats, it has killed millions of people throughout history - most notably during the 14th century Black Death in which more than a third of the population of Europe perished. However, before major historical pandemics, a genetically distinct, prehistoric form of plague circulated throughout Eurasia, beginning around 5,000 years ago. Known today as the Late Neolithic Bronze Age (LNBA) lineage, it infected human populations for nearly 3,000 years before vanishing, presumably going extinct. Surprisingly, the LNBA lineage lacks the key genetic toolkit for flea transmission of both historic and modern plaque strains, making its manner of transmission enigmatic. Other animals must have been involved in its spread, but which? “One of the first steps in understanding how a disease spreads and evolves is to find out where it's hiding, but we haven’t done that yet in the ancient DNA field” says lead author Ian Light-Maka, a PhD candidate focused on the long-term evolution of pathogens. “We have over 200 Y. pestis genomes from ancient humans, but humans aren’t a natural host of plague,” says Light-Maka.

Sheep remains from Arkaim reveal the first prehistoric Y. pestis genome in livestock To try to solve the puzzle of how the infection persisted and spread over thousands of years in Eurasia, an international team of researchers from the Max Planck Institute of Infection Biology, Harvard University, the University of Arkansas, Max Planck Institute of Evolutionary Anthropology, and Seoul National University investigated the bones and teeth of Bronze Age livestock at the pastoralist site Arkaim (Russia), a Eurasian Steppe site belonging to the Sintashta-Petrovka culture known for its innovations in cattle, sheep, and horse husbandry. There they identified a 4,000-year-old sheep infected with the same LNBA lineage of Y. pestis that was infecting people at the time.

“Arkaim was part of the Sintashta cultural complex and offered us a great place to look for plague clues: they were early pastoralist societies without the kind of grain storage that would attract rats and their fleas - and prior Sintashta individuals have been found with Y. pestis infections. Could their livestock be a missing link?” says Dr. Taylor Hermes, Assistant Professor of Anthropology at the University of Arkansas and co-author of the study.

Sheep posed elevated Y. pestis infection risk in pastoralist societies Comparing the ancient Y. pestis genome from the sheep to other ancient and modern genomes revealed that the sheep Y. pestis genome was a very close match to one that had infected a human at a nearby site at around the same time. “If we didn't know it was from a sheep, everyone would have assumed it was just another human infection – it's almost indistinguishable,” says Dr. Christina Warinner, Landon T. Clay Professor of Scientific Archaeology at Harvard University and a group leader at the MPI-EVA. This shows that humans and their animals were both being infected with the same population of Y. pestis, but who was infecting whom? Archaeological and comparative approaches may provide some answers. From parts of the world where Y. pestis is still endemic, it is known that sheep can become infected through direct contact with carcasses of infected animals such as rodents, the natural reservoir of the pathogen, and this can spark local plague outbreaks in humans if the sheep are not properly butchered or cooked. Such a scenario could have also spread LNBA plague in prehistory, linking human and sheep infections. “The Sintashta-Petrovka culture is famous for their extensive herding over vast pastures aided by innovative horse technologies, and this provided plenty of opportunity for their livestock to come into contact with wild animals infected by Y. pestis,” says Christina Warinner. “From then on it is just one more short hop into humans.”

Signatures of natural selections suggest the prehistoric Y. pestis reservoir remains unknown Analyzing the new sheep Y. pestis genome with those available from humans enabled a better reconstruction of the evolutionary dynamics of this ancient, presumably extinct, plague lineage. In contrast to the Y. pestis lineages known today, which are geographically variable and distinct, the ancient LNBA lineage was highly similar across its nearly 6,000 kilometers range at any given time. Differences in the life cycle and possibly natural selection could have played a role, since in many well-known pathogens, like SARS-CoV-2 causing COVID-19, new variants can emerge and become widespread if they are better at infecting and transmitting disease. However, rather than finding such variants, the study unexpectedly found the opposite: the ancient lineage was evolving under strong constraints. Notably, a subset of genes were found to mutate repeatedly and independently, but these parallel changes were only seen for the infections that do not have direct descendants, possibly a kind of genetic footprint of past spillovers.

“We can show that the ancient lineage evolved under elevated pressure, which is in contrast to the Y. pestis still found today. Moreover, the ancient sheep as well as human infections are likely isolated spillovers from the unknown reservoir, which remains at large. Finding that reservoir would be the next step,” says Dr. Felix M. Key, senior author and head of the Evolutionary Pathogenomics Lab at the MPIIB. Despite these new insights, major questions still remain unsolved, like how the pathogen spread so far and wide over short periods of time. Sheep and humans are unlikely to have been the main agents spreading the disease since there are examples of nearly identical LNBA Y. pestis genomes at the same time but thousands of kilometers apart, too far for sick humans or terrestrial animals to travel. Luckily, the search for pathogens in ancient animal remains is just beginning - archaeological digs can yield tens of thousands of animal bones, and results from past excavations are waiting in storerooms to be studied further. “I think”, Key says, “there will be more and more interest in analyzing these collections - they give us insights that no human sample can.”

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