When the plague swept through Europe in 1665, no one could figure out how the devastating disease spread. But after a tailor in the small village of Eyam in central England died that September, people eventually put two and two together. He had received a parcel of cloth infested with fleas just 4 days before dying of bubonic plague. Within a month, five other villagers had succumbed, and the local vicar convinced the town to voluntarily put itself under quarantine. It eventually became clear that it was fleas, probably on rats, that spread the plague so far and so quickly.

But now it appears that the plague did not always infect fleas—and the disease may not have always spread so rapidly or been as devastating. A new study of ancient DNA from the teeth of 101 Bronze Age skeletons has found that seven people living 2800 to 5000 years ago in Europe and Asia were infected with Yersinia pestis, the bacteria that causes the plague. But their strains of Y. pestis were missing a gene that allowed it to infect fleas, according to the study published today in Cell. This pushes back the earliest evidence of the plague by almost 3300 years and offers a key clue about how this disease became so contagious. “It’s really cool that they can pinpoint the acquisition of key genes that allow the movement of this bacteria into fleas,” says evolutionary geneticist Hendrik Poinar of McMaster University in Hamilton, Canada, who was not involved with the study.

The plague has caused death and destruction in Europe at least since Roman times, launching at least three major pandemics that changed the course of history—the Plague of Justinian from 541 to 544, which weakened the Byzantine Empire; the Black Death, which killed almost half the population of Europe between 1347 and 1351; and the Great Plague of 1665, which lasted more than 30 years. Ancient DNA researchers have shown in recent years that Y. pestis caused all three of those pandemics. But until now, they were unable to determine whether Y. pestis caused reported plagues 2224 years ago in China and almost 2500 years ago in Greece. They suspected that ancient versions of the plague were not as devastatingly rapid in spread, but they could not test that idea because they lacked samples of the earlier pathogens.

Now, an international team of ancient DNA researchers and archaeologists has solved the mystery almost by accident after sequencing the genomes of 101 Bronze Age skeletons from Europe and Asia. The team started out by trying to pinpoint the origins and migrations of early Europeans. DNA samples revealed that a group of nomadic herders, the Yamnaya, swept into Europe from the plains of today’s Russia and Ukraine sometime between 5000 and 4800 years ago, bringing their culture and, perhaps, the Proto-Indo-European language with them. But archaeologist Kristian Kristiansen of the University of Gothenberg in Sweden wondered whether they also brought disease—and suggested that researchers test the DNA of Bronze Age humans in Europe and Asia to find out.

The team, led by evolutionary biologist Eske Willerslev of the University of Copenhagen, screened 89 billion short segments of DNA from the teeth of 101 individuals. The raw data included DNA from bacteria in the teeth, usually considered “old waste data,” says Willerslev, because it can contaminate the human DNA samples. They detected Y. pestis in seven people, ranging from Bronze Age skeletons that dated back as early as 4800 years ago in Russia, Estonia, and Poland, to an Iron Age individual who lived almost 3000 years ago in Armenia.

When they sequenced the complete genomes of the Y. pestis DNA in those seven individuals, the team found that the bacterial genomes from the earliest samples lacked two genes that helped Y. pestis evade the immune systems of humans and fleas during the Black Death. In particular, the Y. pestis in the earliest Bronze Age individuals lacked a gene called Yersinia murine toxin, which protects the bacterium from a toxin inside the gut of fleas. So although these Bronze Age people suffered from the plague, they probably got it from airborne droplets, contaminated food, or the transmission of bodily fluids, rather than from fleas that infested rodents, as did Europeans during the Black Death and other pandemics.

Using the same samples, the team also traced the evolution of Y. pestis and confirmed that it evolved from a soil bacteria closely related to Yersinia pseudotuberculosis, a bacterium that causes Far East scarletlike fever in humans, and is most often spread through food. The two bacterial lineages diverged about 55,000 years ago. That date has large margins of error, but suggests that Y. pestis is much older than thought—previous estimates suggested it originated just 3300 years ago. But researchers now realize that it probably wasn’t until the end of the Bronze Age that the bacteria evolved from a less virulent species that may have spread more like the flu, tuberculosis, or AIDS than the bubonic plague, which is transmitted through flea bites to the skin.

“This suggests that it was quite a different disease in the Bronze Age from what it was in medieval times,” says Johannes Krause, a paleogeneticist at the Max Planck Institute for the Science of Human History in Jena, Germany, who was not involved with the study. Poinar agrees that the most exciting part of the paper is that it solves a longstanding mystery about how the bubonic plague was able to spread so rapidly in the Middle Ages. He says: “The whole flea-rodent ecology of plague is what led to major pandemics of the bubonic form of the plague in Europe.”

Plague might have been devastating back in the Bronze Age, too. Researchers speculate that if invading armies from the Russian steppe brought plague with them into Europe—even if it didn’t spread by fleas—it could have wiped out small bands of European farmers and made their territory vulnerable to invasion, much as Spanish conquistadors infected Native Americans with smallpox. And the plague was just one of the armory of devastating diseases that shaped the course of human history. “The most important take-home message is now we can do this for all kinds of diseases,” Willerslev says.