The study's co-lead author Ravneet Sidhu noticed that about a century into the epidemic, one copy of a gene suddenly disappeared from the genome, sparking a multiyear investigation.McMaster University/Supplied
In the largest mass-mortality event ever recorded, the Black Death swept through Europe in the 14th century, killing between 30 to 50 per cent of the human population.
After the initial wave, the plague persisted for more than 500 years in a series of smaller epidemics. History suggests that the bacterium that causes the plague changed as it ran its course, becoming less deadly and potentially allowing the disease to infect more hosts.
Now, a new study has looked at DNA that predates antibiotics as well as rare modern strains of the bacterium to reveal the genetic change that allowed this adaptation. This study, which uses a live version of the adaptation, marks one of the first times a medieval mutation has been tested on modern mice, opening new doors into the study of how pandemics evolve.
“When a pandemic happens, you don’t know what trajectory it’s going to go on. Sometimes we don’t get the foresight until 400 years later,” said Ravneet Sidhu, graduate student at McMaster University in Hamilton and co-lead author of the study, published Thursday in the journal Science.
Yersinia pestis, the bacterium that causes the plague, is mostly a disease of rodents. Spread to humans by fleas, the pathogen has spawned at least two pandemics in addition to the Black Death. The Plague of Justinian, in the 6th century, followed the same pattern: a mass die-off followed by centuries of lesser waves. A modern plague is also happening today, but is mostly limited to rodents because of the discovery of antibiotics.
Studying samples of bacterial DNA from the Black Death from ancient Denmark, Ms. Sidhu noticed that about a century into the epidemic, one copy of a gene suddenly disappeared from the genome of Yersinia pestis.
This sparked a multiyear investigation into the gene, piecing together ancient DNA from strains of the disease throughout its history and bringing together researchers from across the Atlantic.
How the Black Death left its mark on our genes
The gene, called pla, had been reported missing before – its importance in the virulence, or severity, of the disease makes it a point of interest for researchers. One study even suggests that the appearance of pla is what first turned the disease from a mild pathogen to a deadly killer.
In both of the ancient plagues, the team found that after about a century of decimating the human population, there was a sudden depletion of the pla gene.
When “we find the same common patterns occurring in parallel in different pandemics,” said Guillem Mas Fiol, the other co-lead author from the Pasteur Institute in Paris, “it means that there has to be some sort of advantage” for the bacterium.
The team searched for a way to test this hypothesis – a difficult task when working with a strain of the disease that has been dead for more than a quarter-century.
To do this, they needed a live strain with a similar mutation. Luckily, in the 1,800 strains of modern Y. pestis kept at the Pasteur Institute, they managed to find three strains with the same depletion as the ancient strains, a feat likened to finding a needle in a haystack by Javier Pizarro-Cerda, a research director at the Pasteur Institute and a senior author on the study.
With this living strain, the team could test how this mutation actually affected living mice and match up their observations of the heavily degraded ancient DNA to the live DNA – allowing them to fully understand the genetic mechanism that gives this mutation its edge.
“Up until now,” said Dr. Pizarro-Cerda, “all the observations from studies remained theoretical” because the genetic changes they found couldn’t be tested.
Genome evidence points to plague in Stone Age European population crash
In the mouse trials, they were able to prove the strains with depleted pla were a bit less deadly and, importantly, took longer to kill than the usual strains.
The classic “viral attenuation” theory posits that as a disease progresses through a population, it adapts to become less severe, trading virulence (how effectively it kills a host) for transmission (how effectively it spreads). This is because diseases often need a host to do their spreading for them while alive and active.
Yet the plague is unique here, as it often spreads through the blood of victims who are about to die, transferred to new hosts by fleas. This means that, unlike most diseases, a longer infection does not equal more time to infect a new host.
Therefore, the researchers posited a new theory: The initial wave of the pandemic decimated the rat population of Europe, leaving only a patchwork of small populations behind. To stay alive, the bacterium dropped the pla gene, allowing the rats to live longer and travel farther from where they were infected to where they would die, spreading the disease among the remaining fragments of the population.
Ben Krause-Kyora, a researcher of ancient DNA at Germany’s Kiel University, who was not involved in the study, was fascinated by the ability to use live specimens. His group had studied pla depletion in the plague before, but the effects of this mutation were “something we could only speculate,” he said.
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