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Plague Pathogen Population History Informed by Integrative Analysis

Yersinia pestis

NEW YORK – A combination of unstable molecular clocks and slow mutation rates appear to limit the extent to which genetic data from Yersinia pestis bacteria alone can be used to tease apart the evolutionary dynamics and transmission events behind plague epidemics or pandemics, according to new research by investigators in Canada and Australia.

"You can't think of the plague as just a single bacterium. Context is hugely important, which is shown by our data and analysis," senior and corresponding author Hendrik Poinar, a researcher affiliated with McMaster University and the Canadian Institute for Advanced Research, said in a statement.

As they reported in Communications Biology on Thursday, the researchers brought together whole-genome sequences for 601 Y. pestis isolates collected at sites around the world for a phylogenetic analysis. They encompassed 540 modern isolates of the microbe as well as 61 ancient strains in an effort to better understand the origins and dynamics of pandemics ranging from the Justinian plague and the Medieval Black Death plague to the so-called third pandemic plague starting in the 20th century.

Together with more detailed population structure and molecular clock analyses, the team's results highlighted sluggish evolution in Y. pestis and instability in the pathogen's molecular clock, a measure of the mutations that accumulate over a given time frame.

In particular, the authors noted that "a species-wide clock model was methodologically unstable and did not lead to reproducible estimates."

Given the relatively low substitution rates in the Y. pestis genome, the researchers explained, it may take decades to detect informative, lineage-related alterations. Consequently, analyses based on genetic information alone may lead to misinterpretations when attempting to tease apart plague epidemics and dynamics over shorter time frames.

"In isolation, Y. pestis genomic evidence may be unsuitable for inferring point migrations and the directionality of spread," the authors reported. "Alternatively, new methods which incorporate non-genetic evidence, such as outbreak case-occurrence records, into phylogeographic analysis presents an exciting avenue for interdisciplinary collaboration, as explicitly integrative models will complement the strength of genetic and historical evidence, while mitigating their respective weaknesses."

With help from historical, environmental, and cultural clues, the team turned to population-specific analyses of the Y. pestis pathogens, which made it possible to more accurately profile substitution rates, lineage differentiations, geographic origins, and evolutionary histories for the five Y. pestis populations considered.

"Despite this methodological advancement, we only obtain robust divergence dates from populations sampled over a period of at least 90 years," the authors cautioned, "indicating that genetic evidence alone is insufficient for accurately reconstructing the timing and spread of short-term plague epidemics."

When it came to the notorious Black Death plague, for example, the findings pointed to culprit pathogens from an ancient lineage with a long history in Europe, going back decades or centuries. Moreover, the authors argued that the "clonal nature of the Black Death is not an exceptional event, but rather the norm based on the sampling time frame."

More broadly, the researchers suggested that a similar integrative approach may provide more informative insights into other plague outbreaks, including those in the past and future.

"We anticipate these results will impact both retrospective and prospective studies of plague, which seek to date the emergence and spread of past pandemics as well as monitor the progression of ongoing outbreaks," the authors wrote.

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