The Impact of Past Pandemics on Human Evolution: An Archaeogenomic Study of Victims of the Black Death – MORTUI

We will obtain 200 whole genomes of suspected victims of the Black Death and of controls from the post-Black Death medieval population, and estimate their sex, age, pre-existing health conditions and socio-economic status, based on archaeo-anthropological, epigenetic and genetic markers. A genome-wide association study of victims and survivors of the Black Death, combined with the inferred demographic data, will identify genetic and non-genetic factors that affected human susceptibility to Y. pestis infection during the Middle Ages. We will then determine if the genetic risk for plague has decreased with time more than expected under neutrality, supporting polygenic selection for plague resistance since the Middle ages. We will also test if the genetic risk for plague correlates with the genetic risk for chronic inflammatory and auto-immune disorders, which would provide direct evidence that natural selection by the Black Death has increased the prevalence of immune disorders affecting present-day Europe.

Up to now, we have completed the feasibility study of the MORTUI project, the aim of which was to estimate the conservation state of ancient DNA extracted from the archaeological collections. Low-coverage sequencing of 20 samples indicates that more than half of the samples contains >10% of human endogenous DNA. These preliminary results are encouraging and suggest that we will obtain more than a hundred complete, ancient genomes from the entire archeological collections.

Based on the MORTUI project, we will determine if pre-existing health status and human genetic susceptibility contributed to the catastrophic mortality of the Black Death, which may improve epidemiological knowledge required to predict future outbreaks. Furthermore, the project will identify genes and biological functions that participated in the human susceptibility to Y. pestis infection, which may facilitate disease prevention in a context of plague re-emergence. The project will also evaluate new genetic, epigenetic and anthropological markers of health obtained from the archaeological record, which will open new avenues for future epidemiological studies of past pandemics. Finally, the MORTUI project will provide a detailed genomic map of loci that have evolved rapidly in Europe since the Middle Ages, which will improve understanding of the evolutionary arms race between the human host and pathogens, and its consequences on human health.

The MORTUI project has not yet generated scientific productions or patents.

Despite their profound impact on our society and health, little is known about past pandemics and the causes of their exceptional mortality. Host-pathogen interactions are of paramount importance to disease emergence, but the respective role of microbial virulence and host susceptibility factors in past pandemics is ill-defined, limiting the prevention of contemporary outbreaks. The Black Death, caused by the plague bacterium Yersinia pestis, was one of the most devastating pandemics in European history, resulting in the death of 30–60% of its total population from 1347 to 1352. Several factors have been proposed to explain such a catastrophic mortality, including microbial virulence factors or vector expansion, but archaeological evidence supports none of these scenarios. The MORTUI project hypothesizes instead that the massive mortality of the Black Death was primarily due to host susceptibility of Europeans to Y. pestis infection during the Middle Ages. To test this hypothesis, we will take advantage of recent methodological advances in ancient DNA research and archaeo-anthropology to conduct a detailed epidemiological study of Black Death, based on the archaeological record. We will obtain 200 whole genomes of suspected victims of the Black Death and of controls from the post-Black Death medieval population, and estimate their sex, age, pre-existing health conditions and socio-economic status, based on archaeo-anthropological, epigenetic and genetic markers. The genome-wide association study of victims and survivors of the Black Death, combined with the inferred demographic data, will identify genetic and non-genetic factors that affected human susceptibility to Y. pestis infection during the Middle Ages. The MORTUI project also hypothesizes that genetic resistance to plague has been under positive selection in Europeans since the Black Death, resulting in differences in the prevalence of immune-related disorders between present-day human populations. To test this second hypothesis, we will compare the ancient genomes of victims of the Black Death with those of the present-day European population, and search for direct genetic evidence of natural selection due to the Black Death. We will determine if genetic risk to plague has decreased with time more than expected under neutrality, supporting polygenic selection for plague resistance since the Middle ages. We will also test if genetic risk for plague correlates with genetic risk for chronic inflammatory and auto-immune disorders, which would provide direct evidence that natural selection by the Black Death has increased the prevalence of immune disorders affecting present-day Europe. We expect the MORTUI project to determine, for the first time, if pre-existing health status and human genetic susceptibility contributed to the catastrophic mortality of the Black Death, which may improve epidemiological knowledge required to predict future outbreaks. Furthermore, the project will identify genes and biological functions that participated in the human susceptibility to Y. pestis infection, which may facilitate disease prevention in a context of plague re-emergence. The project will also evaluate new genetic, epigenetic and anthropological markers of health obtained from the archaeological record, which will open new avenues for future epidemiological studies of past pandemics. Finally, the MORTUI project will provide a detailed genomic map of loci that have evolved rapidly in Europe since the Middle Ages, which will improve understanding of the evolutionary arms race between the human host and pathogens, and its consequences on human health.