Natural selection for the Black Death sets the direction for how our immune system responds to the disease

Using DNA extracted from the teeth of people who died before, during, and during the Black Death epidemic, the researchers were able to identify the genetic differences
that determine who died from the Black Death.
Source: Matt Clarke/McMaster University

The Black Death shaped the evolution of immune genes, setting the course
for how we respond to disease today.

An international team of scientists analyzed the DNA of victims and survivors of the Black Death pandemic, identifying key genetic differences
that determine who lives and who dies.
They also shed light on how these aspects of our immune system have continued to evolve since then
.

Scientists analyzed and identified the genes
that protected some people from the devastating Black Death pandemic that swept Europe, Asia and Africa nearly 700 years ago.
The study, conducted by researchers from McMaster University, the University of Chicago, the Institut Pasteur and other organizations, was published Oct.
19 in the journal Nature
.

Researchers report that the same genes, which once provided protection against the Black Death, are now associated
with increased susceptibility to autoimmune diseases such as Crohn's disease and rheumatoid arthritis.

The team focused on the 100-year window
before, during, and after the Black Death.
The Black Death arrived in London
in the mid-14th century.
It remains the worst human death on record, killing more than 50 percent
of the deaths in some of the most densely populated areas of the world at the time.

The researchers extracted and screened more than 500 ancient DNA samples from the remains of people who died before, during the Black Death, or in London, including those buried in the plague crater in East Smithfield, which was used for mass burials
in 1348-9.
Additional samples were taken from remains at five other sites in Denmark
.

Scientists looked for signs of genetic adaptations associated with plague, which was caused
by Yersinia pestis.

They identified four genes in a selective state, all of which are involved in the production of proteins that protect our systems from pathogen invasion, and found variants of these genes, called alleles, that either protect one gene or make one gene vulnerable to plague
.

Individuals with two identical copies of a specific gene called ERAP2 have a much higher chance of surviving a pandemic than individuals with opposite copies, because the "good" copy allows immune cells to neutralize Y.
pestis
more effectively.

The researchers extracted DNA from the remains of people buried in East Smithfield plague crater, which was used for mass burials
in 1348 and 1349.
Image credit: Archaeological Museum of London (MOLA)

"When a pandemic of this nature occurs—killing 30 to 50 percent of the population—humans are bound to select for protective alleles, meaning that people susceptible to epidemic pathogens will die
.
" Even a small advantage means the difference
between survival or passing.
Hendrik Poynner, author of the Nature paper and director of the McMaster Ancient DNA Center, and principal investigator at the Michael G.
DeGroot Institute for Infectious Diseases and McMaster Center for Epidemics and Biothreats Global Link, explains: "Of course, those survivors who reach reproductive age will pass
on their genes.
"

Europeans living during the Black Death were initially vulnerable because they had not been exposed to Yersinia
recently.
In the centuries that followed, the mortality rate declined
as the epidemic began in waves.

Researchers estimate that people who carry the ERAP2 protective allele (a good copy of a gene or trait) have a 40 to 50 percent
better survival rate than those who don't.

Luis Barreiro, a human geneticist and professor of genetic medicine at the University of Chicago and one of the authors of the paper, said: "The selective advantage associated with the selected locus is by far the strongest reported in humans, showing how a single pathogen can have such a powerful effect
on the evolution of the immune system.
"

The team reports that over time, our immune systems have evolved to respond to pathogens in different ways, so much so that what was once a protective gene against plague in the Middle Ages is now associated with
increased susceptibility to autoimmune diseases.
This is the balancing effect
of evolution on our genome.

Javier Pizarroo-cerda, head of the Yersinia research group and director of the WHO Collaborating Centre for Plague at the Institut Pasteur, said: "This highly original work
was only possible through successful collaboration between complementary teams studying ancient DNA, the genetics of human populations and the interaction between live Yersinia pestis and immune cells.
"

"Understanding the dynamics that affect the human immune system is key
to understanding how past epidemics, such as the plague, have affected our susceptibility to disease in modern times," Poynar said.

Jennifer Klunk, a graduate student at McMaster Gu DNA Center, and Tauras Vigylas, a postdoc at the University of Chicago, conducted an unprecedented study
of the immune genes of Black Death victims after 7 years of research.

For more on this research, read The Black Death Drives the Selection of Genes Related to Human Immunity.

Reference: The Evolution of Immune Genes and the Black Death by Jennifer Klunk, Tauras P.
Vilgalys, Christian E.
Demeure, Xiaoheng Cheng, Mari Shiratori, Julien Madej, Rémi Beau, Derek Elli, Maria I.
Patino, Rebecca Redfern, Sharon N.
DeWitte, Julia A.
Gamble, Jesper L.
Boldsen, Ann Carmichael, Nükhet Varlik, Katherine Eaton, Jean-Christophe Grenier, G.
Brian Golding, Alison Devault, Jean-Marie Rouillard, Vania Yotova, Renata Sindeaux, Chun Jimmie Ye, Matin Bikaran, Anne Dumaine, Jessica F.
Brinkworth, Dominique Missiakas, Guy A.
Rouleau, Matthias Steinrücken, Javier Pizarro-Cerdá, Hendrik N.
Poinar and Luis B.
Barreiro, October 19, 2022, Nature
.
DOI: 10.
1038 / s41586 - 022 - 05349 - x

The research was funded
in part by the Social and Human Sciences Research Council of Canada (SSHRC), the National Institutes of Health (NIH), and the Canadian Institute for Advanced Study under the Human and Microbiome Project.