The Black Death Selected for Immune-Related Genes, Affecting Susceptibility to Today’s Diseases

The Black Death was the deadliest accident in recorded history.caused by bacteria Yersinia pestis, Nearly 700 years ago, bubonic plague swept across North Africa, Europe, and Asia, killing 30-60% of the population. Newly reported research suggests that pandemics are exerting significant selective pressure on populations, altering the frequency of certain immune-related genetic mutations and affecting susceptibility to today’s diseases. .

Scientists, led by a team at the University of Chicago (UChicago), McMaster University, and the Pasteur Institute, analyzed centuries-old DNA from bubonic plague victims and survivors to determine who lived and who died. And we identified important genetic differences that determine how we decided. These aspects of our immune system have continued to evolve since that time. The result is that the same genes that once conferred protection against infection are now responsible for susceptibility to autoimmune diseases such as Crohn’s disease and rheumatoid arthritis. shows that it is associated with an increase in

“This is, to my knowledge, the first demonstration that the Black Death was a significant selective pressure on the evolution of the human immune system,” said Professor of Genetic Medicine at the University of Chicago. Paper published by the team Nature“There is much debate about how pathogens have shaped human evolution, so being able to formally prove which pathways and genes were targeted would allow humans to adapt and exist today.” It really helps us understand why we did it. It tells us the mechanisms that have allowed us to survive throughout history and why we are still here today.”

The findings are the result of a seven-year study by lead authors, graduate student Jennifer Klunk (formerly at McMaster’s Ancient DNA Centre) and postdoctoral researcher Tauras Vigylas, Ph.D., in a paper entitled reported.Evolution of immune genes is associated with the Black DeathIn their paper, the authors say the study provides “empirical evidence for the role that past pandemics have played in shaping susceptibility to current diseases.”

Infectious diseases have represented one of the strongest selective pressures in the evolution of humans and other animals, the authors write. “Not surprisingly, many candidates for population-specific positive selection in humans involve immune response genes, and we hypothesized that exposure to new and/or re-emerging pathogens promoted adaptation. Uncovering the dynamics that have shaped the human immune system is key to understanding how historical diseases contributed to disease susceptibility today.”

The Black Death killed up to 50% of Europeans. Y. Pestis‘ continued the author. “The high mortality rate suggests that genetic mutations that conferred protection against infection Y. Pestis The infection may have been under strong selection during this time. ”

For their study, Barreiro and colleagues aimed to identify the genetic features of natural selection imposed by the plague. It explores and focuses on the period of 100 years before, during and after the Black Death, which reached London in the mid-1300s. “This was a very direct way to assess the impact of a single pathogen on human evolution,” he said. “People have long speculated that the Black Death could be a powerful cause of choice, but between then and now humans have had to face many other selective pressures. It’s hard to prove that when looking at modern populations because there weren’t. The only way to address this issue is to narrow the time frame we’re looking at.

For their study, scientists extracted and screened more than 500 DNA samples from the remains of individuals who died before the plague, died from the plague, or survived the Black Death in London. . 1348-9. Additional samples were taken from bodies buried at her five other locations across Denmark. “206 ancient DNA extracts from two different European populations before, during and after the Black Death to identify loci that may have been selected during the Black Death. We have characterized genetic variation around immune-related genes from .

Using targeted sequencing of a set of 300 immune-related genes, researchers identified four genes that either protect or sensitize, depending on the variant. Y. Pestis. They belonged to one gene in particular, ERAP2, which showed a particularly strong association with susceptibility. Individuals who have two copies of one particular gene variant, called rs2549794, are able to produce full-length copies of the ERAP2 transcript and are able to produce more of the functional protein. I made it. transcript.

A functional ERAP2 plays a role in helping the immune system recognize the presence of infection. Individuals with her two copies of the beneficial ERAP2 variant survived the pandemic at a much higher rate than those with the opposite set of copies. Y. Pestis by immune cells.

The team further tested how the rs2549794 variant affects the ability of living human cells to help fight the plague and found that macrophages expressing two copies of the variant were more efficient in neutralizing. confirmed. Y. Pestis compared to those who don’t. “This protein increases the presentation of Yersinia-derived antigens to her CD8+ T cells, suggesting that it stimulates a protective immune response against Yersinia pestis,” they wrote in their paper. “Furthermore, macrophages from individuals with selected ERAP2 alleles Y. Pestis can be infected and better restricted Y. Pestis In vitro replication”

“When macrophages encounter a bacterium, they mince it so that it can be presented to other immune cells signaling that there is an infection,” Barreiro said. “Having a functional version of the gene likely creates an advantage by enhancing our immune system’s ability to sense invading pathogens. Those who have one are about 40% more likely to survive the Black Death than those who have two copies of the non-functioning variant.” Europeans who lived during the Black Death , which had not been recently exposed to the Black Death, was initially very vulnerable. Yersinia pestisMortality declined as waves of pandemics broke out over the centuries.

“Examining the effects of ERAP2 variants in vitro allows us to functionally test how different variants affect immune cell behavior in modern humans. Yersinia pestis,said Dr. Javier Pizarro Cerda. Yersinia Research Unit and Director of the World Health Organization Plague Collaborative Center at the Pasteur Institute. “The results support ancient DNA evidence that rs2549794 protects against the plague…” Yersinia pestis And immune cells, said Pizarro-Cerda.

Barreiro continued, “The selective advantage associated with a selected locus is one of the strongest ever reported in humans, suggesting that a single pathogen could have contributed to the evolution of the immune system.” It shows how you can make a strong impact.”

The team further suggested that the selection of rs2549794 represents part of the balancing act that evolution imposes on our genome. This identified ERAP2 variant protects against the Black Death, but in modern populations, the same variant is associated with increased susceptibility to autoimmune diseases, including acting as a known risk factor for Crohn’s disease.

“More broadly, our results highlight the contribution of natural selection to current susceptibility to chronic inflammatory and autoimmune diseases,” they wrote. Variants are also known risk factors for Crohn’s disease, and ERAP2 variants are also associated with other infections…Similarly, another prime candidate locus (rs11571319 near CTLA4) is associated with increased risk of rheumatoid arthritis Carrying alleles putatively favorable during the Black Death, such as arthritis and systemic lupus erythematosus, increases the risk of autoimmune diseases in current populations.”

Understanding the dynamics that shaped the human immune system is key to understanding how past pandemics like epidemics contribute to susceptibility to modern disease, says McMaster University. Hendrik Poiner, Ph.D., professor of anthropology and co-senior author of the study, said. “Disease and epidemics like the Black Death affect our genomes, as archaeological projects detect. “It’s the first time we’ve seen one, but it’s not detected in modern populations. …A tiny advantage can mean the difference between surviving or overtaking. Survivors in the breeding season, of course, will inherit the gene.”

Such genes have therefore been under balanced selection, and those that provided tremendous protection during hundreds of years of epidemics are now found to be associated with autoimmunity. said Michael G. DeGroote Institute for Infectious Disease Research and McMaster’s Global Nexus for Pandemics & Biological Threats. , which may not be very useful in today’s environment.”

The authors further conclude that: Analysis of our ancient genome and function Y. Pestis It is one such pathogen that represents empirical evidence linking the selectivity of past pandemics and current susceptibility to disease. ”

Future studies will expand the project to interrogate the entire genome, not just a selected set of immune-related genes. The team hopes to investigate the genetic variations that affect modern humans’ susceptibility to bacteria and compare them to these ancient DNA samples to determine whether those variations are also the result of natural selection. I’m here.

Comments on newly published research news & views, said Dr. David Enard of the University of Arizona. No other trait set is under such intense evolutionary pressure…In the future, further study of ancient DNA may lead to a better understanding of the evolutionary origins of autoimmune diseases. . ”