Summary: People with selected variants of the ERAP2 and TICAM2 genes were 40% more likely to survive the Black Death, the researchers found. However, in modern humans, those with the ERAP2 gene are more likely to suffer from autoimmune diseases such as Crohn’s disease.
Source: University of Illinois
Infectious diseases are among the strongest selective pressures in human evolution, selecting genetic variants that increase resistance to infection. In the face of a pandemic, disease resistance undergoes strong positive selection which probably affects the genetic make-up of the population thereafter.
The Black Death, also known as the bubonic plague, remains the most devastating pandemic in recorded history, reducing Europe’s population by 30-50% in 4 years (1346-1350) and affecting nearly all of Europe. ‘Afro-Eurasia. The Black Death was caused by Yersinia pestis, a highly contagious and deadly bacterium that quickly spread across the eastern continents.
How did this plague alter the genetic makeup of the population, and did certain alleles confer protection on those who survived?
These questions are explored in a new article published in Nature, featuring a collaboration between the labs of Luis Barreiro, professor of medicine at the University of Chicago; Hendrik Poinar, professor of anthropology at McMaster University; and Javier Pizarro-Cerda, director of the World Health Organization Collaborating Research and Reference Center for Yersinia at the Institut Pasteur.
Poinar, an expert on ancient genomes and Y. pestis, and Barreiro, who pioneered approaches to study how genetic variation affects response to infection, are co-corresponding authors on the paper.
The work was led by co-first authors Jennifer Klunk, a graduate student in Poinar’s lab during the study and now a senior scientist at Daicel Arbor Biosciences, and Tauras Vilgalys, a postdoctoral fellow in Barreiro’s lab.
“It was a huge interdisciplinary team that brought their experiences, knowledge and questions to the project,” Klunk described. “The group was made up of historians, anthropologists, geneticists, etc., offering a wide range of perspectives and tools to work with.”
Researchers collected ancient DNA in London and Denmark from individuals who died shortly before, during or after the Black Death. The DNA was then sequenced and the targeted immune genes were examined at all three time points to look for significant changes in variant frequency over time.
Variants that provide protection against Y. pestis should be more common in post-Black Death samples compared to those that died during the plague, and variants that confer susceptibility should show the opposite pattern. The researchers found that four gene loci, including close variants of ERAP2 and TICAM2, fit this pattern.
ERAP2 is active in antigen-presenting cells, like macrophages, which eat and break down pathogens and present a piece of the pathogen (called an antigen) to other immune cells to help the body learn to fight it off . TICAM2 encodes an adapter protein for a macrophage surface protein called TLR4, which detects foreign gram-negative bacteria in the body, such as Y. pestis.
The selected variants were associated with differences in the expression of these two genes. Using genotype data, the researchers estimated that people with selected variants of these genes were 40% more likely to survive the plague.
To test how these variants promoted Y. pestis infection, monocytes were taken from the blood of live individuals with the different variants for ERAP2 and TICAM2, expanded into macrophages, and exposed in vitro to Y. pestis. Macrophages with variants that caused higher expression of ERAP2 were more effective at eliminating Y. pestis than macrophages without the protective allele.
Jessica Brinkworth (IGOH, GNDP), assistant professor of anthropology at the University of Illinois at Urbana-Champaign who provided functional data to the study, described how macrophages were essential for the infection of Y. pestis: “Y. pestis is really sneaky,” she explained.
“Once at 37 degrees Celsius, it breaks down the lipopolysaccharide on its cell surface so that TLR4 can no longer see it, essentially making itself invisible. This means that there is a real clock to detect it – it may take a few minutes before these massive changes occur. Then it preferentially infects macrophages and turns them into little zombies, forcing them into the lymph nodes so that Y. pestis can multiply.
Immune cells have a small window to detect Y. pestis and destroy it, and macrophages that come into contact with the bacteria must be able to resist hijacking to limit spread.
The researchers’ results show that genetic variation near ERAP2 and TICAM2 can improve detection and resistance to Y. pestis. This likely protected people with these variants during the Black Death, increasing their chances of survival.
“I was surprised that we could actually understand that ERAP2 has an effect on bacterial clearance in vitro,” Vilgalys said.
“And that’s quite surprising given its canonical role is antigen presentation, which involves interactions of multiple cell types, not just macrophages. So what we’re seeing suggests that ERAP2 is doing something non-canonical for affecting the immune response in isolated macrophages.
Nearby variants of ERAP2 and TICAM2 also help against an array of other pathogens, but not without trade-offs. In particular, higher expression of ERAP2 is associated with autoimmune disorders in modern humans, including Crohn’s disease. This balanced selection probably explains why different variants of these genes are still present in the population today.
“It was exciting once we got down to the variants, to see that our variants of interest are showing this selection balancing signal,” Klunk said.
“We were able to say that one of the variants we are looking at clearly shows a selective pressure signal during the Black Death, and we have shown that it is definitely involved in the immune response to Y. pestis, as well as to other pathogens. .
“But today, this variant is also associated with a higher risk of autoimmune and inflammatory diseases. So being able to make that connection was like, wow, that’s something special.
“I think studies like this help us understand why we are at risk for certain diseases and how past pandemics have shaped current disease risks,” Vilgalys said.
“Why does 50% of the population have these ERAP2 variants that put you at increased risk for chronic disease? Part of the reason is that our genomes were shaped by past infectious diseases, like the Black Death. Overall, if we were to look at many risk alleles for modern disorders, you would probably see that they protect against some diseases that we have had in the past.
The team’s next steps are to look at the whole genome, rather than just immune genes, to see if other areas have been affected by the Black Death or may have conferred resistance. Vilgalys described his enthusiasm for examining other aspects of ancient genomes during the Black Death, such as the effects of demography and migration. The team also plans to examine ERAP2 variants to better understand how they convey protection against Y. pestis.
About this genetic research news
Original research: Access closed.
“Evolution of immune genes are associated with the Black Death” by Jennifer Klunk et al. Nature
Evolution of immune genes are associated with the Black Death
Infectious diseases are among the strongest selective pressures driving human evolution.
This includes the largest mortality event in recorded history, the first outbreak of the second plague pandemic, commonly known as the Black Death, which was caused by the bacterium Yersinia pestis. This pandemic devastated Afro-Eurasia, killing up to 30-50% of the population.
To identify loci likely to have been selected during the Black Death, we characterized genetic variation around genes related to the immune system from 206 ancient DNA extracts, from two different European populations before, during and after the plague. Black Plague.
Immune loci are highly enriched for highly differentiated sites compared to a set of non-immune loci, suggesting positive selection. We identify 245 highly differentiated variants in the London dataset, four of which were replicated in an independent cohort from Denmark, and represent the strongest candidates for positive selection.
The selected allele for one of these variants, rs2549794, is associated with the production of a full (versus truncated) allele ERP2 transcript, variation in cytokine response to Y. pestis and an increased ability to control intracellular Y. pestis in macrophages.
Finally, we show that protective variants overlap with alleles that are today associated with increased susceptibility to autoimmune diseases, providing empirical evidence for the role played by past pandemics in shaping current disease susceptibility.