Nature: The diseases that killed the most humans that year drove the selection of human immunity-related genes

The Black Death was the deadliest single event on record, killing as much as 50% of Europe's population
in less than five years.
New research from the University of Chicago, McMaster University and the Pasteur Institute has found evidence that one of the darkest periods on record in human history put significant selective pressure on the human population, altering the frequency of certain immune-related genetic variants that affect our susceptibility to disease today
.
The findings were published Oct.
19 in Nature
.

The global Black Death, which claimed 30 to 60 percent of lives in cities in North Africa, Europe and Asia, had a huge impact on humanity – and apparently, on our genome as well
.

"This is a very straightforward way to assess the evolutionary impact of a single pathogen on humans," said Luis Barreiro, Ph.
D.
, professor of genetic medicine at the University of Chicago and co-senior author of the study, "It has long been speculated that the Black Death may have been a significant reason for selection, but it's hard to prove it when looking at modern populations, because humans have had to face many other selection pressures
between then and now.
" The only solution to this problem is to narrow the window
of time we are considering.
”

In the study, thanks to recent advances in sequencing technology, scientists examined ancient DNA samples from the bones of more than 200 people from London and Denmark who died
before, during, and after the Black Death swept through the region in the late 1340s.
Through targeted sequencing of a group of 300 immune-related genes, they identified 4 genes that, depending on the variant, could protect or increase susceptibility to the disease.

"As far as I know, this is the first time that the Black Death has indeed been shown to be an important selective pressure
in the evolution of the human immune system," Barreiro said.

The team focused on a gene that is particularly closely associated with susceptibility: ERAP2.
Individuals with two copies of a specific gene variant called rs2549794 are able to produce a complete copy of the gene ERAP2 and therefore produce more functional proteins
than another transcript that results in truncated and non-functional versions.
Functional ERAP2 plays a role
in helping the immune system recognize the presence of an infection.

"When a macrophage encounters a bacterium, it cuts the bacterium into pieces and submits it to other immune cells, indicating an
infection," Barreiro said.
Having a functional version of this gene seems to create an advantage, possibly by boosting our immune system's ability to
sense invading pathogens.
We estimate that people with two copies of the RS2549794 variant are 40%
more likely to survive the Black Death than those with two non-functional variants.
”

The team even tested how the RS2549794 variant affects the ability of living human cells to fight plague, determining that macrophages expressing copies of the two variants were more effective at neutralizing than those without it
.

"Studying the effects of the ERAP2 variant in vitro allows us to functionally test how different variants affect the behavior of modern human immune cells, and the findings support ancient DNA evidence that rs2549794 has a protective effect
against plague.
"

The team further concluded that the selection of rs2549794 is part of evolution's role in the balance of our genomes; While ERAP2 has a protective effect against the Black Death, the same variant has been associated with increased susceptibility to autoimmune diseases in modern populations, including as a known risk factor
for Crohn's disease.

"Diseases and epidemics like the Black Death can have an impact on our genomes, just as
archaeology projects need to probe.
This is the first study of how epidemics are altering our genome that has gone undetected
in modern populations.
These genes are in a balanced state of selection – genes that provided great protection during centuries of plague epidemics are now being shown to be linked to
autoimmunity.
An overactive immune system may have been fine in the past, but may not be as helpful
in today's environment.
”

Future research will expand the scale of the project to examine the entire genome, not just a selected set of immune-related genes; The team hopes to explore genetic variants that influence modern people's susceptibility to bacteria and compare them to these ancient DNA samples to determine whether these variants are also the result of
natural selection.

"There's been a lot of discussion about how pathogens have influenced human evolution, so being able to formally show which pathways and genes are locked really helps us understand what has allowed humans to adapt and survive to this day
," Barreiro said.
This tells us what mechanisms have kept us alive in history and why we are still here
today.
”