So, the Black Death.
Pretty exclusively a “back then” thing, right?
But if you’re descended from the European, Middle Eastern,
and North African populations that experienced the plague, and you’re dealing with
an autoimmune disease, for you it could be a “right now” kind of thing.
That’s because evidence is emerging that gene variants that were beneficial
as one of history’s worst plagues was killing off millions…
well, those variants aren’t so hot now.
So here’s how the Black Death and other plagues wrote themselves
into our genes and why that turned out to be such a double-edged sword.
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So let’s start with a brief history lesson.
History’s most notable outbreak of bubonic plague, aka the Black Death,
happened in Europe in the fourteenth century.
It’s thought that a ship arrived in Sicily with rats already infected
with the causative agent of the plague, Yersinia pestis,
and the rats quickly spread the disease all across Europe.
Victims often died within a week, and the death toll
quickly rose to over 25 million people.
In a 2022 article from the journal Nature, an international team of researchers
hypothesized that, with a death toll that high, this likely acted as a gigantic
natural selection event, where the survivors likely had some
genetic advantage over those who died.
And to investigate this they did what
any good research team would: they went grave robbing.
Or more appropriately, grave sampling.
Working with museums who had access to a handful of cemeteries,
the researchers were able to get DNA samples from
several hundred people who died before, during, or after the plague.
Notably, however, these gravesites were from London and Denmark,
so even though the Black Death ravaged the Middle East and North Africa as well,
this study focused only on Europeans.
Their goal was to see if there were specific gene variants
that were more common in the surviving population
than in the pre-plague population.
To find those “plague please spare me” varieties.
As a quick refresher, many genes come in multiple flavors
that can have slightly different effects.
The same gene might come in regular, diet, or cherry vanilla.
And we call those variants or alleles of that gene.
Of all 20,000-ish genes in the human genome,
the researchers focused on a pool of about four hundred immune-related genes.
Which, admittedly, is still a lot of genes.
But now they could analyze these few hundred genes to find ones
whose frequency changed significantly pre to post plague,
and specifically ones that became more common,
since that would mean they had some protective effect.
All of this narrowing down left them with four sections of DNA
that likely helped the survivors, well, survive.
And one gene in particular sparked their curiosity.
They identified two versions of a gene called ERAP2,
one that seemed to end up expressing a lot more of that gene’s product
(and so presumably doing more work) than the other.
And when the team dug a little deeper, they did indeed find that
these two flavors of ERAP had a difference in how they functioned.
One variant produced an A type of ERAP2,
which coded for full length, healthy proteins.
The other was associated with a B type of ERAP2,
which produced protein products that cut off too soon,
causing the cell to degrade them.
So rest in pieces, ERAP2 type B proteins.
Research has already shown that ERAP2 is important for helping to train other
immune cells, clearing pathogens, and modulating inflammatory responses.
Knowing that, the researchers hypothesize that the type A variant
leads to more ERAP2 protein, and thus better immune training.
Essentially, the variant would have helped the immune system
more efficiently identify plague bacteria while also limiting inflammation.
The scientists estimate that people who had two copies
of the type A variant were 40% more likely to survive the plague.
That’s a pretty huge advantage considering
how it wiped out nearly half of Europeans.
But while this might sound like a win for all of humanity, that’s not the full story,
because that same protective version of ERAP2
has also been associated with something else: Crohn’s disease.
We don’t know exactly how it’s involved,
but it might be that immune training function going a bit too paranoid.
And when you back up to that bracket of four variants
the researchers had originally identified as protective against the plague,
a different one is associated with autoimmune diseases
like lupus and rheumatoid arthritis.
So our genetic superheroes are suddenly looking more like double agents.
The vigilant immune variants that kept the plague bacterium in check
are a little too trigger-happy and turning on our own bodies.
And this isn’t unique to the genes identified in this study.
It’s a well documented phenomenon known as antagonistic pleiotropy.
Pleiotropy means that a gene has more than a single effect,
and the word “antagonistic” highlights how these effects
may be at odds with each other.
So the ERAP2 type A variant would be an example of antagonistic pleiotropy:
it may spare you from the plague,
only to harm your descendants with an autoimmune disease.
A study done in 2023 sought to discover how much
antagonistic pleiotropy has affected us.
They surmised that this double-edged sword may be more common
than previously thought, creating an evolutionary tradeoff between
infectious disease protection on the one hand, and autoimmunity on the other.
And they did this by looking at 10,000 years of genomic data.
When examining all this data, a trend appeared: the more fit our genes became in
protecting us against infectious diseases,
the more vulnerable we became to autoimmune diseases.
They could even identify specific variants, such as one that increases the risk of
inflammatory bowel disease or IBD while decreasing the risk of infection
with noroviruses, or a separate one that is associated with protection
against COVID-19 instead while also increasing the risk of IBD.
And the researchers don’t think this is a coincidence.
They tried to pinpoint when selective pressures started favoring
these genetic variants, and they found that most of these changes have occurred
since the start of the Bronze Age, around 4500 years ago depending on the region.
This was a time when people were coming together to live in cities,
traveling more, and raising more livestock.
All of this would have exposed people to more pathogens,
which led to selection for these infectious disease-protective traits,
that just so happen to increase vulnerability to chronic diseases.
Plus, this link does make sense.
When faced with infectious diseases, we might want a strong immune response,
something that ERAP2 helps with in various
immune cells when exposed to the Black Death.
But when that immune response gets too strong,
it can end up harming us, like with Crohn’s disease.
Which means a very, very long history of disease
and survival is written into our DNA.
It’s a curious balancing act, and it shows that
the difference between a beneficial and a harmful trait is razor-thin.
But it also shows us that we can keep surviving,
and adapting to whatever comes next.
Now 14th century victims of the plague would definitely have benefited
from knowing more about subjects like bacteria… or basic hygeine.
But at least you can learn more about them thanks to our spinoff podcast,
SciShow Tangents, which has episodes about both of those things.
Tangents is a lighthearted, lightly competitive podcast made by the same minds
as those behind SciShow, and 100% of episodes
are guaranteed to contain at least one fact about butts.
If that sounds good to you, you can check out
Scishow Tangents wherever you get our podcasts.
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