Episode Transcript
[00:00:14] Speaker A: Two letters in a single gene.
[00:00:20] Speaker B: Welcome to Base by Bass, the papercast that brings genomics to you wherever you are. Thanks for listening and don't forget to follow and rate us in your podcast app. Base by Bass is now on YouTube too, at. Base by Base, where every episode gets a video with chapters in the full description. Come subscribe. So, you know, usually when we think
[00:00:39] Speaker C: about evolution, right, the whole survival of the fittest thing.
[00:00:41] Speaker B: Yeah, exactly. We picture natural selection acting like this, like, ruthless bouncer at a club. Like it stands at the door of our genetic code checking IDs, and it just immediately kicks out any genetic mutations that cause, you know, severe or debilitating diseases.
[00:00:57] Speaker C: It's supposed to protect the population, right?
[00:00:59] Speaker B: It's supposed to protect us. But today we're looking at this massive evolutionary paradox.
[00:01:05] Speaker C: Oh, it really is. It doesn't make intuitive sense at all.
[00:01:07] Speaker B: No, it doesn't. Because how is it mathematically possible that a genetic variant, one that actually puts you at a significantly higher risk for a severe life altering autoimmune disease, how is that not just sneaking past the bouncer, but is actually found in like up to 98% of some human populations?
[00:01:25] Speaker C: Yeah, a supposedly bad gene being incredibly successful.
[00:01:29] Speaker B: Exactly. How could it be so successful? Well, here's where it gets really interesting.
Today's Deep Dive explores our own DNA to unpack an ancient biological trade off. We are looking at a hyperactive immune system that attacks the human body, but which might just be the exact reason our ancestors survived some of the deadliest viral plagues in history.
[00:01:50] Speaker C: It's a fascinating trade off. But before we dive into the microscopic battlegrounds of the human immune system, today we celebrate the work of Samuel J. Virilenan, Matthew T. Werock, Leah C. Katyan, and a massive collaborative research team spanning institutions like Cincinnati Children's Hospital Medical center and the University of Cincinnati, who have advanced our understanding of the genetic trade offs between antiviral defense and autoimmunity.
[00:02:15] Speaker B: Yeah, and this team, I mean, they really cracked open a mystery surrounding sustainability. Systemic lupus erythematosus, which, you know, most of us just know as lupus.
And for anyone who has, like, only heard it used as a medical buzzword, we should probably ground this in what the disease actually looks like for a patient, right?
[00:02:30] Speaker C: Definitely. It's a really severe condition.
[00:02:31] Speaker B: Yeah, it's a debilitating autoimmune condition. It's driven by this widespread chronic inflammation. The body forms these immune complexes and it produces what are called autoantibodies, which
[00:02:44] Speaker C: basically means the body is Turning on itself.
[00:02:46] Speaker B: Exactly. The immune system is literally manufacturing customized WEAP to attack its own healthy tissue, whether that's, you know, the kidneys, the skin, the joints, or even the brain.
[00:02:57] Speaker C: And it has a shockingly high heritability rate, too.
[00:03:00] Speaker B: Oh, yeah. Somewhere between 43% and 66% across different populations. Which is huge.
[00:03:06] Speaker C: It is. And genetics play a foundational role here. I mean, the medical community has spent years running these massive genome wide association studies. Right. Basically just scanning the DNA of thousands of patients patient. To hunt down the specific genetic risk areas for lupus.
[00:03:20] Speaker B: Hunting for the culprit.
[00:03:21] Speaker C: Exactly. And what keeps popping up in these scans is that lupus risk is heavily concentrated in the pathways that control type I interferons.
So to understand this, we need to look at the absolute star of the show today, which is a protein called IRF7.
[00:03:35] Speaker B: Okay. IRF7.
[00:03:36] Speaker C: Yeah, IRF7. It basically operates as the master regulator of this interferon response. So in a healthy scenario, IRF 7 acts as a molecular trip wire.
[00:03:46] Speaker B: A tripwire.
[00:03:47] Speaker C: Right. When receptors inside a cell detect the presence of a virus. Yeah. Maybe they sense like viral RNA floating around where it shouldn't be. They activate IRF7. This protein then travels straight into the command center of the cell, the nucleus, and it binds directly to the DNA.
[00:04:03] Speaker B: Wow. Okay.
[00:04:04] Speaker C: Yeah. And that triggers a massive inflammatory cascade. It forces the cell to secrete interferons, which are basically chemical warning signals that tell neighboring cells to shut down and stop the virus from replicating.
[00:04:15] Speaker A: I always.
[00:04:15] Speaker B: I always picture IRF 7 as a home security system.
[00:04:18] Speaker C: Oh, that's a good way to look at it.
[00:04:20] Speaker B: Yeah. Like, under normal circumstances, it's doing exactly what you want it to do. Right. It senses a burglar breaking a window, the virus. And it immediately triggers the alarm, locks all the doors and calls the police.
[00:04:30] Speaker C: Exactly. It protects the house.
[00:04:32] Speaker B: But in someone with lupus, this alarm system seems to be calibrated so incredibly high and it's so hypersensitive that it goes off when, like a leaf just blows across the lawn.
[00:04:43] Speaker C: Right. A total overreaction.
[00:04:44] Speaker B: Yeah. The body's own natural debris, like the dead cells we naturally shed every day bump into the sensor and the system panics. And suddenly you have a massive SWAT team tearing up the house for no reason, causing immense collateral damage.
[00:04:58] Speaker C: And the problem with an alarm calibrated that high is exactly what the research team wanted to investigate.
They zeroed in on a specific genetic variant on chromosome 11.
[00:05:09] Speaker B: Okay.
[00:05:10] Speaker C: Identified what called a coding haplotype, which is essentially a cluster of DNA Variations that tend to be inherited together. And these specific variations actually change the physical amino acid building blocks of the IRF7 protein.
[00:05:23] Speaker B: They literally change the structure.
[00:05:25] Speaker C: They do. But honestly, the most staggering part of their discovery isn't just the mutation itself. It's the global prevalence. I mean, most autoimmune risk variants are extremely rare. Right. Natural selection usually weeds them out because they harm the host.
[00:05:38] Speaker B: Right, the bouncer kicks them out.
[00:05:39] Speaker C: Exactly. But this lupus risk variant is globally dominant. The data shows it is found in about 42% of people with African ancestry.
[00:05:48] Speaker A: Wow.
[00:05:48] Speaker C: Around 73% in those of European ancestry. And an astonishing 98% in people of East Asian ancestry.
[00:05:55] Speaker B: Wait, 98%?
[00:05:57] Speaker C: Yep. Almost everyone in that group.
[00:05:59] Speaker B: I mean, if nearly everyone in a specific population has it, we can't even call it a rare disease mutation anymore. It is practically standard human operating equipment. In that demographic, it really is.
[00:06:12] Speaker C: It's the norm.
[00:06:12] Speaker B: But if this mutation is so widespread and supposedly ancient, how on earth do researchers today prove what it was doing in our ancestor cells, like tens of thousands of years ago, versus what it's doing in a modern lupus patient? You can't exactly draw blood from a Neanderthal.
[00:06:29] Speaker C: No, you definitely can't. It requires blending ancient archaeology with modern molecular biology. So, to look back in time, the team turned to the ancient genome diversity project.
[00:06:39] Speaker B: Okay, what is that?
[00:06:41] Speaker C: It's this massive database containing genomes sequenced from human remains dating back up to 43,000 years.
[00:06:48] Speaker B: 43,000. That's incredible.
[00:06:50] Speaker C: It is. But ancient DNA is highly degraded. It's fragmented. Meaning the researchers couldn't always find the exact genetic letters of this specific IRF 7 variant in the fossil record.
[00:07:02] Speaker B: Oh, because the DNA literally fell apart over time.
[00:07:05] Speaker C: Right. So to get around this, they used a proxy marker. They found a different nearby genetic variation, specifically Rs112 46213, that is perfectly linked to our lupus risk variant in modern humans.
[00:07:18] Speaker B: Ah, so they always travel together.
[00:07:20] Speaker C: Exactly. By tracking this durable proxy marker through the agent DNA database, they could essentially trace the evolutionary footprint of this hyperactive immune variant across millen.
[00:07:30] Speaker B: So they track its footprint through history to prove it was there. But to figure out the actual mechanics, like how it physically behaves inside a cell, they had to bring it into the modern lab.
[00:07:38] Speaker C: Right, they did.
[00:07:39] Speaker B: The paper mentions they used CRISPR technology to engineer specific human cell lines. They took common laboratory lines of human lung tissue and white blood cells like AG cells, THP1 monocytes, and A549 lung epithelial cells, which are Obviously critical for immunity.
[00:07:58] Speaker A: Right.
[00:07:58] Speaker C: Very standard, reliable models.
[00:08:00] Speaker B: And they essentially went in with molecular scissors, stripped out the natural IRF7 gene, and dropped in either the lupus risk version or the lupus protective version.
[00:08:09] Speaker C: And by creating these custom cell lines, they isolated the variable. They can watch exactly how the two different versions of the protein interact with human DNA.
[00:08:17] Speaker B: How do you even measure that, though?
[00:08:19] Speaker C: Well, they utilize a technology called protein binding microarrays, or PBMs. You can think of it as a massive microscopic testing grid containing over 10,000 different synthetic DNA sequen.
[00:08:30] Speaker B: Wow.
[00:08:31] Speaker C: Yeah. They exposed these arrays to the engineered IRF7 proteins.
This allowed them to measure with incredible precision not just where the proteins bind, but how tightly the risk variant grips the DNA compared to the protective variant and whether the mutation changes its preference for specific genetic codes.
[00:08:50] Speaker B: Okay, I can visualize that. It's like testing different types of Velcro to see which one holds on the tightest.
[00:08:55] Speaker C: That's a great analogy.
[00:08:56] Speaker B: But the methodology didn't stop at petri dishes. They also brought this into mouse models. They used CRISPR to edit the mouse version of this gene, swapping out just one single amino acid to mimic the human lupus risk variant.
[00:09:09] Speaker C: The ARG334GL. Edit. Yeah.
[00:09:12] Speaker B: Okay, let's unpack this for a second. I always push back a little when I see mouse models used for complex human immune diseases. Like, a mouse is not just a tiny human. Right. Their immune systems evolved in completely different environments.
[00:09:23] Speaker C: That is a very valid point.
[00:09:25] Speaker B: So can we really equate a mouse's biological alarm system to ours?
[00:09:29] Speaker C: It is a fundamental question in immunology, and honestly, the researchers address it head on. If you look at the entirety of the human IRF7 protein and the mouse equivalent, they only share about a 69% overall identity.
[00:09:44] Speaker B: See, that doesn't sound very high.
[00:09:46] Speaker C: It doesn't. However, the researchers specifically focused on the domains that matter for this experiment.
The DNA binding domain, which grabs the genetic code, and the inhibitory domain, which acts as the brakes.
[00:09:58] Speaker A: Ah.
[00:09:59] Speaker B: Okay.
[00:10:00] Speaker C: In those specific, highly specialized regions, humans and mice share greater than 95% amino acid identity.
[00:10:07] Speaker B: Oh, wow. Okay. That's huge, right?
[00:10:09] Speaker C: Furthermore, all standard laboratory mouse strains naturally carry the protective non lupus version of this gene.
By using CRISPR to swap just that one targeted amino acid to match the human risk variant. And they created an incredibly precise, highly relevant model.
[00:10:25] Speaker B: So they could observe the systemic effects without other noise.
[00:10:28] Speaker C: Exactly. To observe the full body effects of this specific genetic change without the noise of other human genetic variables.
[00:10:34] Speaker B: Okay.
[00:10:34] Speaker A: Yeah.
[00:10:35] Speaker B: When you frame it around the 95% similarity in the specific braking mechanism of the protein, the mouse model makes a lot of sense. So we have this massive multi tiered investigation.
[00:10:45] Speaker C: We do.
[00:10:46] Speaker B: We have ancient DNA tracing the evolutionary history. We have engineered human lung and immune cells testing the grip struct strength on the DNA. And we have CRISPR edited mice to observe the whole body effects. When they put all this data together, what did they actually find?
[00:11:01] Speaker C: Well, the ancient DNA analysis painted a fascinating picture of human survival. This lupus risk variant was not a recent genetic fluke or some isolated mutation.
[00:11:11] Speaker B: It had been around a while.
[00:11:12] Speaker C: A long while. The proxy markers showed it was already highly prevalent in global populations by 10,000 BCE.
[00:11:18] Speaker B: 10,000 BCE?
[00:11:20] Speaker C: Yep. And more importantly, it persisted steadily through history right up to the modern era. When a gene that causes a severe disease maintains that kind of high frequency across multiple ancestries for tens of thousands of years. I mean, it violates the normal rules of natural selection.
[00:11:36] Speaker B: Right. The bouncer let it stay in the club for millennia.
[00:11:39] Speaker C: Exactly. It strongly suggests that carrying this mutation provided a massive immediate survival benefit. It was being actively selected for by environmental pressures, despite the long term autoimmune risk it carried.
[00:11:52] Speaker B: And the modern cellular work finally revealed the physical mechanics of that survival benefit, right?
[00:11:57] Speaker C: Yes, it did.
[00:11:58] Speaker B: Because when the researchers took those engineered human cells and applied a viral mimic like Polyc or R848, which are basically chemicals that trick the cell into thinking it has just been infected by a dangerous virus, the two different gene variants behaved radically different, completely differently. The lupus risk IRF 7 variant flooded into the cell's nucleus, the command center, significantly faster than the protective variant.
[00:12:23] Speaker C: Because the mutation alters the inhibitory domain of the protein, which effectively removes the biological breaks. And because it rushes into the nucleus so aggressively, the dynamics of how it interacts with our DNA completely change.
[00:12:36] Speaker B: So what did the Velcro test show?
[00:12:38] Speaker C: The protein binding microarray tests showed a dramatic difference in grip strength. The RISC variant binds much more tightly to the DNA. It tends to act as a homodiomer.
[00:12:48] Speaker B: A homodimer. Meaning what Exactly?
[00:12:50] Speaker C: Which means two IRF7 proteins lash together, forming a paired complex that grabs onto the DNA sequence with incredible force. The protective variant, in contrast, exhibited much weaker binding and didn't hold on with the same intensity.
[00:13:05] Speaker B: Okay, so if two proteins are locking together and clamping down on the DNA that tightly, the output of the cell has to change. And. And it does. Because it floods the nucleus and binds like a vice grip, the cells carrying the lupus risk variant pumped out roughly two fold more interferon alpha MRNA and protein compared to the protective variant.
[00:13:23] Speaker C: Double the output.
[00:13:23] Speaker B: Yeah. The biological amplifier is cranked up, it doubling the body's antiviral response. But what does a twofold increase actually mean on the biological battlefield? Like, how does simply doubling the interferon clear a virus or cause a disease?
[00:13:36] Speaker C: Well, to understand the battlefield, we have to look at what interferon actually does.
When a cell secretes interferon, it binds to receptors on the outside of neighboring cells. This triggers a panic response in those neighbors.
[00:13:49] Speaker B: Like sounding the alarm.
[00:13:50] Speaker C: Exactly. It causes them to shut down their internal protein factories and destroy any loose rna. It essentially starves the virus, preventing it from hijacking the cell to make copies of itself.
[00:14:01] Speaker B: That sounds intense.
[00:14:03] Speaker C: It is. A twofold increase means this scorched earth tactic is deployed faster, wider, and with far more intensity. The infection is walled off and eradicated rapidly. But the cost of this intense shutdown is severe cellular stress and tissue damage.
[00:14:17] Speaker B: Ah, I see.
[00:14:19] Speaker C: If this happens constantly, the collateral damage accumulates, leading to the inflammation and organ damage characteristic of an autoimmune disease.
[00:14:26] Speaker B: And that perfectly sets up why the mouse models were the ultimate proof of this trade off. They took those CRISPR edited mice with the risk variant and subjected them to an autoimmune trigger over several weeks. And the mice carrying the risk variant developed significantly higher levels of anti DSDNA autoantibodies. They displayed clear exacerbated lupus like autoimmune symptoms compared to the control mice. That the collateral damage you were just talking about, the alarm system, is tearing the house down.
[00:14:55] Speaker C: It really is.
[00:14:55] Speaker B: But then, to prove the other half of the paradox, they ran a survival test.
[00:15:00] Speaker C: Yes, they infected both groups of mice with a live dangerous pathogen, the vesicular stomatitis virus, or vsv.
And the results were striking. The exact same mice with the risk variant, the ones that had just developed severe autoimmune symptoms, had significantly lower viral titers in their lungs.
They fought off the live virus much more effectively than the control mice. Because their immune system was blasting that double dose of interferon. They cleared the infection faster. What's fascinating here is that this is explicit proof of an evolutionary tradeoff.
[00:15:31] Speaker B: It really is the ultimate evolutionary bargain. The gene dial is turned all the way up to 11 to clear deadly respiratory infections, quickly ensuring that the human host survives the immediate existential threat of a plague.
[00:15:43] Speaker C: Survive today, pay for it tomorrow.
[00:15:45] Speaker B: Exactly. But that same high volume response damages the host's own tissue over time, Driving a chronic autoimmune disease once the acute viral threat is gone.
Surviving a pandemic at age 20 means you might develop lupus at age 40.
[00:16:00] Speaker C: And this trade off mechanism directly addresses the clinical reality we see in modern medicine. This double output amplifier explains the Ifni signature that is clinically observed in over 50% of human lupus patients today.
[00:16:13] Speaker B: Okay, so tying it back to the patients.
[00:16:14] Speaker C: Right. In a healthy scenario, the pathway is triggered by a real virus, does its aggressive job, and then gracefully shuts down.
But in a lupus patient, the endogenous material we mentioned earlier, the body's own dead cells or misplaced DNA, constantly bumps into the sensors.
[00:16:30] Speaker B: Just normal bodily debris.
[00:16:31] Speaker C: Yeah, and because these patients carry this highly prevalent risk variant, Every single time the pathway is accidentally triggered, it produces double the inflammatory interferon over months and years. This recurrent higher amplitude response cumulatively sustains chronic tissue damaging disease.
The researchers have basically pinpointed IRF 7 as the vital nodal point, the exact intersection where host defense and autoimmunity collide.
[00:16:58] Speaker B: Which naturally leads to the big question for anyone suffering from this disease today. I mean, we aren't actively fighting off the historical bubonic or antonine plagues that's selected for this gene.
So what does this all mean for treatments? Could we theoretically just dial down IRF7 in lupus patients to stop the autoantibodies without destroying their ability to fight off a winter fluid?
[00:17:19] Speaker C: I mean, it is the logical next step for drug design, but it highlights a massive clinical limitation discussed in the study. Modulating IRF 7 therapeutically requires extreme precision because you are tinkering with the master switch of antiviral defense.
[00:17:32] Speaker B: It's a delicate balance.
[00:17:33] Speaker C: Very delicate. The paper specifically notes that humans who are born completely deficient in IRF7, where the gene doesn't work at all, are incredibly susceptible to severe life threatening respiratory viruses, including influenza and SARS. COV2.
[00:17:48] Speaker A: Oh, wow.
[00:17:48] Speaker C: Yeah. You cannot just turn the system off to cure the lupus. Doing so would leave the patient dangerously vulnerable to everyday pathogens.
[00:17:55] Speaker B: Right. You can't just unplug the security system entirely because you're annoyed at the false alarms. You need to find a way to recalibrate the sensor so it stops freaking out over blowing leaves, but, you know, still catches the actual burglars.
[00:18:07] Speaker C: Precisely. And looking forward, the researchers suggest that the path to that recalibration lies in specific immune cells.
Future studies need to focus on plasmacytoid dendritic cells, or PDCs.
[00:18:20] Speaker B: PDCs. Okay.
[00:18:21] Speaker C: Yeah. These are rare, specialized immune cells that act as the body's major professional interferon factories, and their function is heavily dependent on IRF 7. Mapping out exactly how this specific risk haplotype behaves inside pdcs is the next logical step to fully unraveling the pathway for targeted therapies.
[00:18:38] Speaker B: That makes sense.
[00:18:38] Speaker C: It is also worth noting that while the ancient DNA data is robust rather regarding the age of the variant, a mystery remains.
The exact historical plagues or evolutionary bottlenecks that drove the dramatic ancestry specific frequency differences like why it reached 98% in East Asian ancestry but remained at 42% in African ancestry, remain unconfirmed.
The sampling of ancient DNA is still geographically uneven, so we cannot yet point to one specific historical viral event that enforce this genetic adaptation.
[00:19:11] Speaker B: Man, it's incredible to think that the unseen viral wars fought by our ancestors thousands of years ago are still actively dictating how our immune systems behave right now. Like we are literally carrying the genetic scars of ancient pandemics.
[00:19:23] Speaker C: We really are. To summarize the core findings of this investigation, the highly prevalent lupus risk IRF7 haplotype acts as a biological amplifier, doubling the production of type I interferons.
While this hyperactive immune response gave our ancestors a critical evolutionary advantage against deadly viruses, it persists today as a potent driver of autoimmune diseases like systemic lupus erythematosis.
[00:19:46] Speaker B: What does this mean for the future of personalized medicine when our own genes represent an ancient compromise between surviving the plague and living with chronic disease? This episode was based on an Open Access article under the CCBY 4.0 license.
You can find a direct link to the paper and the license in our episode Description. If you enjoyed this, follow or subscribe in your podcast app and leave a five star rating. If you'd like to support our work, use the donation link in the Description now. Stay with us for an original track created especially for this episode and inspired by the article you just heard about. Thanks for listening and join us next time as we explore more science. Base by base.
[00:20:38] Speaker A: Two letters in a single gene.
Most of the world is carrying them.
Not the rare thing, the common thing.
Mandra turn it up the virus falls turn it up.
The body turns.
Into the nucleus faster onto the DNA tide more interferon out the other side mantra same die both ways.
Same dial.
Both ways.
In the mouse slow this virus by morning in the same mouse antibodies against its own DNA.
Nobody got to choose one without the other.
Older than the plagues we wrote down already common before the counting started.
It was never waited to become useful.
It already was.
Turn it up, the body turns.
1.18.
Small risk. Carried by almost everyone.
Same da both ways, Same time.
