Human-specific ADSL A429V substitution and a common regulatory haplotype reduce ADSL activity and raise purine substrates in the brain, altering mouse behavior.
0:00Welcome to Base by Base, 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. It's great to be back. Ready for another deep dive.
0:10You know, I was thinking about how we usually frame the story of human evolution. It's always this story of upgrades, right? We split from Neanderthals and Dennis Evans, and we just assume we got the better hardware, faster processors, better graphics, you know.
0:25That is the standard narrative, yeah. We see natural selection as this, um, relentless march toward optimization, a better faster, stronger human. Exactly. But the research we're looking at today just flips that script completely upside down.
0:41It really does. We're doing a deep dive into a genetic change that happened, what, about 600,000 years ago, right after we split from our archaic cousins? And it doesn't look like an upgrade at all. It looks like we broke something.
0:53Broke is a provocative way to put it, but chemically speaking, you're not wrong. We're looking at a critical enzyme in the brain that in us, in modern humans, is just significantly less stable. Less stable and less active than the version in Neanderthals.
1:08Yes, exactly. And that's the real hook for me. Evolution didn't just let this broken version slide through. It seems aggressively selected for it. We actively downgraded our own brain chemistry. Which poses this massive riddle.
1:22I mean, why would nature favor a mutation that reduces the activity of a piece of essential infrastructure? And the really strange part, how could this metabolic throttle possibly make us more competitive, especially when it comes to how females acquire resources?
1:36It's a puzzle. And the answers involve um, humanized mice, a high-tech smart house for rodents, and some really uncomfortable questions about the trade-off between survival and, well, intelligence. It really challenges what fitness even means.
1:51It does. So let's get into it. We are analyzing a really fascinating paper, titled, The Activity and Expression of, at a Nilosux Nate Lais were reduced during modern human evolution, affecting brain and behavior.
2:02It's a heavy title, but the science is just thrilling, and we have to give credit words due. This was a huge collaboration. Right, between the Okinawa Institute of Science and Technology, the Karolinsky Institute in Sweden and the Max Planck Institute for Evolutionary Anthropology.
2:17And looking at that author list, you see some absolute heavyweights. Sponte Paybo is in the mix. Nobel laureate himself? Yeah. And lead authors like Shang-Chenju and Hugo Zimberg. I mean, these are basically the Avengers of Neanderthal DNA.
2:32They really are. The people who figured out how to read the instruction manuals of our extinct relatives. They're the leaders in this field. No question. Okay, so let's start with the protagonist of this story.
2:41This enzyme. ADSL. A denial succinate liaise. I'm just going to say ADSL. Good call. What's its day job? ADSL is a factory worker. It sits on the assembly line of something called purine buyersynthesis.
2:55Okay, pure and biosynthesis. That sounds important, but also like something I definitely slept through in high school biology. Break that down for us. You should care a lot. Purans are the absolute foundation of life.
3:07They are the chemical building blocks that make up your DNA and RNA. You literally cannot build a single new cell without them. So fairly critical. If the factory stops, you stop being biology and start being like geology.
3:19Precisely. But there's a 2nd function that's just as vital. Purines are crucial for energy transfer. You've heard of ATP, right? Energy currency of the cell, the stuff that powers my muscles. Exactly. The A, in ATP, stands for adenosine, that's a purin.
3:34So this enzyme, ADSL, it catalyzes 2 specific steps to make these purines. Without it, you lose DNA replication, and you lose the ability to, you know, view yourselves. Okay, so you needed to build a blueprint of life, and you needed to keep the lights on.
3:48Now, tell me about this break that happened 600,000 years ago. Well, if you look at the genetic kinet of a Neanderthal or a Denisivan, or pretty much any other primate, the ADSL enzyme looks a certain way.
4:00It's the standard model, but if you look at us, modern humans, there's a tiny difference. A single amino acid substitution, just one little change, a position 429 in the protein chain, an alanine was replaced by a volline, it's called the A429 v mutation.
4:15And how common is this, this new version today? It's well, it's effectively universal. The researchers checked a database of 160000000 human genomes. Do you want to guess how many people had the old ancestral version?
4:29I'm guessing not many, if we're doing a deep dive on it? One, one single person out of 16 million. That means this mutation is fixed. It's swept through the entire human population and it's here to stay.
4:41Wow. Okay, so we all have it. But earlier you said, this version is worst. How do we know that? Maybe Velene is just cooler than Elene. It's not about coolness. It's about structural integrity. So previous biochemical studies showed that this specific swap makes the enzyme structure less stable.
4:57It's wobbly. It just does its job less efficiently than the Neanderthal version. This is a part I really struggle with. If I went to a mechanic and he replaced my fuel pump with one that was wobbly and less efficient, I'd be upset.
5:09In a medical context, a slow enzyme is a bad thing, isn't it? Oh, usually, yes. And we have clinical data on this. If you have a severe deficiency in ADSL like, if the enzyme barely works at all, it's a rare and devastating genetic disorder.
5:21What does it cause? It leads to intellectual disability, autism, and often very aggressive behavior and patience. Wow. So if you break it completely, it's catastrophic. Correct. But we are talking about a total failure here, we're talking about a moderate reduction, a functional downgrade that every healthy human has.
5:40So the big question for the researchers was, if severe deficiency is so bad, why is this moderate reduction advantageous? What does it actually do to our brains? Exactly. And that's a hard question to answer because you can't exactly clone a Neanderthal to compare.
5:55No, ethics boards tend to frown on that. They do. And you can't really experiment on living humans to see how their brain metabolism affects their forging skills. Also frowned upon. So the researchers turn to the gold standard of genetic modeling.
6:08Mice. But they had to do something very, very specific. They used CRISPR to create humanized mice. Humanized mice. sounds like something out of a sci-fi movie. Do they start paying taxes? Not quite. It means they went into the mouse genome and they edited the mouse's ADSL gene to match the modern human version.
6:26They put in that specific A 429 V mutation. So they gave the mouse the wobbly human enzyme. They did. And to be incredibly rigorous, they also tweaked one other amino acid nearby, just to make sure the rest of the protein matched the general mammalian baseline.
6:42This is perfectly clean comparison. Exactly. You have one group of mice with the modern human enzyme, and they're litter mates with the wild type or ancestral enzyme. Okay, the stage is set. We have the human mice and the ancestor mice.
6:57Step one. Check the engine. What happened to their chemistry? They used mass spectrometry to look at the metabolites in 7 different organs. They were looking for the substrates of the enzyme. Okay, let's go back to your factory analogy.
7:10Yeah. If ADSL is the worker on the line. Right. So if that worker is slow or he takes too many breaks because he's unstable, the parts on the conveyor belt start to pile up behind him. Okay. Those parts are the substrates chemicals called Seikar and S Ado.
7:24So if the human enzyme is slower, we should see a pile up of these chemicals. And that is exactly what they found. But, and this is the really fascinating part. Not everywhere. The traffic jam was massive in the brain and the liver.
7:35And not in other places. But in the muscles, barely noticeable. Where the difference? Because the brain naturally has very few of these workers to begin with. The expression of ADSL in the brain is inherently low.
7:48So if you replace your few workers with slow ones, the backlog gets huge immediately. But the muscles are full of workers. So a slight drop in efficiency doesn't matter as much. You got it. So we have a humanized brain that's just swimming in these backed up chemicals.
8:03Metabolic traffic jam. That sounds kind of stressful for the brain. Does that backup actually change anything? You'd think it might be toxic. So the next logical question was, does this chemical change affect behavior?
8:17To test this, they use something called the Intelicage. I read about this. This is not your average pet store cage, is it? Oh, far from it. The Intella cage is like a smart home for mice. It's a large automated environment where they live in a social group.
8:29No humans grabbing them, poking them, stressing them out. So it's like big brother for rodents. Basically, yeah. To get water. The mice have to learn to poke their noses into specific corners. The system sees their microchip, recognizes the individual mouse, and opens a little door so they can drink.
8:47So they set up a challenge. A water competition. They started restricting when water was available, 1st 12 hours a day easy, then 8 hours, then they cranked it down to just one hour a day. That creates real scarcity.
9:00You have to hustle to get a drink before the day locks. If you miss your window, you're thirsty. Precisely. They wanted to see who would cope better with resource scarcity. The human mice or the ancestral mice?
9:11Who won? Well, here's the twist. They looked at the male mice. And there was 0 difference. Humanized, wild type. They both performed exactly the same. Huh, okay. That's a bit anticlimactic. But then they looked at the females, and the female humanized mice were operating on a different level.
9:28How so? Once the water got restricted, The humanized females visited the water corners one. times more often than the wild types. They were relentless. And when it got really tough, when only one corner had water, they visited nearly 3 times more often.
9:43That is a massive difference in behavior. So having the broken human enzyme made the female mice way more motivated to find water. It appears so. And the researchers were very careful. They thought, okay, maybe these mice are just stronger.
9:58Maybe they're just pushing the others out of the way. Right, are they bully mice? They checked. They did grip strength tests, run tests, no physical difference. They even did a tube test where 2 mice meet in a narrow tube to see who backs down.
10:11The humanized mice were not more dominant socially. So it's not strength. It's not social dominance. It's just pure drive. The leading hypothesis is a change in motivation or efficiency. The human metabolic state in the brain seems to trigger a different response to scarcity, specifically in females.
10:28They just keep trying, kept checking, kept searching. I'm still stuck on the sex specific part, though. Why only the females? That ties back to the chemistry. The study found that female mice naturally have lower levels of the ADSL protein in their muscles compared to males.
10:42Oh, okay. So they're biologically closer to the threshold where a reduction becomes impactful. The mutation just tips the scale for them more drastically. And from an evolutionary perspective, that makes a lot of sense.
10:53If you're a female responsible for gestating or nursing offspring, your ability to secure resources during a famine is everything. Exactly. It's the difference between your lineage, continuing or ending.
11:05A genetic toggle that ramps up motivation in females during scarcity could be an incredibly powerful selection pressure. But wait, there's more to this story. We talked about the mutation, the A429 V. But you mentioned a double hit.
11:18What does that mean? This is the part that convinces me this was no accident. We talked about the amino acid change, A429 V. That changed the shape of the enzyme, but the researchers found a 2nd change.
11:29They found a change in the non-coding region of the DNA, a regulatory element. Think of it like a volume knob. This specific setting, or hapletype, is found in over 97% of humans today. And what is his volume knob to?
11:43It turns the volume down. It reduces the expression of ADSL even further, but specifically in the brain. Hold on. So 1st we got a mutation that makes the enzyme work poorly. And then we got a 2nd mutation that says, and by the way, make even less of this crappy enzyme.
11:58Precisely. It's a puring paradox. You have 2 distinct evolutionary events. One coding, one regulatory, both pushing for the exact same goal. Minimize ADSL activity in the brain. That's not an accident.
12:12That sounds like a strategy. It certainly looks like one. The researchers analyze the genetics using AR Weaver D, which uses these ancestral recombination graphs to trace the family trees of genes back through time.
12:23That's the heavy math part. Yes. And the math found strong signals of positive selection for both changes. Evolution didn't just stumble into this. It aggressively selected for this metabolic throttling.
12:34Which implies that having this traffic jam of chemicals, this buildup of Seikar in SIDO must be doing something important. Or that the reduction in pure and synthesis itself preserves energy, but the buildup of substrates is the most likely driver.
12:47The question is, what does that do to a human? We know what it does to a mouse. It makes them relentless for water, but we are not mice. Right. I don't usually run around checking corners for water bottles.
12:58So did they look at actual humans? They did. They analyzed data from modern human populations. They looked at cerebrospinal fluid samples from over 2,600 people to measure those chemicals, and then they looked for correlations with human traits.
13:12And this is where I feel like the other shoe is about to drop. What did they find? It's complicated shoe. They found a correlation. High levels of Sedo, that chemical that builds up because of our broken enzyme are negatively correlated with intelligence scores.
13:26Wait, hang on. negatively correlated. So the more of this human chemical buildup you have, the lower your score on an IQ test. The correlation is about negative .13. It is statistically significant, but it's a small effect size.
13:39It's not the whole story of intelligence, obviously. But yes, the data suggests a trade-off. This is mind blowing. And frankly, a little insulting to my genome, so let me get this straight. We have a broken enzyme.
13:51This state was positively selected for, so it helped us survive. In mice, it makes females better at getting resources. But in modern humans, the byproduct of this state is linked to slightly lower cognitive scores.
14:05It suggests that intelligence, at least as we measure it today, you know, pattern matching, abstract reasoning, sitting quietly solving problems, might not have been the absolute top priority for survival 600,000 years ago.
14:18If you're the smartest person in the cave, able to do calculus on the wall, but you don't have the drive to go find water when the river dries up. Yeah. Yeah, and your genes die with you. The researcher suggests a complex evolutionary trade-off.
14:29The reduced enzyme activity provided a survival advantage. Perhaps that grit we saw on the mice, and that advantage was worth the cost of potential downsize and say, cognitive processing speed. It really reframes that whole Neanderthals were dumb, we were smart narrative.
14:44Maybe Neanderthal's head faster processors. Maybe their appearing factories were running at 100% efficiency. Yeah. But we, we were just hungrier. It's possible. Neanderthals might have been metabolically superior in terms of stability.
14:57But metabolic stability doesn't always equal survival in a harsh changing environment. Sometimes you need a system that reacts to stress differently. It makes you wonder what other defects we carry that are actually superpowers in disguise.
15:10We spend so much time trying to fix our biology, you know? Precisely. We often think of health and fitness as the state of seamless optimization. But biology is all about compromise. This puring paradox shows that sometimes breaking a well oiled machine is the only way to survive a new environment.
15:29It's also a great reminder of how much we still have to learn from the metabolic pathways we take for granted. This wasn't a gene for bigger brain or walking upright. It was a gene for metabolic traffic jam.
15:41And yet, it defines us. It separates us from the Neanderthals just as much as our skull shape does. It's a fundamental shift in how our brains are built. Okay, so we've covered the broken enzyme, the motivated mice, the double hit, and the intelligence tradeoff.
15:54What's the one big takeaway you want people to leave with? For me, it's the mechanism of the double hit. To see 2 independent changes. One in the protein, one in the volume knob, both aiming for the same counterintuitive goal.
16:08It shows how directed and powerful selection can be. It reminds us that evolution doesn't really care about clinical perfection. It cares about persistence. And for me, it's the humility of it. We love to think of ourselves as the sleek, optimized pinnacle of creation.
16:23But this study suggests we're a collection of hacks and trade-offs that just worked well enough to keep us alive. We might have traded a bit of raw processing power for the grit to keep going when the water ran out.
16:34A fair trade, I would say, given though we're still here to talk about it, and the Neanderthals are not. Absolutely. It leaves us with a lot to think about. Here's a thought to leave you with. If evolution selected for a broken enzyme that correlates with lower cognitive scores, but better resource acquisition.
16:50What does that tell us about the real priorities of human survival over the last 600,000 years? Maybe grit matters more than wit. A provocative thought to end on? This episode was based on an open access article under the CCVY, 4.0 license.
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