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Big-brained scientists have found the mechanism that may have allowed their brains (and all humans') to get so big.

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I don’t like to brag, but I’ve got a pretty big brain. And so do you.

Compared to gorillas and orangutans — apes that are about our size — our brains are three times as massive. That extra size is likely a big part of what lets us us fly to the moon, write piano concertos, and make YouTube videos. But exactly how we got these bigger brains has puzzled scientists for a long time.

Like, what happened, genetically, to make a more neuron-packed brain? Well, we may finally have a clue. Two teams of American and European researchers announced yesterday in the journal Cell that they’ve identified a gene that helps increase the number of neurons in brains — and it’s only in humans.

The gene is called NOTCH2NL, and it’s not just in our genomes once, but three times. One of the teams stumbled upon it when they were doing experiments with organoids. Organoids are simple miniature organs that are grown using stem cells in Petri dishes.

They’re a bit closer to the real thing than regular cell cultures, because they’re grown to make 3D structures. And scientists find mini brains especially useful for studying the earliest stages of brain development. In this case, they were wondering which genes were getting turned on and off.

And it turned out that NOTCH2NL was one that was very much “on” in human organoids. Even more importantly, there was no NOTCH2NL signal in organoids made from rhesus monkeys. In fact, the monkeys didn’t even have a NOTCH2NL gene when the researchers checked.

Now, there are plenty of genes that are specific to humans that aren’t doing critical things. But the finding was intriguing. Especially because orangutans didn’t have NOTCH2NL either.

Chimps and gorillas have DNA that looks like a NOTCH2NL gene, but those versions can’t actually make proteins. They’re what scientists call pseudogenes. Meanwhile, we have three functional copies, plus a fourth that doesn’t work.

By comparing these species’ DNA, geneticists think that way back in our evolution, like 8 to 14 million years ago, a gene called NOTCH2 got partially duplicated. NOTCH2 makes a receptor on cells that’s one of the key players in organ development. It’s one of four Notch genes that do this sort of thing in all mammals.

It seems like this partial duplication initially couldn’t do anything. And for many apes, that’s the way it stayed. But for some reason, only in our lineage, more NOTCH2 DNA got copied over.

So the pseudogene had the code it needed to make a small protein, and was basically fixed. NOTCH2NL was born. Researchers estimate that the gene popped up some 3 to 4 million years ago — based on the sequence, and the fact that archaic humans also have it, including Neanderthals and Denisovans.

That’s right around the time we think human brains started to get bigger. And soon after, our more recent ancestors ended up with several extra copies of it. The real kicker is that NOTCH2NL does exactly what we might expect of a brain-expanding gene — even though we’re not entirely sure how the protein behaves.

Experiments from both groups of researchers suggest it mainly signals to neural stem cells. See, stem cells can either replicate themselves, making more cells with lots of potential to become other cell types. Or, they can spawn cells that are more limited but specialized, like neurons.

Eventually, you want neurons to make a brain. But if you make too many upfront, and not enough stem cells to make even more neurons later, you end up with a smaller brain. So NOTCH2NL basically pushes things toward self-renewal.

This is especially the case in radial glia cells, which are the neural stem cells that create the bulk of the cortex, the outer layer of brain tissue that’s thought to be responsible for more complex mental tasks. Affecting neuron development in this way can cause some big changes — in the lab and in living humans. For example, deleting NOTCH2NL in organoids leads to faster maturing but smaller mini brains, while adding the gene to cultured human cells creates more neurons.

Plus, two of the NOTCH2NL genes are in a stretch of DNA on the first chromosome that’s often messed up in people with neurological or developmental disorders. Deletions in this area sometimes result in microcephaly, a condition in which the head is unusually small. Duplications can mean the opposite problem: macrocephaly — a head that’s too big.

That means that one of the genes that has arguably helped our species dominate this planet is also responsible for certain disabilities. And it’s no accident. Biologically, the same circumstances that made the duplication of NOTCH2NL likely also make that section of chromosome 1 so dangerous.

Because the DNA in the section repeats, it makes it hard for cells to accurately replicate it. The machinery can easily slip up and either skip over or copy a section twice. This feature also makes the DNA hard to sequence.

In fact, one reason why scientists never suspected NOTCH2NL to be behind any brain size disorders was because for a while, the reference genome was wrong! It had the genes near, but outside, the problematic region. Now, the puzzle’s coming together.

It’s still possible there are other genes involved, but there’s a good chance that you can thank NOTCH2NL — and especially your 3 working copies — for your big ol’ brain. Thanks for watching this episode of SciShow News! If you want to stay up to date on all the latest scientific discoveries with us, we post news episodes every single Friday.

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