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On the genetic level, we're not all that different from chimps. But those small differences in DNA can have huge effects.

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[♪ INTRO].

There’s a widely cited but outdated figure that the human genome is only about one percent different from that of chimpanzees, which are some of our closest living relatives. It’s really more like four percent, though that depends on how you count.

And we now have a very good idea of what those differences actually are. But what we’re still working to understand is how those differences add up to our hairless, awkwardly bipedal, big-brained selves, as opposed to fuzzy, knuckle-walking, tree-swinging chimps. And it turns out that small differences in DNA can have huge effects.

Sometimes that’s in an obvious way, like changing an important gene. Other times, the effects are much more complicated. To find the basic differences in the actual molecules that make up our DNA, we first needed to sequence the full genomes of both humans and chimps.

Then we had to compare the order of their three billion or so As, Cs, Gs, and Ts; the DNA letters of their genetic code. Basically an encyclopedia’s worth of information. This was a pretty big undertaking, but also pretty straightforward once we had genome-sequencing technology.

And researchers published the first draft chimp genome back in 2005. And they found three types of differences:. Single-letter differences, like where an A in chimps is a G in humans, make up about one percent of our DNA.

That’s why you’ll sometimes see people saying there’s a one percent difference in our genetic code. But there are also small-ish insertions and deletions, the type of change that would compare to a word or sentence being added or removed from an encyclopedia set. These make up another three percent or so.

Factoring these in brings us up to around four percent different. Then there’s a smattering of bigger differences, like whole chromosomes or large pieces that have moved around, plus duplications of whole genes. Something on the order of a chapter or a volume of that encyclopedia.

The differences have accumulated gradually in the time since humans and chimps last shared a common ancestor; think several million years ago. And during that time, the lineages that led to humans and chimps evolved separately. That means that out of the four percent or so of the DNA that’s different, about half of the differences evolved in the chimp lineage.

And it’s the stuff that makes them chimps. The other half evolved in ours. And it includes all of the elements that make up our uniquely human traits.

Everything from a skeleton adapted for upright walking, to really precise motor control, to big powerful brains. All that in just two percent of our DNA, give or take, which might not seem like very much. But it still adds up to more than fifteen million differences, mostly tiny ones, scattered around the genome.

Now, not all of those DNA changes add up to functional differences that shape our traits. One of the things about evolution is that most changes to DNA are neutral. They either don’t affect traits at all, or they cause differences that don’t matter much, like the shape of your pinky toe.

So the first trick is spotting for differences that are not neutral. The second is to figure out how those differences make our uniquely human traits. And that’s really hard to do!

To understand something like why we have language and chimps don’t, we need to drill down into how language forms in the brain — and we do not fully understand that yet. In fact, chimps’ brains are organized a lot like ours. And they appear to use similar areas of their brains to communicate.

Yet clearly there’s something very different going on in ours. One thing that is clear:. Our cool human tricks do not require a bunch of totally new types of genes.

This might seem counterintuitive. But it actually makes sense when you think about what genes are:. Usually, they are sections of DNA that code for proteins.

And proteins are what build bodies and make them work. Humans and chimps, and lots of other animals for that matter, are made out of mostly the same stuff. Like, our skin, our bones, our blood, our guts generally work the same way.

And they’re made out of really similar proteins, coded for by really similar genes. In fact, nearly a third of our proteins are completely identical to their counterparts in chimps. Most of the rest are different by just one or two amino acid building blocks, out of the hundreds in a typical protein.

So at the protein level, we’re way more similar to chimps than we are different. Still, even small differences can affect how a protein does its job. This kind of evolutionary tinkering at the protein level is one source of the traits specific to our species.

For example, a change to a certain muscle protein might give us smaller jaw muscles. And a change to a hair follicle protein might make us less hairy. Other kinds of changes can affect our protein-coding genes too.

Small insertions and deletions, if they fall within genes, can disrupt them or change how they work. And well over a hundred genes have been duplicated, so that our genomes now have multiple copies compared to other apes. One example is a protein that digests starch.

Its gene has been duplicated many times over, and that probably helps us get more energy from starchy foods. Another duplicated gene is active in the brain during embryonic development, and it may affect how cells in the outer layers of the brain, which we use for higher-level thinking, connect with one another. But by far most of the differences aren’t in protein-coding areas at all.

They fall in the vast areas between genes. Many of these differences can still affect our proteins, though. Not so much what the proteins do, but how they’re deployed.

And that brings us to gene regulation. Every gene is surrounded by shorter stretches of DNA that work like switches. They control when and where in the body a gene is switched on, and how much protein is made from it.

This is all coordinated through a network of proteins and other molecules that interact with these switches. That coordination is crucial during embryonic development, as body parts take shape. For instance, by tweaking gene expression, you might be able to use the same set of genes to build, let’s say, a pelvis that’s suited for walking on all fours vs. standing upright.

Kind of like a sculptor working in clay, gene regulation can use the same tools to build different shapes. Like with protein differences, changes of just a few DNA letters can have important effects on gene regulation. And researchers think it could be a big part of what makes us different from chimps.

This kind of tinkering might also be less disruptive than changes to the proteins themselves. That’s because many genes that build our bodies work in multiple parts of the body. So changing a protein would affect it everywhere, most likely in a way that’s harmful.

But a change in its regulation can easily target it to a specific place and time. For example, turning up a certain gene’s activity specifically in one area of the brain could theoretically help just that area grow larger. There’s a catch, though:.

Regulatory sequences are super tricky to find and even harder to study. Unlike stretches of DNA that code for proteins, it’s hard to predict the outcome of a change. And finding meaningful changes among all the neutral ones is like searching for a needle in a haystack.

But scientists have used their clever, problem-solving brains to start to figure this out. One approach to do this is to look at patterns of DNA methylation. That’s where molecular flags known as methyl groups are associated with genes that are less active.

In a 2020 study, researchers compared methyl patterns on DNA from chimpanzees and modern humans, as well as a couple of extinct human species, specifically, Neanderthals and Denisovans. They found that modern humans have unique methylation patterns around hundreds of genes. And some of the biggest differences are around genes that affect the anatomy of the face and vocal tract.

Changes in these genes’ regulation may be the reason humans have flatter faces and can make more complex vocalizations. Another approach for finding meaningful differences in gene regulation involves computational tools. See, stretches of DNA that do important jobs tend to remain relatively unchanged over millions of years of evolutionary time.

That’s because changes to them could seriously mess things up. But when there are changes that work well enough to not be immediately filtered out by natural selection, they can lead to all kinds of evolutionary innovations. Computer programs can look for sequences that are the same between chimps and other animals but different in humans.

Researchers call these HARs, for Human Accelerated Regions, because they’ve changed more quickly specifically in our lineage. Changes like this are less likely to be neutral, and more likely to have given our ancestors a reproductive advantage of some kind. Researchers have found thousands of promising DNA elements this way.

A lot of the research so far has involved figuring out which elements act in the right places at the right times to be doing something important. A number of them seem to be working in the immune system, reproduction, and in developing limbs and hearts. And unsurprisingly, many appear to be working in the brain.

Researchers have taken a more in-depth look at a few HARs. For example, a regulatory piece of DNA called HARE5 is active in the developing brain. And it appears to enhance the activity of another gene specifically in the neocortex, an area involved in higher brain functions.

Researchers have been able to show that mice with the human version not only had higher gene activity, it also looks like it caused the cells in the forebrain to divide more quickly, and their brains to grow larger. So researchers could be onto something big with gene regulation. But that’s just the tip of the iceberg!

There’s still a lot of work to be done to connect these differences to traits. Like, measuring the size of a brain is pretty straightforward. But it’s not a given that a larger brain is also better at thinking.

And how do you even design an experiment that connects a DNA difference to an ability like written language? Complex human traits like abstract thinking and long-term planning come from multiple genes working together. Since each trait is more than the sum of its parts, a reductionist approach, like looking at the function of one protein, doesn’t reveal much about how these traits work.

Plus, thousands of promising differences remain unstudied. There are a couple of recent advances that are helping researchers study interconnected gene and protein networks. For example, it’s now possible to take cells from a human or a chimp and make them revert to a stem-cell-like state.

By treating them with certain growth factors, researchers can coax these cells to start developing into organoids: tiny, almost-but-not-quite-organs, like primitive mini brain-ish things. As the organoids develop, researchers can compare patterns of gene expression between the human and the chimp versions. Then they should be able to use gene editing to see what happens to cells or organoids when you change individual DNA sequences.

So, it will take a lot more innovation to drill down into how exactly our DNA differences add up to the human condition. But along the way, we’re learning a lot about what it means to be human. Luckily we have our smart brains to help us figure it all out.

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