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What makes us human?
Is it the way that we walk?
Or talk?
Or think?
Or invent?
Is it the cultures that we create and transmit?
Is it the way we interact with our environment?
Is it all of the above?
Or something else entirely?
We've been asking this question for a long time, from a lot of different perspectives
- from anthropology to religion to psychology
to philosophy - rarely finding simple, clear-cut answers.
But over the last few decades, an entirely new method of introspection has emerged.
We’ve become able to search our DNA for
the hallmarks of human uniqueness at the genetic level.
See, you might’ve heard that our genes are around 99% identical to those of chimpanzees,
our closest living non-human relatives.
So what’s in that remaining 1% that encodes…
humanity?
As simple as the question sounds, answering
it has proven to be a decades-long quest that is still far from over.
And along the way, we’ve had to change how we think about genomes altogether.
Because, in the search for the genes that make us human, some of the most important
answers were hiding not in the genes themselves, but in what was once considered genomic junk.
Now, genetics can sometimes feel like a part of modern science that’s easy to take for granted.
But compared to paleontology or geology or
anthropology, genetics is still a very young field.
I mean, even the now-iconic double helix structure of DNA was only revealed to the world in 1953,
which is within living memory for some people!
And the search for human genetic uniqueness only really began in earnest in the 1970s,
when scientists became able to zero in on individual DNA sequences.
At first, we assumed that the big important differences between us and chimps - the sequences
responsible for ‘humanity’ - would be mostly or entirely found within genes.
Technology at the time meant that deciphering
even short stretches of the As, Ts, Cs, and Gs - the
bases that make up our DNA - was time-consuming, tedious, and expensive.
Human genomes are over 3 billion base pairs in size, so the idea of sequencing and studying
the whole thing seemed like a futuristic sci-fi
dream for much of the second half of the 20th century.
So, instead, we had to carefully pick individual bits of the genome to analyze.
And because of that, it seemed natural to start with the ones that actually code for
proteins - aka the genes.
Now, there was also a pervasive idea at the time
that genes were where everything that was biologically
important happened, and the rest of the genome could be largely written off as non-coding,
non-functional ‘junk DNA’.
And this approach of looking at the genes did reveal some key differences.
Like in FOXP2 for example, a gene that seems to play a role in the ability to speak.
FOXP2 has picked up some important mutations in our lineage since our last common ancestor
with chimps around 6 million years ago.
And a number of other genes that we share with our closest primate relatives have undergone
changes too, like being turned off in our
genomes, or being duplicated, or changing location.
But as cool as those examples are, they alone can’t neatly define or explain our humanity.
Even early on, researchers noticed that human genes and proteins generally
had very few differences from the corresponding ones in chimps, far fewer than they had expected
and, it seemed like, far fewer than could
account for all of the differences that we see between us.
The plot thickened in the early 2000s when
we finally got a good look at an entire human genome.
Before the Human Genome Project was completed, some researchers predicted it would reveal
around 100,000 genes - a large enough number to account for all of this magnificent complexity.
But it turned out there were only around 20,000 to 30,000 genes.
And these genes made up only 1-2% of the genome.
It was non protein-coding DNA - the so-called junk - that represented most of the rest.
Ok, and here's what bothers me:
we have fewer genes than grapes or water fleas.
Like, I don't even know what a water flea is, but grapes are the things that, like,
my kids would throw on the floor from the high chair.
They have more genes than I do? That's how it's gonna be?
Okay.
My point is, this is both humbling and confusing.
I mean, how could we humans be so complex if we have
so few genes – and they’re mostly the
same as those of our closest living non-human relatives?
Well, a few years later, in 2005, the Chimpanzee
Genome Project also produced its first draft sequence.
Having both human and chimp genomes, as well as other more distant relatives like mice,
allowed us to compare not just our genes, but our non-coding regions too.
See, some experts suspected that there were sequences hidden in the junk DNA that
were actually functional.
Not because they directly coded for proteins like genes did, but because they somehow regulated
the activity of those genes.
And changes in those regulatory sequences that were unique to humans could be just as
important - or even more so - than changes in the genes themselves.
After all, genes are basically just biological tools.
And you can use the same set of tools to build a table, a chair, or a figurine.
It all comes down to how you use them.
To sift through all that non-coding DNA for sequences with actual functions and separate
them from the junk, we looked for signs of conservation across vertebrates.
See, all DNA sequences pick up random mutations, and if a sequence is doing something important,
that’s generally bad news, because mutations often disrupt that function.
So, over evolutionary time, natural selection works to purge those mutations - keeping the
important sequences very similar, even between distantly related species, much more similar
than junk sequences, which can accumulate random mutations and diverge between species
more quickly, because they have no functions to maintain.
And in 2006, researchers identified around 5% of the human genome that was non-coding
but tightly conserved across species - which
means some of it probably plays important regulatory roles.
Think of these sequences as switches that control the activity of genes.
And those switches have been around in the non-coding DNA of vertebrates for a long time,
and are generally very similar between species.
But in humans, thousands of them have been tweaked, altering the way they work and how
they control our genes.
Scientists call them Human Accelerated Regions, or HARs.
Many of them are associated with brain and nervous system genes - changing how those
features develop compared to our closest non-human relatives, like chimps.
Ok, so search over right?
Humanity comes down to some mutations in the 1 to 2% of the genome that’s made up of
genes, plus a bunch of tweaks in the 5% that regulates genes.
Job well done everyone, we can go home…
Well, not quite.
In a paper published in 2022, researchers announced that they had found yet another
previously unknown layer of the genomic onion.
They expanded their search to the rest of the genome, the more than 90% that is both
non-coding and not conserved.
And in that bubbling pool of fast-mutating junk, they found something incredible: entirely
new regulatory sequences that are unique to us.
They'd been forged from sequences that used to be junk DNA.
They weren’t conserved in other species, so we’d missed them in our previous searches.
The researchers called them Human Ancestor Quickly Evolved Regions, or HAQERs.
Good work, marketing team.
HAQERs were about as unique to humans as it’s possible to get.
In other species, many of those sequences don’t seem to do anything, but in our ancestors'
genomes, they’d been converted from junk to functional.
And what’s more, these HAQERs were the fastest evolved regions of the entire human genome.
They had emerged quickly, sometime after our lineage split from the chimp lineage, but
before we split from our close relatives, the Neandertals and Denisovans.
Ok, but what do these HAQERs do?
Well, the nearly 1600 HAQER sequences are most commonly associated with regulating genes
involved in the immune system, the gut, and the brain.
Now, the immune system evolves rapidly because
it’s locked in a never-ending game of cat-and-mouse
with pathogens that it has to constantly adapt to.
But the gut and brain connection pointed toward a long-standing idea in anthropology: the
expensive tissue hypothesis.
This hypothesis suggests that the reason our brains are unusually large and our guts are
unusually small, compared to other great apes,
is that both of these tissues require a lot of energy.
I would not call my gut small, but that's where we are...
It was an evolutionary trade-off, and our ancestors went in the direction of big brains,
shrinking our guts to balance out the energy cost.
So finding that many HAQERs affect the expression of both brain and gut-related genes potentially
makes sense when we look at our differences with chimps.
We’ve come a long way from our early assumptions about the importance of genes to our more
recent realization that non-coding DNA might not be totally useless after all.
Maybe the thing that we’ve really found in our search for the genes that make us human
is that it’s actually the genetic raw material - the junk DNA - that’s most useful to have
in your genomic back pocket.
It’s like the stuff in your junk drawer
at home that you keep around, like, not because you
need it right this second, but because one day, it might come in handy.
Suddenly, it’s no longer junk.
Ultimately, the search for human uniqueness at the genetic level has turned out to be
more difficult than we’d hoped, more complex
than we’d imagined, and more humbling than we ever expected.
Because, even though the differences between us and chimps might only be a tiny fraction
of our DNA, our complexity may not actually be about how much unique DNA we have, but
instead about the still-murky ways that DNA operates.
And in that sense, the search for what makes us human still has a very long way to go.
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Riley J. Mangan, a Ph.D. Candidate at Duke University, helped us with this episode and
our staff writer Farhan Mitha had a chance to record an interview with him about his
work on human evolutionary genomics.
And we’re making that fascinating discussion available for our patrons!
Check it out now over at patreon.com/Eons.
If this got you thinking about how we became…us…, be sure to check out our Human Evolution playlist
that covers topics like our place in the primate family tree and when we lost our fur.
Also thanks to this month’s gene-ius Eontologists!
Gale Brown, Juan M., Jacksy Weiss, Melanie
Lam Carnevale, Rafael Haase, Annie & Eric Higgins, John
Davison Ng, Jake Hart, and Colton.
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What's 10 meters long, has scutes on its back, and hurts like heck when you step on it?
- A Legosaurus
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The Expensive Tissue Hypothesis.
It sounds like the name for a prag rock cover band.
I would see that band. The Expensive Tissue Hypothesis, they're really good.
You've got your Yes, you've got your Pink Floyd, Emerson, Lake & Palmer, they're all in there.
LOL!