Genes make proteins that make us – that was the received wisdom. But from big brains to opposable thumbs, some of our signature traits could come from elsewhere
IT WAS a discovery that threatened to overturn everything we thought about what makes us human. At the dawn of the new millennium, two rival teams were vying to be the first to sequence the human genome. Their findings, published in February 2001, made headlines around the world. Back-of-the-envelope calculations had suggested that to account for the sheer complexity of human biology, our genome should contain roughly 100,000 genes. The estimate was wildly off. Both groups put the actual figure at around 30,000. We now think it is even fewer – just 20,000 or so.
“It was a massive shock,” says geneticist John Mattick. “That number is tiny. It’s effectively the same as a microscopic worm that has just 1000 cells.”
We’ve only gradually come to grasp the full implications of this discovery. The blueprint for building a human, or indeed any complex creature, lies not only in our genes but in other, neglected parts of our genome. This long-overlooked DNA could have shaped iconic traits such as our upright stance, opposable thumbs, big brains, capacity for language, even our tendency to form monogamous relationships. We might like to think of ourselves as pinnacles of evolution, but actually we are mostly made of junk.
In fact, one group was less surprised by the genome shock. Evolutionary biologists had long thought 100,000 genes would make for a fatally complicated genome. And we now know that genes – the sequences of DNA that code for proteins – account for just 1 or 2 per cent of our genome. For a long time the rest was considered to have no function at all, earning it the dismissive title “junk DNA”. While researchers still argue over how much of it truly is junk, what’s clear is that this trash hides treasure – bits of DNA that control genes like a conductor directing an orchestra, switching them on and off at different times and in different cells.
These discoveries have come from studies comparing the human genome, junk and all, with those of chimps, mice and other animals. Some have even compared the genomes of Neanderthals and other extinct human species. The aim is to identify bits that look suspiciously different in modern humans, regions that are uniquely ours.
James Noonan at Yale University and Shyam Prabhakar at the Genome Institute of Singapore did this comparison across all mammals. They homed in on one piece of supposedly junk DNA called HACNS1, which has accumulated an unusually large number of mutations since we split from chimps. In other words, it was distinctly human.
Seeking clues to what HACNS1 does, they inserted it into the genomes of mouse embryos, along with a tiny, molecular label that would change colour whenever it was modifying the activity of surrounding genes. The label popped up in the embryos’ paws, in the area where digit 1 forms. In humans, that is either the thumb or big toe, suggesting that HACNS1 might influence their development.
For an idea of how, we can look at the fossil record. “Human thumbs and feet are among the most distinctive features of our species,” says Prabhakar. There is evidence that our ancestors evolved opposable thumbs about 3 million years ago, roughly when they began to use stone tools and only a few million years after we split from chimpanzees. It’s likely that early humans were also standing upright and were starting to walk on two legs around the same time or a little earlier. Doing so was tied to physical changes: toes shrank and foot arches became more rigid.
According to Prabhakar and Noonan, all this could have been happening around the time that HACNS1 began altering gene activity in our hands and feet. By subtly changing when and where genes were switched on, this little piece of DNA could have been modifying our hands and feet.
The study is not the only one to suggest that genetic controllers, rather than genes themselves, played a crucial part in shaping us. Gene activity is often regulated via methylation, a process in which a chemical unit called a methyl group is attached to a gene segment, influencing how much protein it produces. There are hints that junk DNA is involved.
In 2013, a study suggested that DNA methylation had helped our transition to walking on two legs, and perhaps our language skills too. Andrew Sharp of the Icahn School of Medicine at Mount Sinai, New York, and his colleagues compared DNA methylation patterns in humans, chimps, gorillas and orangutans, and found 171 genes with uniquely human patterns. A closer look suggested that these genes were involved in a handful of traits: regulating blood pressure, controlling the development of the inner ear and shaping facial muscles.
“What are the big differences between humans and chimps? We walk upright and we speak,” says Sharp. Walking upright lifted the brain, which meant our ancestors had to change how they regulated blood pressure to keep the brain supplied with enough oxygen. It also demanded exceptional balance, typically improved by modifying the inner ear. Speech, meanwhile, required an unprecedented level of control over the muscles in our face and around our mouth.
“Seeing these methylation changes in genes associated with these human traits, I just felt… wow, that’s incredible,” says Sharp.
A year later, David Gokhman and Liran Carmel at the Hebrew University of Jerusalem in Israel published a pioneering study of methylation in ancient DNA extracted from the fossils of extinct hominins. Using the fact that bits of DNA carrying methyl groups degrade differently from bits that don’t, the pair were able to reconstruct Neanderthal methylation patterns and compare them with human ones. They found key differences in genes that control limb development. “Our hypothesis was that these genes were less active in the archaic humans,” says Gokhman. That’s an exciting finding, because we know that Neanderthals typically had shorter, stouter legs than we do. So by switching some genes on or off, and making them pump out different amounts of proteins, methylation could have contributed to giving us longer legs than our extinct cousins.
“When our ancestors lost this piece of junk DNA, suddenly brain cells could proliferate“
The fact you can see these different methylation signals is tantalizing, says Sharp. “It does suggest that they might have been involved in some major events in human evolution.”
Mattick, who is at the Garvan Institute of Medical Research in Sydney, Australia, thinks that junk DNA controls methylation. He suggests cells might transcribe junk into RNA, molecules typically associated with the process of making proteins (see diagram). But this “non-coding” RNA does something else: it influences when and where DNA methylation occurs.
That’s plausible, says geneticist and evolutionary biologist T. Ryan Gregory at the University of Guelph in Ontario, Canada, and he agrees that non-coding RNA might well be involved in managing methylation.
Carmel and Gokhman also found some unsettling patterns in their study. Some genes that are methylated differently in humans compared with Neanderthals appear to be linked to disease – including neurological and psychiatric disorders. “This suggests some kind of a link between our rapid brain evolution and the fact that many neurological disorders are more prevalent in humans, or even specific to humans,” says Gokhman.
A link between junk DNA and illness makes sense to Mattick. He likes to think of the genome as a set of organic building blocks. The proteins that genes code for are generic components that can be used to construct almost any animal. Encoded in our junk DNA is a set of instructions for how to assemble them to make one species or another. The problem with instruction manuals is that they can get damaged. And indeed, genetic diseases can often be traced to non-coding “junk” regions of the genome.
Just occasionally, damaging or even losing sections of this DNA creates a potent opportunity for useful innovation. For example, a team led by David Kingsley at Stanford University in California identified about 500 regions of our genome that are missing a chunk of genetic information which our primate relatives carry. They focused on two, both found in non-coding regions. One lies near a tumour suppressor gene, the other near a gene that makes a receptor for male hormones. They inserted chimp versions into mouse embryos and watched to see where they were most active. The answer turned out to be the brain and the groin.
The first chimp sequence controlled gene activity in a part of the brain where lots of new brains cells are born. Kingsley suspects that the chimp version exercises careful restraint over that process. When our ancestors lost this piece of DNA, he says, suddenly brain cells could proliferate at unprecedented rates and our brains got much bigger.
More speculatively, the second sequence might have changed our ancestors’ relationships. It was active in spines that are found on mouse penises. The spines appear to play a role in species where several males compete for individual females: male chimps have penile spines, while human males do not. No one really knows what they are for, but if losing them made sex less painful, that might have contributed to the creation of stronger emotional bonds between men and women, boosting monogamous relationships.
All of these examples of how non-coding DNA could have shaped human evolution are suggestive rather than definitive. It’s hard to prove cause and effect in human evolution, says Prabhakar, because you can’t experiment on humans. But a new genetic megaproject could make the case a lot stronger.
Human Genome Project-Write (HGP-Write) aims to build a human genome from scratch. According to Jef Boeke at the New York University Langone Medical Center, one of the researchers behind the project, exploring the role of non-coding DNA will be among its most interesting applications. As the team pieces together a complete human genome, they will be able to delete non-coding segments one by one and see how that affects cells, he says.
That could lead to tangible benefits. Renewed efforts to grow human organs in pigs, and so make up for the shortfall in organ donors, rely on injecting human stem cells into pig embryos. But exactly how those human cells manage to mature into a human organ inside a newborn piglet is still mysterious. HGP-Write could help us understand what’s going on and finesse our organ-growing efforts.
There’s an enormous amount of work still to be done before we really understand how our genome gave rise to unique human characteristics, but the idea that the process starts and ends with genes has never looked more misguided. “Clearly when it comes to turning trillions of cells into a walking, talking human, it’s not the 20,000-strong protein set alone that’s going to get you there,” says Mattick. The answers, it seems, are buried in the trash.
What do you mean, junk?
It was the evolutionary biologist Susumu Ohno who popularized the term “junk DNA” in the early 1970s. At the time, researchers had begun to realize just how much non-coding DNA there is kicking about in our genome. It didn’t code for proteins, but what other purpose it might serve was a mystery.
“The classic argument was: if it’s that abundant and not functional, natural selection would have got rid of it,” says T. Ryan Gregory at the University of Guelph in Ontario, Canada. Ohno dared to question that idea. Non-coding DNA, he said, really was mostly just junk.
The debate continues to this day. Most evolutionary biologists say the evidence in large part backs Ohno’s view. We now know, for instance, that some non-coding DNA acts almost like a parasite, randomly copying and pasting itself into new locations in the genome without apparently altering the way the genome functions. That shows a large fraction of our genome really is useless, they say, with no role to play in human evolution or development.
But some human geneticists take the opposite view. They say the assumption from the early 1970s is correct, and most supposed junk DNA does influence our biology. That’s true for at least some of the junk, but we still don’t know exactly how much.