Editorial: “We are the children of the lost DNA“
ONE of the most fundamental questions of our existence – how our genes make us different from chimpanzees and other animals – comes tantalisingly close to being answered this week by a ground-breaking study of DNA we lost along the way.
It demonstrates experimentally for the first time how specific differences between our DNA and that shared by our nearest relatives can account for traits that make us uniquely human. Crucially, it provides insight into how genetic changes helped us evolve our most prized asset – a large brain that enables us to reason, imagine, think forwards and backwards in time and unravel our own genetic and cosmological origins.
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The key changes are not in bits of DNA that humans acquired as they evolved – extra genes that we have but chimps and other animals do not – but in chunks of DNA that we lost. What’s more, the chunks in question are not even genes at all, but sequences of DNA that lie in between genes and act as switches, orchestrating when and where specific genes are turned on and off through the course of an animal’s development.
“The changes we’ve found would not disrupt protein-coding regions, but alter where and when in the body genes are expressed during development,” says of Stanford University in California. He and his colleagues have shown that losing these regulatory regions caused our ancestors to lose certain features, like facial whiskers, and added new ones, including brain cells in crucial locations.
Kingsley had previously shown that losing DNA could in theory cause major evolutionary differences in other animals. The tail fin of stickleback fish, for instance, shrivelled when he removed chunks of regulatory DNA from their genome.
To find out if large DNA deletions played a role in human evolution, he and his colleague Gill Bejerano compared the genomes of humans, chimps, macaques, chickens and mice. They specifically searched for regulatory regions that are uniquely absent in humans, but apparently vital to the other species.
Their team identified 510 instances where the loss of DNA removed a sequence that is highly conserved in other animals, suggesting that the deletions likely had functional consequences for humans.
The researchers then focused on two of these. Both were enhancers, meaning they boost the production of a protein. The first sits next to AR, a gene that makes receptors for male hormones. The second switches on GADD45G, a gene that stifles growth of brain tissue.
To understand the role of these genetic regulators in developing mice and chimps, they made copies of the chimp and mouse versions, added a DNA tag, then genetically engineered mouse embryos with the total sequence. The DNA tag caused body parts to turn blue where the regulators were active in the modified embryos.
The set-up allowed Kingsley and his colleagues to physically see where the AR and GADD45G genes are switched on in mice and chimp fetuses, and so what humans lack (Nature, ). It revealed that the AR gene causes sensory whiskers to develop on the faces of fetal mice, and makes spines develop on the surface of the mouse penis. So the loss of this control sequence in humans explains why we’ve lost both features.
Penile spines are common in species where many males compete to fertilise females. The researchers speculate that the loss of such spines allowed humans to prolong sex and helped establish the emotional bonds between partners necessary for the long task of raising human infants.
“The loss of penile spines allowed humans to prolong sex and helped to establish emotional bonds”
The GADD45G regulator was active in layers of the brain where cells that ultimately form the cortex are born. Specifically, in mice and chimps, GADD45G suppresses the development of brain regions which in humans are involved in higher cognitive functions like conscious thought and language.
“Completely losing GADD45G would be like losing the brakes,” says Kingsley. That happens in pituitary tumours when the regulator fails and cells grow without restraint, but in healthy humans the regulatory change would have only decreased activity in specific brain areas, causing them to grow larger.
“We think losing highly specific enhancer regions is one of the mechanisms that has contributed to the evolution of human traits,” says Kingsley. It would be foolish to claim that deletions of regulatory DNA were the only genetic changes that made us human. But the study does demonstrate the profound impacts such changes can have.
Others have hailed the findings. “It’s an elegant study that suggests the loss of regulatory elements [led to] uniquely human traits,” says James Noonan of Yale University. He adds that to prove this beyond doubt, Kingsley and his colleagues would need to delete the AR and GADD45G regulatory sequences from mice and check that they grow human-like features.
That experiment is already under way in Kingsley’s lab. For ethical and practical reasons, a similar set-up with chimpanzees is unlikely ever to be attempted. Kingsley is also investigating many of the other 508 lost regions.
“Hats off to them,” says Ewen Birney of Cambridge University. “It has long been thought that evolution would work by deleting as well as creating things, and it has long been thought that the bulk of human evolution occurs in regulatory information,” he says. “However, this is a real example of both of these things being shown to be true rather than people simply making arguments for them.”
of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and a lead researcher into the genetic differences between humans and their close relatives, including chimps and Neanderthals, says the new work is “a beautiful study”. “I’m sure several groups will now study the role of the gene involved in brain cortex formation very carefully,” he says. “I’m hopeful that the other elements in their list of almost 500 conserved features lost in the human genome will turn out to be interesting too.” Watch this space.
Neanderthals lacked penile spines too
The new analysis of human DNA also reveals similarities and differences to our long-lost cousins. A comparison with the Neanderthal genome, by David Kingsley of Stanford University in California, shows that they too had lost the same two key regulatory regions as humans (see main story).
This means that Neanderthals, like humans, had lost features possessed by a common ancestor, including penile spines and facial whiskers. It also confirms what analysis of skulls has suggested: that their brains were at least as large as ours. “Both [losses] had happened already in Neanderthals,” says Kingsley.
“The penile spines is really new information,” says of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and head of the team which recently sequenced the Neanderthal genome. Pääbo has shown that human groups which originated outside Africa share up to 4 per cent of their genome with Neanderthals, meaning they likely mated to produce hybrid offspring.
Ewen Birney of the European Bioinformatics Institute in Cambridge says it would also be interesting to check for the missing regions in homo relatives like “X-woman”, who lived alongside humans and Neanderthals.
