Science

‘Jumping gene’ may have erased tails in humans and other apes—and boosted our risk of birth defects

Mammals from mice to monkeys have tails. But humans and our cousins the great apes lack them. Now, researchers may have unearthed a simple genetic change that led to our abbreviated back end: an itinerant piece of DNA that leapt into a new chromosomal home and changed how great apes make a key developmental protein. The finding also suggests the genetic shift came with a less visible and more dangerous effect: a higher risk of birth defects involving the developing spinal cord.

The work not only addresses an “inherently interesting question about what makes us human,” says Hopi Hoekstra, an evolutionary biologist at Harvard University, but also provides new insights into how such evolutionary changes can occur. “It’s beautiful work.”

Bo Xia, a graduate student studying genome evolution at New York University’s (NYU’s) Grossman School of Medicine, says he wondered as a child why people didn’t have tails, and a tailbone injury a few years ago renewed his curiosity. A wealth of primate genomes has been sequenced in recent years, so he started to search for any ape-specific changes in genes known to play a role in tail development. In a gene called TBXT, he found a strong suspect, a short DNA insertion called an Alu element that was present in all great apes but missing in other primates.

Alu sequences can move around the genome and are sometimes called jumping genes or transposable elements. Possibly remnants of ancient viruses, they’re common in the human genome, making up about 10% of our DNA. Sometimes an Alu insertion interrupts a gene and prevents its protein production; in other cases, the elements have more complex effects, changing where or how a protein is expressed. This makes them a huge driver of evolutionary variation, says Pascal Gagneux, an evolutionary biologist at the University of California, San Diego. An insertion is “often costly but every once in a while you hit the jackpot,” he says, and a beneficial change arises that evolution preserves.

TBXT codes for a protein called brachyury—Greek for “short tail,” because mutations in it can lead to mice with shorter tails. At first glance, however, the ape-specific Alu element did not seem to cause any significant disruption in the gene. On closer inspection, however, Xia noticed a second Alu element lurking nearby. That element is present in monkeys as well as apes, but Xia realized that in apes the two Alus could stick together, forming a loop that would alter TBXT expression so the resulting protein would be a bit shorter than the original. That insight “was very clever,” Hoekstra says. “It wouldn’t have jumped out at me as an obvious mutation to test.”

Indeed, Xia and his colleague found that human embryonic stem cells make two versions of the TBXT messenger RNA (mRNA), one longer and one shorter. Mouse cells, on the other hand, only produce the longer transcript. The researchers then used the genome editor CRISPR to remove one or the other Alu element in human embryonic stem cells. Losing either Alu element made the shorter version of the mRNA disappear.

To see what effect this shortened protein might have, Xia and his colleagues used the gene editor CRISPR to make mice with a shortened version of TBXT. The mice carrying both copies of the shortened gene didn’t survive, but those with one long and one short version were born with a variety of tail lengths—from none at all to nearly normal, the group reports in a preprint posted last week on bioRxiv.

That suggests to Xia and his colleagues that the shorter version of TBXT interferes with tail development. Because the genetically altered mice had a mix of tail lengths, other genes must be working together to eliminate all tail development in apes and humans, but the ape-specific Alu insertion Xia noticed “was likely a critical event” about 25 million years ago as great apes diverged from other simians, says Itai Yanai, a developmental geneticist at NYU Langone Health, who helped coordinate the project.

The genetically modified mice also had unusually high levels of neural tube problems, defects in the developing spinal cord. Such birth defects, which produce spina bifida, where the spinal cord doesn’t close, and anencephaly, where parts of the brain and skull are missing, are fairly common in humans, affecting as many as one in 1000 newborns.

“We apparently paid a cost for the loss of the tail, and we still feel the echoes,” Yanai says. “We must have had a clear benefit for losing the tail, whether it was improved locomotion or something else.” That’s possible, Hoekstra says, but she cautions that the defects seen in the mice could well have a different source than the human disorders.

Overall, the Alu find is “a super interesting story,” Gagneux says, noting it leads to a wealth of questions, including how the shortened protein might help cause neural tube defects. Some people are born with rudimentary tails, he notes, and sequencing their genomes might provide additional clues.

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