“Where’s my tail?”

Geneticist Bo Xia asked that question as a child and it was on his mind again a few years ago, while he was recovering from a tailbone injury during his PhD at New York University (NYU) in New York City.

Xia and his colleagues now have an answer. The researchers identified a genetic change shared by humans and other apes that might have contributed to their ancestors’ tail loss, some 25 million years ago.

Mice carrying similar alterations to their genomes had short or absent tails, the researchers found — but that insight was hard won. The work was published on 28 February1: nearly 900 days after being submitted to Nature and posted as a preprint, because of extra work needed to develop several strains of gene-edited mice and demonstrate that the genetic changes had the predicted effect.

“Respect to the authors,” says Malte Spielmann, a human geneticist at Kiel University in Germany, who reviewed the paper for Nature. “I’m incredibly excited about the fact that they’ve really pulled it off.”
The mice with no tails

Unlike most monkeys, apes — including humans — and their close extinct relatives don’t have tails. Their coccyx, or tailbone, is a vestige of the vertebrae that constitute a tail in other animals. Finding the genetic basis for this trait wasn’t what Xia, now at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, planned to devote his PhD to. But his coccyx injury, sustained during a cab ride, reinvigorated his tail curiosity.

On a hunch, Xia decided to examine a gene famous for its role in tail development. In 1927, Ukrainian scientist Nadine Dobrovolskaya-Zavadskaya described a strain of short-tailed lab mouse that, she proposed, carried a mutation in a gene called T, the human equivalent of which is now known as TBXT. “You’ll find this gene in your first Google search,” says Xia.

A quick search of geneticists’ version of Google — the genome browser maintained by the University of California, Santa Cruz — showed that humans and other apes carry a DNA insertion in TBXT that other primates with tails, such as monkeys, don’t have.
Gene splice

In a preprint2 posted on bioRxiv in September 2021, Xia and his colleagues showed that the ape insertion can lead to a shortened form of the protein that TBXT encodes. They proposed that that the shortening occurs after the gene is transcribed into messenger RNA, and when multiple protein-encoding segments of the gene transcript get spliced together. Gene-edited mice with one clipped copy of the mouse version of TBXT had a range of tail defects. In some, the tail was shortened or missing completely; in others it was kinked or extra-long.

The findings attracted dozens of news stories, but the preprint didn’t show that the ape genetic insertion, when introduced into mouse version of TBXT, could cause tail loss, says Spielmann. “They hadn’t done the main experiment.”

Those experiments were under way when the paper was submitted to Nature, says Itai Yanai, a systems biologist at NYU who co-led the study. They ended up showing that the genetic insertion, when transplanted into the mouse genome, didn’t lead to very high levels of the shortened version of the protein. The resulting mice had normal tails.

The researchers also engineered mice with a different insertion in the mouse version of TBXT. Serendipitously, this caused the gene to be mis-spliced in the same way as it is in humans. Mice carrying this insertion were born with short or entirely missing tails.
Tree swingers

Yanai says the extra experiments added rigour to the study, even if the overall conclusion is largely the same. “Making all those mouse lines is a major undertaking,” says Miriam Konkel, an evolutionary geneticist at Clemson University in South Carolina. “I really felt for those authors when I saw what they did.”

“It turned out to be a much stronger paper,” adds Spielmann. “They clearly show that this change contributes to tail loss. But it’s not the only one.” The researchers analysed 140 genes involved in tail development and identified thousands of genetic changes unique to apes that might also have played a part in tail loss.

“I’m really excited to see work being done on the genetic mechanisms underpinning tail loss and length reduction,” says Gabrielle Russo, a biological anthropologist at Stonybrook University in New York. Xia’s team says that tail loss might have contributed to apes’ ability to walk upright and to them spending less time in trees, but Russo isn’t so sure. Fossils suggest that early apes moved on four legs like tree-dwelling monkeys, and that bipedality evolved millions of years later.

Apes aren’t the only primates without tails: mandrills, some macaques and the big-eyed nocturnal creatures called lorises all lack tails, suggesting that the trait evolved multiple times.

“Probably, there are multiple ways of losing a tail during development. Our ancestors chose this way,” Xia says.