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Tail Loss in Humans, Apes Linked to Transposable Element Impacting Splicing

NEW YORK – A team from NYU Langone Health, the Broad Institute, and other centers has discovered the likely genetic underpinnings of tail loss in the hominoid lineage leading to humans and tailless apes. Their study, published in Nature on Wednesday, focused in on an Alu element insertion that also appears to increase the risk of neural tube defects during embryonic development.

"[W]e propose a plausible scenario for the genetic mechanism that led to the loss of the tail in our ancestors," co-senior and co-corresponding author Itai Yanai, a researcher at NYU Langone Health, said in an email, calling it "surprising that such a big anatomical change can be caused by such a small genetic change."

For their study, Yanai and colleagues turned to available genome sequence data, initially scrutinizing protein sequence conservation for 31 human genes, along with their primate orthologs and Old World monkey versions of them, to look for shared alterations contributing to the absence of a tail in hominoids.

When that search did not turn up tail loss-related alterations, the team went on to expand the analyses to a larger set of 109 genes, bringing in genetic and phenotypic clues from mice with shorter-than-usual or vestigial tails, and focused on a time frame when tail loss turned up in hominoid ancestors.

"We have good evidence that the mutation happened about 25 million years ago (because it's shared with all apes), when hominoid ancestors diverged from the ancestors leading to the lineage of extant Old World monkeys," Yanai explained, noting that "[g]oing tailless may have had an evolutionary advantage in that the loss of the tail facilitated the evolution of bipedal locomotion."

Though the investigators did not find protein-coding variants linked to tail loss when they interrogated tens of thousands of hominoid-specific SNPs, deletions, and insertions, their noncoding sequence analyses led to a hominoid-specific "jumping gene," or Alu element, that inserted itself in the intron of a transcription factor-coding gene called TBXT that has been implicated in tail formation in the past.

The Alu element in question belongs to the AluY subfamily found in humans and other hominoids, they explained. It appears to lead to hominoid-specific alternative splicing of TBXT via interactions with a second Alu element known as AluSx1 that is also found in a TBXT intron, albeit in the reverse orientation from the original insertion.

"We identified a change in the TBXT gene that plays a critical role during embryonic development and in non-hominoids helps govern the development of a tail," Yanai said, explaining that "because of its proximity to another Alu element, it leads to the creation of a different kind of protein [than the one] that usually acts in the development of the tail."

The team backed up that hypothesis with mouse model experiments, including CRISPR-based gene editing experiments that found diminished tail development in animals missing a TBXT exon that is predicted to be skipped in hominoid versions of TBXT with Alu-related alternative splicing.

Moreover, the authors noted that a subset of mice edited to carry the hominoid version of the TBXT transcription factor gene were not only short-tailed or tailless but went on to develop neural tube defects, which are found in roughly one in a thousand human babies.

"We saw in some of the mice that lost their tail that they also had a condition similar to the human spina bifida (a type of neural tube defect) condition," Yanai said. "This suggests that the evolutionary pressure to lose the tail was so great that despite creating the potential for this condition we still lost the tail."