Most primates have tails, but us humans and the other apes (chimps, gorillas, orangutans, and gibbons) are all tail-less. Clearly, having tails was the ancestral primate condition, so how did apes (AKA hominoids) end up losing their tails?
Earlier today a new preprint was released at least partially answering this question:
The paper is well written and IMO very accessible to non-specialists, so I’d recommend checking it out. I’ll summarise it briefly though…
To look for the genetic basis of the loss of tails, the authors started with a list of 31 genes known to be involved in tail development from mouse studies. First, they looked for any protein-coding mutations that might disrupt the ape homologs of these 31 genes, but didn’t find any promising candidates. So they looked at the non-coding sequences.
They found an ape-specific insertion of a ~300bp Alu element in the 6th intron of a gene called TBXT. The image below shows UCSC genome browser tracks of the alignment between a much of primate genomes, with the apes on top. Basically, the black regions show conserved sequence compared to humans, so the white column in the alignment of the non-ape sequences with humans represents a gap where the non-ape primates lack this insertion, implying it occurred only in the last common ancestor of apes, after they diverged from the other primates.
How does this affect the function of the gene? It wasn’t immediately obvious, until the authors noticed that another Alu element (AluSx1) was present nearby in intron 5 in all primate genomes. They hypothesised that these two Alu sequences, being very similar, could bind to each other in the single-stranded transcript, forming a stem and loop structure. This would disrupt the normal splicing of the transcript, excising exon 6 from the mature transcript, producing a different transcript isoform and therefore the resulting protein would be missing 58 amino acid residues from this exon sequence.
Indeed, they identified this transcript in human embryonic cell populations and then used CRISPR deletions of the Alu elements to show that they were the cause of this transcript, as the isoform failed to be produced without those Alu elements.
Finally, they used CRISPR to delete exon 6 of TBXT in mice, and found that heterozygotes for this mutation tended to have short or missing tails.
This wasn’t a fully penetrant phenotype - some mutants showed perfectly normal tails, so it is a variable phenotype that was likely stabilised by other mutations in the course of early ape evolution.
The partial inactivation of TBXT functionality by the loss of exon 6 from the transcript has severe (lethal) consequences in homozygous mouse mutants, suggesting the selection pressure must have been quite strong in the ape common ancestor to keep this mutation around. Alternatively, the genetic background of the ape ancestor may have happened to be more permissive to this mutation than in mice. Further studies of this mutation in a primate context would be interesting, although challenging.
I think this study is an instant classic. Simple experiments, clearly communicated, and impactful.
