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How the Human Lost Its Tail

In 1902’s Just So Stories for Little Children, British author Rudyard Kipling famously explained curiosities of the animal kingdom: How the Leopard Got His Spots, How the Camel got his Hump, How the Rhinoceros got his Skin, to name a few.

Reading Just So Stories was one of my earliest memories of thinking like a scientist. I see them in articles on animals’ oddities, such as How the Tabby Got its Stripes, in which I explored a molecular explanation for fur color patterns set in the fetus, from a report in Nature Communications.

Now new research published in Nature brings the just-so approach to the loss of tails among apes – including us.

Apes R Us

Whether or not taillessness was a liability as we evolved depends upon perspective and imagination. Would absence of a fifth appendage have made walking erect – bipedalism – easier? All mammals other than apes have tails, if only as embryos, which is the case for humans. Our tailbones are the remnants of tails.

In the Nature paper, Bo Xia, Jef Boeke, Itai Yanai and colleagues at NYU Langone Health detail the genetic basis of tail loss among apes (humans, chimpanzees, gorillas, and orangutans and their immediate ancestors; aka hominoids). The apes are a separate branch of the evolutionary tree from monkeys, baboons, and gibbons. Monkeys have tails; apes do not.

(The popular meme of primate evolution as a straight line from monkeys to apes to office workers is incorrect; evolution is a series of branches, as species diverged from shared ancestors.)

We hominoids are the only primates that do not have tails. When the primate lineage split from the evolutionary tree some 65 million years ago, tails were still present, but by the time apes split off 25 million years ago, only tailbones remained.

Did a Genetic Harpoon Lead to Tail Loss?

The researchers searched the DNA of humans and other primates for clues to how we lost our tails. They discovered that a bit of repetitious DNA, called an Alu sequence, inserted into a gene associated with tail development early in the ape lineage. That event blocked synthesis of the protein that signals formation of the tailbone. Evolutionary biologists can estimate points in evolutionary time from known mutation rates of certain genes, using them as molecular “clocks”.

The researchers used mouse embryos to recapitulate the genetic jettisoning of tail-building instructions. They analyzed changes in each of 140 “candidate” genes linked to vertebrate tail development among different primate species.

First, the team looked for gene parts that are transcribed into mRNA and then translated into protein (exons). They didn’t find any changes that might block tail development. But when they scrutinized non-coding regions of the genes (introns), they discovered an unusually large number of Alu repeats in a gene called TBXT, which stands for “Brachyury,” meaning “short tails.” These mutations underlie taillessness in several species, including Manx cats and Algerian mice.

TBXT encodes a transcription factor, controlling the activities of several or many genes.

A Closer Look at Alu Sequences

Alu repeats entered primate genomes about 65 million years ago, and today more than a million pepper primate genomes. Other animal species don’t have them.

An Alu repeat is a “retrotransposon,” a short sequence of RNA that is copied into DNA that then inserts into the genome. It’s about 300 bases long. A human genome may include 300,000 to 500,000 of them, comprising 2 to 3 percent of the genome. Retrotransposons increase in number over time as DNA copies are peeled off of RNA templates.

We don’t know exactly what these common repeats do, if anything. But unusual configurations of Alu repeats are linked to forms of neurofibromatosis, hemophilia, familial hypercholesterolemia, type 2 diabetes, and cancers of the breast, liver, colon, and prostate.

In the apes, loss of the tail seems to come from two Alu repeats in the TBXT gene, oriented in opposite directions. To geneticists, reverse repeats conjure an image of molecular scissors. The two repeats form complementary base pairs, pushing the DNA between them into a “stem-loop,” lollipop-like structure.

Then a DNA-cutting enzyme comes along – part of normal DNA repair – and snips out the material between these two signposts, then splices the gene back together. Jettisoning exon 6 of the 9 in TBXT would have stifled tail formation in half of the offspring in which the initial mutation occurred, depending upon which copy of the chromosome was inherited.

If, over time, tailless apes had a mating advantage, the trait would have persisted.

Embryo Experiments

But the researchers did more than just imagine past genetic events. Hypothesizing that Alu repeats looped out a crucial bit of TBXT in an immediate ancestor of the hominoid line that led only to us, the NYU investigators grew embryonic stem cells from humans and mice until the time when TBXT turns on in the embryo, triggering tail extension.

Mice genomes don’t have Alu repeats, so those embryos transcribed normal-length TBXT. But the embryos derived from human stem cells made normal TBXT mRNAs as well as a stunted type missing exon 6. And that deletion was apparently enough to squelch tail development in an embryo. Mice without any TBXT mRNA didn’t survive beyond the embryo period; those making just some had tails of varying lengths.

In an additional strategy, the researchers used CRISPR–Cas9 to remove TBXT exon 6 from mouse embryos, modeling the situation in apes. They also created ‘humanized’ mice that had the apposed Alu repeats around exon 6, and those animals, too, were tailless or had only tiny lumps on their rears.

Mice with exon 6 deleted in one chromosome and the apposed ape Alu sequences in the other copy also lacked tails. It was an elegant proof-of-principle implicating the TBXT gene in tail formation.

Neural Tube Defects

On a more practical note, some of the mice with tweaked tail genes had neural tube defects (NTDs), such as spina bifida and anencephaly. These affect the brains or spinal cords of one in a thousand human newborns.

The researchers point to NTDs as a possible “adaptive cost,” a rare developmental derailment arising from an evolutionary trend that otherwise offers the advantages of losing tails. And so the evolution of tail loss may have led to an increased likelihood of NTDs in humans and other apes.

Using hints from more than 200 genes associated with NTDs in non-human vertebrates, investigators are searching the genome sequences of people with NTDs to identify patterns of gene variants that could contribute to risk for, or cause, these conditions. A report from 2019 listing genes and pathways associated with increased risk of NTDs will have to add TBXT.

Advantages of Bipedalism

Being bipedal must have brought an evolutionary advantage, or it wouldn’t have persisted.

Fossil evidence indicates that the trait was present in our forebears, such as Ardipithecus ramidus, which lived some 4.4 million years ago in Ethiopia. Perhaps standing tall would have enabled this ancestor to reach higher into trees for fruits.

Imagine how our taillessness might have arisen.

East Africa about 25 million years ago, when the first apes appeared, was a time of tumult. Earthquakes and volcanoes altered habitats, as new lakes and rerouted rivers brought environmental challenges.

Perhaps the Alu insertion into the TBXT gene occurred spontaneously, as these things can, in an individual in a small, reproductively isolated group. It persisted as apes who inherited it after the initial event had an advantage – something that lacking a tail enabled them to do better than apes still burdened with tails.

And so the new trait may have arisen fortuitously, in a small isolated group, and then retained by natural selection because it offered an advantage. Our lack of tails may be an evolutionary just-so-story.

Conclude Miriam K. Konkel and Emily L. Casanova in a News and Views accompanying the research report, “Although the ultimate causality might remain unknowable, Xia and colleagues’ results offer a deeply compelling new chapter in the tale of our tail, and identify ways by which transposable elements can contribute to the diversification of the human repertoire of gene expression and, ultimately, typical human features.”

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