A freak DNA change 25 million years ago is why humans lack tails
Around 25 million years ago, the chance insertion of a transposable element occurred in a gene in the zygote of an ancient creature. The probability of the insertion occurring in that exact region was around one in a million. Yet it did, causing the creat
ne of the most striking anatomical features of apes, which sets them apart from monkeys, is the absence of a tail. All mammals have a tail at some point during their development, but apes, including humans, chimpanzees, bonobos, gorillas, orangutans, and gibbons, lose them in utero, leaving behind three to five vestigial vertebrae called the coccyx, or tailbone.
Apes started to lose their tails in this way around 25 million years ago, when the ape and monkey lineages split from a common ancestor. And until recently, nobody knew why apes started to do this.
OThe compact genome
Every cell of an organism contains a full copy of that organism’s DNA, called the genome. The genome contains the information that the cell uses to make proteins, the workhorses of the cell. Each protein is coded by a specific section of the genome, called the gene.
Not all cells make all the proteins encoded in the genome. For instance, pancreatic cells make insulin, but skin cells don’t. Skin cells make other proteins, such as keratin, that the pancreas cells don’t. A cell achieves this selective protein production by first making a temporary copy of the gene, called the mRNA, that then drives protein production. So pancreas cells will first copy information in the insulin gene into insulin mRNA, and the insulin mRNA will be used to make insulin protein. Skin cells follow the same process to make keratin.
As scientists began to determine the genome sequence of organisms in the mid1990s, they realised simple organisms like bacteria keep their genomes very compact while more complex life forms don’t. In the bacterial genome, the genes are arranged in tandem: where one gene ends, another begins. As a result, genes make up
85–90% of the bacterial genome.
‘Junk’ DNA
But in complex organisms, genes are spaced far apart. In humans, for example, only 1.5% of the genome codes for proteins. At the time, scientists didn’t know what the rest did and called it ‘junk’ DNA.
Today we know this ‘junk’ DNA is responsible for various functions, including controlling when to make a protein and when not to. A significant fraction of the ‘junk’ also contains transposable elements. These are pieces of DNA that can shift their positions within the genome.
One such element, called Alu, is unique to primates (both apes and monkeys). It is tiny, being made up of around 300 base pairs (the human genome is approximately 3 billion base pairs). But due to its ability to copy itself and ‘jump’ within the genome, it is present in 1.4 million different locations in the human genome. Normally, in nearly all cell types, these elements copy themselves, switch to different locations, and insert themselves into the genome again with minimal consequence to health or evolution. This is because the insertion event is unique to a given cell.
For example, if it happens in an essential gene, only that cell will die; others around it will function normally. The sole exception to this rule is if the insertion happens in the zygote: the fertilized cell after fusion of the sperm and egg that develops into the offspring. Then the change to the DNA will be permanent: it will be reflected in every cell of the offspring.
The Alu accident
Twentyfive million years ago, after the ape and monkey lineages separated, a chance insertion of an Alu element occurred in an important gene in the zygote of an ancient creature. The probability of the insertion occurring in that exact region was around one in a million. Yet it still occurred, and it caused that ancient creature to not develop a tail.
And because the insertion had happened in the zygote, it was imprinted in the DNA of every cell of that creature, and its subsequent offspring — all of them. That creature was the ancestor of all modern apes.
New York University (NYU) scientists reported the discovery of this fateful insertion in a paper in Nature in February.
Identifying the insertion was not easy. The NYU group first searched for DNA changes in 31 genes implicated in tail formation, and compared them across apes and monkeys. As a result, they identified 85,064 mutations (single changes to the DNA sequence), 5,533 deletions, and 13,820 insertions that could be the cause. While many of them were possibly involved in tailloss, none of them stood out because the scientists were looking for changes in the part of the DNA that made the protein.
It was eventually found hiding in the ‘junk’ DNA.
A tailoring defect
A peculiar feature of the genome of complex animals is that a gene never exists as one continuous piece in the genome. The gene is divided into segments separated by ‘junk’; it’s stitched together only when the cell makes the mRNA. This strategy has multiple advantages. For example, the pieces can be rearranged differently at the time of stitching to make different proteins from the same DNA code.
The NYU group found the Alu insertion between two pieces of a gene called TB◣T — a gene already known as one of many involved in tail formation in monkeys. As a result of this insertion, apes can’t stitch the pieces together correctly and ultimately produce a TB◣T protein with one part missing. The team realised this insertion was present in all apes and absent in all other monkeys — a strong sign that it’s the cause of tail loss in apes.
The researchers proceeded to compare the size of the TB◣T mRNA produced in human and mouse stem cells. They found that while the mouse mRNA was intact, a large fraction of the human mRNA was defective — which they had predicted.
An unfinished tail
As scientists began to determine the genome sequence of organisms, they realised simple organisms like bacteria keep their genomes compact while more complex life forms don’t
They needed to conduct one more experiment to be absolutely sure the Alu insertion was the culprit. This one had to demonstrate that a defective TB◣T protein led to tail loss.
The NYU team, led by Prof. Itai Yanai, Prof. Jef Boeke, and PhD student Bo ◣ia, engineered the embryos of mice to produce a defective version of TB◣T — the version found in apes. As if by magic, the resulting mice were born without tails.
The team also determined that the defective TB◣T protein caused other problems, including neural tube defects. They predict that there must have been compensatory changes to the genome to overcome these defects. Some of them could be the differences they themselves identified in the proteins involved in tail formation.
Despite the excellent work of the NYU team, we may never fully understand the tale of our tail. Tail loss has been implicated in bipedalism: our ability to walk on two legs. But it is difficult to speculate on exactly what evolutionary benefit was conferred on the ancestral tailless ape that led to its selection by nature. Whatever that selection pressure may have been, what is incredible is how evolution seized upon that oneinamillion event and used it to create an ape that would go on to rule the world.
(Arun Panchapakesan is an assistant professor at the Y.R. Gaithonde Centre for AIDS Research and Education, Chennai.)