Nearly all vertebrate animals, including most mammals, have a tail, making tails an almost universal appendage and seemingly a very handy one. Clearly, instructions for tail development must be embedded in the genetic makeup of a diverse range of animals. A prominent exception to this developmental pattern is the great apes (gorillas, orangutans, bonobos, and chimpanzees) and humans. We and our closest evolutionary cousins lack this common fifth appendage, yet the genetic basis for the absence of our tails has remained unknown. Something happened around 25-30 million years ago when the ancestors of modern great apes and humans split from other primates and became a tailless lineage. Now the remnants of our ancestral tail exist only as part of the tailbone (the coccyx). A recent preprint on the bioRxiv site may have found the answer at last.
The authors of the recent study decided to compare the gene sequences of tailless and tailed primates, looking at 31 genes known to have some role in tail formation. Their comparison revealed an intriguing difference in a gene called TBXT. This gene was discovered in mice nearly 100 years ago and is critical for normal tail development. In mice and other animals, a mutation in one copy of the gene leads to shortened and abnormal tails; mutations in both gene copies cause lethality as TBTX is essential for other aspects of development beyond just tail formation. The TBTX gene encodes a protein named brachyury (Greek for “short tail”) that functions to control the activity of other genes during embryonic development. When TBTX is mutated the mutant protein fails to regulate these genes appropriately and tail formation is distorted. Most animals, including primates and humans, have a TBXT gene as it is necessary for embryonic development. What the new study revealed is that, unlike tailed primates, humans and great apes contain an extra insertion in their TBXT gene of a sequence called an Alu element. Alu elements are short sequences of DNA around 300 base pairs long. They are known as “jumping genes” because they can be replicated and the new copy inserted randomly back into the genome at a new location. Over evolutionary history, these elements have spread throughout primate genomes with human genomes now containing approximately 1 million Alu copies (about 10% of our entire genome). All primates contain one Alu copy in their TBXT genes, but humans and great apes contain two copies. When the study authors recreated the double Alu pattern in the mice TBXT gene the resultant offspring all had tail defects. Apparently, having two Alu copies renders the TBXT gene less functional and somehow interferes with tail development, though the downstream mechanistic steps remain undetermined. Thus, a chance insertion of this second Alu element copy into an ancestral primate TBXT gene likely led to the tailless branch of the primate tree. For this tailless phenotype to have become dominant in the great ape lineage there must have been a survival advantage for these individuals with the extra Alu copy in the TBXT gene. We don’t know the specifics, but the altered TBXT gene likely caused other developmental changes that provided favorable selective pressure which compensated for the tail loss. Unfortunately, one surprising finding in the mouse model was that having a double Alu alteration in one copy of their TBXT genes led to a high level of brain and spinal cord defects similar to spina bifida or anencephaly in humans. Perhaps our double Alu-containing TBXT genes are why these birth defects are so common in humans, occurring at about one in every 1000 newborns. Whatever strongly positive effects this double Alu event must have had on our ancestors, we may still be paying the price in the form of frequent neural tube defects among our offspring.
TrueScience 