Human and Ape Tail Loss: An Evolutionary Accident Caused by an Alu Element Insertion

演化之聲
Mar 13
5 min read

The tail plays an important role in locomotion for many vertebrates, and primates are no exception. Monkeys rely on their tails to maintain balance while moving among branches, and in some species the tail even functions as a fifth limb capable of grasping branches or food. Members of the hominoid lineage—including gibbons, great apes, and humans—lost this structure approximately 25 million years ago when their ancestors diverged from Old World monkeys. In modern humans, only a vestige of this structure remains in the coccyx, which consists of three to five fused caudal vertebrae. For decades, the disappearance of the tail has been considered one of the anatomical changes that may have facilitated upright posture and bipedal locomotion in hominoids. Yet the genetic mechanism behind this transformation remained unclear until recent research identified a key molecular event.

Evolutionary change ultimately arises from alterations in DNA sequences. By comparing genomes across primate species, researchers discovered that a gene called TBXT differs between monkeys and apes. TBXT is a highly conserved gene, meaning that its sequence has remained remarkably stable throughout evolution. For example, the protein encoded by this gene is about 91 percent identical between humans and mice. TBXT produces a transcription factor known as Brachyury, which functions as a molecular switch that activates specific sets of genes during embryonic development. This protein is particularly important during the formation of mesoderm and certain regions of the endoderm, where it helps guide the early organization of the developing embryo.

Because TBXT plays such a fundamental developmental role, complete loss of its function is lethal. Embryos lacking a functional copy of the gene cannot properly develop and fail to survive. Mutations that partially disrupt TBXT can still produce dramatic anatomical effects. In humans, one heterozygous mutation—where only one copy of the gene is altered—has been associated with congenital spinal malformations. Similar mutations in laboratory mice produce both spinal defects and shortened tails, demonstrating that the gene is crucial for proper tail development. A naturally occurring example can also be found in Manx cats, which lack tails due to a heterozygous mutation in TBXT that deletes part of the gene sequence and produces an incomplete Brachyury protein.

Before returning to the evolutionary story of tail loss in hominoids, it is helpful to understand the basic process by which genes produce proteins. A gene is first transcribed from DNA into messenger RNA, or mRNA. This molecule then travels from the nucleus to the cytoplasm, where it is translated into a protein. This entire process is known as gene expression. However, the mRNA produced directly from DNA—called pre-mRNA—initially contains both coding and non-coding segments. The coding segments are known as exons, whereas the non-coding segments are called introns. These regions appear interwoven along the pre-mRNA sequence and must be processed before translation can occur.

During RNA processing, a molecular complex known as the spliceosome identifies the boundaries between introns and exons and removes the introns through a process called RNA splicing. The remaining exons are then joined together to form a mature mRNA molecule that can be translated into protein. The removed intron sequences may subsequently be degraded or occasionally serve regulatory functions as non-coding RNAs.

Splicing is not always performed in exactly the same way. Cells can sometimes choose different combinations of exons when assembling the final mRNA. This process, known as alternative splicing, allows a single gene to generate multiple protein variants with distinct functions. Alternative splicing is extremely common in eukaryotic genomes and greatly expands the diversity of proteins that cells can produce.

(Figure 1) pre-mRNA and mRNA（圖片來源：TedE，採用 CC BY-SA 3.0 授權)

(Figure 2) Alternative splicing（圖片來源：Agathman，採用 CC BY-SA 3.0 授權）

The research that clarified the origin of tail loss in hominoids revealed that an unusual form of alternative splicing occurs in the TBXT gene. Scientists found that, in apes and humans, an Alu element is present within the intron following exon 6 of TBXT. This specific element belongs to the AluY family and does not appear in the corresponding gene of monkeys.

Alu elements are a type of transposable element—segments of DNA capable of moving from one location to another within the genome. They are sometimes called “jumping genes” because they can insert themselves into new genomic positions. The human genome contains more than one million copies of Alu elements. Most of the time these sequences have little immediate effect, but occasionally their insertion can alter the function of nearby genes.

In the ancestor of modern hominoids, around 25 million years ago, an AluY element inserted itself into the intron located after exon 6 of the TBXT gene. Another Alu element, called AluSx1, already existed in the preceding intron. Because these two sequences are oriented in opposite directions, they can pair with each other when the TBXT gene is transcribed into RNA. This pairing causes the RNA strand to fold into a loop-like structure.

When this structure forms during RNA processing, it effectively hides exon 6 from the spliceosome. As a result, the splicing machinery skips this exon and produces a shortened mRNA that lacks exon 6. The resulting transcript is known as TBXTΔexon6. The protein translated from this shortened transcript lacks part of the normal Brachyury sequence and cannot perform its usual function in regulating embryonic development.

Experimental studies confirmed the significance of this change. When researchers engineered mice to produce both the normal TBXT protein and the shortened TBXTΔexon6 variant, the animals frequently developed shortened tails or lost their tails entirely. These results demonstrated that the exon-skipped transcript is sufficient to disrupt normal tail formation during embryonic development.

The degree of tail reduction depends on the relative abundance of the two TBXT forms. When the shortened isoform is present at higher levels compared with the full-length version, tail development becomes increasingly suppressed. In extreme cases, embryos expressing only the truncated form fail to develop properly and may die before birth. These experiments revealed that tail formation is highly sensitive to the balance between the two TBXT protein variants.

Interestingly, the same mechanism may also carry biological costs. Mice expressing the truncated TBXT isoform sometimes develop neural tube defects—abnormalities in the formation of the spinal cord that resemble conditions such as spina bifida in humans. This suggests that the evolutionary disappearance of the tail may have involved a trade-off: a structural change beneficial for locomotion might have increased the risk of certain developmental disorders.

From an evolutionary perspective, the sequence of events is strikingly simple. A single transposable element inserted itself into a gene involved in tail development. Through an interaction with another nearby Alu sequence, this insertion altered RNA splicing and produced a new protein variant that interfered with tail growth. Natural selection then preserved this trait within the hominoid lineage.

Evolution often appears to be driven by grand adaptive strategies, yet many of its most profound outcomes begin with chance molecular events. In this case, a wandering fragment of DNA inserted itself into the genome of an ancient primate ancestor. Over millions of years, that accidental insertion helped shape one of the defining anatomical features of humans and other apes—the absence of a tail.