On the Genetic Basis of Tail-Loss in Humans and Apes

The loss of the tail stands as a prominent anatomical distinction between humans and apes compared to most other primates. While the role this change played in our evolutionary trajectory, particularly facilitating bipedalism, has been proposed for decades, the underlying genetic mechanism remained largely a mystery. Recent research, however, sheds light on this long standing question, suggesting a specific genetic alteration potentially responsible for tail loss in the hominid lineage (humans and apes).

The study identifies a specific genetic element, an Alu element (Junk DNA), as a potential culprit for the tail loss. These Alu elements are mobile pieces of DNA prone to inserting themselves into different locations within the genome. In this case, an Alu element inserted itself into an intron (a non-coding region) of the TBXT gene in the hominoid ancestor. This insertion triggered a unique hominoid-specific alternative splicing event. Junk DNA, introns & alternative splicing are NonDarwinian mechanisms as they do not code for proteins directly.

Splicing is a vital process where specific segments of RNA (copies of DNA instructions) are removed or rearranged before protein production. This alternative splicing event, specific to hominoids, resulted in the production of two isoforms (different versions) of the TBXT protein. Interestingly, mice engineered to express both isoforms displayed either a complete absence or a shortened tail, suggesting a direct link between the altered TBXT protein and tail development.

These findings offer strong support for the idea that the exon-skipped transcript (one of the TBXT isoforms lacking an exon due to the splicing change) is sufficient to trigger tail loss. This implies that the altered protein produced from this transcript actively disrupts tail development in hominoids.

Beyond the TBXT Gene:

The TBXT gene, plays a crucial role in embryonic development, particularly in the formation of the tail and the posterior (back) region of the body.  

Tail Loss in Hominoids: Unveiling the Role of Alu Elements and Alternative Splicing

Alu elements are mobile pieces of DNA known to randomly insert themselves into different genomic locations. In this case, an Alu element found its way into an intron (non-coding region) of the TBXT gene in the hominoid ancestor. This insertion triggered a unique hominoid-specific alternative splicing event.

Splicing is a fundamental process where specific RNA segments (copies of DNA instructions) are removed or rearranged before protein production. The hominoid-specific splicing event resulted in two isoforms (different versions) of the TBXT protein. This gene is crucial for limb and spine development, and mutations in it have been linked to various skeletal malformations in humans.

Non-Darwinian Mechanisms:

1. Random Alu element insertion: The insertion of the Alu element into the TBXT gene is not driven by natural selection. It's a random event, not an adaptation to a specific environmental pressure. Unlike mutations that arise through errors in DNA replication (which can be influenced by environmental factors), Alu element insertions occur independent of external selection pressures.

2. Unpredictable consequences: The insertion itself doesn't guarantee a beneficial outcome. While it triggered alternative splicing, the resulting TBXT isoforms and their impact on tail development were unforeseen. This unpredictability stands in contrast to the gradual, directional changes characteristic of Darwinian evolution, where natural selection favors beneficial mutations.

Trade-offs and Implications:

The study also revealed a potential adaptive cost associated with this genetic change. Mice solely expressing the exon-skipped transcript (lacking an exon due to the splicing change) exhibited neural tube defects, a condition similar to one affecting human newborns. This suggests that the evolutionary process leading to tail loss may have involved a trade-off. While losing the tail potentially offered benefits, it also increased the risk of neural tube defects, highlighting the complex and sometimes detrimental side effects of non-Darwinian mechanisms.

While other hypotheses exist for tail loss (e.g., changes in the pelvic region), this research provides compelling evidence for the involvement of Alu elements and alternative splicing as non-Darwinian mechanisms leading to this unique anatomical feature in hominoids. Understanding these non-Darwinian processes not only enriches our understanding of human evolution but also highlights the intricate and sometimes unpredictable nature of genetic alterations and their impact on development and health.

Challenging Neo-Darwinism: The Unexpected Role of "Junk DNA" in Tail Loss

Recent research throws a curveball at the traditional tenets of Neo-Darwinism, highlighting the involvement of Alu elements and alternative splicing in this evolutionary shift.

Traditionally, Neo-Darwinism emphasizes the role of random mutations and natural selection in driving evolution. Random mutations introduce changes in the DNA, and those beneficial for survival and reproduction are favored by natural selection, leading to gradual changes over generations. However, the involvement of Alu elements and alternative splicing in tail loss presents a challenge to this straightforward narrative.

Alu elements, often dubbed "junk DNA" due to their non-coding nature, constitute a significant portion of the human genome. These mobile DNA segments can insert themselves into various locations within the genome, potentially disrupting gene function. In the case of tail loss, an Alu element found its way into an intron (a non-coding region) of the TBXT gene in the hominoid ancestor. This seemingly random insertion triggered an alternative splicing event, a process where specific segments of RNA (copies of DNA instructions) are removed or rearranged before protein production.

This hominoid-specific splicing event resulted in the production of two isoforms (different versions) of the TBXT protein. One isoform, missing an exon due to the splicing change, is believed to be responsible for the tail loss phenotype. This suggests that a seemingly random insertion of "junk DNA" and a subsequent alteration in splicing, not directly related to survival or reproduction, played a crucial role in a significant evolutionary change.

While the exact reason for the exon skipping in hominoids remains unclear, it highlights the potential for non-adaptive mechanisms to contribute to evolution. This contradicts natural selection as the altered TBXT protein may have offered an incidental benefit for bipedalism, leading to its preservation despite the associated risk of neural tube defects, as the study suggests.

Furthermore, the study challenges the notion of mutations solely arising from random errors during DNA replication. The specific insertion of the Alu element suggests the possibility of directed mutations, where environmental factors or the organism's own regulatory mechanisms might influence the location and nature of mutations.

Moving beyond Neo-Darwinism:

This research emphasizes the need to go beyond Neo-Darwinism and acknowledge the complexities of evolutionary processes. The involvement of "junk DNA" and alternative splicing highlights the potential for non-adaptive and non-random mechanisms to play significant roles in shaping evolutionary trajectories.

On the genetic basis of tail-loss evolution in humans and apes

How humans lost their tails — and why the discovery took 2.5 years to publish