Discovering Alu element's role in the tale of tail loss: One giant leap for human evolution

Abstract

In a recent article published in Nature, Xia et al. found that the insertion of a specific AluY element in the sixth intron of the primate TBXT gene may lead to the evolution of tail loss.¹ The significance of this study emphasizes that uncovering the genetic mechanism in facilitating tail-loss evolution in hominoids can contribute to understanding evolutionary pressure that boosts the formation of human traits and evolutionary diseases.

From a Darwinian evolutionary perspective, the lack of a tail is one of the key features in the evolution from hominids, signifying the anatomical shift from primitive ancestors to modern humans, especially the disappearance of the external tail.² This unique transformation not only illustrates a remarkable chapter in our biological history, but also underscores the intricate interplay of heredity and evolution. The story of the tail, or more precisely, its absence opens a window into how minor genetic alterations can orchestrate remarkable developmental changes. Alu elements are a type of short interspersed nuclear element (SINE) found abundantly in the human genome. Alu elements, as a class of transposable elements unique to the primate genome, exert a profound influence on genome evolution. These elements increase genomic instability by providing the most common homologous sequences for non-allelic homologous recombination events, which can lead to disease. Through delving deeper into the TBXT gene, Xia et al. revealed a human-specific insertion of an Alu element that is oriented in the opposite direction to the neighboring Alu element, forming a pair that may have led to human-specific gene splicing that affects gene expression. Validated by a mouse model, this splicing was found to alter TBXT gene expression, resulting in missing or shortened tails in mice,¹ providing strong support for the theory that exon skipping leads to tail deletion (Figure 1).

To investigate the genetic mechanism of ancient human-specific selective splicing events, Xia et al. used CRISPR-Cas9 to knock out the AluY element and its interaction with the AluSx1 element in human embryonic stem cells. By modeling the developmental expression pattern of the TBXT gene, Xia et al. revealed that the deletion of the AluY element almost completely blocked the TBXT^Δexon6 heterodimeric transcripts production.³ These findings highlight the complex role of transposable factor interactions in gene regulation and the importance of TBXT isoform expression in tail development.

The loss of the tail is a complex and widely debated topic in biological evolution, involving a delicate balance between evolution and degeneration. From an evolutionary perspective, the loss of the tail in humans and other upright walking organisms is considered to be an adaptive evolution to a new environment and way of life, in which the tail may have changed from being useful to being superfluous or burdensome, leading to its gradual disappearance in the course of evolution.⁴ On the other hand, the loss of the tail has been recognized as a degenerative phenomenon that may lead to a decline in body functions. Despite being a topic of controversy, it offers valuable insights into species adaptation to their environment. The tail serves the functions of balance, communication and protection; therefore, the loss of the tail may lead to the loss of these key functions, likely affecting survival and reproduction. Recent studies have emphasized that TBXT is essential for the development of many body structures, notably the spinal cord and its neural components.⁵ Despite its recognized importance in spinal cord development, the regulatory mechanisms of TBXT expression in the mammalian spinal cord are still not well understood. Using a mouse model, Xia et al. found that mouse tail length is strongly correlated with the expression of two forms of the TBXT gene: long-tailed mice predominantly express the full-length TBXT, while short-tailed or tailless mice predominantly express the exon6 deletion form. Mice exclusively expressing the exon6 deletion form undergoes abnormal development, often failing to survive till to birth. Furthermore, these embryos manifest neural tube closure defects akin to those observed in human spina bifida cases. In addition, the expression of different TBXT variant forms in mouse embryonic stem cells may affect the activity of other genes, pointing to a complex network of gene expression regulation. This study deepens the understanding of the role of TBXT genes in tail development and reveals the impact of their variants on overall development and gene regulation.¹ Consequently, the loss of the tail can be seen as an adaptive evolution in specific circumstances.

Authors use of mouse models to mimic human genetic conditions is invaluable. Obviously, these models may not fully recapture the complexity of human development and evolution. Incorporating other model organisms, such as other nonhuman primates or genetically engineered models that more closely mimic human embryonic development, can provide additional insights into evolutionary mechanisms. This study provides compelling evidence for the role of the AluY insertion in the TBXT gene in the evolution of tail loss, However, it's crucial to recognize that this complex trait may be influenced by multiple genetic factors. Future studies may expand the genetic analysis to include a wider range of genes associated with tail development and investigate other potential genetic variants that may contribute to tail loss. This study may benefit from a broader comparative genomic analysis of a wider range of primates and other species with different tail phenotypes. Such analyses could help identify mechanisms of convergent evolution and provide a more complete understanding of the genetic basis of tail loss. The researchers found that a genetic change led to the loss of the tail in anthropoids, identifying thousands of unique genetic changes potentially involved in tail shedding.¹

This study opens new perspectives for understanding the remarkable evolutionary loss of the tail in humans and other hominids. By revealing the decisive influence of specific genetic variants in tail development, it not only deepens our understanding of the genetic basis of human evolution, but also provides new impetus to research in the fields of developmental biology, genetics, and evolutionary biology. In particular, cutting-edge technologies such as CRISPR-Cas9 gene editing used in this study provide powerful new tools for scientists to explore similar biological questions. More importantly, this discovery provides new insights into “evolutionary diseases”—genetic diseases that arose during human evolution and affect our lives today. Some evolutionary diseases may be related to heredity to some extent, and genetic variations in the course of evolution may also lead to some new genetic diseases. In the long history of human evolution, almost all of the genetic variants associated with disease risk have originated from evolutionary processes unique to humans. The profound effects of these genetic diseases extend to contemporary human health and disease, especially those related to the TBXT gene and related genetic pathways. This will provide new clues for disease prevention and treatment.

Overall, the authors in this outstanding study explored the genetic causes of tail deletion in evolution of humans and their close relatives and found that Alu element insertion may promote tail deletion, and confirmed the effect of genetic variation on tail length and its association with neural tube abnormalities by mouse models. Through comparative genomics analysis, researchers should aim to reveal the specific genetic variations in human tail development and provide new insights to resolve the evolutionary mechanism of human tail deletion.

Yongye Huang and Min Wu composed and edited the manuscript. Xiaoyan Liu illustrated the figure and artwork in consultation with coauthors. The article has received approval from all authors.

The authors declare no conflict of interest.

Not applicable.