HOW TAIL GOT LOST IN HUMANS: TRANSPOSABLE ELEMENT IN THE AID FOR EVOLUTION BEFORE 25 MILLION YEARS

 

A 25 million-year question has finally been solved. The question of the tail being lost from humans is an interesting evolution that took place to contribute to orthograde and bipedal locomotion. The tail plays a wide function across vertebrates, for primates in particular, it is adapted to a range of environments and the style of locomotion of the animal. For example, the New World howler monkeys have a prehensile tail that is useful in grasping and holding objects in arboreal habitats (organisms that live in trees). Humans and apes- Hominoids have lost their tails for over 25 million years through evolution. Even though this evolution has made them adapt orthograde and bipedal locomotion (a type of bipedal locomotion that involves walking with the body upright or vertical and with two lower limbs or legs), we still do not know how this evolution has occurred and the genetic mechanism is unknown to knowledge. 

Through recent developments in science and technology, developmental genetic studies on vertebrate and primate genome sequencing projects have given links between genotypic and phenotypic changes. Considering the example of the Mouse Genome Informatics (MGI) database, 100 genes have been identified that have a relation to the shortening and absence of tail phenotype. Moreover, these genes have been from natural mutants (mutations through natural processes) and induced mutagenesis studies (mutations done in the laboratory). Expression of these genes has shown factors for inducing mesoderm and endoderm (layers that develop during gastrulation in the early stages of an embryo's development) such as Tbxt (also called T or Brachyury), Wnt3a and Msgn1 which play a prominent role in the development of primitive streak and posterior body formation. Even though agitation in the genes can lead to the formation of shortening or absence of a tail, the genetic changes that lead to this are still unknown in hominoids. 

This unknown genetic mechanism of losing tail is now known through a paper published in Nature as “On the genetic basis of tail-loss evolution in humans and apes”, where they have explained how this evolution is done at the genetic level.

In the study, aiming to identify the genetic variation in the hominoid tail, 31 human genes that are associated with the tail formation or play an important role in the development of the absence of a tail were screened and their primate orthologues (genes in different species that have evolved from a common ancestral gene and usually retain similar functions) with aiming to identify mutations in the genes leading to the reason for the absence of a tail. The examined orthologue is Old World monkeys (Cercopithecidae) which has the closest lineage to the hominoid genome. However, these data were not enough to identify the evolution of the hominoids.

On examining non-coding hominoid-specific variants on the genes related to tail development, they recognised an Alu element (short DNA sequence that is the most abundant transposable element in the human genome) in the sixth intron of TBXT genes. Through observation they have identified that these elements have interesting features; they are found exclusively in the hominoids, located within or near the genes that are related to the development of tail and have the proximity and orientation of the neighbouring Alu element, stating as repetitive elements, they can somehow have a potential role in gene regulation or genomic rearrangement. In addition, these Alu elements come from a subfamily known as the AluY subfamily which is not a human-specific subfamily and the insertion of this genome correlates with the period when hominoids lost their tails. Moreover, TBXT codes for transcriptional factors which are vital in the development of mesoderm and definitive endoderm formation under embryo development. And heterozygous mutation in the coding region of the TBXT gene of orthologues like mouse, Manx cats, dogs and zebrafish has led to reduced forms of tail.

Through genomic, molecular and bioinformatics analyses, the mechanism behind this reduction of tail is understood. The AluY element is inserted 500bp away from the exon 6 of the TBXT gene and another Alu element, AluSx1 (present in all monkeys and apes) is also located on the intron 5 of TBXT in a reverse orientation, oriented in the opposite direction relative to the direction of transcription of the gene. On transcription,  Alu and AluSx1 element forms a stem-loop structure in the TBXT pre-mRNA that traps the exon 6 within this loop. This leads to an alternative splicing mechanism, the secondary structure development brings the splice donor site of exon 5 and the splice receptor site of exon 7, the sites where splicing machinery recognizes and joins adjacent exons during mRNA processing together removing the exon 6 on splicing. This leads to a hominoid-specific isoform of the TBXT protein, referred to as TBXTΔexon6. Through embryonic stem (ES) cell in vitro differentiation, it was confirmed that TBXTΔexon6 transcript in humans formed  AluY-insertion-induced TBXT(Δexon6) isoform protein that disrupts tail elongation during embryonic development which led to shortening or absence of tail in hominoids.

Researchers conclude that understanding the genetic mechanism behind the evolution of the loss of tail in hominoids may help in understanding the evolutionary pressure that led to the development of human traits like walking in limbs or legs. However, the relation to the evolutionary pressure and loss of tail is still unclear. They hypothesize that the evolutionary decision to forgo the tail, which occurred roughly 25 million years ago, could still have repercussions on human health in the present day.

REFERENCE

Xia B, Zhang W, Zhao G, Zhang X, Bai J, Brosh R, et al. On the genetic basis of tail-loss evolution in humans and apes. Nature. 2024 Feb 28;626(8001):1042–8. doi:10.1038/s41586-024-07095-8

IMAGE CREDIT

 

The Daily Beast, https://images.app.goo.gl/oHnJcpAhXoUhWShw9

Nature, https://images.app.goo.gl/dUzT6WfcHLpJXgWXA