Transposable Elements: Nature and Applications in Genomics

By Wang Jia Hua

The discovery of horizontal gene transfer (HGT) has reshaped the way genomics and phylogenetics is understood and evaluated. Transfer of genetic material is typically characterized by the vertical transfer from parents to offspring during reproduction. In contrast, HGT involves the nonsexual movement of genetic material between different organisms and their genomes (Keeling & Palmer, 2008). Notably, HGT is found to occur across all domains of life and between the three DNA-containing organelles of eukaryotes — namely the nucleus, mitochondrion, and chloroplast (Stegemann et al., 2012). As the incoming genetic material can replace/disrupt existing genes or introduce new genes in the recipient host, mediators of HGT have huge genome-altering potentials. Accordingly, HGT plays a critical role in the evolution of both prokaryotic and eukaryotic genomes (Emamalipour et al., 2020). 

In particular, HGT is widespread between prokaryotes and allows for rapid response to environmental changes via the sharing of genes for antibiotic resistance, virulence and/or metabolic enzymes. While transformation, transduction, and conjugation are three principal mechanisms of HGT in prokaryotes, other mechanisms include gene transfer agents (GTAs), nanotubes and exosomes (Emamalipour et al., 2020). Eukaryotes, however, are less promiscuous with their genetic material and are consequently more resistant to HGT. This is due to the presence of additional biological barriers (e.g. nuclear envelopes) and cytosolic DNases in eukaryotic cells that repel and degrade foreign DNA (Elmer, Christensen & Rege, 2013). Nevertheless, HGT is found to occur in eukaryotes via transposable elements (TEs), alongside novel mediators such as exosomes, apoptotic bodies, and cell-free DNA (cfDNA) (Emamalipour et al., 2020).

TEs, or transposons, are DNA sequences capable of changing their chromosomal location, a process which often results in duplication. Remarkably, TE mobility spans not only within, but also between genomes. Indeed, recent studies revealed that the vertebrate evolutionary history is studded with at least 975 independent horizontal transposon transfer events, although the exact mechanisms and conditions for these events remain largely uncharacterized (Zhang et al., 2020). Current consensus suggests that spatial proximity and intimate ecological interactions, particularly those involving parasites and pathogens, favour the transmission of TEs between highly diverged taxa when coupled with their intrinsic mobility (Bourque et al., 2018). TEs have been identified in all organisms and can occupy a significant proportion of a species’ genome. In eukaryotes, they may form up to 70% of genomic DNA in vertebrates and over 80% in plants (Arkhipova & Yushenova, 2019). 

TEs are primarily selfish genetic elements which can control and enhance their own transmission, often at the expense of host genes. This may compromise the integrity of the genome, leading to reduced host fitness and disease. Specifically, the transposition process (via insertions, excisions, duplications, or translocations in the site of integration) can generate myriad genetic alterations such as deleterious chromosomal rearrangement, gene inactivation, and modulated gene expression  (Munoz-Lopez & Garcia-Perez, 2010). As host survival is critical to TE propagation, strategies have been adopted by both the host and TEs to mitigate the deleterious effects of transposition in order to reach an equilibrium. For instance, some TEs preferentially insert within non-essential regions (e.g. heterochromatic regions) while others may have self-regulatory mechanisms to control their own copy numbers  (Bourque et al., 2018). New insertions may also occur within an existing insertion which inactivates it. Conversely, host organisms possess different defense mechanisms against high levels of transposon activities, including DNA methylation to reduce TE expression, RNA silencing pathways, and inactivation via specific proteins (Munoz-Lopez & Garcia-Perez, 2010). Although usually detrimental, TEs provide raw materials for the derivation of genes which may be co-opted by host organisms to perform essential cellular functions. Key examples of TE-derived genes are the recombination activating genes, Rag1 and Rag2, that catalyse V(D)J somatic recombination in the vertebrate immune system (Dumesic & Madhani, 2014). Besides coding information, TEs also contribute cis-regulatory elements (e.g. promoters, enhancers, transcription factor binding sites) and can modify transcriptional networks by dispersing these elements. It has been estimated that 25% of promoter regions and 4% of exons in humans contain sequences derived from TEs (Munoz-Lopez & Garcia-Perez, 2010). 

In general, TEs can be classified into two distinct classes based on their mechanism of transposition, and each class can be further subdivided based on the mechanism of chromosomal integration. Class I elements, or retrotransposons, use a ‘copy and paste’ mechanism whereby an RNA intermediate is reverse transcribed into a cDNA copy to be integrated back into the genome at a new location. Class I elements are further classified into long terminal repeat (LTR) retrotransposons and non-LTR retrotransposons, which include long and short interspersed nuclear elements (LINEs and SINEs). For LTR retrotransposons, integration is catalysed by integrase much like retroviruses. Conversely, for non-LTR retrotransposons, integration is coupled to reverse transcription via target-primed reverse transcription. Notably, SINEs do not encode their own reverse transcriptase, and instead, parasitize LINE-encoded factors (Bourque et al., 2018). Class II elements, or DNA transposons, primarily adopt a ‘cut and paste’ mechanism which involves a DNA intermediate. DNA transposons contain a transposase gene flanked by 2 terminal inverted repeats (TIRs). These TIRs are in turn recognized by transposase, which excises and inserts the transposon into a new genomic location. Correspondingly, most DNA transposons operate via a non-replicative mechanism, but replicative transposition may also occur (Munoz-Lopez & Garcia-Perez, 2010). In both classes of TE, there are non-autonomous elements (e.g. Alu element, a SINE) which do not encode the required proteins for mobilization (e.g. reverse transcriptase or transposase). Hence, they are dependent on trans-mobilization by the transposition machinery from autonomous elements. Although a significant proportion of the human genome consists of TEs, only a small proportion (<0.05%) of these elements remain active presently. DNA transposons are currently considered to be transcriptionally inactive in most mammals, except certain bats. LINE-1 (or L1) is the only active autonomous TE in humans (Hancks & Kazazian, 2016). 

As TEs are an extensive source of mutations and genetic polymorphisms, and generally mediate their mobility independent of host factors, they can be utilized as genetic tools. Currently, they are used in the analysis of the regulatory genome, embryonic development studies and identification of genes and pathways involved in pathogenesis. There is also a growing interest in developing non-viral gene delivery systems using transposons. While viral gene therapy is highly efficient and has been employed to successfully treat conditions like severe combined immunodeficiency (SCID), clinical progress is hindered by the restriction on gene size (<5–40 kb) and severe side effects such as immune responses, inflammation, and oncogenesis (Munoz-Lopez & Garcia-Perez, 2010). Currently, the most efficient transposons include the Sleeping Beauty (SB), Tol2, and piggyBac (PB) transposons (Elmer, Christensen & Rege, 2013). Each transposon system consists of two general components, namely a transposon vector and a transposase expression vector. The transposon vector consists of the DNA of interest flanked by transposon TIRs, while the transposase expression vector contains the transposase gene fixed downstream of a strong promoter which can be made cell-type restricted. Both components will then be co-delivered into the host (via transfection, injection etc.) for transposition (Munoz-Lopez & Garcia-Perez, 2010). Stable transposition efficiency can also be greatly enhanced by using ‘next-generation’ transposon systems with hyperactivating mutations in the transposases, such as SB100X, the hyperactive version of SB with a 100-fold increase in efficiency (Tipanee, VandenDriessche & Chuah, 2017). Notably, the SB transposon was able to successfully integrate a nitric oxide synthase gene into rat lung cells to prevent pulmonary hypertension, while the PB transposon was able to generate induced pluripotent stem cells through genetic reprogramming of fibroblasts (Elmer, Christensen & Rege, 2013). 

In sum, while TEs have the propensity to create deleterious effects in host organisms as genetic parasites, they are also an important catalyst for genomic variability which serves as the raw material for evolution. Presently, they have emerged as promising vectors for gene therapy which may overcome some of the limitations of commonly used viral vectors. However, there remain many challenges hindering the clinal translation of transposon-mediated gene delivery systems, such as their lower efficiency relative to viral systems and their intrinsic genotoxic potential.


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