Transposable Elements: Major Players in Shaping Genomic and Evolutionary Patterns

Abstract

Transposable elements (TEs) are ubiquitous genetic elements, able to jump from one location of the genome to another, in all organisms. For this reason, on the one hand, TEs can induce deleterious mutations, causing dysfunction, disease and even lethality in individuals. On the other hand, TEs can increase genetic variability, making populations better equipped to respond adaptively to environmental change. To counteract the deleterious effects of TEs, organisms have evolved strategies to avoid their activation. However, their mobilization does occur. Usually, TEs are maintained silent through several mechanisms, but they can be reactivated during certain developmental windows. Moreover, TEs can become de-repressed because of drastic changes in the external environment. Here, we describe the 'double life' of TEs, being both 'parasites' and 'symbionts' of the genome. We also argue that the transposition of TEs contributes to two important evolutionary processes: the temporal dynamic of evolution and the induction of genetic variability. Finally, we discuss how the interplay between two TE-dependent phenomena, insertional mutagenesis and epigenetic plasticity, plays a role in the process of evolution.

Keywords: environmental stress; epigenetics; evolution; transposable elements.

Figure 1

Schematic representation of the different mechanisms of transposition. Generally, TEs can be distinguished in two major classes on the basis of their mechanism of transposition: active eukaryotic Class I (retrotransposons) and active eukaryotic Class II (DNA transposons). Additionally, TEs can be divided into autonomous and non-autonomous. (a) Class I (retrotransposons) require RNA transcription to be able to move to different genome locations. They encode for a reverse transcriptase enzyme that uses the transcript as a template to produce a cDNA sequence that reinserts randomly into a new genomic site. This is the so-called “copy and paste” mechanism. Autonomous Class I RNA transposons encode all proteins necessary for moving. They include long terminal repeats/endogenous retroviruses (LTR/ERV; e.g., the yeast Ty element) and non-LTR retrotransposons such as the long interspersed nuclear elements or LINEs (e.g., human L1). LTR-retrotransposons contain two long terminal repeats (LTRs, grey arrows) and genes encoding for functional proteins, such as Gag (group-specific antigen), Pol (reverse transcriptase), Int (integrase) and Prt (protease). The non-LTR retrotransposons also contain genes encoding for enzymes required for transposition but lack LTRs. Instead, they have two open reading frames flanked by a 5′ and a 3′ untranslated region (UTR). Generally, these TEs mobilize by a target-site primed reverse transcription (TPRT) mechanism. After the hydrolysis of one strand of DNA at a new insertion site, the 3′OH end of this strand is used to prime the reverse transcription of a new LINE cDNA by the reverse transcriptase encoded by the element. Subsequently, hydrolysis of the second DNA strand releasing a 3′OH end that primes replication of the second strand of the LINE cDNA. Finally, the integrase completes the insertion. (b) Non-autonomous retrotransposons rely on “true” (autonomous) retrotransposon activity for mobility. For example, SINE elements (like Alu) have an internal promoter for RNA polymerase III flanked by a 5′ and a 3′ UTR but lack genes encoding enzymes required for transposition. SINEs use the same TPRT mechanism to transpose, but they must borrow the necessary activity from LINE to insert. (c) Class II (DNA transposons) encode the protein transposase (TPase) flanked by terminal inverted repeats (TIRs). TPases are responsible for removing and inserting TEs in a new genomic location according to two different mechanisms. One is the so-called “cut and paste” or “non-replicative pathway” mechanism through which a TE is excised from its locus and reinserted at another site. The second is the “replicative pathway” in which a TE is copied, and the copy is relocated, leaving behind the original.

Figure 2

TEs as ‘molecular parasites’ or ‘functional symbionts’. As ‘molecular parasites’ TEs can produce a variety of detrimental effects on the host genome. (a) The insertion of TEs within coding exons can cause frame shift mutations disrupting protein sequence and function. (b) TEs can cause genomic instability being the substrate for chromosome rearrangements, such as duplications, deletions, inversions and translocations. (c) The insertions of TEs in regulatory stretches such as in 5′ or 3′ regions or introns can cause epigenetic modifications resulting in inappropriate activation or repression of gene expression. The co-option of TEs by the host genome may generate new regulatory signals or coding sequences. This process is referred to as ‘molecular domestication’. (d) TEs may contribute new enhancer sequences for transcription factors (grey circle) changing the spatial/temporal regulation of gene expression. (e) After the loss of telomerase, retrotransposons can actively participate in the maintenance of telomeres. Three non-LTR families, HeT-A, TAHRE, and TART form a head-to-tail array. They express Gag and Reverse Transcriptase proteins that are necessary for the elongation of telomeres. (f) TEs can contribute to the maintenance of genome architecture by providing binding sites for the CTCF protein that is responsible for establishing “topologically associated domains” (TADs). “Created with BioRender tool. https://app.biorender.com/” (accesed on 8 February 2022).

Figure 3

Regulation of TEs in germline and soma under standard and stress conditions. (a) Stepwise model of transcriptional silencing guided by Piwi-interacting RNAs (piRNAs). In the germline of Drosophila the silencing of TEs is guided by specific, small RNAs organized in piRNA clusters enriched in TE sequences. At the core of the pathway is the piRNA-induced silencing complex (pi-RISC) that consists of a single-stranded piRNA bound to a Piwi family protein. Piwi (light green) can guide the transcriptional silencing of TEs through direct assembly of the complex at heterochromatin target sites. Drosophila harbors three Piwi-like proteins: Piwi, Aubergine (Aub, orange), and Argonaute 3 (Ago3, dark green), which, guided by piRNAs, silence TEs post-transcriptionally (in addition to transcriptional silencing referred to above) through homology-dependent cleavage. Anti-sense TE sequences are exported from the nucleus and processed into smaller fragments by Aub before being loaded into Ago3. The resulting piRNA–Ago3 complexes cleave newly antisense piRNA precursors from clusters loaded into Aub to produce anti-sense piRNAs, resulting in a “ping-pong” amplification cycle. Additionally, Aub–piRNA complexes can bind TE transcripts and repress their translation directly. (b) In the soma the repression of TEs is mediated predominantly by the small interfering RNA (siRNA) pathway. siRNA precursors form short hairpin structures before being processed and incorporated into the RNA-induced silencing complex (RISC). Once a siRNA binds to its target TE mRNA, it induces the cleavage of such an mRNA by RISC. Other silencing mechanisms involve chromatin remodeling. Several inhibitory marks, such as DNA methylation and histone methylation and deacetylation play an important role in repressing the mobilization of TEs. These epigenetic modifications may be passed on by dividing cells from one generation to the next. (c) When individuals are exposed to drastic environmental changes, they may experience stress-induced (re)activation of TEs. Epigenetic mechanisms like DNA methylation, histone modifications, expression of non-coding RNAs (ncRNAs) seem particularly relevant for this phenomenon. Additionally, environmental stress, such as heat shock, can induce de-repression of TEs by inducing the disruption of RISC through the action of the inducible Hsp70 chaperone, which targets the complex to the lysosome. The generalized reactivation of TEs can generate genome instability leading to higher risk of disease when occurring in somatic cells and to infertility when arising in germ cells. However, in the latter it brings about increased genetic variability also, which is key for an adaptive response to extreme environmental change.