A mobile threat to genome stability: The impact of non-LTR retrotransposons upon the human genome

Abstract

It is now commonly agreed that the human genome is not the stable entity originally presumed. Deletions, duplications, inversions, and insertions are common, and contribute significantly to genomic structural variations (SVs). Their collective impact generates much of the inter-individual genomic diversity observed among humans. Not only do these variations change the structure of the genome; they may also have functional implications, e.g. altered gene expression. Some SVs have been identified as the cause of genetic disorders, including cancer predisposition. Cancer cells are notorious for their genomic instability, and often show genomic rearrangements at the microscopic and submicroscopic level to which transposable elements (TEs) contribute. Here, we review the role of TEs in genome instability, with particular focus on non-LTR retrotransposons. Currently, three non-LTR retrotransposon families - long interspersed element 1 (L1), SVA (short interspersed element (SINE-R), variable number of tandem repeats (VNTR), and Alu), and Alu (a SINE) elements - mobilize in the human genome, and cause genomic instability through both insertion- and post-insertion-based mutagenesis. Due to the abundance and high sequence identity of TEs, they frequently mislead the homologous recombination repair pathway into non-allelic homologous recombination, causing deletions, duplications, and inversions. While less comprehensively studied, non-LTR retrotransposon insertions and TE-mediated rearrangements are probably more common in cancer cells than in healthy tissue. This may be at least partially attributed to the commonly seen global hypomethylation as well as general epigenetic dysfunction of cancer cells. Where possible, we provide examples that impact cancer predisposition and/or development.

Fig. 1. Structure of non-LTR retrotransposons

Shown is structure of actively mobilizing retrotransposons in the human genome: an Alu element (blue), a full-length L1 (purple), and a full-length SVA (dark green). The non-LTR retrotransposons are not drawn to scale. All full-length non-LTR retrotransposons end in a homopolymeric tract of Adenosines (polyA-tail, yellow). SVA and L1 contain a polyadenylation signal (pA) immediately before the polyA-tail. Insertions are flanked by target site duplications (TSDs, green). Alu (blue): The A and B stand for the A and B boxes of the internal promoter. The left and right monomers are linked by a spacer sequence A₅TACA₅. L1 (purple): Pro stands for the internal Polymerase II promoter within the 5′ untranslated region (UTR). A full-length L1 element contains two open reading frames (ORF1, ORF2). SVA (dark green): A full-length composite element contains from 5′ to 3′ a hexamer (CCCTCT), an Alu-homologous region of two antisense Alu fragments including other sequence of unknown origin, a variable number of tandem repeat (VNTR) region, and ends in a SINE region from parts of HERV-K10, an human endogenous retrovirus.

Fig. 2. Illustration of non-LTR retrotransposon insertion mechanisms

TSDs are shown in green; AAAAA stands for polyA-tail; A) Illustrates a typical non-LTR retrotransposon insertion. These insertions are thought to occur via TPRT. The insertion is 3′ intact (contains a polyA-tail) and is flanked by TSDs. No host sequence is deleted. B) Shown are the typical hallmarks of an insertion-mediated deletion. The non-LTR retrotransposon is 3′ intact, indicated by the polyA-tail. TSDs are absent; upstream (left) of the element, host DNA is deleted. C) Illustrated is an endonuclease-independent insertion with deletion of host DNA 3′ and 5′ of the insertion. However, deletions can be limited to 3′ or 5′ host DNA sequence. The non-LTR retrotransposon usually does not contain a polyA-tail and is not flanked by TSDs.

Fig. 3. Typical TE-mediated NAHR models

The colored arrows represent non-LTR retrotransposons of a given family; e.g. Alu elements. The tip of the arrow indicates the 3′ end of the TE. TE-mediated NAHRs create a chimeric TE element (indicated by two different colors within element). The breakage point can be anywhere within the TE. While TE-mediated NAHRs are here shown for two adjacent elements, these events can occur between far removed TE elements in the geography of the chromosome. For A) to C) TEs are in the same orientation; for D) TEs involved in NAHR are inverted. Del stands for deletion, dup for duplication, and inv for inversion. A) Interchromosal TE-mediated NAHR results in reciprocal deletion and duplication. (If two non-homologous chromosomes are involved a translocation can occur.). B) Intrachromosomal TE-mediated NAHR between two sister chromatids creates reciprocal deletion and duplication. C) Intrachromosomal, intrachromatid TE-mediated NAHR produces only a deletion. D) NAHR between two inverted TEs results in inversion of DNA between involved TEs.