Exon-trapping mediated by the human retrotransposon SVA

Abstract

Although most human retrotransposons are inactive, both inactive and active retrotransposons drive genome evolution and may influence transcription through various mechanisms. In humans, three retrotransposon families are still active, but one of these, SVA, remains mysterious. Here we report the identification of a new subfamily of SVA, which apparently formed after an alternative splicing event where the first exon of the MAST2 gene spliced into an intronic SVA and subsequently retrotransposed. Additional examples of SVA retrotransposing upstream exons due to splicing into SVA were also identified in other primate genomes. After molecular and computational experiments, we found a number of functional 39 splice sites within many different transcribed SVAs across the human and chimpanzee genomes. Using a minigene splicing construct containing an SVA, we observed splicing in cell culture, along with SVA exonization events that introduced premature termination codons (PTCs). These data imply that an SVA residing within an intron in the same orientation as the gene may alter normal gene transcription either by gene-trapping or by introducing PTCs through exonization, possibly creating differences within and across species.[Supplemental material is available online at http://www.genome.org. The 59 RACE sequence data from this study have been submitted to dbEST (http://www.ncbi.nlm.nih.gov/dbEST) under accession nos. Most eukaryotic genomes harbor retrotransposable elements (Malik et al. 1999). About 35% of the human genome is derived from retrotransposed sequences such as LINE-1, Alu, SVA, endogenous retroviruses, and processed pseudogenes (Lander et al. 2001). Although most human retroelement copies are no longer mobile, both active and inactive human elements have been shown to drive genome evolution and influence gene expression (Moran et al. 1999;Han et al. 2004; for reviews, see Belancio et al. 2008;Goodier and Kazazian 2008).SVA RNAs are hominid-specific noncoding RNAs, which vary in size from 700-4000 bp, and are likely mobilized by the human LINE-1 in trans (Ono et al. 1987;Shen et al. 1994;Ostertag et al. 2003;Wang et al. 2005), similar to the human Alu (Dewannieux et al. 2003). There are roughly 2700 SVA copies in the human genome (Wang et al. 2005). A canonical full-length SVA (Fig. 1A) contains a number of sequence features proceeding from its 59 end: (1) a CCCTCT hexameric repeat, ranging in repeat number from a few to as many as 71; (2) a sequence that shares homology with two antisense Alu fragments; (3) a variable number of tandem repeat sequence (VNTR); and (4) a sequence derived from the ENV gene and right LTR of an extinct HERV-K, hereafter referred to as SINE-R. SVAs typically terminate at their own polyA signal, with genomic insertions usually containing a number of adenines at the 39 end. A target site duplication common to other LINE-1-driven retroelements (6-20 bp) flanks the inserted element (Ostertag et al. 2003).Little is known about the biology of SVA apart from its structure. SVAs are c...

Large-scale DNA editing of retrotransposons accelerates mammalian genome evolution

“…In human, the human-specific exon of the SLC22A20 transporter gene overlaps with the edited SVA (SINE-R, VNTR and Alu) element at chr11:64762642-64764372 (build 36; Fig. 4c; see below on SVA) 37,38 . In this gene, editing introduced an adenosine at the nucleotide upstream of the 5′-splice site, modifying the 5′-splice site from the consensus G|GT 39 to A|GT (| indicates the exon-intron boundary).…”

Potential impact of primate-specific SVA retrotransposons during the evolution of human cognitive function

“…Transposable elements (TEs), despite long being thought of as junk DNA, have impacted the human genome during its evolution through a variety of mechanisms causing structural variations including insertional mutagenesis, generation of deletions at the insertion site, 3' or 5' transduction events, non-allelic homologous recombination and exonisation. [1][2][3][4] More than 10,000 TE insertions occurred in the human genome since human-chimpanzee divergence which were suggested to have implications on human evolution and especially its reproductive, cognitive and immune functions that diverged strongly during a relative short time period. 4,5 The large number of such TEs in the genome makes an analysis of their specific contribution to evolution very difficult, and previous studies highlighted the potential role of mainly self-propagating (L1, ERV/ETR) and Alu elements.…”

Human-specific antisense transcripts induced by the insertion of transposable element

“…We found 2 SVAinduced human-specific antisense transcripts. SVA elements are also actively amplified in the human genome (37,38). The 2 HERVs involved in the formation of novel antisense transcripts are of the HERVK subfamily which is an active HERV (35).…”

“…In the remaining cases, the inserted elements contribute a terminal exon (3 cases) or an internal exon (2 cases) to an existing antisense transcript. Addition of an exon cassette into and truncation of the transcripts are commonly induced by transposable elements (37,40,41).…”

“…The Alu, L1 and SVA elements contain cryptic polyadenylation sites and often prematurely truncate the associated transcripts (37,40,41). The antisense EST CN270894 in the TEX11 gene locus ends within the human-specific SVA element.…”