Widespread splicing of repetitive element loci into coding regions of gene transcripts

Abstract

We performed a thorough characterization of expressed repetitive element loci (RE) in the human orbitofrontal cortex (OFC) using directional RNA sequencing data. Considering only sequencing reads that map uniquely onto the human genome, we discovered that the overwhelming majority of intronic and exonic RE are expressed in the same orientation as the gene in which they reside. Our mapping approach enabled the identification of novel differentially expressed RE transcripts between the OFC and peripheral blood lymphocytes. Further analysis revealed that RE are extensively spliced into coding regions of gene transcripts yielding thousands of novel mRNA variants with altered coding potential. Lower frequency splicing of RE into untranslated regions of gene transcripts was also observed. The same pattern of RE splicing in the brain was also detected for Drosophila, zebrafish, mouse, rat, dog and rabbit. RE splicing occurs largely at canonical GT-AG splice junctions with LINE and SINE elements forming the most RE splice junctions in the human OFC. This type of splicing usually gives rise to a minor splice variant of the endogenous gene and in silico analysis suggests that RE splicing has the potential to introduce novel open reading frames. Reanalysis of previously published sequencing data performed in the mouse cerebellum revealed that thousands of RE splice variants are associated with translating ribosomes. Our results demonstrate that RE expression is more complex than previously envisioned and raise the possibility that RE splicing might generate functional protein isoforms.

Snaptron: querying splicing patterns across tens of thousands of RNA-seq samples

“…In a repetitive element locus (REL) exonizaton event, part of the interspersed repeat is spliced into a surrounding gene as an exon. Darby et al (2016) report numerous such events in human, including some specific to brain or blood. We used Snaptron to assess tissue specificity of five events where the spliced-in exon was not annotated.…”

“…( A ) Junctions matching Goldstein et al (2016) ’s prediction of a novel exon in the ABCD3 gene. A1 is the 5′ junction, A2 the novel exon, and A3 the 3′ junction; ( B ) KMT2E gene and unannotated junctions supporting a REL exonization event from Darby et al (2016) . B1 is the 5′ junction, B2 the REL exon, and B3 the 3′ junction; ( C ) ALK spliceforms studied by Wiesner et al (2015) and Nellore et al (2016a ).…”

DNA Methylation of Synaptic Genes in the Prefrontal Cortex Is Associated with Aging and Age-Related Cognitive Impairment

“…Due to the high occurrence of CpGs in repetitive elements across mammalian genomes, we investigated the abundance of the DNA methylation in repetitive elements of the rat mPFC for the aging dataset ( Cordaux and Batzer, 2009 ; Su et al, 2012 ; Darby et al, 2016 ). The genomic locations from repetitive elements were downloaded from the UCSC genome browser identified by RepeatMasker for the rn5 genome which contained several classes of repetitive elements including DNA transposons, long interspersed nuclear elements (LINE), long terminal repeats (LTR), short interspersed nuclear elements (SINE), low complexity repeat, simple repeat, satellites, and RNA repeat.…”

Transcription of human endogenous retroviruses in human brain by RNA-seq analysis

“…Accumulating evidence suggested applicability of high throughput sequencing in capturing expression of specific HERV families in tissues under pathological conditions, such as cancer [16,29] and MS [30]. Recent studies using such technique unveiled expression profiling of repetitive elements in brain samples of subjects with psychiatric diseases[31,32]. The proportion of transcripts generated from HERV repeat sequence in these samples is however not known.…”