Evolutionary Insights into RNA trans-Splicing in Vertebrates

Abstract

Pre-RNA splicing is an essential step in generating mature mRNA. RNA trans-splicing combines two separate pre-mRNA molecules to form a chimeric non-co-linear RNA, which may exert a function distinct from its original molecules. Trans-spliced RNAs may encode novel proteins or serve as noncoding or regulatory RNAs. These novel RNAs not only increase the complexity of the proteome but also provide new regulatory mechanisms for gene expression. An increasing amount of evidence indicates that trans-splicing occurs frequently in both physiological and pathological processes. In addition, mRNA reprogramming based on trans-splicing has been successfully applied in RNA-based therapies for human genetic diseases. Nevertheless, clarifying the extent and evolution of trans-splicing in vertebrates and developing detection methods for trans-splicing remain challenging. In this review, we summarize previous research, highlight recent advances in trans-splicing, and discuss possible splicing mechanisms and functions from an evolutionary viewpoint.

Native RNA sequencing on nanopore arrays redefines the transcriptional complexity of a viral pathogen

“…Read-through transcription provides a simple mechanism for generation of chimeric polyadenylated RNAs. Chimeric RNAs in mammalian cells are thought to arise predominantly from trans -splicing 28 but in compact, gene-dense viral genomes, read through could produce multi-ORF transcripts in which cis -splicing 29 between neighboring ORFs creates novel fusion proteins (Fig. 4b).…”

“…While read through transcription remains the most plausible explanation for the generation of fusion transcripts, we cannot entirely exclude the possibility that they instead arise from trans-splicing events that join separate mRNAs. While rare outside of protozoan parasites, there are examples of intergenic splices between viral mRNAs from JC virus and SV40 28, 34, 35 , as well as rarer hybrids between viral and host transcripts.…”

Giardia lamblia Hsp90 pre‐mRNAs undergo self‐splicing to generate mature RNA in an in vitro trans‐splicing reaction

“…This is essentially an intramolecular reaction [16][17][18]. Trans-splicing on the other hand, is an intermolecular reaction [19].…”

Chimeric RNAs in cancer and normal physiology

“…This type of chimera was discovered in humans, as well as in fruit flies and mice . Although they were once thought to be rather rare, recently, more evidence is emerging, proving that the occurrence of this phenomenon is much more common than previously thought . Currently, available databases list several thousand TS chimeric transcripts, in all three species mentioned above .…”

“…In the TS mechanism, mature RNAs are formed by the fusion of two separate pre‐mRNA molecules, derived either from different genes (intergenic TS), or from the same gene (intragenic TS) . Intragenic TS products include exon repetitions, or shuffling, as well RNAs composed of exons transcribed from opposite strands (Figure ) . In theory, some of the exon shuffling RNAs may occur due to back splicing, and thus form circular RNA.…”