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Review
. 2016 Mar 10;8(3):562-77.
doi: 10.1093/gbe/evw025.

Evolutionary Insights into RNA trans-Splicing in Vertebrates

Quan Lei  1 , Cong Li  1 , Zhixiang Zuo  1 , Chunhua Huang  2 , Hanhua Cheng  3 , Rongjia Zhou  4
Affiliations
Review

Evolutionary Insights into RNA trans-Splicing in Vertebrates

Quan Lei et al. Genome Biol Evol. .

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.

Keywords: RNAs; evolution; functions; trans-splicing; vertebrates.

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Figures

F<sc>ig</sc>. 1.—
Fig. 1.—
Schematic diagram of different types of pre-RNA splicing events. (A) Cis-splicing. After excision of introns, exons of the same pre-mRNA are joined together to form a linear molecule. (B) Intergenic trans-splicing. Transcripts from different genes or even different chromosomes could be spliced and generate a non-linear chimeric molecule. (C) Intragenic trans-splicing. Boxes with vertical line represent exons transcribed from the other strand. In the same gene, splicing reaction occurs between two identical transcripts, alternatively, transcripts from different strands leading to exon-duplication and sense–antisense fusion. (D) SL trans-splicing. Red boxes represent structural genes, while T represents for the TMG cap on Spliced-leader (SL) mini-exon. SL exon produced from tandem repeated SL gene cluster, splicing reaction occurs between SL exon and distinct structural genes of a ploycistronic pre-mRNA to generate an array of mature “capped” transcripts.
F<sc>ig</sc>. 2.—
Fig. 2.—
Phylogenetic analysis of trans-splicing events. Evolutionary tree and time scale refer to Benton et al. ( 2007). Ba, billion years ago; Ma, million years ago. In low panel, the percentage of trans-splicing events and trans-spliced gene numbers are relative to the total amount of gene numbers for a species. Trans-splicing data are from published literatures: Parhyale hawaiensis (Douris et al. 2010), Clytia hemisphaerica (Derelle et al. 2010), Echinococcus multilocularis (Brehm et al. 2000), Heterochone sp. (Douris et al. 2010), Hydra vulgaris (Stover et al. 2001), Pleurobrachia pileus (Derelle et al. 2010), Spadella cephaloptera (Marletaz et al. 2008; Marletaz and Le Parco 2008), Ciona intestinalis (Vandenberghe et al 2001; Satou et al. 2006; Satou et al. 2008; Matsumoto et al. 2010), Adineta ricciae (Pouchkina-Stantcheva et al. 2005), C. elegans (Krause et al. 1987; Huang et al. 1989; Zorio et al. 1994), Ascaris sp. (Nilsen et al. 1989; Maroney et al. 1995), Trypanosoma brucei (Murphy et al. 1986; Sutton et al. 1986; Perry et al. 1987; Liang et al. 2003), Amphidinium carterae (Bachvaroff et al. 2008; Zhang et al. 2009) and Karlodinium micrum (Zhang et al. 2007). In the other species, the percentage of trans-splicing events are calculated by counting known trans-splicing molecules including T4 bacteria phage (Galloway Salvo et al. 1990), HIV (Caudevilla, Da Silva-Azevedo, et al. 2001), SV40 (Caudevilla, Da Silva-Azevedo, et al. 2001), Pv2 (ORF3) (Gao et al. 2013), Lactococcus lactis (Belhocine et al. 2007), Nanoarchaeum equitans (Randau et al. 2005), Drosophila (Dorn et al. 2001 Horiuch et al. 2003), Anopheles gambiae (Robertson et al. 2007), Bombyx mori (Shao et al. 2012; Duan et al. 2013), Danio rerio (Cadieux et al. 2005), Gallus (Vellard et al. 1991), Sus scrofa (Ma et al. 2012), Rattus norvegicus (Sullivan et al. 1991; Caudevilla et al. 1998; Akopian et al. 1999; Takahara et al. 2002; Zhang et al. 2003; Fitzgerald et al. 2006; Ni et al. 2011), Mus musculus (Hirano et al. 2004; Zhang et al. 2010) and Homo sapiens (Vellard et al. 1991; Breen et al. 1997; Yu et al. 1999; Chatterjee et al. 2000; Takahara et al. 2000; Finta et al. 2002; Flouriot et al. 2002; Jehan et al. 2007; Guerra et al. 2008; Li et al. 2008; Brooks et al. 2009; Kannan et al. 2011; Kowarz et al. 2011, 2012; Fang et al. 2012; Hu et al. 2013; Kawakami et al. 2013; Yuan, Qin, et al. 2013; Li et al. 2014; Wu et al. 2014). Percentages in insects are consistent with recent mega-data study (Kong et al. 2015).
F<sc>ig</sc>. 3.—
Fig. 3.—
Phylogenetic analysis of spliceosome-associated proteins hnRNPA1, hnRNPI (PTBP1), SRSF1, and SRSF2. Ma, million years ago. Species with SL trans-splicing are marked with asterisks. Phylogenetic analysis was performed with MEGA 6 using maximum likelihood method. Numbers on the branches represent the bootstrap values from 1,000 replicates obtained. The scale bar corresponds to the estimated evolutionary distance units. GenBank accession numbers are as follows: Homo sapiens, NP_002127.1 (hnRNPA1), NP_002810.1 (PTBP1), NP_001071634.1 (SRSF1), NP_001182356.1 (SRSF2); Mus musculus, NP_001034218.1 (hnRNPA1), NP_001070831.1 (PTBP1), NP_001071635.1 (SRSF1); NP_035488.1 (SRSF2); Rattus norvegicus, NP_058944.1 (hnRNPA1), NP_001257986.1 (PTBP1), NP_001103022.1, (SRSF1), NP_001009720.1 (SRSF2); Sus scrofa, NP_001070686.1 (hnRNPA1), NP_999396.1 (PTBP1), NP_001033096.1 (SRSF1), NP_001070697.1 (SRSF2); Gallus gallus, XP_004950342.1 (hnRNPA1), NP_001026106.1 (PTBP1), NP_001107213.1 (SRSF1), NP_001001305.1 (SRSF2); Danio rerio, NP_956398.1 (hnRNPA1), NP_001116126.1 (PTBP1), NP_956887.2 (SRSF1), NP_998547.1 (SRSF2); Drosophila, NP_001262538.1 (hnRNPA1), NP_001097994.1 (PTBP1), NP_001247139.1 (SRSF1), NP_001188794.1 (SRSF2); Bombyx mori, NP_001093319.1 (hnRNPA1), XP_012546585.1 (PTBP1), XP_012548197.1 (SRSF1), NP_001040152.1 (SRSF2); C. elegans, NP_500326.2 (hnRNPA1), NP_741041.1 (PTBP1), NP_499649.2 (SRSF1), NP_495013.1 (SRSF2); Ciona intestinalis, XP_002128542.1 (hnRNPA1), XP_002127727.3 (PTBP1), XP_002124933.3 (SRSF1), XP_004227013.1 (SRSF2); Hydra vulgaris, XP_002156158.1 (PTBP1), XP_002159641.1 (SRSF1), XP_002161458.1 (SRSF2); Anopheles gambiae, XP_318405.4 (PTBP1), XP_318826.3 (SRSF2); Trypanosoma brucei, XP_827198.1 (PTBP1).
F<sc>ig</sc>. 4.—
Fig. 4.—
Schematic representation of proposed models of trans-splicing mechanisms. (A) tRNA-mediated trans-splicing model. Pre-tRNA halve adjacent to pre-mRNA context narrowing two associated molecules through complementary sequences, then the hybrid molecule is cleaved precisely at the sites of the tRNA intron by tRNA splicing endonuclease. (B) Transcriptional slippage model. Gray boxes represent pairing of SHSs. A pre-RNA is transcribed from Gene 1 and then misaligns to the DNA template of gene 2 via the SHSs. Transcription machinery keeps on moving on the strand of gene 2, after removal of introns, resulting in the chimeric molecule. (C) Special case of transcriptional slippage model. Both partner genes share a forward direction repeat sequence in the junction site of chimeric RNA. (D) Spliceosome mediated trans-splicing model. Like canonical cis-splicing, pre-RNA 1 and pre-RNA 2 is precisely spliced at the 5′- and 3′-splicing site and ligated as a non-linear chimeric molecule. (E) Trans-acting factor mediated model. Blurry region represent consensus DNA motif in parental gene 1 and gene 2. They can be recognized by trans-acting factor like CTCF and recruited to the shared transcription factory, and then coordinate the transcription by the same or similar transcription machinery. Transcription occurs between the Gene 1 and 2, the chimeric transcript is finally generated after intron removal. (F) Nucleotide fragments - mediated trans-splicing model. Short nucleotide fragments could induce transcription or be added into pre-mRNA. Trans-splicing could occur through base paring between two fragments. Through intermolecular splicing, this nucleotide fragments can be introduced into the chimeric molecule.
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