Long-distance splicing

With the draft sequence of the human genome came the surprise that there were fewer genes than imagined. From where does complexity spring if not from the number of genes in an organism? RNA splicing provides at least part of the answer. Pre-mRNA splicing by alternative pathways is well known to expand an organism's protein diversity by generating distinct protein isoforms. Beyond cis-splicing at a single locus (Fig. 1 a), there is evidence for specialized cis-splicing that results from read-through transcription of adjacent loci followed by splicing to generate transcription-induced chimeras (TICs) from two genes (Fig. 1 b) (1, 2), as in the TNSF12/TNSF13 chimera expressed in human T cells (3). In contrast to these cis-splicing events, trans-splicing joins exons from separate pre-mRNA transcripts. These transcripts can be encoded by different DNA strands at the same locus, as in trans-splicing of the mod(mdg4) gene in Drosophila, or by different alleles at the same locus, as for the lola gene, also in Drosophila (Fig. 1 c) (4). All of these RNA splicing events involve transcripts from the same general region of the genome. In the work by Di Segni et al. in this issue of PNAS (5), the authors provide evidence suggesting yet another pathway to increase protein diversity, a pathway that involves cis-splicing of a single mRNA or trans-splicing of distinct mRNAs from distant genes by the tRNA-splicing machinery (Fig. 1 d and e).

*To whom correspondence should be addressed. E-mail: jstaley{at}uchicago.edu