Plasticity and evolutionary dynamics of alternative RNA splicing

Abstract

AbstractMost eukaryotic genes are expressed in multiple RNA isoforms representing variants of the respective genes. Full-length RNA sequencing techniques have uncovered an extreme diversity of RNA isoforms, but a subset of them might be generated by noise in the splicing machinery. For some genes, it has been shown that environmental influences can lead to isoform switching, implying that isoform diversity could also be subject to plastic changes in response to environmental conditions. Further, it has been suggested that isoform diversity could be a basis for adaptive evolutionary novelty. However, explicit tests of all three of these assumptions are missing. To address these questions, we have analyzed here the variation of full-length brain RNA transcripts from natural populations and subspecies ofMus musculus, as well as the outgroup speciesMus spretusandMus spicilegus. We find a substantial influence of splicing noise in generating rare isoform variants. However, after filtering these out, we reliably identify more than 117,000 distinct isoforms in the dataset, about doubling the number of the currently annotated set. Comparisons with individuals raised under different environmental conditions show a very strong plasticity effect in shaping isoform expression, including major isoform switching in proteins that bind to splice site enhancers. Using site frequency spectra tests in comparison to SNP data from the same individuals, we find no evidence for lineage-specific isoforms to become frequently fixed. We conclude that lineage-specific isoforms do not contribute much to novel adaptations, either because they are generated mainly through noise in the splicing machinery or are subject to negative selection. However, isoform diversity is strongly shaped by environmental conditions, both for lineage-specific isoforms, as well as conserved ones. Therefore, the functional role of isoform diversity may mostly be related to trigger plastic responses to environmental changes.