Ultra‐Conserved Poison Exons Enable Rapid and Safe Splicing Factor Gene Expression Switches: A Hypothesis

Most vertebrate genes are split up into exons and introns, with exons being spliced together to make mRNA. Many of the proteins involved in splicing, called splicing factors, exert concentration-dependent effects on gene expression through post-transcriptional modification of mRNAs. These include the serine/arginine-enriched (SR) proteins that have essential roles in normal development and physiology. All SR proteins (and many other splicing factors) regulate their own expression levels, often using negative feedback pathways involving alternative splicing of "poison exons" (PEs), which lead to mRNA degradation. The PEs within SR protein genes are encoded by ultra-conserved genome sequences, suggesting they have been under extreme selective pressure despite not encoding protein sequences. Here, we discuss the hypothesis that PEs enable rapid switches in SR protein concentrations, yet prevent these splicing regulators from increasing to toxic levels that cause cell death or interfere with cell function. This hypothesis is based on analysis of an ultra-conserved PE in the TRA2B gene during male meiosis. Distinct roles for this TRA2B PE in different tissues further predict cell type-specific effects on development and physiology that will need to be experimentally detected using animal models.