The evolving roles of alternative splicing

Abstract

Alternative splicing is now commonly thought to affect more than half of all human genes. Recent studies have investigated not only the scope but also the biological impact of alternative splicing on a large scale, revealing that its role in generating proteome diversity may be augmented by a role in regulation. For instance, protein function can be regulated by the removal of interaction or localization domains by alternative splicing. Alternative splicing can also regulate gene expression by splicing transcripts into unproductive mRNAs targeted for degradation. To fully understand the scope of alternative splicing, we must also determine how many of the predicted splice variants represent functional forms. Comparisons of alternative splicing between human and mouse genes show that predominant splice variants are usually conserved, but rare variants are less commonly shared. Evolutionary conservation of splicing patterns suggests functional importance and provides insight into the evolutionary history of alternative splicing. The definition of functional splicing has evolved to match our increased understanding of gene expression.At the same time that we realized the human genome has far fewer genes than expected, we began to appreciate the full extent of alternative splicing. Many concluded that alternative splicing led to proteome expansion, bridging a perceived complexity gap. However, complexity is not determined simply by proteome size; it also encompasses interactions and regulation. Recently, we have begun to better understand alternative splicing as a regulatory process, contributing to biological complexity through its ability to control the expression of proteins. A recent paper provides a modern definition of functional splicing: ''An mRNA variant can be defined as being 'functional' if it is required during the life-cycle of the organism and activated in a regulated manner'' [2 ]. In some cases, functional splice forms may not even be required in their own right, but their production is required to regulate active protein levels. Moreover, the meaning of 'required' can be generalized by defining functional splicing as that which conveys a selective advantage.Well before alternative splicing was known to be widespread, studies showed that control of splicing could act as a general on/off switch to regulate gene expression [3]. Work on mRNA stability in Caenorhabditis elegans indicated that alternative splicing of serine/argininerich (SR) proteins, themselves involved in alternative splicing, could regulate their expression [4]. Recently, the combination of large-scale studies, enabled by the large data sets now available (Table 1), and studies of individual alternatively spliced genes has shed light on the regulatory roles and evolution of alternative splicing.Large-scale studies of the regulatory impact of alternative splicingThe first large-scale studies of alternative splicing were inventory-style analyses, designed to determine the extent of alternative splicing. The results of those surveys, tha...

Allele‐specific transcript isoforms in human

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Pseudo–Messenger RNA: Phantoms of the Transcriptome

“…These include transcribed pseudogenes, for which, again, isolated examples have been known for some time [4,5], and recent studies show more widespread transcription of pseudogenes [6–8]. There are also many variants of protein-coding genes with disrupted reading frames [9]: these have been dismissed as experimental noise, biological noise, or, at best, regulated splicing of unproductive transcripts as a form of gene regulation [10]. A final category are the recoded mRNAs, which encode proteins but violate the standard genetic code in various ways, e.g., using the opal stop codon to encode selenocysteine, or employing programmed ribosomal frameshifting or stop codon readthrough [11].…”

Human tRNA synthetase catalytic nulls with diverse functions

“…A few literature examples show natural proteolysis or alternative splicing of AARS can reveal novel AARS proteins (7, 8) with new functions (9–11). With this in mind, we investigated potential mechanisms for achieving genetic efficiency through functional expansions.…”