Differential evolution of signal-responsive RNA elements and upstream factors that control alternative splicing

Abstract

Cell signal-regulated alternative splicing occurs for many genes but the evolutionary origin of the regulatory components and their relationship remain unclear. This review focuses on the alternative splicing components of several systems based on the available bioinformatics data. Eight mammalian RNA elements for signal-regulated splicing were aligned among corresponding sequences from dozens of representative vertebrate species to allow for assessment of the trends in evolutionary changes. Four distinct trends were observed. Four of the elements are highly conserved in bird, reptile and fish species examined (i); two elements can be found in fish but the sequences have been changing till in marsupials or higher mammals (ii); one element is almost exclusively found in mammals with mostly the same sequence (iii); and one element can be found in birds or lower vertebrates but expanded abruptly to have variable numbers of copies in mammals (iv). All examined prototype trans-acting factors and protein kinases emerged earlier than the RNA elements but additional (paralog) factors emerged in the same or later species. Thus, after their emergence mainly in fish or mammals with pre-existing prototype trans-acting factors/kinases, half of the elements have been highly conserved from fish to humans but the other half have evolved differentially with additional trans-acting factors. Their differential evolution likely contributes to the exon- and species/class-specific control of alternative splicing and its regulation by cell signals. The evolvement of a group of mammal-specific components would help relay signals from extracellular stimuli to the splicing machinery and thus contribute to higher proteomic diversity.

Evolutionary Emergence of a Novel Splice Variant with an Opposite Effect on the Cell Cycle

“…The evolved element allows trans-acting factors to bind (Fig. 3) and, moreover, is likely to relay upstream signals for further regulation of alternative splicing of the mammalian genes, as in other cases (75). The presence of such elements in a group of genes implies that the impact of this molecular mechanism likely goes beyond the genes involved in cell cycle regulation, reaching a wider range of cellular processes in different tissues ( Fig.…”

Expression and function analysis of two naturally truncated MyD88 variants in the Pacific oyster Crassostrea gigas

“…They can skip the complex regulation of AS and be directly transcribed into specific mRNA. For invertebrate it seems wise to encode directly in the genome in case of unnecessary errors in the process of AS [27].…”

Transcriptome protection by the expanded family of hnRNPs

“…Based on the different target RNA motifs and effects on exons/genes by different hnRNPs, their expansion in metazoans probably matches the sequence complexity of pre-mRNA transcripts in different species. Although systematic assessments remain to be carried out, as an example for individual hnRNPs and corresponding RNA motifs, the hnRNP LL emergence in vertebrates accompanies the increased CA/AC content of the CaRRE1 element of the Slo1 gene (from one copy in the 3ʹ splice site of a fish Slo1 to as many as five copies in mammals) [27,28]. Similar co-appearance of hnRNP and RNA motifs are also observed in other cases [28].…”