Evolution of alternative and constitutive regions of mammalian 5'UTRs

Alissa M Resch,Eugene V Koonin,Svetlana A Shabalina,Igor B Rogozin,Aleksey Y Ogurtsov

doi:10.1186/1471-2164-10-162

Abstract

BackgroundAlternative splicing (AS) in protein-coding sequences has emerged as an important mechanism of regulation and diversification of animal gene function. By contrast, the extent and roles of alternative events including AS and alternative transcription initiation (ATI) within the 5'-untranslated regions (5'UTRs) of mammalian genes are not well characterized.ResultsWe evaluated the abundance, conservation and evolution of putative regulatory control elements, namely, upstream start codons (uAUGs) and open reading frames (uORFs), in the 5'UTRs of human and mouse genes impacted by alternative events. For genes with alternative 5'UTRs, the fraction of alternative sequences (those present in a subset of the transcripts) is much greater than that in the corresponding coding sequence, conceivably, because 5'UTRs are not bound by constraints on protein structure that limit AS in coding regions. Alternative regions of mammalian 5'UTRs evolve faster and are subject to a weaker purifying selection than constitutive portions. This relatively weak selection results in over-abundance of uAUGs and uORFs in the alternative regions of 5'UTRs compared to constitutive regions. Nevertheless, even in alternative regions, uORFs evolve under a stronger selection than the rest of the sequences, indicating that some of the uORFs are conserved regulatory elements; some of the non-conserved uORFs could be involved in species-specific regulation.ConclusionThe findings on the evolution and selection in alternative and constitutive regions presented here are consistent with the hypothesis that alternative events, namely, AS and ATI, in 5'UTRs of mammalian genes are likely to contribute to the regulation of translation.

Highlights

Alternative splicing (AS) in protein-coding sequences has emerged as an important mechanism of regulation and diversification of animal gene function
We further addressed the question whether uORFs are more prevalent in 5'untranslated regions (5'UTRs) of genes that contain alternative regions? Comparison of uORF abundance between genes in the ALT and nonALT control sets indicates that ~53% of human and ~51% of mouse ALT genes contain uORFs, whereas only ~44% of human and ~42% of mouse nonALT control genes contain uORFs, suggesting that uORFs are more common in 5'UTRs containing alternative regions (Table 1)
Human and mouse genes with alternative 5'UTRs are significantly enriched for keywords associated with biological functions such as signal transduction, receptor activity and translation (Table 7 and Additional file 2). This subset of genes includes a large fraction of growth factors and transcription factors, which are known to be finely and strongly regulated [53,54]. In accordance with this observation, we found that over 17% of the annotated genes in our data set of human genes with alternative events in the 5'UTRs are classified as "precursor" proteins, which is compatible with the tight regulation of protein expression in this set of genes

Summary

Introduction

Alternative splicing (AS) in protein-coding sequences has emerged as an important mechanism of regulation and diversification of animal gene function. The extent and roles of alternative events including AS and alternative transcription initiation (ATI) within the 5'untranslated regions (5'UTRs) of mammalian genes are not well characterized. Alternative splicing (AS) has emerged as a major mechanism for regulating gene expression and function in animals, in mammals. Little is known about the prevalence and impact of alternative events, such as AS and alternative transcription initiation (ATI), in 5'-untranslated regions (5'UTRs). AS and ATI are the primary sources of 5'UTR transcript diversity, and several reports have conjectured that these mechanisms might play an important role in orchestrating complex regulatory mechanisms within the 5'UTRs [9,10,11,12,13]. Studies have shown that alternative events are responsible for 5'UTR transcript diversity in mammals, but to our knowledge, there have been no detailed, genome-wide studies aimed at elucidating the functional role of transcript diversity in mammalian 5'UTRs

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