Conserved and species-specific alternative splicing in mammalian genomes

Ramil N Nurtdinov,Andrey A Mironov,Alexey D Neverov,Mikhail S Gelfand,Alexander V Favorov

doi:10.1186/1471-2148-7-249

Abstract

BackgroundAlternative splicing has been shown to be one of the major evolutionary mechanisms for protein diversification and proteome expansion, since a considerable fraction of alternative splicing events appears to be species- or lineage-specific. However, most studies were restricted to the analysis of cassette exons in pairs of genomes and did not analyze functionality of the alternative variants.ResultsWe analyzed conservation of human alternative splice sites and cassette exons in the mouse and dog genomes. Alternative exons, especially minor-isofom ones, were shown to be less conserved than constitutive exons. Frame-shifting alternatives in the protein-coding regions are less conserved than frame-preserving ones. Similarly, the conservation of alternative sites is highest for evenly used alternatives, and higher when the distance between the sites is divisible by three. The rate of alternative-exon and site loss in mouse is slightly higher than in dog, consistent with faster evolution of the former. The evolutionary dynamics of alternative sites was shown to be consistent with the model of random activation of cryptic sites.ConclusionConsistent with other studies, our results show that minor cassette exons are less conserved than major-alternative and constitutive exons. However, our study provides evidence that this is caused not only by exon birth, but also lineage-specific loss of alternative exons and sites, and it depends on exon functionality.

Highlights

Alternative splicing has been shown to be one of the major evolutionary mechanisms for protein diversification and proteome expansion, since a considerable fraction of alternative splicing events appears to be species- or lineage-specific
New sites can emerge as a result of activating mutations creating both alternative sites and cassette exons [30]; this is true for acceptor sites where many splicing-related genetic diseases are caused by de novo sites [29]
We demonstrate that conservation of cassette exons depends on the exon inclusion level, and that conservation of alternative sites depends on the relative site usage and show that both are dependent on the exon functionality

Summary

Introduction

Alternative splicing has been shown to be one of the major evolutionary mechanisms for protein diversification and proteome expansion, since a considerable fraction of alternative splicing events appears to be species- or lineage-specific. Alternative splicing is emerging as one of the major evolutionary mechanisms for protein diversification and proteome expansion. More than half of mammalian genes are alternatively spliced [1,2,3], but a considerable fraction of alternative splicing events appears to be species- or lineage-specific, at the level of comparison of genes from human and mouse [4,5,6,7], rodents [8] or other mammals [9,10]; fruit flies Functionality of minor isoforms is supported by the fact that many of them are tissue-specific [5], in a study that used oligonucleotide microarrays, NMD-inducing isoforms have been shown to be expressed at uniform, low level [16]

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Discussion

Conclusion