Abstract
BackgroundAlternative splicing (AS) is important for evolution and major biological functions in complex organisms. However, the extent of AS in mammals other than human and mouse is largely unknown, making it difficult to study AS evolution in mammals and its biomedical implications.ResultsHere we describe a cross-species EST-to-genome comparison algorithm (ENACE) that can identify novel exons for EST-scanty species and distinguish conserved and lineage-specific exons. The identified exons represent not only novel exons but also evolutionarily meaningful AS events that are not previously annotated. A genome-wide AS analysis in human, mouse and rat using ENACE reveals a total of 758 novel cassette-on exons and 167 novel retained introns that have no EST evidence from the same species. RT-PCR-sequencing experiments validated ~50 ~80% of the tested exons, indicating high presence of exons predicted by ENACE. ENACE is particularly powerful when applied to closely related species. In addition, our analysis shows that the ENACE-identified AS exons tend not to pass the nonsynonymous-to-synonymous substitution ratio test and not to contain protein domain, implying that such exons may be under positive selection or relaxed negative selection. These AS exons may contribute to considerable inter-species functional divergence. Our analysis further indicates that a large number of exons may have been gained or lost during mammalian evolution. Moreover, a functional analysis shows that inter-species divergence of AS events may be substantial in protein carriers and receptor proteins in mammals. These exons may be of interest to studies of AS evolution. The ENACE programs and sequences of the ENACE-identified AS events are available for download.ConclusionENACE can identify potential novel cassette exons and retained introns between closely related species using a comparative approach. It can also provide information regarding lineage- or species-specificity in transcript isoforms, which are important for evolutionary and functional studies.
Highlights
Alternative splicing (AS) is important for evolution and major biological functions in complex organisms
The remaining exonic sequences are defined as novel exons with expressed sequence tag (EST) evidence from a non-human species but not from human itself
Our results show that ENACE is capable of identifying novel exons and lineage-specific exons that are involved in AS events, which makes ENACE a convenient tool for AS and evolutionary studies
Summary
Alternative splicing (AS) is important for evolution and major biological functions in complex organisms. The extent of AS in mammals other than human and mouse is largely unknown, making it difficult to study AS evolution in mammals and its biomedical implications. Alternative splicing (AS) is suggested to be a major source of transcriptome/proteome complexity and gene function diversity [1,2,3,4,5,6,7], and highly relevant to several human diseases [8,9,10]. Adequate information of AS variants in more mammalian species other than human and mouse can further our understanding on the evolution of AS and its implications in functional divergence. It is desirable to identify unannotated AS variants and evolutionarily meaningful AS events in mammals, in species of which AS events have remained largely undiscovered
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