Abstract
BackgroundRecent discoveries have highlighted the fact that alternative splicing and alternative transcripts are the rule, rather than the exception, in metazoan genes. Since multiple transcript and protein variants expressed by the same gene are, by definition, structurally distinct and need not to be functionally equivalent, the concept of gene orthology should be extended to the transcript level in order to describe evolutionary relationships between structurally similar transcript variants. In other words, the identification of true orthology relationships between gene products now should progress beyond primary sequence and "splicing orthology", consisting in ancestrally shared exon-intron structures, is required to define orthologous isoforms at transcript level.ResultsAs a starting step in this direction, in this work we performed a large scale human- mouse gene comparison with a twofold goal: first, to assess if and to which extent traditional gene annotations such as RefSeq capture genuine splicing orthology; second, to provide a more detailed annotation and quantification of true human-mouse orthologous transcripts defined as transcripts of orthologous genes exhibiting the same splicing patterns.ConclusionsWe observed an identical exon/intron structure for 32% of human and mouse orthologous genes. This figure increases to 87% using less stringent criteria for gene structure similarity, thus implying that for about 13% of the human RefSeq annotated genes (and about 25% of the corresponding transcripts) we could not identify any mouse transcript showing sufficient similarity to be confidently assigned as a splicing ortholog. Our data suggest that current gene and transcript data may still be rather incomplete - with several splicing variants still unknown. The observation that alternative splicing produces large numbers of alternative transcripts and proteins, some of them conserved across species and others truly species-specific, suggests that, still maintaining the conventional definition of gene orthology, a new concept of "splicing orthology" can be defined at transcript level.
Highlights
Recent discoveries have highlighted the fact that alternative splicing and alternative transcripts are the rule, rather than the exception, in metazoan genes
As well as comparing human and mouse RefSeq collections, we compared the RefSeq transcript collection to the transcripts included in ASPicDB [13], which collects all putative alternative isoforms for a given gene determined by the ASPIC algorithm [28,29]
This argument in itself raises the need to consider a new terminology for orthology of gene products, extending it to “orthologous splicing isoforms” for which we propose the name of “iso-orthologous“ transcripts, that is, transcript pairs corresponding to the same splicing variant of orthologous genes
Summary
Recent discoveries have highlighted the fact that alternative splicing and alternative transcripts are the rule, rather than the exception, in metazoan genes. Extensive investigations carried out so far, using sequence and microarray data, have shown different levels of AS in eukaryotes [2,3] with a considerable fraction of AS splicing events resulting species- or lineage-specific at level of comparisons involving even very closely related species such as human and chimp [4], and human and mouse [5,6,7], orthology relationship at the gene level, at the transcript level requires the introduction of a new concept of “splicing orthology” to identify structurally similar splicing variants whose products may be more likely functionally related. While mechanisms of evolution of patterns of alternative splicing are not yet well understood, splicing patterns shared between orthologous genes in closely related organisms are likely to reflect descent from an ancestral splicing pattern Taken together, these considerations suggest that it is important to extend the notion of orthology from genes to single transcripts, in order to relate structurally similar splicing variants, i.e. those variants sharing the same exon-intron structure and using the same homologous splicing sites. The multiple isoforms expressed by two orthologous genes, depending on their sequence/ structure similarity in coding and non-coding portions, can be more or less functionally related with some isoform pairs largely functionally equivalent and others possibly species-specific
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