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The implications of alternative splicing in the ENCODE protein complement.

ABSTRACT: Alternative premessenger RNA splicing enables genes to generate more than one gene product. Splicing events that occur within protein coding regions have the potential to alter the biological function of the expressed protein and even to create new protein functions. Alternative splicing has been suggested as one explanation for the discrepancy between the number of human genes and functional complexity. Here, we carry out a detailed study of the alternatively spliced gene products annotated in the ENCODE pilot project. We find that alternative splicing in human genes is more frequent than has commonly been suggested, and we demonstrate that many of the potential alternative gene products will have markedly different structure and function from their constitutively spliced counterparts. For the vast majority of these alternative isoforms, little evidence exists to suggest they have a role as functional proteins, and it seems unlikely that the spectrum of conventional enzymatic or structural functions can be substantially extended through alternative splicing.

SUBMITTER: Tress ML

PROVIDER: S-EPMC1838448 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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The implications of alternative splicing in the ENCODE protein complement.

Tress Michael L ML Martelli Pier Luigi PL Frankish Adam A Reeves Gabrielle A GA Wesselink Jan Jaap JJ Yeats Corin C Olason Páll Isólfur PI Albrecht Mario M Hegyi Hedi H Giorgetti Alejandro A Raimondo Domenico D Lagarde Julien J Laskowski Roman A RA López Gonzalo G Sadowski Michael I MI Watson James D JD Fariselli Piero P Rossi Ivan I Nagy Alinda A Kai Wang W Størling Zenia Z Orsini Massimiliano M Assenov Yassen Y Blankenburg Hagen H Huthmacher Carola C Ramírez Fidel F Schlicker Andreas A Denoeud France F Jones Phil P Kerrien Samuel S Orchard Sandra S Antonarakis Stylianos E SE Reymond Alexandre A Birney Ewan E Brunak Søren S Casadio Rita R Guigo Roderic R Harrow Jennifer J Hermjakob Henning H Jones David T DT Lengauer Thomas T Orengo Christine A CA Patthy László L Thornton Janet M JM Tramontano Anna A Valencia Alfonso A

Proceedings of the National Academy of Sciences of the United States of America 20070319 13

Alternative premessenger RNA splicing enables genes to generate more than one gene product. Splicing events that occur within protein coding regions have the potential to alter the biological function of the expressed protein and even to create new protein functions. Alternative splicing has been suggested as one explanation for the discrepancy between the number of human genes and functional complexity. Here, we carry out a detailed study of the alternatively spliced gene products annotated in ...[more]

PMID: 17372197

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Project description:BackgroundAlternatively spliced exons play an important role in the diversification of gene function in most metazoans and are highly regulated by conserved motifs in exons and introns. Two contradicting properties have been associated to evolutionary conserved alternative exons: higher sequence conservation and higher rate of non-synonymous substitutions, relative to constitutive exons. In order to clarify this issue, we have performed an analysis of the evolution of alternative and constitutive exons, using a large set of protein coding exons conserved between human and mouse and taking into account the conservation of the transcript exonic structure. Further, we have also defined a measure of the variation of the arrangement of exonic splicing enhancers (ESE-conservation score) to study the evolution of splicing regulatory sequences. We have used this measure to correlate the changes in the arrangement of ESEs with the divergence of exon and intron sequences.ResultsWe find evidence for a relation between the lack of conservation of the exonic structure and the weakening of the sequence evolutionary constraints in alternative and constitutive exons. Exons in transcripts with non-conserved exonic structures have higher synonymous (dS) and non-synonymous (dN) substitution rates than exons in conserved structures. Moreover, alternative exons in transcripts with non-conserved exonic structure are the least constrained in sequence evolution, and at high EST-inclusion levels they are found to be very similar to constitutive exons, whereas alternative exons in transcripts with conserved exonic structure have a dS significantly lower than average at all EST-inclusion levels. We also find higher conservation in the arrangement of ESEs in constitutive exons compared to alternative ones. Additionally, the sequence conservation at flanking introns remains constant for constitutive exons at all ESE-conservation values, but increases for alternative exons at high ESE-conservation values.ConclusionWe conclude that most of the differences in dN observed between alternative and constitutive exons can be explained by the conservation of the transcript exonic structure. Low dS values are more characteristic of alternative exons with conserved exonic structure, but not of those with non-conserved exonic structure. Additionally, constitutive exons are characterized by a higher conservation in the arrangement of ESEs, and alternative exons with an ESE-conservation similar to that of constitutive exons are characterized by a conservation of the flanking intron sequences higher than average, indicating the presence of more intronic regulatory signals.

Dataset Information

The implications of alternative splicing in the ENCODE protein complement.

Publications

The implications of alternative splicing in the ENCODE protein complement.

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