Dataset Information

Accurate prediction of NAGNAG alternative splicing.

ABSTRACT: Alternative splicing (AS) involving NAGNAG tandem acceptors is an evolutionarily widespread class of AS. Recent predictions of alternative acceptor usage reported better results for acceptors separated by larger distances, than for NAGNAGs. To improve the latter, we aimed at the use of Bayesian networks (BN), and extensive experimental validation of the predictions. Using carefully constructed training and test datasets, a balanced sensitivity and specificity of >or=92% was achieved. A BN trained on the combined dataset was then used to make predictions, and 81% (38/47) of the experimentally tested predictions were verified. Using a BN learned on human data on six other genomes, we show that while the performance for the vertebrate genomes matches that achieved on human data, there is a slight drop for Drosophila and worm. Lastly, using the prediction accuracy according to experimental validation, we estimate the number of yet undiscovered alternative NAGNAGs. State of the art classifiers can produce highly accurate prediction of AS at NAGNAGs, indicating that we have identified the major features of the 'NAGNAG-splicing code' within the splice site and its immediate neighborhood. Our results suggest that the mechanism behind NAGNAG AS is simple, stochastic, and conserved among vertebrates and beyond.

SUBMITTER: Sinha R

PROVIDER: S-EPMC2699507 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Accurate prediction of NAGNAG alternative splicing.

Sinha Rileen R Nikolajewa Swetlana S Szafranski Karol K Hiller Michael M Jahn Niels N Huse Klaus K Platzer Matthias M Backofen Rolf R

Nucleic acids research 20090409 11

Alternative splicing (AS) involving NAGNAG tandem acceptors is an evolutionarily widespread class of AS. Recent predictions of alternative acceptor usage reported better results for acceptors separated by larger distances, than for NAGNAGs. To improve the latter, we aimed at the use of Bayesian networks (BN), and extensive experimental validation of the predictions. Using carefully constructed training and test datasets, a balanced sensitivity and specificity of >or=92% was achieved. A BN traine ...[more]

PMID: 19359358

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Project description:BACKGROUND: Alternative splicing (AS) involving tandem acceptors that are separated by three nucleotides (NAGNAG) is an evolutionarily widespread class of AS, which is well studied in Homo sapiens (human) and Mus musculus (mouse). It has also been shown to be common in the model seed plants Arabidopsis thaliana and Oryza sativa (rice). In one of the first studies involving sequence-based prediction of AS in plants, we performed a genome-wide identification and characterization of NAGNAG AS in the model plant Physcomitrella patens, a moss. RESULTS: Using Sanger data, we found 295 alternatively used NAGNAG acceptors in P. patens. Using 31 features and training and test datasets of constitutive and alternative NAGNAGs, we trained a classifier to predict the splicing outcome at NAGNAG tandem splice sites (alternative splicing, constitutive at the first acceptor, or constitutive at the second acceptor). Our classifier achieved a balanced specificity and sensitivity of >or= 89%. Subsequently, a classifier trained exclusively on data well supported by transcript evidence was used to make genome-wide predictions of NAGNAG splicing outcomes. By generation of more transcript evidence from a next-generation sequencing platform (Roche 454), we found additional evidence for NAGNAG AS, with altogether 664 alternative NAGNAGs being detected in P. patens using all currently available transcript evidence. The 454 data also enabled us to validate the predictions of the classifier, with 64% (80/125) of the well-supported cases of AS being predicted correctly. CONCLUSION: NAGNAG AS is just as common in the moss P. patens as it is in the seed plants A. thaliana and O. sativa (but not conserved on the level of orthologous introns), and can be predicted with high accuracy. The most informative features are the nucleotides in the NAGNAG and in its immediate vicinity, along with the splice sites scores, as found earlier for NAGNAG AS in animals. Our results suggest that the mechanism behind NAGNAG AS in plants is similar to that in animals and is largely dependent on the splice site and its immediate neighborhood.

Project description:BACKGROUND: Several recent studies indicate that alternative splicing in Arabidopsis and other plants is a common mechanism for post-transcriptional modulation of gene expression. However, few analyses have been done so far to elucidate the functional relevance of alternative splicing in higher plants. Representing a frequent and universal subtle alternative splicing event among eukaryotes, alternative splicing at NAGNAG acceptors contributes to transcriptome diversity and therefore, proteome plasticity. Alternatively spliced NAGNAG acceptors are overrepresented in genes coding for proteins with RNA-recognition motifs (RRMs). As SR proteins, a family of RRM-containing important splicing factors, are known to be extensively alternatively spliced in Arabidopsis, we analyzed alternative splicing at NAGNAG acceptors in SR and SR-related genes. RESULTS: In a comprehensive analysis of the Arabidopsis thaliana genome, we identified 6,772 introns that exhibit a NAGNAG acceptor motif. Alternative splicing at these acceptors was assessed using available EST data, complemented by a sequence-based prediction method. Of the 36 identified introns within 30 SR and SR-related protein-coding genes that have a NAGNAG acceptor, we selected 15 candidates for an experimental analysis of alternative splicing under several conditions. We provide experimental evidence for 8 of these candidates being alternatively spliced. Quantifying the ratio of NAGNAG-derived splice variants under several conditions, we found organ-specific splicing ratios in adult plants and changes in seedlings of different ages. Splicing ratio changes were observed in response to heat shock and most strikingly, cold shock. Interestingly, the patterns of differential splicing ratios are similar for all analyzed genes. CONCLUSION: NAGNAG acceptors frequently occur in the Arabidopsis genome and are particularly prevalent in SR and SR-related protein-coding genes. A lack of extensive EST coverage can be compensated by using the proposed sequence-based method to predict alternative splicing at these acceptors. Our findings indicate that the differential effects on NAGNAG alternative splicing in SR and SR-related genes are organ- and condition-specific rather than gene-specific.

Dataset Information

Accurate prediction of NAGNAG alternative splicing.

Publications

Accurate prediction of NAGNAG alternative splicing.

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