Model-based detection of alternative splicing signals.
BACKGROUND
Transcripts from approximately 95% of human multi-exon genes are subject to alternative splicing (AS). The growing interest in AS is propelled by its prominent contribution to transcriptome and proteome complexity and the role of aberrant AS in numerous diseases. Recent technological advances enable thousands of exons to be simultaneously profiled across diverse cell types and cellular conditions, but require accurate identification of condition-specific splicing changes. It is necessary to accurately identify such splicing changes to elucidate the underlying regulatory programs or link the splicing changes to specific diseases.


RESULTS
We present a probabilistic model tailored for high-throughput AS data, where observed isoform levels are explained as combinations of condition-specific AS signals. According to our formulation, given an AS dataset our tasks are to detect common signals in the data and identify the exons relevant to each signal. Our model can incorporate prior knowledge about underlying AS signals, measurement quality and gene expression level effects. Using a large-scale multi-tissue AS dataset, we demonstrate the advantage of our method over standard alternative approaches. In addition, we describe newly found tissue-specific AS signals which were verified experimentally, and discuss associated regulatory features.


BACKGROUND
Supplementary data are available at Bioinformatics online.
Banting and Best Department of Medical Research, University of Toronto, ON, Canada. yoseph@psi.utoronto.ca
Yoseph
Y
Barash
Benjamin J
BJ
Blencowe
Brendan J
BJ
Frey
D000465:Algorithms; D017398:Alternative Splicing / Q000235:genetics*; D005091:Exons; D020869:Gene Expression Profiling; D015233:Models, Statistical; D012326:RNA Splicing