Recognition of Unknown Conserved Alternatively Spliced Exons

Abstract

The split structure of most mammalian protein-coding genes allows for the potential to produce multiple different mRNA and protein isoforms from a single gene locus through the process of alternative splicing (AS). We propose a computational approach called UNCOVER based on a pair hidden Markov model to discover conserved coding exonic sequences subject to AS that have so far gone undetected. Applying UNCOVER to orthologous introns of known human and mouse genes predicts skipped exons or retained introns present in both species, while discriminating them from conserved noncoding sequences. The accuracy of the model is evaluated on a curated set of genes with known conserved AS events. The prediction of skipped exons in the ~1% of the human genome represented by the ENCODE regions leads to more than 50 new exon candidates. Five novel predicted AS exons were validated by RT-PCR and sequencing analysis of 15 introns with strong UNCOVER predictions and lacking EST evidence. These results imply that a considerable number of conserved exonic sequences and associated isoforms are still completely missing from the current annotation of known genes. UNCOVER also identifies a small number of candidates for conserved intron retention.

Caffeine Regulates Alternative Splicing in a Subset of Cancer-Associated Genes: a Role for SC35

“…Despite these complexities, considerable progress has been made in the identification of trans-acting regulators and cisacting elements involved in the choice of splice sites for a few specific genes, and recent genome-wide computational annotations on expressed sequence tags (35,43,54) as well as SELEX analyses (16,25,49) have begun to provide a broader view of splice site regulation. Nevertheless, the detailed molecular mechanism of alternative splicing regulation remains largely unclear, hampered by a loose definition of splice site sequences in higher eukaryotes, a high degeneracy of RNA regulatory elements, a limited understanding of RNA secondary structure, the extreme complexity of spliceosomal components and functions and, particularly, a paucity of means to manipulate and control alternative splicing in an experimental system.…”

Can RNA selection pressure distort the measurement of Ka/Ks?

“…We will refer to such selection pressure as "RNA selection pressure" throughout our manuscript. Recently, there is a new wave of evidence for widespread RNA selection pressure in the eukaryotic genomes (Cartegni et al, 2002;Buratti and Baralle, 2004;Fairbrother et al, 2004;Pagani and Baralle, 2004;Baek and Green, 2005;Carlini and Genut, 2005;Ohler et al, 2005;Pagani et al, 2005;Parmley et al, 2006;Xing and Lee, 2005). Sequence motifs that are important for transcript processing (e.g.…”

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“…AltSplice Database is one of the most popular data sources for alternative splicing study [44,45]. Although alternative splicing was discovered many years ago, the computational prediction of alternative splicing sites based purely on genomic sequences is still a challenging task [46,47]. Xia et al introduced the competitive mechanism of nearby splicing sites into the prediction model, which greatly improved the prediction performance [48].…”