alternative splicing of rna triplets is often regulated and accelerates proteome evolution可变剪接的rna三胞胎往往是监管和加速蛋白质组进化.pdfVIP

Alternative Splicing of RNA Triplets Is Often Regulated and Accelerates Proteome Evolution ¤ Robert K. Bradley , Jason Merkin, Nicole J. Lambert, Christopher B. Burge* Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America Abstract Thousands of human genes contain introns ending in NAGNAG (N any nucleotide), where both NAGs can function as 3 9 splice sites, yielding isoforms that differ by inclusion/exclusion of three bases. However, few models exist for how such splicing might be regulated, and some studies have concluded that NAGNAG splicing is purely stochastic and nonfunctional. Here, we used deep RNA-Seq data from 16 human and eight mouse tissues to analyze the regulation and evolution of NAGNAG splicing. Using both biological and technical replicates to estimate false discovery rates, we estimate that at least 25% of alternatively spliced NAGNAGs undergo tissue-specific regulation in mammals, and alternative splicing of strongly tissue-specific NAGNAGs was 10 times as likely to be conserved between species as was splicing of non-tissue- specific events, implying selective maintenance. Preferential use of the distal NAG was associated with distinct sequence features, including a more distal location of the branch point and presence of a pyrimidine immediately before the first NAG, and alteration of these features in a splicing reporter shifted splicing away from the distal site. Strikingly, alignments of orthologous exons revealed a ,15-fold increase in the frequency of three base pair gaps at 39 splice sites relative to nearby exon positions in both mammals and in Drosophila. Alternative splicing of NAGNAGs in human was associated with dramatically increased frequency of exon length changes at orthologous exo