Journal
GENOME RESEARCH
Volume 27, Issue 4, Pages 639-649Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.202820.115
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Funding
- National Institutes of Health
- National Institute of General Medical Sciences (NIGMS) [P30GM103410]
- NCRR [P30RR031153, P20RR018728, S10RR02763]
- National Science Foundation (EPSCoR) [0554548]
- Lifespan Rhode Island Hospital
- Division of Biology and Medicine, Brown University
- National Institutes of Health [R01GR527276]
- NIGMS [R01GM105681]
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The coding sequence of each human pre-mRNA is interrupted, on average, by 11 introns that must be spliced out for proper gene expression. Each intron contains three obligate signals: a 5' splice site, a branch site, and a 3' splice site. Splice site usage has been mapped exhaustively across different species, cell types, and cellular states. In contrast, only a small fraction of branch sites have been identified even once. The few reported annotations of branch site are imprecise as reverse transcriptase skips several nucleotides while traversing a 2-5 linkage. Here, we report large-scale mapping of the branchpoints from deep sequencing data in three different species and in the SF3B1 K700E oncogenic mutant background. We have developed a novel method whereby raw lariat reads are refined by U2snRNP/pre-mRNA base-pairing models to return the largest current data set of branchpoint sequences with quality metrics. This analysis discovers novel modes of U2snRNA:pre-mRNA base-pairing conserved in yeast and provides insight into the biogenesis of intron circles. Finally, matching branch site usage with isoform selection across the extensive panel of ENCODE RNA-seq data sets offers insight into the mechanisms by which branchpoint usage drives alternative splicing.
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