Abstract
BackgroundThe pervasive expression of circular RNA is a recently discovered feature of gene expression in highly diverged eukaryotes, but the functions of most circular RNAs are still unknown. Computational methods to discover and quantify circular RNA are essential. Moreover, discovering biological contexts where circular RNAs are regulated will shed light on potential functional roles they may play.ResultsWe present a new algorithm that increases the sensitivity and specificity of circular RNA detection by discovering and quantifying circular and linear RNA splicing events at both annotated and un-annotated exon boundaries, including intergenic regions of the genome, with high statistical confidence. Unlike approaches that rely on read count and exon homology to determine confidence in prediction of circular RNA expression, our algorithm uses a statistical approach. Using our algorithm, we unveiled striking induction of general and tissue-specific circular RNAs, including in the heart and lung, during human fetal development. We discover regions of the human fetal brain, such as the frontal cortex, with marked enrichment for genes where circular RNA isoforms are dominant.ConclusionsThe vast majority of circular RNA production occurs at major spliceosome splice sites; however, we find the first examples of developmentally induced circular RNAs processed by the minor spliceosome, and an enriched propensity of minor spliceosome donors to splice into circular RNA at un-annotated, rather than annotated, exons. Together, these results suggest a potentially significant role for circular RNA in human development.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0690-5) contains supplementary material, which is available to authorized users.
Highlights
The pervasive expression of circular RNA is a recently discovered feature of gene expression in highly diverged eukaryotes, but the functions of most circular RNAs are still unknown
We demonstrate a reduction of false positive and negative results compared with other methods, and show that our improved accuracy can have significant implications for genome-wide analysis
We found high levels of circular RNA isoforms in the developing brain, including in genes essential to neurogenesis, such as lncRNA RMST [11], adding to the recent report that circular RNA is enriched in the aging fly brain [8]
Summary
The pervasive expression of circular RNA is a recently discovered feature of gene expression in highly diverged eukaryotes, but the functions of most circular RNAs are still unknown. The pervasive expression of circular RNA from proteinand non-coding loci is a recently discovered feature of highly diverged eukaryotic gene expression programs, conserved from humans to very simple organisms such as fungi [1,2,3,4,5]. We and others have shown that, in humans, thousands of genes have circular RNA isoforms, their expression relative to that of cognate linear RNA and their alternative splicing varying by cell type [3, 6].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
