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Genome Biol. 2015 Jun 16;16:126. doi: 10.1186/s13059-015-0690-5.

Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development.

Author information

1
Stanford Department of Biochemistry and Stanford Cancer Institute, Stanford, CA, USA. lszabo@stanford.edu.
2
UC San Diego Department of Reproductive Medicine, San Diego, CA, USA. robmoreyucsd@gmail.com.
3
Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, Departments of Pathology, Bioengineering and Medicine/Cardiology, University of Washington, Seattle, WA, 98109, USA. npalpant@uw.edu.
4
Stanford Department of Biochemistry and Stanford Cancer Institute, Stanford, CA, USA. plwang@stanford.edu.
5
UC San Diego Department of Reproductive Medicine, San Diego, CA, USA. naafari@ucsd.edu.
6
UC San Diego Department of Reproductive Medicine, San Diego, CA, USA. Connectikid@gmail.com.
7
UC San Diego Department of Pathology, San Diego, CA, USA. mparast@ucsd.edu.
8
Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, Departments of Pathology, Bioengineering and Medicine/Cardiology, University of Washington, Seattle, WA, 98109, USA. murry@u.washington.edu.
9
UC San Diego Department of Reproductive Medicine, San Diego, CA, USA. llaurent@ucsd.edu.
10
Stanford Department of Biochemistry and Stanford Cancer Institute, Stanford, CA, USA. julia.salzman@stanford.edu.

Abstract

BACKGROUND:

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. 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.

RESULTS:

We 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.

CONCLUSIONS:

The 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.

PMID:
26076956
PMCID:
PMC4506483
DOI:
10.1186/s13059-015-0690-5
[Indexed for MEDLINE]
Free PMC Article

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