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High levels of RNA-editing site conservation amongst 15 laboratory mouse strains

Petr Danecek1, Christoffer Nellåker2, Rebecca E McIntyre1, Jorge E Buendia-Buendia1, Suzannah Bumpstead1, Chris P Ponting12, Jonathan Flint3, Richard Durbin1, Thomas M Keane1* and David J Adams1*

Author Affiliations

1 Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1HH, UK

2 MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK

3 The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK

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Genome Biology 2012, 13:r26  doi:10.1186/gb-2012-13-4-r26

Published: 23 April 2012

Abstract

Background

Adenosine-to-inosine (A-to-I) editing is a site-selective post-transcriptional alteration of double-stranded RNA by ADAR deaminases that is crucial for homeostasis and development. Recently the Mouse Genomes Project generated genome sequences for 17 laboratory mouse strains and rich catalogues of variants. We also generated RNA-seq data from whole brain RNA from 15 of the sequenced strains.

Results

Here we present a computational approach that takes an initial set of transcriptome/genome mismatch sites and filters these calls taking into account systematic biases in alignment, single nucleotide variant calling, and sequencing depth to identify RNA editing sites with high accuracy. We applied this approach to our panel of mouse strain transcriptomes identifying 7,389 editing sites with an estimated false-discovery rate of between 2.9 and 10.5%. The overwhelming majority of these edits were of the A-to-I type, with less than 2.4% not of this class, and only three of these edits could not be explained as alignment artifacts. We validated 24 novel RNA editing sites in coding sequence, including two non-synonymous edits in the Cacna1d gene that fell into the IQ domain portion of the Cav1.2 voltage-gated calcium channel, indicating a potential role for editing in the generation of transcript diversity.

Conclusions

We show that despite over two million years of evolutionary divergence, the sites edited and the level of editing at each site is remarkably consistent across the 15 strains. In the Cds2 gene we find evidence for RNA editing acting to preserve the ancestral transcript sequence despite genomic sequence divergence.