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. 2012 Apr 23;13(4):26.
doi: 10.1186/gb-2012-13-4-r26.

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

Petr Danecek  1 , Christoffer Nellåker, Rebecca E McIntyre, Jorge E Buendia-Buendia, Suzannah Bumpstead, Chris P Ponting, Jonathan Flint, Richard Durbin, Thomas M Keane, David J Adams
Affiliations

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

Petr Danecek et al. Genome Biol. .

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.

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Figures

Figure 1
Figure 1
Editing pattern of (a) the initial raw candidate set and (b) the final filtered set.
Figure 2
Figure 2
The extent of RNA editing in individual mouse strains. (a) Total number of edits per strain with error bars indicating the low-depth correction as explained in the text. (b) The editing rate is shown as the number of edited bases per 100 kbp of genomic reference sequence and as the number of inosines in 100 kbp of transcribed sequence. The error rate is calculated as the proportion of non A-to-G mismatches per strain.
Figure 3
Figure 3
RNA editing sites characterized by the level of editing and their presence in multiple mouse strains. (a) The overall level of editing is determined by the number of reads with/without the edited base per site and is shown over all sites/strains (solid line). The variability in the level of editing is shown as the distribution of standard deviations (std dev) from average values at each site both within (dashed line) and across strains (dotted line). For example, 90% of all sites have 60% or fewer reads edited and the standard deviation for 90% of all sites is less than 10 to 15%. (b) The frequency of sharing of sites (solid bars) and clusters across the strains (dashed bars). The lines show the hypothetical number of shared edits/clusters when uneven coverage and expression are taken into account, as explained in text.
Figure 4
Figure 4
Depletion/enrichment of RNA editing clusters in (a) genic regions and (b) associated GO slim terms. SS, sequence specific; TF, transcription factor.
Figure 5
Figure 5
RNA editing of the Cacna1d gene. (a) The Cacna1d gene contains two non-synonymous edits in close proximity in the calmodulin binding part of Cav1.2 voltage-gated calcium channel (PDB ID:2BE6). (b, c) Editing levels for each strain replicate for the two sites.
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