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Accurate identification of A-to-I RNA editing in human by transcriptome sequencing.

ABSTRACT: RNA editing enhances the diversity of gene products at the post-transcriptional level. Approaches for genome-wide identification of RNA editing face two main challenges: separating true editing sites from false discoveries and accurate estimation of editing levels. We developed an approach to analyze transcriptome sequencing data (RNA-seq) for global identification of RNA editing in cells for which whole-genome sequencing data are available. We applied the method to analyze RNA-seq data of a human glioblastoma cell line, U87MG. Around 10,000 DNA-RNA differences were identified, the majority being putative A-to-I editing sites. These predicted A-to-I events were associated with a low false-discovery rate (?5%). Moreover, the estimated editing levels from RNA-seq correlated well with those based on traditional clonal sequencing. Our results further facilitated unbiased characterization of the sequence and evolutionary features flanking predicted A-to-I editing sites and discovery of a conserved RNA structural motif that may be functionally relevant to editing. Genes with predicted A-to-I editing were significantly enriched with those known to be involved in cancer, supporting the potential importance of cancer-specific RNA editing. A similar profile of DNA-RNA differences as in U87MG was predicted for another RNA-seq data set obtained from primary breast cancer samples. Remarkably, significant overlap exists between the putative editing sites of the two transcriptomes despite their difference in cell type, cancer type, and genomic backgrounds. Our approach enabled de novo identification of the RNA editome, which sets the stage for further mechanistic studies of this important step of post-transcriptional regulation.

SUBMITTER: Bahn JH

PROVIDER: S-EPMC3246201 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Accurate identification of A-to-I RNA editing in human by transcriptome sequencing.

Bahn Jae Hoon JH Lee Jae-Hyung JH Li Gang G Greer Christopher C Peng Guangdun G Xiao Xinshu X

Genome research 20110929 1

RNA editing enhances the diversity of gene products at the post-transcriptional level. Approaches for genome-wide identification of RNA editing face two main challenges: separating true editing sites from false discoveries and accurate estimation of editing levels. We developed an approach to analyze transcriptome sequencing data (RNA-seq) for global identification of RNA editing in cells for which whole-genome sequencing data are available. We applied the method to analyze RNA-seq data of a hum ...[more]

PMID: 21960545

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Project description:BackgroundRNA editing is a co-transcriptional modification that increases the molecular diversity, alters secondary structure and protein coding sequences by changing the sequence of transcripts. The most common RNA editing modification is the single base substitution (A→I) that is catalyzed by the members of the Adenosine deaminases that act on RNA (ADAR) family. Typically, editing sites are identified as RNA-DNA-differences (RDDs) in a comparison of genome and transcriptome data from next-generation sequencing experiments. However, a method for robust detection of site-specific editing events from replicate RNA-seq data has not been published so far. Even more surprising, condition-specific editing events, which would show up as differences in RNA-RNA comparisons (RRDs) and depend on particular cellular states, are rarely discussed in the literature.ResultsWe present JACUSA, a versatile one-stop solution to detect single nucleotide variant positions from comparing RNA-DNA and/or RNA-RNA sequencing samples. The performance of JACUSA has been carefully evaluated and compared to other variant callers in an in silico benchmark. JACUSA outperforms other algorithms in terms of the F measure, which combines precision and recall, in all benchmark scenarios. This performance margin is highest for the RNA-RNA comparison scenario. We further validated JACUSA's performance by testing its ability to detect A→I events using sequencing data from a human cell culture experiment and publicly available RNA-seq data from Drosophila melanogaster heads. To this end, we performed whole genome and RNA sequencing of HEK-293 cells on samples with lowered activity of candidate RNA editing enzymes. JACUSA has a higher recall and comparable precision for detecting true editing sites in RDD comparisons of HEK-293 data. Intriguingly, JACUSA captures most A→I events from RRD comparisons of RNA sequencing data derived from Drosophila and HEK-293 data sets.ConclusionOur software JACUSA detects single nucleotide variants by comparing data from next-generation sequencing experiments (RNA-DNA or RNA-RNA). In practice, JACUSA shows higher recall and comparable precision in detecting A→I sites from RNA-DNA comparisons, while showing higher precision and recall in RNA-RNA comparisons.

Dataset Information

Accurate identification of A-to-I RNA editing in human by transcriptome sequencing.

Publications

Accurate identification of A-to-I RNA editing in human by transcriptome sequencing.

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