A-to-I RNA editing uncovers hidden signals of adaptive genome evolution in animals

Popitsch, Niko; Buchumenski, Ilana; Eisenberg, Eli; Jantsch, Michael F.; Haeseler, Arndt von; Gallach, Miguel

doi:10.1101/228734

Cited by 3 publications

References 47 publications

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ADAR1 can drive Multiple Myeloma progression by acting both as an RNA editor of specific transcripts and as a DNA mutator of their cognate genes

Tasakis

Laganà

Stamkopoulou

et al. 2020

Preprint

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RNA editing is an epitranscriptomic modification of emerging relevance to disease development and manifestations. ADAR1, which resides on human chromosome 1q21, is an RNA editor whose over-expression, either by interferon (IFN) induction or through gene amplification, is associated with increased editing and poor outcomes in Multiple Myeloma (MM). Here we explored the role of ADAR1 in the context of MM progression, by focusing on a group of 23 patients in the MMRF CoMMpass Study for which RNAseq and WES datasets exist for matched pre-and post-relapse samples. Our analysis reveals an acquisition of new DNA mutations on disease progression at specific loci surrounding the sites of ADAR associated (A-to-I) RNA editing. These analyses suggest that the RNA editing enzyme ADAR1 can function as a DNA mutator during Multiple Myeloma (MM) progression. These data imply that guide-targeted RNA editing has the capacity to generate specific mutational signatures at predetermined locations. More generally, these data suggest that a dual role of RNA editor and DNA mutator might be shared by other deaminases, such as APOBECs, so that DNA mutation might be the result of collateral damage on the genome by an editing enzyme whose primary job is to re-code the cognate transcript toward specific functional outcomes.

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ADAR1 can drive Multiple Myeloma progression by acting both as an RNA editor of specific transcripts and as a DNA mutator of their cognate genes

Tasakis

Laganà

Stamkopoulou

et al. 2020

Preprint

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A-to-I RNA editing contributes to the persistence of predicted damaging mutations in populations

Mai

Chuang

2019

Genome Res.

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Adenosine-to-inosine (A-to-I) RNA editing is a very common co-/posttranscriptional modification that can lead to A-to-G changes at the RNA level and compensate for G-to-A genomic changes to a certain extent. It has been shown that each healthy individual can carry dozens of missense variants predicted to be severely deleterious. Why strongly detrimental variants are preserved in a population and not eliminated by negative natural selection remains mostly unclear. Here, we ask if RNA editing correlates with the burden of deleterious A/G polymorphisms in a population. Integrating genome and transcriptome sequencing data from 447 human lymphoblastoid cell lines, we show that nonsynonymous editing activities (prevalence/level) are negatively correlated with the deleteriousness of A-to-G genomic changes and positively correlated with that of G-to-A genomic changes within the population. We find a significantly negative correlation between nonsynonymous editing activities and allele frequency of A within the population. This negative editing-allele frequency correlation is particularly strong when editing sites are located in highly important genes/loci. Examinations of deleterious missense variants from the 1000 Genomes Project further show a significantly higher proportion of rare missense mutations for G-to-A changes than for other types of changes. The proportion for G-to-A changes increases with increasing deleterious effects of the changes. Moreover, the deleteriousness of G-to-A changes is significantly positively correlated with the percentage of editing enzyme binding motifs at the variants. Overall, we show that nonsynonymous editing is associated with the increased burden of G-to-A missense mutations in healthy individuals, expanding RNA editing in pathogenomics studies.

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Evolutionarily significant A-to-I RNA editing events originated through G-to-A mutations in primates

Ding

Yang

et al. 2019

Genome Biol

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BackgroundRecent studies have revealed thousands of A-to-I RNA editing events in primates, but the origination and general functions of these events are not well addressed.ResultsHere, we perform a comparative editome study in human and rhesus macaque and uncover a substantial proportion of macaque A-to-I editing sites that are genomically polymorphic in some animals or encoded as non-editable nucleotides in human. The occurrence of these recent gain and loss of RNA editing through DNA point mutation is significantly more prevalent than that expected for the nearby regions. Ancestral state analyses further demonstrate that an increase in recent gain of editing events contribute to the over-representation, with G-to-A mutation site as a favorable location for the origination of robust A-to-I editing events. Population genetics analyses of the focal editing sites further reveal that a portion of these young editing events are evolutionarily significant, indicating general functional relevance for at least a fraction of these sites.ConclusionsOverall, we report a list of A-to-I editing events that recently originated through G-to-A mutations in primates, representing a valuable resource to investigate the features and evolutionary significance of A-to-I editing events at the population and species levels. The unique subset of primate editome also illuminates the general functions of RNA editing by connecting it to particular gene regulatory processes, based on the characterized outcome of a gene regulatory level in different individuals or primate species with or without these editing events.Electronic supplementary materialThe online version of this article (10.1186/s13059-019-1638-y) contains supplementary material, which is available to authorized users.

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A-to-I RNA editing uncovers hidden signals of adaptive genome evolution in animals

Abstract: 35In animals, the most common type of RNA editing is the deamination of adenosines 36 (A) into inosines (I). Because inosines base-pair with cytosines (C), they are interpreted as 37

Cited by 3 publications

References 47 publications

ADAR1 can drive Multiple Myeloma progression by acting both as an RNA editor of specific transcripts and as a DNA mutator of their cognate genes

ADAR1 can drive Multiple Myeloma progression by acting both as an RNA editor of specific transcripts and as a DNA mutator of their cognate genes

A-to-I RNA editing contributes to the persistence of predicted damaging mutations in populations

Evolutionarily significant A-to-I RNA editing events originated through G-to-A mutations in primates

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