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Genome Biol
2014 Jun 25;156:R83. doi: 10.1186/gb-2014-15-6-r83.
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Conserved microRNA editing in mammalian evolution, development and disease.
Warnefors M
,
Liechti A
,
Halbert J
,
Valloton D
,
Kaessmann H
.
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BACKGROUND: Mammalian microRNAs (miRNAs) are sometimes subject to adenosine-to-inosine RNA editing, which can lead to dramatic changes in miRNA target specificity or expression levels. However, although a few miRNAs are known to be edited at identical positions in human and mouse, the evolution of miRNA editing has not been investigated in detail. In this study, we identify conserved miRNA editing events in a range of mammalian and non-mammalian species.
RESULTS: We demonstrate deep conservation of several site-specific miRNA editing events, including two that date back to the common ancestor of mammals and bony fishes some 450 million years ago. We also find evidence of a recent expansion of an edited miRNA family in placental mammals and show that editing of these miRNAs is associated with changes in target mRNA expression during primate development and aging. While global patterns of miRNA editing tend to be conserved across species, we observe substantial variation in editing frequencies depending on tissue, age and disease state: editing is more frequent in neural tissues compared to heart, kidney and testis; in older compared to younger individuals; and in samples from healthy tissues compared to tumors, which together suggests that miRNA editing might be associated with a reduced rate of cell proliferation.
CONCLUSIONS: Our results show that site-specific miRNA editing is an evolutionarily conserved mechanism, which increases the functional diversity of mammalian miRNA transcriptomes. Furthermore, we find that although miRNA editing is rare compared to editing of long RNAs, miRNAs are greatly overrepresented among conserved editing targets.
Figure 1. Conservation of miRNA editing in vertebrates. The identifier of the edited miRNA and the position at which editing occurs are indicated on the left. Observed miRNA editing with a frequency of >1% is indicated as blue boxes for the species in the core set (Table 1) and as dark green boxes for the 10 additional species. For completeness, cases where A-to-G mismatches were present at a frequency <1% (‘trace reads’) are shown as light green boxes, although it should be noted that such trace events cannot be readily distinguished from sequencing errors. Gray shading indicates that the presence of miRNA editing could not be assessed due to a lack of sequencing reads for the miRNA in question (which might be explained by the rigorous filtering criteria, lack of expression in the investigated samples or absence of the miRNA in the genome). An asterisk following the species name indicates that no quality scores were available for the species in question. Divergence times were taken from the TimeTree database [20]. Note that the analysis presented here was performed using a stringent detection algorithm to avoid false positives; editing of a given miRNA might therefore have escaped detection in some species (compare Figure 3).
Figure 2. Conserved editing and 5′ length variation of miR-411. (A) As a result of A-to-I editing (here represented as A-to-G) and alternative 5′ cleavage, the miR-411 precursor gives rise to four variants with distinct seed sequences. The short, unedited variant is the annotated form. (B) Venn diagram of the predicted targets for each miR-411 variant. Targets were predicted with TargetScan release 6.0 [25] and were required to be present in at least 10 species, including human, macaque and mouse. (C) Relative abundance of the four miR-411 variants in (from top to bottom) human, macaque and mouse, when considering reads from all five tissues together.
Figure 3. Frequency of miRNA editing across tissues and species. (A) Estimated miRNA frequencies in brain (B), cerebellum (C), heart (H), kidney (K) and testis (T). From left to right, the animal silhouettes represent human, macaque, mouse, opossum, platypus and chicken. The miRNA identifiers are given in the left-hand column and are followed by the position of the edited site within the mature or star miRNA. The color of each circle corresponds to the proportion of edited reads, while the size of the circle corresponds to the total number of reads for the miRNA in question. Note that these data are not normalized and that expression levels therefore should not be compared across samples. Gray shading indicates the absence of an annotated miRNA ortholog in that particular species, based on the information in Table S1 in Additional file 2. The data used to generate this figure are provided in Table S2 in Additional file 2. (B) Comparison of editing frequencies in neural (brain and cerebellum) versus non-neural (heart, kidney and testis) tissues in human, macaque and mouse, for miRNAs with at least 10 reads in all relevant samples. The median frequency is indicated by a blue line. (C) Comparison of editing frequencies in human and mouse samples for the same miRNAs as in (B). The median frequency is indicated by a blue line. (D) Hierarchical clustering of the same miRNAs as in (B), based on editing frequencies in five tissues in human (hsa), macaque (mml) and mouse (mmu). Orthologous miRNAs have been given the same color. The clustering was performed using the R function hclust and Ward’s method.
Figure 4. Changes in miRNA editing frequencies during primate postnatal development and aging. (A) Spearman correlation coefficients for miRNA editing frequencies and age in human and macaque (see main text for details). The respective correlations for ADAR and ADARB1 mRNA expression levels are indicated as squares. Cases where the correlation coefficients were significant in both species are highlighted in red. (B) Editing frequencies for the six significant miRNAs (see (A)) in samples from different ages, with younger individuals on the left and older on the right. (C) Distribution of correlation coefficients for age and expression levels, calculated for mRNAs predicted to be targeted either by edited or unedited miRNAs. If expression is independent of age, the expected correlation coefficient is 0, as indicated by the dotted line. Statistical significance is indicated by double (0.001 < P < 0.01) or triple (P < 0.001) asterisks.
Figure 5. Comparison of editing frequencies in samples from cancerous and healthy tissues. (A) Each point represents the estimated editing frequency of a single miRNA in a matched sample (cancer and control) from the same patient. Cases where a significant difference in editing was detected between the two conditions (χ2-test with Benjamini-Hochberg correction) are highlighted in red. (B) Summary of the significant cases in (A). Sample identifiers consist of a letter giving the cancer type and a number that refers to the patient identifier in the original study. Blue bars represent significant downregulation of miRNA editing in cancer samples, with the top of the bar corresponding to the editing frequency in the control sample and the bottom of the bar corresponding to the editing frequency in the cancer sample. Red bars represent significant editing upregulation, with the bottom of the bar corresponding to the editing frequency in the control sample and the top of the bar corresponding to the editing frequency in the cancer sample.
Alon,
Systematic identification of edited microRNAs in the human brain.
2012, Pubmed
Alon,
Systematic identification of edited microRNAs in the human brain.
2012,
Pubmed
Ameres,
Diversifying microRNA sequence and function.
2013,
Pubmed
Andreassen,
Discovery and characterization of miRNA genes in Atlantic salmon (Salmo salar) by use of a deep sequencing approach.
2013,
Pubmed
Bartel,
MicroRNAs: target recognition and regulatory functions.
2009,
Pubmed
Berezikov,
Deep annotation of Drosophila melanogaster microRNAs yields insights into their processing, modification, and emergence.
2011,
Pubmed
Blow,
RNA editing of human microRNAs.
2006,
Pubmed
Buchold,
Analysis of microRNA expression in the prepubertal testis.
2010,
Pubmed
Burroughs,
A comprehensive survey of 3' animal miRNA modification events and a possible role for 3' adenylation in modulating miRNA targeting effectiveness.
2010,
Pubmed
Chiang,
Mammalian microRNAs: experimental evaluation of novel and previously annotated genes.
2010,
Pubmed
Choudhury,
Attenuated adenosine-to-inosine editing of microRNA-376a* promotes invasiveness of glioblastoma cells.
2012,
Pubmed
Davidson,
Sequencing the genome of the Atlantic salmon (Salmo salar).
2010,
Pubmed
Edgar,
MUSCLE: multiple sequence alignment with high accuracy and high throughput.
2004,
Pubmed
Ekdahl,
A-to-I editing of microRNAs in the mammalian brain increases during development.
2012,
Pubmed
Flicek,
Ensembl 2013.
2013,
Pubmed
Grimson,
MicroRNA targeting specificity in mammals: determinants beyond seed pairing.
2007,
Pubmed
Heale,
Editing independent effects of ADARs on the miRNA/siRNA pathways.
2009,
Pubmed
Hedges,
TimeTree: a public knowledge-base of divergence times among organisms.
2006,
Pubmed
Heimberg,
microRNAs reveal the interrelationships of hagfish, lampreys, and gnathostomes and the nature of the ancestral vertebrate.
2010,
Pubmed
Kawahara,
Redirection of silencing targets by adenosine-to-inosine editing of miRNAs.
2007,
Pubmed
Kawahara,
RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer-TRBP complex.
2007,
Pubmed
Kawahara,
Frequency and fate of microRNA editing in human brain.
2008,
Pubmed
Kiran,
Darned in 2013: inclusion of model organisms and linking with Wikipedia.
2013,
Pubmed
Kozomara,
miRBase: integrating microRNA annotation and deep-sequencing data.
2011,
Pubmed
Lagos-Quintana,
Identification of novel genes coding for small expressed RNAs.
2001,
Pubmed
Landgraf,
A mammalian microRNA expression atlas based on small RNA library sequencing.
2007,
Pubmed
Langmead,
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
2009,
Pubmed
Levanon,
Systematic identification of abundant A-to-I editing sites in the human transcriptome.
2004,
Pubmed
Lewis,
Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.
2005,
Pubmed
Lewis,
Prediction of mammalian microRNA targets.
2003,
Pubmed
Li,
Evolutionary and ontogenetic changes in RNA editing in human, chimpanzee, and macaque brains.
2013,
Pubmed
Li,
Comparative mRNA and microRNA expression profiling of three genitourinary cancers reveals common hallmarks and cancer-specific molecular events.
2011,
Pubmed
Lindsay,
Unique small RNA signatures uncovered in the tammar wallaby genome.
2012,
Pubmed
Luciano,
RNA editing of a miRNA precursor.
2004,
Pubmed
Lyson,
MicroRNAs support a turtle + lizard clade.
2012,
Pubmed
Meunier,
Birth and expression evolution of mammalian microRNA genes.
2013,
Pubmed
Murchison,
The Tasmanian devil transcriptome reveals Schwann cell origins of a clonally transmissible cancer.
2010,
Pubmed
Nishikura,
Functions and regulation of RNA editing by ADAR deaminases.
2010,
Pubmed
Ota,
ADAR1 forms a complex with Dicer to promote microRNA processing and RNA-induced gene silencing.
2013,
Pubmed
Patterson,
Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase.
1995,
Pubmed
Paul,
Inosine exists in mRNA at tissue-specific levels and is most abundant in brain mRNA.
1998,
Pubmed
Paz,
Altered adenosine-to-inosine RNA editing in human cancer.
2007,
Pubmed
Pinto,
Mammalian conserved ADAR targets comprise only a small fragment of the human editosome.
2014,
Pubmed
Ramaswami,
Accurate identification of human Alu and non-Alu RNA editing sites.
2012,
Pubmed
Ramaswami,
Identifying RNA editing sites using RNA sequencing data alone.
2013,
Pubmed
Seitz,
A large imprinted microRNA gene cluster at the mouse Dlk1-Gtl2 domain.
2004,
Pubmed
Shaffer,
The western painted turtle genome, a model for the evolution of extreme physiological adaptations in a slowly evolving lineage.
2013,
Pubmed
Sherry,
dbSNP: the NCBI database of genetic variation.
2001,
Pubmed
Somel,
MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain.
2010,
Pubmed
Sorefan,
Reducing ligation bias of small RNAs in libraries for next generation sequencing.
2012,
Pubmed
St John,
Sequencing three crocodilian genomes to illuminate the evolution of archosaurs and amniotes.
2012,
Pubmed
Starega-Roslan,
Structural basis of microRNA length variety.
2011,
Pubmed
Venkatesh,
Elephant shark genome provides unique insights into gnathostome evolution.
2014,
Pubmed
Vesely,
Adenosine deaminases that act on RNA induce reproducible changes in abundance and sequence of embryonic miRNAs.
2012,
Pubmed
Warf,
Effects of ADARs on small RNA processing pathways in C. elegans.
2012,
Pubmed
Wei,
Transcriptome-wide analysis of small RNA expression in early zebrafish development.
2012,
Pubmed
Wu,
Alternative processing of primary microRNA transcripts by Drosha generates 5' end variation of mature microRNA.
2009,
Pubmed
Yang,
Modulation of microRNA processing and expression through RNA editing by ADAR deaminases.
2006,
Pubmed
Zhang,
The identification of microRNAs in the whitespotted bamboo shark (Chiloscyllium plagiosum) liver by Illumina sequencing.
2013,
Pubmed
,
Xenbase
Zhou,
Integrated profiling of microRNAs and mRNAs: microRNAs located on Xq27.3 associate with clear cell renal cell carcinoma.
2010,
Pubmed
de Hoon,
Cross-mapping and the identification of editing sites in mature microRNAs in high-throughput sequencing libraries.
2010,
Pubmed