Computational and Experimental Identification of C. elegans microRNAs

Grad, Yonatan H.; Aach, John; Hayes, Gabriel D.; Reinhart, Brenda J.; Church, George M.; Ruvkun, Gary; Kim, John

doi:10.1016/s1097-2765(03)00153-9

Cited by 265 publications

(215 citation statements)

References 37 publications

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“…The majority of Caenorhabditis miRNA families within each species are conserved miRNAs in C. elegans are well-characterized (Lau et al 2001;Lee and Ambros 2001;Grad et al 2003;Lim et al 2003;Ruby et al 2006;Kato et al 2009;Gerstein et al 2010); however, miRNAs in C. briggsae and C. remanei have been only partially characterized (de Wit et al 2009), and miRNAs in C. brenneri have not been examined. To identify miRNAs in each of the four species, we used the miRDeep2 program (Mackowiak 2011;Friedlander et al 2012).…”

Section: Resultsmentioning

confidence: 99%

High-throughput sequencing reveals extraordinary fluidity of miRNA, piRNA, and siRNA pathways in nematodes

Shi

Montgomery

et al. 2013

Genome Res.

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The nematode Caenorhabditis elegans contains each of the broad classes of eukaryotic small RNAs, including microRNAs (miRNAs), endogenous small-interfering RNAs (endo-siRNAs), and piwi-interacting RNAs (piRNAs). To better understand the evolution of these regulatory RNAs, we deep-sequenced small RNAs from C. elegans and three closely related nematodes: C. briggsae, C. remanei, and C. brenneri. The results reveal a fluid landscape of small RNA pathways with essentially no conservation of individual sequences aside from a subset of miRNAs. We identified 54 miRNA families that are conserved in each of the four species, as well as numerous miRNAs that are species-specific or shared between only two or three species. Despite a lack of conservation of individual piRNAs and siRNAs, many of the features of each pathway are conserved between the different species. We show that the genomic distribution of 26G siRNAs and the tendency for piRNAs to cluster is conserved between C. briggsae and C. elegans. We also show that, in each species, 26G siRNAs trigger stage-specific secondary siRNA formation. piRNAs in each species also trigger secondary siRNA formation from targets containing up to three mismatches. Finally, we show that the production of male-and female-specific piRNAs is conserved in all four species, suggesting distinct roles for piRNAs in male and female germlines.

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Section: Resultsmentioning

confidence: 99%

High-throughput sequencing reveals extraordinary fluidity of miRNA, piRNA, and siRNA pathways in nematodes

Shi

Montgomery

et al. 2013

Genome Res.

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“…Most of the moderately to highly expressed miRNAs are completely conserved in this genus. The extreme conservation of miRs, noted many times before (26)(27)(28), may be explained by the large num- ber of targets (>50) each miR regulates. Likewise, proteins that have many interacting partners also tend to evolve slowly (12).…”

Section: Resultsmentioning

confidence: 99%

Testing hypotheses on the rate of molecular evolution in relation to gene expression using microRNAs

Shen

Huang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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There exists an inverse relationship between the rate of molecular evolution and the level of gene expression. Among the many explanations, the "toxic-error" hypothesis is a most general one, which posits that processing errors may often be toxic to the cells. However, toxic errors that constrain the evolution of highly expressed genes are often difficult to measure. In this study, we test the toxic-error hypothesis by using microRNA (miRNA) genes because their processing errors can be directly measured by deep sequencing. A miRNA gene consists of a small mature product (≈22 nt long) and a "backbone." Our analysis shows that (i) like the mature miRNA, the backbone is highly conserved; (ii) the rate of sequence evolution in the backbone is negatively correlated with expression; and (iii) although conserved between distantly related species, the error rate in miRNA processing is also negatively correlated with the expression level. The observations suggest that, as a miRNA gene becomes more highly (or more ubiquitously) expressed, its sequence evolves toward a structure that minimizes processing errors.evolutionary rate | microRNA biogenesis | microRNA evolution

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“…7, Table S1, and Dataset S4). This similarity in their seed regions generally suggests overlapping sets of targets and shared or related functions (65)(66)(67). Nonetheless, the remainder of the miRNA sequence can also assist in defining the eventual targetome.…”

Section: Discussionmentioning

confidence: 99%

Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs

Londin

Lohera

Telonis

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

383

365

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Two decades after the discovery of the first animal microRNA (miRNA), the number of miRNAs in animal genomes remains a vexing question. Here, we report findings from analyzing 1,323 short RNA sequencing samples (RNA-seq) from 13 different human tissue types. Using stringent thresholding criteria, we identified 3,707 statistically significant novel mature miRNAs at a false discovery rate of ≤0.05 arising from 3,494 novel precursors; 91.5% of these novel miRNAs were identified independently in 10 or more of the processed samples. Analysis of these novel miRNAs revealed tissue-specific dependencies and a commensurate low Jaccard similarity index in intertissue comparisons. Of these novel miRNAs, 1,657 (45%) were identified in 43 datasets that were generated by cross-linking followed by Argonaute immunoprecipitation and sequencing (Ago CLIP-seq) and represented 3 of the 13 tissues, indicating that these miRNAs are active in the RNA interference pathway. Moreover, experimental investigation through stemloop PCR of a random collection of newly discovered miRNAs in 12 cell lines representing 5 tissues confirmed their presence and tissue dependence. Among the newly identified miRNAs are many novel miRNA clusters, new members of known miRNA clusters, previously unreported products from uncharacterized arms of miRNA precursors, and previously unrecognized paralogues of functionally important miRNA families (e.g., miR-15/107). Examination of the sequence conservation across vertebrate and invertebrate organisms showed 56.7% of the newly discovered miRNAs to be human-specific whereas the majority (94.4%) are primate lineage-specific. Our findings suggest that the repertoire of human miRNAs is far more extensive than currently represented by public repositories and that there is a significant number of lineage-and/or tissue-specific miRNAs that are uncharacterized. SignificanceMicroRNAs (miRNAs) are small ∼22-nt RNAs that are important regulators of posttranscriptional gene expression. Since their initial discovery, they have been shown to be involved in many cellular processes, and their misexpression is associated with disease etiology. Currently, nearly 2,800 human miRNAs are annotated in public repositories. A key question in miRNA research is how many miRNAs are harbored by the human genome. To answer this question, we examined 1,323 short RNA sequence samples and identified 3,707 novel miRNAs, many of which are human-specific and tissue-specific. Our findings suggest that the human genome expresses a greater number of miRNAs than has previously been appreciated and that many more miRNA molecules may play key roles in disease etiology.

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Computational and Experimental Identification of C. elegans microRNAs

Cited by 265 publications

References 37 publications

High-throughput sequencing reveals extraordinary fluidity of miRNA, piRNA, and siRNA pathways in nematodes

High-throughput sequencing reveals extraordinary fluidity of miRNA, piRNA, and siRNA pathways in nematodes

Testing hypotheses on the rate of molecular evolution in relation to gene expression using microRNAs

Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs

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