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Cited by 405MicroRNA in disease regulationPlant Molecular Biology ResearchChromosomal and Genetic Variations

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

Open access
Londin, Eric, Loher, Phillipe, Telonis, Aristeidis G., Quann, Kevin, Clark, Peter, Jing, Yi, Hatzimichael, Eleftheria, Kirino, Yohei +30 more·2015·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1420955112PMC PMC4364231
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Abstract

Significance: MicroRNAs (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.

AI snapshot

Written from the paper’s full text.

TL;DR

Analyzing 1,323 short RNA-seq samples from 13 human cell types, this study identifies 3,707 novel mature miRNAs from 3,494 precursors at FDR ≤ 0.05, many of which are tissue-specific and primate-specific. The authors argue that public repositories substantially underrepresent the human miRNA repertoire.

Key findings

  • From >23 billion sequenced reads, ~8.2 billion mapped unambiguously; 3,707 novel mature miRNAs were identified, and 91.5% (3,392 of 3,707) were discovered independently in at least 10 samples.
  • Ago CLIP-seq supported 1,657 of 3,707 novel miRNAs (44.7%), compared with 1,517 of 2,772 miRBase release 20 miRNAs (54.7%).
  • Novel miRNAs showed strong tissue dependence: low intertissue Jaccard similarity, PCA clustering by tissue, and stem-loop RT-PCR confirmation of 20 novel miRNAs in 12 cell lines representing 5 tissues.
  • Conservation analysis found 56.7% of novel miRNAs human-specific and 94.4% primate lineage-specific; 2,140 (58.1%) precursor/mature combinations were human-specific, 476 (12.8%) shared across Hominidae, 109 (2.9%) present in mouse, and none in Drosophila or worm.

Methods

  • Analyzed 1,323 short RNA-seq samples (100 in-house, 1,223 public) from 13 human cell types; reads were mapped to hg19 with SHRiMP2, processed per sample with miRDeep2, and filtered to mature miRNAs with FDR ≤ 0.05 after removing known miRNAs, mirtrons, tRNAs, snRNAs, and rRNAs.
  • Used 43 Ago CLIP-seq samples (10 in-house, 33 public) to assess Argonaute loading, requiring complete coincidence with a CLIP-seq site, observation in at least one sample, and support by five or more reads.
  • Validated selected novel miRNAs by stem-loop RT-PCR in 12 cell lines, assessed DICER dependence in MCF7 knockdown data, performed GLSEARCH conservation analysis, seed-based clustering, and RNA22 target prediction.

Limitations

  • The paper states that the 43 Ago CLIP-seq samples represent only 3 of the 13 tissue types used for discovery, so not all novel or miRBase miRNAs are expected to be observed; lower Ago support for novel miRNAs is expected given their higher tissue specificity.
  • The paper states that the study focused only on canonical Dicer-dependent miRNAs, while bona fide miRNAs can arise through other mechanisms, suggesting an even larger miRNA-ome.
  • The paper states that RNA22 target predictions require additional experimental validation; only 20 novel miRNAs were experimentally tested by stem-loop RT-PCR.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1073/pnas.1420955112

Cites

74 of 74 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 34 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The authors identified 3,707 statistically significant novel mature miRNAs at a false discovery rate of ≤0.05 arising from 3,494 novel precursors.

    “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.”
    Quote in the paperSubstantial claim
  • Findingown data

    94.4% of the newly discovered miRNAs are primate lineage-specific.

    “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.”
    Quote in the paperSubstantial claim
  • Findingown data

    709 miRBase release 20 miRNAs and 278 novel miRNAs were endogenously expressed in MCF7 cells.

    “Our analysis showed that 709 of the miRNAs in release 20 of miRBase and 278 of our novel miRNAs were endogenously expressed in MCF7 cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Findingown data

    Only 10% of the precursor/mature miRNA combinations from miRBase were human-specific.

    “we found that only 10% of the precursor/mature miRNA combinations from miRBase were human-specific”
    Quote in the paperSubstantial claim
  • Findingown data

    The average expression level of the novel miRNAs is somewhat lower than that of miRBase miRNAs.

    “Generally, we found their average expression level to be somewhat lower than that of miRBase miRNAs”
    Quote in the paperNot a substantial claim
  • May combine two claims. 26
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingown data

    Relaxing the precursor conservation requirement to 50% left the results largely unchanged, with the large majority of newly identified sequences continuing to be primate-specific.

    “The results remained largely unchanged, with the large majority of the newly identified sequences continuing to be primate-specific”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    After siRNA knockdown of DICER1, miRBase miRNAs showed a median decrease in expression of ∼2×, and novel miRNAs showed a median decrease of ∼1.6×.

    “After siRNA knockdown of DICER1, the miRBase miRNAs showed a median decrease in expression of ∼2×, and our novel miRNAs showed a median decrease in expression of ∼1.6×”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingown data

    The authors identified 31 miRNA clusters, 21 of which were comprised exclusively of novel miRNAs.

    “We identified 31 such clusters, 21 of which were comprised exclusively of novel miRNAs”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    The authors computationally predicted mRNA targets using RNA22 for each of the 3,707 newly discovered miRNAs.

    “we computationally predicted their mRNA targets using RNA22 (30,58) to generate predictions of the mRNA targets for each of the 3,707 newly discovered miRNAs.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [30]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [58]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • The authors state this as an assumption: The novel miRNAs will affect many pathways and exert their effects on a wide range of targets.

  • May combine two claims.

    Findingown data

    The second group of 8 novel miRNAs was ubiquitously expressed and present in all examined cell lines.

    “the second group of novel miRNAs was ubiquitously expressed and present in all of the examined cell lines.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The first group of 12 tested tissue-specific novel miRNAs exhibited tissue-specific expression patterns, and each was present in one or more of the tested cell lines.

    “the first group of tested miRNAs indeed exhibited tissue-specific expression patterns: Each of the 12 miRNAs was present in one or more of the tested cell lines.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The 873 common seeds captured 2,146 novel miRNAs, and the remaining 1,561 novel miRNAs had 888 distinct seed sequences not present in an annotated miRBase miRNA.

    “The 873 common seeds captured 2,146 of our novel miRNAs; the remaining 1,561 novel miRNAs had 888 distinct seed sequences not present in an annotated miRBase miRNA”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    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.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The authors identified 13 sense/antisense instances, 9 of which comprise only novel miRNA pairs.

    “identified 13 such instances, 9 of which comprise only novel miRNA pairs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Analysis of the novel miRNAs revealed tissue-specific dependencies and a commensurate low Jaccard similarity index in intertissue comparisons.

    “Analysis of these novel miRNAs revealed tissue-specific dependencies and a commensurate low Jaccard similarity index in intertissue comparisons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    109 (2.9%) precursor/mature miRNA combinations were present in mouse, whereas none were present in the Drosophila or worm genomes.

    “109 (2.9%) of them were present in mouse whereas none were present in the Drosophila or worm genomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    56.7% of newly discovered miRNAs are human-specific and 94.4% are primate-specific.

    “not surprisingly then, 56.7% of our newly discovered miRNAs are human-specific whereas 94.4% are primate-specific (Table 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 2

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    10 of the novel miRNAs discovered were included in release 21 of miRBase.

    “Analysis of our collection of identified miRNAs revealed that 10 of the novel miRNAs that we discovered were included in release 21 of miRBase.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The identified novel miRNAs display patterns of tissue specificity and can distinguish among tissue types.

    “Taken together, these results suggest that the identified novel miRNAs display patterns of tissue specificity and can distinguish among tissue types.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: miRNAs exhibit tissue-specific behavior similar to protein-coding genes.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Identified mature miRNAs and precursors were postprocessed to remove predicted mature miRNAs already represented in miRBase release 20 or the mirtron catalog and those colocalized with snRNAs, tRNAs, and rRNAs.

    “We further postprocessed the identified mature miRNAs and precursors to remove any predicted mature miRNA that (i) is already represented in miRBase release 20 or in the mirtron catalog (28) and/or (ii) colocalized with snRNAs, tRNAs, and rRNAs even though such loci have been previously linked with miRNA production”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    The small overlap with the other effort is due to the two studies having only one dataset in common and to the tissue-specificity of the novel miRNAs.

    “There are two reasons for this small overlap: first, the 1,323 samples that we analyzed and the 94 samples analyzed in ref. 33 have only one dataset in common (NIH GEO accession no.GSE15229; 30 samples).And second, our novel miRNAs (as evidenced by Fig. 3A) and those discovered in ref. 33 are tissue-specific.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    The existence of novel miRNAs that are primate- and tissue-specific indicates molecular interactions that cannot be recapitulated by mouse models and has potential implications for disease and research.

    “the existence of novel miRNAs that are primate-and tissue-specific indicates the existence of molecular interactions that cannot be recapitulated by mouse models and, thus, has potential implications for both disease and research endeavors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: There is no reason to think that there will not be lineage-specific adaptive evolution in regulatory sequences and regulatory molecules.

  • May combine two claims.

    Interpretationown data

    About half of the newly identified miRNAs are loaded onto the Ago-silencing complex and are imputed to be posttranscriptionally functional or biologically active.

    “These results suggest that about half of our newly identified miRNAs are loaded onto the Ago-silencing complex and thus are imputed to be posttranscriptionally functional.”
    • Also stated in: § Discussion · hedged
      “many of the novel miRNAs are loaded onto the Ago-silencing complex, which suggests that they are biologically active.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    Expression levels were normalized separately for each sample, and only very abundant novel miRNAs with expression ≥1/100 the expression of endogenous SNORD44 were kept.

    “we normalized the expression level of each miRNA as previously described (44,45) and separately for each sample.From each analyzed sample, we kept only very abundant novel miRNAs [i.e., novel miRNAs with expression levels ≥1/100 the expression of the endogenous small nucleolar RNA (snoRNA) SNORD44 (44, 45)]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [44]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [45]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    The newly discovered miRNAs that are endogenous to MCF7 cells are DICER-dependent and follow the canonical biogenesis pathway.

    “This result indicates that those of our newly discovered miRNAs that are endogenous to MCF7 cells are DICER-dependent and follow the canonical biogenesis pathway.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Each mature miRNA candidate had to completely coincide with an Ago CLIP-seq site, be observed in at least 1 of the 43 CLIP-seq samples, and be supported by five or more unambiguously mapped CLIP-seq reads.

    “Each mature miRNA candidate had to completely coincide with an Ago CLIP-seq site, be observed in at least 1 of the 43 CLIP-seq samples, and be supported by five or more unambiguously mapped CLIP-seq reads.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Discovered miRNAs were kept only if they had an associated FDR ≤ 0.05.

    “Additionally, to eliminate noisy lowly expressed miRs, we kept a discovered miRNA only if it had an associated FDR ≤ 0.05.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RNA22 is not confined to the 3′ UTR alone but can generate predictions across the entire length of an mRNA.

    “One important property of RNA22 is that it is not confined on the 3′ UTR alone but can generate predictions across the entire length of an mRNA.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [30]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [58]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    RNA22 has a demonstrated ability to correctly predict targets in amino acid coding regions, in 5′ UTRs, and targets that do not contain contiguous Watson-Crick base pairs in their seed region.

    “We opted to use RNA22 (https://cm.jefferson.edu/rna22v2/) because of its demonstrated ability to correctly predict targets in amino acid coding regions and in 5′ UTRs, as well as targets that do not contain contiguous Watson-Crick base pairs in their seed region.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [30]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [58]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Members of the miR-29 family share the same seed sequence but display differences in predicted targetomes: miR-29b localizes predominantly in the nucleus whereas miR-29a and miR-29c do not.

    “For example, the members of the miR-29 family share the same seed sequence but display differences in the predicted targetomes: miR-29b localizes predominantly in the nucleus whereas miR-29a and miR-29c do not (69).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Release 20 of miRBase comprises 1,871 precursor sequences and 2,772 mature miRNAs.

    “This release of miRBase comprises 1,871 precursor sequences and 2,772 mature miRNAs.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [32]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Conservation required at least 85% of miRNA precursor positions identically conserved and at least 85% of human mature miRNA positions identically present including an identically present seed.

    “During these searches, we required that (i) at least 85% of the miRNA precursor positions be identically conserved in the searched genome and (ii) at least 85% of the human mature miRNA positions be identically present in the identified orthologous precursor, including an identically present seed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Enforcing an organism-conservation requirement during miRNA searches limits the number of potential miRNAs that can be discovered, leaving organism- and lineage-specific miRNAs undiscovered.

    “Therefore, enforcing an organism-conservation requirement during miRNA searches is bound to limit the number of potential miRNAs that can be discovered, leaving organism-and lineage-specific miRNAs undiscovered (53)(54)(55)(56).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (53)(54)(55)(56)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    For conservation searches, the authors required at least 85% of miRNA precursor positions to be identically present in the searched genome and at least 85% of the human mature miRNA sequence, including an identical seed, to be identically present in the identified orthologous precursor.

    “we imposed two requirements: (i) At least 85% of the miRNA precursor positions should be identically present in the genome being searched, and (ii) at least 85% of the human mature miRNA sequence should be identically present in the identified orthologous precursor, including an identically present seed.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    At least some novel primate-specific miRNAs participate in unexplored aspects of regulatory processes that cannot be captured by currently available mouse disease models.

    “Indeed, it is reasonable to expect that at least some of these novel primate-specific miRNAs participate in unexplored aspects of regulatory processes that cannot be captured by the currently available mouse disease models.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    A negative control scrambled miRNA primer and U6 RT-PCR were used to control for RNA concentrations.

    “As a negative control, a primer to a scrambled miRNA sequence was designed.U6 RT-PCR was performed on all samples to control for the RNA concentrations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The FDR procedure compensates for differences in sequence depth among samples and selects only miRNAs with statistically significant abundance.

    “These steps allow us to compensate for differences in sequence depth among the various samples and to select only miRNAs with statistically significant abundance in the sample being considered each time.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The miRNAs currently listed in public repositories represent only a small fraction of the total human miRNA repertoire and many more human miRNAs await discovery.

    “Based on the results presented here and taking into account previous studies (28,33), we conclude that the miRNAs currently listed in the public repositories represent only a small fraction of the total human miRNA repertoire and that many more human miRNAs await discovery.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [33]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The sheer magnitude of the identified miRNAs and the very high number of predicted targets for each such miRNA make experimental validation of the targetome by a single laboratory an intractable proposition.

    “The sheer magnitude of the identified miRNAs and the very high number of predicted targets for each such miRNA make the experimental validation of the targetome by a single laboratory an intractable proposition.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The remainder of the miRNA sequence can assist in defining the eventual targetome.
34 of 34

  • The authors state this as an assumption.

    The novel miRNAs will affect many pathways and exert their effects on a wide range of targets.

    “It is reasonable to assume that these novel miRNAs will affect many pathways and exert their effects on a wide range of targets.”

  • The authors state this as an assumption.

    miRNAs exhibit tissue-specific behavior similar to protein-coding genes.

    “Just as protein-coding genes display tissue-specific patterns of expression, it is reasonable to assume that miRNAs would exhibit a similar behavior.”

  • The paper relies on this without support.

    Many more miRNAs are present and can be identified through analysis of additional samples representing more diverse tissue types.

    “We reasoned that many more miRNAs are present and can be identified through the analysis of additional samples representing more diverse tissue types.”

  • The paper relies on this without support.

    There is no reason to think that there will not be lineage-specific adaptive evolution in regulatory sequences and regulatory molecules.

    “Indeed, there is no reason to think that there will not be lineage-specific adaptive evolution in regulatory sequences and regulatory molecules.”

  • The paper relies on this without support.

    MiRNAs loaded onto the Argonaute complex are capable of interacting with target RNAs.

    “MiRNAs exert their function through their association with the Argonaute complex, and, thus, those miRNAs loaded onto Ago are expected to be capable of interacting with target RNAs.”

  • The paper relies on this without support.

    The remainder of the miRNA sequence can assist in defining the eventual targetome.

    “Nonetheless, the remainder of the miRNA sequence can also assist in defining the eventual targetome.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The remaining miRBase microRNAs had modest conservation and were similarly distributed to both the putative novel microRNAs reported here and the 3707 novel TJU microRNAs.

    “The remaining miRBase microRNAs had modest conservation and were similarly distributed to both the putative novel microRNAs reported here and the 3707 novel microRNAs reported as TJU microRNAs (Fig. 3B; Londin et al. 2015).”

    From Toward the human cellular microRNAome (2017) · cites this paper as Londin et al. 2015

  • PhyloP conservation data show that beyond the most ideal microRNAs in miRGeneDB, there is a lack of genetic conservation, with overlap among a large segment of miRBase microRNAs and the novel microRNAs reported here and in a prior large study.

    “The PhyloP conservation data (Fig. 3B) show that, beyond the most ideal microRNAs identified in miRGeneDB, there is a lack of genetic conservation, with overlap in a large segment of miRBase microRNAs and the novel microRNAs reported here and in a prior large study (Londin et al. 2015).”

    From Toward the human cellular microRNAome (2017) · cites this paper as Londin et al. 2015

  • Only 257 (52%) of the putative novel microRNAs were shared between both data sets (with the 3707 novel TJU microRNAs).

    “In comparison to the 3707 novel TJU microRNAs (Londin et al. 2015), only 257 (52%) were shared between both data sets.”

    From Toward the human cellular microRNAome (2017) · cites this paper as Londin et al. 2015

  • Too many 'novel miRNAs' lack clear miRNA features and have only served to further complicate the miRNA field.

    “Too many “novel miRNAs” lack clear miRNA features and have only served to further complicate the miRNA field [17, 35, 36].”

    From A curated human cellular microRNAome based on 196 primary cell types (2022) · cites this paper as [35]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Drosophila conservation percentage is miscalculated

    Minor

    Table 2 reports six of 3,707 novel combinations as 0.25%; that fraction is about 0.16%.

    Reported 0.25 · recomputed 0.161856

  • Figure 5 assigns different meanings to its rows

    Minor

    The caption says each row represents one miRNA, then says each row represents a cell line.

  • Claim of no invertebrate conservation conflicts with Table 2

    Minor

    The prose says none of the novel combinations were present in Drosophila or worm, but Table 2 lists six and two, respectively.

  • The number of analyzed short RNA samples changes to 1,232

    Minor

    The paper consistently gives 1,323 as the number of analyzed short RNA-seq samples, but the Ago CLIP-seq discussion calls the analyzed collection 1,232 samples.

4 of 4

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Authors
Londin, E., Loher, P., Telonis, A. G., Quann, K., Clark, P., Jing, Y., Hatzimichael, E., Kirino, Y., Honda, S., Lally, M., Ramratnam, B., Comstock, C. E. S., Knudsen, K. E., Gomella, L., Spaeth, G. L., Hark, L., Katz, L. J., Witkiewicz, A., Rostami, A., Jimenez, S. A., Hollingsworth, M. A., Yeh, J. J., Shaw, C. A., McKenzie, S. E., Bray, P., Nelson, P. T., Zupo, S., Van Roosbroeck, K., Keating, M. J., Calin, G. A., Yeo, C., Jimbo, M., Cozzitorto, J., Brody, J. R., Delgrosso, K., Mattick, J. S., Fortina, P., & Rigoutsos, I.
Affiliations
  • Thomas Jefferson University (US)
  • Computational Medicine Center, Sidney Kimmel Medical School at Thomas Jefferson University, Philadelphia, PA 19107;
  • Brown University (US)
  • American Association For Cancer Research (US)
  • Wills Eye Hospital (US)
  • The University of Texas Southwestern Medical Center (US)
  • Jefferson Institute of Molecular Medicine and The Scleroderma Center, Sidney Kimmel Medical School at Thomas Jefferson University, Philadelphia, PA 19107;
  • University of Nebraska Medical Center (US)
  • University of North Carolina at Chapel Hill (US)
  • Baylor College of Medicine (US)
  • University of Kentucky (US)
  • Ospedale Policlinico San Martino (IT)
  • Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
  • The University of Texas MD Anderson Cancer Center (US)
  • Leukemia Department, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
  • Garvan Institute of Medical Research (AU)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2015-02-23
Volume
112
Issue
10
Pages
E1106-15
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1420955112
PMC
PMC4364231
OpenAlex
W2022326327
Cited by
404
References
74
Citations by year
2026: 6 · 2025: 16 · 2024: 10 · 2023: 22 · 2022: 22 · 2021: 22 · 2020: 27 · 2019: 51 · 2018: 49 · 2017: 76 · 2016: 75 · 2015: 28
FWCI
24.06
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
  • UKnowledge (University of Kentucky) (submittedVersion)
Funders
  • U.S. Department of Defense
  • W. M. Keck Foundation
  • RGK Foundation
  • Hirshberg Foundation for Pancreatic Cancer Research
  • CLL Global Research Foundation
  • Thomas Jefferson University (P30CA56036)
  • Deutsches Krebsforschungszentrum
  • Laura and John Arnold Foundation
  • Weizmann Institute of Science
  • National Institutes of Health (#AG028383)
  • University of Texas MD Anderson Cancer Center
  • Center for AIDS Research, University of Washington
  • National Institute on Aging (P30AG028383, R01AG042419)
  • National Heart, Lung, and Blood Institute (R01HL116713, R01HL102482)
  • National Cancer Institute (R01CA140424, P50CA127297, R01CA099996, P30CA016672, P30CA056036, P30CA036727)
  • National Institute of General Medical Sciences (R01GM106047)
  • National Institute of Allergy and Infectious Diseases (U19AI056363, P30AI042853)
  • National Institute of Neurological Disorders and Stroke (R21NS085830)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR019616)
  • National Institute on Minority Health and Health Disparities (R01MD007880)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
Keywords
microRNA, novel miRNA discovery, microRNA precursors, tissue-specific gene expression, miRNA clusters, RNA interference, human cell lines
MeSH terms
Animals, Base Sequence, Primates, Sequence Alignment, Genome, MicroRNAs, Ribonuclease III, Gene Knockdown Techniques

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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