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Cited by 119MicroRNA in disease regulationCancer-related molecular mechanisms researchRNA modifications and cancer

A mouse tissue atlas of small noncoding RNA

Open access
Isakova, Alina, Fehlmann, Tobias, Keller, Andreas, Quake, Stephen R.·2020·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2002277117PMC PMC7568261
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Abstract

Significance: We report a systematic unbiased analysis of small RNA molecule expression in 11 different tissues of the model organism mouse. We discovered uncharacterized noncoding RNA molecules and identified that ∼30% of total noncoding small RNA transcriptome are distributed across the body in a tissue-specific manner with some also being sexually dimorphic. Distinct distribution patterns of small RNA across the body suggest the existence of tissue-specific mechanisms involved in noncoding RNA processing.

Verified 2026-11-06 · 1 reference not checked yet

AI snapshot

Written from the paper’s full text.

TL;DR

This study presents a small noncoding RNA atlas across 11 adult mouse tissues, identifying tissue-specific and sex-dimorphic expression across miRNA, snoRNA, snRNA, scaRNA, tRF, and other ncRNA classes. It also reports novel miRNAs, tissue-dependent miRNA arm switching, and integration with scATAC-seq to infer cell-type origins.

Key findings

  • From 140 small RNA-seq libraries across 11 tissues, the authors identified 1,317 miRNAs, 733 snRNAs, 583 snoRNAs, 25 scaRNAs, 346 tRNAs, 22 mitochondrial tRNAs, and 193 other small ncRNAs; ∼30% of the total noncoding small RNA transcriptome was tissue-specific, with 897 of 3,219 detected genes (28%) contributing to tissue-specific signatures at FDR < 1%, and brain containing the highest number of unique transcripts (∼400).
  • Tissue specificity extended beyond miRNAs: >200 snoRNAs showed tissue-specific patterns, Snora35 and Snord116 were brain-exclusive (TSI = 1), Rny1 was high in brain, Terc was highest in bone marrow and spleen, and ∼400 miRNAs were differentially expressed across tissues, nearly one-quarter of them brain-specific; ∼5% of miRNAs switched arm preference between tissues, including mir-141 and mir-350.
  • Sex-biased miRNAs were identified at FDR < 0.01, with kidney and lung containing the most (27 and 18), followed by brain (7), muscle (5), and heart (2); four of five male-specific brain miRNAs came from a 5-kb region of the imprinted Dlk1-Dio3 locus, and all six sex-specific novel miRNAs were male-dominant.
  • Novel miRNA discovery yielded 473 candidate regions, 214 supported by AGO-CLIP, 87 previously reported, and 12 validated; tRFs made up about a quarter of libraries, with nuclear tRNA fragments mostly 33 nt and mitochondrial fragments spanning 18–54 nt; an SVM tissue classifier reached 0.96 accuracy on postnatal ENCODE data and 0.69 on embryonic data.

Methods

  • Small RNA-seq was performed on 11 tissues from adult C57BL/6J mice (4 males, 10 females, ∼3 mo old), generating 140 libraries; RNA was extracted, prepared with Illumina TruSeq Small RNA, and sequenced on NextSeq500.
  • Reads were mapped to GRCm38 with STAR and quantified using GENCODE M20, miRBase v22, and GtRNAdb annotations; tRFs were analyzed with unitas.
  • Analyses included DESeq2 normalization, t-SNE, tissue specificity index (TSI), likelihood-ratio test differential expression, sex comparisons with Wald tests and permutation, target correlation, miRDeep2 for novel miRNAs with AGO-CLIP/literature/RT-qPCR validation, SVM tissue classification trained on 1,973 miRNAs and tested on ENCODE data, and integration with scATAC-seq/Cicero and 10X mouse brain data.

Limitations

  • The paper states that resolution limitations of the mouse ATAC atlas prevented unambiguous cell-type assignment for the majority of brain-specific ncRNAs, and that lung open chromatin data did not provide sufficient resolution to infer cell types for most transcripts; direct validation of cell-specific transcripts remains desirable.
  • The paper notes technical limitations of small RNA sequencing, which has not yet been applied to single neurons and still relies on enrichment of certain cell types.
  • Evident from the text: sex-specific comparisons used an unbalanced sample (4 males vs 10 females), and tissue-level bulk profiling cannot fully resolve cell-type composition.

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

Integrity signals

Registry

Crossref · 10.1073/pnas.2002277117

Cites

138 of 139 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

1 of 69 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured

  • Findingown data

    Some tissue-specific small ncRNAs are also sexually dimorphic.

    “with some also being sexually dimorphic”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Integrating ncRNA expression measurements with scATAC-seq data enabled mapping cell type specificity of small ncRNA expressed in the adult mouse brain.

    “integrating our ncRNA expression measurements with the scATAC-seq data (28) enabled us to map cell type specificity of small ncRNA expressed in the adult mouse brain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Cusanovich D. A., A single-cell atlas of in vivo mammalian chromatin accessibility. Cell 174, 1309– 1324.e18 (2018). 30078704 PMC6158300 source

      Queued — the background check reaches it, usually within a day.

  • Findingown data

    The study provides insights on the tissue-dependent distribution of miRNA arms and tRNA fragments.

    “provide insights on the tissue-dependent distribution of miRNA arms and tRNA fragments”
    Quote in the paperSubstantial claim
  • Findingown data

    Approximately 30% of the total noncoding small RNA transcriptome is distributed across the body in a tissue-specific manner.

    “identified that ∼30% of total noncoding small RNA transcriptome are distributed across the body in a tissue-specific manner”
    Quote in the paperSubstantial claim
  • Findingown data

    Within profiled tissues, 95.1% of miRNA precursors denoted by miRBase v22 as high-confidence transcripts were detected.

    “we detected 95.1% of miRNA precursors denoted by miRBase v22 database as high-confidence transcripts (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Kozomara A., Griffiths-Jones S., miRBase: Annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 42, D68– D73 (2014). 24275495 PMC3965103 source
  • Classified as probably not a substantial claim. 34
  • May combine two claims. 43
  • The quote only partly states this claim. 1

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

    Premisecitation

    Small ncRNAs are endogenously expressed transcripts 18 to 200 nt long.

    “Small noncoding RNAs (ncRNAs) are a large family of endogenously expressed transcripts, 18 to 200 nt long”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [1] Bartel D. P., Metazoan microRNAs. Cell 173, 20– 51 (2018). 29570994 PMC6091663 source

      The Introduction (page unavailable) describes endogenous small RNAs as a larger class and identifies lin-4 and let-7 products as noncoding RNAs about 22 nt long. It does not give an 18–200 nt range for small ncRNAs generally, so the stated length range is unsupported by this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [2] Cech T. R., Steitz J. A., The noncoding RNA revolution-trashing old rules to forge new ones. Cell 157, 77– 94 (2014). 24679528 source

  • May combine two claims.

    Findingown data

    The identified genes correspond to 60%, 53%, 39%, 96%, 92%, 100%, and 34% of annotated transcripts of each respective class.

    “which correspond to 60%, 53%, 39%, 96%, 92%, 100%, and 34% of annotated transcripts of each respective class”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miRNA was the most abundant small ncRNA type in the libraries, followed by snoRNA, snRNA, and tRFs.

    “miRNA was the most abundant small ncRNA type in our libraries, followed by snoRNA, snRNA, and tRFs”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The number of distinct ncRNA greatly varied across tissues; lymphoid tissues (lung, spleen, and bone marrow) contained the largest number of distinct ncRNA, while pancreas and liver contained the fewest.

    “The number of distinct ncRNA greatly varied across tissues; for example, lymphoid tissues (lung, spleen, and bone marrow) contained the largest number of distinct ncRNA, while pancreas and liver contained the fewest”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Certain miRNAs are broadly sexually dimorphic, while others show sex bias in the context of specific tissues.

    “We have also discovered that certain miRNAs are broadly sexually dimorphic, while other show sex bias in the context of specific tissues.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    The study mapped tissue-specific and broadly transcribed small ncRNA attributed to five different classes across 11 mammalian tissues.

    “we mapped tissue-specific as well as broadly transcribed small ncRNA attributed to five different classes and spanning a large spectrum of expression levels”
    Quote in the paperSubstantial claim
    • Rests on an assumption: No prior study encompasses a spectrum of mammalian tissues from both female and male individuals, nor includes the other noncoding RNA types that have recently been identified to carry out tissue- and cell type-specific functions.

  • May combine two claims.

    Findingown data

    Detected tRFs were intergenic, snoRNAs were of intronic origin, snRNAs and scaRNAs were intronic and intergenic, and miRNAs were transcribed from introns, exons, or intergenic regions.

    “the detected tRFs were intergenic, snoRNAs were of intronic origin, snRNAs and scaRNAs were intronic and intergenic (63/35% and 64/36%, respectively), and miRNAs were transcribed from either introns (53%), exons (11%), or intergenic regions (11%)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Each library yielded ∼5 to 20 million reads mapping to the mouse genome, with on average ∼7 million mapped to exons of small ncRNA genes, resulting in a total of ∼100 million ncRNA reads per tissue.

    “Each library yielded ∼5 to 20 million reads mapping to the mouse genome, out of which, on average ∼7 million mapped to the exons of small ncRNA genes (Materials and Methods), resulting in a total of ∼100 million ncRNA reads per tissue”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among all tissues, the study identified 1,317 distinct miRNA, 733 snRNA, 583 snoRNA, 25 scaRNA, 346 tRNA, 22 mitochondrial tRNA, and 193 other miscellaneous small ncRNA genes.

    “we identified a total of 1,317 distinct miRNA, 733 snRNA, 583 snoRNA, 25 scaRNA, 346 tRNA, 22 mitochondrial tRNA, and 193 other miscellaneous small ncRNA genes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    mtRFs followed a similar trend of fragment shift; 5′tRFs of proline-transferring mt-Tp were found in the heart and 5′tRFs of asparagine-transferring mt-Tn in the liver, while other tissues had different fragment types.

    “mtRFs followed a similar trend of fragment shift. We found 5′tRFs of proline-transferring mt-Tp in the heart and 5′tRFs of asparagine-transferring mt-Tn in the liver, while within other tissues we detected different fragment types of these tRNAs”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Novel miRNAs 17_8620, 4_6440, and 9_15723 are supported by AGO-CLIP data, prior reports, or both, but their existence could not be confirmed through RT-qPCR.

    “we identified novel miRNAs (17_8620, 4_6440, 9_15723) that are supported by AGO-CLIP data, prior reports, or both, but for which we could not confirm the existence through RT-qPCR”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Well-described brain-specific miRNAs include mir-9, mir-124, mir-219, mir-338, and miRNAs missing from existing catalogs include mir-666, mir-878, mir-433.

    “We identified both well-described brain-specific miRNAs, such as mir-9, mir-124, mir-219, mir-338 (16, 24, 33), as well as those which are missing from existing catalogs, such as mir-666, mir-878, mir-433, etc.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Landgraf P., A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401– 1414 (2007). 17604727 PMC2681231 source
    • cites [24] McCall M. N., Toward the human cellular microRNAome. Genome Res. 27, 1769– 1781 (2017). 28877962 PMC5630040 source

      Queued — the background check reaches it, usually within a day.

    • cites [33] Ludwig N., Distribution of miRNA expression across human tissues. Nucleic Acids Res. 44, 3865– 3877 (2016). 26921406 PMC4856985 source

      Queued — the background check reaches it, usually within a day.

  • May combine two claims.

    Findingcitation

    Muscle-specific mir-133a-2 is expressed in cardiomyocytes, while mir-148a is expressed in hepatocytes and duct cells and mir-194-2 comes from enterocytes in the gut.

    “we could identify that muscle-specific mir-133a-2 is expressed in cardiomyocytes, while mir-148a is expressed in hepatocytes and duct cells (Fig. 6 C and D) and mir-194–2 comes from the enterocytes in the gut (24, 25).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] McCall M. N., Toward the human cellular microRNAome. Genome Res. 27, 1769– 1781 (2017). 28877962 PMC5630040 source

      Not checked in the free run.

    • cites [25] de Rie D..; FANTOM Consortium, An integrated expression atlas of miRNAs and their promoters in human and mouse. Nat. Biotechnol. 35, 872– 878 (2017). 28829439 PMC5767576 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In nuclear tRFs, the vast majority of fragments in each tissue were attributed to glycine, glutamine, valine, and lysine tRNA, with the intestine containing the largest amounts of the respective 5′tR-halves.

    “In the case of nuclear tRFs, the vast majority of fragments in each tissue were attributed to glycine, glutamine, valine, and lysine tRNA, with the intestine containing the largest amounts of the respective 5′tR-halves.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Differential expression analysis on putative novel miRNAs identified six miRNAs also expressed in a sex-specific manner; all six were male-dominant, with one consistently up-regulated in male muscle and pancreas.

    “Differential expression analysis on putative novel miRNAs identified six miRNAs to be also expressed in a sex-specific manner. Strikingly, all six were male-dominant, with one of them even found to be consistently up-regulated in two tissues, male muscle and pancreas”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    mir-187 and mir-142 are expressed in microglia.

    “we identified mir-187 and mir-142 to be expressed in microglia”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Other miRNAs previously unknown to be tissue-specific include mir-499 in the heart, mir-3073b in the kidney, and mir-215 and mir-194 in the intestine.

    “Examples of other miRNAs previously unknown to be tissue-specific include mir-499 in the heart, mir-3073b in the kidney, and mir-215 and mir-194 in the intestine”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The SVM model accurately classified postnatal forebrain, midbrain, hindbrain, and neural tube as brain tissue, as well as accurately inferred tissue types for heart, intestine, kidney, liver, and muscle samples, yielding an overall accuracy of 0.96.

    “our SVM model accurately classified postnatal forebrain, midbrain, hindbrain, and neural tube as brain tissue, as well as accurately inferred the tissue types for heart, intestine, kidney, liver, and muscle samples, yielding an overall accuracy of 0.96”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Using the top 400 tissue-specific ncRNAs, average ATAC-seq activity scores and ncRNA levels across eight tissues showed a strong correlation for brain, liver, and heart, and a weaker correlation for kidney and mixed scores between spleen, bone marrow, and lung.

    “Using the top 400 ncRNAs identified in our analysis as tissue-specific, we correlated average ATAC-seq activity scores and ncRNA levels across eight tissues for which both types of data were available. We observed a strong correlation of both measurements for the brain, liver, and heart, and a weaker correlation for kidney and mixed scores between spleen, bone marrow, and lung”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Terc is present in analyzed somatic tissues, with the highest levels seen in the bone marrow and spleen.

    “we detected the presence of telomerase RNA component (Terc) in analyzed somatic tissues, with the highest levels seen in the bone marrow and spleen.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Snord53 and mir-802 are predominantly present in glutamatergic neurons.

    “predominantly present in either glutamatergic (Snord53, mir-802)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mouse bone marrow and spleen had the highest correlation with human B cells, T cells, dendritic cells, and macrophages (0.5 < rs < 0.6), muscle correlated most with myoblasts and myotubes (rs = 0.47), while brain correlated best with neural stem cells, spinal cord, and pineal and pituitary glands (rs = 0.49).

    “we observed that mouse bone marrow and spleen had the highest correlation with human B cells, T cells, dendritic cells, and macrophages (0.5 < rs < 0.6), muscle correlated the most with myoblasts and myotubes (rs = 0.47), while brain correlated best with neural stem cells, spinal cord, and pineal and pituitary glands (rs = 0.49)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    De novo identified miRNA 14_6588 has coordinates that strictly overlap with mir-802a and is only present in the brain.

    “We observed this phenomenon on the de novo identified miRNA 14_6588, whose coordinates strictly overlap with mir-802a and that is only present in the brain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    miR-423, up-regulated in male lung and bone marrow, negatively correlates with its target Esrrg (rs = −0.9, FDR < 0.1).

    “we found miR-423, up-regulated in male lung and bone marrow, to negatively correlate with its target, estrogen-related receptor gamma (Esrrg) (rs = −0.9, FDR < 0.1)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the lung, mir-449c is expressed in alveolar macrophages, mir-34b and mir-34c in type II pneumocytes, and mir-155 is found in B cells.

    “we found that in the lung, mir-449c in expressed in alveolar macrophages, mir-34b and mir-34c in type II pneumocytes (Fig. 6E), and mir-155 is found in B cells”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The genomic coordinates of 14_6588 matched the coordinates of annotated mir-802a, but 14_6588 is transcribed from the negative DNA strand and is only present in the brain.

    “the genomic coordinates of this miRNA, 14_6588, matched the coordinates of another, annotated one, mir-802a. Unlike mir-802a, however, 14_6588 is transcribed from the negative DNA strand and is only present in the brain”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    FANTOM5 embryonic and neonatal cerebellum tissues strongly correlated with the study's brain samples (rs = 0.89 to 0.9), while erythroid cells had the strongest correlation with spleen and bone marrow (rs = 0.93).

    “we found that FANTOM5 embryonic and neonatal cerebellum tissues strongly correlated with our brain samples (rs = 0.89 to 0.9), while erythroid cells had the strongest correlation with spleen and bone marrow (rs = 0.93)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The majority of ntRNA fragments were 33 nt long, while mtRNA fragments spanned a size range of 18 to 54 nt.

    “While the majority of ntRNA fragments were 33 nt long, mtRNA fragments spanned a large size range of 18 to 54 nt”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Novel miRNAs demonstrate a spectrum of tissue specificity with some being ubiquitously expressed, while others are only present in one tissue.

    “Similar to annotated transcripts, novel miRNAs demonstrate a spectrum of tissue specificity with some being ubiquitously expressed, while others are only present in one tissue”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    mir-124a-3, mir-1983, mir-212, and others are expressed in neurons.

    “mir-124a-3, mir-1983, mir-212, and others in neurons (Fig. 6G)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Among ubiquitously expressed ncRNAs are let-7d-3p, miR-320-3p, Snord4a, Snord55, and endothelial miR-151-5p.

    “Among these are ncRNAs known to be expressed in a large number of cell types, such as let-7d-3p, miR-320-3p (25), ncRNAs the cell type specificity of which is still unknown, such as Snord4a and Snord55, as well as those known to be expressed in the cell types that are abundant in all tissues (like endothelial miR-151-5p)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] de Rie D..; FANTOM Consortium, An integrated expression atlas of miRNAs and their promoters in human and mouse. Nat. Biotechnol. 35, 872– 878 (2017). 28829439 PMC5767576 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The majority of putative miRNAs are present in only one tissue (312), but a small number (4) are found in all 11 tissues.

    “We found that the majority of putative miRNAs are present in only one tissue (312), but a small number (4) are found in all 11 tissues”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Kidney and lung contained the highest number of sex-biased miRNAs (27 and 18, respectively), while only two were detected in the heart, five in the muscle, and seven in the brain.

    “Kidney and lung contained the highest number of sex-biased miRNAs (27 and 18, respectively), while only two were detected in the heart, five in the muscle, and seven in the brain”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mouse Rnu11 and Scarna6 are preferentially found in lymphoid tissues, while Gm25793, Gm22448, and Gm23814 are specific to the brain.

    “mouse Rnu11 and Scarna6 are preferentially found in lymphoid tissues, while three snRNAs of unverified function, Gm25793, Gm22448, and Gm23814, are specific to the brain”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Snord17 and mir-700 are in macrophages.

    “we identified Snord17 and mir-700 in macrophages”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Out of these 400 miRNAs, nearly one-quarter are specific to the brain, with some being uniquely expressed within the tissue.

    “Out of these 400, nearly one-quarter are specific to the brain, with some being uniquely expressed within the tissue”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Some miRNAs are globally sexually dimorphic, while the majority are sex-biased only within a specific tissue.

    “Some of them are globally sexually dimorphic, while the majority are sex-biased only within a specific tissue.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    mir-155 is found in B cells and correlates with its maturation status.

    “mir-155 is found in B cells and even correlates with its maturation status (Fig. 6F)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For many miRNAs, dominance of either the 3p or 5p arm was observed, while for some high levels of both arms were detected in one or multiple tissues.

    “For many miRNAs, we generally observed the dominance of either 3p or 5p arm, while for some we also detected high levels of both arms present in one or multiple tissues”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Snora35 and Snord116, known to be involved in neurodevelopmental disorders, are brain exclusive (TSI = 1).

    “we also identified Snora35 (MBI-36) and Snord116 (MBII-85), known to be involved in neurodevelopmental disorders (34), to be brain exclusive (TSI = 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Gallagher R. C., Pils B., Albalwi M., Francke U., Evidence for the role of PWCR1/HBII-85 C/D box small nucleolar RNAs in Prader–Willi syndrome. Am. J. Hum. Genet. 71, 669– 678 (2002). 12154412 PMC379204 source

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

    Premisecitation

    Through their interactions with ribosomes and mRNA, small noncoding molecules shape the dynamic molecular spectrum of tissues.

    “Through their interactions with ribosomes and mRNA, these small noncoding molecules shape the dynamic molecular spectrum of tissues (4, 17).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Gebetsberger J., Wyss L., Mleczko A. M., Reuther J., Polacek N., A tRNA-derived fragment competes with mRNA for ribosome binding and regulates translation during stress. RNA Biol. 14, 1364– 1373 (2017). 27892771 PMC5711459 source
    • cites [17] Faridani O. R., Single-cell sequencing of the small-RNA transcriptome. Nat. Biotechnol. 34, 1264– 1266 (2016). 27798564 source

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

    Premisecitation

    Small ncRNAs are involved in nearly all developmental and pathological processes in mammals.

    “today small ncRNAs are believed to be involved in nearly all developmental and pathological processes in mammals (2–4)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Cech T. R., Steitz J. A., The noncoding RNA revolution-trashing old rules to forge new ones. Cell 157, 77– 94 (2014). 24679528 source
    • cites [3] Esteller M., Non-coding RNAs in human disease. Nat. Rev. Genet. 12, 861– 874 (2011). 22094949 source
    • cites [4] Gebetsberger J., Wyss L., Mleczko A. M., Reuther J., Polacek N., A tRNA-derived fragment competes with mRNA for ribosome binding and regulates translation during stress. RNA Biol. 14, 1364– 1373 (2017). 27892771 PMC5711459 source

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

    Premisecitation

    Various small ncRNAs directly regulate gene expression at posttranscriptional mRNA processing and ribosome biogenesis.

    “numerous studies have revealed the direct involvement of various small ncRNAs in regulation of gene expression at the levels of posttranscriptional mRNA processing (5–7) and ribosome biogenesis (8)”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [5] Becker D., Nuclear pre-snRNA export is an essential quality assurance mechanism for functional spliceosomes. Cell Rep. 27, 3199– 3214.e3 (2019). 31189105 source
    • cites [6] Gebert L. F. R., MacRae I. J., Regulation of microRNA function in animals. Nat. Rev. Mol. Cell Biol. 20, 21– 37 (2019). 30108335 PMC6546304 source
    • cites [7] Telonis A. G., Dissecting tRNA-derived fragment complexities using personalized transcriptomes reveals novel fragment classes and unexpected dependencies. Oncotarget 6, 24797– 24822 (2015). 26325506 PMC4694795 source
    • cites [8] Reichow S. L., Hamma T., Ferré-D’Amaré A. R., Varani G., The structure and function of small nucleolar ribonucleoproteins. Nucleic Acids Res. 35, 1452– 1464 (2007). 17284456 PMC1865073 source

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

    Premisecitation

    snoRNA and snRNA are believed to yield incomplete recovery in small RNA-seq experiments due to their secondary structure.

    “snoRNA and snRNA are believed to yield incomplete recovery in small RNA-seq experiments due to their secondary structure (32).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Boivin V., Simultaneous sequencing of coding and noncoding RNA reveals a human transcriptome dominated by a small number of highly expressed noncoding genes. RNA 24, 950– 965 (2018). 29703781 PMC6004057 source

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

    Premisecitation

    Aberrant expression of small ncRNAs is associated with cancer, autoimmune disease, and several neurodegenerative disorders.

    “Aberrant expression of small ncRNAs, in turn, has been associated with diseases such as cancer, autoimmune disease, and several neurodegenerative disorders (9, 10).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Keller A., Toward the blood-borne miRNome of human diseases. Nat. Methods 8, 841– 843 (2011). 21892151 source
    • cites [10] Somel M., MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain. Genome Res. 20, 1207– 1218 (2010). 20647238 PMC2928499 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Some small ncRNAs are expressed in a tissue-, cell type-, or cell state-specific manner.

    “with some being shown to be expressed in a tissue- (16), cell type- (17), or even cell state-specific manner (18)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [16] Landgraf P., A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401– 1414 (2007). 17604727 PMC2681231 source
    • cites [17] Faridani O. R., Single-cell sequencing of the small-RNA transcriptome. Nat. Biotechnol. 34, 1264– 1266 (2016). 27798564 source
    • cites [18] Sherstyuk V. V., Genome-wide profiling and differential expression of microRNA in rat pluripotent stem cells. Sci. Rep. 7, 2787 (2017). 28584262 PMC5459850 source

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

    Premisecitation

    Mammalian cells express several classes of small ncRNA including miRNA, siRNA, snoRNA, snRNA, piRNA, and tRFs.

    “Mammalian cells express several classes of small ncRNA, including microRNA (miRNA) (11), small interfering RNAs (siRNA), small nucleolar RNAs (snoRNA) (12), small nuclear RNA (snRNA) (13), PIWI-interacting RNA (piRNA) (14), and tRNA-derived small RNAs (tRFs) (15)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [11] Ha M., Kim V. N., Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 15, 509– 524 (2014). 25027649 source
    • cites [12] Matera A. G., Terns R. M., Terns M. P., Non-coding RNAs: Lessons from the small nuclear and small nucleolar RNAs. Nat. Rev. Mol. Cell Biol. 8, 209– 220 (2007). 17318225 source
    • cites [13] Kiss T., Biogenesis of small nuclear RNPs. J. Cell Sci. 117, 5949– 5951 (2004). 15564372 source

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

    Premisecitation

    Small ncRNAs play a crucial role in regulating cell function.

    “that play a crucial role in regulating cell function (1, 2)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Bartel D. P., Metazoan microRNAs. Cell 173, 20– 51 (2018). 29570994 PMC6091663 source

      Not checked in the free run.

    • cites [2] Cech T. R., Steitz J. A., The noncoding RNA revolution-trashing old rules to forge new ones. Cell 157, 77– 94 (2014). 24679528 source

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

    Premisecitation

    Arm switching was previously thought to be strictly pathogenic in mammals.

    “a process previously thought to be strictly pathogenic in mammals (43, 45, 67).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [43] Chen L., miRNA arm switching identifies novel tumour biomarkers. EBioMedicine 38, 37– 46 (2018). 30425004 PMC6306400 source
    • cites [45] Kern F., miRSwitch: Detecting microRNA arm shift and switch events. Nucleic Acids Res. 48, W268– W274 (2020). 32356893 PMC7319450 source
    • cites [67] Lin M., Comprehensive identification of microRNA arm selection preference in lung cancer: miR-324-5p and -3p serve oncogenic functions in lung cancer. Oncol. Lett. 15, 9818– 9826 (2018). 29844840 PMC5958786 source

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

    Premisecitation

    Small ncRNA plays an indispensable role in shaping cellular identity in health and disease by orchestrating vital cellular processes and altering the expression of protein-coding genes.

    “Small ncRNA plays an indispensable role in shaping cellular identity in health and disease by orchestrating vital cellular processes and altering the expression of protein-coding genes (12).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Matera A. G., Terns R. M., Terns M. P., Non-coding RNAs: Lessons from the small nuclear and small nucleolar RNAs. Nat. Rev. Mol. Cell Biol. 8, 209– 220 (2007). 17318225 source

  • May combine two claims.

    Study design and conductown data

    The quantification approach was more inclusive for reads uniquely mapping within the miRNA exon but missing one base at the 5′ end, and more strict in counting reads mapping elsewhere in the genome, for which levels were consistently overestimated by the other method.

    “it proved to be more inclusive for the reads uniquely mapping within the miRNA exon but missing one base at the 5′ prime end of the molecule and more strict in counting reads mapping elsewhere in the genome, for which the levels were consistently overestimated by the other method.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The genomic location of a novel miRNA might match with that of a previously annotated one, while the molecule itself could be transcribed from an opposite DNA strand.

    “the genomic location of a novel miRNA might match with that of a previously annotated one, while the molecule itself could be transcribed from an opposite DNA strand.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Several groups have observed a sex bias in the levels of miRNA in blood, cancer tissues, and human lymphoblastoid cell lines.

    “Several groups have observed a sex bias in the levels of miRNA in blood, cancer tissues, and human lymphoblastoid cell lines (57, 58).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [57] Guo L., Zhang Q., Ma X., Wang J., Liang T., miRNA and mRNA expression analysis reveals potential sex-biased miRNA expression. Sci. Rep. 7, 39812 (2017). 28045090 PMC5206641 source
    • cites [58] Loher P., Londin E. R., Rigoutsos I., IsomiR expression profiles in human lymphoblastoid cell lines exhibit population and gender dependencies. Oncotarget 5, 8790– 8802 (2014). 25229428 PMC4226722 source

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

    Study design and conductnone given

    All procedures followed animal care and biosafety guidelines approved by Stanford University's Administrative Panel on Laboratory Animal Care and Administrative Panel of Biosafety.

    “All procedures followed animal care and biosafety guidelines approved by Stanford University’s Administrative Panel on Laboratory Animal Care and Administrative Panel of Biosafety.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Recent profiling of miRNA across cells and tissues demonstrated the existence of tissue- and cell type-specific short noncoding transcripts.

    “Recent efforts in profiling of the most studied types of small ncRNA, miRNA, across cells and tissues demonstrated the existence of tissue- and cell type-specific short noncoding transcripts (16, 24, 25, 33).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [16] Landgraf P., A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401– 1414 (2007). 17604727 PMC2681231 source
    • cites [24] McCall M. N., Toward the human cellular microRNAome. Genome Res. 27, 1769– 1781 (2017). 28877962 PMC5630040 source

      Not checked in the free run.

    • cites [25] de Rie D..; FANTOM Consortium, An integrated expression atlas of miRNAs and their promoters in human and mouse. Nat. Biotechnol. 35, 872– 878 (2017). 28829439 PMC5767576 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    AGO-CLIP is often used as a gold standard of miRNA validation.

    “the AGO-CLIP, while often used as a “gold standard” of miRNA validation (24)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] McCall M. N., Toward the human cellular microRNAome. Genome Res. 27, 1769– 1781 (2017). 28877962 PMC5630040 source

      Not checked in the free run.

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

    Premisecitation

    miRNA has been previously used to train classifiers capable of differentiating cancer/tissue types.

    “miRNA has been previously used to train classifiers capable of differentiating cancer/tissue types (71).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Sherafatian M., Tree-based machine learning algorithms identified minimal set of miRNA biomarkers for breast cancer diagnosis and molecular subtyping. Gene 677, 111– 118 (2018). 30055304 source

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

    Study design and conductnone given

    Train and test datasets were normalized and scaled separately.

    “We normalized and scaled train and test datasets separately.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Batch effects were corrected using limma R package.

    “Batch effects were corrected using limma R package (79).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Ritchie M. E., Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015). 25605792 PMC4402510 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The abundance of specific tRFs correlates with the levels of functional angiogenin in the cell.

    “Since the abundance of these specific fragments has been shown to correlate with the levels of functional angiogenin in the cell (54)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Thomas S. P., Hoang T. T., Ressler V. T., Raines R. T., Human angiogenin is a potent cytotoxin in the absence of ribonuclease inhibitor. RNA 24, 1018– 1027 (2018). 29748193 PMC6049508 source

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A putative miRNA was counted as supported if it had >5 AGO-CLIP counts.

    “We counted a putative miRNA as “supported” if it had >5 AGO-CLIP counts.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    mir-340 was reported to be down-regulated in response to elevated androgen levels.

    “another miRNA, mir-340, was reported to be down-regulated in response to elevated androgen levels (60).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Fletcher C. E., Dart D. A., Bevan C. L., Interplay between steroid signalling and microRNAs: Implications for hormone-dependent cancers. Endocr. Relat. Cancer 21, R409– R429 (2014). 25062737 source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    For independent validation, RT-qPCR was performed using custom Small RNA TaqMan probes designed on the star consensus sequence reported by miRDeep2.

    “For independent validation, we performed RT-qPCR using custom Small RNA TaqMan probes (Life Technologies; catalog #4398987) designed on the star consensus sequence reported by miRDeep2.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The current miRbase annotation of mammalian miRNA remains incomplete but can be readily expanded with the help of emerging small RNA-seq data.

    “We have recently demonstrated that the current miRbase annotation of mammalian miRNA remains incomplete but can be readily expanded with the help of emerging small RNA-seq data (46).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Alles J., An estimate of the total number of true human miRNAs. Nucleic Acids Res. 47, 3353– 3364 (2019). 30820533 PMC6468295 source

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

    Premisecitation

    Three out of eight female-dominant miRNAs: mir-182, mir-148a, and mir-145a, were also shown previously to be estrogen regulated.

    “Three out of eight female-dominant miRNAs: mir-182, mir-148a, and mir-145a, were also shown previously to be estrogen regulated (59)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Klinge C. M., Estrogen regulation of microRNA expression. Curr. Genomics 10, 169– 183 (2009). 19881910 PMC2705850 source

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Only miRNAs supported by >5 reads were reported.

    “Only miRNAs supported by >5 reads were reported in this study.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    RNA integrity was assessed using Agilent Bioanalyzer.

    “RNA integrity was assessed using Agilent Bioanalyzer using RNA 6000 pico kit”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Accuracy was computed using 10-fold cross-validation.

    “The accuracy was computed using 10-fold cross-validation procedure.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The precise biological function of Rny1 and Rny3 is undefined, although they have been suggested to maintain RNA stability.

    “The precise biological function of Rny1 and Rny3 is so far undefined, although they have been suggested to maintain RNA stability (38).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Kowalski M. P., Krude T., Functional roles of non-coding Y RNAs. Int. J. Biochem. Cell Biol. 66, 20– 29 (2015). 26159929 PMC4726728 source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    P values obtained from the LRT test were corrected using Benjamini-Hochberg procedure to obtain an FDR estimate of tissue specificity scores for each gene.

    “P values obtained from the LRT test were corrected using Benjamini–Hochberg procedure to obtain an FDR estimate of tissue specificity scores for each gene.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    A permutation test was performed in which sex labels were randomly reassigned to 14 samples across each tissue to test the null hypothesis.

    “To test for the NULL hypothesis, we performed a permutation test in which we randomly reassigned the sex labels to 14 samples across each tissue and plotted the distribution of DESeq2 P values computed for the two groups (i.e., female and male) (SI Appendix, Fig. S7A).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Tissue and sex specificity of identified miRNAs was analyzed based on transcripts supported by at least 50 sequencing reads across all samples.

    “We analyzed tissue and sex specificity of identified miRNAs based on transcripts supported by at least 50 sequencing reads across all samples.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Benjamini-Hochberg-corrected P values (FDR) were used to assess statistical significance of computed DE scores.

    “We used Benjamini–Hochberg-corrected P values (FDR) to assess the statistical significance of the computed DE scores (Fig. 5 and SI Appendix, Fig. S7A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The phenomenon of tissue- and cell type-specific short noncoding transcripts extends beyond one ncRNA class and involves not only tissue-specific but also sex-specific ncRNA expression.

    “In this work, we show that this phenomenon extends beyond one ncRNA class and involves not only tissue-specific but also sex-specific ncRNA expression.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Only targets present in two or more databases were used.

    “Only targets present in two or more databases were used.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    tRFs are fragments of either mature or precursor tRNA molecules enzymatically cleaved by angiogenin, Dicer, RNaseZ, and RNaseP.

    “fragments of either mature of precursor tRNA molecules enzymatically cleaved by angiogenin (Ang), Dicer, RNaseZ, and RNaseP (7, 53)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Telonis A. G., Dissecting tRNA-derived fragment complexities using personalized transcriptomes reveals novel fragment classes and unexpected dependencies. Oncotarget 6, 24797– 24822 (2015). 26325506 PMC4694795 source
    • cites [53] Lee Y. S., Shibata Y., Malhotra A., Dutta A., A novel class of small RNAs: tRNA-derived RNA fragments (tRFs). Genes Dev. 23, 2639– 2649 (2009). 19933153 PMC2779758 source
76 of 76

  • The paper relies on this without support.

    No prior study encompasses a spectrum of mammalian tissues from both female and male individuals, nor includes the other noncoding RNA types that have recently been identified to carry out tissue- and cell type-specific functions.

    “However, no prior study encompasses a spectrum of mammalian tissues from both female and male individuals, nor includes the other noncoding RNA types that have recently been identified to carry out tissue- and cell type-specific functions (26, 27).”

  • The paper relies on this without support.

    Surprisingly little is known about cell type-specific small ncRNA in the brain.

    “surprisingly little is known about cell type-specific small ncRNA in the brain.”

  • The paper relies on this without support.

    The brain remains one of the most underrepresented tissue within available tissue-level ncRNA resources.

    “the brain remains one of the most underrepresented tissue.”

  • The paper relies on this without support.

    Small ncRNAs have long been known to regulate the development and function of the brain.

    “Small ncRNAs have been long known to regulate the development and function of the brain.”
4 of 4

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.

  • The same clustering analysis uses 400 or 250 genes

    Minor

    The Results describe clustering the top 400 differentially expressed ncRNA and cite Fig. S3B, whereas the Methods state that the clusters in Fig. S3B were computed on 250 genes.

  • The overlapping annotated miRNA has two identities

    Minor

    The Results identify mir-802a as the annotated miRNA overlapping novel miRNA 14_6588, but the Fig. 3 caption identifies it as mir-208a.

2 of 2

Cites

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Related

Authors
Isakova, A., Fehlmann, T., Keller, A., & Quake, S. R.
Affiliations
  • Stanford University (US)
  • Saarland University (DE)
  • Stanford Medicine (US)
  • Chan Zuckerberg Biohub San Francisco (US)
Corresponding author
Quake, Stephen R.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2020-09-25
Volume
117
Issue
41
Pages
25634-25645
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2002277117
PMC
PMC7568261
OpenAlex
W3088117294
Semantic Scholar
4fba20e6bf188463c6a22af45a486765a5869886
Cited by
119
References
138
Citations by year
2026: 19 · 2025: 18 · 2024: 16 · 2023: 13 · 2022: 18 · 2021: 33 · 2020: 1 · 2019: 1
FWCI
5.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Publications of the UdS (Saarland University)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords
small RNA, tissue-specific gene expression, mouse tissues, microRNA, small nucleolar RNA, small nuclear RNA, tRNA-derived fragments, sexual dimorphism, single-cell chromatin accessibility, tissue atlas
MeSH terms
Animals, Brain, Female, Male, Mice, Inbred C57BL, Organ Specificity, Sex Characteristics, Mice, RNA, Small Untranslated, Single-Cell Analysis, Transcriptome

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.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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