The DOI matches its Crossref record; 113 of the 117 references it cites were found in a registry or an index; 2 of the 47 sources its claims cite were checked for support.
A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains
Open accessAbstract
Summary Alternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide ‘microexons’ display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein interaction networks during neurogenesis, the misregulation of which is linked to autism.
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TL;DR
This paper defines a large neural-regulated alternative splicing program in mammals, showing that 3–27 nucleotide microexons are exceptionally conserved, dynamically regulated during neuronal differentiation, and often controlled by nSR100/SRRM4. It further reports that microexons are frequently misregulated in autistic brains and that this misregulation correlates with reduced nSR100 expression.
Key findings
- Across human and mouse cell/tissue datasets, the authors identified about 2,500 neural-regulated AS events per species; microexons showed stronger neural-specific inclusion than longer exons (60.7% of microexons with ΔPSI>15 versus 9.5% of longer exons).
- Of 308 human neural-regulated microexons, 225 (73.5%) were also neural-differentially spliced in mouse, compared with 527 of 1,390 (37.9%) longer neural-regulated exons; many microexons were deeply conserved across vertebrates.
- During mouse ES-cell-to-cortical-neuron differentiation, 151 of 219 profiled neural-regulated microexons (69%) showed a PSI switch ≥50, and 65 (30%) showed a switch ≥90; nSR100 knockdown/overexpression affected more than half of profiled microexons.
- In ASD post-mortem superior temporal gyrus samples, 126 of 504 detected microexons (30%) had mean ΔPSI>10 between ASD and control, versus 825 of 15,405 longer exons (5.4%); nSR100 mRNA was downregulated on average by about 10% in ASD samples (p=0.014).
Methods
- The authors developed an RNA-Seq analysis pipeline to detect all AS classes, including microexons, and applied it to deep datasets from more than 50 human and mouse cell/tissue types, developmental stages, and several vertebrate species.
- They analyzed microexon regulation across six time points of mouse embryonic stem cell differentiation into cortical glutamatergic neurons, and used knockdown/overexpression plus PAR-iCLIP data to test nSR100/SRRM4 regulation.
- Protein interaction effects were tested with LUMIER assays and co-immunoprecipitation-western blotting for Apbb1 and AP1S2 microexons; ASD analyses used 24 autistic individuals and 24 matched controls, with 12 ASD samples showing the strongest ASD-associated expression signature and 12 controls selected for downstream comparisons.
Limitations
- The paper does not state a dedicated limitations section.
- Evident from the text: the ASD splicing analysis focused on a selected subset of 12 ASD and 12 control samples stratified by a pre-existing ASD gene-expression signature, so findings may not generalize to all autistic individuals.
- Evident from the text: the link between reduced nSR100 and microexon misregulation in ASD is correlational, and the authors do not establish causation; microexon detection also depends on a specialized pipeline and sufficient RNA-Seq read coverage.
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Claims the paper makes
67 Own result · 25 Not checked yet · 17 Own interpretation · 4 Own method · 2 No basis given · 1 Partly supported · accuracy not yet measured
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals.”
- Also stated in: § Global features of neural-regulated AS · plain
“These data reveal the largest program of neural-regulated AS events defined to date, and that this program is associated with a broader range of functional processes and pathways linked to nervous system biology than previously detected (Boutz et al., 2007; Fagnani et al., 2007; Ule et al., 2005).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
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- Also stated in: § Global features of neural-regulated AS · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further analysis of the neural-regulated AS program revealed a striking inverse relationship between the length of an alternative exon and its propensity to be specifically included in neural tissues.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Nearly half of the neural-regulated AS events, including alternative retained introns, are predicted to generate protein isoforms both when the alternative sequence is included and skipped.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
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In the paper
“In contrast, only ∼20% of AS events not subject to neural regulation (hereafter ‘non-neural’ events) have the potential to generate alternative protein isoforms (Figure 1B; p=2.7×10-248, proportion test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
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In the paper
“By applying this pipeline to more than 50 diverse cell and tissue types each from human and mouse (Table S1), we identified ∼2,500 neural-regulated AS events in each species (Figure 1A and Table S2; Extended Experimental Procedures).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
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In the paper
“This trend extends to microexons as short as 3 nt.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Gene Ontology (GO) analysis shows that genes with neural-regulated AS events predicted to generate alternative protein isoforms form highly interconnected networks based on functions associated with neuronal biology, signaling pathways, structural components of the cytoskeleton and the plasma membrane (Figure 1C).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100.”
- Also stated in: § Microexons are misregulated in individuals with Autism Spectrum Disorder · plain
“These data reveal frequent misregulation of microexon splicing in the brain cortices of some individuals with ASD.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Microexons are misregulated in individuals with Autism Spectrum Disorder · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Relative to longer alternative exons, microexons, in particular those that are 3-15-nt long and neural-specifically included, are strongly enriched in multiple features indicative of functionally important AS.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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In the paper
“the vast majority (>90%) of neural-regulated microexons display highest PSIs in neurons compared to all other cell and tissue types analyzed (Figure S2B-D, and Supplemental Information).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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- It may state two separate claims as one. 28
- Probably not a substantial claim. 19
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the results suggest that the misregulation of microexons, as well as of longer alternative exons (Corominas et al., 2014; Voineagu et al., 2011), may impact protein interaction networks that are required for normal neuronal development and synaptic function”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
What the sources say
- Partly supportedcites Corominas et al., 2014 sourceExperimental — accuracy not yet measured
The Results section, “Splicing isoform interactions expand ASIN” (page unavailable), reports that inclusion or exclusion of specific exons changes protein interaction partners and suggests that differential exon usage can alter interaction networks. Our copy does not establish the claim about microexon misregulation or show that the affected networks are required for normal neuronal development and synaptic function. (LLM, conf=0.84)
- Partly supportedcites Voineagu et al., 2011 sourceExperimental — accuracy not yet measured
The paper reports differential splicing of alternative exons in ASD brain (p. 5) and says many affected exons belong to genes involved in synaptic function (p. 6). It does not identify microexons or longer exons as distinct groups, or link their misregulation to protein interaction networks required for neuronal development. (LLM, conf=0.85)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Relative to all other types of AS within this program, 3-15 nucleotide ‘microexons’ display the most striking evolutionary conservation and switch-like regulation.”
- Also stated in: § Introduction · boosted
“Strikingly, neural-included microexons represent the most highly conserved and dynamically-regulated component of this program, and the corresponding genes are highly enriched in neuronal functions.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
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- Also stated in: § Introduction · boosted
None of the sources cited for this claim have been checked yet.
In the paper
“Consistent with previous results (Fagnani et al., 2007; Pan et al., 2004), there is little overlap (8.5%) between genes with neural-regulated AS and mRNA expression, although these subsets of genes are highly enriched in overlapping GO terms (40% in common; Figure S1).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“60.7% of alternative microexons show increased neural ‘percent spliced in’ (PSI) (ΔPSI>15) versus 9.5% of longer (average ∼135 nt) alternative exons (p=1.9×10-220, proportion test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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In the paper
“Supporting this view, among 49 available and de novo-modeled tertiary protein structures containing microexons, the corresponding residues are largely surface accessible amd unlikely to significantly affect the folding of the overlapping or adjacent protein domains (Figure S6A; Extended Experimental Procedures).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Distinct protein regulatory properties of microexons
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In the paper
“They are also significantly more often conserved at the levels of genomic sequence, detection in alternatively spliced transcripts, and neural-differential regulation (Figure 2D; Figure S2E, neural-regulated exons; p<0.001 for all pairwise comparisons, proportion tests.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Among several analyzed splicing regulators (Extended Experimental Procedures), knockdown and overexpression of nSR100 had the strongest effect on microexon regulation, with more than half of the profiled microexons displaying a pronounced change in inclusion level compared to controls (Figure 4A and S4A-S4H).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > The neural-specific splicing factor nSR100/SRRM4 regulates most neural microexons
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, proteins containing microexons are significantly more often central in protein-protein interaction networks and detected in protein complexes compared to proteins with other types of alternative exons (Figures 5H and S5O,P, p≤0.004 for all comparisons, Wilcoxon Rank Sum test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
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In the paper
“Of 308 neural-regulated microexons in human, 225 (73.5%) are neural-differentially spliced in mouse, compared to only 527 of 1390 (37.9%) longer neural-regulated exons.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Despite the small number of genes representing clusters of kinetically-distinct sets of regulated microexons, each cluster revealed significant enrichment of specific GO terms including “regulation of GTPase activity” (Cluster I), “glutamate receptor binding” and “actin cytoskeleton organization” (Cluster V) (Table S4).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Dynamic regulation of microexons during neuronal differentiation
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Remarkably, while microexons represent only ∼1% of all AS events, they comprise approximately one third of all neural-regulated AS events conserved between human and mouse that are predicted to generate alternative protein isoforms (Figure S2F).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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In the paper
“In contrast, microexon residues overlapping protein domains are significantly more often surface-accessible and enriched in charged residues (Figures 5C,D, and S5F-I; p<10-7 for all comparisons, proportion test) than are residues overlapping longer neural or non-neural exons.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Distinct protein regulatory properties of microexons
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Substitution of both microexon residues with alanine also enhanced the Kat5 interaction, although to a lesser extent than the presence of Arg and Glu (Figure 6C).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
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In the paper
“LUMIER and co-immunoprecipitation-western analysis reveals that inclusion of the microexon significantly enhances the interaction with Kat5, whereas there is little to no effect on the interaction with App (Figures 6C,D and Figure S6B,C).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These stages correspond to maturing post-mitotic neurons when pan-neuronal markers are already expressed, and are subsequent to the expression of most neurogenic transcription factors (Figure S3A).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Dynamic regulation of microexons during neuronal differentiation
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In the paper
“Remarkably, of 219 neural-regulated microexons with sufficient read coverage across time points, 151 (69%) displayed a PSI switch ≥ 50 between ES cells and mature neurons, and 65 (30%) a switch of ≥ 90 (Figure 3).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Dynamic regulation of microexons during neuronal differentiation
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In the paper
“Furthermore, comparable numbers of alternative microexons were detected in all analyzed vertebrate species, the majority of which are also strongly neural-specifically included (Figure 2E; Supplemental Information for details).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“alternative microexons display the highest degrees of genomic sequence conservation, tissue-specific regulatory conservation, and frame-preservation potential, relative to all other classes of AS detected to date in vertebrate species”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
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In the paper
“Many of the corresponding genes act in common pathways and/or physically interact through protein-protein interactions (Figure 7F)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
None of the sources cited for this claim have been checked yet.
In the paper
“An important advance that is facilitating a more general understanding of the role of individual AS events is the observation that many cell/tissue type- and developmentally-regulated AS events are coordinately controlled by individual RBPs, and that these events are significantly enriched in genes that operate in common biological processes and pathways (Calarco et al., 2011; Irimia and Blencowe,”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Calarco et al., 2011 source
- Not checked yetcites Irimia and Blencowe, 2012
- Not checked yetcites Licatalosi and Darnell, 2010
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Alternative splicing (AS) – the process by which different pairs of splice sites are selected in precursor mRNA to generate multiple mRNA and protein products – is responsible for greatly expanding the functional and regulatory capacity of metazoan genomes (Braunschweig et al., 2013; Chen and Manley, 2009; Kalsotra and Cooper, 2011).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Braunschweig et al., 2013 source
- Not checked yetcites Chen and Manley, 2009
- Not checked yetcites Kalsotra and Cooper, 2011
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein interaction networks during neurogenesis, the misregulation of which is linked to autism.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Indeed, among a set of analyzed neural-specific exons enriched in disordered regions, approximately one third promoted or disrupted interactions with partner proteins (Ellis et al., 2012).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Ellis et al., 2012 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“changes in the expression of the RBP RBFOX1 have been linked to misregulation of AS in the brains of individuals with autism spectrum disorder (ASD) (Voineagu et al., 2011).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Voineagu et al., 2011 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“These data reveal the largest program of neural-regulated AS events defined to date, and that this program is associated with a broader range of functional processes and pathways linked to nervous system biology than previously detected (Boutz et al., 2007; Fagnani et al., 2007; Ule et al., 2005).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Human disease mutations often disrupt cis-elements that control splicing and result in aberrant AS patterns (Cartegni et al., 2002).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Cartegni et al., 2002 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“However, the function of the vast majority of AS events detected to date are not known, and new landscapes of AS regulation remain to be discovered and characterized(Braunschweig et al., 2014; Eom et al., 2013).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Other disease changes affect the activity or expression of RBPs, causing entire programs of AS to be misregulated.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“While cell and tissue differentially-regulated AS events are significantly under-represented in functionally defined, folded domains in proteins, they are enriched in regions of protein disorder that typically are surface accessible and embed short linear interaction motifs (Buljan et al., 2012; Ellis et al., 2012; Romero et al., 2006).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Recently, we have shown that nSR100 promotes the inclusion of a subset of (longer) neural exons via binding to intronic UGC motifs proximal to suboptimal 3′ splice sites (Raj et al., 2014).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > The neural-specific splicing factor nSR100/SRRM4 regulates most neural microexons
What the sources say
- Not checked yetcites Raj et al., 2014 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, mutations in AP1S2 have been previously implicated in phenotypic features associated with ASD and X-linked mental retardation (Borck et al., 2008; Tarpey et al., 2006).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The properties of microexons described above suggest that their misregulation could be associated with neurological disorders.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
hedgedcorrelationaln = 12- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Rests on an assumption: Misregulation of alternative splicing frequently causes or contributes to human disease.
None of the sources cited for this claim have been checked yet.
In the paper
“The AP1 complex functions in the intracellular transport of cargo proteins between the trans-Golgi apparatus and endosomes by linking clathrin to the cargo proteins during vesicle membrane formation (Kirchhausen, 2000), and is important for the somatodendritic transport of proteins required for neuronal polarity (Farias et al., 2012).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Apbb1 contains two phosphotyrosine binding domains, PTB1 and PTB2, which bind Kat5 and App, respectively (Cao and Sudhoff, 2001).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
What the sources say
- Not checked yetcites Cao and Sudhoff, 2001
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sample selection was independent of any information on splicing changes.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Experimental Procedures > Comparison of ASD and control brain samples
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“an alternative microexon overlapping the SH3A domain of Intersectin 1 (Itsn1) has been reported to promote an interaction with Dynamin 1, and was proposed to modulate roles of Itsn1 in endocytosis, cell signaling and/or actin-cytoskeleton dynamics (Dergai et al., 2010)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
- Not checked yetcites Dergai et al., 2010 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The discovery and characterization of widespread, neural-regulated microexons in the present study thus enables a systematic investigation of new and highly conserved mechanisms controlling protein interaction networks associated with vertebrate nervous system development and neurological disorders.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“A neural-specific microexon in Protrudin/Zfyve27 was recently shown to increase its interaction with the vesicle-associated membrane protein-associated protein (VAP), and to promote neurite outgrowth (Ohnishi et al., 2014)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
- Not checked yetcites Ohnishi et al., 2014 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“recent reports have begun to link individual microexons with neurodevelopmental disorders, including ASD (Zhu et al., 2014), schizophrenia (Ovadia and Shifman, 2011) and epilepsy (Rusconi et al., 2014)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
- Not checked yetcites Zhu et al., 2014 source
- Not checked yetcites Ovadia and Shifman, 2011
- Not checked yetcites Rusconi et al., 2014
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“we have previously shown that nSR100 promotes neurite outgrowth (Calarco et al., 2009)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
- Not checked yetcites Calarco et al., 2009 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Apbb1 is an adapter protein that functions in neurite outgrowth (Cheung et al., 2014; Ikin et al., 2007) and synaptic plasticity (Sabo et al., 2003), processes that have been linked to neurological disorders including ASD (Hussman et al., 2011)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
Misregulation of alternative splicing frequently causes or contributes to human disease.
“since the misregulation of AS frequently causes or contributes to human disease, there is a pressing need to systematically define the functions of splice variants in disease contexts.”
The paper relies on this without support.
Gene prediction algorithms, high-throughput RNA sequencing analysis methods, and RNA-Seq datasets generally lack the sensitivity and/or depth required to detect specific types of alternative splicing.
“Gene prediction algorithms, high-throughput RNA sequencing (RNA-Seq) analysis methods, and RNA-Seq datasets generally lack the sensitivity and/or depth required to detect specific types of AS.”
The paper relies on this without support.
It is generally not known which disease-misregulated alternative splicing events cause or contribute to disease phenotypes.
“As is the case with assessing the normal functions of AS, it is generally not known which disease-misregulated AS events cause or contribute to disease phenotypes.”
The paper relies on this without support.
Several genes with misregulated microexons have been linked to learning or intellectual disability.
“Other genes with misregulated microexons have been linked to learning or intellectual disability (e.g. APBB1, TRAPPC9, RAB3GAP1)”
The paper relies on this without support.
The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
“We analyzed 24 autistic individuals and 24 controls matched by age and gender.”
The paper relies on this without support.
nSR100 mRNA expression levels reflect nSR100 protein activity or functional nSR100 levels.
“nSR100 mRNA expression is, on average, significantly downregulated in the brains of the analyzed ASD versus control subjects”
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?
In the citing paper
“the known positive correlation between SRRM4 and RBFOX1 and anticorrelation between PTBP1 and SRRM4 (refs 14,19)”
From Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism (2016) · cites this paper as [14]
In the citing paper
“Previous studies have identified alterations in local splicing events in ASD (19, 30) and in smaller cohorts in SCZ (2, 24) and BD (31).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [30]
In the citing paper
“several studies have demonstrated that genes carrying microexons are preferentially expressed in brain and their splicing is dysregulated in ASD (30, 82, 83).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [30]
In the citing paper
“nSR100 controls alternative splicing of 3–15 nucleotide “microexons,” which in turn alters protein-protein interactions, during neurogenesis. Reduced levels of nSR100 and dysregulated neuronal microexons are implicated in some cases of autism (Irimia et al., 2014).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Irimia et al., 2014
In the citing paper
“Recent studies have highlighted the importance of aberrant alternative splicing of mRNA in the brains of subjects with an ASD diagnosis (Corominas et al., 2014; Gandal et al., 2018; Irimia et al., 2014; Parikshak et al., 2016; Voineagu et al., 2011).”
From Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice (2019) · cites this paper as Irimia et al., 2014
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
“126 of 504 (30%) detected alternative microexons display a mean ΔPSI > 10 between ASD and control subjects”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
Reported 30 · recomputed 25
Citations
Cites
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Sorted by citations
GENCODE reference annotation for the human and mouse genomes
Frankish, A., Diekhans, M., Ferreira, A.-M., Johnson, R., Jungreis, I., Loveland, J. E., Mudge, J. M., Sisu, C., Wright, J. C., Armstrong, J. C., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky955 · Cited by 3,006
“We have also completed an effort to capture all recently described unannotated microexons (18) into GENCODE, and further added an additional 146 novel microexons mined from public SLRseq data (19).”
BackgroundPredicting splicing from primary sequence with deep learning
Jaganathan, K., Kyriazopoulou Panagiotopoulou, S., McRae, J. F., Darbandi, S. F., Knowles, D., Li, Y. I., Kosmicki, J. A., Arbelaez, J., Cui, W., Schwartz, G. B., et al. (2019) · Cell · doi:10.1016/j.cell.2018.12.015 · Cited by 2,853
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BackgroundAlternative splicing as a regulator of development and tissue identity
Baralle, F. E., & Giudice, J. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.27 · Cited by 1,333
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Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder
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“Finally, several studies have demonstrated that genes carrying microexons are preferentially expressed in the brain and their splicing is dysregulated in ASD (30, 82, 83).”
Self-citationHuman Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice
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“In contrast to longer neurally regulated exons that are enriched within IDRs, as described above, neural microexons significantly overlap or are adjacent to modular domains that function in mediating protein and other ligand interactions (Irimia et al., 2014).”
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Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism
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“…differential splicing events in ASD. j , Clustering dendrogram and heat map for neuronal splicing factor gene expression levels across samples demonstrating three major clusters and the known positive correlation between SRRM4 and RBFOX1 and anticorrelation between PTBP1 and SRRM4 (refs 14,19).”
Self-citationThe physiology of alternative splicing
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“Thus, inclusion of microexons represents a complementary mechanism for regulating PPI networks and other ligand interactions that are important for neuronal function (Irimia et al., 2014; Li et al., 2015).”
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“Interestingly, microexon splicing events often occur in neuronal cells and the functions of proteins found in NSs may also be altered by such microexon-dependent mechanisms, as has been shown for SR100/SRRM4 (189,190).”
BackgroundTapial, J., Ha, K., Sterne-Weiler, T., Gohr, A., Braunschweig, U., Hermoso, A., Quesnel-Vallières, M., Permanyer, J., Sodaei, R., Márquez, Y., et al. (2017) · Genome Research · doi:10.1101/gr.220962.117 · Cited by 441
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“The definition of sufficient read coverage was the same as described before.(77) We only considered the alternative splicing genes that were subjected to at least 2 types of junctions (EEJ, IR, ALTD, or ALTA) in one given cell/sample.”
MethodGenetics and genomics of psychiatric disease
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Self-citationCell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex
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“nSR100, Ptbp1 and Rbfox proteins have also been reported to regulate AS of neuronal microexons (Irimia et al., 2014; Li et al., 2015).”
BackgroundInfluentialLessons from non-canonical splicing
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“Microexon splicing events generally lead to the skipping of one to nine amino acids, which would be sufficient to remove specific motifs in IDRs important for phase separation including short linear motif (SLiM), multivalent repeats, or a stretch of low-complexity sequence (Irimia et al., 2014) (Box 1).”
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“For example, transcriptomic analyses have found consistent deviations in AS patterns in the cortical regions of autism spectrum disorder (ASD) cases [62], [63], pointing to splicing misregulation as an ASD mechanism.”
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Alternative splicing during mammalian organ development
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RBFOX and PTBP1 proteins regulate the alternative splicing of micro-exons in human brain transcriptsPreprint
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“Irimia et al. (2014) recently reported that the smallest micro-exons (3–15 nt) preferentially encode amino acids that alter the molecular function of proteins involved in neurogenesis.”
BackgroundModified penetrance of coding variants by cis-regulatory variation contributes to disease risk
Castel, S. E., Cervera, A., Mohammadi, P., Aguet, F., Reverter, F., Wolman, A., Guigo, R., Iossifov, I., Vasileva, A., & Lappalainen, T. (2018) · Nature Genetics · doi:10.1038/s41588-018-0192-y · Cited by 217
Widespread RNA editing dysregulation in brains from autistic individuals
Tran, S. S., Jun, H.-I., Bahn, J. H., Azghadi, A., Ramaswami, G., Nostrand, E. L. V., Nguyen, T. B., Hsiao, Y.-H. E., Lee, C., Pratt, G. A., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0287-x · Cited by 221
Self-citationSterne-Weiler, T., Weatheritt, R. J., Best, A. J., Ha, K., & Blencowe, B. J. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.08.018 · Cited by 210
“Whippet Facilitates Accurate Analysis of Alternative Splicing To assess Whippet’s accuracy, we compared its J values with those measured from RT-PCR data and commonly used RNAseq event-level analysis tools (Irimia et al., 2014; Katz et al., 2010; Wang et al., 2017; Vaquero-Garcia et al., 2016)—which quantify J using r…”
MethodSelf-citationA spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain
Joglekar, A., Prjibelski, A., Mahfouz, A., Collier, P., Lin, S., Schlusche, A. K., Marrocco, J., Williams, S. R., Haase, B., Hayes, A., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20343-5 · Cited by 229
Defective control of pre–messenger RNA splicing in human disease
Chabot, B., & Shkreta, L. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201510032 · Cited by 220
“, 2015) and is reported to be reduced in autistic brain tissues (Irimia et al., 2014).”
BackgroundMartín, G., Márquez, Y., Mantica, F., Duque, P., & Irimia, M. (2021) · Genome biology · doi:10.1186/s13059-020-02258-y · Cited by 217
Self-citationAlternative Splicing and Protein Diversity: Plants Versus Animals
Chaudhary, S., Khokhar, W., Jabre, I., Reddy, A. S. N., Byrne, L. J., Wilson, C. M., & Syed, N. H. (2019) · Frontiers in Plant Science · doi:10.3389/fpls.2019.00708 · Cited by 209
Takata, A., Matsumoto, N., & Kato, T. (2017) · Nature Communications · doi:10.1038/ncomms14519 · Cited by 192
“Comprehensive detection of AS events was performed by using vast-tools (version 0.2.1) 13 .”
InfluentialQAPA: a new method for the systematic analysis of alternative polyadenylation from RNA-seq data
Ha, K., Blencowe, B. J., & Morris, Q. (2018) · Genome biology · doi:10.1186/s13059-018-1414-4 · Cited by 184
“We also compared genes with QAPA-detected APA with an independently defined set of genes with neural-regulated AS events [50] and, again, did not observe any significant overlap (p = 0.”
ResultSelf-citationMultilayered Control of Alternative Splicing Regulatory Networks by Transcription Factors
Han, H. R., Braunschweig, U., Gonatopoulos-Pournatzis, T., Weatheritt, R. J., Hirsch, C. L., Ha, K., Radovani, E., Nabeel‐Shah, S., Sterne‐Weiler, T., Wang, J., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.01.011 · Cited by 182
Self-citationAutism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing
Parras, A., Anta, H., Santos‐Galindo, M., Swarup, V., Elorza, A., Nieto-González, J. L., Picó, S., Hernández, I. H., Díaz‐Hernandéz, J. I., Belloc, E., et al. (2018) · Nature · doi:10.1038/s41586-018-0423-5 · Cited by 175
Self-citationGenomic variants, genes, and pathways of Alzheimer's disease: An overview
Naj, A. C., & Schellenberg, G. D. (2016) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32499 · Cited by 186
“CYP1A1 encodes aromatase, which is involved in estrogen regulation, while SRRM4 regulates alternative splicing of microexons in the brain, and misregulation of which has been linked to autism spectrum dis- orders [Irimia et al., 2014].”
BackgroundRegulation of Neuronal Differentiation, Function, and Plasticity by Alternative Splicing
Furlanis, E., & Scheiffele, P. (2018) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100617-062826 · Cited by 177
“For example in autism - at least in some individuals - there might be an elevation of the excitation/inhibition ratio (“E/I balance”) (Rubenstein and Merzenich, 2003) and such persistent modifications of network activity may precipitate broad changes in activitydependent alternative splicing (Irimia et al., 2014; Ques…”
BackgroundYan, Q., Weyn‐Vanhentenryck, S. M., Wu, J., Sloan, S. A., Zhang, Y., Chen, K., Wu, J. Q., Barres, B. A., & Zhang, C. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1502849112 · Cited by 169
The Relationship between Alternative Splicing and Proteomic Complexity
Blencowe, B. J. (2017) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2017.04.001 · Cited by 178
“[84_TD$DIFF] he majority of these ribosome-engaged exon-skipping events [85_TD$DIFF]have frame-preservation potential, and all of them correspond to AS events detected previously in transcript sequence data from diverse cell and tissue types [13].”
BackgroundSelf-citationAn extensive program of periodic alternative splicing linked to cell cycle progression
Dominguez, D., Tsai, Y., Weatheritt, R. J., Wang, Y., Blencowe, B. J., & Wang, Z. (2016) · eLife · doi:10.7554/elife.10288 · Cited by 167
Self-citationAutism spectrum disorder: insights into convergent mechanisms from transcriptomics
Quesnel-Vallières, M., Weatheritt, R. J., Cordes, S. P., & Blencowe, B. J. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0066-2 · Cited by 167
Self-citationIntron retention and nuclear loss of SFPQ are molecular hallmarks of ALS
Luisier, R., Tyzack, G. E., Hall, C. E., Mitchell, J. S., Devine, H. E., Taha, D. M., Malik, B. A., Meyer, I., Greensmith, L., Newcombe, J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04373-8 · Cited by 164
Quesnel-Vallières, M., Dargaei, Z., Irimia, M., Gonatopoulos-Pournatzis, T., Ip, J. Y., Wu, M., Sterne-Weiler, T., Nakagawa, S., Woodin, M. A., Blencowe, B. J., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.11.033 · Cited by 178
“As such, they recapitulate misregulated patterns of splicing observed in autistic human brains (Irimia et al., 2014). nSR100+/D7-8 mutant mice appear normal in tests for locomotion, habituation, short-term memory, olfaction, and hearing (Figure S1, available online), and they display either mild or…”
BackgroundMethodInfluentialSelf-citationClark, M. B., Wrzesiński, T., Garcia, A. B., Hall, N., Kleinman, J. E., Hyde, T. M., Weinberger, D. R., Harrison, P. J., Haerty, W., & Tunbridge, E. M. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0583-1 · Cited by 155
RNA Sequencing Data: Hitchhiker's Guide to Expression Analysis
den Berge, K. V., Hembach, K., Soneson, C., Tiberi, S., Clement, L., Love, M. I., Patro, R., & Robinson, M. D. (2019) · Annual Review of Biomedical Data Science · doi:10.1146/annurev-biodatasci-072018-021255 · Cited by 153
“Transcriptomic studies identified previously unknown phenomena, such as microexons [27], cryptic exons [28], “skiptic” exons [29], circular RNAs [30], enhancer RNAs [31], fusion genes [32] and so-called epi-transcriptomics involving RNA base modifications [33].”
The ribosome-engaged landscape of alternative splicing
Weatheritt, R. J., Sterne-Weiler, T., & Blencowe, B. J. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3317 · Cited by 162
Self-citationEssential roles for the splicing regulator nSR100/SRRM4 during nervous system development
Quesnel-Vallières, M., Irimia, M., Cordes, S. P., & Blencowe, B. J. (2015) · Genes & Development · doi:10.1101/gad.256115.114 · Cited by 155
“…“ percent spliced in ” (PSI) values for alternative cassette exons, “ percent splice site usage ” (PSU) values for sequences formed by alternative 5 ′ /3 ′ splice site selection, and “ percent intron retained ” (PIR) values for intron retention events (Braunschweig et al. 2014; Irimia et al. 2014).”
InfluentialSelf-citationGueroussov, S., Weatheritt, R. J., O’Hanlon, D., Lin, Z., Narula, A., Gingras, A., & Blencowe, B. J. (2017) · Cell · doi:10.1016/j.cell.2017.06.037 · Cited by 150
“0 (Irimia et al., 2014) https://github.com/vastgroup/vast-tools ProHits v4 Anne-Claude Gingras’ lab http://prohitsms.com/Prohits_download/ list.php Trans-Proteomic Pipeline v4.”
InfluentialSelf-citationOlfactory receptor pseudo-pseudogenes
Prieto-Godino, L. L., Rytz, R., Bargeton, B., Abuin, L., Arguello, J. R., Peraro, M. D., & Benton, R. (2016) · Nature · doi:10.1038/nature19824 · Cited by 149
Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms
D’Gama, A. M., Pochareddy, S., Li, M., Jamuar, S. S., Rodin, R. E., Lam, A.-T. N., Šestan, N., & Walsh, C. A. (2015) · Neuron · doi:10.1016/j.neuron.2015.11.009 · Cited by 153
“…studies of ASD risk have analyzed DNA from blood, saliva, or cell lines (De Rubeis et al., 2014; Iossifov et al., 2014; O'Roak et al., 2011), postmortem ASD brain samples have been utilized mostly to study neuropathology, transcriptomics, and splicing (Chen et al., 2015; Irimia et al., 2014).”
MethodDaguenet, É., Dujardin, G., & Valcárcel, J. (2015) · EMBO Reports · doi:10.15252/embr.201541116 · Cited by 159
“Recently, a class of microexons (3–15 nucleotides in length) was discovered that are specifically included in neurons and which are frequently misregulated in patients with autism [123].”
Determining exon connectivity in complex mRNAs by nanopore sequencing
Bolisetty, M. T., Rajadinakaran, G., & Graveley, B. R. (2015) · Genome biology · doi:10.1186/s13059-015-0777-z · Cited by 139
“For instance, there are many micro-exons in the human genome [15], and these exons would be difficult to identify if they overlapped a portion of a read that contained errors.”
BackgroundFurlanis, E., Traunmüller, L., Fucile, G., & Scheiffele, P. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0465-5 · Cited by 145
Merico, D., Roifman, M., Braunschweig, U., Yuen, R. K. C., Alexandrova, R., Bates, A., Reid, B. E., Nalpathamkalam, T., Wang, Z., Thiruvahindrapuram, B., et al. (2015) · Nature Communications · doi:10.1038/ncomms9718 · Cited by 147
Self-citationGenetics and epigenetics of autism: A Review
Waye, M. M. Y., & Cheng, H. Y. (2017) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12606 · Cited by 164
“Such misregulated patterns of splicing have also been demonstrated in autistic human brains by the same group in Toronto.(67) Thus it is hoped that nSR100 protein could be one of the future drug targets for changing the behavior of autistic children.”
BackgroundResultInfluentialGenetic and Epigenetic Etiology Underlying Autism Spectrum Disorder
Yoon, S. H., Choi, J., Lee, W. Y., & Do, J. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9040966 · Cited by 175
“23 Neuronal cells and misregulated neural ‘microexons’ in the brains nSR100/SRRM4 [171]”
BackgroundAn alternative splicing event amplifies evolutionary differences between vertebrates
Gueroussov, S., Gonatopoulos-Pournatzis, T., Irimia, M., Raj, B., Lin, Z.-Y., Gingras, A.-C., & Blencowe, B. J. (2015) · Science · doi:10.1126/science.aaa8381 · Cited by 148
Self-citationGenetic Changes Shaping the Human Brain
Bae, B.-I., Jayaraman, D., & Walsh, C. A. (2015) · Developmental Cell · doi:10.1016/j.devcel.2015.01.035 · Cited by 135
“Microcephaly is largely caused by mutations that disrupt genes encoding centrosomal proteins: MCPH1, ASPM, CDK5RAP2, CENPJ, STIL, WDR62, CEP152, and CEP63 (Bilguvar et al., 2010; Bond et al., 2002; Bond et al., 2005; Guernsey et al., 2010; Jackson et al., 2002; Kumar et al., 2009; Nicholas et al., 2010; Sir et al., 20…”
BackgroundAlternative splicing modulation by G-quadruplexes
Georgakopoulos‐Soares, I., Parada, G. E., Wong, H. Y., Medhi, R., Furlan, G., Munita, R., Miska, E. A., Kwok, C. K., & Hemberg, M. (2022) · Nature Communications · doi:10.1038/s41467-022-30071-7 · Cited by 133
Anything but Ordinary – Emerging Splicing Mechanisms in Eukaryotic Gene Regulation
Gehring, N. H., & Roignant, J. (2020) · Trends in Genetics · doi:10.1016/j.tig.2020.10.008 · Cited by 145
Gonatopoulos-Pournatzis, T., Wu, M., Braunschweig, U., Roth, J. F., Han, H. R., Best, A. J., Raj, B., Aregger, M., O’Hanlon, D., Ellis, J. D., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.10.008 · Cited by 122
“This microexon regulatory network is disrupted in the brains of approximately one-third of analyzed autistic subjects (Irimia et al., 2014), and individual microexons within the network have been linked to important neurodevelopmental and brain functions (Parras et al.”
BackgroundInfluentialSelf-citationFunnell, T., Tasaki, S., Oloumi, A., Araki, S., Kong, E., Yap, D., Nakayama, Y., Hughes, C. S., Cheng, S., Tozaki, H., et al. (2017) · Nature Communications · doi:10.1038/s41467-016-0008-7 · Cited by 139
Structural Basis for Teneurin Function in Circuit-Wiring: A Toxin Motif at the Synapse
Li, J., Shalev-Benami, M., Sando, R. C., Jiang, X., Kibrom, A., Wang, J., Leon, K., Katanski, C. D., Nazarko, O. V., Lu, Y. C., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.036 · Cited by 127
Alternative splicing: the pledge, the turn, and the prestige
Gallego-Paez, L. M., Bordone, M. C., Leote, A. C., Saraiva-Agostinho, N., Ascensão-Ferreira, M., & Barbosa‐Morais, N. L. (2017) · Human Genetics · doi:10.1007/s00439-017-1790-y · Cited by 143
“In fact, one of the most important roles of SRRM4 is the negative regulation of a transcriptional repressor of genes required for neurogenesis (REST).”
InfluentialStructural Basis for Regulation of GPR56/ADGRG1 by Its Alternatively Spliced Extracellular Domains
Salzman, G., Ackerman, S. D., Ding, C., Koide, A., Leon, K., Luo, R., Stoveken, H. M., Fernandez, C., Tall, G. G., Piao, X., et al. (2016) · Neuron · doi:10.1016/j.neuron.2016.08.022 · Cited by 127
DNA Methylation and Susceptibility to Autism Spectrum Disorder
Tremblay, M. W., & Jiang, Y. (2019) · Annual Review of Medicine · doi:10.1146/annurev-med-120417-091431 · Cited by 139
Perspective on Alternative Splicing and Proteome Complexity in Plants
Chaudhary, S., Jabre, I., Reddy, A. S. N., Staiger, D., & Syed, N. H. (2019) · Trends in Plant Science · doi:10.1016/j.tplants.2019.02.006 · Cited by 135
RNA-binding proteins in neurological development and disease
Prashad, S., & Gopal, P. P. (2020) · RNA Biology · doi:10.1080/15476286.2020.1809186 · Cited by 124
“dysregulation of RNA binding proteins [2-5].”
BackgroundRahimi, K., Venø, M. T., Dupont, D. M., & Kjems, J. (2021) · Nature Communications · doi:10.1038/s41467-021-24975-z · Cited by 149
PRMT inhibition induces a viral mimicry response in triple-negative breast cancer
Wu, Q., Nie, D. Y., Ba-Alawi, W., Ji, Y., Zhang, Z., Cruickshank, J., Haight, J., Ciamponi, F. E., Chen, J., Duan, S., et al. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01024-4 · Cited by 132
Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk
Galarza-Muñoz, G., Briggs, F. B. S., Evsyukova, I. Y., Schott, G., Kennedy, E. M., Nyanhete, T. E., Wang, L., Bergamaschi, L., Widen, S. G., Tomaras, G. D., et al. (2017) · Cell · doi:10.1016/j.cell.2017.03.007 · Cited by 124
An oomycete plant pathogen reprograms host pre-mRNA splicing to subvert immunity
Huang, J., Gu, L., Zhang, Y., Yan, T., Kong, G., Kong, L., Guo, B., Qiu, M., Wang, Y., Jing, M., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-02233-5 · Cited by 125
Gonatopoulos-Pournatzis, T., Niibori, R., Salter, E. W., Weatheritt, R. J., Tsang, B., Farhangmehr, S., Liang, X., Braunschweig, U., Roth, J. F., Zhang, S., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.01.006 · Cited by 120
“Srrm4, Srrm3, and Srsf11, but not GFP (analyzed as a negative control), form binding peaks proximally upstream of both microexons, supporting a direct role in their regulation (Figures 2C, 2D, S2D, and S2E; Gonatopoulos-Pournatzis et al., 2018; Irimia et al., 2014; Raj et al., 2014).”
BackgroundMethodResultInfluentialSelf-citationAltered expression of histamine signaling genes in autism spectrum disorder
Wright, C., Shin, J. H., Rajpurohit, A., Deep‐Soboslay, A., Collado‐Torres, L., Brandon, N. J., Hyde, T. M., Kleinman, J. E., Jaffe, A. E., Cross, A. J., et al. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.87 · Cited by 123
Prenatal stress and the developing brain: Risks for neurodevelopmental disorders
den Bergh, B. R. H. V., Dahnke, R., & Mennes, M. (2018) · Development and Psychopathology · doi:10.1017/s0954579418000342 · Cited by 173
“mak, Vukšić, & Judaš, 2015) as well as changes in noncoding RNAs modulating gene expression/misregulation of genes expressed during early brain development (e.g., nSR100/ SRRM4; Irimia et al., 2014; Ziats et al., 2015).”
BackgroundMethodSingle-nuclei isoform RNA sequencing unlocks barcoded exon connectivity in frozen brain tissue
Hardwick, S. A., Hu, W., Joglekar, A., Fan, L., Collier, P. G., Foord, C., Balacco, J., Lanjewar, S., Sampson, M. M., Koopmans, F., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01231-3 · Cited by 119
Joglekar, A., Hu, W., Zhang, B., Narykov, O., Diekhans, M., Marrocco, J., Balacco, J., Ndhlovu, L. C., Milner, T. A., Fedrigo, O. D., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01616-4 · Cited by 126
“Exons in E3 and E5, that is, those with adult cell-type specificity regardless of earlier cell-type specificity, were markedly shorter, suggesting a link to microexons 29,41 .”
Genetic Control of Expression and Splicing in Developing Human Brain Informs Disease Mechanisms
Walker, R. L., Ramaswami, G., Hartl, C., Mancuso, N., Gandal, M. J., de la Torre-Ubieta, L., Paşaniuc, B., Stein, J. L., & Geschwind, D. H. (2019) · Cell · doi:10.1016/j.cell.2019.09.021 · Cited by 262
Self-citationA novel protein domain in an ancestral splicing factor drove the evolution of neural microexons
Torres-Méndez, A., Bonnal, S., Márquez, Y., Roth, J. F., Iglesias, M., Permanyer, J., Almudí, I., O’Hanlon, D., Guitart, T., Soller, M., et al. (2019) · Nature Ecology & Evolution · doi:10.1038/s41559-019-0813-6 · Cited by 93
Self-citationThe Emerging Field of Epitranscriptomics in Neurodevelopmental and Neuronal Disorders
Angelova, M. T., Dimitrova, D. G., Dinges, N., Lenče, T., Worpenberg, L., Carré, C., & Roignant, J. (2018) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2018.00046 · Cited by 109
“…processing events in the brain, including the high rates of alternative splicing and recursive splicing (Duff et al., 2015; Sibley et al., 2015), the inclusion of microexons (Irimia et al., 2014) and the biogenesis of circular RNAs (cirRNAs) can all in principle be affected by RNA modifications.”
BackgroundCoexpression networks identify brain region–specific enhancer RNAs in the human brain
Yao, P., Lin, P., Gokoolparsadh, A., Assareh, A. A., Thang, M. W. C., & Voineagu, I. (2015) · Nature Neuroscience · doi:10.1038/nn.4063 · Cited by 94
Microexons: discovery, regulation, and function
Ustianenko, D., Weyn‐Vanhentenryck, S. M., & Zhang, C. (2017) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1418 · Cited by 104
“For example, during in vitro differentiation of mouse embryonic stem cells to glutamatergic excitatory neurons, 30% of exons go from near complete exclusion to near complete inclusion (or vice versa) and 69% show a change > 50%.(28) This includes the 12 nt microexon of the Enah gene [enabled homolog (Drosophila), a ph…”
BackgroundMethodInfluentialNeurodegenerative diseases: a hotbed for splicing defects and the potential therapies
Li, D., McIntosh, C. S., Mastaglia, F. L., Wilton, S. D., & Aung-Htut, M. T. (2021) · Translational Neurodegeneration · doi:10.1186/s40035-021-00240-7 · Cited by 98
“Several SRRM4-regulated micro-exons have demonstrated high levels of inclusion during neuronal maturation, which is directly correlated to the high levels of SRRM4 [58, 60, 61].”
BackgroundInfluentialExon Junction Complex Shapes the Transcriptome by Repressing Recursive Splicing
Blázquez, L., Emmett, W., Faraway, R., Pineda, J. M. B., Bajew, S., Gohr, A., Haberman, N., Sibley, C. R., Bradley, R. K., Irimia, M., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.09.033 · Cited by 84
Self-citationHäsler, R., Sheibani‐Tezerji, R., Sinha, A. N., Barann, M., Rehman, A., Esser, D., Aden, K., Knecht, C., Brandt, B., Nikolaus, S., et al. (2016) · Gut · doi:10.1136/gutjnl-2016-311651 · Cited by 89
Transcriptome-wide splicing network reveals specialized regulatory functions of the core spliceosome
Rogalska, M. E., Mancini, E., Bonnal, S., Gohr, A., Dunyak, B. M., Arecco, N., Smith, P. G., Vaillancourt, F. H., & Valcárcel, J. (2024) · Science · doi:10.1126/science.adn8105 · Cited by 106
Shah, S., Molinaro, G., Liu, B., Wang, R., Huber, K. M., & Richter, J. D. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.02.076 · Cited by 95
“Furthermore, a number of skipped exons in Fmr1 KO have been linked to neurological disorders such as autism (skipped microexon 4 in Cpeb4; Irimia et al., 2014; Parras et al., 2018; Quesnel-Vallières et al., 2016), Alzheimer’s disease (skipped exon 7 in APP; Fragkouli et al.”
BackgroundWaterhouse, L. H., London, E., & Gillberg, C. (2016) · Review Journal of Autism and Developmental Disorders · doi:10.1007/s40489-016-0085-x · Cited by 106
Risk factors diagnosis prognosis and treatment of autism
Al-Dewik, N. I. E. (2020) · Frontiers in bioscience · doi:10.2741/4873 · Cited by 123
RNA seq analysis for the diagnosis of muscular dystrophy
Gonorazky, H. D., Liang, M., Cummings, B. B., Lek, M., Micallef, J., Hawkins, C. E., Basran, R. K., Cohn, R. D., Wilson, M. D., MacArthur, D. G., et al. (2015) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.267 · Cited by 88
Transcriptomic Perspectives on Neocortical Structure, Development, Evolution, and Disease
Lein, E. S., Belgard, T. G., Hawrylycz, M., & Molnár, Z. (2017) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-070815-013858 · Cited by 92
Microexons: at the nexus of nervous system development, behaviour and autism spectrum disorder
Gonatopoulos-Pournatzis, T., & Blencowe, B. J. (2020) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2020.03.007 · Cited by 79
“Functions of neuronal microexons As mentioned above, the vast majority of neuronal microexon coding sequences overlap with and preserve open reading frames [5,6,28].”
BackgroundInfluentialSelf-citationPorter, R. S., Jaamour, F., & Iwase, S. (2017) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2017.10.006 · Cited by 82
The Musashi 1 Controls the Splicing of Photoreceptor-Specific Exons in the Vertebrate Retina
Murphy, D., Cieply, B. W., Carstens, R. P., Ramamurthy, V., & Stoilov, P. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1006256 · Cited by 84
“Characteristically, neurons broadly utilize microexons that are defined by different groups as being no longer than 27nt or 51nt [10,15].”
BackgroundGene architecture directs splicing outcome in separate nuclear spatial regions
Tammer, L., Hameiri, O., Keydar, I., Roy, V. R., Ashkenazy-Titelman, A., Custódio, N., Sason, I., Shayevitch, R., Rodríguez-Vaello, V., Rino, J., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.02.001 · Cited by 80
Self-citationBerto, S., Usui, N., Konopka, G., & Fogel, B. L. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw110 · Cited by 80
Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration
Bangru, S., Arif, W., Seimetz, J., Bhate, A., Chen, J., Rashan, E. H., Carstens, R. P., Anakk, S., & Kalsotra, A. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0129-2 · Cited by 85
Ortiz-Sánchez, P., Villalba‐Orero, M., López-Olañeta, M. M., Larrasa-Alonso, J., Sánchez‐Cabo, F., Martí‐Gómez, C., Camafeita, E., Gómez-Salinero, J. M., Ramos-Hernández, L., Nielsen, P. J., et al. (2019) · Circulation Research · doi:10.1161/circresaha.118.314515 · Cited by 76
“28,29 Gene ontology categories and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways were downloaded from the Enrichr website, 28 and enrichment analysis of genes undergoing both differential expression or splicing was performed with one-sided Fisher tests and Benjamini-Hochberg False…”
Choi, Y., Nam, J., Whitcomb, D. J., Song, Y. S., Kim, D., Jeon, S., Um, J. W., Lee, S.-G., Woo, J., Kwon, S., et al. (2016) · Scientific Reports · doi:10.1038/srep26676 · Cited by 75
Metadata
- Authors
- Irimia, M., Weatheritt, R. J., Ellis, J. D., Parikshak, N. N., Gonatopoulos-Pournatzis, T., Babor, M., Quesnel-Vallières, M., Tapial, J., Raj, B., O’Hanlon, D., Barrios-Rodiles, M., Sternberg, M. J. E., Cordes, S. P., Roth, F. P., Wrana, J. L., Geschwind, D. H., & Blencowe, B. J.
- Affiliations
- University of Toronto (CA)
- MRC Laboratory of Molecular Biology (GB)
- University of California, Los Angeles (US)
- Centre for Genomic Regulation (ES)
- Imperial College London (GB)
- Mount Sinai Hospital (CA)
- Canadian Institute for Advanced Research (CA)
- Corresponding author
- Irimia, Manuel
- Blencowe, Benjamin J.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 159
- Issue
- 7
- Pages
- 1511-1523
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4390143
- OpenAlex
- W2139480055
- Semantic Scholar
- 50b56e7b67ca01c7c25009821818d9e4a479c378
- Cited by
- 693
- References
- 117
- Citations by year
- 2026: 59 · 2025: 63 · 2024: 64 · 2023: 62 · 2022: 59 · 2021: 87 · 2020: 69 · 2019: 49 · 2018: 56 · 2017: 47 · 2016: 40 · 2015: 32 · 2014: 4
- FWCI
- 16.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (5r01mh094714-04)
- Canadian Institutes of Health Research
- National Institute of Mental Health (5R01MH094714, R01-MH094714, F30MH099886, R37MH060233)
- National Human Genome Research Institute (U01HG001715, R01HG003224, P50HG004233)
- National Institute of General Medical Sciences (T32GM008042)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- microexons, alternative splicing, autism spectrum disorder, SRRM4, neurogenesis, protein-protein interaction domains, evolutionary conservation, brain transcriptome
- MeSH terms
- Animals, Child Development Disorders, Pervasive, Humans, Models, Molecular, Nerve Tissue Proteins, Neurons, Temporal Lobe, Alternative Splicing, Sequence Analysis, RNA, Mice, Protein Interaction Domains and Motifs, Neurogenesis
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.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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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