Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene <i>CACNA1C</i> in human brain

Clark, Michael B.; Wrzesiński, Tomasz; Garcia, Aintzane B.; Hall, Nicola A. L.; Kleinman, Joel E.; Hyde, Thomas M.; Weinberger, Daniel R.; Harrison, Paul J.; Haerty, Wilfried; Tunbridge, Elizabeth

doi:10.1101/260562

Cited by 37 publications

(44 citation statements)

References 57 publications

(51 reference statements)

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“…Finally, it would be of interest to study intracellular [Ca 2+ ] in glia in bipolar disorder, since these cells are implicated in its pathophysiology [76,77], and Ca 2+ dysregulation in the disorder may involve these cells as well as the presumed primary neuronal locus of dysfunction. Despite the uncertainties as to its cause and molecular basis, the increase in intracellular [Ca 2+ ] found in bipolar disorder is broadly supportive of the possibility that novel calcium channel antagonists, or related drugs acting upon calcium signalling, could be of potential therapeutic value, especially if designed to be brain selective [78][79][80].…”

Section: Discussionmentioning

confidence: 99%

Cellular calcium in bipolar disorder: systematic review and meta-analysis

et al. 2019

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Calcium signalling has long been implicated in bipolar disorder, especially by reports of altered intracellular calcium ion concentrations ([Ca 2+ ]). However, the evidence has not been appraised critically. We carried out a systematic review and metaanalysis of studies of cellular calcium indices in bipolar disorder. 2281 records were identified and 117 screened, of which 32 were eligible and 21 were suitable for meta-analyses. The latter each involved up to 642 patients and 404 control subjects. We found that basal free intracellular [Ca 2+ ] is increased in bipolar disorder, both in platelets and in lymphocytes. The effect size is 0.55, with an estimated elevation of 29%. It is observed in medication-free patients. It is present in mania and bipolar depression, but data are equivocal for euthymia. Cells from bipolar disorder individuals also show an enhanced [Ca 2+ ] response to stimulation with 5-HT or thrombin, by an estimated 25%, with an effect size of 0.63. In studies which included other diagnoses, intracellular basal [Ca 2+ ] was higher in bipolar disorder than in unipolar depression, but not significantly different from schizophrenia. Functional parameters of cellular Ca 2+ (e.g. calcium transients), and neuronal [Ca 2+ ], have been much less investigated, and no firm conclusions can be drawn. In summary, there is a robust, medium effect size elevation of basal and stimulated free intracellular [Ca 2+ ] in bipolar disorder. The results suggest altered calcium functioning in the disorder, and encourage further investigations into the underlying mechanisms, and the implications for pathophysiology and therapeutics.

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Section: Discussionmentioning

confidence: 99%

Cellular calcium in bipolar disorder: systematic review and meta-analysis

et al. 2019

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“…For the other genes, the potential for isoform-specific effects are less clear: there are only 2 annotated human MAOA transcripts and a single DBH transcript (34). However, recent findings demonstrate that current human brain transcript annotations are far from complete (35), suggesting transcript-specific polymorphic effects as an avenue for future research.…”

Section: Functional Dopamine Polymorphismsmentioning

confidence: 99%

Which Dopamine Polymorphisms Are Functional? Systematic Review and Meta-analysis of COMT, DAT, DBH, DDC, DRD1–5, MAOA, MAOB, TH, VMAT1, and VMAT2

Tunbridge

Narajos

Harrison

et al. 2019

Biological Psychiatry

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BACKGROUND: Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are causal, mediated by a direct effect of the polymorphism on the gene product itself. However, the supporting evidence is not always clear. METHODS: We conducted systematic reviews and meta-analyses to assess the empirical evidence for functional polymorphisms in genes encoding dopaminergic enzymes (COMT, DBH, DDC, MAOA, MAOB, and TH), dopamine receptors (DRD1, DRD2, DRD3, DRD4, and DRD5), the dopamine transporter (DAT), and vesicular transporters (VMAT1 and VMAT2). We defined functionality as an effect of the polymorphism on the expression, abundance, activity, or affinity of the gene product. RESULTS: We screened 22,728 articles and identified 255 eligible studies. We found robust and medium to large effects for polymorphisms in 4 genes. For catechol-O-methyltransferase (COMT), the Val 158 Met polymorphism (rs4680) markedly affected enzyme activity, protein abundance, and protein stability. Dopamine b-hydroxylase (DBH) activity was associated with rs1611115, rs2519152, and the DBH-STR polymorphism. Monoamine oxidase A (MAOA) activity was associated with a 5 0 VNTR polymorphism. Dopamine D 2 receptor (DRD2) binding was influenced by the Taq1A (rs1800497) polymorphism, and rs1076560 affected DRD2 splicing. CONCLUSIONS: Some widely studied dopaminergic polymorphisms clearly and substantially affect the abundance or activity of the encoded gene product. However, for other polymorphisms, evidence of such an association is negative, inconclusive, or lacking. These findings are relevant when selecting polymorphisms as "markers" of dopamine function, and for interpreting the biological plausibility of associations between these polymorphisms and aspects of brain function or dysfunction.

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“…Given the recent discovery of numerous novel functional transcripts in multiple organs (3,58), the re-evaluation of transcript diversity and complexity in model organisms (4,5,59,60) and the growing interest in Oxford Nanopore direct-RNA multiple assets in viral transcriptome research (61-64), TALC's capacity to correct the entire gamut of transcripts, and preserve the correct transcript structure may prove increasingly valuable. Table 1: Usual alignment-based statistics for the 7 correction methods tested: primary alignment rates and base accuracy (real LR data corrected by real SR data).…”

Section: Discussionmentioning

confidence: 99%

TALC: Transcript-level Aware Long Read Correction

Broseus

Thomas

Oldfield

et al. 2020

Preprint

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Long-read sequencing technologies are invaluable for determining complex RNA transcript architectures but are error-prone. Numerous "hybrid correction" algorithms have been developed for genomic data that correct long reads by exploiting the accuracy and depth of short reads sequenced from the same sample. These algorithms are not suited for correcting more complex transcriptome sequencing data. We have created a novel algorithm called TALC (Transcription Aware Long Read Correction) which models changes in RNA expression and isoform representation in a weighted De-Bruijn graph to correct long reads from transcriptome studies. We tested TALC on a dataset of short and long reads generated for this study. TALC correction results in more accurate reads with less structural errors than existing methods. TALC is implemented in C++ and available at https://gitlab.igh.cnrs.fr/lbroseus/TALC. INTRODUCTIONRecent advances in RNA sequencing (RNA-seq) technologies have revealed that transcription is more pervasive(1), more diverse (2) and more cryptic (3) than expected. Given the major role that RNA processing plays in disease and normal biology, it is crucial to ascertain the existence of novel isoforms and to accurately quantify their abundance. Second generation RNA-seq technologies such as Illumina are well suited to the tasks of assessing gene expression levels and determining proximal exon connectivity. They produce numerous sequencing reads at a low cost ensuring sufficient representation of most transcripts. However, because the RNA or cDNA is fragmented during short RNA-seq protocols, long range connectivity can only be computationally inferred. These predictions based on short reads struggle to correctly identify transcript isoforms that contain multiple alternative exons (4) or that contain retained introns (5). In these cases, long-read (LR) sequencing technologies are invaluable because they can sequence entire molecules in one pass and thus capture long-range connectivity of complex isoforms. LR technologies however produce less reads than short read (SR) sequencing approaches (6) for similar costs and have higher error rates. In many cases these higher error rates can prevent the correct identification of isoforms.Although several alignment software (7-9) are optimized to handle long erroneous sequences, they still display several issues which confound transcript identification and annotation. Many reads fail to be aligned and regions where the sequencing error rates are higher such as UTRs frequently produce ambiguous alignments. Secondly, they struggle to identify splice junctions, notably those flanking small structural variants such as small exons or alternative 5' and 3' splice sites. This impacts the evaluation of exon skipping events and worsens the quality of . CC-BY-NC-ND 4.0

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Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain

Cited by 37 publications

References 57 publications

Cellular calcium in bipolar disorder: systematic review and meta-analysis

Cellular calcium in bipolar disorder: systematic review and meta-analysis

Which Dopamine Polymorphisms Are Functional? Systematic Review and Meta-analysis of COMT, DAT, DBH, DDC, DRD1–5, MAOA, MAOB, TH, VMAT1, and VMAT2

TALC: Transcript-level Aware Long Read Correction

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