scholarly journals Assessment of branch point prediction tools to predict physiological branch points and their alteration by variants

2019 ◽  
Author(s):  
Raphael Leman ◽  
Hélène Tubeuf ◽  
Sabine Raad ◽  
Isabelle Tournier ◽  
Céline Derambure ◽  
...  
Keyword(s):  
Branch Point ◽  
Mrna Splicing ◽  
Large Set ◽  
Branch Points ◽  
Splice Sites ◽  
Prediction Tools ◽  
Mature Mrna ◽  
Bioinformatics Tools ◽  
The Impact

Abstract Background: Branch points (BPs) map within short motifs upstream of acceptor splice sites (3’ss) and are essential for splicing of pre-mature mRNA. Several BP-dedicated bioinformatics tools, including HSF, SVM-BPfinder, BPP, Branchpointer, LaBranchoR and RNABPS were developed during the last decade. Here, we evaluated their capability to detect the position of BPs, and also to predict the impact on splicing of variants occurring upstream of 3’ss. Results: We used a large set of constitutive and alternative human 3’ss collected from Ensembl (n = 264,787 3’ss) and from in-house RNAseq experiments (n = 51,986 3’ss). We also gathered an unprecedented collection of functional splicing data for 120 variants (62 unpublished) occurring in BP areas of disease-causing genes. Branchpointer showed the best performance to detect the relevant BPs upstream of constitutive and alternative 3’ss (99.48 % and 65.84 % accuracies, respectively). For variants occurring in a BP area, BPP emerged as having the best performance to predict effects on mRNA splicing, with an accuracy of 89.17 %. Conclusions: Our investigations revealed that Branchpointer was optimal to detect BPs upstream of 3’ss, and that BPP was most relevant to predict splicing alteration due to variants in the BP area. Keywords: Branch Point, Prediction, RNA, Benchmark, HSF, SVM-BPfinder, BPP, Branchpointer, LaBranchoR, RNABPS, Variants

scholarly journals Assessment of branch point prediction tools to predict physiological branch points and their alteration by variants

2020 ◽  
Author(s):  
Raphael Leman ◽  
Hélène Tubeuf ◽  
Sabine Raad ◽  
Isabelle Tournier ◽  
Céline Derambure ◽  
...  
Keyword(s):  
Branch Point ◽  
Mrna Splicing ◽  
Large Set ◽  
Branch Points ◽  
Splice Sites ◽  
Prediction Tools ◽  
Mature Mrna ◽  
Bioinformatics Tools ◽  
The Impact

Abstract Background: Branch points (BPs) map within short motifs upstream of acceptor splice sites (3’ss) and are essential for splicing of pre-mature mRNA. Several BP-dedicated bioinformatics tools, including HSF, SVM-BPfinder, BPP, Branchpointer, LaBranchoR and RNABPS were developed during the last decade. Here, we evaluated their capability to detect the position of BPs, and also to predict the impact on splicing of variants occurring upstream of 3’ss. Results: We used a large set of constitutive and alternative human 3’ss collected from Ensembl (n = 264,787 3’ss) and from in-house RNAseq experiments (n = 51,986 3’ss). We also gathered an unprecedented collection of functional splicing data for 120 variants (62 unpublished) occurring in BP areas of disease-causing genes. Branchpointer showed the best performance to detect the relevant BPs upstream of constitutive and alternative 3’ss (99.48 % and 65.84 % accuracies, respectively). For variants occurring in a BP area, BPP emerged as having the best performance to predict effects on mRNA splicing, with an accuracy of 89.17 %. Conclusions: Our investigations revealed that Branchpointer was optimal to detect BPs upstream of 3’ss, and that BPP was most relevant to predict splicing alteration due to variants in the BP area. Keywords: Branch Point, Prediction, RNA, Benchmark, HSF, SVM-BPfinder, BPP, Branchpointer, LaBranchoR, RNABPS, Variants

scholarly journals Assessment of branch point prediction tools to predict physiological branch points and their alteration by variants

2019 ◽  
Author(s):  
Raphael Leman ◽  
Hélène Tubeuf ◽  
Sabine Raad ◽  
Isabelle Tournier ◽  
Céline Derambure ◽  
...  
Keyword(s):  
Branch Point ◽  
Mrna Splicing ◽  
Large Set ◽  
Branch Points ◽  
Splice Sites ◽  
Prediction Tools ◽  
Mature Mrna ◽  
Bioinformatics Tools ◽  
The Impact

Abstract Branch points (BPs) map within short motifs upstream of acceptor splice sites (3’ss) and are essential for splicing of pre-mature mRNA. Several BP-dedicated bioinformatics tools, including HSF, SVM-BPfinder, BPP, Branchpointer, LaBranchoR and RNABPS were developed during the last decade. Here, we evaluated their capability to detect the position of BPs, and also to predict the impact on splicing of variants occurring upstream of 3’ss. We used a large set of constitutive and alternative human 3’ss collected from Ensembl (n = 264,787 3’ss) and from in-house RNAseq experiments (n = 51,986 3’ss). We also gathered an unprecedented collection of functional splicing data for 120 variants (62 unpublished) occurring in BP areas of disease-causing genes. Branchpointer showed the best performance to detect the relevant BPs upstream of constitutive and alternative 3’ss (99.48 % and 65.84 % accuracies, respectively). For variants occurring in a BP area, BPP emerged as having the best performance to predict effects on mRNA splicing, with an accuracy of 89.17 %. Our investigations revealed that Branchpointer was optimal to detect BPs upstream of 3’ss, and that BPP was most relevant to predict splicing alteration due to variants in the BP area.

scholarly journals Widespread separation of the polypyrimidine tract from 3’ AG by G tracts in association with alternative exons in metazoa and plants

2018 ◽  
Author(s):  
Hai Nguyen ◽  
Jiuyong Xie
Keyword(s):  
Alternative Splicing ◽  
Branch Point ◽  
Intron Retention ◽  
Regulatory Elements ◽  
Protein Isoforms ◽  
Model Organisms ◽  
Branch Points ◽  
Splice Sites ◽  
Polypyrimidine Tract ◽  
Whole Genome Analysis

SummaryAt the end of introns, the polypyrimidine tract (Py) is often close to the 3’ AG in a consensus (Y)20NCAGgt in humans. Interestingly, we have found that they could also be separated by purine-rich elements including G tracts in thousands of human genes. These regulatory elements between the Py and 3’AG (REPA) mainly regulate alternative 3’ splice sites (3’SS) and intron retention. Here we show their widespread distribution and special properties across kingdoms. The purine-rich 3’SS are found in up to about 60% of the introns among more than 1000 species/lineages by whole genome analysis, and up to 18% of these introns contain the REPA G tracts in about 2.4 millions of 3’SS in total. In particular, they are significantly enriched over their 3’SS and genome backgrounds in metazoa and plants, and highly associated with alternative splicing of genes in diverse functional clusters. They are also highly enriched (3-6 folds) in the canonical as well as aberrantly used 3’ splice sites in cancer patients carrying mutations of the branch point factor SF3B1 or the 3’AG binding factor U2AF35. Moreover, the REPA G tract-harbouring 3’SS have significantly reduced occurrences of branch point (BP) motifs between the −24 and −4 positions, in particular absent from the −7 - −5 positions in several model organisms examined. The more distant branch points are associated with increased occurrences of alternative splicing in human and zebrafish. The branch points, REPA G tracts and associated 3’SS motifs appear to have emerged differentially in a phylum- or species-specific way during evolution. Thus, there is widespread separation of the Py and 3’AG by REPA G tracts, likely evolved among different species or branches of life. This special 3’SS arrangement contributes to the generation of diverse transcript or protein isoforms in biological functions or diseases through alternative or aberrant splicing.

scholarly journals Assessment of branch point prediction tools to predict physiological branch points and their alteration by variants

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Raphaël Leman ◽  
Hélène Tubeuf ◽  
Sabine Raad ◽  
Isabelle Tournier ◽  
Céline Derambure ◽  
...  
Keyword(s):  
Branch Point ◽  
Branch Points ◽  
Prediction Tools

Enigmatic rhodopsin mutation creates an exceptionally strong splice acceptor site

2019 ◽  
Vol 29 (2) ◽  
pp. 295-304
Author(s):  
Lisa M Riedmayr ◽  
Sybille Böhm ◽  
Martin Biel ◽  
Elvir Becirovic
Keyword(s):  
Branch Point ◽  
Protein Level ◽  
Mrna Splicing ◽  
Hek293 Cells ◽  
Splice Acceptor Site ◽  
Mouse Retina ◽  
Acceptor Site ◽  
Splice Acceptor ◽  
The Core ◽  
The Impact

Abstract The c.620 T > G mutation in rhodopsin found in the first mapped autosomal dominant retinitis pigmentosa (adRP) locus is associated with severe, early-onset RP. Intriguingly, another mutation affecting the same nucleotide (c.620 T > A) is related to a mild, late-onset RP. Assuming that both mutations are missense mutations (Met207Arg and Met207Lys) hampering the ligand-binding pocket, previous work addressed how they might differentially impair rhodopsin function. Here, we investigated the impact of both mutations at the mRNA and protein level in HEK293 cells and in the mouse retina. We show that, in contrast to c.620 T > A, c.620 T > G is a splicing mutation, which generates an exceptionally strong splice acceptor site (SAS) resulting in a 90 bp in-frame deletion and protein mislocalization in vitro and in vivo. Moreover, we identified the core element underlying the c.620 T > G SAS strength. Finally, we demonstrate that the c.620 T > G SAS is very flexible in branch point choice, which might explain its remarkable performance. Based on these results, we suggest that (i) point mutations should be routinely tested for mRNA splicing to avoid dispensable analysis of mutations on protein level, which do not naturally exist. (ii) Puzzling disease courses of mutations in other genes might also correlate with their effects on mRNA splicing. (iii) Flexibility in branch point choice might be another factor influencing the SAS strength. (iv) The core splice element identified in this study could be useful for biotechnological applications requiring effective SAS.

scholarly journals Evaluating the Impact of Intensive Case Management for Severe Vocational Injuries on Work Incapacity and Costs

2021 ◽  
Author(s):  
Rolando Leiva ◽  
Lise Rochaix ◽  
Noémie Kiefer ◽  
Jean-Claude K. Dupont
Keyword(s):  
Treatment Group ◽  
Case Management ◽  
Sick Leave ◽  
Insurance Fund ◽  
Large Set ◽  
Intensive Case Management ◽  
Exact Matching ◽  
Case Management Program ◽  
The Impact ◽  
Permanent Work

AbstractPurpose This study investigates the impact of an intensive case management program on sick leave days, permanent work incapacity levels and treatment costs for severe vocational injuries set up by the French National Insurance Fund in five health insurance districts. Methods The method employed relies on a four-step matching procedure combining Coarsened Exact Matching and Propensity Score Matching, based on an original administrative dataset. Average Treatment effects on the Treated were estimated using a parametric model with a large set of covariates. Results After one-year follow-up, workers in the treatment group had higher sickness absence rates, with 22 extra days, and the program led to 2.7 (95% CI 2.3–3.1) times more diagnoses of permanent work incapacity in the treatment group. With an estimated yearly operational cost of 2,722 € per treated worker, the average total extra treatment cost was 4,569 € for treated workers, which corresponds to a cost increase of 29.2% for the insurance fund. Conclusions The higher costs found for the treatment group are mainly due to longer sick leave duration for the moderate severity group, implying higher cash transfers in the form of one-off indemnities. Even though workers in the treated group have more diagnoses of permanent work incapacity, the difference of severity between groups is small. Our results on longer sick leave duration are partly to be explained by interactions between the case managers and the occupational physicians that encouraged patients to stay longer off-work for better recovery, despite the higher costs that this represented for the insurance fund and the well-documented adverse side effects of longer periods off-work.

Abstract 313: Nonionic Acid is a Target Metabolite of Diabetic Microvasculopathy

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Yasuko K Bando ◽  
Haruya Kawase ◽  
Kazuyuki Nishimura ◽  
Akio Monji ◽  
Toyoaki Murohara
Keyword(s):  
Diabetic Microangiopathy ◽  
Tube Length ◽  
Nonanoic Acid ◽  
Branch Points ◽  
Metabolome Analysis ◽  
Whole Heart ◽  
The Impact ◽  
Type 2 Diabetic

Aim: The purpose of this study is to screen the target metabolites of diabetic microangiopathy in heart by use of whole heart metabolome analysis. Methods: Diet-induced type 2 diabetic mouse were divided into two groups; control and those treated with diabetic remedy GLP-1 receptor agonist Ex-4 for 5 weeks. Mice were euthanized and analyzed at the age of 16 week-old. Results: The capillary density of the T2DM was reduced as compared to those non-diabetic counterparts, which was restored by Ex4 treatment. Changes in angiogenic signals detected by immunoblotting analysis revealed that the phosphorylation levels of eNOS and AMPK were elevated by Ex-4, but those Akt remained unchanged. Tube formation assay revealed that Ex-4 increased tube length and branch points in HUVECs. Consistently with the trend that was observed in vivo experiment, AMPK and eNOS phosphorylation levels were enhanced by Ex4 without affecting Akt phosphorylation. To screen the candidate metabolites that is responsible for the diabetic microvasculopathy in GLP-1-dependent fashion, we performed metabolome analysis by using the whole heart of each mouse. The hierarchical cluster analysis revealed that nonanoic acid (NNA) was the only metabolite that increased in type 2 diabetic mice with concomitant decline by Ex-4 treatment. We next examined the impact of nonanoic acid on in vitro angiogenesis and found that NNA suppressed tube length and branch points in HUVECs in a dose-dependent fashion. Interestingly, NNA canceled eNOS and AMPK phosphorylation that was enhanced by Ex4. Conclusion: GLP-1 ameliorated diabetic microvasculopathy via the AMPK and eNOS axis. NNA is presumably one of the novel anti-angiogenic metabolites that causes diabetic microangiopathy.

scholarly journals Cryptic Transcription and Early Termination in the Control of Gene Expression

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Jessie Colin ◽  
Domenico Libri ◽  
Odil Porrua
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Regulatory Function ◽  
Large Set ◽  
Control Of Gene Expression ◽  
Alternative Transcription ◽  
Cryptic Transcription ◽  
Nuclear Exosome ◽  
The Impact

Recent studies on yeast transcriptome have revealed the presence of a large set of RNA polymerase II transcripts mapping to intergenic and antisense regions or overlapping canonical genes. Most of these ncRNAs (ncRNAs) are subject to termination by the Nrd1-dependent pathway and rapid degradation by the nuclear exosome and have been dubbed cryptic unstable transcripts (CUTs). CUTs are often considered as by-products of transcriptional noise, but in an increasing number of cases they play a central role in the control of gene expression. Regulatory mechanisms involving expression of a CUT are diverse and include attenuation, transcriptional interference, and alternative transcription start site choice. This review focuses on the impact of cryptic transcription on gene expression, describes the role of the Nrd1-complex as the main actor in preventing nonfunctional and potentially harmful transcription, and details a few systems where expression of a CUT has an essential regulatory function. We also summarize the most recent studies concerning other types of ncRNAs and their possible role in regulation.

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