scholarly journals Localized structural frustration for evaluating the impact of sequence variants

2013 ◽  
Vol 44 (21) ◽  
Author(s):  
Sushant Kumar ◽  
Declan Clarke ◽  
Mark Gerstein
Keyword(s):  
Protein Structures ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Local Interactions ◽  
Opposite Pattern ◽  
Single Nucleotide ◽  
Coding Regions ◽  
Local Perturbations ◽  
Large Numbers ◽  
The Impact

Abstract Population-scale sequencing is increasingly uncovering large numbers of rare single-nucleotide variants (SNVs) in coding regions of the genome. The rarity of these variants makes it challenging to evaluate their deleteriousness with conventional phenotype–genotype associations. Protein structures provide a way of addressing this challenge. Previous efforts have focused on globally quantifying the impact of SNVs on protein stability. However, local perturbations may severely impact protein functionality without strongly disrupting global stability (e.g. in relation to catalysis or allostery). Here, we describe a workflow in which localized frustration, quantifying unfavorable local interactions, is employed as a metric to investigate such effects. Using this workflow on the Protein Databank, we find that frustration produces many immediately intuitive results: for instance, disease-related SNVs create stronger changes in localized frustration than non-disease related variants, and rare SNVs tend to disrupt local interactions to a larger extent than common variants. Less obviously, we observe that somatic SNVs associated with oncogenes and tumor suppressor genes (TSGs) induce very different changes in frustration. In particular, those associated with TSGs change the frustration more in the core than the surface (by introducing loss-of-function events), whereas those associated with oncogenes manifest the opposite pattern, creating gain-of-function events.

scholarly journals Localized structural frustration for evaluating the impact of sequence variants

2016 ◽  
Author(s):  
Sushant Kumar ◽  
Declan Clarke ◽  
Mark Gerstein
Keyword(s):  
Global Stability ◽  
Rare Variants ◽  
Protein Structures ◽  
Genomic Variation ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Local Perturbations ◽  
Large Numbers ◽  
Human Genomes ◽  
The Impact

AbstractThe rapidly declining costs of sequencing human genomes and exomes are providing deeper insights into genomic variation than previously possible. Growing sequence datasets are uncovering large numbers of rare single-nucleotide variants (SNVs) in coding regions, many of which may even be unique to single individuals. The rarity of such variants makes it difficult to use conventional variant-phenotype associations as a means of predicting their potential impacts. As such, protein structures may help to provide the needed means for inferring otherwise difficult-to-discern rare SNV-phenotype associations. Previous efforts have sought to quantify the effects of SNVs on structures by evaluating their impacts on global stability. However, local perturbations can severely impact functionality (such as catalysis, allosteric regulation, interactions and specificity) without strongly disrupting global stability. Here, we describe a workflow in which localized frustration (which quantifies unfavorable residue-residue interactions) is employed as a metric to investigate such effects. We apply frustration to study the impacts of a large number of SNVs available throughout a number of next-generation sequencing datasets. Most of our observations are intuitively consistent: we observe that disease-associated SNVs have a strong proclivity to induce strong changes in localized frustration, and rare variants tend to disrupt local interactions to a larger extent than do common variants. Furthermore, we observe that somatic SNVs associated with oncogenes induce stronger perturbations at the surface, whereas those associated with tumor suppressor genes (TSGs) induce stronger perturbations in the interior. These findings are consistent with the notion that gain-of-function (for oncogenes) and loss-of-function events (for TSGs) may act through changes in regulatory interactions and basic functionality, respectively

scholarly journals Fido-SNP: the first webserver for scoring the impact of single nucleotide variants in the dog genome

2019 ◽  
Vol 47 (W1) ◽  
pp. W136-W141 ◽  
Author(s):  
Emidio Capriotti ◽  
Ludovica Montanucci ◽  
Giuseppe Profiti ◽  
Ivan Rossi ◽  
Diana Giannuzzi ◽  
...  
Keyword(s):  
Matthews Correlation Coefficient ◽  
Genomic Variation ◽  
Gradient Boosting ◽  
Binary Classifier ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Coding Regions ◽  
Variation Data ◽  
Boosting Algorithm ◽  
The Impact

Abstract As the amount of genomic variation data increases, tools that are able to score the functional impact of single nucleotide variants become more and more necessary. While there are several prediction servers available for interpreting the effects of variants in the human genome, only few have been developed for other species, and none were specifically designed for species of veterinary interest such as the dog. Here, we present Fido-SNP the first predictor able to discriminate between Pathogenic and Benign single-nucleotide variants in the dog genome. Fido-SNP is a binary classifier based on the Gradient Boosting algorithm. It is able to classify and score the impact of variants in both coding and non-coding regions based on sequence features within seconds. When validated on a previously unseen set of annotated variants from the OMIA database, Fido-SNP reaches 88% overall accuracy, 0.77 Matthews correlation coefficient and 0.91 Area Under the ROC Curve.

scholarly journals Prediction of genome-wide effects of single nucleotide variants on transcription factor binding

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sebastian Carrasco Pro ◽  
Katia Bulekova ◽  
Brian Gregor ◽  
Adam Labadorf ◽  
Juan Ignacio Fuxman Bass
Keyword(s):  
Binding Sites ◽  
Cancer Type ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Regulatory Regions ◽  
Genome Wide ◽  
Transcriptional Regulatory ◽  
Gene Regulatory ◽  
The Impact ◽  
The Relationship

Abstract Single nucleotide variants (SNVs) located in transcriptional regulatory regions can result in gene expression changes that lead to adaptive or detrimental phenotypic outcomes. Here, we predict gain or loss of binding sites for 741 transcription factors (TFs) across the human genome. We calculated ‘gainability’ and ‘disruptability’ scores for each TF that represent the likelihood of binding sites being created or disrupted, respectively. We found that functional cis-eQTL SNVs are more likely to alter TF binding sites than rare SNVs in the human population. In addition, we show that cancer somatic mutations have different effects on TF binding sites from different TF families on a cancer-type basis. Finally, we discuss the relationship between these results and cancer mutational signatures. Altogether, we provide a blueprint to study the impact of SNVs derived from genetic variation or disease association on TF binding to gene regulatory regions.

scholarly journals Re-evaluation of single nucleotide variants and identification of structural variants in a cohort of 45 sudden unexplained death cases

2021 ◽  
Author(s):  
Jacqueline Neubauer ◽  
Shouyu Wang ◽  
Giancarlo Russo ◽  
Cordula Haas
Keyword(s):  
Sudden Death ◽  
Cardiac Diseases ◽  
Structural Variants ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Sudden Unexplained Death ◽  
Unexplained Death ◽  
Pathogenic Variants ◽  
The Impact ◽  
Death Cases

AbstractSudden unexplained death (SUD) takes up a considerable part in overall sudden death cases, especially in adolescents and young adults. During the past decade, many channelopathy- and cardiomyopathy-associated single nucleotide variants (SNVs) have been identified in SUD studies by means of postmortem molecular autopsy, yet the number of cases that remain inconclusive is still high. Recent studies had suggested that structural variants (SVs) might play an important role in SUD, but there is no consensus on the impact of SVs on inherited cardiac diseases. In this study, we searched for potentially pathogenic SVs in 244 genes associated with cardiac diseases. Whole-exome sequencing and appropriate data analysis were performed in 45 SUD cases. Re-analysis of the exome data according to the current ACMG guidelines identified 14 pathogenic or likely pathogenic variants in 10 (22.2%) out of the 45 SUD cases, whereof 2 (4.4%) individuals had variants with likely functional effects in the channelopathy-associated genes SCN5A and TRDN and 1 (2.2%) individual in the cardiomyopathy-associated gene DTNA. In addition, 18 structural variants (SVs) were identified in 15 out of the 45 individuals. Two SVs with likely functional impairment were found in the coding regions of PDSS2 and TRPM4 in 2 SUD cases (4.4%). Both were identified as heterozygous deletions, which were confirmed by multiplex ligation-dependent probe amplification. In conclusion, our findings support that SVs could contribute to the pathology of the sudden death event in some of the cases and therefore should be investigated on a routine basis in suspected SUD cases.

scholarly journals CSIG-22. CANCER-ASSOCIATED MISSENSE SINGLE NUCLEOTIDE VARIANTS REGULATE THE STABILITY AND SUBCELLULAR LOCALIZATION OF NF2/MERLIN

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii32-ii32
Author(s):  
Charlotte Eaton ◽  
Paola Bisignano ◽  
David Raleigh
Keyword(s):  
Tumor Suppressor ◽  
Subcellular Localization ◽  
Function Analysis ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Ferm Domain ◽  
Binding Partners ◽  
Subcellular Compartments ◽  
The Stability ◽  
The Impact

Abstract BACKGROUND Alterations in the NF2 tumor suppressor gene lead to meningiomas and schwannomas, but the tumor suppressor functions of the NF2 gene product, Merlin, are incompletely understood. To address this problem, we performed a structure-function analysis of Merlin by expressing cancer-associated missense single-nucleotide variants (mSNVs) in primary cancer cells for biochemical and cell biology experiments. METHODS All NF2 mSNVs were assembled from cBioPortal and COSMIC, and modelled on the FERM, a-helical, and C-terminal domains of Merlin (PDB 4ZRJ) using comparative structure prediction on the Robetta server and visually inspected using Pymol. mSNV hotspots were defined from sliding windows with at least 10 mutations within 5 residues in either direction. mSNVs from hotspots in meningiomas, schwannomas, or both, were selected for in vitro mechanistic analyses using immunofluorescence and immunoblotting of whole cell, plasma membrane, cytoskeletal, cytoplasmic, nuclear, and chromatin subcellular fractions from M10G meningioma cells and HEI-193 schwannoma cells. RESULTS We identified the following cancer-associated hotspot mSNVs in NF2, which were over-expressed for mechanistic studies: L46R, S156N, W191R, A211D, V219M, R418C and R462K. Endogenous Merlin was detected in all subcellular compartments, but was enriched in the nucleus. L46R and A211D mapped to hydrophobic pockets in the FERM domain, destabilized Merlin, and excluded Merlin from all subcellular compartments except the cytoskeleton. S156N, W191R and V219M also mapped to the FERM domain, but did not affect Merlin stability, and V219M attenuated chromatin localization, suggesting this motif may be involved in binding events that regulate subcellular localization. R418C and R463K mapped to the a-helical domain, but only R418C destabilized Merlin. CONCLUSION Our results suggest that cancer-associated mSNVs inactive the tumor suppressor functions of NF2 by altering the stability, subcellular localization, or binding partners of Merlin. Further work is required to identify and understand the impact of binding partners and subcellular localization on Merlin function.

scholarly journals RegSNPs-intron: a computational framework for predicting pathogenic impact of intronic single nucleotide variants

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Hai Lin ◽  
Katherine A. Hargreaves ◽  
Rudong Li ◽  
Jill L. Reiter ◽  
Yue Wang ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Evolutionary Conservation ◽  
Random Forest Classifier ◽  
Training Data ◽  
Reporter Assay ◽  
Single Nucleotide Variants ◽  
Excellent Performance ◽  
Computational Framework ◽  
Single Nucleotide ◽  
The Impact

AbstractSingle nucleotide variants (SNVs) in intronic regions have yet to be systematically investigated for their disease-causing potential. Using known pathogenic and neutral intronic SNVs (iSNVs) as training data, we develop the RegSNPs-intron algorithm based on a random forest classifier that integrates RNA splicing, protein structure, and evolutionary conservation features. RegSNPs-intron showed excellent performance in evaluating the pathogenic impacts of iSNVs. Using a high-throughput functional reporter assay called ASSET-seq (ASsay for Splicing using ExonTrap and sequencing), we evaluate the impact of RegSNPs-intron predictions on splicing outcome. Together, RegSNPs-intron and ASSET-seq enable effective prioritization of iSNVs for disease pathogenesis.

scholarly journals Recent Advances in Understanding the Genetic Architecture of Autism

2020 ◽  
Vol 21 (1) ◽  
pp. 289-304 ◽  
Author(s):  
Caroline M. Dias ◽  
Christopher A. Walsh
Keyword(s):  
Genetic Architecture ◽  
De Novo ◽  
Clinical Care ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Recent Advances ◽  
Insight Into

Recent advances in understanding the genetic architecture of autism spectrum disorder have allowed for unprecedented insight into its biological underpinnings. New studies have elucidated the contributions of a variety of forms of genetic variation to autism susceptibility. While the roles of de novo copy number variants and single-nucleotide variants—causing loss-of-function or missense changes—have been increasingly recognized and refined, mosaic single-nucleotide variants have been implicated more recently in some cases. Moreover, inherited variants (including common variants) and, more recently, rare recessive inherited variants have come into greater focus. Finally, noncoding variants—both inherited and de novo—have been implicated in the last few years. This work has revealed a convergence of diverse genetic drivers on common biological pathways and has highlighted the ongoing importance of increasing sample size and experimental innovation. Continuing to synthesize these genetic findings with functional and phenotypic evidence and translating these discoveries to clinical care remain considerable challenges for the field.

Single Nucleotide Variations In Spectrin-1β Accentuate The Red Blood Cell Storage Lesion

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3422-3422
Author(s):  
Melinda M Dean ◽  
Katrina Kildey ◽  
Thu V Tran ◽  
Kelly Rooks ◽  
Shoma Baidya ◽  
...  
Keyword(s):  
Time Course ◽  
Conflicts Of Interest ◽  
Flow Cytometric Analysis ◽  
Osmotic Fragility ◽  
Blood Component ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Storage Lesion ◽  
Background Strain ◽  
The Impact

Abstract Introduction During routine storage packed red blood cells (PRBC) undergo biochemical and biophysical changes collectively referred to as the “RBC storage lesion”. Donor-to-donor variability in the severity of the storage lesion has been reported. The extent to which donor-associated differences in blood component storage affect blood product quality and post-transfusion outcome remains unknown. Murine models with single nucleotide variants (SNV) in gene encoding spectrin-1β were used to investigate the impact of mutations on the RBC storage lesion. Methods Two murine lineages with N-ethyl-N-nitrosourea (ENU) generated single SNV in Spnb1, encoding spectrin-1β (Table 1), were selected from the Australian Phenomics Facility library (http://databases.apf.edu.au/mutations). Using genetic selection, homozygous (HOM), heterozygous (HET) and unaffected (WT) mice from each strain were generated (C57BL/6 background strain). Murine blood was leucoreduced, prepared in SAGM (0.4 HCT) and stored at 4°C for time course assessment of RBC characteristics. At day (D), D2, D7, D14 and D21 of storage, RBC integrity and evidence of storage-related changes were investigated using RBC osmotic fragility and flow cytometric analysis of CD44, CD47, TER119 and phosphatidylserine (PS). Data were generated from analysis of blood from Spnb1 (pedigree spectrin-1β a) homozygous (HOM, n=3), heterozygous (HET, n=3) and unaffected (WT, n=2 ); Spnb1 (pedigree spectrin-1β b) HOM (n=4), HET( n=4); C57BL/6 (n=4). The Mann-Whitney Test and ANOVA were utilised for statistical analyses (95% CI). Results At D2 of storage SNV in Spnb1 did not alter RBC characteristics, with all mice studied demonstrating a similar resistance to osmotic lysis and levels of CD44, CD47, TER119 and PS. By D7 of storage, clear pedigree-related differences in RBC characteristics were evident. At D7, RBC from spectrin-1β(a) HOM mice had significantly increased osmotic fragility and exposure of PS as well as significantly reduced CD44 and TER119 expression compared to unaffected siblings and background strain. Of note, these changes were not evident in the spectrin-1β(b) HOM mice at D7. For both strains at D7, heterozygous SNV did not exhibit altered storage parameters. By D14 both HOM and HET spectrin-1β(a) mice demonstrated a phenotype consistent with an exacerbated RBC storage lesion, characterised by significantly increased osmotic fragility and exposure of PS, and reduced CD44 and CD47 compared to background strain. At D14 there was also evidence of exacerbation of the storage lesion in stored RBC from HOM spectrin-1β(b) mice (significantly increased PS), though this was not to the extent observed in the spectrin-1β(a) mice. By D21 all murine RBC were substantially degraded under these storage conditions. Conclusions SNV in Spnb1,encoding RBC structural protein spectrin-1β, resulted in both early onset and exacerbation of the RBC storage lesion. Further, the degree of storage lesion and the point at which RBC degradation was observed was not only dependent on the homozygous or heterozygous status, but the mutation itself. These data demonstrate that minor genetic variation in genes encoding important RBC proteins contribute to donor related differences in PRBC storage. Disclosures: No relevant conflicts of interest to declare.

scholarly journals SimRVSequences: an R package to simulate genetic sequence data for pedigrees

2019 ◽  
Vol 36 (7) ◽  
pp. 2295-2297
Author(s):  
Christina Nieuwoudt ◽  
Angela Brooks-Wilson ◽  
Jinko Graham
Keyword(s):  
Sequence Data ◽  
R Package ◽  
Supplementary Information ◽  
Supplementary Data ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Genetic Sequence ◽  
Large Numbers

Abstract Summary We present the R package SimRVSequences to simulate sequence data for pedigrees. SimRVSequences allows for simulations of large numbers of single-nucleotide variants (SNVs) and scales well with increasing numbers of pedigrees. Users provide a sample of pedigrees and SNV data from a sample of unrelated individuals. Availability and implementation SimRVSequences is publicly-available on CRAN https://cran.r-project.org/web/packages/SimRVSequences/. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Estimated prevalence of mucopolysaccharidoses from population-based exomes and genomes

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Pâmella Borges ◽  
Gabriela Pasqualim ◽  
Roberto Giugliani ◽  
Filippo Vairo ◽  
Ursula Matte
Keyword(s):  
In Silico ◽  
Splice Variants ◽  
Population Based ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Prevalence Studies ◽  
Coding Regions ◽  
Exome Aggregation Consortium ◽  
Different Types ◽  
Mps I

Abstract Background In this study, the prevalence of different types of mucopolysaccharidoses (MPS) was estimated based on data from the exome aggregation consortium (ExAC) and the genome aggregation database (gnomAD). The population-based allele frequencies were used to identify potential disease-causing variants on each gene related to MPS I to IX (except MPS II). Methods We evaluated the canonical transcripts and excluded homozygous, intronic, 3′, and 5′ UTR variants. Frameshift and in-frame insertions and deletions were evaluated using the SIFT Indel tool. Splice variants were evaluated using SpliceAI and Human Splice Finder 3.0 (HSF). Loss-of-function single nucleotide variants in coding regions were classified as potentially pathogenic, while synonymous variants outside the exon–intron boundaries were deemed non-pathogenic. Missense variants were evaluated by five in silico prediction tools, and only those predicted to be damaging by at least three different algorithms were considered disease-causing. Results The combined frequencies of selected variants (ranged from 127 in GNS to 259 in IDUA) were used to calculate prevalence based on Hardy–Weinberg's equilibrium. The maximum estimated prevalence ranged from 0.46 per 100,000 for MPSIIID to 7.1 per 100,000 for MPS I. Overall, the estimated prevalence of all types of MPS was higher than what has been published in the literature. This difference may be due to misdiagnoses and/or underdiagnoses, especially of the attenuated forms of MPS. However, overestimation of the number of disease-causing variants by in silico predictors cannot be ruled out. Even so, the disease prevalences are similar to those reported in diagnosis-based prevalence studies. Conclusion We report on an approach to estimate the prevalence of different types of MPS based on publicly available population-based genomic data, which may help health systems to be better prepared to deal with these conditions and provide support to initiatives on diagnosis and management of MPS.

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