scholarly journals In Silico Investigation of the Functional Impact of SCN10A Mutations in Human Atrial Cells

2018 ◽  
Author(s):  
Inas A Al Nemi ◽  
Haibo Ni ◽  
Henggui Zhang
Keyword(s):  
In Silico ◽  
Functional Impact ◽  
Atrial Cells

scholarly journals Computational modelling of trans-synaptic nanocolumns, a modulator of synaptic transmission

2021 ◽  
Author(s):  
Xiaoting Li ◽  
Gabriel Hémond ◽  
Antoine G. Godin ◽  
Nicolas Doyon
Keyword(s):  
Synaptic Transmission ◽  
In Silico ◽  
Neurotransmitter Release ◽  
Computer Modelling ◽  
Computational Modelling ◽  
Synaptic Current ◽  
Functional Impact ◽  
Postsynaptic Receptors ◽  
In Silico Model ◽  
Presynaptic Vesicle

AbstractNanocolumns are trans-synaptic structures which align presynaptic vesicles release sites and postsynaptic receptors. However, how these nano structures shape synaptic signaling remains little understood. Given the difficulty to probe submicroscopic structures experimentally, computer modelling is a usefull approach to investigate the possible functional impacts of nanocolumns. In our in silico model, as has been experimentally observed, a nanocolumn is characterized by a tight distribution of postsynaptic receptors aligned with the presynaptic vesicle release site and by the presence of trans-synaptic molecules which can modulate neurotransmitter diffusion. We found that nanocolumns can play an important role in reinforcing synaptic current mostly when the presynaptic vesicle contains a small number of neurotransmitters. We also show that synapses with and without nanocolumns could have differentiated responses to spontaneous or evoked events. Our work provides a new methodology to investigate in silico the role of the submicroscopic organization of the synapse.Author summaryNeurotransmitter release, diffusion, and binding to postsynaptic receptors are key steps in synaptic transmission. However, the submicroscopic arrangement of receptors and presynaptic sites of neurotransmitter release remains little investigated. Experimental observations revealed the presence of trans-synaptic nanocolumns which span both the pre and post synaptic sites and fine tune the position of the post synaptic receptors. The functional impact of these nanocolumns (i.e. their influence on synaptic current) is both little understood and difficult to investigate experimentally. Here we construct a novel in silico model to investigate the functional impact of nanocolumns and show that they could play a functional role in reinforcing weak synapses.

scholarly journals Identification of SNPs in rice GPAT genes and in silico analysis of their functional impact on GPAT proteins

2021 ◽  
Vol 49 (3) ◽  
pp. 12346
Author(s):  
Imran SAFDER ◽  
Gaoneng SHAO ◽  
Zhonghua SHENG ◽  
Peisong HU ◽  
Shaoqing TANG
Keyword(s):  
In Silico ◽  
Association Studies ◽  
Rice Genome ◽  
In Silico Analysis ◽  
Gene Families ◽  
Coding Region ◽  
Rice Varieties ◽  
Functional Impact ◽  
Functional Snps ◽  
Silico Analysis

SNPs are the most common nucleotide variations in the genome. Functional SNPs in the coding region, known as nonsynonymous SNPs (nsSNPs), change amino acid residues and affect protein function. Identifying functional SNPs is an uphill task as it is difficult to correlate between variation and phenotypes in association studies. Computational in silico analysis provides an opportunity to understand the SNPs functional impact to proteins and facilitate experimental approaches in understanding the relationship between the phenotype and genotype. Advancement in sequencing technologies contributed to sequencing thousands of genomes. As a result, many public databases have been designed incorporating this sequenced data to explore nucleotide variations. In this study, we explored functional SNPs in the rice GPAT family (as a model plant gene family), using 3000 Rice Genome Sequencing Project data. We identified 1056 SNPs, among hundred rice varieties in 26 GPAT genes, and filtered 98 nsSNPs. We further investigated the structural and functional impact of these nsSNPs using various computational tools and shortlisted 13 SNPs having high damaging effects on protein structure. We found that rice GPAT genes can be influenced by nsSNPs and they might have a major effect on regulation and function of GPAT genes. This information will be useful to understand the possible relationships between genetic mutation and phenotypic variation, and their functional implication on rice GPAT proteins. The study will also provide a computational pathway to identify SNPs in other rice gene families.

scholarly journals Prediction of the functional impact of missense variants in BRCA1 and BRCA2 with BRCA-ML

2019 ◽  
Author(s):  
Steven N. Hart ◽  
Eric C. Polley ◽  
Hermella Shimelis ◽  
Siddhartha Yadav ◽  
Fergus J. Couch
Keyword(s):  
Machine Learning ◽  
In Silico ◽  
Accurate Method ◽  
Machine Learning Algorithms ◽  
Data Sources ◽  
Brca1 And Brca2 ◽  
Functional Impact ◽  
Missense Variants ◽  
Functional Assays ◽  
Uncertain Significance

AbstractIn silico predictions of missense variants is an important consideration when interpreting variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes. We trained and evaluated hundreds of machine learning algorithms based on results from validated functional assays to better predict missense variants in these genes as damaging or neutral. This new optimal “BRCA-ML” model yielded a substantially more accurate method than current algorithms for interpreting the functional impact of variants in these genes, making BRCA-ML a valuable addition to data sources for VUS classification.

scholarly journals Rare Missense Functional Variants at COL4A1 and COL4A2 in Sporadic Intracerebral Hemorrhage

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012227
Author(s):  
Jaeyoon Chung ◽  
Graham Hamilton ◽  
Minsup Kim ◽  
Sandro Marini ◽  
Bailey Montgomery ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
In Silico ◽  
Minor Allele ◽  
Sequencing Data ◽  
Functional Impact ◽  
Impact Prediction ◽  
Missense Variants ◽  
Association Testing ◽  
Rare Variant Analysis ◽  
Functional Variants

ObjectiveTo test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH.MethodsWe performed sequencing across 559Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in US-based and 1,492 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling.ResultsWe identified 107 rare nonsynonymous variants in sporadic ICH, of which two missense variants, rs138269346 (COL4A1I110T) and rs201716258 (COL4A2H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the US-based cohort. The minor allele of rs201716258 was also present in Scottish ICH patients, and rs138269346 was observed in two ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with non-lobar ICH risk (P=0.05), but not with lobar ICH (P=0.08), while associations between rs201716258 and ICH subtypes were non-significant (P>0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in EUR), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen).ConclusionsWe identified rare missense variants in COL4A1/A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up.

scholarly journals Differential effects on neurodevelopment of FTO variants in obesity and bipolar disorder suggested by in silico prediction of functional impact: An analysis in Mexican population

2019 ◽  
Vol 9 (6) ◽  
Author(s):  
Erasmo Saucedo‐Uribe ◽  
Alma Delia Genis‐Mendoza ◽  
Adriana Díaz‐Anzaldúa ◽  
José Jaime Martínez‐Magaña ◽  
Carlos Alfonso Tovilla‐Zarate ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
In Silico ◽  
Mexican Population ◽  
In Silico Prediction ◽  
Functional Impact ◽  
Differential Effects
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