Insights Into Functional and Structural Impacts of nsSNPs in XPA-DNA Repairing Gene

Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation in people. SNPs are valuable resource for exploring the genetic basis of disease. The XPA gene provides a way to produce a protein used to repair damaged DNA. This study used the computational methods to classify SNPs and estimate their probability of being neutral or deleterious. The purpose of this analysis is to predict the effect of nsSNPs on the structure and function of XPA proteins. Data was collected from the NCBI hosted dbSNP. The authors examined the pathogenic effect of 194 nsSNPs in the XPA gene with computational tools. Four nsSNPs (C126S, C126W, R158S, and R227Q) those potentially effect on structure and function of the XPA protein were identified with combination of SIFT, PolyPhen, Provean, PHD-SNP, I-Mutant, ConSurf server and Project HOPE. This is the first comprehensive analysis in which XPA gene variants studied using in silico methods and this research able to gain further insight into XPA protein variants and function.

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Investigating Variations/SNPs in AUH Gene Causing 3-Methylglutaconic Aciduria, Type I

International Journal of Applied Research in Bioinformatics ◽

10.4018/ijarb.2022010104 ◽

2022 ◽

Vol 12 (1) ◽

pp. 1-13

Author(s):

Malik Muhammad Sajjad ◽

Sarah Bukhari ◽

Omer Aziz

Keyword(s):

Structure And Function ◽

Genomic Variation ◽

Type I ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

A Genome ◽

Project Hope ◽

And Function ◽

The Impact ◽

Methylglutaconic Aciduria

A Single nucleotide polymorphisms (SNPs) is a source variation in a genome. The AUH gene gives guidance about how to generate an enzyme named 3-methylglutaconyl-CoA hydratase. Mutations in AUH gene leads to 3-Methylglutaconic aciduria type I disease. The authors used multiple bioinformatics tools SIFT, Provean, PolyPhen, PHD-SNP, I-Mutant, ConSurf server and Project HOPE to isolate missense SNPs that should be deleterious to the structure and function of the AUH protein. This research aims to analyze the impact of missense SNPs on the structure and function of AUH protein. There have been a total of 259 Missense SNPs obtained, of which 13 mutations were identified as deleterious to the structure and function of the AUH protein. This is the first study in relation to AUH gene missense SNPs where most damaging SNPs associated with the AUH gene were examined using computational analysis. This research could be useful in designing specific medicines for treatment of genomic variation diseases.

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Structural Characterization of Carbonic Anhydrase VIII and Effects of Missense Single Nucleotide Variations to Protein Structure and Function

International Journal of Molecular Sciences ◽

10.3390/ijms21082764 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2764

Author(s):

Taremekedzwa Allan Sanyanga ◽

Özlem Tastan Bishop

Keyword(s):

Carbonic Anhydrase ◽

Binding Site ◽

Cross Correlation ◽

Structure And Function ◽

The Body ◽

Conformational Sampling ◽

Nucleotide Polymorphisms ◽

Ip3 Receptor ◽

Single Nucleotide ◽

And Function

Human carbonic anhydrase 8 (CA-VIII) is an acatalytic isoform of the α -CA family. Though the protein cannot hydrate CO2, CA-VIII is essential for calcium (Ca2+) homeostasis within the body, and achieves this by allosterically inhibiting the binding of inositol 1,4,5-triphosphate (IP3) to the IP3 receptor type 1 (ITPR1) protein. However, the mechanism of interaction of CA-VIII to ITPR1 is not well understood. In addition, functional defects to CA-VIII due to non-synonymous single nucleotide polymorphisms (nsSNVs) result in Ca2+ dysregulation and the development of the phenotypes such as cerebellar ataxia, mental retardation and disequilibrium syndrome 3 (CAMRQ3). The pathogenesis of CAMRQ3 is also not well understood. The structure and function of CA-VIII was characterised, and pathogenesis of CAMRQ3 investigated. Structural and functional characterisation of CA-VIII was conducted through SiteMap and CPORT to identify potential binding site residues. The effects of four pathogenic nsSNVs, S100A, S100P, G162R and R237Q, and two benign S100L and E109D variants on CA-VIII structure and function was then investigated using molecular dynamics (MD) simulations, dynamic cross correlation (DCC) and dynamic residue network (DRN) analysis. SiteMap and CPORT analyses identified 38 unique CA-VIII residues that could potentially bind to ITPR1. MD analysis revealed less conformational sampling within the variant proteins and highlighted potential increases to variant protein rigidity. Dynamic cross correlation (DCC) showed that wild-type (WT) protein residue motion is predominately anti-correlated, with variant proteins showing no correlation to greater residue correlation. DRN revealed variant-associated increases to the accessibility of the N-terminal binding site residues, which could have implications for associations with ITPR1, and further highlighted differences to the mechanism of benign and pathogenic variants. SNV presence is associated with a reduction to the usage of Trp37 in all variants, which has implications for CA-VIII stability. The differences to variant mechanisms can be further investigated to understand pathogenesis of CAMRQ3, enhancing precision medicine-related studies into CA-VIII.

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Comprehensive Analysis of HEXB Protein Reveal Forty Two Novel nsSNPs That May Lead to Sandhoff disease (SD) Using Bioinformatics

10.1101/853077 ◽

2019 ◽

Author(s):

Tebyan A. Abdelhameed ◽

Mosab M. Gasmelseed ◽

Mujahed I. Mustafa ◽

Dina N. Abdelrahman ◽

Fatima A. Abdelrhman ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Sandhoff Disease ◽

Structure And Function ◽

Beta Subunit ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Bioinformatics Tools ◽

Hexosaminidase A ◽

And Function ◽

Hexb Gene

ABSTRACTBackgroundSingle Nucleotide Polymorphisms (SNPs) in the HEXB gene are associated with a neurodegenerative disorder called Sandhoff disease (SD) (GM2 gangliosidosis-O variant). This study aimed to predict the possible pathogenic SNPs of this gene and their impact on the protein using different bioinformatics tools.MethodsSNPs retrieved from the NCBI database were analyzed using several bioinformatics tools. The different algorithms collectively predicted the effect of single nucleotide substitution on both structure and function of beta subunit beta subunit of both hexosaminidase A and hexosaminidase B proteins.ResultsForty nine mutations were found to be extremely damaging to the structure and function of the HEXB gene protein.ConclusionAccording to this study, forty two novel nsSNP in HEXB are predicted to have possible role in Sandhoff disease using different bioinformatics tools, beside two SNPs found to have effect on miRNAs binding site affecting expression of HEXB gene. Our findings may assist in genetic study and diagnosis of Sandhoff disease.

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Identification of novel key biomarkers in Simpson-Golabi-Behmel Syndrome: Evidence from bioinformatics analysis

10.1101/608927 ◽

2019 ◽

Author(s):

Mujahed I. Mustafa ◽

Abdelrahman H. Abdelmoneim ◽

Nafisa M. Elfadol ◽

Naseem S. Murshed ◽

Zainab O. Mohammed ◽

...

Keyword(s):

Structural Model ◽

3D Structure ◽

Data Bank ◽

Missense Mutations ◽

Single Nucleotide ◽

Overgrowth Syndrome ◽

Project Hope ◽

Single Nucleotide Polymorphism Database ◽

And Function ◽

Insight Into

AbstractBackgroundThe Simpson-Golabi-Behmel Syndrome (SGBS) or overgrowth Syndrome is a rare inherited X-linked condition characterized by pre- and postnatal overgrowth. The aim of the present study is to identify functional non-synonymous SNPs of GPC3 gene using various in silico approaches. These SNPs are supposed to have a direct effect on protein stability through conformation changes.Material and methodsThe SNPs were retrieved from the Single Nucleotide Polymorphism database (dbSNP) and further used to investigate a damaging effect using SIFT, PolyPhen, PROVEAN, SNAP2, SNPs&GO, PHD-SNP and P-mut, While we used I-mutant and MUPro to study the effect of SNPs on GPC3 protein structure. The 3D structure of human GPC3 protein is not available in the Protein Data Bank, so we used RaptorX to generate a 3D structural model for wild-type GPC3 to visualize the amino acids changes by UCSF Chimera. For biophysical validation we used project HOPE. Lastly we run conservational analysis by BioEdit and Consurf web server respectively.Resultsour results revealed three novel missense mutations (rs1460413167, rs1295603457 and rs757475450) that are found to be the most deleterious which effect on the GPC3 structure and function.ConclusionThis present study could provide a novel insight into the molecular basis of overgrowth Syndrome.

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Prediction of Deleterious Single Nucleotide Polymorphisms in Human p53 Gene

10.1101/408476 ◽

2018 ◽

Author(s):

Saruar Alam ◽

Mohammad Sayem ◽

Md. Kamrul Hasan ◽

Zinat Sharmin ◽

Mahmud Arif Pavel ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Deleterious Effect ◽

P53 Gene ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Computational Tools ◽

Genome Wide ◽

Project Hope ◽

Functional Part ◽

Different Populations

AbstractWith a variety of accessible Single Nucleotide Polymorphisms (SNPs) data on human p53 gene, this investigation is intended to deal with detrimental SNPs in p53 gene by executing diverse valid computational tools, including Filter, SIFT, PredictSNP, Fathmm, UTRScan, ConSurf, Phyre, Tm-Adjust, I-Mutant, Task Seek after practical and basic appraisal, dissolvable openness, atomic progression, and analysing the energy minimization. Of 581 p53 SNPs, 420 SNPs are found to be missense or non-synonymous and 435 SNPs are in the 3 prime UTR and 112 SNPs are of every 5 prime UTR from which 16 non synonymous SNPs (nsSNPs) as non-tolerable while PredictSNP package predicted 14 (taking consideration SNP colored green by two or more than 2 analyses is neutral). By concentrating on six bioinformatics tools of various dimensions a combined output is generated where 14 nsSNPs are prone to exert a deleterious effect. By using diverse SNP analysing tools we have found 5 missense SNPs in the 3 crucial amino acids position in the DNA binding domain. The underlying discoveries are fortified by I-Mutant and Project HOPE. The ExPASy-PROSITE tools characterized whether the mutations located in the functional part of the protein or not. This study provides a decisive outcome concluding the accessible SNPs information by recognizing the five harming nsSNPs: rs28934573 (S241F), rs11540652 (R248Q), rs121913342 (R248W), rs121913343 (R273C) and rs28934576 (R273H). The findings of this investigation recognize the detrimental nsSNPs which enhance the danger of various kinds of oncogenesis in patients of different populations’ in genome-wide studies (GWS).

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In-Silico Methods for Investigating the Effect of Single Nucleotide Polymorphisms on the Structure and Function of Proteins: A Review

10.20944/preprints201912.0131.v1 ◽

2019 ◽

Author(s):

Ebenezer Asiedu

Keyword(s):

Single Nucleotide Polymorphisms ◽

In Silico ◽

Drug Response ◽

Fast Track ◽

Structure And Function ◽

Nucleotide Polymorphisms ◽

Laboratory Studies ◽

Single Nucleotide ◽

And Function ◽

In Silico Methods

Single nucleotide polymorphisms (SNP) are associated with diseases and drug response variabilities in humans. Elucidating the damaging and disease-associated SNPs using wet-laboratory approaches can be challenging and resource-demanding due to the large number of SNPs in the human genome. Due to the growth in the field of computational biology and bioinformatics, algorithms have been developed to help screen and filter out the most deleterious SNPs that are worth considering for wet-laboratory studies. Here we review the existing in-silico based methods used to predict and characterize the effects of SNPs on protein structure and function. This cutting-edge approach will facilitate the search for novel therapeutics, help understand the etiology of diseases and fast-track the personalized medicine agenda.

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Comprehensive Characterization of the Coding and Non-coding Single Nucleotide Polymorphisms in the Tumor Protein p63 (TP63) Gene Using In Silico Tools.

10.21203/rs.3.rs-265434/v1 ◽

2021 ◽

Author(s):

Shamima Akter ◽

Shafaat Hossain ◽

Md. Ismail Hosen ◽

Hossain Uddin Shekhar

Keyword(s):

Hydrogen Bonds ◽

Single Nucleotide Polymorphisms ◽

Genome Wide Association Study ◽

Urinary Bladder Cancer ◽

Structure And Function ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

And Function ◽

Structural Significance

Abstract Single Nucleotide Polymorphisms (SNPs) help to understand the phenotypic variations in humans. Numerous studies have examined the association of SNPs with various complex diseases. Researchers have identified the association of SNPs of genes through Genome-wide association study (GWAS). A number of GWAS have identified a loci located in the TP63 gene to be significantly associated with the risk of urinary bladder cancer. However, there is not any study characterizing the SNPs located at the TP63 gene for their functional and structural significance. Hence, the study aimed to comprehensively characterize SNPs in the human TP63 gene for their functional and structural significance. We investigated and evaluated the genomic variations affecting the expression, structure, and function of the TP63 protein. The study systematically retrieved nsSNPs information for the TP63 gene from the dbSNP database. We screened and analyzed both nsSNPs and non-coding SNPs in TP63 protein using a wide variety of computational tools to find the risk of pathogenicity. A total of 17 nsSNPs were identified using the 13 bioinformatics tools (i.e., SIFT, CADD, PROVEAN, PolyPhen2, PANTHER, PhD-SNP, SNP&GO, I-Mutant 2.0, ClinVar, Mutpred2, ConSurf, HOPE, and Mutation 3D) along with domain analysis. These pathogenic mutations cause a decrease in protein stability according to I-Mutant2.0. HOPE predicted 17 SNPs to have significant effect on TP63 protein structure and function. 12 nsSNPs were found in highly conserved position in TP63 inferring the damaging effect on the structure and function of the protein. Swiss PDB Viewer showed loss of hydrogen bonds and increased energy due to the SNPs. Molecular docking showed the reduction of the binding affinity of proteins for DNA and loss of hydrogen bonds. Six non-coding SNPs were found in miRNA binding sites in gene showing the effect on protein regulation using PolymiRTS and five non-coding SNPs were identified in single tissue expression quantitative trait loci (eQTL) in lung tissue, heart tissue (LV), and cerebral hemisphere (Brain) according to GTEx portal. The characterization of nsSNPs and non-coding SNPs will support researchers to focus on TP63 gene loci and ascertain their association with certain diseases.

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Structure and function of neural networks in the retina

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100102213 ◽

1988 ◽

Vol 46 ◽

pp. 26-27

Author(s):

Peter Sterling

Keyword(s):

Ganglion Cells ◽

Three Dimensional ◽

Structure And Function ◽

Synaptic Connections ◽

Visual Axis ◽

One Dimensional ◽

Cat Retina ◽

Ultrathin Sections ◽

And Function ◽

Insight Into

The synaptic connections in cat retina that link photoreceptors to ganglion cells have been analyzed quantitatively. Our approach has been to prepare serial, ultrathin sections and photograph en montage at low magnification (˜2000X) in the electron microscope. Six series, 100-300 sections long, have been prepared over the last decade. They derive from different cats but always from the same region of retina, about one degree from the center of the visual axis. The material has been analyzed by reconstructing adjacent neurons in each array and then identifying systematically the synaptic connections between arrays. Most reconstructions were done manually by tracing the outlines of processes in successive sections onto acetate sheets aligned on a cartoonist's jig. The tracings were then digitized, stacked by computer, and printed with the hidden lines removed. The results have provided rather than the usual one-dimensional account of pathways, a three-dimensional account of circuits. From this has emerged insight into the functional architecture.

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Computational Approaches to Predict the Non-canonical DNAs

Current Bioinformatics ◽

10.2174/1574893614666190126143438 ◽

2019 ◽

Vol 14 (6) ◽

pp. 470-479 ◽

Cited By ~ 3

Author(s):

Nazia Parveen ◽

Amen Shamim ◽

Seunghee Cho ◽

Kyeong Kyu Kim

Keyword(s):

Computational Methods ◽

Genetic Instability ◽

Computational Prediction ◽

Structure And Function ◽

Sequence Motifs ◽

Computational Approaches ◽

Functional Roles ◽

And Function ◽

Genetic Events ◽

Insight Into

Background: Although most nucleotides in the genome form canonical double-stranded B-DNA, many repeated sequences transiently present as non-canonical conformations (non-B DNA) such as triplexes, quadruplexes, Z-DNA, cruciforms, and slipped/hairpins. Those noncanonical DNAs (ncDNAs) are not only associated with many genetic events such as replication, transcription, and recombination, but are also related to the genetic instability that results in the predisposition to disease. Due to the crucial roles of ncDNAs in cellular and genetic functions, various computational methods have been implemented to predict sequence motifs that generate ncDNA. Objective: Here, we review strategies for the identification of ncDNA motifs across the whole genome, which is necessary for further understanding and investigation of the structure and function of ncDNAs. Conclusion: There is a great demand for computational prediction of non-canonical DNAs that play key functional roles in gene expression and genome biology. In this study, we review the currently available computational methods for predicting the non-canonical DNAs in the genome. Current studies not only provide an insight into the computational methods for predicting the secondary structures of DNA but also increase our understanding of the roles of non-canonical DNA in the genome.

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Interactions of COMT and ALDH2 Genetic Polymorphisms on Symptoms of Parkinson’s Disease

Brain Sciences ◽

10.3390/brainsci11030361 ◽

2021 ◽

Vol 11 (3) ◽

pp. 361

Author(s):

Rwei-Ling Yu ◽

Shao-Ching Tu ◽

Ruey-Meei Wu ◽

Pei-An Lu ◽

Chun-Hsiang Tan

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Detrimental Effect ◽

Personal Hygiene ◽

Nucleotide Polymorphisms ◽

Monoamine Neurotransmitters ◽

Single Nucleotide ◽

Detrimental Impact ◽

Reduced Activity ◽

Insight Into

(1) Background: Monoamine neurotransmitters play essential roles in the normal functioning of our nervous system. However, the metabolism of monoamine neurotransmitters is accompanied by the production of neurotoxic metabolites, and inefficient removal of the metabolites has been suggested to cause neurodegeneration. (2) Methods: To examine the effect of reduced activity of catechol-O-methyltransferase (COMT) and aldehyde dehydrogenase 2 (ALDH2) conferred by single nucleotide polymorphisms COMT rs4680(A) and ALDH2 rs671(A) on the symptoms of patients with Parkinson’s disease (PD), a total of 114 PD patients were recruited cross-sectionally and received genotyping for rs4680 and rs671 along with MDS-UPDRS evaluation. (3) Results: We found that patients carrying rs4680(A) had more severe bradykinesia in the upper extremity and rest tremor. Besides, patients carrying rs671(A) had more difficulty maintaining personal hygiene, while patients with genotype rs671(GG) had higher scores in the item “depressed mood.” More importantly, we found the effect of rs4680 to be moderated by rs671 SNP for the symptom of “hand movements.” The detrimental impact of rs4680(A) is more pronounced in the presence of genotype rs671(GG). (4) Conclusions: This study facilitates a deeper understanding of the detrimental effect of reduced activity of COMT and ALDH2 conferred by genetic variation and provides novel insight into the interactions between enzymes metabolizing monoamine neurotransmitters in the pathogenesis of PD.

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