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

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.

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

2022 ◽  
Vol 12 (1) ◽  
pp. 1-12
Author(s):  
Nadeem Ahmad ◽  
Zubair Sharif ◽  
Sarah Bukhari ◽  
Omer Aziz
Keyword(s):  
Genetic Basis ◽  
Structure And Function ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Computational Tools ◽  
Project Hope ◽  
Structural Impacts ◽  
And Function ◽  
Protein Variants ◽  
Insight Into

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.

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

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.

scholarly journals Re-analysis of a Genome-Wide Gene-By-Environment Interaction Study of Case Parent Trios, Adjusted for Population Stratification

2021 ◽  
Vol 11 ◽  
Author(s):  
Pulindu Ratnasekera ◽  
Brad McNeney
Keyword(s):  
East Asian ◽  
Environment Interaction ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Multivitamin Supplementation ◽  
Gene Environment ◽  
Genome Wide ◽  
A Genome ◽  
The Impact ◽  
East Asian Ancestry

We investigate the impact of confounding on the results of a genome-wide association analysis by Beaty et al., which identified multiple single nucleotide polymorphisms that appeared to modify the effect of maternal smoking, alcohol consumption, or multivitamin supplementation on risk of cleft palate. The study sample of case-parent trios was primarily of European and East Asian ancestry, and the distribution of all three exposures differed by ancestral group. Such differences raise the possibility that confounders, rather than the exposures, are the risk modifiers and hence that the inference of gene-environment (G×E) interaction may be spurious. Our analyses generally confirmed the result of Beaty et al. and suggest the interaction G×E is driven by the European trios, whereas the East Asian trios were less informative.

scholarly journals Biological Significance of the Genomic Variation and Structural Dynamics of SARS-CoV-2 B.1.617

2021 ◽  
Vol 12 ◽  
Author(s):  
Lin-qian Fan ◽  
Xiao-yun Hu ◽  
Yi-yue Chen ◽  
Xiang-lei Peng ◽  
Yuan-hui Fu ◽  
...  
Keyword(s):  
Biological Significance ◽  
Haplotype Network ◽  
Genomic Variation ◽  
Mitigation Measures ◽  
Nucleotide Polymorphisms ◽  
Nonstructural Proteins ◽  
Single Nucleotide ◽  
Genome Wide ◽  
A Genome

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have been emerging and circulating globally since the start of the COVID-19 pandemic, of which B.1.617 lineage that was first reported in India at the end of 2020, soon became predominant. Tracing genomic variations and understanding their impact on the viral properties are the foundations for the vaccine and drug development and for the mitigation measures to be taken or lifted. In this study, 1,051 near-complete genomes and 1,559 spike (S) sequences belonging to the B.1.617 were analyzed. A genome-wide spread of single nucleotide polymorphisms (SNPs) was identified. Of the high frequency mutations identified, 61% (11/18) involved structural proteins, despite two third of the viral genome encoding nonstructural proteins. There were 22 positive selection sites, mostly distributed across the S protein, of which 16 were led by non-C to U transition and should be of a special attention. Haplotype network revealed that a large number of daughter haplotypes were continually derived throughout the pandemic, of which H177, H181 H219 and H286 from the ancestor haplotype H176 of B.1.617.2 were widely prevalent. Besides the well known substitutions of L452R, P681R and deletions of E156 and F157, as well as the potential biological significance, structural analysis in this study still indicated that new amino acid changes in B.1.617, such as E484Q and N501Y, had reshaped the viral bonding network, and increasingly sequenced N501Y mutant with a potential enhanced binding ability was detected in many other countries in the follow-up monitoring. Although we can’t conclude the properties of all the mutants including N501Y thoroughly, it merits focusing on their spread epidemically and biologically.

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

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.

scholarly journals In silico analysis of non-synonymous single nucleotide polymorphisms of human DEFB1 gene

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Harini Venkata Subbiah ◽  
Polani Ramesh Babu ◽  
Usha Subbiah
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
In Silico ◽  
In Silico Analysis ◽  
Gene Interaction ◽  
Nucleotide Polymorphisms ◽  
Amino Acid Residues ◽  
Single Nucleotide ◽  
Project Hope ◽  
The Impact ◽  
Structure And Functions

Abstract Background Single nucleotide polymorphisms (SNPs) play a significant role in differences in individual’s susceptibility to diseases, and it is imperative to differentiate potentially harmful SNPs from neutral ones. Defensins are small cationic antimicrobial peptides that serve as antimicrobial and immunomodulatory molecules, and SNPs in β-defensin 1 (DEFB1 gene) have been associated with several diseases. In this study, we have determined deleterious SNPs of the DEFB1 gene that can affect the susceptibility to diseases by using different computational methods. Non-synonymous SNPs (nsSNPs) of the DEFB1 gene that have the ability to affect protein structure and functions were determined by several in silico tools—SIFT, PolyPhen v2, PROVEAN, SNAP, PhD-SNP, and SNPs&GO. Then, nsSNPs identified to be potentially deleterious were further analyzed by I-Mutant and ConSurf. Post-translational modifications mediated by nsSNPs were predicted by ModPred, and gene-gene interaction was studied by GeneMANIA. Finally, nsSNPs were submitted to Project HOPE analysis. Results Ten nsSNPs of the DEFB1 gene were found to be potentially deleterious: rs1800968, rs55874920, rs56270143, rs140503947, rs145468425, rs146603349, rs199581284, rs201260899, rs371897938, rs376876621. I-Mutant server showed that nsSNPs rs140503947 and rs146603349 decreased stability of the protein, and ConSurf analysis revealed that SNPs were located in conserved regions. The physiochemical properties of the polymorphic amino acid residues and their effect on structure were determined by Project HOPE. Conclusion This study has determined high-risk deleterious nsSNPs of β-defensin 1 and could increase the knowledge of nsSNPs towards the impact of mutations on structure and functions mediated by β-defensin 1 protein.

scholarly journals Natural Occurring Non-Synonymous Single Nucleotide Polymorphisms in Integrase and RNase H Regulate Assembly and Autoprocessing of HIV-1

2021 ◽  
Author(s):  
Tomozumi Imamichi ◽  
John G. Bernbaum ◽  
Sylvain Laverdure ◽  
Jun Yang ◽  
Qian Chen ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Rnase H ◽  
Viral Fitness ◽  
Nucleotide Polymorphisms ◽  
Virus Release ◽  
Single Nucleotide ◽  
Hiv Rna ◽  
A Genome ◽  
The Impact ◽  
Hiv 1

AbstractRecently, a genome-wide association study using plasma HIV RNA reported that 14 naturally occurring non-synonymous single nucleotide polymorphisms (SNPs) in HIV derived from anti-retrovirus naïve patients were associated with virus load (VL). However, the impact of each mutation on viral fitness was not investigated. Here, we constructed a series of HIV variants encoding each SNP using site-directed mutagenesis and examined their replicative abilities and biological properties. An HIV variant containing Met-to-Ile change at codon 50 in integrase (HIV(IN:M50I)) was found an impaired virus. Despite the mutation being in integrase, a quantification assay demonstrated that the virus release was significantly suppressed (P<0.001). Transmission electron microscopy analyses revealed that the accumulation of abnormal shapes of buds on the plasma membrane and the released virus particles retained immature forms. Western blot analysis demonstrated a defect in autoprocessing of GagPol and Gag polyproteins in the HIV(IN:M50I) particles. Förster Resonance Energy Transfer (FRET) assay displayed that GagPol containing IN:M50I (GagPol(IN:M50I)) significantly increased the efficiency of homodimerization (P<0.05) and heterodimerization with Gag (P<0.001), compared to GagPol(WT). HIV replication assay using a series of variants of HIV(IN:M50I) elucidated that the C-terminus residues, Asn at codon 288, plays a key role in the defect and the impaired maturation and replication capability was rescued by two other VL-associated SNPs, Ser-to-Asn change at codon 17 in integrase or Asn-to-Ser change at codon 79 in RNase H. These data demonstrate that Gag and GagPol assembly, virus release and autoprocessing are not only regulated by integrase but also RNase H.ImportanceA nascent HIV-1 is noninfectious. To become an infectious virus, Gag and GagPol polyproteins in the particles need to be cleaved by mature HIV protease (PR). PR is initially translated as an inactive embedded enzyme in a GagPol polyprotein. The embedded PR in homodimerized GagPol polyproteins catalyzes a proteolytic reaction to release the mature PR. This excision step by a self-cleavage is called autoprocessing. Here, during the evaluation of roles of naturally emerging non-synonymous SNPs in HIV RNA, we found that autoprocessing is inhibited by Met-to-Ile change at codon 50 in integrase in GagPol which increases the efficiency of heterodimerization with Gag. This defect was recovered by co-existing of other SNPs: Ser-to-Asn change at codon 17 in integrase or Asn-to-Ser mutation at codon 79 in RNase H, suggesting that autoprocessing is regulated by not only integrase but also RNase H in GagPol polyprotein.

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

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.

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

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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