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      In-Silico Computing of the Most Deleterious nsSNPs in HBA1 Gene

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      PLoS ONE
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          Abstract

          Background

          α-Thalassemia (α-thal) is a genetic disorder caused by the substitution of single amino acid or large deletions in the HBA1 and/or HBA2 genes.

          Method

          Using modern bioinformatics tools as a systematic in-silico approach to predict the deleterious SNPs in the HBA1 gene and its significant pathogenic impact on the functions and structure of HBA1 protein was predicted.

          Results and Discussion

          A total of 389 SNPs in HBA1 were retrieved from dbSNP database, which includes: 201 non-coding synonymous (nsSNPs), 43 human active SNPs, 16 intronic SNPs, 11 mRNA 3′ UTR SNPs, 9 coding synonymous SNPs, 9 5′ UTR SNPs and other types. Structural homology-based method (PolyPhen) and sequence homology-based tool (SIFT), SNPs&Go, PROVEAN and PANTHER revealed that 2.4% of the nsSNPs are pathogenic.

          Conclusions

          A total of 5 nsSNPs (G60V, K17M, K17T, L92F and W15R) were predicted to be responsible for the structural and functional modifications of HBA1 protein. It is evident from the deep comprehensive in-silico analysis that, two nsSNPs such as G60Vand W15R in HBA1 are highly deleterious. These “2 pathogenic nsSNPs” can be considered for wet-lab confirmatory analysis.

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          Most cited references18

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          The SWISS-MODEL Repository and associated resources

          SWISS-MODEL Repository (http://swissmodel.expasy.org/repository/) is a database of 3D protein structure models generated by the SWISS-MODEL homology-modelling pipeline. The aim of the SWISS-MODEL Repository is to provide access to an up-to-date collection of annotated 3D protein models generated by automated homology modelling for all sequences in Swiss-Prot and for relevant models organisms. Regular updates ensure that target coverage is complete, that models are built using the most recent sequence and template structure databases, and that improvements in the underlying modelling pipeline are fully utilised. As of September 2008, the database contains 3.4 million entries for 2.7 million different protein sequences from the UniProt database. SWISS-MODEL Repository allows the users to assess the quality of the models in the database, search for alternative template structures, and to build models interactively via SWISS-MODEL Workspace (http://swissmodel.expasy.org/workspace/). Annotation of models with functional information and cross-linking with other databases such as the Protein Model Portal (http://www.proteinmodelportal.org) of the PSI Structural Genomics Knowledge Base facilitates the navigation between protein sequence and structure resources.
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            The PredictProtein server.

            PredictProtein (http://www.predictprotein.org) is an Internet service for sequence analysis and the prediction of protein structure and function. Users submit protein sequences or alignments; PredictProtein returns multiple sequence alignments, PROSITE sequence motifs, low-complexity regions (SEG), nuclear localization signals, regions lacking regular structure (NORS) and predictions of secondary structure, solvent accessibility, globular regions, transmembrane helices, coiled-coil regions, structural switch regions, disulfide-bonds, sub-cellular localization and functional annotations. Upon request fold recognition by prediction-based threading, CHOP domain assignments, predictions of transmembrane strands and inter-residue contacts are also available. For all services, users can submit their query either by electronic mail or interactively via the World Wide Web.
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              PredictProtein—an open resource for online prediction of protein structural and functional features

              PredictProtein is a meta-service for sequence analysis that has been predicting structural and functional features of proteins since 1992. Queried with a protein sequence it returns: multiple sequence alignments, predicted aspects of structure (secondary structure, solvent accessibility, transmembrane helices (TMSEG) and strands, coiled-coil regions, disulfide bonds and disordered regions) and function. The service incorporates analysis methods for the identification of functional regions (ConSurf), homology-based inference of Gene Ontology terms (metastudent), comprehensive subcellular localization prediction (LocTree3), protein–protein binding sites (ISIS2), protein–polynucleotide binding sites (SomeNA) and predictions of the effect of point mutations (non-synonymous SNPs) on protein function (SNAP2). Our goal has always been to develop a system optimized to meet the demands of experimentalists not highly experienced in bioinformatics. To this end, the PredictProtein results are presented as both text and a series of intuitive, interactive and visually appealing figures. The web server and sources are available at http://ppopen.rostlab.org.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                29 January 2016
                2016
                : 11
                : 1
                : e0147702
                Affiliations
                [001]Institute for Research and Medical Consultation (IRMC), University of Dammam, Dammam, Saudi Arabia
                University of Michigan, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SA JFB. Performed the experiments: SA JFB. Analyzed the data: SA JFB. Contributed reagents/materials/analysis tools: SA JFB. Wrote the paper: SA JFB.

                Article
                PONE-D-15-49877
                10.1371/journal.pone.0147702
                4733110
                26824843
                8386e8ff-30df-4ce3-8073-d01491ff4af3
                © 2016 AbdulAzeez, Borgio

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 November 2015
                : 7 January 2016
                Page count
                Figures: 4, Tables: 4, Pages: 13
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Biology and Life Sciences
                Molecular Biology
                Macromolecular Structure Analysis
                Protein Structure
                Protein Structure Prediction
                Biology and Life Sciences
                Biochemistry
                Proteins
                Protein Structure
                Protein Structure Prediction
                Biology and Life Sciences
                Molecular Biology
                Macromolecular Structure Analysis
                Protein Structure
                Biology and Life Sciences
                Biochemistry
                Proteins
                Protein Structure
                Biology and Life Sciences
                Molecular Biology
                Macromolecular Structure Analysis
                Protein Structure
                Protein Structure Comparison
                Biology and Life Sciences
                Biochemistry
                Proteins
                Protein Structure
                Protein Structure Comparison
                Research and Analysis Methods
                Chemical Characterization
                Binding Analysis
                Biology and Life Sciences
                Biochemistry
                Proteins
                Structural Proteins
                Biology and Life Sciences
                Genetics
                Mutation
                Substitution Mutation
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Amino Acids
                Amino Acid Substitution
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Amino Acids
                Amino Acid Substitution
                Biology and Life Sciences
                Biochemistry
                Proteins
                Amino Acids
                Amino Acid Substitution
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Amino Acid Analysis
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Amino Acid Analysis
                Custom metadata
                All relevant data are within the paper and its Supporting Files.

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