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      Computational Methods to Work as First-Pass Filter in Deleterious SNP Analysis of Alkaptonuria

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      1 , 2 , *
      The Scientific World Journal
      The Scientific World Journal

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          Abstract

          A major challenge in the analysis of human genetic variation is to distinguish functional from nonfunctional SNPs. Discovering these functional SNPs is one of the main goals of modern genetics and genomics studies. There is a need to effectively and efficiently identify functionally important nsSNPs which may be deleterious or disease causing and to identify their molecular effects. The prediction of phenotype of nsSNPs by computational analysis may provide a good way to explore the function of nsSNPs and its relationship with susceptibility to disease. In this context, we surveyed and compared variation databases along with in silico prediction programs to assess the effects of deleterious functional variants on protein functions. In other respects, we attempted these methods to work as first-pass filter to identify the deleterious substitutions worth pursuing for further experimental research. In this analysis, we used the existing computational methods to explore the mutation-structure-function relationship in HGD gene causing alkaptonuria.

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          Most cited references34

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          Human non-synonymous SNPs: server and survey.

          Human single nucleotide polymorphisms (SNPs) represent the most frequent type of human population DNA variation. One of the main goals of SNP research is to understand the genetics of the human phenotype variation and especially the genetic basis of human complex diseases. Non-synonymous coding SNPs (nsSNPs) comprise a group of SNPs that, together with SNPs in regulatory regions, are believed to have the highest impact on phenotype. Here we present a World Wide Web server to predict the effect of an nsSNP on protein structure and function. The prediction method enabled analysis of the publicly available SNP database HGVbase, which gave rise to a dataset of nsSNPs with predicted functionality. The dataset was further used to compare the effect of various structural and functional characteristics of amino acid substitutions responsible for phenotypic display of nsSNPs. We also studied the dependence of selective pressure on the structural and functional properties of proteins. We found that in our dataset the selection pressure against deleterious SNPs depends on the molecular function of the protein, although it is insensitive to several other protein features considered. The strongest selective pressure was detected for proteins involved in transcription regulation.
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            McKusick's Online Mendelian Inheritance in Man (OMIM®)

            McKusick's Online Mendelian Inheritance in Man (OMIM®; http://www.ncbi.nlm.nih.gov/omim), a knowledgebase of human genes and phenotypes, was originally published as a book, Mendelian Inheritance in Man, in 1966. The content of OMIM is derived exclusively from the published biomedical literature and is updated daily. It currently contains 18 961 full-text entries describing phenotypes and genes. To date, 2239 genes have mutations causing disease, and 3770 diseases have a molecular basis. Approximately 70 new entries are added and 700 entries are updated per month. OMIM® is expanding content and organization in response to shifting biological paradigms and advancing biotechnology.
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              PANTHER version 7: improved phylogenetic trees, orthologs and collaboration with the Gene Ontology Consortium

              Protein Analysis THrough Evolutionary Relationships (PANTHER) is a comprehensive software system for inferring the functions of genes based on their evolutionary relationships. Phylogenetic trees of gene families form the basis for PANTHER and these trees are annotated with ontology terms describing the evolution of gene function from ancestral to modern day genes. One of the main applications of PANTHER is in accurate prediction of the functions of uncharacterized genes, based on their evolutionary relationships to genes with functions known from experiment. The PANTHER website, freely available at http://www.pantherdb.org, also includes software tools for analyzing genomic data relative to known and inferred gene functions. Since 2007, there have been several new developments to PANTHER: (i) improved phylogenetic trees, explicitly representing speciation and gene duplication events, (ii) identification of gene orthologs, including least diverged orthologs (best one-to-one pairs), (iii) coverage of more genomes (48 genomes, up to 87% of genes in each genome; see http://www.pantherdb.org/panther/summaryStats.jsp), (iv) improved support for alternative database identifiers for genes, proteins and microarray probes and (v) adoption of the SBGN standard for display of biological pathways. In addition, PANTHER trees are being annotated with gene function as part of the Gene Ontology Reference Genome project, resulting in an increasing number of curated functional annotations.
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                Author and article information

                Journal
                ScientificWorldJournal
                ScientificWorldJournal
                TSWJ
                The Scientific World Journal
                The Scientific World Journal
                1537-744X
                2012
                19 April 2012
                : 2012
                : 738423
                Affiliations
                1Department of Biotechnology, Faculty of Biomedical Sciences, Technology & Research, Sri Ramachandra University, Chennai 600116, India
                2Centre for Nanobiotechnology, Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Tamil Nadu, Vellore 632014, India
                Author notes
                *C. George Priya Doss: georgecp77@ 123456yahoo.co.in

                Academic Editor: Andrew Walley

                Article
                10.1100/2012/738423
                3349151
                22606059
                e5003c20-f63b-4c7c-9bbc-1e117b18d013
                Copyright © 2012 R. Magesh and C. George Priya Doss.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 September 2011
                : 31 October 2011
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