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Computational refinement of functional single nucleotide polymorphisms associated with ATM gene.

ABSTRACT: BACKGROUND:Understanding and predicting molecular basis of disease is one of the major challenges in modern biology and medicine. SNPs associated with complex disorders can create, destroy, or modify protein coding sites. Single amino acid substitutions in the ATM gene are the most common forms of genetic variations that account for various forms of cancer. However, the extent to which SNPs interferes with the gene regulation and affects cancer susceptibility remains largely unknown. PRINCIPAL FINDINGS:We analyzed the deleterious nsSNPs associated with ATM gene based on different computational methods. An integrative scoring system and sequence conservation of amino acid residues was adapted for a priori nsSNP analysis of variants associated with cancer. We further extended our approach on SNPs that could potentially influence protein Post Translational Modifications in ATM gene. SIGNIFICANCE:In the lack of adequate prior reports on the possible deleterious effects of nsSNPs, we have systematically analyzed and characterized the functional variants in both coding and non coding region that can alter the expression and function of ATM gene. In silico characterization of nsSNPs affecting ATM gene function can aid in better understanding of genetic differences in disease susceptibility.

SUBMITTER: George Priya Doss C

PROVIDER: S-EPMC3326031 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Computational refinement of functional single nucleotide polymorphisms associated with ATM gene.

George Priya Doss C C Rajith B B

PloS one 20120413 4

<h4>Background</h4>Understanding and predicting molecular basis of disease is one of the major challenges in modern biology and medicine. SNPs associated with complex disorders can create, destroy, or modify protein coding sites. Single amino acid substitutions in the ATM gene are the most common forms of genetic variations that account for various forms of cancer. However, the extent to which SNPs interferes with the gene regulation and affects cancer susceptibility remains largely unknown.<h4> ...[more]

PMID: 22529920

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Project description:Background A group of genes called oncogenes includes the Harvey rat sarcoma virus (hRAS) gene. Along with hRAS, Kirsten rat sarcoma viral oncogene homolog (kRAS) and neuroblastoma RAS viral oncogene homolog (nRAS) genes belong to the Rat sarcoma (Ras) family of oncogenes. These three genes result in Rho guanosine triphosphate hydrolases (GTPases) as their protein product. Instructions for producing the protein hRAS, which is mainly involved in controlling cell division, are provided by the hRAS gene. The hRAS protein transfers signals from outside through a process called signal transduction. Because the hRAS protein is a GTPase, it changes the chemical guanosine-5'-triphosphate (GTP) into guanosine diphosphate (GDP). GTP and GDP molecules operate as switches to turn on and off the hRAS. This study aimed to anticipate the structure and stability of the protein resulting from missense single-nucleotide polymorphisms (SNPs) in the human hRAS genes. Methodology To investigate the possible negative effects associated with these SNPs, bioinformatic analysis is typically essential. The following tools were employed for forecasting harmful SNPs: Scale-Invariant Feature Transform (SIFT), Protein Analysis Through Evolutionary Relationships (PANTHER), non-synonymous SNP by Protein Variation Effect Analyzer (PROVEAN), and non-synonymous SNP by Single Nucleotide Polymorphism Annotation Platform (SNAP). Results The present study identified a total of 11 SNPs using the SIFT approach, which were shown to have functional significance. Only two of these 11 SNPs were determined to be tolerable, whereas nine were shown to be detrimental. Among the 11 SNPs analyzed, seven (Q61H, Q99H, K117R, A121D, A146V, R169W, R169Q) were classified as possibly damaging,and four (G13V, Q22K, Q61K, Q13V) were categorized as probably benign according to the predictions made by PANTHER tools. Therefore, the seven SNPs were identified as high-risk SNPs. Conclusions Given that SNPs have the potential to be candidates for cellular alterations brought on by mutations that are associated with cancer, this study provides vital information about how SNPs might be utilized as a diagnostic marker for cancer.

Dataset Information

Computational refinement of functional single nucleotide polymorphisms associated with ATM gene.

Publications

Computational refinement of functional single nucleotide polymorphisms associated with ATM gene.

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