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Journal ArticleDOI

Applications of computational algorithm tools to identify functional SNPs

19 Jun 2008-Functional & Integrative Genomics (Springer-Verlag)-Vol. 8, Iss: 4, pp 309-316
TL;DR: This work analyzed the SNPs that can alter the expression and function of transcriptional factor TP53 as a pipeline and proposed modeled structure for the mutant proteins and compared them with the native protein.
Abstract: Single nucleotide polymorphisms (SNPs) are the most common type of genetic variations in humans Understanding the functions of SNPs can greatly help to understand the genetics of the human phenotype variation and especially the genetic basis of human complex diseases The method to identify functional SNPs from a pool, containing both functional and neutral SNPs is challenging by experimental protocols To explore possible relationships between genetic mutation and phenotypic variation, different computational algorithm tools like Sorting Intolerant from Tolerant, Polymorphism Phenotyping, UTRscan, FASTSNP, and PupaSuite were used for prioritization of high-risk SNPs in coding region (exonic nonsynonymous SNPs) and noncoding regions (intronic and exonic 5' and 3'-untranslated region (UTR) SNPs) In this work, we have analyzed the SNPs that can alter the expression and function of transcriptional factor TP53 as a pipeline and for providing a guide to experimental work We identified the possible mutations and proposed modeled structure for the mutant proteins and compared them with the native protein These nsSNPs play a critical role in cancer association studies aiming to explain the disparity in cancer treatment responses as well as to improve the effectiveness of the cancer treatments Our results endorse the study with in vivo experimental protocols
Citations
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Journal ArticleDOI
TL;DR: This review highlights the latest advances in the field of translational bioinformatics, focusing on the advances of computational techniques to search for and classify disease genes.
Abstract: Over a 100 years ago, William Bateson provided, through his observations of the transmission of alkaptonuria in first cousin offspring, evidence of the application of Mendelian genetics to certain human traits and diseases. His work was corroborated by Archibald Garrod (Archibald AE. The incidence of alkaptonuria: a study in chemical individuality. Lancert 1902;ii:1616-20) and William Farabee (Farabee WC. Inheritance of digital malformations in man. In: Papers of the Peabody Museum of American Archaeology and Ethnology. Cambridge, Mass: Harvard University, 1905; 65-78), who recorded the familial tendencies of inheritance of malformations of human hands and feet. These were the pioneers of the hunt for disease genes that would continue through the century and result in the discovery of hundreds of genes that can be associated with different diseases. Despite many ground-breaking discoveries during the last century, we are far from having a complete understanding of the intricate network of molecular processes involved in diseases, and we are still searching for the cures for most complex diseases. In the last few years, new genome sequencing and other high-throughput experimental techniques have generated vast amounts of molecular and clinical data that contain crucial information with the potential of leading to the next major biomedical discoveries. The need to mine, visualize and integrate these data has motivated the development of several informatics approaches that can broadly be grouped in the research area of 'translational bioinformatics'. This review highlights the latest advances in the field of translational bioinformatics, focusing on the advances of computational techniques to search for and classify disease genes.

102 citations

Journal ArticleDOI
29 Apr 2011-PLOS ONE
TL;DR: It is suggested that the risk of hepatocellular carcinoma was associated with TLR4 sequence variation, and single nucleotide polymorphisms ofTLR4 may play an important protective role in the development of liver cancer.
Abstract: Background Toll-like receptor 4 (TLR4) is a key innate immunity receptor that initiates an inflammatory response. Growing evidence suggests that mutation of TLR4 gene may play a role in the development of cancers. This study aimed to investigate the temporal relationship of single nucleotide polymorphisms of TLR4 and the risk of hepatocellular carcinoma, a single center-based case-control study was conducted. Methods A systematic genetic analysis of sequence variants of TLR4 by evaluating ten single-nucleotide polymorphisms was performed from 216 hepatocellular carcinoma cases and 228 controls. Results Six single nucleotide polymorphisms of the TLR4 in the 5′-untranslated region and intron were associated with risk of hepatocellular carcinoma. Individuals carrying the heterozygous genotypes for the rs10759930, rs2737190, rs10116253, rs1927914, rs12377632 and rs1927911 had significantly decreased risk of hepatocellular carcinoma (adjusted odds ratio [OR], from 0.527 to 0.578, P<0.01) comparing with those carrying wild-type homozygous genotypes. In haplotype analysis, one haplotype (GCCCTTAG) of TLR4 was associated significantly with decrease of the occurrence of hepatocellular carcinoma (OR, 0.556, 95% confidence interval [CI], 0.407–0.758, P = 0.000). Conclusions Collectively, these results suggested that the risk of hepatocellular carcinoma was associated with TLR4 sequence variation. TLR4 single nucleotide polymorphisms may play an important protective role in the development of hepatocellular carcinoma.

62 citations


Cites background from "Applications of computational algor..."

  • ...However, there are accumulating evidences that mutations in the splice, donor and acceptor sites or enhancer, intron and promoter elements may be important in genetic expression and regulation [31]....

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Journal ArticleDOI
28 Aug 2012-PLOS ONE
TL;DR: This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD.
Abstract: Toll-like receptors (TLRs) participate in the defence against bacterial infections that are common in patients with Chronic Obstructive Pulmonary Disease (COPD). We studied all tagging SNPs in TLR2 and TLR4 and their associations with the level and change over time of both FEV1 and sputum inflammatory cells in moderate-to-severe COPD. Nine TLR2 SNPs and 17 TLR4 SNPs were genotyped in 110 COPD patients. Associations of SNPs with lung function and inflammatory cells in induced sputum were analyzed cross-sectionally with linear regression and longitudinally with linear mixed-effect models. Two SNPs in TLR2 (rs1898830 and rs11938228) were associated with a lower level of FEV1 and accelerated decline of FEV1 and higher numbers of sputum inflammatory cells. None of the TLR4 SNPs was associated with FEV1 level. Eleven out of 17 SNPs were associated with FEV1 decline, including rs12377632 and rs10759931, which were additionally associated with higher numbers of sputum inflammatory cells at baseline and with increase over time. This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD.

52 citations

Journal ArticleDOI
TL;DR: A comprehensive analysis of the functional and structural impact of all known SNPs in this gene using publicly available computational prediction tools shows that a mutation from arginine to cysteine at position 1216 on the surface of the protein caused the greatest impact on stability.
Abstract: Insulin-like growth factor 1 receptor (IGF1R) acts as a critical mediator of cell proliferation and survival. Many single nucleotide polymorphisms (SNPs) found in the IGF1R gene have been associated with various diseases, including both breast and prostate cancer. The genetics of these diseases could be better understood by knowing the functions of these SNPs. In this study, we performed a comprehensive analysis of the functional and structural impact of all known SNPs in this gene using publicly available computational prediction tools. Out of a total of 2412 SNPs in IGF1R retrieved from dbSNP, we found 32 nsSNPs, 58 sSNPs, 83 mRNA 3' UTR SNPs, and 2225 intronic SNPs. Among the nsSNPs, a total of six missense nsSNPs were found to be damaging by both a sequence homology-based tool (SIFT) and a structural homology-based method (PolyPhen), and one nonsense nsSNP was found. Further, we modeled mutant proteins and compared the total energy values with the native IGF1R protein, and showed that a mutation from arginine to cysteine at position 1216 (rs61740868) on the surface of the protein caused the greatest impact on stability. Also, the FASTSNP tool suggested that 31 sSNPs and 3 intronic SNPs might affect splicing regulation. Based on our investigation, we report potential candidate SNPs for future studies on IGF1R mutations.

50 citations


Cites background from "Applications of computational algor..."

  • ...Although wetlab-based approaches used to identify disease-associated SNPs from a large number of neutral SNPs remain crucial evidence for the functional role of SNPs [8], numerous disease associations published could not be confirmed by subsequent independent studies [6, 9]....

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Journal ArticleDOI
TL;DR: Findings indicated that the function‐validated and potentially functional variations in TERT‐CLPTM1L locus, modified by smoking, may play a substantial role in the susceptibility to lung cancer.
Abstract: Recent genome-wide association studies (GWAS) have reported multiple genetic variations at 5p15.33 (TERT-CLPTM1L) associated with risk of lung cancer. However, most of the associated variations identified by GWAS thus far are unlikely to be the actual causal variants, but may be mostly marker-single nucleotide polymorphisms tagging functional variations that influence gene expression. This study aimed to explore the function-validated and potentially functional variations in TERT-CLPTM1L locus conferring susceptibility to lung cancer. A case–control study including 502 cases and 502 controls in Chinese Han population was firstly conducted. Bioinformatic approaches are applied to prioritize genetic variations based on their potential functionality. In the logistic regression analysis, TERT-rs2853669, rs2736108, and CLPTM1L-rs31490 were significant associated with increased risk of lung cancer (OR = 1.46, 95% CI = 1.22–1.75; OR = 1.22, 95% CI = 1.00–1.49 and OR = 1.74, 95% CI = 1.35–2.23 under additive model, respectively). The significant associations were observed in non-small-cell lung cancer but not-in-small-cell lung cancer, and more prominent in adenocarcinoma. Haplotype analysis presented a significant allele-dose effect of haplotypes in increasing risk of lung cancer (P for trend = 1.894 × 10−6). Moreover, significant multiplicative interactions were observed between smoking and these three polymorphisms of TERT-rs2853669, rs2736108, and CLPTM1L-rs31490, even after bonferroni correction for multiple comparisons (Pinteraction = 1.316 × 10−9, 3.912 × 10−4, and 2.483 × 10−5, respectively). These findings indicated that the function-validated and potentially functional variations in TERT-CLPTM1L locus, modified by smoking, may play a substantial role in the susceptibility to lung cancer. © 2013 Wiley Periodicals, Inc.

45 citations


Cites methods from "Applications of computational algor..."

  • ...Two integrated bioinformatics tools, “F-SNP” [18] (http://compbio.cs.queensu.ca/F-SNP/) and “FAST SNP” [19] (http://fastsnp.ibms.sinica.edu.tw/pages/input_CandidateGeneSearch.jsp), were applied to predict the potential function of SNPs....

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  • ...ca/F-SNP/) and “FAST SNP” [19] (http://fastsnp....

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  • ...In addition to the functional SNP TERT-rs2853669, two other candidate SNPs, TERT-rs2736108 and CLPTM1L-rs31490, were selected utilizing the union of two tools by bioinformatics approaches [18,19]....

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References
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Journal ArticleDOI
05 Jul 1991-Science
TL;DR: The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues as mentioned in this paper.
Abstract: Mutations in the evolutionarily conserved codons of the p53 tumor suppressor gene are common in diverse types of human cancer. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain, and lymphoid malignancies, whereas G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung and liver. Mutations at A:T base pairs are seen more frequently in esophageal carcinomas than in other solid tumors. Most transitions in colorectal carcinomas, brain tumors, leukemias, and lymphomas are at CpG dinucleotide mutational hot spots. G to T transversions in lung, breast, and esophageal carcinomas are dispersed among numerous codons. In liver tumors in persons from geographic areas in which both aflatoxin B1 and hepatitis B virus are cancer risk factors, most mutations are at one nucleotide pair of codon 249. These differences may reflect the etiological contributions of both exogenous and endogenous factors to human carcinogenesis.

8,063 citations

Journal ArticleDOI
16 Nov 2000-Nature
TL;DR: The p53 tumour-suppressor gene integrates numerous signals that control cell life and death, and the disruption of p53 has severe consequences when a highly connected node in the Internet breaks down.
Abstract: The p53 tumour-suppressor gene integrates numerous signals that control cell life and death. As when a highly connected node in the Internet breaks down, the disruption of p53 has severe consequences.

6,605 citations


"Applications of computational algor..." refers background or methods in this paper

  • ...Using the human transcription factor TP53 as a test case The human gene TP53 (tumor suppressor gene) is mutated in more than 50% of human cancers and p53 dysfunction is caused through a direct mutation within the DNA binding domain of the gene (Vogelstein et al. 2000)....

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  • ...The human gene TP53 (tumor suppressor gene) is mutated in more than 50% of human cancers and p53 dysfunction is caused through a direct mutation within the DNA binding domain of the gene (Vogelstein et al. 2000)....

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Journal ArticleDOI
TL;DR: The dbSNP database is a general catalog of genome variation to address the large-scale sampling designs required by association studies, gene mapping and evolutionary biology, and is integrated with other sources of information at NCBI such as GenBank, PubMed, LocusLink and the Human Genome Project data.
Abstract: In response to a need for a general catalog of genome variation to address the large-scale sampling designs required by association studies, gene mapping and evolutionary biology, the National Center for Biotechnology Information (NCBI) has established the dbSNP database [S.T.Sherry, M.Ward and K.Sirotkin (1999) Genome Res., 9, 677–679]. Submissions to dbSNP will be integrated with other sources of information at NCBI such as GenBank, PubMed, LocusLink and the Human Genome Project data. The complete contents of dbSNP are available to the public at website: http://www.ncbi.nlm.nih.gov/SNP. The complete contents of dbSNP can also be downloaded in multiple formats via anonymous FTP at ftp:// ncbi.nlm.nih.gov/snp/.

6,449 citations


"Applications of computational algor..." refers methods in this paper

  • ...SNP dataset from dbSNP SNP dataset for TP53 gene investigated in this work was retrieved from dbSNP (Sherry et al. 2001) http://www.ncbi. nlm.nih.gov/SNP/ for our computational analysis....

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  • ...SNP dataset for TP53 gene investigated in this work was retrieved from dbSNP (Sherry et al. 2001) http://www....

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Journal ArticleDOI
TL;DR: SIFT is a program that predicts whether an amino acid substitution affects protein function so that users can prioritize substitutions for further study and can distinguish between functionally neutral and deleterious amino acid changes in mutagenesis studies and on human polymorphisms.
Abstract: Single nucleotide polymorphism (SNP) studies and random mutagenesis projects identify amino acid substitutions in protein-coding regions. Each substitution has the potential to affect protein function. SIFT (Sorting Intolerant From Tolerant) is a program that predicts whether an amino acid substitution affects protein function so that users can prioritize substitutions for further study. We have shown that SIFT can distinguish between functionally neutral and deleterious amino acid changes in mutagenesis studies and on human polymorphisms. SIFT is available at http://blocks.fhcrc.org/sift/SIFT.html.

5,318 citations

Journal ArticleDOI
TL;DR: A tool that uses sequence homology to predict whether a substitution affects protein function is constructed, which may be used to identify plausible disease candidates among the SNPs that cause missense substitutions.
Abstract: Many missense substitutions are identified in single nucleotide polymorphism (SNP) data and large-scale random mutagenesis projects. Each amino acid substitution potentially affects protein function. We have constructed a tool that uses sequence homology to predict whether a substitution affects protein function. SIFT, which sorts intolerant from tolerant substitutions, classifies substitutions as tolerated or deleterious. A higher proportion of substitutions predicted to be deleterious by SIFT gives an affected phenotype than substitutions predicted to be deleterious by substitution scoring matrices in three test cases. Using SIFT before mutagenesis studies could reduce the number of functional assays required and yield a higher proportion of affected phenotypes. may be used to identify plausible disease candidates among the SNPs that cause missense substitutions.

2,374 citations