FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization

Nucleic Acids Research, Jul 2006

Single nucleotide polymorphism (SNP) prioritization based on the phenotypic risk is essential for association studies. Assessment of the risk requires access to a variety of heterogeneous biological databases and analytical tools. FASTSNP (function analysis and selection tool for single nucleotide polymorphisms) is a web server that allows users to efficiently identify and prioritize high-risk SNPs according to their phenotypic risks and putative functional effects. A unique feature of FASTSNP is that the functional effect information used for SNP prioritization is always up-to-date, because FASTSNP extracts the information from 11 external web servers at query time using a team of web wrapper agents. Moreover, FASTSNP is extendable by simply deploying more Web wrapper agents. To validate the results of our prioritization, we analyzed 1569 SNPs from the SNP500Cancer database. The results show that SNPs with a high predicted risk exhibit low allele frequencies for the minor alleles, consistent with a well-known finding that a strong selective pressure exists for functional polymorphisms. We have been using FASTSNP for 2 years and FASTSNP enables us to discover a novel promoter polymorphism. FASTSNP is available at http://fastsnp.ibms.sinica.edu.tw.

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FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization

FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization Hsiang-Yu Yuan 2 Jen-Jie Chiou 1 Wen-Hsien Tseng 1 Chia-Hung Liu 1 Chuan-Kun Liu 0 Yi-Jung Lin 0 Hui-Hung Wang 2 Adam Yao 0 2 Yuan-Tsong Chen 2 Chun-Nan Hsu 1 0 National Genotyping Center , Academia Sinica, Taipei , Taiwan 1 Institute of Information Science , Academia Sinica, Taipei , Taiwan 2 Institute of Biomedical Sciences , Academia Sinica, Taipei , Taiwan Single nucleotide polymorphism (SNP) prioritization based on the phenotypic risk is essential for association studies. Assessment of the risk requires access to a variety of heterogeneous biological databases and analytical tools. FASTSNP (function analysis and selection tool for single nucleotide polymorphisms) is a web server that allows users to efficiently identify and prioritize high-risk SNPs according to their phenotypic risks and putative functional effects. A unique feature of FASTSNP is that the functional effect information used for SNP prioritization is always up-to-date, because FASTSNP extracts the information from 11 external web servers at query time using a team of web wrapper agents. Moreover, FASTSNP is extendable by simply deploying more Web wrapper agents. To validate the results of our prioritization, we analyzed 1569 SNPs from the SNP500Cancer database. The results show that SNPs with a high predicted risk exhibit low allele frequencies for the minor alleles, consistent with a well-known finding that a strong selective pressure exists for functional polymorphisms. We have been using FASTSNP for 2 years and FASTSNP enables us to discover a novel promoter polymorphism. FASTSNP is available at http://fastsnp.ibms.sinica. edu.tw. INTRODUCTION An important approach to disease gene mapping is investigating whether a single nucleotide polymorphism (SNP) is functionally involved in a disease. For complex diseases, the problem is complicated because, unlike Mendelian diseases, their genetic causes might involve many genes and hundreds of alleles. Although there are millions of SNPs deposited in public SNP databases, only a small proportion of them are functional polymorphisms that contribute to disease phenotypes. Thus, prioritizing SNPs based on their phenotypic risks is essential for association studies ( 1 ). Assessment of the risk requires access to a variety of heterogeneous biological databases and analytical tools. FASTSNP (function analysis and selection tool for single nucleotide polymorphisms) is a web server that allows users to efficiently identify the SNPs most likely to have functional effects. It prioritizes SNPs according to 13 phenotypic risks and putative functional effects, such as changes to the transcriptional level, pre-mRNA splicing, protein structure and so on. A unique feature of FASTSNP is that the prediction of functional effects is always based on the most up-to-date information, which FASTSNP extracts from 11 external web servers at query time using a team of re-configurable web wrapper agents ( 2,3 ). These web wrapper agents automate web browsing and data extraction and can be easily configured and maintained with a tool that uses a machine learning algorithm. This allows users to configure/repair a web wrapper agent without programming. Another benefit of using web wrapper agents is that FASTSNP is extendable, so we can include new functions by simply deploying more web wrapper agents. In this manner, we have already built several new functionalities, such as the inclusion of information on haplotype blocks from HapMap (4). SNP prioritization Recent studies show that SNPs may have functional effects on the following. (i) protein structures, by changing single amino acids ( 5,6 ); (ii) transcriptional regulation, by affecting transcription factor binding sites in promoter or intronic enhancer regions ( 7,8 ); and (iii) alternative splicing regulation, by disrupting exonic splicing enhancers ( 9 ) or silencers. SNPs may also lead to premature termination of peptides (non-sense), which would disable the protein function. Each of these distinct functional effects may incur a risk that causes a disease. Therefore, to prioritize SNPs for the study of complex diseases, it is critical to identify the functional variants that are most likely to have functional effects leading to disease phenotypes before genotyping. Based on previous studies of the functional effects of polymorphisms, Tabor et al. ( 1 ) presented a prioritization strategy that associates the relative risk of a SNP with its location and the type of sequence variants. We extended their strategy with our recent findings and developed a decision tree to assess the risk of a SNP. The decision tree, shown in Figure 1, classifies a SNP into 1 of 13 types of the functional effects, each of which is assigned a risk ranking number between 0 and 5. A high risk rank implies a high-risk level. Table 1 gives the definitions of the function types, (...truncated)


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Hsiang-Yu Yuan, Jen-Jie Chiou, Wen-Hsien Tseng, Chia-Hung Liu, Chuan-Kun Liu, Yi-Jung Lin, Hui-Hung Wang, Adam Yao, Yuan-Tsong Chen, Chun-Nan Hsu. FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization, Nucleic Acids Research, 2006, pp. W635-W641, 34/suppl 2, DOI: 10.1093/nar/gkl236