MedRefSNP: A database of medically investigated SNPs

Genetic association studies and linkage analyses using single nucleotide polymorphisms (SNPs) are rapidly increasing in number, and the results are important for evaluating the utility of SNPs in the biomedical sciences. Although many SNP databases have been established, there is no database focusing on published SNPs, where the research results of scientific investigations are available. To enhance the utilization of such SNP data, we have developed the MedRefSNP database ( http://www.medclue.com/medrefsnp ) to provide integrated information about SNPs collected from the PubMed and OMIM databases. The RefSNP identifiers are automatically identified and are linked to various information sources such as the dbSNP, the HapMap database, the Entrez Gene database, the UCSC genome browser, the CGAP Pathway Searcher, and genetic association databases. And, each SNP is checked to determine whether the PolyDoms, SNPs3D or PolyPhen databases predicts that the SNP affects the phenotype of the protein encoded by the gene carrying the SNP. Also, neighboring SNPs showing strong linkage disequilibrium (LD) with published SNPs are included, using HapMap data. Currently, 36199 unique SNPs (including 31368 neighboring SNPs) collected from 25906 PubMed abstracts and 590 OMIM records are stored along with 2491 human genes related to 466 molecular pathways. The MedRefSNP database will help researchers to review previously investigated results more efficiently, and will expand knowledge by using the genomic and functional contexts of the SNPs. © 2008 Wiley‐Liss, Inc.     

Data mining of public SNP databases for the selection of intragenic SNPs

Different strategies to search public single nucleotide polymorphism (SNP) databases for intragenic SNPs were evaluated. First, we assembled a strategy to annotate SNPs onto candidate genes based on a BLAST search of public SNP databases (Intragenic SNP Annotation by BLAST, ISAB). Only BLAST hits that complied with stringent criteria according to 1) percentage identity (minimum 98%), 2) BLAST hit length (the hit covers at least 98% of the length of the SNP entry in the database, or the hit is longer than 250 base pairs), and 3) location in non-repetitive DNA, were considered as valid SNPs. We assessed the intragenic context and redundancy of these SNPs, and demonstrated that the SNP content of the dbSNP and HGBASE/HGVbase databases are highly complementary but also overlap significantly. Second, we assessed the validity of intragenic SNP annotation available on the dbSNP and HGVbase websites by comparison with the results of the ISAB strategy. Only a minority of all annotated SNPs was found in common between the respective public SNP database websites and the ISAB annotation strategy. A detailed analysis was performed aiming to explain this discrepancy. As a conclusion, we recommend the application of an independent strategy (such as ISAB) to annotate intragenic SNPs, complementary to the annotation provided at the dbSNP and HGVbase websites. Such an approach might be useful in the selection process of intragenic SNPs for genotyping in genetic studies. Hum Mutat 20:162-173, 2002.     

SNP databases and pharmacogenetics: great start,but a long way to go

With the recent publication of the human genome project there has been an explosion of data available for pharmacogenetic research. Web-based databases containing information on single nucleotide polymorphisms (SNPs) are readily accessible to researchers, but there has been little comment on their utility. We used seven major international databases to identify SNPs in 74 genes involved in drug pathways. Very little overlap was seen among the databases, with only eight out of a putative 893 SNPs ( approximately 1%) common to the most commonly used databases. Problems with false positives, secondary to a high degree of homology in gene families, were also observed. These studies suggest researchers limiting their studies to one database would miss a great deal of information. Effort to update compilation databases, such as HGVbase, GeneSNP, PharmGKB, and HOWDY, and the aggressive removal of false positives from all databases is required if these resources are to facilitate the intended growth in pharmacogenetics research.     

dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions

With the advance of sequencing technologies, whole exome sequencing has increasingly been used to identify mutations that cause human diseases, especially rare Mendelian diseases. Among the analysis steps, functional prediction (of being deleterious) plays an important role in filtering or prioritizing nonsynonymous SNP (NS) for further analysis. Unfortunately, different prediction algorithms use different information and each has its own strength and weakness. It has been suggested that investigators should use predictions from multiple algorithms instead of relying on a single one. However, querying predictions from different databases/Web-servers for different algorithms is both tedious and time consuming, especially when dealing with a huge number of NSs identified by exome sequencing. To facilitate the process, we developed dbNSFP (database for nonsynonymous SNPs' functional predictions). It compiles prediction scores from four new and popular algorithms (SIFT, Polyphen2, LRT, and MutationTaster), along with a conservation score (PhyloP) and other related information, for every potential NS in the human genome (a total of 75,931,005). It is the first integrated database of functional predictions from multiple algorithms for the comprehensive collection of human NSs. dbNSFP is freely available for download at http://sites.google.com/site/jpopgen/dbNSFP.     

InSNP: a tool for automated detection and visualization of SNPs and InDels

Availability of high quality SNP data is a rate-limiting factor in understanding the impact of genetic variability on gene function and phenotype. Although global projects like HAPMAP generate large numbers of SNPs in an even spacing throughout the human genome, many variation studies have a more focused approach: in the follow-up of positional association findings, candidate gene studies, and functional genomics experiments, knowledge of all variations in a limited amount of sequence (e.g., a gene) is needed. This leads to a large number of resequencing experiments, for which there is a surprising lack of analysis software. We have thus developed specialized software (InSNP) for targeted mutation detection and compared its performance to Polyphred and Mutation Surveyor using 28 amplicons. Out of a total of 579 (InSNP), 644 (Polyphred), and 526 (Mutation Surveyor) SNP predictions, 39 SNPs were confirmed by human expert inspection, with five SNPs missed by Polyphred and one missed by InSNP using the default settings. For InDel detection, out of 70 (InSNP), 28 (Polyphred), and 693 (Mutation Surveyor) InDel predictions, two InDels were confirmed by human expert inspection, with one InDel missed by Polyphred. InSNP provides a user-friendly interface with better functionality for mutation detection than general-purpose sequence handling software. It provides similar SNP detection sensitivity and specificity as the public domain and commercial alternatives in the investigated dataset. We hope that InSNP lowers the barriers to the use of automated mutation detection software and aids in the improvement of the efficiency of such experiments. The Windows installer (setup) program and sample datasets are available at www.mucosa.de/insnp/.     

SNP uniqueness problem: a proof-of-principle in HapMap SNPs

SNP-based research strongly affects our biomedical and clinically associated knowledge. Nonunique and false-positive SNP existence in commonly used datasets may thus lead to biased, inaccurate clinically associated conclusions. We designed a computational study to reveal the degree of nonunique/false-positive SNPs in the HapMap dataset. Two sets of SNP flanking sequences were used as queries for BLAT analysis against the human genome. 4.2% and 11.9% of HapMap SNPs align to the genome nonuniquely (long and short, respectively). Furthermore, an average of 7.9% nonunique SNPs are included in common commercial genotyping arrays (according to our designed probes). Nonunique SNPs identified in this study are represented to various degrees in clinically associated databases, stressing the consequence of inaccurate SNP annotation and hence SNP utilization. Unfortunately, our results question some disease-related genotyping analyses, raising a worrisome concern on their validity.     

单核苷酸多态性及其数据库的应用

随着人类基因组研究计划（human genome project, HGP）DNA序列测定工作的迅速发展,研究人类基因组变异越来越受到重视。基因组变异最常见的一种形式就是单核苷酸多态性（single nucleotide polymorphism,SNPs）,SNPs已成为继限制性酶切片断长度多态性（restriction fragment length polymorphism,RFLP）和微卫星之后的第3代遗传标记,大规模的SNPs鉴定和SNP公共数据库已经建立。研究SNPs不仅有利于基因组测序,更有利于复杂性疾病相关基因的研究和药学基因组学的发展。     

Thailand mutation and variation database (ThaiMUT)

With the completion of the human genome project, novel sequencing and genotyping technologies had been utilized to detect mutations. Such mutations have continually been produced at exponential rate by researchers in various communities. Based on the population's mutation spectra, occurrences of Mendelian diseases are different across ethnic groups. A proportion of Mendelian diseases can be observed in some countries at higher rates than others. Recognizing the importance of mutation effects in Thailand, we established a National and Ethnic Mutation Database (NEMDB) for Thai people. This database, named Thailand Mutation and Variation database (ThaiMUT), offers a web-based access to genetic mutation and variation information in Thai population. This NEMDB initiative is an important informatics tool for both research and clinical purposes to retrieve and deposit human variation data. The mutation data cataloged in ThaiMUT database were derived from journal articles available in PubMed and local publications. In addition to collected mutation data, ThaiMUT also records genetic polymorphisms located in drug related genes. ThaiMUT could then provide useful information for clinical mutation screening services for Mendelian diseases and pharmacogenomic researches. ThaiMUT can be publicly accessed from http://gi.biotec.or.th/thaimut.     

Identification of 46 novel SNPs in the 130-kb region containing a myocardial infarction susceptibility gene on chromosomal band 6p21

We identified a total of 187 single-nucleotide polymorphisms (SNPs) at 11 gene loci in the 130-kb region on chromosome 6p21 containing a gene strongly associated with myocardial infarction (MI). By comparing our data with SNPs deposited in the dbSNP database at the National Center for Biotechnology Information, 46 of these SNPs (24.6%) were considered to be novel: four were identified in the P5-1 locus, 14 in the MICB locus, nine in the BAT1 locus, one in the ATP6V1G2 locus, six in the NFKBIL1 locus, one in the LTA locus, one in the TNF locus, five in the LST1 locus, four in the LY117a locus, and one in the AIF-1 locus. The SNP map presented here should provide as useful resource not only for examining the relationships between genotypes and susceptibility to the MI phenotype, but also for scanning of complex diseases mapped to this local segment on chromosome 6.     

IMGT/HLA database--a sequence database for the human major histocompatibility complex

The IMGT/HLA Database is a specialist database for sequences of the human major histocompatibility (MHC) system. It includes all the HLA sequences officially recognised and named by the WHO Nomenclature Committee for Factors of the HLA System. The database provides users with online tools and facilities for the retrieval and analysis of these sequences. These include allele reports, alignment tools and a detailed database of all source cells. The online IMGT/HLA submission tool allows the submission of both new and confirmatory allele sequences directly to the WHO Nomenclature Committee for Factors of the HLA System. The latest version (release 1.4.1, November 1999) contains 1,015 HLA alleles from over 2,270 component sequences derived from the EMBL/GenBank/DDBJ databases. From its release in December 1998 until December 1999 the IMGT/HLA website received approximately 100,000 hits. The database currently focuses on the human major histocompatibility complex but will be used as a model system to provide specialist databases for the MHC sequences of other species.     

Systematic analysis and functional annotation of variations in the genome of an Indian individual

Whole genome sequencing of personal genomes has revealed a large repertoire of genomic variations and has provided a rich template for identification of common and rare variants in genomes in addition to understanding the genetic basis of diseases. The widespread application of personal genome sequencing in clinical settings for predictive and preventive medicine has been limited due to the lack of comprehensive computational analysis pipelines. We have used next-generation sequencing technology to sequence the whole genome of a self-declared healthy male of Indian origin. We have generated around 28X of the reference human genome with over 99% coverage. Analysis revealed over 3 million single nucleotide variations and about 490,000 small insertion-deletion events including several novel variants. Using this dataset as a template, we designed a comprehensive computational analysis pipeline for the systematic analysis and annotation of functionally relevant variants in the genome. This study follows a systematic and intuitive data analysis workflow to annotate genome variations and its potential functional effects. Moreover, we integrate predictive analysis of pharmacogenomic traits with emphasis on drugs for which pharmacogenomic testing has been recommended. This study thus provides the template for genome-scale analysis of personal genomes for personalized medicine.     

ABCMdb: A database for the comparative analysis of protein mutations in ABC transporters,and a potential framework for a general application

To overcome the pathological phenomena caused by altered function of ABC (ATP Binding Cassette) proteins, their mechanisms of action are extensively investigated, often involving the design of mutant constructs for experiments. Designing mutagenetic constructs, interpreting the result of mutagenetic experiments, and finding individual genetic variants require an extensive knowledge of previously published mutations. To aid the recapitulation of mutations described in the literature, we set up a database of ABC protein mutations (ABCMdb) extracted from full‐text papers using an automatic mining approach. We have also developed a Web application interface to compare mutations in different ABC proteins using sequence alignments and to interactively map the mutations to 3D structural models. Currently our database contains protein mutations published for ABCB1, ABCB11, ABCC1, ABCC6, ABCC7, and the proteins of the ABCG subfamily. The database will be extended to include other members and subfamilies, and to provide information on whether or not a mutation is disease causing, represents a high‐incidence polymorphism, or was generated only in vitro. The ABCMdb database should already help to compare the effects of mutations at homologous positions in different ABC proteins, and its interactive tools aim to advance the design of experiments for a wider range of proteins. Hum Mutat 33:1547–1556, 2012. © 2012 Wiley Periodicals, Inc.     

中国大陆柯萨奇病毒A组16型全基因参照序列的初步建立和分析

目的建立中国大陆柯萨奇病毒A组16型（CoxA16）流行株的全基因参照序列。方法从GenBank中获得CoxA16中国大陆分离株的所有全基因序列和氨基酸序列,用DNAstar/MegAlign软件对所得序列进行多序列比对和进化分析,按照参照序列标准拟定CoxA16的全基因参照序列和氨基酸序列,并与参考序列进行比对分析。结果中国大陆分离的CoxA16毒株全基因序列共8株,分离于2005-2009年,其中2008年5株,广东省5株;通过序列比对获得了大陆CoxA16全基因和氨基酸参照序列;参考毒株间核苷酸序列同源性介于79.0%～98.8%,氨基酸序列同源性为94.3%～99.9%,与参照序列的核苷酸同源性为79.7%～97.0%,氨基酸同源性介于95.1%～99.5%之间,同源性最低的为2008年安徽阜阳的FY18株。结论比对分析了中国大陆CoxA16毒株全序列,成功建立了中国大陆CoxA16全基因和氨基酸参照序列。