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PubMed2004

The challenge of documenting mutation across the genome: the human genome variation society approach.

New methods for the detection of mutations and the completion of the human genome sequencing project have contributed to an exponential rise in variation information that must be collected, quality controlled, documented, and stored safely to ensure future availability to health care professionals, researchers, and others. There may be anywhere from one to more than 1,000 mutations in any given gene. To date, this information has been collected by general databases such as Online Mendelian Inheritance in Man (OMIM) or the Human Gene Mutation Database (HGMD), which collect only published mutations and, in the case of OMIM, selected published mutations. Unpublished mutations have made their way into Locus Specific Databases (LSDBs), and these can often contain as many unpublished mutations as published ones, in addition to other more detailed gene-specific information. LSDBs, however, do not exist for all genes at this time. Through their interactions, a number of members of the Human Genome Variation Society (HGVS) have developed nomenclature, standard software to curate mutations in gene specific databases, a WayStation to collect and review new mutations from research and diagnostic laboratories, and central databases to store and display these mutations and their associated phenotypes. Nomenclature is now well defined for the commonest types of mutation, with work continuing on systematically naming the more complex types. Other projects, such as dedicated specialized software for LSDBs, are in the early stages of development.

Computational Biology↗
PubMed2005

PolyMAPr: programs for polymorphism database mining, annotation, and functional analysis.

Pharmacogenomic and disease-association studies rely on identifying a comprehensive set of polymorphisms within candidate genes. Public SNP databases are a rich source of polymorphism data, but mining them effectively requires overcoming at least four challenges: ensuring accurate annotations for genes and polymorphisms, eliminating both inter- and intra-database redundancy, integrating data from multiple public sources with data generated locally, and prioritizing the variants for further study. PolyMAPr (Polymorphism Mining and Annotation Programs)' was developed to overcome these challenges and to improve the efficiency of database mining and polymorphism annotation. PolyMAPr takes as input a file containing a list of genes to be processed and files containing each annotated gene sequence. Polymorphic sequences obtained from public databases (dbSNP, CGAP, and JSNP) or through local SNP discovery efforts, as well as oligonucleotide sequences (e.g., PCR primers), are mapped to the annotated gene sequences and named according to suggested nomenclature guidelines. The functional effects of nonsynonymous coding-region SNPs (cSNPs) and any variants that might alter exon splicing enhancer (ESE) sites, putative transcription factor binding sites, or intron-exon splice sites are predicted. The output files are accessible though a browser interface. In addition, the results are also provided in Extensible Markup Language (XML) format to facilitate uploading them into a local relational database. PolyMAPr increases the efficiency of mining public databases for genetic variants within candidate genes and provides a mechanism by which data from multiple sources (both public and private) can be uniformly integrated, thereby significantly reducing the effort required to obtain a comprehensive set of polymorphisms for pharmacogenomic and disease-association studies. PolyMAPr can be obtained from http://pharmacogenomics.wustl.edu.

Databases, Nucleic Acid↗
PubMed2005

TCOF1 mutation database: novel mutation in the alternatively spliced exon 6A and update in mutation nomenclature.

Recently, a novel exon was described in TCOF1 that, although alternatively spliced, is included in the major protein isoform. In addition, most published mutations in this gene do not conform to current mutation nomenclature guidelines. Given these observations, we developed an online database of TCOF1 mutations in which all the reported mutations are renamed according to standard recommendations and in reference to the genomic and novel cDNA reference sequences (www.genoma.ib.usp.br/TCOF1_database). We also report in this work: 1) results of the first screening for large deletions in TCOF1 by Southern blot in patients without mutation detected by direct sequencing; 2) the identification of the first pathogenic mutation in the newly described exon 6A; and 3) statistical analysis of pathogenic mutations and polymorphism distribution throughout the gene.

Alternative Splicing↗
PubMed2005

eOPA1: an online database for OPA1 mutations.

Autosomal dominant optic atrophy (ADOA), also known as Kjer disease, is characterized by moderate to severe loss of visual acuity with an insidious onset in early childhood, blue-yellow dyschromatopsia, and central scotoma. An optic atrophy gene, called OPA1, has been identified in most cases of the disease. A total of 83 OPA1 mutations, often family-specific, have been reported so far, and the observations support the hypothesis that haploinsufficiency and the functional loss of a single allele may lead to ADOA. We have developed a new locus-specific database (LSDB), eOPA1 (http://lbbma.univ-angers.fr/eOPA1/) aimed at collecting published and unpublished sequence variations in OPA1. The database has been designed to incorporate new submissions rapidly and will provide a secured online catalog of OPA1 mutations and nonpathogenic sequence variants (NPSVs). The LSDB should prove useful for molecular diagnosis, large-scale mutation statistics, and the determination of original genotype-phenotype correlations in studies on ADOA.

Base Sequence↗
PubMed2005

LOVD: easy creation of a locus-specific sequence variation database using an "LSDB-in-a-box" approach.

The completion of the human genome project has initiated, as well as provided the basis for, the collection and study of all sequence variation between individuals. Direct access to up-to-date information on sequence variation is currently provided most efficiently through web-based, gene-centered, locus-specific databases (LSDBs). We have developed the Leiden Open (source) Variation Database (LOVD) software approaching the "LSDB-in-a-Box" idea for the easy creation and maintenance of a fully web-based gene sequence variation database. LOVD is platform-independent and uses PHP and MySQL open source software only. The basic gene-centered and modular design of the database follows the recommendations of the Human Genome Variation Society (HGVS) and focuses on the collection and display of DNA sequence variations. With minimal effort, the LOVD platform is extendable with clinical data. The open set-up should both facilitate and promote functional extension with scripts written by the community. The LOVD software is freely available from the Leiden Muscular Dystrophy pages (www.DMD.nl/LOVD/). To promote the use of LOVD, we currently offer curators the possibility to set up an LSDB on our Leiden server.

Computational Biology↗
PubMed2005

Molecular diagnosis of inherited disorders: lessons from hemoglobinopathies.

Hemoglobinopathies constitute a major health problem worldwide, with a high carrier frequency, particularly in certain regions where malaria has been endemic. These disorders are characterized by a vast clinical and hematological phenotypic heterogeneity. Over 1,200 different genetic alterations that affect the DNA sequence of the human alpha-like (HBZ, HBA2, HBA1, and HBQ1) and beta-like (HBE1, HBG2, HBG1, HBD, and HBB) globin genes are mainly responsible for the observed clinical heterogeneity. These mutations, together with detailed information about the resulting phenotype, are documented in the globin locus-specific HbVar database. Family studies and comprehensive hematological analyses provide useful insights for accurately diagnosing thalassemia at the DNA level. For this purpose, numerous techniques can provide accurate, rapid, and cost-effective identification of the underlying genetic defect in affected individuals. The aim of this article is to review the diverse methodological and technical platforms available for the molecular diagnosis of inherited disorders, using thalassemia and hemoglobinopathies as a model. This article also attempts to shed light on issues closely related to thalassemia diagnostics, such as prenatal and preimplantation genetic diagnoses and genetic counseling, for better-quality disease management.

Databases, Nucleic Acid↗
PubMed2005

Predicting the oncogenicity of missense mutations reported in the International Agency for Cancer Research (IARC) mutation database on p53.

Many mutation databases, comprising thousands of reported mutations, are available. Often the clinical significance of the reported mutations is unknown. In this study we developed an algorithm that allows prediction of the clinical significance of missense mutations reported in a mutation database. Nonsense mutations are used as a referent group for this assessment. We used the International Association for Research on Cancer (IARC) mutation database on TP53 to implement the algorithm. First, on the basis of published data [Nachman MW, Crowell SL. 2000. Genetics 156:297-304], we ascribed mutation rates to every single nucleotide substitution (SNS) in the core domain of the TP53 gene. Second, for every possible SNS we computed the expected number of missense mutations, under the assumption that missense mutations are as oncogenic as nonsense ones. The natural logarithm of the ratio of the observed to the expected number of missense mutations (LR) was used as a quantitative measure of oncogenicity (i.e., the ability of a mutation to produce cancer). We estimated the relative oncogenicity of all missense mutations reported in the IARC p53 mutation database, and constructed a profile of oncogenicity of the missense mutations along the DNA-binding region of p53.

Algorithms↗
PubMed2005

Locus-specific databases: from ethical principles to practice.

Locus-specific databases (LSDBs) play an essential role in clinical care and research. They differ from traditional genetic databases in that they propose to place the mutations of "anonymized" patients directly on the World Wide Web. The proliferation of ethical guidelines and legal requirements affects the rapid and free transmission of clinical data, which is vital for both the daily management of patients and research into better diagnostics and treatment. This paper proposes a review of ethical principles endorsed by international instruments that are of particular relevance to LSDBs. It aims to translate them into 12 proposed practical guidelines that LSDB curators can use in collecting data for clinical research. Perhaps these guideposts will serve as a first step toward translating principles into practice.

Databases, Nucleic Acid↗
PubMed2006

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.

Ten years ago, the groundwork for the discovery of the genetic basis of chronic pancreatitis was laid by linkage analyses of large kindreds with autosomal dominant hereditary chronic pancreatitis. Subsequent candidate gene sequencing of the 7q35 chromosome region revealed a strong association of the c.365G > A (p.R122 H) mutation of the PRSS1 gene encoding cationic trypsinogen with hereditary pancreatitis. In the following years, further mutations of this gene were discovered in patients with hereditary or idiopathic chronic pancreatitis. In vitro the mutations increase autocatalytic conversion of trypsinogen to active trypsin and thus probably cause premature, intrapancreatic trypsinogen activation in vivo. The clinical presentation is highly variable, but most affected mutation carriers have relatively mild disease. In this review, we summarize the current knowledge on trypsinogen mutations and their role in pancreatic diseases.

DNA Mutational Analysis↗
PubMed2006

Interactive visual analysis of SNP data for rapid autozygosity mapping in consanguineous families.

Autozygosity mapping of recessive disorders using small numbers of highly inbred families is a powerful tool for disease gene identification. With the advent of cheap rapid methods for whole-genome SNP genotyping, data analysis, rather than laboratory work, has become rate-limiting for this approach. Here, we describe AutoSNPa, a computer program used for handling and visually presenting large amounts of SNP data, in such a way as to facilitate the rapid identification and subsequent scrutiny of autozygous regions.

Algorithms↗
PubMed2007

Single base-pair substitutions in exon-intron junctions of human genes: nature, distribution, and consequences for mRNA splicing.

Although single base-pair substitutions in splice junctions constitute at least 10% of all mutations causing human inherited disease, the factors that determine their phenotypic consequences at the RNA level remain to be fully elucidated. Employing a neural network for splice-site recognition, we performed a meta-analysis of 478 disease-associated splicing mutations, in 38 different genes, for which detailed laboratory-based mRNA phenotype assessment had been performed. Inspection of the +/-50-bp DNA sequence context of the mutations revealed that exon skipping was the preferred phenotype when the immediate vicinity of the affected exon-intron junctions was devoid of alternative splice-sites. By contrast, in the presence of at least one such motif, cryptic splice-site utilization, became more prevalent. This association was, however, confined to donor splice-sites. Outside the obligate dinucleotide, the spatial distribution of pathological mutations was found to differ significantly from that of SNPs. Whereas disease-associated lesions clustered at positions -1 and +3 to +6 for donor sites and -3 for acceptor sites, SNPs were found to be almost evenly distributed over all sequence positions considered. When all putative missense mutations in the vicinity of splice-sites were extracted from the Human Gene Mutation Database for the 38 studied genes, a significantly higher proportion of changes at donor sites (37/152; 24.3%) than at acceptor splice-sites (1/142; 0.7%) was found to reduce the neural network signal emitted by the respective splice-site. Based upon these findings, we estimate that some 1.6% of disease-causing missense substitutions in human genes are likely to affect the mRNA splicing phenotype. Taken together, our results are consistent with correct donor splice-site recognition being a key step in exon recognition.

DNA Mutational Analysis↗
PubMed2007

Italian Rett database and biobank.

Rett syndrome is the second most common cause of severe mental retardation in females, with an incidence of approximately 1 out of 10,000 live female births. In addition to the classic form, a number of Rett variants have been described. MECP2 gene mutations are responsible for about 90% of classic cases and for a lower percentage of variant cases. Recently, CDKL5 mutations have been identified in the early onset seizures variant and other atypical Rett patients. While the high percentage of MECP2 mutations in classic patients supports the hypothesis of a single disease gene, the low frequency of mutated variant cases suggests genetic heterogeneity. Since 1998, we have performed clinical evaluation and molecular analysis of a large number of Italian Rett patients. The Italian Rett Syndrome (RTT) database has been developed to share data and samples of our RTT collection with the scientific community (http://www.biobank.unisi.it). This is the first RTT database that has been connected with a biobank. It allows the user to immediately visualize the list of available RTT samples and, using the "Search by" tool, to rapidly select those with specific clinical and molecular features. By contacting bank curators, users can request the samples of interest for their studies. This database encourages collaboration projects with clinicians and researchers from around the world and provides important resources that will help to better define the pathogenic mechanisms underlying Rett syndrome.

Databases as Topic↗
PubMed2007

HbVar database of human hemoglobin variants and thalassemia mutations: 2007 update.

HbVar (http://globin.bx.psu.edu/hbvar) is a locus-specific database (LSDB) developed in 2001 by a multi-center academic effort to provide timely information on the genomic sequence changes leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies. Database records include extensive phenotypic descriptions, biochemical and hematological effects, associated pathology, and ethnic occurrence, accompanied by mutation frequencies and references. In addition to the regular updates to entries, we report significant advances and updates, which can be useful not only for HbVar users but also for other LSDB development and curation in general. The query page provides more functionality but in a simpler, more user-friendly format and known single nucleotide polymorphisms in the human alpha- and beta-globin loci are provided automatically. Population-specific beta-thalassemia mutation frequencies for 31 population groups have been added and/or modified and the previously reported delta- and alpha-thalassemia mutation frequency data from 10 population groups have also been incorporated. In addition, an independent flat-file database, named XPRbase (http://www.goldenhelix.org/xprbase), has been developed and linked to the main HbVar web page to provide a succinct listing of 51 experimental protocols available for globin gene mutation screening. These updates significantly augment the database profile and quality of information provided, which should increase the already high impact of the HbVar database, while its combination with the UCSC powerful genome browser and the ITHANET web portal paves the way for drawing connections of clinical importance, that is from genome to function to phenotype.

DNA Mutational Analysis↗
PubMed2002

Identification of cancer/testis genes by database mining and mRNA expression analysis.

Cancer/testis (CT) antigens are immunogenic proteins expressed predominantly in gametogenic tissue and cancer; they are considered promising target molecules for cancer vaccines. The identification of new CT genes is essential to the development of polyvalent cancer vaccines designed to overcome tumor heterogeneity and antigen loss. In the current study, a search for new CT genes was conducted by mining the Unigene database for gene clusters that contain expressed sequence tags derived solely from both normal testis and tumor-derived cDNA libraries. This search identified 1,325 different cancer/testis-associated Unigene clusters. The mRNA expression pattern of 73 cancer/testis-associated Unigene clusters was assessed by reverse transcriptase polymerase chain reaction. Three gene products, CT15/Hs.177959, CT16/Hs.245431 and CT17/Hs.178062, were detected only in testis and in tumor tissue. CT15 is equivalent to ADAM2/fertilin-beta. CT16, an uncharacterized gene product, has homology (30-50%) to members of the GAGE gene family and is 89% identical to CT16.2/Hs.293317, indicating that CT16 and CT16.2 are members of a new GAGE gene family. The uncharacterized gene product, CT17, has homology (30%) to phospholipase A1. RT-PCR analysis showed that CT15 is expressed exclusively in renal cancer, whereas CT16 and CT17 are expressed in a range of human cancers. Real-time RT-PCR analysis of newly defined CT genes and the prototype CT antigens, MAGE-3 and NY-ESO-1, revealed low levels (less than 3% of the level detected in testis) of CT15, CT16 and NY-ESO-1 in a limited range of normal, non-gametogenic tissues. This study demonstrates the merits of database mining with respect to the identification of tissue-restricted gene products expressed in cancer.

Antigens, Neoplasm↗
PubMedDate not supplied

Arresting evidence.

Explore the source record for details and available documents.

Criminal Law↗
PubMed2004

Exclusion of repetitive DNA elements from gnathostome Hox clusters.

Despite their homology and analogous function, the Hox gene clusters of vertebrates and invertebrates are subject to different constraints on their structural organization. This is demonstrated by a drastically different distribution of repetitive DNA elements in the Hox cluster regions. While gnathostomes have a strong tendency to exclude repetitive DNA elements from the inside of their Hox clusters, no such trend can be detected in the Hox gene clusters of protostomes. Repeats "invade" the gnathostome Hox clusters from the 5' and 3' ends while the core of the clusters remains virtually free of repetitive DNA. This invasion appears to be correlated with relaxed constraints associated with gene loss after cluster duplications.

Animals↗
PubMed2005

A database of recombinant viruses and recombinant viral vectors available from the RIKEN DNA bank.

BACKGROUND: Viral vectors are required as gene-delivery systems for gene therapy and basic research. Recombinant adenoviruses (rAds) expressing genes of interest are being developed as research tools and many studies in vitro and in vivo have already been performed with such rAds. METHODS: Shuttle vectors for rAds were constructed with full-length cDNAs and rAds were generated in HEK293 cells by the COS-TPC method. The rAds and shuttle vectors were developed by the Japanese research community and deposited in the RIKEN DNA Bank (RDB; http://www.brc.riken.jp/lab/dna/en/) for distribution to the scientific community. The Recombinant Virus Database (RVD; http://www.brc.riken.jp/lab/dna/rvd/) was established at the RIKEN BioResource Center (BRC) in Japan as the source of information about and distribution of the various resources. RESULTS: The RIKEN BRC is releasing more than 300 recombinant viruses (RVs) and 500 shuttle vectors, as well as all related information, which is included in a newly established database, the RVD. The RVD consists of (i) information about the RVs, the inserted cDNAs and the shuttle vectors; (ii) data about sequence-tagged sites (STSs) that are markers of viral DNAs; and (iii) experimental protocols for the use of RVs. CONCLUSIONS: The new database and available resources should be very useful to scientists who are studying human gene therapy and performing related basic research. It is a web-interfaced flat-file database that can be accessed through the internet. Moreover, all of the resources deposited in the RDB, which is a public facility in Japan, are available to researchers around the world.

Adenoviridae↗