The Rat Genome Database, update 2007--easing the path from disease to data and back again.

The Rat Genome Database (RGD, http://rgd.mcw.edu) is one of the core resources for rat genomics and recent developments have focused on providing support for disease-based research using the rat model. Recognizing the importance of the rat as a disease model we have employed targeted curation strategies to curate genes, QTL and strain data for neurological and cardiovascular disease areas. This work has centered on rat but also includes data for mouse and human to create 'disease portals' that provide a unified view of the genes, QTL and strain models for these diseases across the three species. The disease curation efforts combined with normal curation activities have served to greatly increase the content of the database, particularly for biological information, including gene ontology, disease, pathway and phenotype ontology annotations. In addition to improving the features and database content, community outreach has been expanded to demonstrate how investigators can leverage the resources at RGD to facilitate their research and to elicit suggestions and needs for future developments. We have published a number of papers that provide additional information on the ontology annotations and the tools at RGD for data mining and analysis to better enable researchers to fully utilize the database.

Integrative annotation of 21,037 human genes validated by full-length cDNA clones.

The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms, non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for non-protein-coding RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources needed for the exploration of human biology and pathology.

The Rat Genome Database (RGD): developments towards a phenome database.

The Rat Genome Database (RGD) (http://rgd.mcw.edu) aims to meet the needs of its community by providing genetic and genomic infrastructure while also annotating the strengths of rat research: biochemistry, nutrition, pharmacology and physiology. Here, we report on RGD's development towards creating a phenome database. Recent developments can be categorized into three groups. (i) Improved data collection and integration to match increased volume and biological scope of research. (ii) Knowledge representation augmented by the implementation of a new ontology and annotation system. (iii) The addition of quantitative trait loci data, from rat, mouse and human to our advanced comparative genomics tools, as well as the creation of new, and enhancement of existing, tools to enable users to efficiently browse and survey research data. The emphasis is on helping researchers find genes responsible for disease through the use of rat models. These improvements, combined with the genomic sequence of the rat, have led to a successful year at RGD with over two million page accesses that represent an over 4-fold increase in a year. Future plans call for increased annotation of biological information on the rat elucidated through its use as a model for human pathobiology. The continued development of toolsets will facilitate integration of these data into the context of rat genomic sequence, as well as allow comparisons of biological and genomic data with the human genomic sequence and of an increasing number of organisms.

Tools and strategies for physiological genomics: the Rat Genome Database.

The broad goal of physiological genomics research is to link genes to their functions using appropriate experimental and computational techniques. Modern genomics experiments enable the generation of vast quantities of data, and interpretation of this data requires the integration of information derived from many diverse sources. Computational biology and bioinformatics offer the ability to manage and channel this information torrent. The Rat Genome Database (RGD; http://rgd.mcw.edu) has developed computational tools and strategies specifically supporting the goal of linking genes to their functional roles in rat and, using comparative genomics, to human and mouse. We present an overview of the database with a focus on these unique computational tools and describe strategies for the use of these resources in the area of physiological genomics.

Exploring phenotypic data at the rat genome database.

The laboratory rat, Rattus norvegicus, is an important model of human health and disease, and experimental findings in the rat have direct relevance to human-based research. The Rat Genome Database (RGD, http://rgd.mcw.edu) is a model-organism database that provides access to wide variety of curated rat data such as genes and their homologs, quantitative trait loci, phenotypes, comparative mapping, and genome analysis. We present an overview of the database followed by specific examples that can be used to gain experience in employing RGD to explore the wealth of functional data available for the rat. We show how to make associations with the genome and use comparative tools to link the rat with human and mouse in order to integrate results from these three species of critical biomedical importance.

Using multiple ontologies to integrate complex biological data.

The strength of the rat as a model organism lies in its utility in pharmacology, biochemistry and physiology research. Data resulting from such studies is difficult to represent in databases and the creation of user-friendly data mining tools has proved difficult. The Rat Genome Database has developed a comprehensive ontology-based data structure and annotation system to integrate physiological data along with environmental and experimental factors, as well as genetic and genomic information. RGD uses multiple ontologies to integrate complex biological information from the molecular level to the whole organism, and to develop data mining and presentation tools. This approach allows RGD to indicate not only the phenotypes seen in a strain but also the specific values under each diet and atmospheric condition, as well as gender differences. Harnessing the power of ontologies in this way allows the user to gather and filter data in a customized fashion, so that a researcher can retrieve all phenotype readings for which a high hypoxia is a factor. Utilizing the same data structure for expression data, pathways and biological processes, RGD will provide a comprehensive research platform which allows users to investigate the conditions under which biological processes are altered and to elucidate the mechanisms of disease.

Integrative genomics: in silico coupling of rat physiology and complex traits with mouse and human data.

Integration of the large variety of genome maps from several organisms provides the mechanism by which physiological knowledge obtained in model systems such as the rat can be projected onto the human genome to further the research on human disease. The release of the rat genome sequence provides new information for studies using the rat model and is a key reference against which existing and new rat physiological results can be aligned. Previously, we described comparative maps of the rat, mouse, and human based on EST sequence comparisons combined with radiation hybrid maps. Here, we use new data and introduce the Integrated Genomics Environment, an extensive database of curated and integrated maps, markers, and physiological results. These results are integrated by using VCMapview, a java-based map integration and visualization tool. This unique environment allows researchers to relate results from cytogenetic, genetic, and radiation hybrid studies to the genome sequence and compare regions of interest between human, mouse, and rat. Integrating rat physiology with mouse genetics and clinical results from human by using the respective genomes provides a novel route to capitalize on comparative genomics and the strengths of model organism biology.

High-density rat radiation hybrid maps containing over 24,000 SSLPs, genes, and ESTs provide a direct link to the rat genome sequence.

The laboratory rat is a major model organism for systems biology. To complement the cornucopia of physiological and pharmacological data generated in the rat, a large genomic toolset has been developed, culminating in the release of the rat draft genome sequence. The rat draft sequence used a variety of assembly packages, as well as data from the Radiation Hybrid (RH) map of the rat as part of their validation. As part of the Rat Genome Project, we have been building a high-density RH map to facilitate data integration from multiple maps and now to help validate the genome assembly. By incorporating vectors from our lab and several other labs, we have doubled the number of simple sequence length polymorphisms (SSLPs), genes, expressed sequence tags (ESTs), and sequence-tagged sites (STSs) compared to any other genome-wide rat map, a total of 24,437 elements. During the process, we also identified a novel approach for integrating the RH placement results from multiple maps. This new integrated RH map contains approximately 10 RH-mapped elements per Mb on the genome assembly, enabling the RH maps to serve as a scaffold for a variety of data visualization tools.