Naomi Rosen

GeneCards Version 3: the human gene integrator

GeneCards (www.genecards.org) is a comprehensive, authoritative compendium of annotative information about human genes, widely used for nearly 15 years. Its gene-centric content is automatically mined and integrated from over 80 digital sources, resulting in a web-based deep-linked card for each of >73 000 human gene entries, encompassing the following categories: protein coding, pseudogene, RNA gene, genetic locus, cluster and uncategorized. We now introduce GeneCards Version 3, featuring a speedy and sophisticated search engine and a revamped, technologically enabling infrastructure, catering to the expanding needs of biomedical researchers. A key focus is on gene-set analyses, which leverage GeneCards’ unique wealth of combinatorial annotations. These include the GeneALaCart batch query facility, which tabulates user-selected annotations for multiple genes and GeneDecks, which identifies similar genes with shared annotations, and finds set-shared annotations by descriptor enrichment analysis. Such set-centric features address a host of applications, including microarray data analysis, cross-database annotation mapping and gene-disorder associations for drug targeting. We highlight the new Version 3 database architecture, its multi-faceted search engine, and its semi-automated quality assurance system. Data enhancements include an expanded visualization of gene expression patterns in normal and cancer tissues, an integrated alternative splicing pattern display, and augmented multi-source SNPs and pathways sections. GeneCards now provides direct links to gene-related research reagents such as antibodies, recombinant proteins, DNA clones and inhibitory RNAs and features gene-related drugs and compounds lists. We also portray the GeneCards Inferred Functionality Score annotation landscape tool for scoring a gene’s functional information status. Finally, we delineate examples of applications and collaborations that have benefited from the GeneCards suite. Database URL: www.genecards.org

Human Gene-Centric Databases at the Weizmann Institute of Science: GeneCards, UDB, CroW 21 and HORDE

Recent enhancements and current research in the GeneCards (GC) (http://bioinfo.weizmann.ac.il/cards/) project are described, including the addition of gene expression profiles and integrated gene locations. Also highlighted are the contributions of specialized associated human gene-centric databases developed at the Weizmann Institute. These include the Unified Database (UDB) (http://bioinfo.weizmann.ac.il/udb) for human genome mapping, the human Chromosome 21 database at the Weizmann Insti-tute (CroW 21) (http://bioinfo.weizmann.ac.il/crow21), and the Human Olfactory Receptor Data Explora-torium (HORDE) (http://bioinfo.weizmann.ac.il/HORDE). The synergistic relationships amongst these efforts have positively impacted the quality, quantity and usefulness of the GeneCards gene compendium.

GeneCards™ 2002: towards a complete, object-oriented, human gene compendium

MOTIVATION In the post-genomic era, functional analysis of genes requires a sophisticated interdisciplinary arsenal. Comprehensive resources are challenged to provide consistently improving, state-of-the-art tools. RESULTS GeneCards (Rebhan et al., 1998) has made innovative strides: (a). regular updates and enhancements incorporating new genes enriched with sequences, genomic locations, cDNA assemblies, orthologies, medical information, 3D protein structures, gene expression, and focused SNP summaries; (b). restructured software using object-oriented Perl, migration to schema-driven XML, and (c). pilot studies, introducing methods to produce cards for novel and predicted genes.

In-silico human genomics with GeneCards

Since 1998, the bioinformatics, systems biology, genomics and medical communities have enjoyed a synergistic relationship with the GeneCards database of human genes (http://www.genecards.org). This human gene compendium was created to help to introduce order into the increasing chaos of information flow. As a consequence of viewing details and deep links related to specific genes, users have often requested enhanced capabilities, such that, over time, GeneCards has blossomed into a suite of tools (including GeneDecks, GeneALaCart, GeneLoc, GeneNote and GeneAnnot) for a variety of analyses of both single human genes and sets thereof. In this paper, we focus on inhouse and external research activities which have been enabled, enhanced, complemented and, in some cases, motivated by GeneCards. In turn, such interactions have often inspired and propelled improvements in GeneCards. We describe here the evolution and architecture of this project, including examples of synergistic applications in diverse areas such as synthetic lethality in cancer, the annotation of genetic variations in disease, omics integration in a systems biology approach to kidney disease, and bioinformatics tools.

The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses.

GeneCards, the human gene compendium, enables researchers to effectively navigate and inter‐relate the wide universe of human genes, diseases, variants, proteins, cells, and biological pathways. Our recently launched Version 4 has a revamped infrastructure facilitating faster data updates, better‐targeted data queries, and friendlier user experience. It also provides a stronger foundation for the GeneCards suite of companion databases and analysis tools. Improved data unification includes gene‐disease links via MalaCards and merged biological pathways via PathCards, as well as drug information and proteome expression. VarElect, another suite member, is a phenotype prioritizer for next‐generation sequencing, leveraging the GeneCards and MalaCards knowledgebase. It automatically infers direct and indirect scored associations between hundreds or even thousands of variant‐containing genes and disease phenotype terms. VarElects capabilities, either independently or within TGex, our comprehensive variant analysis pipeline, help prepare for the challenge of clinical projects that involve thousands of exome/genome NGS analyses.

GeneHancer: genome-wide integration of enhancers and target genes in GeneCards

Abstract A major challenge in understanding gene regulation is the unequivocal identification of enhancer elements and uncovering their connections to genes. We present GeneHancer, a novel database of human enhancers and their inferred target genes, in the framework of GeneCards. First, we integrated a total of 434 000 reported enhancers from four different genome-wide databases: the Encyclopedia of DNA Elements (ENCODE), the Ensembl regulatory build, the functional annotation of the mammalian genome (FANTOM) project and the VISTA Enhancer Browser. Employing an integration algorithm that aims to remove redundancy, GeneHancer portrays 285 000 integrated candidate enhancers (covering 12.4% of the genome), 94 000 of which are derived from more than one source, and each assigned an annotation-derived confidence score. GeneHancer subsequently links enhancers to genes, using: tissue co-expression correlation between genes and enhancer RNAs, as well as enhancer-targeted transcription factor genes; expression quantitative trait loci for variants within enhancers; and capture Hi-C, a promoter-specific genome conformation assay. The individual scores based on each of these four methods, along with gene–enhancer genomic distances, form the basis for GeneHancer’s combinatorial likelihood-based scores for enhancer–gene pairing. Finally, we define ‘elite’ enhancer–gene relations reflecting both a high-likelihood enhancer definition and a strong enhancer–gene association. GeneHancer predictions are fully integrated in the widely used GeneCards Suite, whereby candidate enhancers and their annotations are displayed on every relevant GeneCard. This assists in the mapping of non-coding variants to enhancers, and via the linked genes, forms a basis for variant–phenotype interpretation of whole-genome sequences in health and disease. Database URL: http://www.genecards.org/

An Overview of Synergistic Data Tools for Biological Scrutiny

A network of biological databases is reviewed, supplying a framework for studies of human genes and the association of their genomic variations with human pheno- types. The network is composed of GeneCards, the human gene compendium, which provides comprehensive informa- tion on all known and predicted human genes, along with its suite members GeneDecks and GeneLoc. Two databases are shown that address genes and variations focusing on ol- factory reception (HORDE) and transduction (GOSdb). In the realm of disease scrutiny, we portray MalaCards, a novel comprehensive database of human diseases and their anno- tations. Also shown is GeneKid, a tool aimed at generating novel kidney disease biomarkers using systems biology, as well as Xome, a database for whole-exome next-generation DNA sequences for human diseases in the Israeli popula- tion. Finally, we show LifeMap Discovery, a database of em- bryonic development, stem cell research and regenerative medicine, which links to both GeneCards and MalaCards.

The GeneCards/spl trade/ family of databases: GeneCards, GeneLoc, GeneNote and GeneAnnot

The popular GeneCards/spl trade/ integrated database of human genes, genomic maps, proteins and diseases has recently spawned three related functional genomics efforts. As sequence data rapidly accumulates, the bottleneck in biology shifts from data production to analysis; researchers seek a profound understanding of the role of each gene, and of the way genes function together. GeneLoc integrates human gene collections by comparing genomic coordinates at the exon level, eliminating redundancies, and assigning unique and meaningful location-based identifiers. GeneCards expression tissue vectors are provided by GeneNote, the first effort to present sophisticated expression analyses for a variety of normal human tissues using the full complement of gene representations (Affymetrix arrays HG-U95A-E). The GeneAnnot system aligns probe-sets with the major public repositories of human mRNA sequences, and provides detailed annotation for each probe-set, with links to GeneCards.

GeneCards/spl trade/ 2002: an evolving human gene compendium

GeneCards/spl trade/ (http://bioinfo.weizmann.ac.il/cards/) is an automated, integrated database of human genes, genomic maps, proteins, and diseases, with software that retrieves, consolidates, searches, and displays human genome information. Over the past few years, the system has consistently, added new features including sequence accessions, genomic locations, cDNA assemblies, orthologies, medical information, 3D protein structures, SNP summaries, and gene expression. In parallel, its infrastructure is being upgraded to use object-oriented Perl to produce, display, and search data that is formatted in Extensible Markup Language (XML, (http://www.w3.org/XML), providing a basis for schema-driven display code and context-specific searches.