A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Physical Interactions <s> The Database of Interacting Proteins (http://dip.doe-mbi.ucla.edu) aims to integrate the diverse body of experimental evidence on protein–protein interactions into a single, easily accessible online database. Because the reliability of experimental evidence varies widely, methods of quality assessment have been developed and utilized to identify the most reliable subset of the interactions. This CORE set can be used as a reference when evaluating the reliability of high-throughput protein–protein interaction data sets, for development of prediction methods, as well as in the studies of the properties of protein interaction networks. <s> BIB001 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Physical Interactions <s> Human Protein Reference Database (HPRD—http://www.hprd.org/), initially described in 2003, is a database of curated proteomic information pertaining to human proteins. We have recently added a number of new features in HPRD. These include PhosphoMotif Finder, which allows users to find the presence of over 320 experimentally verified phosphorylation motifs in proteins of interest. Another new feature is a protein distributed annotation system—Human Proteinpedia (http://www.humanproteinpedia.org/)—through which laboratories can submit their data, which is mapped onto protein entries in HPRD. Over 75 laboratories involved in proteomics research have already participated in this effort by submitting data for over 15 000 human proteins. The submitted data includes mass spectrometry and protein microarray-derived data, among other data types. Finally, HPRD is also linked to a compendium of human signaling pathways developed by our group, NetPath (http://www.netpath.org/), which currently contains annotations for several cancer and immune signaling pathways. Since the last update, more than 5500 new protein sequences have been added, making HPRD a comprehensive resource for studying the human proteome. <s> BIB002 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Physical Interactions <s> Protein complexes are key molecular entities that integrate multiple gene products to perform cellular functions. The CORUM (http://mips.gsf.de/genre/proj/corum/index.html) database is a collection of experimentally verified mammalian protein complexes. Information is manually derived by critical reading of the scientific literature from expert annotators. Information about protein complexes includes protein complex names, subunits, literature references as well as the function of the complexes. For functional annotation, we use the FunCat catalogue that enables to organize the protein complex space into biologically meaningful subsets. The database contains more than 1750 protein complexes that are built from 2400 different genes, thus representing 12% of the protein-coding genes in human. A web-based system is available to query, view and download the data. CORUM provides a comprehensive dataset of protein complexes for discoveries in systems biology, analyses of protein networks and protein complex-associated diseases. Comparable to the MIPS reference dataset of protein complexes from yeast, CORUM intends to serve as a reference for mammalian protein complexes. <s> BIB003 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Physical Interactions <s> InnateDB (http://www.innatedb.com) is an integrated analysis platform that has been specifically designed to facilitate systems-level analyses of mammalian innate immunity networks, pathways and genes. In this article, we provide details of recent updates and improvements to the database. InnateDB now contains >196 000 human, mouse and bovine experimentally validated molecular interactions and 3000 pathway annotations of relevance to all mammalian cellular systems (i.e. not just immune relevant pathways and interactions). In addition, the InnateDB team has, to date, manually curated in excess of 18 000 molecular interactions of relevance to innate immunity, providing unprecedented insight into innate immunity networks, pathways and their component molecules. More recently, InnateDB has also initiated the curation of allergy- and asthma-related interactions. Furthermore, we report a range of improvements to our integrated bioinformatics solutions including web service access to InnateDB interaction data using Proteomics Standards Initiative Common Query Interface, enhanced Gene Ontology analysis for innate immunity, and the availability of new network visualizations tools. Finally, the recent integration of bovine data makes InnateDB the first integrated network analysis platform for this agriculturally important model organism. <s> BIB004 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Physical Interactions <s> IntAct (freely available at http://www.ebi.ac.uk/intact) is an open-source, open data molecular interaction database populated by data either curated from the literature or from direct data depositions. IntAct has developed a sophisticated web-based curation tool, capable of supporting both IMEx- and MIMIx-level curation. This tool is now utilized by multiple additional curation teams, all of whom annotate data directly into the IntAct database. Members of the IntAct team supply appropriate levels of training, perform quality control on entries and take responsibility for long-term data maintenance. Recently, the MINT and IntAct databases decided to merge their separate efforts to make optimal use of limited developer resources and maximize the curation output. All data manually curated by the MINT curators have been moved into the IntAct database at EMBL-EBI and are merged with the existing IntAct dataset. Both IntAct and MINT are active contributors to the IMEx consortium (http://www.imexconsortium.org). <s> BIB005 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Physical Interactions <s> Systems-level approaches require access to comprehensive ::: genome-wide and proteome-wide databases. A comprehensive ::: resource that archives all published protein-protein interactions ::: (PPIs) is not available. In fact, primary PPI databases capture ::: only a fraction of published data. <s> BIB006 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Physical Interactions <s> Protein interactions form a network whose structure drives cellular function and whose organization informs biological inquiry. Using high-throughput affinity-purification mass spectrometry, we identify interacting partners for 2,594 human proteins in HEK293T cells. The resulting network (BioPlex) contains 23,744 interactions among 7,668 proteins with 86% previously undocumented. BioPlex accurately depicts known complexes, attaining 80%-100% coverage for most CORUM complexes. The network readily subdivides into communities that correspond to complexes or clusters of functionally related proteins. More generally, network architecture reflects cellular localization, biological process, and molecular function, enabling functional characterization of thousands of proteins. Network structure also reveals associations among thousands of protein domains, suggesting a basis for examining structurally related proteins. Finally, BioPlex, in combination with other approaches, can be used to reveal interactions of biological or clinical significance. For example, mutations in the membrane protein VAPB implicated in familial amyotrophic lateral sclerosis perturb a defined community of interactors. <s> BIB007 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Physical Interactions <s> HitPredict is a consolidated resource of experimentally identified, physical protein–protein interactions with confidence scores to indicate their reliability. The study of genes and their inter-relationships using methods such as network and pathway analysis requires high quality protein–protein interaction information. Extracting reliable interactions from most of the existing databases is challenging because they either contain only a subset of the available interactions, or a mixture of physical, genetic and predicted interactions. Automated integration of interactions is further complicated by varying levels of accuracy of database content and lack of adherence to standard formats. To address these issues, the latest version of HitPredict provides a manually curated dataset of 398 696 physical associations between 70 808 proteins from 105 species. Manual confirmation was used to resolve all issues encountered during data integration. For improved reliability assessment, this version combines a new score derived from the experimental information of the interactions with the original score based on the features of the interacting proteins. The combined interaction score performs better than either of the individual scores in HitPredict as well as the reliability score of another similar database. HitPredict provides a web interface to search proteins and visualize their interactions, and the data can be downloaded for offline analysis. Data usability has been enhanced by mapping protein identifiers across multiple reference databases. Thus, the latest version of HitPredict provides a significantly larger, more reliable and usable dataset of protein–protein interactions from several species for the study of gene groups. ::: ::: Database URL: http://hintdb.hgc.jp/htp <s> BIB008 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Physical Interactions <s> The Biological General Repository for Interaction Datasets (BioGRID: https://thebiogrid.org) is an open access database dedicated to the annotation and archival of protein, genetic and chemical interactions for all major model organism species and humans. As of September 2016 (build 3.4.140), the BioGRID contains 1 072 173 genetic and protein interactions, and 38 559 post-translational modifications, as manually annotated from 48 114 publications. This dataset represents interaction records for 66 model organisms and represents a 30% increase compared to the previous 2015 BioGRID update. BioGRID curates the biomedical literature for major model organism species, including humans, with a recent emphasis on central biological processes and specific human diseases. To facilitate network-based approaches to drug discovery, BioGRID now incorporates 27 501 chemical-protein interactions for human drug targets, as drawn from the DrugBank database. A new dynamic interaction network viewer allows the easy navigation and filtering of all genetic and protein interaction data, as well as for bioactive compounds and their established targets. BioGRID data are directly downloadable without restriction in a variety of standardized formats and are freely distributed through partner model organism databases and meta-databases. <s> BIB009 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Physical Interactions <s> Affinity purification–mass spectrometry elucidates protein interaction networks and co-complexes to build, to our knowledge, the largest experimentally derived human protein interaction network so far, termed BioPlex 2.0. <s> BIB010
Gene prioritization approaches are based on guilt-by-association principle and assume that the most promising candidates are in some way associated with seed genes. Physical PPI point to potential functional interaction between these proteins and subsequently, to the association between corresponding genes. Physical PPI can be experimentally identified using high-throughput methods, such as yeast two-hybrid assay, affinity purification with mass spectrometry or confirmed in single experiments, e.g. X-ray crystallography. Primary PPI databases obtain data from curation of published literature, e.g. DIP BIB001 , HPRD BIB002 , BioGRID BIB009 , Innat-eDB BIB004 or MatrixDB  or from single large-scale experiments BIB007 , BIB010 . Other PPI databases, such as IntAct BIB005 , MINT  , MENTHA BIB006 , HitPredict BIB008 , integrate protein interaction data from multiple primary databases and assign interaction reliability scores according to the supporting evidence. In order to facilitate an access to a large number of redundant PPI databases, a standardized query interface PSIQUIC was created. In addition to direct physical contacts, proteins can also interact indirectly, collectively performing their function. For example, since a protein complex functions as a whole, all its members, including those noninteracting directly, are strongly functionally related. CORUM BIB003 and Complex Portal  provide curated human and animal protein complexes, their subunit composition, structure and functions.