A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Predicted Interactions <s> In order to extract the maximum amount of information from the rapidly accumulating genome sequences, all conserved genes need to be classified according to their homologous relationships. Comparison of proteins encoded in seven complete genomes from five major phylogenetic lineages and elucidation of consistent patterns of sequence similarities allowed the delineation of 720 clusters of orthologous groups (COGs). Each COG consists of individual orthologous proteins or orthologous sets of paralogs from at least three lineages. Orthologs typically have the same function, allowing transfer of functional information from one member to an entire COG. This relation automatically yields a number of functional predictions for poorly characterized genomes. The COGs comprise a framework for functional and evolutionary genome analysis. <s> BIB001 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Predicted Interactions <s> Protein interaction mapping using large-scale two-hybrid analysis has been proposed as a way to functionally annotate large numbers of uncharacterized proteins predicted by complete genome sequences. This approach was examined in Caenorhabditis elegans, starting with 27 proteins involved in vulval development. The resulting map reveals both known and new potential interactions and provides a functional annotation for approximately 100 uncharacterized gene products. A protein interaction mapping project is now feasible for C. elegans on a genome-wide scale and should contribute to the understanding of molecular mechanisms in this organism and in human diseases. <s> BIB002 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Predicted Interactions <s> Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component. <s> BIB003 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Predicted Interactions <s> The determination of protein functions is one of the most challenging problems of the post-genomic era. The sequencing of entire genomes and the possibility to access gene's co-expression patterns has moved the attention from the study of single proteins or small complexes to that of the entire proteome. In this context, the search for reliable methods for proteins' function assignment is of uttermost importance. Previous approaches to deduce the unknown function of a class of proteins have exploited sequence similarities or clustering of co-regulated genes, phylogenetic profiles, protein-protein interactions, and protein complexes. We propose to assign functional classes to proteins from their network of physical interactions, by minimizing the number of interacting proteins with different categories. The function assignment is made on a global scale and depends on the entire connectivity pattern of the protein network. Multiple functional assignments are made possible as a consequence of the existence of multiple equivalent solutions. The method is applied to the yeast Saccharomices Cerevisiae protein-protein interaction network. Robustness is tested in presence of a high percentage of unclassified proteins and under deletion/insertion of interactions. <s> BIB004 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Predicted Interactions <s> MOTIVATION ::: The development of experimental methods for genome scale analysis of molecular interaction networks has made possible new approaches to inferring protein function. This paper describes a method of assigning functions based on a probabilistic analysis of graph neighborhoods in a protein-protein interaction network. The method exploits the fact that graph neighbors are more likely to share functions than nodes which are not neighbors. A binomial model of local neighbor function labeling probability is combined with a Markov random field propagation algorithm to assign function probabilities for proteins in the network. ::: ::: ::: RESULTS ::: We applied the method to a protein-protein interaction dataset for the yeast Saccharomyces cerevisiae using the Gene Ontology (GO) terms as function labels. The method reconstructed known GO term assignments with high precision, and produced putative GO assignments to 320 proteins that currently lack GO annotation, which represents about 10% of the unlabeled proteins in S. cerevisiae. <s> BIB005 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Predicted Interactions <s> The identification of orthologous groups is useful for genome annotation, studies on gene/protein evolution, comparative genomics, and the identification of taxonomically restricted sequences. Methods successfully exploited for prokaryotic genome analysis have proved difficult to apply to eukaryotes, however, as larger genomes may contain multiple paralogous genes, and sequence information is often incomplete. OrthoMCL provides a scalable method for constructing orthologous groups across multiple eukaryotic taxa, using a Markov Cluster algorithm to group (putative) orthologs and paralogs. This method performs similarly to the INPARANOID algorithm when applied to two genomes, but can be extended to cluster orthologs from multiple species. OrthoMCL clusters are coherent with groups identified by EGO, but improved recognition of "recent" paralogs permits overlapping EGO groups representing the same gene to be merged. Comparison with previously assigned EC annotations suggests a high degree of reliability, implying utility for automated eukaryotic genome annotation. OrthoMCL has been applied to the proteome data set from seven publicly available genomes (human, fly, worm, yeast, Arabidopsis, the malaria parasite Plasmodium falciparum, and Escherichia coli). A Web interface allows queries based on individual genes or user-defined phylogenetic patterns (http://www.cbil.upenn.edu/gene-family). Analysis of clusters incorporating P. falciparum genes identifies numerous enzymes that were incompletely annotated in first-pass annotation of the parasite genome. <s> BIB006 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Predicted Interactions <s> The Gene Ontology (GO) is a comprehensive resource of computable knowledge regarding the functions of genes and gene products. As such, it is extensively used by the biomedical research community for the analysis of -omics and related data. Our continued focus is on improving the quality and utility of the GO resources, and we welcome and encourage input from researchers in all areas of biology. In this update, we summarize the current contents of the GO knowledgebase, and present several new features and improvements that have been made to the ontology, the annotations and the tools. Among the highlights are 1) developments that facilitate access to, and application of, the GO knowledgebase, and 2) extensions to the resource as well as increasing support for descriptions of causal models of biological systems and network biology. To learn more, visit http://geneontology.org/. <s> BIB007 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Predicted Interactions <s> Gene co-expression networks can be used to associate genes of unknown function with biological processes, to prioritize candidate disease genes or to discern transcriptional regulatory programmes. With recent advances in transcriptomics and next-generation sequencing, co-expression networks constructed from RNA sequencing data also enable the inference of functions and disease associations for non-coding genes and splice variants. Although gene co-expression networks typically do not provide information about causality, emerging methods for differential co-expression analysis are enabling the identification of regulatory genes underlying various phenotypes. Here, we introduce and guide researchers through a (differential) co-expression analysis. We provide an overview of methods and tools used to create and analyse co-expression networks constructed from gene expression data, and we explain how these can be used to identify genes with a regulatory role in disease. Furthermore, we discuss the integration of other data types with co-expression networks and offer future perspectives of co-expression analysis. <s> BIB008
Since biological pathways are mediated by gene products, proteins or RNAs, pathway data is the invaluable source of functional relationships between genes. However, known pathways cover only a small part of all the existing interactions and not all human genes are fully functionally annotated. Unknown gene functions and interactions can be computationally predicted on the basis of gene co-expression BIB008 , sequence similarity  or interactions BIB004 , BIB005 with well-annotated genes. Genes or proteins with expression level correlated across different conditions are likely to be co-regulated and may share functions BIB008 . Sequence similarity and domain composition can also give a clue about a function of an unannotated protein and help to identify its interaction partners. Recent paralogs may have the same function BIB006 , but later their functions tend to diverge. Orthologs are more functionally conservative BIB001 and therefore functional annotations of genes from related species and PPI BIB002 may be transferred on their human orthologs. The amount of knowledge regarding gene and protein roles in the cell is diverse, enormous and continuously growing. The unification and formalization of this knowledge are crucial to ensure its computational processing and analysis. Gene Ontology consortium BIB003 created in 1999, develops and maintains a controlled vocabulary of concepts describing gene functions, localizations and participation in biological processes. GO consortium provides regularly updating BIB007 whole-genome annotations, either supported by experimental evidence or computationally predicted, for multiple species, from human to bacteria, which allows within and between-species comparisons of gene functions. GO term enrichment analysis became a community standard for functional annotation of gene sets and interpretation of the experiment results. Since genes sharing GO terms are considered to be functionally related, many gene prioritization tools utilize GO as an additional source of evidence.