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Many efforts are still devoted to the discovery of genes involved with specific phenotypes, in particular, diseases. High-throughput techniques are thus applied frequently to detect dozens or even hundreds of candidate genes. However, the experimental validation of many candidates is often an expensive and time-consuming task. Therefore, a great variety of computational approaches has been developed to support the identification of the most promising candidates for follow-up studies. The biomedical knowledge already available about the disease of interest and related genes is commonly exploited to find new gene-disease associations and to prioritize candidates. In this review, we highlight recent methodological advances in this research field of candidate gene prioritization. We focus on approaches that use network information and integrate heterogeneous data sources. Furthermore, we discuss current benchmarking procedures for evaluating and comparing different prioritization methods. WIREs Syst Biol Med 2012. doi: 10.1002/wsbm.1177 For further resources related to this article, please visit the WIREs website. [ABSTRACT FROM AUTHOR]

Some plant resistance genes occur as allelic series, with each member conferring specific resistance against a subset of pathogen races. In wheat, there are 17 alleles of the Pm3 gene. They encode nucleotide-binding (NB-ARC) and leucine-rich-repeat (LRR) domain proteins, which mediate resistance to distinct race spectra of powdery mildew. It is not known if specificities from different alleles can be combined to create resistance genes with broader specificity. Here, we used an approach based on avirulence analysis of pathogen populations to characterize the molecular basis of Pm3 recognition spectra. A large survey of mildew races for avirulence on the Pm3 alleles revealed that Pm3a has a resistance spectrum that completely contains that of Pm3f, but also extends towards additional races. The same is true for the Pm3b and Pm3c gene pair. The molecular analysis of these allelic pairs revealed a role of the NB-ARC protein domain in the efficiency of effector-dependent resistance. Analysis of the wild-type and chimeric Pm3 alleles identified single residues in the C-terminal LRR motifs as the main determinant of allele specificity. Variable residues of the N-terminal LRRs are necessary, but not sufficient, to confer resistance specificity. Based on these data, we constructed a chimeric Pm3 gene by intragenic allele pyramiding of Pm3d and Pm3e that showed the combined resistance specificity and, thus, a broader recognition spectrum compared with the parental alleles. Our findings support a model of stepwise evolution of Pm3 recognition specificities. [ABSTRACT FROM AUTHOR]

Arginine/lysine-rich motifs typically function as targeting signals for the translocation of proteins to the nucleus. Here, we demonstrate that such a motif consisting of four basic amino acids in the polyglutamine protein ataxin-3 (Atx-3) serves as a recognition site for the interaction with the molecular chaperone VCP. Through this interaction, VCP modulates the fibrillogenesis of pathogenic forms of Atx-3 in a concentration-dependent manner, with low concentrations of VCP stimulating fibrillogenesis and excess concentrations suppressing it. No such effect was observed with a mutant Atx-3 variant, which does not contain a functional VCP interaction motif. Strikingly, a stretch of four basic amino acids in the ubiquitin chain assembly factor E4B was also discovered to be critical for VCP binding, indicating that arginine/lysine-rich motifs might be generally utilized by VCP for the targeting of proteins. In vivo studies with Drosophila models confirmed that VCP selectively modulates aggregation and neurotoxicity induced by pathogenic Atx-3. Together, these results define the VCP–Atx-3 association as a potential target for therapeutic intervention and suggest that it might influence the progression of spinocerebellar ataxia type 3. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia types 2 (SCA2) and 3 (SCA3) are autosomal-dominantly inherited, neurodegenerative diseases caused by CAG repeat expansions in the coding regions of the genes encoding ataxin-2 and ataxin-3, respectively. To provide a rationale for further functional experiments, we explored the protein architectures of ataxin-2 and ataxin-3. Using structure-based multiple sequence alignments of homologous proteins, we investigated domains, sequence motifs, and interaction partners. Our analyses focused on presumably functional amino acids and the construction of tertiary structure models of the RNA-binding Lsm domain of ataxin-2 and the deubiquitinating Josephin domain of ataxin-3. We also speculate about distant evolutionary relationships of ubiquitin-binding UIM, GAT, UBA and CUE domains and helical ANTH and UBX domain extensions. [ABSTRACT FROM AUTHOR]

Sm and Sm-like proteins of the Lsm (like Sm) domain family are generally involved in essential RNA-processing tasks. While recent research has focused on the function and structure of small family members, little is known about Lsm domain proteins carrying additional domains. Using an integrative bioinformatics approach, we discovered five novel groups of Lsm domain proteins (Lsm12-16) with long C-terminal tails and investigated their functions. All of them are evolutionarily conserved in eukaryotes with an N-terminal Lsm domain to bind nucleic acids followed by as yet uncharacterized C-terminal domains and sequence motifs. Based on known yeast interaction partners, Lsm12-16 may play important roles in RNA metabolism. Particularly, Lsm12 is possibly involved in mRNA degradation or tRNA splicing, and Lsm13-16 in the regulation of the mitotic G2/M phase. Lsm16 proteins have an additional C-terminal YjeF_N domain of as yet unknown function. The identification of an additional methyltransferase domain at the C-terminus of one of the Lsm12 proteins also led to the recognition of three new groups of methyltransferases, presumably dependent on S-adenosyl-l-methionine. Further computational analyses revealed that some methyltransferases contain putative RNA-binding helix–turn–helix domains and zinc fingers. [Copyright &y& Elsevier]

Several autoinflammatory diseases with distinct clinical manifestations have been associated with sequence variations in the gene products PYPAF1/CIAS1 and NOD2/CARD15. Both proteins belong to the PYD/CARD-containing family of apoptosis regulators and activators of pro-inflammatory caspases. To gain insight into the dysfunctional role of sequence alterations, we assembled a structure-based multiple sequence alignment of family members and related proteins. This allowed us to analyze the putative effect of the alterations on the function of nucleotide-binding (NACHT) and leucine-rich repeat (LRR) domains shared by the family members. In support of this analysis, we carefully selected template structures for the NACHT and LRR domains and mapped the genetic variations onto 3D domain models. Additionally, we propose a model of the NACHT and LRR domain complex. Our study revealed that many of the disease-associated sequence variants are located close to highly conserved sequence regions of functional relevance and are spatially adjacent in the predicted 3D structure. The implications on the domain functions such as NTP-hydrolysis or oligomerization are discussed. [Copyright &y& Elsevier]

PYRIN- and CARD-containing proteins belong to a recently identified protein family involved in the regulation of apoptosis and inflammatory processes. Variations in the gene products of the family members PYPAF1 and NOD2/CARD15 have been associated with several autoinflammatory diseases. We could identify the mouse orthologs of PYPAF1, PYPAF5, NOD1, NOD2 and the rat ortholog of PYPAF5. Intriguingly, we found that PYPAF5 has been reported previously not only as regulator of NF-κB and caspase-1, but also as angiotensin II and vasopressin receptor. In particular, based on a comprehensive sequence analysis, we propose a structural model for this hormone receptor that is different from the model suggested previously. [Copyright &y& Elsevier]