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1.
Network Properties of Complex Human Disease Genes Identified through Genome-Wide Association Studies
Background
Previous studies of network properties of human disease genes have mainly focused on monogenic diseases or cancers and have suffered from discovery bias. Here we investigated the network properties of complex disease genes identified by genome-wide association studies (GWAs), thereby eliminating discovery bias.Principal findings
We derived a network of complex diseases (n = 54) and complex disease genes (n = 349) to explore the shared genetic architecture of complex diseases. We evaluated the centrality measures of complex disease genes in comparison with essential and monogenic disease genes in the human interactome. The complex disease network showed that diseases belonging to the same disease class do not always share common disease genes. A possible explanation could be that the variants with higher minor allele frequency and larger effect size identified using GWAs constitute disjoint parts of the allelic spectra of similar complex diseases. The complex disease gene network showed high modularity with the size of the largest component being smaller than expected from a randomized null-model. This is consistent with limited sharing of genes between diseases. Complex disease genes are less central than the essential and monogenic disease genes in the human interactome. Genes associated with the same disease, compared to genes associated with different diseases, more often tend to share a protein-protein interaction and a Gene Ontology Biological Process.Conclusions
This indicates that network neighbors of known disease genes form an important class of candidates for identifying novel genes for the same disease. 相似文献2.
Nikolaos Refenes Juliane Bolbrinker Georgios Tagaris Antonio Orlacchio Nikolaos Drakoulis Reinhold Kreutz 《BMC neurology》2009,9(1):26
Background
The extended tau haplotype (H1) that covers the entire human microtubule-associated protein tau (MAPT) gene has been implicated in Parkinson's disease (PD). Nevertheless, controversial results, such as two studies in Greek populations with opposite effects, have been reported. Therefore, we set out to determine whether the H1 haplotype and additional single nucleotide polymorphisms (SNPs) included in H1 are associated with PD in a sample of Greek patients. 相似文献3.
Background
Streptococcus pneumoniae can be carried asymptomatically in the nasopharynx of its human host but can also cause a wide range of infections. A role for pneumococcal phase variants in the different lifestyles of this bacterium has been suggested but no systematic survey of the colony phenotypes of isolates associated with human infections has been undertaken. 相似文献4.
Background
The identification and characterization of genes that influence the risk of common, complex multifactorial disease primarily through interactions with other genes and environmental factors remains a statistical and computational challenge in genetic epidemiology. We have previously introduced a genetic programming optimized neural network (GPNN) as a method for optimizing the architecture of a neural network to improve the identification of gene combinations associated with disease risk. The goal of this study was to evaluate the power of GPNN for identifying high-order gene-gene interactions. We were also interested in applying GPNN to a real data analysis in Parkinson's disease. 相似文献5.
Background
Whether for cell culture studies of protein function, construction of mouse models to enable in vivo analysis of disease epidemiology, or ultimately gene therapy of human diseases, a critical enabling step is the ability to achieve finely controlled regulation of gene expression. Previous efforts to achieve this goal have explored inducible drug regulation of gene expression, and construction of synthetic promoters based on two-hybrid paradigms, among others. 相似文献6.
Chen Yao Hongdong Li Chenggui Zhou Lin Zhang Jinfeng Zou Zheng Guo 《BMC systems biology》2010,4(1):151
Background
It has been suggested that, in the human protein-protein interaction network, changes of co-expression between highly connected proteins ("hub") and their interaction neighbours might have important roles in cancer metastasis and be predictive disease signatures for patient outcome. However, for a cancer, such disease signatures identified from different studies have little overlap. 相似文献7.
Background
Mutations in the PLA2G6 gene have been identified in autosomal recessive neurodegenerative diseases classified as infantile neuroaxonal dystrophy (INAD), neurodegeneration with brain iron accumulation (NBIA), and dystonia-parkinsonism. These clinical syndromes display two significantly different disease phenotypes. NBIA and INAD are very similar, involving widespread neurodegeneration that begins within the first 1–2 years of life. In contrast, patients with dystonia-parkinsonism present with a parkinsonian movement disorder beginning at 15 to 30 years of age. The PLA2G6 gene encodes the PLA2G6 enzyme, also known as group VIA calcium-independent phospholipase A2, which has previously been shown to hydrolyze the sn-2 acyl chain of phospholipids, generating free fatty acids and lysophospholipids.Methodology/Principal Findings
We produced purified recombinant wildtype (WT) and mutant human PLA2G6 proteins and examined their catalytic function using in vitro assays with radiolabeled lipid substrates. We find that human PLA2G6 enzyme hydrolyzes both phospholipids and lysophospholipids, releasing free fatty acids. Mutations associated with different disease phenotypes have different effects on catalytic activity. Mutations associated with INAD/NBIA cause loss of enzyme activity, with mutant proteins exhibiting less than 20% of the specific activity of WT protein in both lysophospholipase and phospholipase assays. In contrast, mutations associated with dystonia-parkinsonism do not impair catalytic activity, and two mutations produce a significant increase in specific activity for phospholipid but not lysophospholipid substrates.Conclusions/Significance
These results indicate that different alterations in PLA2G6 function produce the different disease phenotypes of NBIA/INAD and dystonia-parkinsonism. INAD/NBIA is caused by loss of the ability of PLA2G6 to catalyze fatty acid release from phospholipids, which predicts accumulation of PLA2G6 phospholipid substrates and provides a mechanistic explanation for the accumulation of membranes in neuroaxonal spheroids previously observed in histopathological studies of INAD/NBIA. In contrast, dystonia-parkinsonism mutations do not appear to directly impair catalytic function, but may modify substrate preferences or regulatory mechanisms for PLA2G6. 相似文献8.
9.
Background
The accumulation of high-throughput data greatly promotes computational investigation of gene function in the context of complex biological systems. However, a biological function is not simply controlled by an individual gene since genes function in a cooperative manner to achieve biological processes. In the study of human diseases, rather than to discover disease related genes, identifying disease associated pathways and modules becomes an essential problem in the field of systems biology. 相似文献10.
Background
Human heart failure is a complex disease that manifests from multiple genetic and environmental factors. Although ischemic and non-ischemic heart disease present clinically with many similar decreases in ventricular function, emerging work suggests that they are distinct diseases with different responses to therapy. The ability to distinguish between ischemic and non-ischemic heart failure may be essential to guide appropriate therapy and determine prognosis for successful treatment. In this paper we consider discriminating the etiologies of heart failure using gene expression libraries from two separate institutions. 相似文献11.
Background
Gene targeting would offer a number of advantages over current transposon-based strategies for insect transformation. These include freedom from both position effects associated with quasi-random integration and concerns over transgene instability mediated by endogenous transposases, independence from phylogenetic restrictions on transposon mobility and the ability to generate gene knockouts. 相似文献12.
Background
Pseudomonas aeruginosa is the major pathogen associated with chronic and ultimately fatal lung infections in patients with cystic fibrosis (CF). To investigate how P. aeruginosa-derived vesicles may contribute to lung disease, we explored their ability to associate with human lung cells. 相似文献13.
Background
Glucose inhibition of gluconeogenic growth suppressor 2 protein (Gis2p) and zinc-finger protein 9 (ZNF9) are conserved yeast and human zinc-finger proteins. The function of yeast Gis2p is unknown, but human ZNF9 has been reported to bind nucleic acids, and mutations in the ZNF9 gene cause the neuromuscular disease myotonic dystrophy type 2. To explore the impact of these proteins on RNA regulation, we undertook a systematic analysis of the RNA targets and of the global implications for gene expression. 相似文献14.
Background
Domains are basic units of proteins, and thus exploring associations between protein domains and human inherited diseases will greatly improve our understanding of the pathogenesis of human complex diseases and further benefit the medical prevention, diagnosis and treatment of these diseases. Within a given domain-domain interaction network, we make the assumption that similarities of disease phenotypes can be explained using proximities of domains associated with such diseases. Based on this assumption, we propose a Bayesian regression approach named "domainRBF" (domain Rank with Bayes Factor) to prioritize candidate domains for human complex diseases. 相似文献15.
Jo EB Halliday Margo E Chase-Topping Michael C Pearce Iain J McKendrick Lesley Allison Dave Fenlon Chris Low Dominic J Mellor George J Gunn Mark EJ Woolhouse 《BMC microbiology》2006,6(1):99-5
Background
E. coli O157 is a bacterial pathogen that is shed by cattle and can cause severe disease in humans. Phage type (PT) 21/28 is a subtype of E. coli O157 that is found across Scotland and is associated with particularly severe human morbidity. 相似文献16.
Allan?R?Shepard Nasreen?Jacobson Ruifang?Sui H?Thomas?Steely Andrew?J?Lotery Edwin?M?Stone Abbot?F?Clark
Background
Mutations in the gene encoding human myocilin (MYOC ) have been shown to cause juvenile- and adult-onset glaucoma. In addition, myocilin has been associated with glucocorticoid-induced ocular hypertension and steroid-induced glaucoma. To better understand the role myocilin plays in steroid-induced glaucoma and open-angle glaucoma, we examined rabbit myocilin for use in the rabbit animal model of steroid-induced glaucoma. 相似文献17.
Background
Inferences about protein function are often made based on sequence homology to other gene products of known activities. This approach is valuable for small families of conserved proteins but can be difficult to apply to large superfamilies of proteins with diverse function. In this study we looked at sequence homology between members of the DJ-1/ThiJ/PfpI superfamily, which includes a human protein of unclear function, DJ-1, associated with inherited Parkinson's disease. 相似文献18.
Background
Comparative analysis of gene expression profiling of multiple biological categories, such as different species of organisms or different kinds of tissue, promises to enhance the fundamental understanding of the universality as well as the specialization of mechanisms and related biological themes. Grouping genes with a similar expression pattern or exhibiting co-expression together is a starting point in understanding and analyzing gene expression data. In recent literature, gene module level analysis is advocated in order to understand biological network design and system behaviors in disease and life processes; however, practical difficulties often lie in the implementation of existing methods. 相似文献19.
Background
Enhancements in sequencing technology have recently yielded assemblies of large genomes including rat, mouse, human, fruit fly, and zebrafish. The availability of large-scale genomic and genic sequence data coupled with advances in microarray technology have made it possible to study the expression of large numbers of sequence products under several different conditions in days where traditional molecular biology techniques might have taken months, or even years. Therefore, to efficiently study a number of gene products associated with a disease, pathway, or other biological process, it is necessary to be able to design primer pairs or oligonucleotides en masse rather than using a time consuming and laborious gene-by-gene method. 相似文献20.
Steve Horvath Yafeng Zhang Peter Langfelder René S Kahn Marco PM Boks Kristel van Eijk Leonard H van den Berg Roel A Ophoff 《Genome biology》2012,13(10):1-18