Note: This page contains sample records for the topic identifying disease genes from Science.gov.
While these samples are representative of the content of Science.gov,
they are not comprehensive nor are they the most current set.
We encourage you to perform a real-time search of Science.gov
to obtain the most current and comprehensive results.
Last update: November 12, 2013.
1

Identifying modifier genes of monogenic disease: strategies and difficulties  

PubMed Central

Substantial clinical variability is observed in many Mendelian diseases, so that patients with the same mutation may develop a very severe form of disease, a mild form or show no symptoms at all. Among the factors that may explain these differences in disease expression are modifier genes. In this paper, we review the different strategies that can be used to identify modifier genes and explain their advantages and limitations. We focus mainly on the statistical aspects but illustrate our points with a variety of examples from the literature.

Genin, Emmanuelle; Feingold, Josue; Clerget-Darpoux, Francoise

2008-01-01

2

Identifying Mendelian disease genes with the Variant Effect Scoring Tool  

PubMed Central

Background Whole exome sequencing studies identify hundreds to thousands of rare protein coding variants of ambiguous significance for human health. Computational tools are needed to accelerate the identification of specific variants and genes that contribute to human disease. Results We have developed the Variant Effect Scoring Tool (VEST), a supervised machine learning-based classifier, to prioritize rare missense variants with likely involvement in human disease. The VEST classifier training set comprised ~ 45,000 disease mutations from the latest Human Gene Mutation Database release and another ~45,000 high frequency (allele frequency >1%) putatively neutral missense variants from the Exome Sequencing Project. VEST outperforms some of the most popular methods for prioritizing missense variants in carefully designed holdout benchmarking experiments (VEST ROC AUC = 0.91, PolyPhen2 ROC AUC = 0.86, SIFT4.0 ROC AUC = 0.84). VEST estimates variant score p-values against a null distribution of VEST scores for neutral variants not included in the VEST training set. These p-values can be aggregated at the gene level across multiple disease exomes to rank genes for probable disease involvement. We tested the ability of an aggregate VEST gene score to identify candidate Mendelian disease genes, based on whole-exome sequencing of a small number of disease cases. We used whole-exome data for two Mendelian disorders for which the causal gene is known. Considering only genes that contained variants in all cases, the VEST gene score ranked dihydroorotate dehydrogenase (DHODH) number 2 of 2253 genes in four cases of Miller syndrome, and myosin-3 (MYH3) number 2 of 2313 genes in three cases of Freeman Sheldon syndrome. Conclusions Our results demonstrate the potential power gain of aggregating bioinformatics variant scores into gene-level scores and the general utility of bioinformatics in assisting the search for disease genes in large-scale exome sequencing studies. VEST is available as a stand-alone software package at http://wiki.chasmsoftware.org and is hosted by the CRAVAT web server at http://www.cravat.us

2013-01-01

3

Identifying Candidate Disease Gene GAD2 for Obesity by Computational Gene Prioritization Tool ENDEAVOUR  

Microsoft Academic Search

Identifying potential disease genes for complex disease is very important for understanding disease pathogenesis and providing\\u000a preventive measures. The computational gene prioritization tools provide a promising and effective way for disease gene identification.\\u000a Gene GAD2 on Chromosome 10p12 is a disputing candidate disease gene for obesity because of the contradictory conclusions obtained\\u000a by association studies of different researchers. In this

Huanping Zhang; Xiaofeng Song; Huinan Wang

4

Reconstructability Analysis as a Tool for Identifying Gene-Gene Interactions in Studies of Human Diseases*  

PubMed Central

There are a number of common human diseases for which the genetic component may include an epistatic interaction of multiple genes. Detecting these interactions with standard statistical tools is difficult because there may be an interaction effect, but minimal or no main effect. Reconstructability analysis (RA) uses Shannon’s information theory to detect relationships between variables in categorical datasets. We applied RA to simulated data for five different models of gene-gene interaction, and find that even with heritability levels as low as 0.008, and with the inclusion of 50 non-associated genes in the dataset, we can identify the interacting gene pairs with an accuracy of ?80%. We applied RA to a real dataset of type 2 non-insulin-dependent diabetes (NIDDM) cases and controls, and closely approximated the results of more conventional single SNP disease association studies. In addition, we replicated prior evidence for epistatic interactions between SNPs on chromosomes 2 and 15.

Shervais, Stephen; Kramer, Patricia L.; Westaway, Shawn K.; Cox, Nancy J.; Zwick, Martin

2010-01-01

5

Integrative systems biology approaches to identify and prioritize disease and drug candidate genes.  

PubMed

Although a number of computational approaches have been developed to integrate data from multiple sources for the purpose of predicting or prioritizing candidate disease genes, relatively few of them focus on identifying or ranking drug targets. To address this deficit, we have developed an approach to specifically identify and prioritize disease and drug candidate genes. In this chapter, we demonstrate the applicability of integrative systems-biology-based approaches to identify potential drug targets and candidate genes by employing information extracted from public databases. We illustrate the method in detail using examples of two neurodegenerative diseases (Alzheimer's and Parkinson's) and one neuropsychiatric disease (Schizophrenia). PMID:21204038

Kaimal, Vivek; Sardana, Divya; Bardes, Eric E; Gudivada, Ranga Chandra; Chen, Jing; Jegga, Anil G

2011-01-01

6

Genes to Diseases (G2D) Computational Method to Identify Asthma Candidate Genes  

PubMed Central

Asthma is a complex trait for which different strategies have been used to identify its environmental and genetic predisposing factors. Here, we describe a novel methodological approach to select candidate genes for asthma genetic association studies. In this regard, the Genes to Diseases (G2D) computational tool has been used in combination with a genome-wide scan performed in a sub-sample of the Saguenay?Lac-St-Jean (SLSJ) asthmatic familial collection (n?=?609) to identify candidate genes located in two suggestive loci shown to be linked with asthma (6q26) and atopy (10q26.3), and presenting differential parent-of-origin effects. This approach combined gene selection based on the G2D data mining analysis of the bibliographic and protein public databases, or according to the genes already known to be associated with the same or a similar phenotype. Ten genes (LPA, NOX3, SNX9, VIL2, VIP, ADAM8, DOCK1, FANK1, GPR123 and PTPRE) were selected for a subsequent association study performed in a large SLSJ sample (n?=?1167) of individuals tested for asthma and atopy related phenotypes. Single nucleotide polymorphisms (n?=?91) within the candidate genes were genotyped and analysed using a family-based association test. The results suggest a protective association to allergic asthma for PTPRE rs7081735 in the SLSJ sample (p?=?0.000463; corrected p?=?0.0478). This association has not been replicated in the Childhood Asthma Management Program (CAMP) cohort. Sequencing of the regions around rs7081735 revealed additional polymorphisms, but additional genotyping did not yield new associations. These results demonstrate that the G2D tool can be useful in the selection of candidate genes located in chromosomal regions linked to a complex trait.

Tremblay, Karine; Lemire, Mathieu; Potvin, Camille; Tremblay, Alexandre; Hunninghake, Gary M.; Raby, Benjamin A.; Hudson, Thomas J.; Perez-Iratxeta, Carolina; Andrade-Navarro, Miguel A.; Laprise, Catherine

2008-01-01

7

MIClique: An Algorithm to Identify Differentially Coexpressed Disease Gene Subset from Microarray Data  

PubMed Central

Computational analysis of microarray data has provided an effective way to identify disease-related genes. Traditional disease gene selection methods from microarray data such as statistical test always focus on differentially expressed genes in different samples by individual gene prioritization. These traditional methods might miss differentially coexpressed (DCE) gene subsets because they ignore the interaction between genes. In this paper, MIClique algorithm is proposed to identify DEC gene subsets based on mutual information and clique analysis. Mutual information is used to measure the coexpression relationship between each pair of genes in two different kinds of samples. Clique analysis is a commonly used method in biological network, which generally represents biological module of similar function. By applying the MIClique algorithm to real gene expression data, some DEC gene subsets which correlated under one experimental condition but uncorrelated under another condition are detected from the graph of colon dataset and leukemia dataset.

Zhang, Huanping; Song, Xiaofeng; Wang, Huinan; Zhang, Xiaobai

2009-01-01

8

IDENTIFYING DISEASE RESISTANCE GENES AND PATHWAYS THROUGH HOST-PATHOGEN PROTEIN INTERACTIONS  

Technology Transfer Automated Retrieval System (TEKTRAN)

A major objective of both animal and plant genomics research is to identify disease resistance genes and pathways. Popular approaches to achieve this goal include candidate gene testing, genome-wide QTL screens, and DNA microarrays. We argue that the two-hybrid assay, which detects protein-protein...

9

A proposal of a novel experimental procedure to genetically identify disease gene loci in humans  

PubMed Central

Forward genetics in humans is beneficial in terms of diagnosis and treatment of genetic diseases, and discovery of gene functions. However, experimental mating is not possible among humans. In order to overcome this problem, I propose a novel experimental procedure to genetically identify human disease gene loci. To accomplish this, somatic cells from patients or their parents are reprogrammed to the pluripotent state, oogenesis is induced, the oocytes are parthenogenetically activated in the presence of cytochalasin, and embryonic stem cells are established from the parthenogenetic blastocysts. This protocol produces a set of diploid pluripotent stem cell clones having maternal and paternal chromosomes in different manners to each other. The genetic loci for the disease genes are determined through the conventional processes of positional cloning. Thus, taking advantage of the strategy proposed here, if the abnormality is reproducible using patient-derived pluripotent stem cells, a single carrier of the genetic mutations would be adequate to identify the disease gene loci.

MUTO, Taro

2011-01-01

10

Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease.  

PubMed

The molecular mechanisms behind human liver disease progression to cirrhosis remain elusive. Nuclear receptor small heterodimer partner (SHP/Nr0b2) is a hepatic tumor suppressor and a critical regulator of liver function. SHP expression is diminished in human cirrhotic livers, suggesting a regulatory role in human liver diseases. The goal of this study was to identify novel SHP-regulated genes that are involved in the development and progression of chronic liver disease. To achieve this, we conducted the first comprehensive RNA sequencing (RNA-seq) analysis of Shp(-/-) mice, compared the results with human hepatitis C cirrhosis RNA-seq and nonalcoholic steatohepatitis (NASH) microarray datasets, and verified novel results in human liver biospecimens. This approach revealed new gene signatures associated with chronic liver disease and regulated by SHP. Several genes were selected for validation of physiological relevance based on their marked upregulation, novelty with regard to liver function, and involvement in gene pathways related to liver disease. These genes include peptidoglycan recognition protein 2, dual specific phosphatase-4, tetraspanin 4, thrombospondin 1, and SPARC-related modular calcium binding protein-2, which were validated by qPCR analysis of 126 human liver specimens, including steatosis, fibrosis, and NASH, alcohol and hepatitis C cirrhosis, and in mouse models of liver inflammation and injury. This RNA-seq analysis identifies new genes that are regulated by the nuclear receptor SHP and implicated in the molecular pathogenesis of human chronic liver diseases. The results provide valuable transcriptome information for characterizing mechanisms of these diseases. PMID:23812039

Smalling, Rana L; Delker, Don A; Zhang, Yuxia; Nieto, Natalia; McGuiness, Michael S; Liu, Shuanghu; Friedman, Scott L; Hagedorn, Curt H; Wang, Li

2013-06-27

11

Gene Expression Profiling Combined with Bioinformatics Analysis Identify Biomarkers for Parkinson Disease  

PubMed Central

Parkinson disease (PD) progresses relentlessly and affects approximately 4% of the population aged over 80 years old. It is difficult to diagnose in its early stages. The purpose of our study is to identify molecular biomarkers for PD initiation using a computational bioinformatics analysis of gene expression. We downloaded the gene expression profile of PD from Gene Expression Omnibus and identified differentially coexpressed genes (DCGs) and dysfunctional pathways in PD patients compared to controls. Besides, we built a regulatory network by mapping the DCGs to known regulatory data between transcription factors (TFs) and target genes and calculated the regulatory impact factor of each transcription factor. As the results, a total of 1004 genes associated with PD initiation were identified. Pathway enrichment of these genes suggests that biological processes of protein turnover were impaired in PD. In the regulatory network, HLF, E2F1 and STAT4 were found have altered expression levels in PD patients. The expression levels of other transcription factors, NKX3-1, TAL1, RFX1 and EGR3, were not found altered. However, they regulated differentially expressed genes. In conclusion, we suggest that HLF, E2F1 and STAT4 may be used as molecular biomarkers for PD; however, more work is needed to validate our result.

Diao, Hongyu; Li, Xinxing; Hu, Sheng; Liu, Yunhui

2012-01-01

12

Variance of gene expression identifies altered network constraints in neurological disease.  

PubMed

Gene expression analysis has become a ubiquitous tool for studying a wide range of human diseases. In a typical analysis we compare distinct phenotypic groups and attempt to identify genes that are, on average, significantly different between them. Here we describe an innovative approach to the analysis of gene expression data, one that identifies differences in expression variance between groups as an informative metric of the group phenotype. We find that genes with different expression variance profiles are not randomly distributed across cell signaling networks. Genes with low-expression variance, or higher constraint, are significantly more connected to other network members and tend to function as core members of signal transduction pathways. Genes with higher expression variance have fewer network connections and also tend to sit on the periphery of the cell. Using neural stem cells derived from patients suffering from Schizophrenia (SZ), Parkinson's disease (PD), and a healthy control group, we find marked differences in expression variance in cell signaling pathways that shed new light on potential mechanisms associated with these diverse neurological disorders. In particular, we find that expression variance of core networks in the SZ patient group was considerably constrained, while in contrast the PD patient group demonstrated much greater variance than expected. One hypothesis is that diminished variance in SZ patients corresponds to an increased degree of constraint in these pathways and a corresponding reduction in robustness of the stem cell networks. These results underscore the role that variation plays in biological systems and suggest that analysis of expression variance is far more important in disease than previously recognized. Furthermore, modeling patterns of variability in gene expression could fundamentally alter the way in which we think about how cellular networks are affected by disease processes. PMID:21852951

Mar, Jessica C; Matigian, Nicholas A; Mackay-Sim, Alan; Mellick, George D; Sue, Carolyn M; Silburn, Peter A; McGrath, John J; Quackenbush, John; Wells, Christine A

2011-08-11

13

DNA methylation map of mouse and human brain identifies target genes in Alzheimer's disease.  

PubMed

The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer's disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5'-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer's disease. We were able to translate these findings to patients with Alzheimer's disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease. PMID:24030951

Sanchez-Mut, Jose V; Aso, Ester; Panayotis, Nicolas; Lott, Ira; Dierssen, Mara; Rabano, Alberto; Urdinguio, Rocio G; Fernandez, Agustin F; Astudillo, Aurora; Martin-Subero, Jose I; Balint, Balazs; Fraga, Mario F; Gomez, Antonio; Gurnot, Cecile; Roux, Jean-Christophe; Avila, Jesus; Hensch, Takao K; Ferrer, Isidre; Esteller, Manel

2013-09-11

14

DNA methylation map of mouse and human brain identifies target genes in Alzheimer's disease  

PubMed Central

The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer’s disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5’-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer’s disease. We were able to translate these findings to patients with Alzheimer’s disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease.

Sanchez-Mut, Jose V.; Aso, Ester; Panayotis, Nicolas; Lott, Ira; Dierssen, Mara; Rabano, Alberto; Urdinguio, Rocio G.; Fernandez, Agustin F.; Astudillo, Aurora; Martin-Subero, Jose I.; Balint, Balazs; Fraga, Mario F.; Gomez, Antonio; Gurnot, Cecile; Roux, Jean-Christophe; Avila, Jesus; Hensch, Takao K.; Ferrer, Isidre

2013-01-01

15

Identifying genes for coronary artery disease: An idea whose time has come  

PubMed Central

BACKGROUND: Coronary artery disease (CAD) remains the number one killer in the western world. Genetics accounts for greater than 50% of the risk for CAD. Genetic screening and early prevention in individuals identified as being at increased risk could dramatically reduce the prevalence of CAD, thus necessitating the identification of genes predisposing to CAD. Studies of genes identified by the candidate gene approach have not been replicated due, in part, to inadequate sample size. Genome-wide scan association studies have been limited by the use of thousands of markers rather than the hundreds of thousands required, and by the use of hundreds of individuals rather than the thousands required. Replication of positive findings in an independent population is essential. To detect a minor allele frequency of 5% or greater with an odds ratio for risk of 1.3 or greater and 90% power, an estimated 14,000 (9000 affected and 5000 control) subjects are required. METHODS: The Affymetrix GeneChip Human Mapping 500K Array Set (Affymetrix Inc, USA) provides a marker every 6000 base pairs as required, and is being used to genotype 1000 cases of premature CAD and 1000 normal subjects, followed by replication in 8000 affected individuals and 4000 control subjects. The phenotype is confirmed or excluded by coronary arteriograms by catheterization or multislice computed tomography. RESULTS: Since 2005, more than 800 million genotypes have been performed and analyses performed on 500 control subjects and 500 affected individuals. Several thousand significant single nucleotide polymorphisms and 130 clusters associated with CAD have been identified. CONCLUSIONS: This is the first genome-wide scan using the 500,000 marker set in a case-control association study for CAD genes. Several genes associated with CAD appear promising.

Roberts, Robert; Stewart, Alexandre FR; Wells, George A; Williams, Kathryn A; Kavaslar, Nihan; McPherson, Ruth

2007-01-01

16

Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease  

PubMed Central

The only recognised genetic determinant of the common forms of Alzheimer’s disease (AD) is the ?4 allele of the apolipoprotein E gene (APOE). To identify new candidate genes, we recently performed transcriptomic analysis of 2,741 genes in chromosomal regions of interest using brain tissue of AD cases and controls. From 82 differentially expressed genes, 1,156 polymorphisms were genotyped in two independent discovery sub-samples (n=945). Seventeen genes exhibited at least one polymorphism associated with AD risk and following correction for multiple testing, we retained the IL-33 gene. We first confirmed that the IL-33 expression was decreased in the brain of AD cases compared with that of controls. Further genetic analysis led us to select 3 polymorphisms within this gene, which we analysed in three independent case-control studies. These polymorphisms and a resulting protective haplotype were systematically associated with AD risk in non-APOE ?4 carriers. Using a large prospective study, these associations were also detected when analyzing the prevalent and incident AD cases together or the incident AD cases alone. These polymorphisms were also associated with less cerebral amyloid angiopathy (CAA) in the brain of non-APOE ?4 AD cases. Immunohistochemistry experiments finally indicated that the IL-33 expression was consistently restricted to vascular capillaries in the brain. Moreover, IL-33 overexpression in cellular models led to a specific decrease in secretion of the A?40 peptides, the main CAA component. In conclusion, our data suggest that genetic variants in IL-33 gene may be associated with a decrease in AD risk potentially in modulating CAA formation.

Chapuis, J; Hot, D; Hansmannel, F; Kerdraon, O; Ferreira, S; Hubans, C; Maurage, CA; Huot, L; Bensemain, F; Laumet, G; Ayral, AM; Fievet, N; Hauw, JJ; DeKosky, ST; Lemoine, Y; Iwatsubo, T; Wavrant-Devrieze, F; Dartigues, JF; Tzourio, C; Buee, L; Pasquier, F; Berr, C; Mann, D; Lendon, C; Alperovitch, A; Kamboh, MI; Amouyel, P; Lambert, JC

2010-01-01

17

[Analysis of disease-pathway by identifying susceptibility genes to primary biliary cirrhosis].  

PubMed

High concordance rate in monozygotic twins and familial clustering of patients with primary biliary cirrhosis (PBC) indicate the involvement of strong genetic factors in the development of PBC. Recent genome-wide association studies (GWASs) and subsequent meta-analyses in European descent have identified HLA and 21 non-HLA susceptibility loci which are involved in IL12/IL12R signaling, TNF/TLR-NFKB signaling and B cell differentiation in the development of PBC. To identify susceptibility loci for PBC in Japanese population, a GWAS and subsequent replication study was performed in a total of 1327 PBC cases and 1120 healthy controls. In addition to the most significant susceptibility region at HLA, two significant (p<5×10(-8)) susceptibility loci (TNFSF15 and POU2AF1) were identified. Although these susceptibility loci are different from those identified in European descent (IL12A, IL12RB2, SPIB), these loci are involved in the same signaling pathways, differentiation of T lymphocyte to Th1 cells and differentiation of B lymphocyte to plasma cells. Among 21 non-HLA susceptibility loci for PBC identified in GWASs of European descent, 10 loci (CD80, IKZF3, IL7R, NFKB1, STAT4, TNFAIP2, CXCR5, MAP3K7IP1, rs6974491, DENND1B) showed significant associations in the Japanese population. The comparative analysis of disease-susceptibility genes in multiple ethnicities may provide an important clue for the dissection of disease-pathogenesis. PMID:23291485

Makamura, Minoru

2012-01-01

18

Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene  

PubMed Central

The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes.

Davison, Lucy J.; Wallace, Chris; Cooper, Jason D.; Cope, Nathan F.; Wilson, Nicola K.; Smyth, Deborah J.; Howson, Joanna M.M.; Saleh, Nada; Al-Jeffery, Abdullah; Angus, Karen L.; Stevens, Helen E.; Nutland, Sarah; Duley, Simon; Coulson, Richard M.R.; Walker, Neil M.; Burren, Oliver S.; Rice, Catherine M.; Cambien, Francois; Zeller, Tanja; Munzel, Thomas; Lackner, Karl; Blankenberg, Stefan; Fraser, Peter; Gottgens, Berthold; Todd, John A.

2012-01-01

19

A COMPREHENSIVE SCREEN FOR MAREK'S DISEASE VIRUS CHICKEN PROTEIN INTERACTIONS TO IDENTIFY DISEASE RESISTANCE GENES  

Technology Transfer Automated Retrieval System (TEKTRAN)

Marek's disease (MD) is a lymphoproliferative disease of chickens and an estimated $1 billion problem annually to the worldwide poultry industry. The causative agent is the Marek's disease virus (MDV), a ubiquitous herpesvirus. Vaccines limit tumor incidence but do not block MDV replication and sp...

20

Extended tracts of homozygosity identify novel candidate genes associated with late onset Alzheimer's Disease  

PubMed Central

Large tracts of extended homozygosity are more prevalent in outbred populations than previously thought. With the advent of high-density genotyping platforms, regions of extended homozygosity can be accurately located allowing for the identification of rare recessive risk variants contributing to disease. We compared measures of extended homozygosity (greater than 1 megabase in length) in a population of 837 late onset Alzheimer’s disease (LOAD) cases and 550 controls. In our analyses, we identify one homozygous region on chromosome 8 that is significantly associated with LOAD after adjusting for multiple testing. This region contains seven genes from which the most biologically plausible candidates are STAR, EIF4EBP1 and ADRB3. We also compared the total numbers of homozygous runs and the total length of these runs between cases and controls, showing a suggestive difference in these measures (p-values 0.052-0.062). This research suggests a recessive component to the etiology of LOAD.

Nalls, M. A.; Guerreiro, R. J.; Simon-Sanchez, J.; Bras, J. T.; Traynor, B. J.; Gibbs, J. R.; Launer, L.; Hardy, J.; Singleton, A. B.

2010-01-01

21

Functional genomics complements quantitative genetics in identifying disease-gene associations.  

PubMed

An ultimate goal of genetic research is to understand the connection between genotype and phenotype in order to improve the diagnosis and treatment of diseases. The quantitative genetics field has developed a suite of statistical methods to associate genetic loci with diseases and phenotypes, including quantitative trait loci (QTL) linkage mapping and genome-wide association studies (GWAS). However, each of these approaches have technical and biological shortcomings. For example, the amount of heritable variation explained by GWAS is often surprisingly small and the resolution of many QTL linkage mapping studies is poor. The predictive power and interpretation of QTL and GWAS results are consequently limited. In this study, we propose a complementary approach to quantitative genetics by interrogating the vast amount of high-throughput genomic data in model organisms to functionally associate genes with phenotypes and diseases. Our algorithm combines the genome-wide functional relationship network for the laboratory mouse and a state-of-the-art machine learning method. We demonstrate the superior accuracy of this algorithm through predicting genes associated with each of 1157 diverse phenotype ontology terms. Comparison between our prediction results and a meta-analysis of quantitative genetic studies reveals both overlapping candidates and distinct, accurate predictions uniquely identified by our approach. Focusing on bone mineral density (BMD), a phenotype related to osteoporotic fracture, we experimentally validated two of our novel predictions (not observed in any previous GWAS/QTL studies) and found significant bone density defects for both Timp2 and Abcg8 deficient mice. Our results suggest that the integration of functional genomics data into networks, which itself is informative of protein function and interactions, can successfully be utilized as a complementary approach to quantitative genetics to predict disease risks. All supplementary material is available at http://cbfg.jax.org/phenotype. PMID:21085640

Guan, Yuanfang; Ackert-Bicknell, Cheryl L; Kell, Braden; Troyanskaya, Olga G; Hibbs, Matthew A

2010-11-11

22

Functional Genomics Complements Quantitative Genetics in Identifying Disease-Gene Associations  

PubMed Central

An ultimate goal of genetic research is to understand the connection between genotype and phenotype in order to improve the diagnosis and treatment of diseases. The quantitative genetics field has developed a suite of statistical methods to associate genetic loci with diseases and phenotypes, including quantitative trait loci (QTL) linkage mapping and genome-wide association studies (GWAS). However, each of these approaches have technical and biological shortcomings. For example, the amount of heritable variation explained by GWAS is often surprisingly small and the resolution of many QTL linkage mapping studies is poor. The predictive power and interpretation of QTL and GWAS results are consequently limited. In this study, we propose a complementary approach to quantitative genetics by interrogating the vast amount of high-throughput genomic data in model organisms to functionally associate genes with phenotypes and diseases. Our algorithm combines the genome-wide functional relationship network for the laboratory mouse and a state-of-the-art machine learning method. We demonstrate the superior accuracy of this algorithm through predicting genes associated with each of 1157 diverse phenotype ontology terms. Comparison between our prediction results and a meta-analysis of quantitative genetic studies reveals both overlapping candidates and distinct, accurate predictions uniquely identified by our approach. Focusing on bone mineral density (BMD), a phenotype related to osteoporotic fracture, we experimentally validated two of our novel predictions (not observed in any previous GWAS/QTL studies) and found significant bone density defects for both Timp2 and Abcg8 deficient mice. Our results suggest that the integration of functional genomics data into networks, which itself is informative of protein function and interactions, can successfully be utilized as a complementary approach to quantitative genetics to predict disease risks. All supplementary material is available at http://cbfg.jax.org/phenotype.

Guan, Yuanfang; Ackert-Bicknell, Cheryl L.; Kell, Braden; Troyanskaya, Olga G.; Hibbs, Matthew A.

2010-01-01

23

Systematic Association Mapping Identifies NELL1 as a Novel IBD Disease Gene  

PubMed Central

Crohn disease (CD), a sub-entity of inflammatory bowel disease (IBD), is a complex polygenic disorder. Although recent studies have successfully identified CD-associated genetic variants, these susceptibility loci explain only a fraction of the heritability of the disease. Here, we report on a multi-stage genome-wide scan of 393 German CD cases and 399 controls. Among the 116,161 single-nucleotide polymorphisms tested, an association with the known CD susceptibility gene NOD2, the 5q31 haplotype, and the recently reported CD locus at 5p13.1 was confirmed. In addition, SNP rs1793004 in the gene encoding nel-like 1 precursor (NELL1, chromosome 11p15.1) showed a consistent disease-association in independent German population- and family-based samples (942 cases, 1082 controls, 375 trios). Subsequent fine mapping and replication in an independent sample of 454 French/Canadian CD trios supported the authenticity of the NELL1 association. Further confirmation in a large German ulcerative colitis (UC) sample indicated that NELL1 is a ubiquitous IBD susceptibility locus (combined p<10?6; OR?=?1.66, 95% CI: 1.30–2.11). The novel 5p13.1 locus was also replicated in the French/Canadian sample and in an independent UK CD patient panel (453 cases, 521 controls, combined p<10?6 for SNP rs1992660). Several associations were replicated in at least one independent sample, point to an involvement of ITGB6 (upstream), GRM8 (downstream), OR5V1 (downstream), PPP3R2 (downstream), NM_152575 (upstream) and HNF4G (intron).

Franke, Andre; Hampe, Jochen; Rosenstiel, Philip; Becker, Christian; Wagner, Florian; Hasler, Robert; Little, Randall D.; Huse, Klaus; Ruether, Andreas; Balschun, Tobias; Wittig, Michael; ElSharawy, Abdou; Mayr, Gabriele; Albrecht, Mario; Prescott, Natalie J.; Onnie, Clive M.; Fournier, Helene; Keith, Tim; Radelof, Uwe; Platzer, Matthias; Mathew, Christopher G.; Stoll, Monika; Krawczak, Michael; Nurnberg, Peter; Schreiber, Stefan

2007-01-01

24

Method for Identifying Carriers of an Extra Dosage of Amyloid Gene Associated with Alzheimer's Disease.  

National Technical Information Service (NTIS)

Using a cloned cDNA probe for the gene encoding brain amyloid polypeptide, AD-AP gene, on Southern blots, the leukocyte DNA from patients with sporadic Alzheimer's disease were tested. The genomes of all tested patients were found to contain three copies ...

D. Y. Goldgaber J. M. Delabar P. M. Sinet D. C. Gajdusek

1987-01-01

25

Large-scale gene-centric analysis identifies novel variants for coronary artery disease  

Microsoft Academic Search

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in approximately 2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases

A. S. Butterworth; P. S. Braund; R. J. Hardwick; D. Saleheen; J. F. Peden; N. Soranzo; J. C. Chambers; M. E. Kleber; B. Keating; A. Qasim; N. Klopp; J. Erdmann; H. Basart; J. H. Baumert; C. R. Bezzina; B. O. Boehm; J. Brocheton; P. Bugert; F. Cambien; R. Collins; D. Couper; J. S. de Jong; P. Diemert; K. Ejebe; C. C. Elbers; P. Elliott; M. Fornage; P. Frossard; S. Garner; S. E. Hunt; J. J. Kastelein; O. H. Klungel; H. Kluter; K. Koch; I. R. Konig; A. S. Kooner; K. Liu; R. McPherson; M. D. Musameh; S. Musani; G. Papanicolaou; A. Peters; B. J. Peters; S. Potter; B. M. Psaty; A. Rasheed; J. Scott; U. Seedorf; J. S. Sehmi; N. Sotoodehnia; K. Stark; J. Stephens; C. E. van der Schoot; Y. T. van der Schouw; P. van der Harst; R. S. Vasan; A. A. Wilde; C. Willenborg; B. R. Winkelmann; M. Zaidi; W. Zhang; A. Ziegler; W. Koenig; W. Matz; M. D. Trip; M. P. Reilly; S. Kathiresan; H. Schunkert; A. Hamsten; A. S. Hall; J. S. Kooner; S. G. Thompson; J. R. Thompson; H. Watkins; J. Danesh; T. Barnes; S. Rafelt; V. Codd; N. Bruinsma; L. R. Dekker; J. P. Henriques; R. J. de Winter; M. Alings; C. F. Allaart; A. P. Gorgels; F. W. A. Verheugt; M. Mueller; C. Meisinger; S. DerOhannessian; N. N. Mehta; J. Ferguson; H. Hakonarson; W. Matthai; R. Wilensky; J. C. Hopewell; S. Parish; P. Linksted; J. Notman; H. Gonzalez; A. Young; T. Ostley; A. Munday; N. Goodwin; V. Verdon; S. Shah; C. Edwards; C. Mathews; R. Gunter; J. Benham; C. Davies; M. Cobb; L. Cobb; J. Crowther; A. Richards; M. Silver; S. Tochlin; S. Mozley; S. Clark; M. Radley; K. Kourellias; P. Olsson; S. Barlera; G. Tognoni; S. Rust; G. Assmann; S. Heath; D. Zelenika; I. Gut; F. Green; M. Farrall; A. Goel; H. Ongen; M. G. Franzosi; M. Lathrop; R. Clarke; A. Aly; K. Anner; K. Bjorklund; G. Blomgren; B. Cederschiold; K. Danell-Toverud; P. Eriksson; U. Grundstedt; M. Heinonen; M. L. Hellenius; F. van't Hooft; K. Husman; J. Lagercrantz; A. Larsson; M. Larsson; M. Mossfeldt; A. Malarstig; G. Olsson; M. Sabater-Lleal; B. Sennblad; A. Silveira; R. Strawbridge; B. Soderholm; J. Ohrvik; K. S. Zaman; N. H. Mallick; M. Azhar; A. Samad; M. Ishaq; N. Shah; M. Samuel; T. L. Assimes; H. Holm; M. Preuss; A. F. Stewart; M. Barbalic; C. Gieger; D. Absher; Z. Aherrahrou; H. Allayee; D. Altshuler; S. Anand; K. Andersen; J. L. Anderson; D. Ardissino; S. G. Ball; A. J. Balmforth; L. C. Becker; D. M. Becker; K. Berger; J. C. Bis; S. M. Boekholdt; E. Boerwinkle; M. J. Brown; M. S. Burnett; I. Buysschaert; J. F. Carlquist; L. Chen; R. W. Davies; G. Dedoussis; A. Dehghan; S. Demissie; J. Devaney; A. Doering; N. E. El Mokhtari; S. G. Ellis; R. Elosua; J. C. Engert; S. Epstein; U. de Faire; M. Fischer; A. R. Folsom; J. Freyer; B. Gigante; D. Girelli; S. Gretarsdottir; V. Gudnason; J. R. Gulcher; S. Tennstedt; E. Halperin; N. Hammond; S. L. Hazen; A. Hofman; B. D. Horne; T. Illig; C. Iribarren; G. T. Jones; J. W. Jukema; M. A. Kaiser; L. M. Kaplan; K. T. Khaw; J. W. Knowles; G. Kolovou; A. Kong; R. Laaksonen; D. Lambrechts; K. Leander; M. Li; W. Lieb; G. Lettre; C. Loley; A. J. Lotery; P. M. Mannucci; N. Martinelli; P. P. McKeown; T. Meitinger; O. Melander; P. A. Merlini; V. Mooser; T. Morgan; Muhleisen T. W; J. B. Muhlestein; K. Musunuru; J. Nahrstaedt; M. M. Nothen; O. Olivieri; F. Peyvandi; R. S. Patel; C. C. Patterson; L. Qu; A. A. Quyyumi; D. J. Rader; L. S. Rallidis; C. Rice; F. R. Roosendaal; D. Rubin; V. Salomaa; M. L. Sampietro; M. S. Sandhu; E. Schadt; A. Schafer; A. Schillert; S. Schreiber; J. Schrezenmeir; S. M. Schwartz; D. S. Siscovick; M. Sivananthan; S. Sivapalaratnam; A. V. Smith; T. B. Smith; J. D. Snoep; J. A. Spertus; K. Stefansson; K. Stirrups; M. Stoll; W. H. Tang; G. Thorgeirsson; G. Thorleifsson; M. Tomaszewski; A. G. Uitterlinden; A. M. van Rij; B. F. Voight; N. J. Wareham; G. AWells; H. E. Wichmann; J. C. Witteman; B. J. Wright; S. Ye; L. A. Cupples; T. Quertermous; W. Marz; S. Blankenberg; U. Thorsteinsdottir; R. Roberts; C. J. O'Donnell; N. C. Onland-Moret; J. van Setten; P. I. de Bakker; W. M. Verschuren; J. M. Boer; C. Wijmenga; M. H. Hofker; A. H. Maitland-van der Zee; A. de Boer; D. E. Grobbee; T. Attwood; S. Belz; J. Cooper; A. Crisp-Hihn; P. Deloukas; N. Foad; A. H. Goodall; J. Gracey; E. Gray; R. Gwilliams; S. Heimerl; C. Hengstenberg; J. Jolley; U. Krishnan; H. Lloyd-Jones; I. Lugauer; P. Lundmark; S. Maouche; J. S. Moore; D. Muir; E. Murray; C. P. Nelson; J. Neudert; D. Niblett; K. O'Leary; W. H. Ouwehand; H. Pollard; A. Rankin; H. Sager; N. J. Samani; J. Sambrook; G. Schmitz; M. Scholz; L. Schroeder; A. C. Syvannen; C. Wallace

2011-01-01

26

Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes  

PubMed Central

Background Multiple genes have been implicated by association studies in altering inflammatory bowel disease (IBD) predisposition. Paediatric patients often manifest more extensive disease and a particularly severe disease course. It is likely that genetic predisposition plays a more substantial role in this group. Objective To identify the spectrum of rare and novel variation in known IBD susceptibility genes using exome sequencing analysis in eight individual cases of childhood onset severe disease. Design DNA samples from the eight patients underwent targeted exome capture and sequencing. Data were processed through an analytical pipeline to align sequence reads, conduct quality checks, and identify and annotate variants where patient sequence differed from the reference sequence. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. Results Across the panel of 169 known IBD susceptibility genes, approximately 300 variants in 104 genes were found. Excluding splicing and HLA-class variants, 58 variants across 39 of these genes were classified as rare, with an alternative allele frequency of <5%, of which 17 were novel. Only two patients with early onset Crohn's disease exhibited rare deleterious variations within NOD2: the previously described R702W variant was the sole NOD2 variant in one patient, while the second patient also carried the L1007 frameshift insertion. Both patients harboured other potentially damaging mutations in the GSDMB, ERAP2 and SEC16A genes. The two patients severely affected with ulcerative colitis exhibited a distinct profile: both carried potentially detrimental variation in the BACH2 and IL10 genes not seen in other patients. Conclusion For each of the eight individuals studied, all non-synonymous, truncating and frameshift mutations across all known IBD genes were identified. A unique profile of rare and potentially damaging variants was evident for each patient with this complex disease.

Christodoulou, Katja; Wiskin, Anthony E; Gibson, Jane; Tapper, William; Willis, Claire; Afzal, Nadeem A; Upstill-Goddard, Rosanna; Holloway, John W; Simpson, Michael A; Beattie, R Mark; Collins, Andrew

2013-01-01

27

Peakwide mapping on chromosome 3q13 identifies the kalirin gene as a novel candidate gene for coronary artery disease.  

PubMed

A susceptibility locus for coronary artery disease (CAD) has been mapped to chromosome 3q13-21 in a linkage study of early-onset CAD. We completed an association-mapping study across the 1-LOD-unit-down supporting interval, using two independent white case-control data sets (CATHGEN, initial and validation) to evaluate association under the peak. Single-nucleotide polymorphisms (SNPs) evenly spaced at 100-kb intervals were screened in the initial data set (N=468). Promising SNPs (P<.1) were then examined in the validation data set (N=514). Significant findings (P<.05) in the combined initial and validation data sets were further evaluated in multiple independent data sets, including a family-based data set (N=2,954), an African American case-control data set (N=190), and an additional white control data set (N=255). The association between genotype and aortic atherosclerosis was examined in 145 human aortas. The peakwide survey found evidence of association in SNPs from multiple genes. The strongest associations were found in three SNPs from the kalirin (KALRN) gene, especially in patients with early-onset CAD (P=.00001-00028 in the combined CATHGEN data sets). In-depth investigation of the gene found that an intronic SNP, rs9289231, was associated with early-onset CAD in all white data sets examined (P<.05). In the joint analysis of all white early-onset CAD cases (N=332) and controls (N=546), rs9289231 was highly significant (P=.00008), with an odds-ratio estimate of 2.1. Furthermore, the risk allele of this SNP was associated with atherosclerosis burden (P=.03) in 145 human aortas. KALRN is a protein with many functions, including the inhibition of inducible nitric oxide synthase and guanine-exchange-factor activity. KALRN and two other associated genes identified in this study (CDGAP and MYLK) belong to the Rho GTPase-signaling pathway. Our data suggest the importance of the KALRN gene and the Rho GTPase-signaling pathway in the pathogenesis of CAD. PMID:17357071

Wang, Liyong; Hauser, Elizabeth R; Shah, Svati H; Pericak-Vance, Margaret A; Haynes, Carol; Crosslin, David; Harris, Marco; Nelson, Sarah; Hale, A Brent; Granger, Christopher B; Haines, Jonathan L; Jones, Christopher J H; Crossman, David; Seo, David; Gregory, Simon G; Kraus, William E; Goldschmidt-Clermont, Pascal J; Vance, Jeffery M

2007-02-08

28

Transcriptional Profiling of Human Liver Identifies Sex-Biased Genes Associated with Polygenic Dyslipidemia and Coronary Artery Disease  

PubMed Central

Sex-differences in human liver gene expression were characterized on a genome-wide scale using a large liver sample collection, allowing for detection of small expression differences with high statistical power. 1,249 sex-biased genes were identified, 70% showing higher expression in females. Chromosomal bias was apparent, with female-biased genes enriched on chrX and male-biased genes enriched on chrY and chr19, where 11 male-biased zinc-finger KRAB-repressor domain genes are distributed in six clusters. Top biological functions and diseases significantly enriched in sex-biased genes include transcription, chromatin organization and modification, sexual reproduction, lipid metabolism and cardiovascular disease. Notably, sex-biased genes are enriched at loci associated with polygenic dyslipidemia and coronary artery disease in genome-wide association studies. Moreover, of the 8 sex-biased genes at these loci, 4 have been directly linked to monogenic disorders of lipid metabolism and show an expression profile in females (elevated expression of ABCA1, APOA5 and LDLR; reduced expression of LIPC) that is consistent with the lower female risk of coronary artery disease. Female-biased expression was also observed for CYP7A1, which is activated by drugs used to treat hypercholesterolemia. Several sex-biased drug-metabolizing enzyme genes were identified, including members of the CYP, UGT, GPX and ALDH families. Half of 879 mouse orthologs, including many genes of lipid metabolism and homeostasis, show growth hormone-regulated sex-biased expression in mouse liver, suggesting growth hormone might play a similar regulatory role in human liver. Finally, the evolutionary rate of protein coding regions for human-mouse orthologs, revealed by dN/dS ratio, is significantly higher for genes showing the same sex-bias in both species than for non-sex-biased genes. These findings establish that human hepatic sex differences are widespread and affect diverse cell metabolic processes, and may help explain sex differences in lipid profiles associated with sex differential risk of coronary artery disease.

Zhang, Yijing; Klein, Kathrin; Sugathan, Aarathi; Nassery, Najlla; Dombkowski, Alan; Zanger, Ulrich M.; Waxman, David J.

2011-01-01

29

Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning  

PubMed Central

Dominant human genetic diseases that impair reproductive fitness and have high locus heterogeneity constitute a problem for gene discovery because the usual criterion of finding more mutations in specific genes than expected by chance may require extremely large populations. Heterotaxy (Htx), a congenital heart disease resulting from abnormalities in left-right (LR) body patterning, has features suggesting that many cases fall into this category. In this setting, appropriate model systems may provide a means to support implication of specific genes. By high-resolution genotyping of 262 Htx subjects and 991 controls, we identify a twofold excess of subjects with rare genic copy number variations in Htx (14.5% vs. 7.4%, P = 1.5 × 10?4). Although 7 of 45 Htx copy number variations were large chromosomal abnormalities, 38 smaller copy number variations altered a total of 61 genes, 22 of which had Xenopus orthologs. In situ hybridization identified 7 of these 22 genes with expression in the ciliated LR organizer (gastrocoel roof plate), a marked enrichment compared with 40 of 845 previously studied genes (sevenfold enrichment, P < 10?6). Morpholino knockdown in Xenopus of Htx candidates demonstrated that five (NEK2, ROCK2, TGFBR2, GALNT11, and NUP188) strongly disrupted both morphological LR development and expression of pitx2, a molecular marker of LR patterning. These effects were specific, because 0 of 13 control genes from rare Htx or control copy number variations produced significant LR abnormalities (P = 0.001). These findings identify genes not previously implicated in LR patterning.

Fakhro, Khalid A.; Choi, Murim; Ware, Stephanie M.; Belmont, John W.; Towbin, Jeffrey A.; Lifton, Richard P.; Khokha, Mustafa K.; Brueckner, Martina

2011-01-01

30

Power and Pitfalls of the Genome-Wide Association Study Approach to Identify Genes for Alzheimer's Disease  

PubMed Central

Until recently, the search for genes contributing to Alzheimer's disease (AD) had been slow and disappointing, with the notable exception of the APOE ?4 allele, which increases risk and reduces the age at onset of AD in a dose-dependent fashion. Findings from genome-wide association studies (GWAS) made up of fewer than several thousand cases and controls each have not been replicated. Efforts of several consortia—each assembling much larger datasets with sufficient power to detect loci conferring small changes in AD risk—have resulted in robust associations with many novel genes involved in multiple biological pathways. Complex data mining strategies are being used to identify additional members of these pathways and gene–gene interactions contributing to AD risk. Guided by GWAS results, next-generation sequencing and functional studies are under way with the hope of helping us better understand AD pathology and providing new drug targets.

Sherva, Richard

2011-01-01

31

TM4SF10 gene sequencing in XLMR patients identifies common polymorphisms but no disease-associated mutation  

PubMed Central

Background The TM4SF10 gene encodes a putative four-transmembrane domains protein of unknown function termed Brain Cell Membrane Protein 1 (BCMP1), and is abundantly expressed in the brain. This gene is located on the short arm of human chromosome X at p21.1. The hypothesis that mutations in the TM4SF10 gene are associated with impaired brain function was investigated by sequencing the gene in individuals with hereditary X-linked mental retardation (XLMR). Methods The coding region (543 bp) of TM4SF10, including intronic junctions, and the long 3' untranslated region (3 233 bp), that has been conserved during evolution, were sequenced in 16 male XLMR patients from 14 unrelated families with definite, or suggestive, linkage to the TM4SF10 gene locus, and in 5 normal males. Results Five sequence changes were identified but none was found to be associated with the disease. Two of these changes correspond to previously known SNPs, while three other were novel SNPs in the TM4SF10 gene. Conclusion We have investigated the majority of the known MRX families linked to the TM4SF10 gene region. In the absence of mutations detected, our study indicates that alterations of TM4SF10 are not a frequent cause of XLMR.

Christophe-Hobertus, Christiane; Kooy, Frank; Gecz, Jozef; Abramowicz, Marc J; Holinski-Feder, Elke; Schwartz, Charles; Christophe, Daniel

2004-01-01

32

Hippocampal Atrophy as a Quantitative Trait in a Genome-Wide Association Study Identifying Novel Susceptibility Genes for Alzheimer's Disease  

PubMed Central

Background With the exception of APOE ?4 allele, the common genetic risk factors for sporadic Alzheimer's Disease (AD) are unknown. Methods and Findings We completed a genome-wide association study on 381 participants in the ADNI (Alzheimer's Disease Neuroimaging Initiative) study. Samples were genotyped using the Illumina Human610-Quad BeadChip. 516,645 unique Single Nucleotide Polymorphisms (SNPs) were included in the analysis following quality control measures. The genotype data and raw genetic data are freely available for download (LONI, http://www.loni.ucla.edu/ADNI/Data/). Two analyses were completed: a standard case-control analysis, and a novel approach using hippocampal atrophy measured on MRI as an objectively defined, quantitative phenotype. A General Linear Model was applied to identify SNPs for which there was an interaction between the genotype and diagnosis on the quantitative trait. The case-control analysis identified APOE and a new risk gene, TOMM40 (translocase of outer mitochondrial membrane 40), at a genome-wide significance level of?10?6 (10?11 for a haplotype). TOMM40 risk alleles were approximately twice as frequent in AD subjects as controls. The quantitative trait analysis identified 21 genes or chromosomal areas with at least one SNP with a p-value?10?6, which can be considered potential “new” candidate loci to explore in the etiology of sporadic AD. These candidates included EFNA5, CAND1, MAGI2, ARSB, and PRUNE2, genes involved in the regulation of protein degradation, apoptosis, neuronal loss and neurodevelopment. Thus, we identified common genetic variants associated with the increased risk of developing AD in the ADNI cohort, and present publicly available genome-wide data. Supportive evidence based on case-control studies and biological plausibility by gene annotation is provided. Currently no available sample with both imaging and genetic data is available for replication. Conclusions Using hippocampal atrophy as a quantitative phenotype in a genome-wide scan, we have identified candidate risk genes for sporadic Alzheimer's disease that merit further investigation.

Potkin, Steven G.; Guffanti, Guia; Lakatos, Anita; Turner, Jessica A.; Kruggel, Frithjof; Fallon, James H.; Saykin, Andrew J.; Orro, Alessandro; Lupoli, Sara; Salvi, Erika; Weiner, Michael; Macciardi, Fabio

2009-01-01

33

A novel protein-coding ORF72.2 gene was identified from Marek's disease virus strain CVI988  

PubMed Central

Marek's disease is a highly contagious disease of poultry characterized by rapid-on set of T-cell lymphomas, which is caused by Marek's disease virus (MDV), but its pathogenic mechanism is still not very clear. Recently, some new progress were achieved in molecular character of MDV. Along with the genomic sequencing of MDV serotype 1, some novel open reading frames (ORFs) were predicted, and ORF72.2 was one of them which have no homologues in other MDV serotypes or in other alphaherpesvirus. In the study, ORF72.2 was firstly identified as a protein-coding gene by the method of reverse transcription polymerase chain reaction (RT-PCR), western blotting and indirect immunofluorescence assay. This study paved the way to conduct further studies to determine whether ORF72.2 plays a role in MDV replication and pathogenicity.

2010-01-01

34

Genetic analysis of fin development in zebrafish identifies furin and hemicentin1 as potential novel fraser syndrome disease genes.  

PubMed

Using forward genetics, we have identified the genes mutated in two classes of zebrafish fin mutants. The mutants of the first class are characterized by defects in embryonic fin morphogenesis, which are due to mutations in a Laminin subunit or an Integrin alpha receptor, respectively. The mutants of the second class display characteristic blistering underneath the basement membrane of the fin epidermis. Three of them are due to mutations in zebrafish orthologues of FRAS1, FREM1, or FREM2, large basement membrane protein encoding genes that are mutated in mouse bleb mutants and in human patients suffering from Fraser Syndrome, a rare congenital condition characterized by syndactyly and cryptophthalmos. Fin blistering in a fourth group of zebrafish mutants is caused by mutations in Hemicentin1 (Hmcn1), another large extracellular matrix protein the function of which in vertebrates was hitherto unknown. Our mutant and dose-dependent interaction data suggest a potential involvement of Hmcn1 in Fraser complex-dependent basement membrane anchorage. Furthermore, we present biochemical and genetic data suggesting a role for the proprotein convertase FurinA in zebrafish fin development and cell surface shedding of Fras1 and Frem2, thereby allowing proper localization of the proteins within the basement membrane of forming fins. Finally, we identify the extracellular matrix protein Fibrillin2 as an indispensable interaction partner of Hmcn1. Thus we have defined a series of zebrafish mutants modelling Fraser Syndrome and have identified several implicated novel genes that might help to further elucidate the mechanisms of basement membrane anchorage and of the disease's aetiology. In addition, the novel genes might prove helpful to unravel the molecular nature of thus far unresolved cases of the human disease. PMID:20419147

Carney, Thomas J; Feitosa, Natália Martins; Sonntag, Carmen; Slanchev, Krasimir; Kluger, Johannes; Kiyozumi, Daiji; Gebauer, Jan M; Coffin Talbot, Jared; Kimmel, Charles B; Sekiguchi, Kiyotoshi; Wagener, Raimund; Schwarz, Heinz; Ingham, Phillip W; Hammerschmidt, Matthias

2010-04-15

35

Chicks and single-nucleotide polymorphisms: an entree into identifying genes conferring disease resistance in chicken  

Technology Transfer Automated Retrieval System (TEKTRAN)

Marek's disease (MD) is one of the most serious chronic infectious disease threats to the U.S. poultry industry. Selecting for increased genetic resistance to MD is a control strategy that can augment current vaccinal control measures. Although our previous efforts integrating various genomic scre...

36

Saccharomyces Fungemia Associated with Esophageal Disease Identified by D1/D2 Ribosomal RNA Gene Sequence  

Technology Transfer Automated Retrieval System (TEKTRAN)

Disseminated Saccharomyces infection has been reported in immunosuppressed patients treated with probiotics, but disseminated Saccharomyces cerevisiae infection associated with underlying esophageal disease is not previously described. Saccharomyces cerevisiae (which occasionally colonizes the gast...

37

Phase analysis identifies compound heterozygous deletions of the PARK2 gene in patients with early-onset Parkinson disease.  

PubMed

Exon rearrangements and point mutations are common in PARK2, the most important causative gene of autosomal recessive early-onset Parkinson disease (EOPD). However, gene dosage analysis alone cannot conclusively determine the phase of exon rearrangements and the incidence of molecularly confirmed parkin-type EOPD may be underestimated. To fully characterize the mutation spectrum, we performed sequencing and gene dosage analyses of SNCA, PARK2, PINK1, and PARK7 in 114 unrelated EOPD patients with onset age ?40 years. Mutational phase of exon rearrangements was determined by reverse-transcriptase PCR (RT-PCR) and sequence analysis using a patient's own RNA. Fourteen different PARK2 mutations (3 point mutations plus 11 exon rearrangements) were identified in 18 patients, comprising 1 homozygote (0.9%), 13 compound heterozygotes (11.4%), 3 single heterozygotes (2.6%), and 1 with unknown phase (0.9%). By phase determination, more than 80% (5 of 6) of patients with apparently contiguous multi-exon deletions and 30% (5 of 18) of all PARK2 mutation carriers were additionally diagnosed as compound heterozygotes, respectively. This study shows that compound heterozygous mutations constituted a significant portion of patients with apparently contiguous multi-exon deletions. Phase determination is a prerequisite to molecular diagnosis for autosomal recessive EOPD, especially in subjects with PARK2 exon rearrangements. PMID:21534944

Kim, S Y; Seong, M W; Jeon, B S; Kim, S Y; Ko, H S; Kim, J Y; Park, S S

2011-05-29

38

Identifying disease-causal genes using Semantic Web-based representation of integrated genomic and phenomic knowledge.  

PubMed

Most common chronic diseases are caused by the interactions of multiple factors including the influences and responses of susceptibility and modifier genes that are themselves subject to etiologic events, interactions, and environmental factors. These entities, interactions, mechanisms, and phenotypic consequences can be richly represented using graph networks with semantically definable nodes and edges. To use this form of knowledge representation for inferring causal relationships, it is critical to leverage pertinent prior knowledge so as to facilitate ranking and probabilistic treatment of candidate etiologic factors. For example, genomic studies using linkage analyses detect quantitative trait loci that encompass a large number of disease candidate genes. Similarly, transcriptomic studies using differential gene expression profiling generate hundreds of potential disease candidate genes that themselves may not include genetically variant genes that are responsible for the expression pattern signature. Hypothesizing that the majority of disease-causal genes are linked to biochemical properties that are shared by other genes known to play functionally important roles and whose mutations produce clinical features similar to the disease under study, we reasoned that an integrative genomics-phenomics approach could expedite disease candidate gene identification and prioritization. To approach the problem of inferring likely causality roles, we generated Semantic Web methods-based network data structures and performed centrality analyses to rank genes according to model-driven semantic relationships. Our results indicate that Semantic Web approaches enable systematic leveraging of implicit relations hitherto embedded among large knowledge bases and can greatly facilitate identification of centrality elements that can lead to specific hypotheses and new insights. PMID:18755295

Gudivada, Ranga Chandra; Qu, Xiaoyan A; Chen, Jing; Jegga, Anil G; Neumann, Eric K; Aronow, Bruce J

2008-08-23

39

Identifying disease-causal genes using Semantic Web-based representation of integrated genomic and phenomic knowledge  

Microsoft Academic Search

Most common chronic diseases are caused by the interactions of multiple factors including the influences and responses of susceptibility and modifier genes that are themselves subject to etiologic events, interactions, and environmental factors. These entities, interactions, mechanisms, and phenotypic consequences can be richly represented using graph networks with semantically definable nodes and edges. To use this form of knowledge representation

Ranga Chandra Gudivada; Xiaoyan A. Qu; Jing Chen; Anil G. Jegga; Eric K. Neumann; Bruce J. Aronow

2008-01-01

40

Survival Analysis of Genome-Wide Gene Expression Profiles of Prostate Cancers Identifies New Prognostic Targets of Disease Relapse1,2  

Microsoft Academic Search

Current models of prostate cancer classification are poor at distinguish- ing between tumors that have similar histopathological features but vary in clinical course and outcome. Here, we applied classical survival analysis to genome-wide gene expression profiles of prostate cancers and pre- operative prostate-specific antigen (PSA) levels from each patient, to identify prognostic markers of disease relapse that provide additional predictive

Susan M. Henshall; Daniel E. H. Afar; Jordan Hiller; Lisa G. Horvath; David I. Quinn; Krishan K. Rasiah; Kurt Gish; Dorian Willhite; James G. Kench; Margaret Gardiner-Garden; Phillip D. Stricker; Howard I. Scher; John J. Grygiel; David B. Agus; David H. Mack; Robert L. Sutherland

2003-01-01

41

Positively Selected Disease Response Orthologous Gene Sets in the Cereals Identified Using Sorghum bicolor L. Moench Expression Profiles and Comparative Genomics  

PubMed Central

Disease response genes (DRGs) diverge under recurrent positive selection as a result of a molecular arms race between hosts and pathogens. Most of these studies were conducted in animals, and few defense genes have been shown to evolve adaptively in plants. To test for adaptation in the molecules mediating disease resistance in the cereals, we first combined information from the expression pattern of Sorghum bicolor genes and from divergence to the full genome of rice to identify candidate DRGs. We then used evolutionary analyses of orthologous gene sets from several grass species, to determine whether the DRGs show signals of positive selection and the residues targeted. We found 140 divergent genes upregulated under biotic stress in S. bicolor by evaluating the relative abundance of expressed sequence tags in different libraries and comparing them with rice genes. For 10 of these genes, we found sets of orthologs including sequences from rice and three other cereals; six genes showed a pattern of substitution that was consistent with positive selection. Three of these genes, a thaumatin, a peroxidase, and a barley mlo homolog, are known antifungal proteins. The other three genes with evidence of positive selection were a MCM-1 agamous deficiens SRF- (MADS) box transcription factor, an eIF5 translation initiation factor, and a gene of unknown function but with evidence of expression during stress. Permutation analyses, using different ortholog and paralog sequences, consistently identified five positively selected codons in the peroxidase, a member of a cluster of genes and a large gene family. We mapped the positively selected residues onto the structure of the peroxidase and thaumatin and found that all sites are on the surface of these proteins and several are close to biochemically determined active sites. Identifying new positively selected plant disease resistance genes and the critical amino acid sites provides a basis for functional studies that may increase our understanding of their underlying molecular mechanisms of action. Additionally, it may lead to the identification of individuals having variation at functionally important sites, as well as eventually using this information in the rational design and engineering of proteins involved in plant disease resistance.

Zamora, Alejandro; Sun, Qi; Hamblin, Martha T.; Aquadro, Charles F.; Kresovich, Stephen

2009-01-01

42

Novel Crohn Disease Locus Identified by Genome-Wide Association Maps to a Gene Desert on 5p13.1 and Modulates Expression of PTGER4  

PubMed Central

To identify novel susceptibility loci for Crohn disease (CD), we undertook a genome-wide association study with more than 300,000 SNPs characterized in 547 patients and 928 controls. We found three chromosome regions that provided evidence of disease association with p-values between 10?6 and 10?9. Two of these (IL23R on Chromosome 1 and CARD15 on Chromosome 16) correspond to genes previously reported to be associated with CD. In addition, a 250-kb region of Chromosome 5p13.1 was found to contain multiple markers with strongly suggestive evidence of disease association (including four markers with p < 10?7). We replicated the results for 5p13.1 by studying 1,266 additional CD patients, 559 additional controls, and 428 trios. Significant evidence of association (p < 4 × 10?4) was found in case/control comparisons with the replication data, while associated alleles were over-transmitted to affected offspring (p < 0.05), thus confirming that the 5p13.1 locus contributes to CD susceptibility. The CD-associated 250-kb region was saturated with 111 SNP markers. Haplotype analysis supports a complex locus architecture with multiple variants contributing to disease susceptibility. The novel 5p13.1 CD locus is contained within a 1.25-Mb gene desert. We present evidence that disease-associated alleles correlate with quantitative expression levels of the prostaglandin receptor EP4, PTGER4, the gene that resides closest to the associated region. Our results identify a major new susceptibility locus for CD, and suggest that genetic variants associated with disease risk at this locus could modulate cis-acting regulatory elements of PTGER4.

Libioulle, Cecile; Louis, Edouard; Hansoul, Sarah; Sandor, Cynthia; Farnir, Frederic; Franchimont, Denis; Vermeire, Severine; Dewit, Olivier; de Vos, Martine; Dixon, Anna; Demarche, Bruno; Gut, Ivo; Heath, Simon; Foglio, Mario; Liang, Liming; Laukens, Debby; Mni, Myriam; Zelenika, Diana; Gossum, Andre Van; Rutgeerts, Paul; Belaiche, Jacques; Lathrop, Mark; Georges, Michel

2007-01-01

43

Analysis of SNPs with an effect on gene expression identifies UBE2L3 and BCL3 as potential new risk genes for Crohn's disease  

Microsoft Academic Search

Genome-wide association studies (GWAS) for Crohn's disease (CD) have identified loci explaining similar to 20% of the total genetic risk of CD. Part of the other genetic risk loci is probably partly hidden among signals discarded by the multiple testing correction needed in the analysis of GWAS data. Strategies for finding these hidden loci require large replication cohorts and are

K. Fransen; M. C. Visschedijk; S. van Sommeren; J. Y. Y. Fu; L. Franke; E. A. M. Festen; P. C. F. Stokkers; A. A. van Bodegraven; J. B. A. Crusius; D. W. Hommes; P. Zanen; D. J. de Jong; C. Wijmenga; C. C. van Diemen; R. K. Weersma

2010-01-01

44

Regulatory gene networks and signaling pathways from primary osteoarthritis and Kashin-Beck disease, an endemic osteoarthritis, identified by three analysis software.  

PubMed

Three new software systems, Ingenuity pathway analysis(IPA, TranscriptomeBrowser and MetaCore, were compared by analyzing chondrocyte microarray data of Kashin-Beck disease (KBD) and primary knee osteoarthritis(OA) to understand the pathway or network analysis software which has a superior function to identify target genes with easy operation and effective for differential diagnosis and treatment of KBD and OA. RNA was isolated from cartilage samples taken from KBD patients and OA ones. Agilent 44K human whole genome oligonucleotide microarrays were used to detect differentially expressed genes. From IPA, we identified one significant canonical pathway and two significant networks. From GeneHub analysis, we got three networks. One significant canonical pathway and one significant network were obtained from TranscriptomeBrowser analysis. POSTN and LEF1 which were got from IPA, RAC2 which was identified by both of the IPA and TranscriptomeBrowser may be most closely related to the etiopathogenesis of KBD. According to our data analysis, IPA and TranscriptomeBrowser are suitable for pathway analysis, while, TranscriptomeBrowser is suitable for network analysis. The significant genes obtained from IPA and TranscriptomeBrowser analysis may thus provide a better understanding of the molecular details in the pathogenesis of KBD and also provide useful pathways and network maps for future research in osteochondrosis. PMID:23069848

Wang, Sen; Duan, Chen; Zhang, Feng; Ma, Weijuan; Guo, Xiong

2012-10-13

45

A novel protein-coding ORF72.2 gene was identified from Marek's disease virus strain CVI988  

Microsoft Academic Search

Marek's disease is a highly contagious disease of poultry characterized by rapid-on set of T-cell lymphomas, which is caused by Marek's disease virus (MDV), but its pathogenic mechanism is still not very clear. Recently, some new progress were achieved in molecular character of MDV. Along with the genomic sequencing of MDV serotype 1, some novel open reading frames (ORFs) were

Mingxing Tian; Yang Zhao; Min Shi; Yan Lin; Nianli Zou; Ping Liu; Xintian Wen; Sanjie Cao; Yong Huang

2010-01-01

46

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.  

PubMed

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and A? plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma A?42/A?40 ratio (best signal, P=5.4 × 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD. PMID:22430674

Lambert, J-C; Grenier-Boley, B; Harold, D; Zelenika, D; Chouraki, V; Kamatani, Y; Sleegers, K; Ikram, M A; Hiltunen, M; Reitz, C; Mateo, I; Feulner, T; Bullido, M; Galimberti, D; Concari, L; Alvarez, V; Sims, R; Gerrish, A; Chapman, J; Deniz-Naranjo, C; Solfrizzi, V; Sorbi, S; Arosio, B; Spalletta, G; Siciliano, G; Epelbaum, J; Hannequin, D; Dartigues, J-F; Tzourio, C; Berr, C; Schrijvers, E M C; Rogers, R; Tosto, G; Pasquier, F; Bettens, K; Van Cauwenberghe, C; Fratiglioni, L; Graff, C; Delepine, M; Ferri, R; Reynolds, C A; Lannfelt, L; Ingelsson, M; Prince, J A; Chillotti, C; Pilotto, A; Seripa, D; Boland, A; Mancuso, M; Bossù, P; Annoni, G; Nacmias, B; Bosco, P; Panza, F; Sanchez-Garcia, F; Del Zompo, M; Coto, E; Owen, M; O'Donovan, M; Valdivieso, F; Caffarra, P; Caffara, P; Scarpini, E; Combarros, O; Buée, L; Campion, D; Soininen, H; Breteler, M; Riemenschneider, M; Van Broeckhoven, C; Alpérovitch, A; Lathrop, M; Trégouët, D-A; Williams, J; Amouyel, P

2012-03-20

47

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease  

PubMed Central

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case–control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43–1.96); P=1.1 × 10?10). We finally searched for association between SNPs within the FRMD4A locus and A? plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma A?42/A?40 ratio (best signal, P=5.4 × 10?7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

Lambert, J-C; Grenier-Boley, B; Harold, D; Zelenika, D; Chouraki, V; Kamatani, Y; Sleegers, K; Ikram, M A; Hiltunen, M; Reitz, C; Mateo, I; Feulner, T; Bullido, M; Galimberti, D; Concari, L; Alvarez, V; Sims, R; Gerrish, A; Chapman, J; Deniz-Naranjo, C; Solfrizzi, V; Sorbi, S; Arosio, B; Spalletta, G; Siciliano, G; Epelbaum, J; Hannequin, D; Dartigues, J-F; Tzourio, C; Berr, C; Schrijvers, E M C; Rogers, R; Tosto, G; Pasquier, F; Bettens, K; Van Cauwenberghe, C; Fratiglioni, L; Graff, C; Delepine, M; Ferri, R; Reynolds, C A; Lannfelt, L; Ingelsson, M; Prince, J A; Chillotti, C; Pilotto, A; Seripa, D; Boland, A; Mancuso, M; Bossu, P; Annoni, G; Nacmias, B; Bosco, P; Panza, F; Sanchez-Garcia, F; Del Zompo, M; Coto, E; Owen, M; O'Donovan, M; Valdivieso, F; Caffara, P; Scarpini, E; Combarros, O; Buee, L; Campion, D; Soininen, H; Breteler, M; Riemenschneider, M; Van Broeckhoven, C; Alperovitch, A; Lathrop, M; Tregouet, D-A; Williams, J; Amouyel, P

2013-01-01

48

Comparative Genomics Identifies a Flagellar and Basal Body Proteome that Includes the BBS5 Human Disease Gene  

Microsoft Academic Search

Cilia and flagella are microtubule-based structures nucleated by modified centrioles termed basal bodies. These biochemically complex organelles have more than 250 and 150 polypeptides, respectively. To identify the proteins involved in ciliary and basal body biogenesis and function, we undertook a comparative genomics approach that subtracted the nonflagellated proteome of Arabidopsis from the shared proteome of the ciliated\\/flagellated organisms Chlamydomonas

Jin Billy Li; Jantje M. Gerdes; Courtney J. Haycraft; Yanli Fan; Tanya M. Teslovich; Helen May-Simera; Haitao Li; Oliver E. Blacque; Linya Li; Carmen C. Leitch; Richard Allan Lewis; Jane S Green; Patrick S Parfrey; Michel R Leroux; William S Davidson; Philip L Beales; Lisa M Guay-Woodford; Bradley K Yoder; Gary D Stormo; Nicholas Katsanis; Susan K Dutcher

2004-01-01

49

Candidate genes for panhypopituitarism identified by gene expression profiling  

PubMed Central

Mutations in the transcription factors PROP1 and PIT1 (POU1F1) lead to pituitary hormone deficiency and hypopituitarism in mice and humans. The dysmorphology of developing Prop1 mutant pituitaries readily distinguishes them from those of Pit1 mutants and normal mice. This and other features suggest that Prop1 controls the expression of genes besides Pit1 that are important for pituitary cell migration, survival, and differentiation. To identify genes involved in these processes we used microarray analysis of gene expression to compare pituitary RNA from newborn Prop1 and Pit1 mutants and wild-type littermates. Significant differences in gene expression were noted between each mutant and their normal littermates, as well as between Prop1 and Pit1 mutants. Otx2, a gene critical for normal eye and pituitary development in humans and mice, exhibited elevated expression specifically in Prop1 mutant pituitaries. We report the spatial and temporal regulation of Otx2 in normal mice and Prop1 mutants, and the results suggest Otx2 could influence pituitary development by affecting signaling from the ventral diencephalon and regulation of gene expression in Rathke's pouch. The discovery that Otx2 expression is affected by Prop1 deficiency provides support for our hypothesis that identifying molecular differences in mutants will contribute to understanding the molecular mechanisms that control pituitary organogenesis and lead to human pituitary disease.

Mortensen, Amanda H.; MacDonald, James W.; Ghosh, Debashis

2011-01-01

50

NIH Researchers Identify OCD Risk Gene  

MedlinePLUS

... Issues Research News From NIH NIH Researchers Identify OCD Risk Gene Past Issues / Summer 2006 Table of ... gene variant that doubles an individual's risk for obsessive-compulsive disorder (OCD). The new functional variant, or allele, is ...

51

A vector space model approach to identify genetically related diseases  

PubMed Central

Objective The relationship between diseases and their causative genes can be complex, especially in the case of polygenic diseases. Further exacerbating the challenges in their study is that many genes may be causally related to multiple diseases. This study explored the relationship between diseases through the adaptation of an approach pioneered in the context of information retrieval: vector space models. Materials and Methods A vector space model approach was developed that bridges gene disease knowledge inferred across three knowledge bases: Online Mendelian Inheritance in Man, GenBank, and Medline. The approach was then used to identify potentially related diseases for two target diseases: Alzheimer disease and Prader-Willi Syndrome. Results In the case of both Alzheimer Disease and Prader-Willi Syndrome, a set of plausible diseases were identified that may warrant further exploration. Discussion This study furthers seminal work by Swanson, et al. that demonstrated the potential for mining literature for putative correlations. Using a vector space modeling approach, information from both biomedical literature and genomic resources (like GenBank) can be combined towards identification of putative correlations of interest. To this end, the relevance of the predicted diseases of interest in this study using the vector space modeling approach were validated based on supporting literature. Conclusion The results of this study suggest that a vector space model approach may be a useful means to identify potential relationships between complex diseases, and thereby enable the coordination of gene-based findings across multiple complex diseases.

2012-01-01

52

Limitations of Pseudogenes in Identifying Gene Losses  

Microsoft Academic Search

The loss of previously established genes has been proposed as a major force in evolutionary change. While the sequencing of\\u000a many new species offers the opportunity to identify cases of gene loss, the best method to do this with is unclear. A number\\u000a of methods to identify gene losses rely on the presence of a pseudogene for each loss. If

James C. Costello; Mira V. Han; Matthew W. Hahn

2008-01-01

53

Gene expression profiling: can we identify the right target genes?  

Microsoft Academic Search

Gene expression profiling allows the simultaneous monitoring of the transcriptional behaviour of thousands of genes, which may potentially be involved in disease development. Several studies have been performed in idiopathic pulmonary fibrosis (IPF), which aim to define genetic links to the disease in an attempt to improve the current understanding of the underlying pathogenesis of the disease and target pathways

J. E. Loyd

2008-01-01

54

A microarray approach for identifying mutated genes  

Microsoft Academic Search

This study was performed to evaluate if microarray technology can identify genes using their transcriptionally defective mutant alleles. Three barley (Hordeum vulgare L.) mutant strains, xantha-h57, xantha-f27 and xantha-g28, with mutations in the genes encoding the three subunits of the chlorophyll biosynthetic enzyme magnesium chelatase, were used in a reconstruction experiment. The mutation xantha-h57 prevents transcription of Xantha-h mRNA. Microarrays

Shakhira Zakhrabekova; C. Gamini Kannangara; Diter von Wettstein; Mats Hansson

2002-01-01

55

Systems biology approaches to identify developmental bases for lung diseases  

PubMed Central

A greater understanding of the regulatory processes contributing to lung development could be helpful to identify strategies to ameliorate morbidity and mortality in premature infants and to identify individuals at risk for congenital and/or chronic lung diseases. Over the past decade, genomics technologies have enabled the production of rich gene expression databases providing information for all genes across developmental time or in diseased tissue. These data sets facilitate systems biology approaches for identifying underlying biological modules and programs contributing to the complex processes of normal development, and those that may be associated with disease states. The next decade will undoubtedly see rapid and significant advances in redefining both lung development and disease at the systems level.

Bhattacharya, Soumyaroop; Mariani, Thomas J.

2013-01-01

56

High-Resolution Melting (HRM) of the Cytochrome B Gene: A Powerful Approach to Identify Blood-Meal Sources in Chagas Disease Vectors  

PubMed Central

Methods to determine blood-meal sources of hematophagous Triatominae bugs (Chagas disease vectors) are serological or based on PCR employing species-specific primers or heteroduplex analysis, but these are expensive, inaccurate, or problematic when the insect has fed on more than one species. To solve those problems, we developed a technique based on HRM analysis of the mitochondrial gene cytochrome B (Cyt b). This technique recognized 14 species involved in several ecoepidemiological cycles of the transmission of Trypanosoma cruzi and it was suitable with DNA extracted from intestinal content and feces 30 days after feeding, revealing a resolution power that can display mixed feedings. Field samples were analyzed showing blood meal sources corresponding to domestic, peridomiciliary and sylvatic cycles. The technique only requires a single pair of primers that amplify the Cyt b gene in vertebrates and no other standardization, making it quick, easy, relatively inexpensive, and highly accurate.

Pena, Victor H.; Fernandez, Geysson J.; Gomez-Palacio, Andres M.; Mejia-Jaramillo, Ana M.; Cantillo, Omar; Triana-Chavez, Omar

2012-01-01

57

Computational disease gene identification: a concert of methods prioritizes type 2 diabetes and obesity candidate genes  

Microsoft Academic Search

Genome-wide experimental methods to identify disease genes, such as linkage analysis and association studies, generate increasingly large candidate gene sets for which comprehensive empirical analysis is impractical. Computational methods employ data from a variety of sources to identify the most likely candidate disease genes from these gene sets. Here, we review seven independent computational disease gene prioritization methods, and then

Nicki Tiffin; Euan Adie; Frances Turner; Han G. Brunner; Marc A. van Driel; Martin Oti; Nuria Lopez-Bigas; Christos Ouzounis; Carolina Perez-Iratxeta; Miguel A. Andrade-Navarro; Adebowale Adeyemo; Mary Elizabeth Patti; Colin A. M. Semple; Winston Hide

2006-01-01

58

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease, and shows evidence for additional susceptibility genes  

PubMed Central

We undertook a two-stage genome-wide association study of Alzheimer's disease involving over 16,000 individuals. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the APOE locus (most significant SNP: rs2075650, p= 1.8×10?157) and observed genome-wide significant association with SNPs at two novel loci: rs11136000 in the CLU or APOJ gene (p= 1.4×10?9) and rs3851179, a SNP 5? to the PICALM gene (p= 1.9×10?8). Both novel associations were supported in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with AD in the combined dataset (rs11136000: p= 8.5×10?10, odds ratio= 0.86; rs3851179: p= 1.3×10?9, odds ratio= 0.86). We also observed more variants associated at p< 1×10?5 than expected by chance (p=7.5×10?6), including polymorphisms at the BIN1, DAB1 and CR1 loci.

Harold, Denise; Abraham, Richard; Hollingworth, Paul; Sims, Rebecca; Gerrish, Amy; Hamshere, Marian; Singh Pahwa, Jaspreet; Moskvina, Valentina; Dowzell, Kimberley; Williams, Amy; Jones, Nicola; Thomas, Charlene; Stretton, Alexandra; Morgan, Angharad; Lovestone, Simon; Powell, John; Proitsi, Petroula; Lupton, Michelle K; Brayne, Carol; Rubinsztein, David C.; Gill, Michael; Lawlor, Brian; Lynch, Aoibhinn; Morgan, Kevin; Brown, Kristelle; Passmore, Peter; Craig, David; McGuinness, Bernadette; Todd, Stephen; Holmes, Clive; Mann, David; Smith, A. David; Love, Seth; Kehoe, Patrick G.; Hardy, John; Mead, Simon; Fox, Nick; Rossor, Martin; Collinge, John; Maier, Wolfgang; Jessen, Frank; Schurmann, Britta; van den Bussche, Hendrik; Heuser, Isabella; Kornhuber, Johannes; Wiltfang, Jens; Dichgans, Martin; Frolich, Lutz; Hampel, Harald; Hull, Michael; Rujescu, Dan; Goate, Alison; Kauwe, John S.K.; Cruchaga, Carlos; Nowotny, Petra; Morris, John C.; Mayo, Kevin; Sleegers, Kristel; Bettens, Karolien; Engelborghs, Sebastiaan; De Deyn, Peter; van Broeckhoven, Christine; Livingston, Gill; Bass, Nicholas J.; Gurling, Hugh; McQuillin, Andrew; Gwilliam, Rhian; Deloukas, Panagiotis; Al-Chalabi, Ammar; Shaw, Christopher E.; Tsolaki, Magda; Singleton, Andrew; Guerreiro, Rita; Muhleisen, Thomas W.; Nothen, Markus M.; Moebus, Susanne; Jockel, Karl-Heinz; Klopp, Norman; Wichmann, H-Erich; Carrasquillo, Minerva M.; Pankratz, V. Shane; Younkin, Steven G.; Holmans, Peter; O'Donovan, Michael; Owen, Michael J.; Williams, Julie

2010-01-01

59

Detection of disseminated tumor cells in the bone marrow of breast cancer patients using multiplex gene expression measurements identifies new therapeutic targets in patients at high risk for the development of metastatic disease.  

PubMed

Disseminated tumor cells (DTCs) detected in the bone marrow (BM) of breast cancer patients identify women at high risk of recurrence. DTCs are traditionally detected by immunocytochemical staining for cytokeratins or single gene expression measurements, which limit both specificity and sensitivity. We evaluated the Nanostring nCounter™ platform for multi-marker, gene expression-based detection and classification of DTCs in the BM of breast cancer patients. Candidate genes exhibiting tumor cell-specific expression were identified from microarray datasets and validated by qRT-PCR analysis in non-malignant human BM and identical samples spiked with predefined numbers of molecularly diverse breast tumor cell lines. Thirty-eight validated transcripts were designed for the nCounter™ platform and a subset of these transcripts was technically validated against qRT-PCR measurements using identical spiked BM controls. Bilateral iliac crest BM aspirates were collected and analyzed from twenty breast cancer patients, prior to neoadjuvant therapy, using the full 38-gene nCounter™ code set. Tumor cell-specific gene expression by nCounter™ was detected with a sensitivity of one cancer cell per 1 × 10(6) nucleated BM cells after optimization. Measurements were quantitative, log linear over a 20-fold range, and correlated with qRT-PCR measurements. Using the nCounter™ 38-gene panel, 6 of 8 patients (75 %) who developed metastatic disease had detectable expression of at least one transcript. Notably, three of these patients had detectable expression of ERBB2 in their BM, despite the fact that their corresponding primary tumors were HER2/ERBB2 negative and therefore did not receive trastuzumab therapy. Four of these patients also expressed the PTCH1 receptor, a newly recognized therapeutic target based on hedgehog signaling pathway inhibition. The presumptive detection and classification of DTCs in the BM of breast cancer patients, based on sensitive and quantitative multi-marker detection of gene expression using the nCounter™ platform, provide an opportunity to both predict early distant recurrence and, more importantly, identify opportunities for preventing the spread of disease based on the expression of unique, therapeutically actionable gene targets. This study demonstrates the application of a new technology for multiplexed gene expression-based detection of DTCs in the BM of breast cancer patients and identifies at least two therapeutically targetable genes that are frequently expressed in the BM of patients who develop metastatic disease. PMID:23129172

Siddappa, Chidananda M; Watson, Mark A; Pillai, Sreeraj G; Trinkaus, Kathryn; Fleming, Timothy; Aft, Rebecca

2012-11-06

60

Genetics of Sputum Gene Expression in Chronic Obstructive Pulmonary Disease  

Microsoft Academic Search

Previous expression quantitative trait loci (eQTL) studies have performed genetic association studies for gene expression, but most of these studies examined lymphoblastoid cell lines from non-diseased individuals. We examined the genetics of gene expression in a relevant disease tissue from chronic obstructive pulmonary disease (COPD) patients to identify functional effects of known susceptibility genes and to find novel disease genes.

Weiliang Qiu; Michael H. Cho; John H. Riley; Wayne H. Anderson; Dave Singh; Per Bakke; Amund Gulsvik; Augusto A. Litonjua; David A. Lomas; James D. Crapo; Terri H. Beaty; Bartolome R. Celli; Stephen Rennard; Ruth Tal-Singer; Steven M. Fox; Edwin K. Silverman; Craig P. Hersh; Mark M. Wurfel

2011-01-01

61

Integrative Genomics Identifies Gene Signature Associated with Melanoma Ulceration  

PubMed Central

Background Despite the extensive research approaches applied to characterise malignant melanoma, no specific molecular markers are available that are clearly related to the progression of this disease. In this study, our aims were to define a gene expression signature associated with the clinical outcome of melanoma patients and to provide an integrative interpretation of the gene expression -, copy number alterations -, and promoter methylation patterns that contribute to clinically relevant molecular functional alterations. Methods Gene expression profiles were determined using the Affymetrix U133 Plus2.0 array. The NimbleGen Human CGH Whole-Genome Tiling array was used to define CNAs, and the Illumina GoldenGate Methylation platform was applied to characterise the methylation patterns of overlapping genes. Results We identified two subclasses of primary melanoma: one representing patients with better prognoses and the other being characteristic of patients with unfavourable outcomes. We assigned 1,080 genes as being significantly correlated with ulceration, 987 genes were downregulated and significantly enriched in the p53, Nf-kappaB, and WNT/beta-catenin pathways. Through integrated genome analysis, we defined 150 downregulated genes whose expression correlated with copy number losses in ulcerated samples. These genes were significantly enriched on chromosome 6q and 10q, which contained a total of 36 genes. Ten of these genes were downregulated and involved in cell-cell and cell-matrix adhesion or apoptosis. The expression and methylation patterns of additional genes exhibited an inverse correlation, suggesting that transcriptional silencing of these genes is driven by epigenetic events. Conclusion Using an integrative genomic approach, we were able to identify functionally relevant molecular hotspots characterised by copy number losses and promoter hypermethylation in distinct molecular subtypes of melanoma that contribute to specific transcriptomic silencing and might indicate a poor clinical outcome of melanoma.

Toth, Reka; Vizkeleti, Laura; Herandez-Vargas, Hector; Lazar, Viktoria; Emri, Gabriella; Szatmari, Istvan; Herceg, Zdenko; Adany, Roza; Balazs, Margit

2013-01-01

62

From SNPs to Genes: Disease Association at the Gene Level  

PubMed Central

Interpreting Genome-Wide Association Studies (GWAS) at a gene level is an important step towards understanding the molecular processes that lead to disease. In order to incorporate prior biological knowledge such as pathways and protein interactions in the analysis of GWAS data it is necessary to derive one measure of association for each gene. We compare three different methods to obtain gene-wide test statistics from Single Nucleotide Polymorphism (SNP) based association data: choosing the test statistic from the most significant SNP; the mean test statistics of all SNPs; and the mean of the top quartile of all test statistics. We demonstrate that the gene-wide test statistics can be controlled for the number of SNPs within each gene and show that all three methods perform considerably better than expected by chance at identifying genes with confirmed associations. By applying each method to GWAS data for Crohn's Disease and Type 1 Diabetes we identified new potential disease genes.

Lehne, Benjamin; Lewis, Cathryn M.; Schlitt, Thomas

2011-01-01

63

Repressor- and Activator-Type Ethylene Response Factors Functioning in Jasmonate Signaling and Disease Resistance Identified via a Genome-Wide Screen of Arabidopsis Transcription Factor Gene Expression[w  

PubMed Central

To identify transcription factors (TFs) involved in jasmonate (JA) signaling and plant defense, we screened 1,534 Arabidopsis (Arabidopsis thaliana) TFs by real-time quantitative reverse transcription-PCR for their altered transcript at 6 h following either methyl JA treatment or inoculation with the incompatible pathogen Alternaria brassicicola. We identified 134 TFs that showed a significant change in expression, including many APETALA2/ethylene response factor (AP2/ERF), MYB, WRKY, and NAC TF genes with unknown functions. Twenty TF genes were induced by both the pathogen and methyl JA and these included 10 members of the AP2/ERF TF family, primarily from the B1a and B3 subclusters. Functional analysis of the B1a TF AtERF4 revealed that AtERF4 acts as a novel negative regulator of JA-responsive defense gene expression and resistance to the necrotrophic fungal pathogen Fusarium oxysporum and antagonizes JA inhibition of root elongation. In contrast, functional analysis of the B3 TF AtERF2 showed that AtERF2 is a positive regulator of JA-responsive defense genes and resistance to F. oxysporum and enhances JA inhibition of root elongation. Our results suggest that plants coordinately express multiple repressor- and activator-type AP2/ERFs during pathogen challenge to modulate defense gene expression and disease resistance.

McGrath, Ken C.; Dombrecht, Bruno; Manners, John M.; Schenk, Peer M.; Edgar, Cameron I.; Maclean, Donald J.; Scheible, Wolf-Rudiger; Udvardi, Michael K.; Kazan, Kemal

2005-01-01

64

Identifying genes of gene regulatory networks using formal concept analysis.  

PubMed

In order to understand the behavior of a gene regulatory network, it is essential to know the genes that belong to it. Identifying the correct members (e.g., in order to build a model) is a difficult task even for small subnetworks. Usually only few members of a network are known and one needs to guess the missing members based on experience or informed speculation. It is beneficial if one can additionally rely on experimental data to support this guess. In this work we present a new method based on formal concept analysis to detect unknown members of a gene regulatory network from gene expression time series data. We show that formal concept analysis is able to find a list of candidate genes for inclusion into a partially known basic network. This list can then be reduced by a statistical analysis so that the resulting genes interact strongly with the basic network and therefore should be included when modeling the network. The method has been applied to the DNA repair system of Mycobacterium tuberculosis. In this application, our method produces comparable results to an already existing method of component selection while it is applicable to a broader range of problems. PMID:18312149

Gebert, Jutta; Motameny, Susanne; Faigle, Ulrich; Forst, Christian V; Schrader, Rainer

2008-03-01

65

Network Topology Reveals Key Cardiovascular Disease Genes  

PubMed Central

The structure of protein-protein interaction (PPI) networks has already been successfully used as a source of new biological information. Even though cardiovascular diseases (CVDs) are a major global cause of death, many CVD genes still await discovery. We explore ways to utilize the structure of the human PPI network to find important genes for CVDs that should be targeted by drugs. The hope is to use the properties of such important genes to predict new ones, which would in turn improve a choice of therapy. We propose a methodology that examines the PPI network wiring around genes involved in CVDs. We use the methodology to identify a subset of CVD-related genes that are statistically significantly enriched in drug targets and “driver genes.” We seek such genes, since driver genes have been proposed to drive onset and progression of a disease. Our identified subset of CVD genes has a large overlap with the Core Diseasome, which has been postulated to be the key to disease formation and hence should be the primary object of therapeutic intervention. This indicates that our methodology identifies “key” genes responsible for CVDs. Thus, we use it to predict new CVD genes and we validate over 70% of our predictions in the literature. Finally, we show that our predicted genes are functionally similar to currently known CVD drug targets, which confirms a potential utility of our methodology towards improving therapy for CVDs.

Stojkovic, Neda; Radak, Djordje; Przulj, Natasa

2013-01-01

66

Use of Gene Networks for Identifying and Validating Drug Targets  

Microsoft Academic Search

We propose a new method for identifying and validating drug targets by using gene networks, which are estimated from cDNA microarray gene expression prole data. We created novel gene disruption and drug response microarray gene expression prole data libraries for the purpose of drug target elucidation. We use two types of microarray gene expression prole data for estimating gene networks

Seiya Imoto; Christopher J. Savoie; Sachiyo Aburatani; Sunyong Kim; Kousuke Tashiro; Satoru Kuhara; Satoru Miyano

2003-01-01

67

Differences in Pathogenesis for Salmonella enterica serovar Typhimurium in the Mouse Versus the Swine Model Identify Bacterial Gene Products Required for Systemic but not Gastrointestinal Disease  

Technology Transfer Automated Retrieval System (TEKTRAN)

Over the last several decades, the mouse model of Typhoid fever has been an extremely productive model to investigate Salmonella enterica serovar Typhimurium pathogenesis. The mouse is the paradigm for investigating systemic disease due to infection by Salmonella; however, the swine model of gastro...

68

Gene expression profiling identifies molecular subtypes of inflammatory breast cancer.  

PubMed

Breast cancer is a heterogeneous disease. Comprehensive gene expression profiles obtained using DNA microarrays have revealed previously indistinguishable subtypes of noninflammatory breast cancer (NIBC) related to different features of mammary epithelial biology and significantly associated with survival. Inflammatory breast cancer (IBC) is a rare, particular, and aggressive form of disease. Here we have investigated whether the five molecular subtypes described for NIBC (luminal A and B, basal, ERBB2 overexpressing, and normal breast-like) were also present in IBC. We monitored the RNA expression of approximately 8,000 genes in 83 breast tissue samples including 37 IBC, 44 NIBC, and 2 normal breast samples. Hierarchical clustering identified the five subtypes of breast cancer in both NIBC and IBC samples. These subtypes were highly similar to those defined in previous studies and associated with similar histoclinical features. The robustness of this classification was confirmed by the use of both alternative gene set and analysis method, and the results were corroborated at the protein level. Furthermore, we show that the differences in gene expression between NIBC and IBC and between IBC with and without pathologic complete response that we have recently reported persist in each subtype. Our results show that the expression signatures defining molecular subtypes of NIBC are also present in IBC. Obtained using different patient series and different microarray platforms, they reinforce confidence in the expression-based molecular taxonomy but also give evidence for its universality in breast cancer, independently of a specific clinical form. PMID:15781628

Bertucci, François; Finetti, Pascal; Rougemont, Jacques; Charafe-Jauffret, Emmanuelle; Cervera, Nathalie; Tarpin, Carole; Nguyen, Catherine; Xerri, Luc; Houlgatte, Rémi; Jacquemier, Jocelyne; Viens, Patrice; Birnbaum, Daniel

2005-03-15

69

Extended haplotype association study in Crohn's disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-?B pathway gene, HEATR3.  

PubMed

The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn's disease (CD) compared with non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to CD etiology in this population, most notably at NOD2, in which three causal, uncommon and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes that showed significantly greater association to CD in the Ashkenazi Jewish population compared with a non-Jewish population (145 haplotypes and no haplotypes with P-value <10(-3), respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established CD loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-?B signaling. The BRD7 signal showed conditional dependence with only the downstream rare CD-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association. PMID:23615072

Zhang, W; Hui, K Y; Gusev, A; Warner, N; Ng, S M E; Ferguson, J; Choi, M; Burberry, A; Abraham, C; Mayer, L; Desnick, R J; Cardinale, C J; Hakonarson, H; Waterman, M; Chowers, Y; Karban, A; Brant, S R; Silverberg, M S; Gregersen, P K; Katz, S; Lifton, R P; Zhao, H; Nuñez, G; Pe'er, I; Peter, I; Cho, J H

2013-04-25

70

A 6-gene signature identifies four molecular subgroups of neuroblastoma  

PubMed Central

Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB); Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA) and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. Results The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples). Four distinct clusters were identified by Principal Components Analysis (PCA) in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples) using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p < 0.05, one-way ANOVA test). PCA clusters p1, p2, and p3 were found to correspond well to the postulated subtypes 1, 2A, and 2B, respectively. Remarkably, a fourth novel cluster was detected in all three independent data sets. This cluster comprised mainly 11q-deleted MNA-negative tumours with low expression of ALK, BIRC5, and PHOX2B, and was significantly associated with higher tumour stage, poor outcome and poor survival compared to the Type 1-corresponding favourable group (INSS stage 4 and/or dead of disease, p < 0.05, Fisher's exact test). Conclusions Based on expression profiling we have identified four molecular subgroups of neuroblastoma, which can be distinguished by a 6-gene signature. The fourth subgroup has not been described elsewhere, and efforts are currently made to further investigate this group's specific characteristics.

2011-01-01

71

Network-Based Inference Framework for Identifying Cancer Genes from Gene Expression Data  

PubMed Central

Great efforts have been devoted to alleviate uncertainty of detected cancer genes as accurate identification of oncogenes is of tremendous significance and helps unravel the biological behavior of tumors. In this paper, we present a differential network-based framework to detect biologically meaningful cancer-related genes. Firstly, a gene regulatory network construction algorithm is proposed, in which a boosting regression based on likelihood score and informative prior is employed for improving accuracy of identification. Secondly, with the algorithm, two gene regulatory networks are constructed from case and control samples independently. Thirdly, by subtracting the two networks, a differential-network model is obtained and then used to rank differentially expressed hub genes for identification of cancer biomarkers. Compared with two existing gene-based methods (t-test and lasso), the method has a significant improvement in accuracy both on synthetic datasets and two real breast cancer datasets. Furthermore, identified six genes (TSPYL5, CD55, CCNE2, DCK, BBC3, and MUC1) susceptible to breast cancer were verified through the literature mining, GO analysis, and pathway functional enrichment analysis. Among these oncogenes, TSPYL5 and CCNE2 have been already known as prognostic biomarkers in breast cancer, CD55 has been suspected of playing an important role in breast cancer prognosis from literature evidence, and other three genes are newly discovered breast cancer biomarkers. More generally, the differential-network schema can be extended to other complex diseases for detection of disease associated-genes.

Yang, Bo; Zhang, Junying; Yin, Yaling; Zhang, Yuanyuan

2013-01-01

72

Integrating human and rodent data to identify the genetic factors involved in chronic kidney disease.  

PubMed

The increasing numbers of patients with chronic kidney disease combined with no satisfying interventions for preventing or curing the disease emphasize the need to better understand the genes involved in the initiation and progression of complex renal diseases, their interactions with other host genes, and the environment. Linkage and association studies in human, rat, and mouse have been successful in identifying genetic loci for various disease-related phenotypes but have thus far not been very successful identifying underlying genes. The purpose of this review is to summarize the progress in human, rat, and mouse genetic studies to show the concordance between the loci among the different species. The collective utilization of human and nonhuman mammalian datasets and resources can lead to a more rapid narrowing of disease loci and the subsequent identification of candidate genes. In addition, genes identified through these methods can be further characterized and investigated for interactions using animal models, which is not possible in humans. PMID:20133484

Garrett, Michael R; Pezzolesi, Marcus G; Korstanje, Ron

2010-02-04

73

Gene expression profiling identifies clinically relevant subtypes of prostate cancer  

PubMed Central

Prostate cancer, a leading cause of cancer death, displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. To explore potential molecular variation underlying this clinical heterogeneity, we profiled gene expression in 62 primary prostate tumors, as well as 41 normal prostate specimens and nine lymph node metastases, using cDNA microarrays containing ?26,000 genes. Unsupervised hierarchical clustering readily distinguished tumors from normal samples, and further identified three subclasses of prostate tumors based on distinct patterns of gene expression. High-grade and advanced stage tumors, as well as tumors associated with recurrence, were disproportionately represented among two of the three subtypes, one of which also included most lymph node metastases. To further characterize the clinical relevance of tumor subtypes, we evaluated as surrogate markers two genes differentially expressed among tumor subgroups by using immunohistochemistry on tissue microarrays representing an independent set of 225 prostate tumors. Positive staining for MUC1, a gene highly expressed in the subgroups with “aggressive” clinicopathological features, was associated with an elevated risk of recurrence (P = 0.003), whereas strong staining for AZGP1, a gene highly expressed in the other subgroup, was associated with a decreased risk of recurrence (P = 0.0008). In multivariate analysis, MUC1 and AZGP1 staining were strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative prostate-specific antigen levels. Our results suggest that prostate tumors can be usefully classified according to their gene expression patterns, and these tumor subtypes may provide a basis for improved prognostication and treatment stratification.

Lapointe, Jacques; Li, Chunde; Higgins, John P.; van de Rijn, Matt; Bair, Eric; Montgomery, Kelli; Ferrari, Michelle; Egevad, Lars; Rayford, Walter; Bergerheim, Ulf; Ekman, Peter; DeMarzo, Angelo M.; Tibshirani, Robert; Botstein, David; Brown, Patrick O.; Brooks, James D.; Pollack, Jonathan R.

2004-01-01

74

Gene therapy for Parkinson's disease  

Microsoft Academic Search

Gene therapy is a potentially powerful approach to the treatment of neurological diseases. The discovery of neurotrophic factors\\u000a inhibiting neurodegenerative processes and neurotransmitter-synthesizing enzymes provides the basis for current gene therapy\\u000a strategies for Parkinson's disease. Genes can be transferred by viral or nonviral vectors. Of the various possible vectors,\\u000a recombinant retroviruses are the most efficient for genetic modification of cells

Philippe Horellou; Jacques Mallet

1997-01-01

75

Identifying differentially expressed genes using false discovery rate controlling procedures  

Microsoft Academic Search

Motivation: DNA microarrays have recently been used for the purpose of monitoring expression levels of thousands of genes simultaneously and identifying those genes that are differentially expressed. The probability that a false identification (type I error) is committed can increase sharply when the number of tested genes gets large. Correlation between the test statistics attributed to gene co-regulation and dependency

Anat Reiner; Daniel Yekutieli; Yoav Benjamini

2003-01-01

76

Gene therapy for ocular diseases  

PubMed Central

The eye is an easily accessible, highly compartmentalised and immune-privileged organ that offers unique advantages as a gene therapy target. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been implicated as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of-concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis. This review describes current developments and future prospects for ocular gene therapy. Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirus-mediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future.

Liu, Melissa M; Tuo, Jingsheng; Chan, Chi-Chao

2011-01-01

77

Strategies to identify long noncoding RNAs involved in gene regulation  

PubMed Central

Long noncoding RNAs (lncRNAs) have been detected in nearly every cell type and found to be fundamentally involved in many biological processes. The characterization of lncRNAs has immense potential to advance our comprehensive understanding of cellular processes and gene regulation, along with implications for the treatment of human disease. The recent ENCODE (Encyclopedia of DNA Elements) study reported 9,640 lncRNA loci in the human genome, which corresponds to around half the number of protein-coding genes. Because of this sheer number and their functional diversity, it is crucial to identify a pool of potentially relevant lncRNAs early on in a given study. In this review, we evaluate the methods for isolating lncRNAs by immunoprecipitation and review the advantages, disadvantages, and applications of three widely used approaches – microarray, tiling array, and RNA-seq – for identifying lncRNAs involved in gene regulation. We also look at ways in which data from publicly available databases such as ENCODE can support the study of lncRNAs.

2012-01-01

78

Use of gene networks for identifying and validating drug targets.  

PubMed

We propose a new method for identifying and validating drug targets by using gene networks, which are estimated from cDNA microarray gene expression profile data. We created novel gene disruption and drug response microarray gene expression profile data libraries for the purpose of drug target elucidation. We use two types of microarray gene expression profile data for estimating gene networks and then identifying drug targets. The estimated gene networks play an essential role in understanding drug response data and this information is unattainable from clustering methods, which are the standard for gene expression analysis. In the construction of gene networks, we use the Bayesian network model. We use an actual example from analysis of the Saccharomyces cerevisiae gene expression profile data to express a concrete strategy for the application of gene network information to drug discovery. PMID:15290765

Imoto, Seiya; Savoie, Christopher J; Aburatani, Sachiyo; Kim, Sunyong; Tashiro, Kousuke; Kuhara, Satoru; Miyano, Satoru

2003-10-01

79

Mining biological databases for candidate disease genes  

NASA Astrophysics Data System (ADS)

The publicly-funded effort to sequence the complete nucleotide sequence of the human genome, the Human Genome Project (HGP), has currently produced more than 93% of the 3 billion nucleotides of the human genome into a preliminary `draft' format. In addition, several valuable sources of information have been developed as direct and indirect results of the HGP. These include the sequencing of model organisms (rat, mouse, fly, and others), gene discovery projects (ESTs and full-length), and new technologies such as expression analysis and resources (micro-arrays or gene chips). These resources are invaluable for the researchers identifying the functional genes of the genome that transcribe and translate into the transcriptome and proteome, both of which potentially contain orders of magnitude more complexity than the genome itself. Preliminary analyses of this data identified approximately 30,000 - 40,000 human `genes.' However, the bulk of the effort still remains -- to identify the functional and structural elements contained within the transcriptome and proteome, and to associate function in the transcriptome and proteome to genes. A fortuitous consequence of the HGP is the existence of hundreds of databases containing biological information that may contain relevant data pertaining to the identification of disease-causing genes. The task of mining these databases for information on candidate genes is a commercial application of enormous potential. We are developing a system to acquire and mine data from specific databases to aid our efforts to identify disease genes. A high speed cluster of Linux of workstations is used to analyze sequence and perform distributed sequence alignments as part of our data mining and processing. This system has been used to mine GeneMap99 sequences within specific genomic intervals to identify potential candidate disease genes associated with Bardet-Biedle Syndrome (BBS).

Braun, Terry A.; Scheetz, Todd; Webster, Gregg L.; Casavant, Thomas L.

2001-07-01

80

A Genetic Screen Identifies Novel Polycomb Group Genes in Drosophila  

Microsoft Academic Search

Polycomb group (PcG) genes encode evolutionarily conserved transcriptional repressors that are re- quired for the long-term silencing of particular developmental control genes in animals and plants. PcG genes were first identified in Drosophila as regulators that keep HOX genes inactive in cells where these genes must remain silent during development. Here, we report the results of a genetic screen aimed

A. G. de Ayala Alonso; Luis Gutierrez; Cornelia Fritsch; Bernadett Papp; Dirk Beuchle; Jurg Muller

2007-01-01

81

Multiplex PCR for identifying DMD gene deletions.  

PubMed

The identification of dystrophin as the defective protein in patients with Duchenne and Becker muscular dystrophies (DMD and BMD) has allowed the development of sensitive and specific tests to establish a diagnosis and to aid in genetic counseling and prenatal diagnosis. The Basic Protocol describes three complementary multiplex PCR assays that detect 26 dystrophin gene exons. The multiplex nature of these assays allows the detection of up to ten different exons in a single reaction. At least one of these exons is missing in >95% of deletions. The Support Protocol describes preparation and storage of stock PCR reaction mixes with primers for each of the three diagnostic assays. The Alternate Protocol is a modification of the Basic Protocol for radioactive detection of duplications in males and deletions in carrier females. PMID:18428400

den Dunnen, Johan T; Beggs, Alan H

2006-05-01

82

Integrative Approach to Pain Genetics Identifies Pain Sensitivity Loci across Diseases  

Microsoft Academic Search

Identifying human genes relevant for the processing of pain requires difficult-to-conduct and expensive large-scale clinical trials. Here, we examine a novel integrative paradigm for data-driven discovery of pain gene candidates, taking advantage of the vast amount of existing disease-related clinical literature and gene expression microarray data stored in large international repositories. First, thousands of diseases were ranked according to a

David Ruau; Joel T. Dudley; Rong Chen; Nicholas G. Phillips; Gary E. Swan; Laura C. Lazzeroni; J. David Clark; Atul J. Butte; Martin S. Angst

2012-01-01

83

Differential Gene Repertoire in Mycobacterium ulcerans Identifies Candidate Genes for Patho-Adaptation  

PubMed Central

Background Based on large genomic sequence polymorphisms, several haplotypes belonging to two major lineages of the human pathogen Mycobacterium ulcerans could be distinguished among patient isolates from various geographic origins. However, the biological relevance of insertional/deletional diversity is not understood. Methodology Using comparative genomics, we have investigated the genes located in regions of difference recently identified by DNA microarray based hybridisation analysis. The analysed regions of difference comprise ?7% of the entire M. ulcerans genome. Principal Findings Several different mechanisms leading to loss of functional genes were identified, ranging from pseudogenization, caused by frame shift mutations or mobile genetic element interspersing, to large sequence polymorphisms. Four hot spot regions for genetic instability were unveiled. Altogether, 229 coding sequences were found to be differentially inactivated, constituting a repertoire of coding sequence variation in the rather monomorphic M. ulcerans. Conclusions/Significance The differential gene inactivation patterns associated with the M. ulcerans haplotypes identified candidate genes that may confer enhanced adaptation upon ablation of expression. A number of gene conversions confined to the classical lineage may contribute to particular virulence of this group comprising isolates from Africa and Australia. Identification of this spectrum of anti-virulence gene candidates expands our understanding of the pathogenicity and ecology of the emerging infectious disease Buruli ulcer.

Kaser, Michael; Pluschke, Gerd

2008-01-01

84

Identifying and validating biomarkers for Alzheimer's disease  

PubMed Central

The identification and validation of biomarkers for diagnosing Alzheimer's disease (AD) and other forms of dementia are increasingly important. To date, ELISA measurement of ?-amyloid(1–42), total tau and phospho-tau-181 in cerebrospinal fluid (CSF) is the most advanced and accepted method to diagnose probable AD with high specificity and sensitivity. However, it is a great challenge to search for novel biomarkers in CSF and blood by using modern potent methods, such as microarrays and mass spectrometry, and to optimize the handling of samples (e.g. collection, transport, processing, and storage), as well as the interpretation using bioinformatics. It seems likely that only a combined analysis of several biomarkers will define a patient-specific signature to diagnose AD in the future.

Humpel, Christian

2011-01-01

85

Brucella abortus Genes Identified following Constitutive Growth and Macrophage Infection  

PubMed Central

The chronicity of Brucella abortus infection in humans and animals depends on the organism's ability to escape host defenses by gaining entry and surviving inside the macrophage. Although no human vaccine exists for Brucella, vaccine development in other bacteria has been based on deletions of selective nutritional as well as regulatory systems. Our goal is to develop a vaccine for Brucella. To further this aim, we have used a green fluorescent protein (GFP) reporter system to identify constitutively and intracellularly induced B. abortus genes. Constitutively producing gfp clones exhibited sequence homology with genes associated with protein synthesis and metabolism (initiation factor-1 and tRNA ribotransferase) and detoxification (organic hydroperoxidase resistance). Of greater interest, clones negative for constitutively produced gfp in agar were examined by fluorescence microscopy to detect promoter activity induced within macrophages 4 and 24 h following infection. Bacterial genes activated in macrophages 4 h postinfection appear to be involved in adapting to intracellular environmental conditions. Included in this group were genes for detoxification (lactoglyglutathione lyase gene), repair (formamidopyrimidine-DNA glycosylase gene), osmotic protection (K+ transport gene), and site-specific recombination (xerD gene). A gene involved in metabolism and biosynthesis (deoxyxylulose 5? phosphate synthase gene) was also identified. Genes activated 24 h following infection were biosynthesis- and metabolism-associated genes (iron binding protein and rhizopine catabolism). Identification of B. abortus genes that are activated following macrophage invasion provides insight into Brucella pathogenesis and thus is valuable in vaccine design utilizing selective targeted deletions of newly identified Brucella genes.

Eskra, Linda; Canavessi, Aurea; Carey, Merriann; Splitter, Gary

2001-01-01

86

Activation tag screening to identify novel genes for trichothecene resistance  

Technology Transfer Automated Retrieval System (TEKTRAN)

The goal of our research is to identify plant genes which enhance trichothecene resistance and, ultimately, Fusarium Head Blight resistance in wheat and barley. We are taking a two pronged approach using Arabidopsis to identify plant genes which confer resistance to trichothecenes. The first approac...

87

Blood Pressure Loci Identified with a Gene-Centric Array  

PubMed Central

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10?7 study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r2 = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10?7 at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

Johnson, Toby; Gaunt, Tom R.; Newhouse, Stephen J.; Padmanabhan, Sandosh; Tomaszewski, Maciej; Kumari, Meena; Morris, Richard W.; Tzoulaki, Ioanna; O'Brien, Eoin T.; Poulter, Neil R.; Sever, Peter; Shields, Denis C.; Thom, Simon; Wannamethee, Sasiwarang G.; Whincup, Peter H.; Brown, Morris J.; Connell, John M.; Dobson, Richard J.; Howard, Philip J.; Mein, Charles A.; Onipinla, Abiodun; Shaw-Hawkins, Sue; Zhang, Yun; Smith, George Davey; Day, Ian N.M.; Lawlor, Debbie A.; Goodall, Alison H.; Fowkes, F. Gerald; Abecasis, Goncalo R.; Elliott, Paul; Gateva, Vesela; Braund, Peter S.; Burton, Paul R.; Nelson, Christopher P.; Tobin, Martin D.; van der Harst, Pim; Glorioso, Nicola; Neuvrith, Hani; Salvi, Erika; Staessen, Jan A.; Stucchi, Andrea; Devos, Nabila; Jeunemaitre, Xavier; Plouin, Pierre-Francois; Tichet, Jean; Juhanson, Peeter; Org, Elin; Putku, Margus; Sober, Siim; Veldre, Gudrun; Viigimaa, Margus; Levinsson, Anna; Rosengren, Annika; Thelle, Dag S.; Hastie, Claire E.; Hedner, Thomas; Lee, Wai K.; Melander, Olle; Wahlstrand, Bjorn; Hardy, Rebecca; Wong, Andrew; Cooper, Jackie A.; Palmen, Jutta; Chen, Li; Stewart, Alexandre F.R.; Wells, George A.; Westra, Harm-Jan; Wolfs, Marcel G.M.; Clarke, Robert; Franzosi, Maria Grazia; Goel, Anuj; Hamsten, Anders; Lathrop, Mark; Peden, John F.; Seedorf, Udo; Watkins, Hugh; Ouwehand, Willem H.; Sambrook, Jennifer; Stephens, Jonathan; Casas, Juan-Pablo; Drenos, Fotios; Holmes, Michael V.; Kivimaki, Mika; Shah, Sonia; Shah, Tina; Talmud, Philippa J.; Whittaker, John; Wallace, Chris; Delles, Christian; Laan, Maris; Kuh, Diana; Humphries, Steve E.; Nyberg, Fredrik; Cusi, Daniele; Roberts, Robert; Newton-Cheh, Christopher; Franke, Lude; Stanton, Alice V.; Dominiczak, Anna F.; Farrall, Martin; Hingorani, Aroon D.; Samani, Nilesh J.; Caulfield, Mark J.; Munroe, Patricia B.

2011-01-01

88

Blood pressure loci identified with a gene-centric array.  

PubMed

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies. PMID:22100073

Johnson, Toby; Gaunt, Tom R; Newhouse, Stephen J; Padmanabhan, Sandosh; Tomaszewski, Maciej; Kumari, Meena; Morris, Richard W; Tzoulaki, Ioanna; O'Brien, Eoin T; Poulter, Neil R; Sever, Peter; Shields, Denis C; Thom, Simon; Wannamethee, Sasiwarang G; Whincup, Peter H; Brown, Morris J; Connell, John M; Dobson, Richard J; Howard, Philip J; Mein, Charles A; Onipinla, Abiodun; Shaw-Hawkins, Sue; Zhang, Yun; Davey Smith, George; Day, Ian N M; Lawlor, Debbie A; Goodall, Alison H; Fowkes, F Gerald; Abecasis, Gonçalo R; Elliott, Paul; Gateva, Vesela; Braund, Peter S; Burton, Paul R; Nelson, Christopher P; Tobin, Martin D; van der Harst, Pim; Glorioso, Nicola; Neuvrith, Hani; Salvi, Erika; Staessen, Jan A; Stucchi, Andrea; Devos, Nabila; Jeunemaitre, Xavier; Plouin, Pierre-François; Tichet, Jean; Juhanson, Peeter; Org, Elin; Putku, Margus; Sõber, Siim; Veldre, Gudrun; Viigimaa, Margus; Levinsson, Anna; Rosengren, Annika; Thelle, Dag S; Hastie, Claire E; Hedner, Thomas; Lee, Wai K; Melander, Olle; Wahlstrand, Björn; Hardy, Rebecca; Wong, Andrew; Cooper, Jackie A; Palmen, Jutta; Chen, Li; Stewart, Alexandre F R; Wells, George A; Westra, Harm-Jan; Wolfs, Marcel G M; Clarke, Robert; Franzosi, Maria Grazia; Goel, Anuj; Hamsten, Anders; Lathrop, Mark; Peden, John F; Seedorf, Udo; Watkins, Hugh; Ouwehand, Willem H; Sambrook, Jennifer; Stephens, Jonathan; Casas, Juan-Pablo; Drenos, Fotios; Holmes, Michael V; Kivimaki, Mika; Shah, Sonia; Shah, Tina; Talmud, Philippa J; Whittaker, John; Wallace, Chris; Delles, Christian; Laan, Maris; Kuh, Diana; Humphries, Steve E; Nyberg, Fredrik; Cusi, Daniele; Roberts, Robert; Newton-Cheh, Christopher; Franke, Lude; Stanton, Alice V; Dominiczak, Anna F; Farrall, Martin; Hingorani, Aroon D; Samani, Nilesh J; Caulfield, Mark J; Munroe, Patricia B

2011-11-17

89

Defining the Role of Essential Genes in Human Disease  

PubMed Central

A greater understanding of the causes of human disease can come from identifying characteristics that are specific to disease genes. However, a full understanding of the contribution of essential genes to human disease is lacking, due to the premise that these genes tend to cause developmental abnormalities rather than adult disease. We tested the hypothesis that human orthologs of mouse essential genes are associated with a variety of human diseases, rather than only those related to miscarriage and birth defects. We segregated human disease genes according to whether the knockout phenotype of their mouse ortholog was lethal or viable, defining those with orthologs producing lethal knockouts as essential disease genes. We show that the human orthologs of mouse essential genes are associated with a wide spectrum of diseases affecting diverse physiological systems. Notably, human disease genes with essential mouse orthologs are over-represented among disease genes associated with cancer, suggesting links between adult cellular abnormalities and developmental functions. The proteins encoded by essential genes are highly connected in protein-protein interaction networks, which we find correlates with an over-representation of nuclear proteins amongst essential disease genes. Disease genes associated with essential orthologs also are more likely than those with non-essential orthologs to contribute to disease through an autosomal dominant inheritance pattern, suggesting that these diseases may actually result from semi-dominant mutant alleles. Overall, we have described attributes found in disease genes according to the essentiality status of their mouse orthologs. These findings demonstrate that disease genes do occupy highly connected positions in protein-protein interaction networks, and that due to the complexity of disease-associated alleles, essential genes cannot be ignored as candidates for causing diverse human diseases.

Robertson, David L.; Hentges, Kathryn E.

2011-01-01

90

Using Text Analysis to Identify Functionally Coherent Gene Groups  

PubMed Central

The analysis of large-scale genomic information (such as sequence data or expression patterns) frequently involves grouping genes on the basis of common experimental features. Often, as with gene expression clustering, there are too many groups to easily identify the functionally relevant ones. One valuable source of information about gene function is the published literature. We present a method, neighbor divergence, for assessing whether the genes within a group share a common biological function based on their associated scientific literature. The method uses statistical natural language processing techniques to interpret biological text. It requires only a corpus of documents relevant to the genes being studied (e.g., all genes in an organism) and an index connecting the documents to appropriate genes. Given a group of genes, neighbor divergence assigns a numerical score indicating how “functionally coherent” the gene group is from the perspective of the published literature. We evaluate our method by testing its ability to distinguish 19 known functional gene groups from 1900 randomly assembled groups. Neighbor divergence achieves 79% sensitivity at 100% specificity, comparing favorably to other tested methods. We also apply neighbor divergence to previously published gene expression clusters to assess its ability to recognize gene groups that had been manually identified as representative of a common function.

Raychaudhuri, Soumya; Schutze, Hinrich; Altman, Russ B.

2002-01-01

91

Identifying candidate Hirschsprung disease-associated RET variants.  

PubMed

Patients with sporadic Hirschsprung disease (HSCR) show increased allele sharing at markers in the 5' region of the RET locus, indicating the presence of a common ancestral RET mutation. In a previous study, we found a haplotype of six SNPs that was transmitted to 55.6% of our patients, whereas it was present in only 16.2% of the controls we used. Among the patients with that haplotype, 90.8% had it on both chromosomes, which led to a much higher risk of developing HSCR than when the haplotype occurred heterozygously. To more precisely define the HSCR-associated region and to identify candidate disease-associated variant(s), we sequenced the shared common haplotype region from 10 kb upstream of the RET gene through intron 1 and exon 2 (in total, 33 kb) in a patient homozygous for the common risk haplotype and in a control individual homozygous for the most common nonrisk haplotype. A comparison of these sequences revealed 86 sequence differences. Of these 86 variations, 8 proved to be in regions highly conserved among different vertebrates and within putative transcription factor binding sites. We therefore considered these as candidate disease-associated variants. Subsequent genotyping of these eight variants revealed a strong disease association for six of the eight markers. These six markers also showed the largest distortions in allele transmission. Interspecies comparison showed that only one of the six variations was located in a region also conserved in a nonmammalian species, making it the most likely candidate HSCR-associated variant. PMID:15759212

Burzynski, Grzegorz M; Nolte, Ilja M; Bronda, Agnes; Bos, Krista K; Osinga, Jan; Plaza Menacho, Ivan; Twigt, Bas; Maas, Saskia; Brooks, Alice S; Verheij, Joke B G M; Buys, Charles H C M; Hofstra, Robert M W

2005-03-09

92

Identifying Candidate Hirschsprung Disease-Associated RET Variants  

PubMed Central

Patients with sporadic Hirschsprung disease (HSCR) show increased allele sharing at markers in the 5? region of the RET locus, indicating the presence of a common ancestral RET mutation. In a previous study, we found a haplotype of six SNPs that was transmitted to 55.6% of our patients, whereas it was present in only 16.2% of the controls we used. Among the patients with that haplotype, 90.8% had it on both chromosomes, which led to a much higher risk of developing HSCR than when the haplotype occurred heterozygously. To more precisely define the HSCR-associated region and to identify candidate disease-associated variant(s), we sequenced the shared common haplotype region from 10 kb upstream of the RET gene through intron 1 and exon 2 (in total, 33 kb) in a patient homozygous for the common risk haplotype and in a control individual homozygous for the most common nonrisk haplotype. A comparison of these sequences revealed 86 sequence differences. Of these 86 variations, 8 proved to be in regions highly conserved among different vertebrates and within putative transcription factor binding sites. We therefore considered these as candidate disease-associated variants. Subsequent genotyping of these eight variants revealed a strong disease association for six of the eight markers. These six markers also showed the largest distortions in allele transmission. Interspecies comparison showed that only one of the six variations was located in a region also conserved in a nonmammalian species, making it the most likely candidate HSCR-associated variant.

Burzynski, Grzegorz M.; Nolte, Ilja M.; Bronda, Agnes; Bos, Krista K.; Osinga, Jan; Plaza Menacho, Ivan; Twigt, Bas; Maas, Saskia; Brooks, Alice S.; Verheij, Joke B. G. M.; Buys, Charles H. C. M.; Hofstra, Robert M. W.

2005-01-01

93

Intermediate Phenotypes Identify Divergent Pathways to Alzheimer's Disease  

PubMed Central

Background Recent genetic studies have identified a growing number of loci with suggestive evidence of association with susceptibility to Alzheimer's disease (AD). However, little is known of the role of these candidate genes in influencing intermediate phenotypes associated with a diagnosis of AD, including cognitive decline or AD neuropathologic burden. Methods/Principal Findings Thirty-two single nucleotide polymorphisms (SNPs) previously implicated in AD susceptibility were genotyped in 414 subjects with both annual clinical evaluation and completed brain autopsies from the Religious Orders Study and the Rush Memory and Aging Project. Regression analyses evaluated the relation of SNP genotypes to continuous measures of AD neuropathology and cognitive function proximate to death. A SNP in the zinc finger protein 224 gene (ZNF224, rs3746319) was associated with both global AD neuropathology (p?=?0.009) and global cognition (p?=?0.002); whereas, a SNP at the phosphoenolpyruvate carboxykinase locus (PCK1, rs8192708) was selectively associated with global cognition (p?=?3.57×10?4). The association of ZNF224 with cognitive impairment was mediated by neurofibrillary tangles, whereas PCK1 largely influenced cognition independent of AD pathology, as well as Lewy bodies and infarcts. Conclusions/Significance The findings support the association of several loci with AD, and suggest how intermediate phenotypes can enhance analysis of susceptibility loci in this complex genetic disorder.

Shulman, Joshua M.; Chibnik, Lori B.; Aubin, Cristin; Schneider, Julie A.; Bennett, David A.; De Jager, Philip L.

2010-01-01

94

SPRIT: Identifying horizontal gene transfer in rooted phylogenetic trees  

Microsoft Academic Search

BACKGROUND: Phylogenetic trees based on sequences from a set of taxa can be incongruent due to horizontal gene transfer (HGT). By identifying the HGT events, we can reconcile the gene trees and derive a taxon tree that adequately represents the species' evolutionary history. One HGT can be represented by a rooted Subtree Prune and Regraft (RSPR) operation and the number

Tobias Hill; Karl JV Nordström; Mikael Thollesson; Tommy M Säfström; Andreas KE Vernersson; Robert Fredriksson; Helgi B Schiöth

2010-01-01

95

Potential New Genes for Resistance to Mycosphaerella Graminicola Identified in Triticum Aestivum x Lophopyrum Elongatum Disomic Substitution Lines  

Technology Transfer Automated Retrieval System (TEKTRAN)

Lophopyrum species carry many desirable agronomic traits, including disease resistance, which can be transferred to wheat by interspecific hybridizations. To identify potentially new genes for disease and insect resistance carried by individual Lophopyrum chromosomes, 19 of 21 possible wheat cultiv...

96

How to identify essential genes from molecular networks?  

PubMed Central

Background The prediction of essential genes from molecular networks is a way to test the understanding of essentiality in the context of what is known about the network. However, the current knowledge on molecular network structures is incomplete yet, and consequently the strategies aimed to predict essential genes are prone to uncertain predictions. We propose that simultaneously evaluating different network structures and different algorithms representing gene essentiality (centrality measures) may identify essential genes in networks in a reliable fashion. Results By simultaneously analyzing 16 different centrality measures on 18 different reconstructed metabolic networks for Saccharomyces cerevisiae, we show that no single centrality measure identifies essential genes from these networks in a statistically significant way; however, the combination of at least 2 centrality measures achieves a reliable prediction of most but not all of the essential genes. No improvement is achieved in the prediction of essential genes when 3 or 4 centrality measures were combined. Conclusion The method reported here describes a reliable procedure to predict essential genes from molecular networks. Our results show that essential genes may be predicted only by combining centrality measures, revealing the complex nature of the function of essential genes.

del Rio, Gabriel; Koschutzki, Dirk; Coello, Gerardo

2009-01-01

97

Norrie disease and MAO genes: nearest neighbors.  

PubMed

The Norrie disease and MAO genes are tandemly arranged in the p11.4-p11.3 region of the human X chromosome in the order tel-MAOA-MAOB-NDP-cent. This relationship is conserved in the mouse in the order tel-MAOB-MAOA-NDP-cent. The MAO genes appear to have arisen by tandem duplication of an ancestral MAO gene, but their positional relationship to NDP appears to be random. Distinctive X-linked syndromes have been described for mutations in the MAOA and NDP genes, and in addition, individuals have been identified with contiguous gene syndromes due to chromosomal deletions which encompass two or three of these genes. Loss of function of the NDP gene causes a syndrome of congenital blindness and progressive hearing loss, sometimes accompanied by signs of CNS dysfunction, including variable mental retardation and psychiatric symptoms. Other mutations in the NDP gene have been found to underlie another X-linked eye disease, exudative vitreo-retinopathy. An MAOA deficiency state has been described in one family to date, with features of altered amine and amine metabolite levels, low normal intelligence, apparent difficulty in impulse control and cardiovascular difficulty in affected males. A contiguous gene syndrome in which all three genes are lacking, as well as other as yet unidentified flanking genes, results in severe mental retardation, small stature, seizures and congenital blindness, as well as altered amine and amine metabolites. Issues that remain to be resolved are the function of the NDP gene product, the frequency and phenotype of the MAOA deficiency state, and the possible occurrence and phenotype of an MAOB deficiency state. PMID:8541872

Chen, Z Y; Denney, R M; Breakefield, X O

1995-01-01

98

Highly interconnected genes in disease-specific networks are enriched for disease-associated polymorphisms  

PubMed Central

Background Complex diseases are associated with altered interactions between thousands of genes. We developed a novel method to identify and prioritize disease genes, which was generally applicable to complex diseases. Results We identified modules of highly interconnected genes in disease-specific networks derived from integrating gene-expression and protein interaction data. We examined if those modules were enriched for disease-associated SNPs, and could be used to find novel genes for functional studies. First, we analyzed publicly available gene expression microarray and genome-wide association study (GWAS) data from 13, highly diverse, complex diseases. In each disease, highly interconnected genes formed modules, which were significantly enriched for genes harboring disease-associated SNPs. To test if such modules could be used to find novel genes for functional studies, we repeated the analyses using our own gene expression microarray and GWAS data from seasonal allergic rhinitis. We identified a novel gene, FGF2, whose relevance was supported by functional studies using combined small interfering RNA-mediated knock-down and gene expression microarrays. The modules in the 13 complex diseases analyzed here tended to overlap and were enriched for pathways related to oncological, metabolic and inflammatory diseases. This suggested that this union of the modules would be associated with a general increase in susceptibility for complex diseases. Indeed, we found that this union was enriched with GWAS genes for 145 other complex diseases. Conclusions Modules of highly interconnected complex disease genes were enriched for disease-associated SNPs, and could be used to find novel genes for functional studies.

2012-01-01

99

Linking genes to diseases: it's all in the data  

Microsoft Academic Search

Genome-wide association analyses on large patient cohorts are generating large sets of candidate disease genes. This is coupled\\u000a with the availability of ever-increasing genomic databases and a rapidly expanding repository of biomedical literature. Computational\\u000a approaches to disease-gene association attempt to harness these data sources to identify the most likely disease gene candidates\\u000a for further empirical analysis by translational researchers, resulting

Nicki Tiffin; Miguel A Andrade-Navarro; Carolina Perez-Iratxeta

2009-01-01

100

Evaluation of differentially expressed genes identified in keratoconus  

PubMed Central

Purpose To identify the differentially expressed genes (DEGs) in the human keratocytes in keratoconus. Methods Total RNA extracted from cultured corneal stromal fibroblasts from normal and keratoconic corneas were used for the synthesis of cDNA. DEGs were screened by an annealing control primerTM-based PCR method using GeneFishing™ DEG kits. The differentially expressed bands were sequenced and analyzed. The genes identified were further evaluated by reverse transcriptase PCR and quantitative real-time PCR. Results Overexpression of bone morphogenetic protein 4 (BMP4), cofilin 1 (CFL1), and JAW1-related protein (MRVI1) and underexpression of actin, alpha 2 (ACTA2), gene rich cluster, and C 10 gene (GRCC10), tissue inhibitor of metalloproteinase 3 (TIMP3), tissue inhibitor of metalloproteinase 1 (TIMP1), and somatostatin receptor 1 (SSTR1) were verified, and these results were confirmed by reverse transcriptase PCR and quantitative real-time PCR. Conclusions Eight genes were identified to be differentially expressed in keratoconus and related with apoptosis, the cytoskeleton, wound healing, and nerve fibers. The genes identified may be involved in the mechanism underlying stromal thinning; thus, they could be important and deserve further investigation.

Lee, Ji-Eun; Oum, Boo Sup; Choi, Hee Young; Lee, Seung Uk

2009-01-01

101

Computational and experimental analysis identifies many novel human genes.  

PubMed

Because of advances in automation, human genomic sequences are being deposited in public databases at a dramatic rate. However, the process of detecting genes in these sequences is still something of an art. Here we describe the implementation and testing of a relatively straightforward computational approach, the Virtual Transcribed Sequence project, which analyzes their gene content using the gene prediction program GENSCAN (GENSCAN 1.0 1,2) in combination with similarity-based methods. This approach identifies many novel human genes not found even in EST databases. PMID:10860834

Miyajima, N; Burge, C B; Saito, T

2000-06-16

102

Patching genes to fight disease  

SciTech Connect

The National Institutes of Health has approved the first gene therapy experiments, one of which will try to cure cancer by bolstering the immune system. The applications of such therapy are limited, but the potential aid to people with genetic diseases is great.

Holzman, D.

1990-09-03

103

Improved human disease candidate gene prioritization using mouse phenotype  

PubMed Central

Background The majority of common diseases are multi-factorial and modified by genetically and mechanistically complex polygenic interactions and environmental factors. High-throughput genome-wide studies like linkage analysis and gene expression profiling, tend to be most useful for classification and characterization but do not provide sufficient information to identify or prioritize specific disease causal genes. Results Extending on an earlier hypothesis that the majority of genes that impact or cause disease share membership in any of several functional relationships we, for the first time, show the utility of mouse phenotype data in human disease gene prioritization. We study the effect of different data integration methods, and based on the validation studies, we show that our approach, ToppGene , outperforms two of the existing candidate gene prioritization methods, SUSPECTS and ENDEAVOUR. Conclusion The incorporation of phenotype information for mouse orthologs of human genes greatly improves the human disease candidate gene analysis and prioritization.

Chen, Jing; Xu, Huan; Aronow, Bruce J; Jegga, Anil G

2007-01-01

104

A Gene Recommender Algorithm to Identify Coexpressed Genes in C. elegans  

PubMed Central

One of the most important uses of whole-genome expression data is for the discovery of new genes with similar function to a given list of genes (the query) already known to have closely related function. We have developed an algorithm, called the gene recommender, that ranks genes according to how strongly they correlate with a set of query genes in those experiments for which the query genes are most strongly coregulated. We used the gene recommender to find other genes coexpressed with several sets of query genes, including genes known to function in the retinoblastoma complex. Genetic experiments confirmed that one gene (JC8.6) identified by the gene recommender acts with lin-35 Rb to regulate vulval cell fates, and that another gene (wrm-1) acts antagonistically. We find that the gene recommender returns lists of genes with better precision, for fixed levels of recall, than lists generated using the C. elegans expression topomap.

Owen, Art B.; Stuart, Josh; Mach, Kathy; Villeneuve, Anne M.; Kim, Stuart

2003-01-01

105

Classification of Missense Mutations of Disease Genes  

PubMed Central

Clinical management of individuals found to harbor a mutation at a known disease-susceptibility gene depends on accurate assessment of mutation-specific disease risk. For missense mutations (MMs)—mutations that lead to a single amino acid change in the protein coded by the gene—this poses a particularly challenging problem. Because it is not possible to predict the structural and functional changes to the protein product for a given amino acid substitution, and because functional assays are often not available, disease association must be inferred from data on individuals with the mutation. Inference is complicated by small sample sizes and by sampling mechanisms that bias toward individuals at high familial risk of disease. We propose a Bayesian hierarchical model to classify the disease association of MMs given pedigree data collected in the high-risk setting. The model’s structure allows simultaneous characterization of multiple MMs. It uses a group of pedigrees identified through probands tested positive for known disease associated mutations and a group of test-negative pedigrees, both obtained from the same clinic, to calibrate classification and control for potential ascertainment bias. We apply this model to study MMs of breast-ovarian susceptibility genes BRCA1 and BRCA2, using data collected at the Duke University Medical Center in Durham, North Carolina.

Zhou, Xi; Iversen, Edwin S.; Parmigiani, Giovanni

2008-01-01

106

Disease-specific gene repositioning in breast cancer  

PubMed Central

Genomes are nonrandomly organized within the three-dimensional space of the cell nucleus. Here, we have identified several genes whose nuclear positions are altered in human invasive breast cancer compared with normal breast tissue. The changes in positioning are gene specific and are not a reflection of genomic instability within the cancer tissue. Repositioning events are specific to cancer and do not generally occur in noncancerous breast disease. Moreover, we show that the spatial positions of genes are highly consistent between individuals. Our data indicate that cancer cells have disease-specific gene distributions. These interphase gene positioning patterns may be used to identify cancer tissues.

Meaburn, Karen J.; Gudla, Prabhakar R.; Khan, Sameena; Lockett, Stephen J.

2009-01-01

107

Integrative genomics identifies APOE ?4 effectors in Alzheimer's disease.  

PubMed

Late-onset Alzheimer's disease (LOAD) risk is strongly influenced by genetic factors such as the presence of the apolipoprotein E ?4 allele (referred to here as APOE4), as well as non-genetic determinants including ageing. To pursue mechanisms by which these affect human brain physiology and modify LOAD risk, we initially analysed whole-transcriptome cerebral cortex gene expression data in unaffected APOE4 carriers and LOAD patients. APOE4 carrier status was associated with a consistent transcriptomic shift that broadly resembled the LOAD profile. Differential co-expression correlation network analysis of the APOE4 and LOAD transcriptomic changes identified a set of candidate core regulatory mediators. Several of these--including APBA2, FYN, RNF219 and SV2A--encode known or novel modulators of LOAD associated amyloid beta A4 precursor protein (APP) endocytosis and metabolism. Furthermore, a genetic variant within RNF219 was found to affect amyloid deposition in human brain and LOAD age-of-onset. These data implicate an APOE4 associated molecular pathway that promotes LOAD. PMID:23883936

Rhinn, Herve; Fujita, Ryousuke; Qiang, Liang; Cheng, Rong; Lee, Joseph H; Abeliovich, Asa

2013-07-24

108

Speeding disease gene discovery by sequence based candidate prioritization  

Microsoft Academic Search

BACKGROUND: Regions of interest identified through genetic linkage studies regularly exceed 30 centimorgans in size and can contain hundreds of genes. Traditionally this number is reduced by matching functional annotation to knowledge of the disease or phenotype in question. However, here we show that disease genes share patterns of sequence-based features that can provide a good basis for automatic prioritization

Euan A. Adie; Richard R. Adams; Kathryn L. Evans; David J. Porteous; Ben S. Pickard

2005-01-01

109

Tissue-Specific Gene Expression Identifies a Gene in the Lysogenic Phage Gifsy-1 That Affects Salmonella enterica Serovar Typhimurium Survival in Peyer's Patches  

Microsoft Academic Search

In vivo expression technology was used to identify Salmonella enterica serovar Typhimurium genes that are transcriptionally induced when the bacteria colonize the small intestines of mice. These genes were subse- quently screened for those that are transcriptionally inactive during the systemic stages of disease. This procedure identified gipA, a gene that is specifically induced in the small intestine of the

THERESA L. STANLEY; CRAIG D. ELLERMEIER; JAMES M. SLAUCH

2000-01-01

110

MICA gene polymorphism in Takayasu's arteritis and Buerger's disease  

Microsoft Academic Search

To further clarify the HLA-linked genes susceptible to arterio-vasculitis of unknown etiology, Takayasu's arteritis and Buerger's disease, polymorphism in the MICA gene, a newly identified gene near the HLA-B gene and expressed in epithelial cell lineage, was investigated. Polymerase chain reaction (PCR)-DNA conformation polymorphism (DCP) analysis and subsequent sequencing of the MICA gene have revealed that there are 5 MICA

Akinori Kimura; Yasushi Kobayashi; Megumi Takahashi; Nobuhisa Ohbuchi; Hitoshi Kitamura; Takeyuki Nakamura; Manatsu Satoh; Taishi Sasaoka; Shitoshi Hiroi; Takuro Arimura; Jun Akai; Wulin Aerbajinai; Yukio Yasukochi; Fujio Numano

1998-01-01

111

MatchMiner: a tool for batch navigation among gene and gene product identifiers  

PubMed Central

MatchMiner is a freely available program package for batch navigation among gene and gene product identifier types commonly encountered in microarray studies and other forms of 'omic' research. The user inputs a list of gene identifiers and then uses the Merge function to find the overlap with a second list of identifiers of either the same or a different type or uses the LookUp function to find corresponding identifiers.

Bussey, Kimberly J; Kane, David; Sunshine, Margot; Narasimhan, Sudar; Nishizuka, Satoshi; Reinhold, William C; Zeeberg, Barry; Ajay; Weinstein, John N

2003-01-01

112

Tracing evolutionary footprints to identify novel gene functional linkages.  

PubMed

Systematic determination of gene function is an essential step in fully understanding the precise contribution of each gene for the proper execution of molecular functions in the cell. Gene functional linkage is defined as to describe the relationship of a group of genes with similar functions. With thousands of genomes sequenced, there arises a great opportunity to utilize gene evolutionary information to identify gene functional linkages. To this end, we established a computational method (called TRACE) to trace gene footprints through a gene functional network constructed from 341 prokaryotic genomes. TRACE performance was validated and successfully tested to predict enzyme functions as well as components of pathway. A so far undescribed chromosome partitioning-like protein ro03654 of an oleaginous bacteria Rhodococcus sp. RHA1 (RHA1) was predicted and verified experimentally with its deletion mutant showing growth inhibition compared to RHA1 wild type. In addition, four proteins were predicted to act as prokaryotic SNARE-like proteins, and two of them were shown to be localized at the plasma membrane. Thus, we believe that TRACE is an effective new method to infer prokaryotic gene functional linkages by tracing evolutionary events. PMID:23825567

Chen, Yong; Yang, Li; Ding, Yunfeng; Zhang, Shuyan; He, Tong; Mao, Fenglou; Zhang, Congyan; Zhang, Huina; Huo, Chaoxing; Liu, Pingsheng

2013-06-25

113

Identifying gene-Specific Variations in Biomedical Text  

Microsoft Academic Search

The influence of genetic variations on diseases or cellular processes is a main focus of many investigations and results of biomedical studies are often only accessible through scientific publications. Automatic extraction of this informa- tion requires recognition of the gene names and the accompanied allelic variant information. In a previous work, the OSIRIS system for detection of allelic variation in

Roman Klinger; Christoph M. Friedrich; Heinz-theodor Mevissen; Juliane Fluck; Martin Hofmann-apitius; Laura Inés Furlong; Ferran Sanz

2007-01-01

114

Gene therapy of benign gynecological diseases  

Microsoft Academic Search

Gene therapy is the introduction of genetic material into patient's cells to achieve therapeutic benefit. Advances in molecular biology techniques and better understanding of disease pathogenesis have validated the use of a variety of genes as potential molecular targets for gene therapy based approaches. Gene therapy strategies include: mutation compensation of dysregulated genes; replacement of defective tumor-suppressor genes; inactivation of

Memy H. Hassan; Essam E. Othman; Daniela Hornung; Ayman Al-Hendy

2009-01-01

115

Novel methods to identify biologically relevant genes for leukemia and prostate cancer from gene expression profiles  

PubMed Central

Background High-throughput microarray experiments now permit researchers to screen thousands of genes simultaneously and determine the different expression levels of genes in normal or cancerous tissues. In this paper, we address the challenge of selecting a relevant and manageable subset of genes from a large microarray dataset. Currently, most gene selection methods focus on identifying a set of genes that can further improve classification accuracy. Few or none of these small sets of genes, however, are biologically relevant (i.e. supported by medical evidence). To deal with this critical issue, we propose two novel methods that can identify biologically relevant genes concerning cancers. Results In this paper, we propose two novel techniques, entitled random forest gene selection (RFGS) and support vector sampling technique (SVST). Compared with results from six other methods developed in this paper, we demonstrate experimentally that RFGS and SVST can identify more biologically relevant genes in patients with leukemia or prostate cancer. Among the top 25 genes selected using SVST method, 15 genes were biologically relevant genes in patients with leukemia and 13 genes were biologically relevant genes in patients with prostate cancer. Meanwhile, the RFGS method, while less effective than SVST, still identified an average of 9 biologically relevant genes in both leukemia and prostate cancers. In contrast to traditional statistical methods, which only identify less than 8 genes in patients with leukemia and less than 8 genes in patients with prostate cancer, our methods yield significantly better results. Conclusions Our proposed SVST and RFGS methods are novel approaches that can identify a greater number of biologically relevant genes. These methods have been successfully applied to both leukemia and prostate cancers. Research in the fields of biology and medicine should benefit from the identification of biologically relevant genes by confirming recent discoveries in cancer research or suggesting new avenues for exploration.

2010-01-01

116

Exploring candidate genes for human brain diseases from a brain-specific gene network  

Microsoft Academic Search

It is believed that large numbers of genes are involved in common human brain diseases. Here, we propose a novel computational strategy for simultaneously identifying multiple candidate genes for genetic human brain diseases from a brain-specific gene network-level perspective. By integrating diverse genomic and proteomic datasets based on Bayesian statistical model, we built a large-scale human brain-specific gene network. Based

Bing Liu; Tianzi Jiang; Songde Ma; Huizhi Zhao; Jun Li; Xingpeng Jiang; Jing Zhang

2006-01-01

117

Integrating Autoimmune Risk Loci with Gene-Expression Data Identifies Specific Pathogenic Immune Cell Subsets  

PubMed Central

Although genome-wide association studies have implicated many individual loci in complex diseases, identifying the exact causal alleles and the cell types within which they act remains greatly challenging. To ultimately understand disease mechanism, researchers must carefully conceive functional studies in relevant pathogenic cell types to demonstrate the cellular impact of disease-associated genetic variants. This challenge is highlighted in autoimmune diseases, such as rheumatoid arthritis, where any of a broad range of immunological cell types might potentially be impacted by genetic variation to cause disease. To this end, we developed a statistical approach to identify potentially pathogenic cell types in autoimmune diseases by using a gene-expression data set of 223 murine-sorted immune cells from the Immunological Genome Consortium. We found enrichment of transitional B cell genes in systemic lupus erythematosus (p = 5.9 × 10?6) and epithelial-associated stimulated dendritic cell genes in Crohn disease (p = 1.6 × 10?5). Finally, we demonstrated enrichment of CD4+ effector memory T cell genes within rheumatoid arthritis loci (p < 10?6). To further validate the role of CD4+ effector memory T cells within rheumatoid arthritis, we identified 436 loci that were not yet known to be associated with the disease but that had a statistically suggestive association in a recent genome-wide association study (GWAS) meta-analysis (pGWAS < 0.001). Even among these putative loci, we noted a significant enrichment for genes specifically expressed in CD4+ effector memory T cells (p = 1.25 × 10?4). These cell types are primary candidates for future functional studies to reveal the role of risk alleles in autoimmunity. Our approach has application in other phenotypes, outside of autoimmunity, where many loci have been discovered and high-quality cell-type-specific gene expression is available.

Hu, Xinli; Kim, Hyun; Stahl, Eli; Plenge, Robert; Daly, Mark; Raychaudhuri, Soumya

2011-01-01

118

Immunogenetic Mechanisms Leading to Thyroid Autoimmunity: Recent Advances in Identifying Susceptibility Genes and Regions  

PubMed Central

The autoimmune thyroid diseases (AITD) include Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), which are characterised by a breakdown in immune tolerance to thyroid antigens. Unravelling the genetic architecture of AITD is vital to better understanding of AITD pathogenesis, required to advance therapeutic options in both disease management and prevention. The early whole-genome linkage and candidate gene association studies provided the first evidence that the HLA region and CTLA-4 represented AITD risk loci. Recent improvements in; high throughput genotyping technologies, collection of larger disease cohorts and cataloguing of genome-scale variation have facilitated genome-wide association studies and more thorough screening of candidate gene regions. This has allowed identification of many novel AITD risk genes and more detailed association mapping. The growing number of confirmed AITD susceptibility loci, implicates a number of putative disease mechanisms most of which are tightly linked with aspects of immune system function. The unprecedented advances in genetic study will allow future studies to identify further novel disease risk genes and to identify aetiological variants within specific gene regions, which will undoubtedly lead to a better understanding of AITD patho-physiology.

Brand, Oliver J; Gough, Stephen C.L

2011-01-01

119

Midlife gene expressions identify modulators of aging through dietary interventions.  

PubMed

Dietary interventions are effective ways to extend or shorten lifespan. By examining midlife hepatic gene expressions in mice under different dietary conditions, which resulted in different lifespans and aging-related phenotypes, we were able to identify genes and pathways that modulate the aging process. We found that pathways transcriptionally correlated with diet-modulated lifespan and physiological changes were enriched for lifespan-modifying genes. Intriguingly, mitochondrial gene expression correlated with lifespan and anticorrelated with aging-related pathological changes, whereas peroxisomal gene expression showed an opposite trend. Both organelles produce reactive oxygen species, a proposed causative factor of aging. This finding implicates a contribution of peroxisome to aging. Consistent with this hypothesis, lowering the expression levels of peroxisome proliferation genes decreased the cellular peroxide levels and extended the lifespan of Drosophila melanogaster and Caenorhabditis elegans. These findings show that transcriptional changes resulting from dietary interventions can effectively reflect causal factors in aging and identify previously unknown or under-appreciated longevity pathways, such as the peroxisome pathway. PMID:22509016

Zhou, Bing; Yang, Liu; Li, Shoufeng; Huang, Jialiang; Chen, Haiyang; Hou, Lei; Wang, Jinbo; Green, Christopher D; Yan, Zhen; Huang, Xun; Kaeberlein, Matt; Zhu, Li; Xiao, Huasheng; Liu, Yong; Han, Jing-Dong J

2012-04-16

120

A gene sets approach for identifying prognostic gene signatures for outcome prediction  

PubMed Central

Background Gene expression profiling is a promising approach to better estimate patient prognosis; however, there are still unresolved problems, including little overlap among similarly developed gene sets and poor performance of a developed gene set in other datasets. Results We applied a gene sets approach to develop a prognostic gene set from multiple gene expression datasets. By analyzing 12 independent breast cancer gene expression datasets comprising 1,756 tissues with 2,411 pre-defined gene sets including gene ontology categories and pathways, we found many gene sets that were prognostic in most of the analyzed datasets. Those prognostic gene sets were related to biological processes such as cell cycle and proliferation and had additional prognostic values over conventional clinical parameters such as tumor grade, lymph node status, estrogen receptor (ER) status, and tumor size. We then estimated the prediction accuracy of each gene set by performing external validation using six large datasets and identified a gene set with an average prediction accuracy of 67.55%. Conclusion A gene sets approach is an effective method to develop prognostic gene sets to predict patient outcome and to understand the underlying biology of the developed gene set. Using the gene sets approach we identified many prognostic gene sets in breast cancer.

Kim, Seon-Young; Kim, Yong Sung

2008-01-01

121

Candidate Olfaction Genes Identified within the Helicoverpa armigera Antennal Transcriptome  

PubMed Central

Antennal olfaction is extremely important for insect survival, mediating key behaviors such as host preference, mate choice, and oviposition site selection. Multiple antennal proteins are involved in olfactory signal transduction pathways. Of these, odorant receptors (ORs) and ionotropic receptors (IRs) confer specificity on olfactory sensory neuron responses. In this study, we identified the olfactory gene repertoire of the economically important agricultural pest moth, Helicoverpa armigera, by assembling the adult male and female antennal transcriptomes. Within the male and female antennal transcriptomes we identified a total of 47 OR candidate genes containing 6 pheromone receptor candidates. Additionally, 12 IR genes as well as 26 odorant-binding proteins and 12 chemosensory proteins were annotated. Our results allow a systematic functional analysis across much of conventional ORs repertoire and newly reported IRs mediating the key olfaction-mediated behaviors of H. armigera.

Liu, Yang; Gu, Shaohua; Zhang, Yongjun; Guo, Yuyuan; Wang, Guirong

2012-01-01

122

A statistical method for identifying differential gene-gene co-expression patterns  

Microsoft Academic Search

Motivation: To understand cancer etiology, it is important to explore molecular changes in cellular processes from normal state to cancerous state. Because genes interact with each other during cellular processes, carcinogenesis related genes may form differential co-expression patterns with other genes in different cell states. In this study, we develop a statistical method for identifying differential gene-gene co-expression patterns in

Yinglei Lai; Baolin Wu; Liang Chen; Hongyu Zhao

2004-01-01

123

Gene-Network Analysis Identifies Susceptibility Genes Related to Glycobiology in Autism  

Microsoft Academic Search

The recent identification of copy-number variation in the human genome has opened up new avenues for the discovery of positional candidate genes underlying complex genetic disorders, especially in the field of psychiatric disease. One major challenge that remains is pinpointing the susceptibility genes in the multitude of disease-associated loci. This challenge may be tackled by reconstruction of functional gene-networks from

Bert van der Zwaag; Lude Franke; Martin Poot; Ron Hochstenbach; Henk A. Spierenburg; Jacob A. S. Vorstman; Emma van Daalen; Maretha V. de Jonge; Nienke E. Verbeek; Eva H. Brilstra; Ruben van't Slot; Roel A. Ophoff; Michael A. van Es; Hylke M. Blauw; Jan H. Veldink; Jacobine E. Buizer-Voskamp; Frits A. Beemer; Leonard H. van den Berg; Cisca Wijmenga; Hans Kristian Ploos van Amstel; Herman van Engeland; J. Peter H. Burbach; Wouter G. Staal; Katharina Domschke

2009-01-01

124

Time course analysis of gene expression identifies multiple genes with differential expression in patients with in-stent restenosis  

PubMed Central

Background The vascular disease in-stent restenosis (ISR) is characterized by formation of neointima and adverse inward remodeling of the artery after injury by coronary stent implantation. We hypothesized that the analysis of gene expression in peripheral blood mononuclear cells (PBMCs) would demonstrate differences in transcript expression between individuals who develop ISR and those who do not. Methods and Results We determined and investigated PBMC gene expression of 358 patients undergoing an index procedure to treat in de novo coronary artery lesions with bare metallic stents, using a novel time-varying intercept model to optimally assess the time course of gene expression across a time course of blood samples. Validation analyses were conducted in an independent sample of 97 patients with similar time-course blood sampling and gene expression data. We identified 47 probesets with differential expression, of which 36 were validated upon independent replication testing. The genes identified have varied functions, including some related to cellular growth and metabolism, such as the NAB2 and LAMP genes. Conclusions In a study of patients undergoing bare metallic stent implantation, we have identified and replicated differential gene expression in peripheral blood mononuclear cells, studied across a time series of blood samples. The genes identified suggest alterations in cellular growth and metabolism pathways, and these results provide the basis for further specific functional hypothesis generation and testing of the mechanisms of ISR.

2011-01-01

125

Integrative approach to pain genetics identifies pain sensitivity loci across diseases.  

PubMed

Identifying human genes relevant for the processing of pain requires difficult-to-conduct and expensive large-scale clinical trials. Here, we examine a novel integrative paradigm for data-driven discovery of pain gene candidates, taking advantage of the vast amount of existing disease-related clinical literature and gene expression microarray data stored in large international repositories. First, thousands of diseases were ranked according to a disease-specific pain index (DSPI), derived from Medical Subject Heading (MESH) annotations in MEDLINE. Second, gene expression profiles of 121 of these human diseases were obtained from public sources. Third, genes with expression variation significantly correlated with DSPI across diseases were selected as candidate pain genes. Finally, selected candidate pain genes were genotyped in an independent human cohort and prospectively evaluated for significant association between variants and measures of pain sensitivity. The strongest signal was with rs4512126 (5q32, ABLIM3, P?=?1.3×10?¹?) for the sensitivity to cold pressor pain in males, but not in females. Significant associations were also observed with rs12548828, rs7826700 and rs1075791 on 8q22.2 within NCALD (P?=?1.7×10??, 1.8×10??, and 2.2×10?? respectively). Our results demonstrate the utility of a novel paradigm that integrates publicly available disease-specific gene expression data with clinical data curated from MEDLINE to facilitate the discovery of pain-relevant genes. This data-derived list of pain gene candidates enables additional focused and efficient biological studies validating additional candidates. PMID:22685391

Ruau, David; Dudley, Joel T; Chen, Rong; Phillips, Nicholas G; Swan, Gary E; Lazzeroni, Laura C; Clark, J David; Butte, Atul J; Angst, Martin S

2012-06-07

126

Integrative Approach to Pain Genetics Identifies Pain Sensitivity Loci across Diseases  

PubMed Central

Identifying human genes relevant for the processing of pain requires difficult-to-conduct and expensive large-scale clinical trials. Here, we examine a novel integrative paradigm for data-driven discovery of pain gene candidates, taking advantage of the vast amount of existing disease-related clinical literature and gene expression microarray data stored in large international repositories. First, thousands of diseases were ranked according to a disease-specific pain index (DSPI), derived from Medical Subject Heading (MESH) annotations in MEDLINE. Second, gene expression profiles of 121 of these human diseases were obtained from public sources. Third, genes with expression variation significantly correlated with DSPI across diseases were selected as candidate pain genes. Finally, selected candidate pain genes were genotyped in an independent human cohort and prospectively evaluated for significant association between variants and measures of pain sensitivity. The strongest signal was with rs4512126 (5q32, ABLIM3, P?=?1.3×10?10) for the sensitivity to cold pressor pain in males, but not in females. Significant associations were also observed with rs12548828, rs7826700 and rs1075791 on 8q22.2 within NCALD (P?=?1.7×10?4, 1.8×10?4, and 2.2×10?4 respectively). Our results demonstrate the utility of a novel paradigm that integrates publicly available disease-specific gene expression data with clinical data curated from MEDLINE to facilitate the discovery of pain-relevant genes. This data-derived list of pain gene candidates enables additional focused and efficient biological studies validating additional candidates.

Ruau, David; Dudley, Joel T.; Chen, Rong; Phillips, Nicholas G.; Swan, Gary E.; Lazzeroni, Laura C.; Clark, J. David

2012-01-01

127

The Wilson disease gene: Haplotypes and mutations  

SciTech Connect

Wilson disease (WND) is an autosomal recessive defect of copper transport. The gene involved in WND, located on chromosome 13, has recently been shown to be a putative copper transporting P-type ATPase, designated ATP7B. The gene is highly similar to ATP7A, located on the X chromosome, which is defective in Menkes disease, another disorder of copper transport. We have available for study WND families from Canada (34 families), the United Kingdom (32 families), Japan (4 families), Iceland (3 families) and Hong Kong (2 families). We have utilized four highly polymorphic CA repeat markers (D13S296, D13S301, D13S314 and D13S316) surrounding the ATP7B locus to construct haplotypes in these families. Analysis indicates that there are many unique WND haplotypes not present on normal chromosomes and that there may be a large number of different WND mutations. We have screened the WND patients for mutations in the ATP7B gene. Fifty six patients, representing all of the identified haplotypes, have been screened using single strand conformational polymorphism (SSCP), followed by selective sequencing. To date, 19 mutations and 12 polymorphisms have been identified. All of the changes are nucleotide substitutions or small insertions/deletions and there is no evidence for larger deletions as seen in the similar gene on the X chromosome, ATP7A. Haplotypes of close markers and the ability to detect some of the mutations present in the gene allow for more reliable molecular diagnosis of presymptomatic sibs of WND patients. A reassessment of individuals previously diagnosed in the presymptomatic phase is now required, as we have have identified some heterozygotes who are biochemically indistinguishable from affected homozygotes. The identification of specific mutations will soon allow direct diagnosis of WND patients with a high level of certainty.

Thomas, G.R.; Roberts, E.A.; Cox, D.W. [Hospital for Sick Children, Toronto (Canada); Walshe, J.M. [Middlesex Hospital, London (United Kingdom)

1994-09-01

128

Computationally Identifying Novel NF-?B-Regulated Immune Genes in the Human Genome  

PubMed Central

Identifying novel NF-?B-regulated immune genes in the human genome is important to our understanding of immune mechanisms and immune diseases. We fit logistic regression models to the promoters of 62 known NF-?B-regulated immune genes, to find patterns of transcription factor binding in the promoters of genes with known immune function. Using these patterns, we scanned the promoters of additional genes to find matches to the patterns, selected those with NF-?B binding sites conserved in the mouse or fly, and then confirmed them as NF-?B-regulated immune genes based on expression data. Among 6440 previously identified promoters in the human genome, we found 28 predicted immune gene promoters, 19 of which regulate genes with known function, allowing us to calculate specificity of 93%–100% for the method. We calculated sensitivity of 42% when searching the 62 known immune gene promoters. We found nine novel NF-?B-regulated immune genes which are consistent with available SAGE data. Our method of predicting gene function, based on characteristic patterns of transcription factor binding, evolutionary conservation, and expression studies, would be applicable to finding genes with other functions.

Liu, Rongxiang; McEachin, Richard C.; States, David J.

2003-01-01

129

The evolution of disease resistance genes  

Microsoft Academic Search

Several common themes have shaped the evolution of plant disease resistance genes. These include duplication events of progenitor resistance genes and further expansion to create clustered gene families. Variation can arise from both intragenic and intergenic recombination and gene conversion. Recombination has also been implicated in the generation of novel resistance specificities. Resistance gene clusters appear to evolve more rapidly

Todd E. Richter; Pamela C. Ronald

2000-01-01

130

Adipose Co-expression networks across Finns and Mexicans identify novel triglyceride-associated genes  

PubMed Central

Background High serum triglyceride (TG) levels is an established risk factor for coronary heart disease (CHD). Fat is stored in the form of TGs in human adipose tissue. We hypothesized that gene co-expression networks in human adipose tissue may be correlated with serum TG levels and help reveal novel genes involved in TG regulation. Methods Gene co-expression networks were constructed from two Finnish and one Mexican study sample using the blockwiseModules R function in Weighted Gene Co-expression Network Analysis (WGCNA). Overlap between TG-associated networks from each of the three study samples were calculated using a Fisher’s Exact test. Gene ontology was used to determine known pathways enriched in each TG-associated network. Results We measured gene expression in adipose samples from two Finnish and one Mexican study sample. In each study sample, we observed a gene co-expression network that was significantly associated with serum TG levels. The TG modules observed in Finns and Mexicans significantly overlapped and shared 34 genes. Seven of the 34 genes (ARHGAP30, CCR1, CXCL16, FERMT3, HCST, RNASET2, SELPG) were identified as the key hub genes of all three TG modules. Furthermore, two of the 34 genes (ARHGAP9, LST1) reside in previous TG GWAS regions, suggesting them as the regional candidates underlying the GWAS signals. Conclusions This study presents a novel adipose gene co-expression network with 34 genes significantly correlated with serum TG across populations.

2012-01-01

131

Genome-Wide Association Mapping in Arabidopsis Identifies Previously Known Flowering Time and Pathogen Resistance Genes  

Microsoft Academic Search

There is currently tremendous interest in the possibility of using genome-wide association mapping to identify genes responsible for natural variation, particularly for human disease susceptibility. The model plant Arabidopsis thaliana is in many ways an ideal candidate for such studies, because it is a highly selfing hermaphrodite. As a result, the species largely exists as a collection of naturally occurring

María José Aranzana; Sung Kim; Keyan Zhao; Erica Bakker; Matthew Horton; Katrin Jakob; Clare Lister; John Molitor; Chikako Shindo; Chunlao Tang; Christopher Toomajian; Brian Traw; Honggang Zheng; Joy Bergelson; Caroline Dean; Paul Marjoram; Magnus Nordborg

2005-01-01

132

A cross-study gene set enrichment analysis identifies critical pathways in endometriosis  

Microsoft Academic Search

BACKGROUND: Endometriosis is an enigmatic disease. Gene expression profiling of endometriosis has been used in several studies, but few studies went further to classify subtypes of endometriosis based on expression patterns and to identify possible pathways involved in endometriosis. Some of the observed pathways are more inconsistent between the studies, and these candidate pathways presumably only represent a fraction of

Hongbo Zhao; Qishan Wang; Chunyan Bai; Kan He; Yuchun Pan

2009-01-01

133

Next-generation sequencing identifies transportin 3 as the causative gene for LGMD1F.  

PubMed

Limb-girdle muscular dystrophies (LGMD) are genetically and clinically heterogeneous conditions. We investigated a large family with autosomal dominant transmission pattern, previously classified as LGMD1F and mapped to chromosome 7q32. Affected members are characterized by muscle weakness affecting earlier the pelvic girdle and the ileopsoas muscles. We sequenced the whole exome of four family members and identified a shared heterozygous frame-shift variant in the Transportin 3 (TNPO3) gene, encoding a member of the importin-? super-family. The TNPO3 gene is mapped within the LGMD1F critical interval and its 923-amino acid human gene product is also expressed in skeletal muscle. In addition, we identified an isolated case of LGMD with a new missense mutation in the same gene. We localized the mutant TNPO3 around the nucleus, but not inside. The involvement of gene related to the nuclear transport suggests a novel disease mechanism leading to muscular dystrophy. PMID:23667635

Torella, Annalaura; Fanin, Marina; Mutarelli, Margherita; Peterle, Enrico; Del Vecchio Blanco, Francesca; Rispoli, Rossella; Savarese, Marco; Garofalo, Arcomaria; Piluso, Giulio; Morandi, Lucia; Ricci, Giulia; Siciliano, Gabriele; Angelini, Corrado; Nigro, Vincenzo

2013-05-07

134

Gene expression analysis in cardiac tissues from infants identifies candidate agents for tetralogy of fallot.  

PubMed

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect and the most common cause of blue baby syndrome. Although great progress has been made, the molecular mechanisms of TOF are far from being fully understood, and treatment of this disease remains palliative. In this study, we downloaded gene expression data of TOF subjects with those of normally developing subjects from the Gene Expression Omnibus database and employed computational bioinformatics analyses to compare their gene expression patterns. Furthermore, small molecules that induce inverse gene changes to TOF were identified. A total of 2,274 genes involved in energy metabolism and protein binding were differentially expressed in TOF samples compared with samples from normal controls. Pathways associated with cellular oxygen tension were dysfunctional. In addition, we identified a group of small molecules that may be exploited as adjuvant drug to alleviate some symptoms for TOF patients. These drugs are clearly a direction that warrants additional consideration. PMID:23563574

Yang, Dicheng; Li, Jing; Yuan, Zhongxiang

2013-04-07

135

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease  

Microsoft Academic Search

the gene encoding apolipoprotein e (APOE) on chromosome 19 is the only confirmed susceptibility locus for late-onset Alzheimer's disease. to identify other risk loci, we conducted a large genome-wide association study of 2,032 individuals from France with Alzheimer's disease (cases) and 5,328 controls. Markers outside APO e with suggestive evidence of association (P < 10 ?5 ) were examined in

Denise Harold; Richard Abraham; Paul Hollingworth; Rebecca Sims; Amy Gerrish; Marian L Hamshere; Jaspreet Singh Pahwa; Valentina Moskvina; Kimberley Dowzell; Amy Williams; Nicola Jones; Charlene Thomas; Alexandra Stretton; Angharad R Morgan; Simon Lovestone; John Powell; Petroula Proitsi; Michelle K Lupton; Carol Brayne; David C Rubinsztein; Michael Gill; Brian Lawlor; Aoibhinn Lynch; Kevin Morgan; Kristelle S Brown; Peter A Passmore; David Craig; Bernadette McGuinness; Stephen Todd; Clive Holmes; David Mann; A David Smith; Seth Love; Patrick G Kehoe; John Hardy; Simon Mead; Nick Fox; Martin Rossor; John Collinge; Wolfgang Maier; Frank Jessen; Britta Schürmann; Hendrik van den Bussche; Isabella Heuser; Johannes Kornhuber; Jens Wiltfang; Martin Dichgans; Lutz Frölich; Harald Hampel; Michael Hüll; Dan Rujescu; Alison M Goate; John S K Kauwe; Carlos Cruchaga; Petra Nowotny; John C Morris; Kevin Mayo; Kristel Sleegers; Karolien Bettens; Sebastiaan Engelborghs; Peter P De Deyn; Christine Van Broeckhoven; Gill Livingston; Nicholas J Bass; Hugh Gurling; Andrew McQuillin; Rhian Gwilliam; Panagiotis Deloukas; Ammar Al-Chalabi; Christopher E Shaw; Magda Tsolaki; Andrew B Singleton; Rita Guerreiro; Thomas W Mühleisen; Markus M Nöthen; Susanne Moebus; Karl-Heinz Jöckel; Norman Klopp; H-Erich Wichmann; Minerva M Carrasquillo; V Shane Pankratz; Steven G Younkin; Peter A Holmans; Michael O'Donovan; Michael J Owen; Julie Williams

2009-01-01

136

Isolation of genes identified in mouse renal proximal tubule by comparing different gene expression profiles  

Microsoft Academic Search

Isolation of genes identified in mouse renal proximal tubule by comparing different gene expression profiles. An expression profile is a list based on a large scale sequencing of 1000 cDNA clones, showing the expressed genes and the abundance of their transcripts in a given cell or tissue (Okubo K et al: Nature Genet 2:173, 1992). We constructed an expression profile

Masaru Takenaka; Enyu Imai; Tetsuya Kaneko; Takahito Ito; Toshiki Moriyama; Atsushi Yamauchi; Masatsugu Hori; Shoko Kawamoto; Kousaku Okubo

1998-01-01

137

Animal Models of GWAS-Identified Type 2 Diabetes Genes  

PubMed Central

More than 65 loci, encoding up to 500 different genes, have been implicated by genome-wide association studies (GWAS) as conferring an increased risk of developing type 2 diabetes (T2D). Whilst mouse models have in the past been central to understanding the mechanisms through which more penetrant risk genes for T2D, for example, those responsible for neonatal or maturity-onset diabetes of the young, only a few of those identified by GWAS, notably TCF7L2 and ZnT8/SLC30A8, have to date been examined in mouse models. We discuss here the animal models available for the latter genes and provide perspectives for future, higher throughput approaches towards efficiently mining the information provided by human genetics.

da Silva Xavier, Gabriela; Bellomo, Elisa A.; McGinty, James A.; French, Paul M.; Rutter, Guy A.

2013-01-01

138

Animal models of GWAS-identified type 2 diabetes genes.  

PubMed

More than 65 loci, encoding up to 500 different genes, have been implicated by genome-wide association studies (GWAS) as conferring an increased risk of developing type 2 diabetes (T2D). Whilst mouse models have in the past been central to understanding the mechanisms through which more penetrant risk genes for T2D, for example, those responsible for neonatal or maturity-onset diabetes of the young, only a few of those identified by GWAS, notably TCF7L2 and ZnT8/SLC30A8, have to date been examined in mouse models. We discuss here the animal models available for the latter genes and provide perspectives for future, higher throughput approaches towards efficiently mining the information provided by human genetics. PMID:23710470

da Silva Xavier, Gabriela; Bellomo, Elisa A; McGinty, James A; French, Paul M; Rutter, Guy A

2013-04-11

139

Genes Necessary for Bacterial Magnetite Biomineralization Identified by Transposon Mutagenesis  

NASA Astrophysics Data System (ADS)

Magnetic bacteria synthesize nanoscale crystals of magnetite in intracellular, membrane-bounded organelles (magnetosomes). These crystals are preserved in the fossil record at least as far back as the late Neoproterozoic and have been tentatively identified in much older rocks (1). This fossil record may provide deep time calibration points for molecular evolution studies once the genes involved in biologically controlled magnetic mineralization (BCMM) are known. Further, a genetic and biochemical understanding of BCMM will give insight into the depositional environment and biogeochemical cycles in which magnetic bacteria play a role. The BCMM process is not well understood, though proteins have been identified from the magnetosome membrane and genetic manipulation and biochemical characterization of these proteins are underway. Most of the proteins currently thought to be involved are encoded within the mam cluster, a large cluster of genes whose products localize to the magnetosome membrane and are conserved among magnetic bacteria (2). In an effort to identify all of the genes necessary for bacterial BCMM, we undertook a transposon mutagenesis of Magnetospirillum magneticum AMB-1. Non-magnetic mutants (MNMs) were identified by growth in liquid culture followed by a magnetic assay. The insertion site of the transposon was identified two ways. First MNMs were screened with a PCR assay to determine if the transposon had inserted into the mam cluster. Second, the transposon was rescued from the mutant DNA and cloned for sequencing. The majority insertion sites are located within the mam cluster. Insertion sites also occur in operons which have not previously been suspected to be involved in magnetite biomineralization. None of the insertion sites have occurred within genes reported from previous transposon mutagenesis studies of AMB-1 (3, 4). Two of the non-mam cluster insertion sites occur in operons containing genes conserved particularly between MS-1 and MC-1. We are undertaking a complementation strategy to demonstrate the necessity of these novel genes in BCMM as well as characterizing the phenotypes of the mutants. 1. S. B. R. Chang, J. F. Stolz, J. L. Kirschvink, S. M. Awramik, Precambrian Res. 43, 305-315 (1989). 2. K. Grünberg, C. Wawer, B. M. Tebo, D. Schüler, Appl. Environ. Microbiol. 67, 4573-4582 (2001). 3. A. T. Wahyudi, H. Takeyama, T. Matsunaga, Appl. Biochem. Biotechnol. 91-3, 147-154 (2001). 4. T. Matsunaga, C. Nakamura, J. G. Burgess, K. Sode, J. Bacteriol. 174, 2748-2753 (1992).

Nash, C. Z.; Komeili, A.; Newman, D. K.; Kirschvink, J. L.

2004-12-01

140

Flavobacterium johnsoniae Gliding Motility Genes Identified by mariner Mutagenesis  

PubMed Central

Cells of Flavobacterium johnsoniae glide rapidly over surfaces. The mechanism of F. johnsoniae gliding motility is not known. Eight gld genes required for gliding motility have been described. Disruption of any of these genes results in complete loss of gliding motility, deficiency in chitin utilization, and resistance to bacteriophages that infect wild-type cells. Two modified mariner transposons, HimarEm1 and HimarEm2, were constructed to allow the identification of additional motility genes. HimarEm1 and HimarEm2 each transposed in F. johnsoniae, and nonmotile mutants were identified and analyzed. Four novel motility genes, gldK, gldL, gldM, and gldN, were identified. GldK is similar in sequence to the lipoprotein GldJ, which is required for gliding. GldL, GldM, and GldN are not similar in sequence to proteins of known function. Cells with mutations in gldK, gldL, gldM, and gldN were defective in motility and chitin utilization and were resistant to bacteriophages that infect wild-type cells. Introduction of gldA, gldB, gldD, gldFG, gldH, gldI, and gldJ and the region spanning gldK, gldL, gldM, and gldN individually into 50 spontaneous and chemically induced nonmotile mutants restored motility to each of them, suggesting that few additional F. johnsoniae gld genes remain to be identified.

Braun, Timothy F.; Khubbar, Manjeet K.; Saffarini, Daad A.; McBride, Mark J.

2005-01-01

141

Haplotype analysis in multiple crosses to identify a QTL gene.  

PubMed

Identifying quantitative trait locus (QTL) genes is a challenging task. Herein, we report using a two-step process to identify Apoa2 as the gene underlying Hdlq5, a QTL for plasma high-density lipoprotein cholesterol (HDL) levels on mouse chromosome 1. First, we performed a sequence analysis of the Apoa2 coding region in 46 genetically diverse mouse strains and found five different APOA2 protein variants, which we named APOA2a to APOA2e. Second, we conducted a haplotype analysis of the strains in 21 crosses that have so far detected HDL QTLs; we found that Hdlq5 was detected only in the nine crosses where one parent had the APOA2b protein variant characterized by an Ala61-to-Val61 substitution. We then found that strains with the APOA2b variant had significantly higher (P < or = 0.002) plasma HDL levels than those with either the APOA2a or the APOA2c variant. These findings support Apoa2 as the underlying Hdlq5 gene and suggest the Apoa2 polymorphisms responsible for the Hdlq5 phenotype. Therefore, haplotype analysis in multiple crosses can be used to support a candidate QTL gene. PMID:15310659

Wang, Xiaosong; Korstanje, Ron; Higgins, David; Paigen, Beverly

2004-08-12

142

Haplotype Analysis in Multiple Crosses to Identify a QTL Gene  

PubMed Central

Identifying quantitative trait locus (QTL) genes is a challenging task. Herein, we report using a two-step process to identify Apoa2 as the gene underlying Hdlq5, a QTL for plasma high-density lipoprotein cholesterol (HDL) levels on mouse chromosome 1. First, we performed a sequence analysis of the Apoa2 coding region in 46 genetically diverse mouse strains and found five different APOA2 protein variants, which we named APOA2a to APOA2e. Second, we conducted a haplotype analysis of the strains in 21 crosses that have so far detected HDL QTLs; we found that Hdlq5 was detected only in the nine crosses where one parent had the APOA2b protein variant characterized by an Ala61-to-Val61 substitution. We then found that strains with the APOA2b variant had significantly higher (P ? 0.002) plasma HDL levels than those with either the APOA2a or the APOA2c variant. These findings support Apoa2 as the underlying Hdlq5 gene and suggest the Apoa2 polymorphisms responsible for the Hdlq5 phenotype. Therefore, haplotype analysis in multiple crosses can be used to support a candidate QTL gene.

Wang, Xiaosong; Korstanje, Ron; Higgins, David; Paigen, Beverly

2004-01-01

143

Identifying polymorphism in enamelin gene in amelogenesis imperfecta (AI).  

PubMed

Amelogenesis imperfecta (AI) is a developmental defect of dental enamel formation. This enamel defect can be caused by mutation in ENAM gene. Hence this study investigated the molecular defect in the enamelin gene in a patient with the clinical features of AI. The genomic DNA was extracted from patient's whole blood samples and the DNA was subjected to the polymerase chain reaction (PCR) in the presence of 16 pairs of oligonucleotide primers specifically designed to amplify all the 10 exons, g2382, g6395 and g8344 of the enamelin (ENAM) gene in the long arm of the chromosome 4. The PCR products were gel purified and sequenced to identify any mutation. The ENAM gene sequences from the patient were aligned with the reference sequence (GenBank accession no. AY167999) using VectorNTI software. We identified a single base difference at location g359 A-->G on exon 1 between the reference sequence and patient's sequence. We successfully ruled out any possible mutation on exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, g2382, g6395 and g8344. PMID:18466877

Gopinath, V K; Yoong, Tan Pang; Yean, Chan Yean; Ravichandran, M

2008-05-08

144

Identifying genes underlying skin pigmentation differences among human populations  

Microsoft Academic Search

Skin pigmentation is a human phenotype that varies greatly among human populations and it has long been speculated that this\\u000a variation is adaptive. We therefore expect the genes that contribute to these large differences in phenotype to show large\\u000a allele frequency differences among populations and to possibly harbor signatures of positive selection. To identify the loci\\u000a that likely contribute to

Sean Myles; Mehmet Somel; Kun Tang; Janet Kelso; Mark Stoneking

2007-01-01

145

Zebrafish promoter microarrays identify actively transcribed embryonic genes  

Microsoft Academic Search

We have designed a zebrafish genomic microarray to identify DNA-protein interactions in the proximal promoter regions of over\\u000a 11,000 zebrafish genes. Using these microarrays, together with chromatin immunoprecipitation with an antibody directed against\\u000a tri-methylated lysine 4 of Histone H3, we demonstrate the feasibility of this method in zebrafish. This approach will allow\\u000a investigators to determine the genomic binding locations of

Fiona C Wardle; Duncan T Odom; George W Bell; Bingbing Yuan; Timothy W Danford; Elizabeth L Wiellette; Elizabeth Herbolsheimer; Hazel L Sive; Richard A Young; James C Smith

2006-01-01

146

Translatome analysis of CHO cells to identify key growth genes.  

PubMed

We report the first investigation of translational efficiency on a global scale, also known as translatome, of a Chinese hamster ovary (CHO) DG44 cell line producing monoclonal antibodies (mAb). The translatome data was generated via combined use of high resolution and streamlined polysome profiling technology and proprietary Nimblegen microarrays probing for more than 13K annotated CHO-specific genes. The distribution of ribosome loading during the exponential growth phase revealed the translational activity corresponding to the maximal growth rate, thus allowing us to identify stably and highly translated genes encoding heterogeneous nuclear ribonucleoproteins (Hnrnpc and Hnrnpa2b1), protein regulator of cytokinesis 1 (Prc1), glucose-6-phosphate dehydrogenase (G6pdh), UTP6 small subunit processome (Utp6) and RuvB-like protein 1 (Ruvbl1) as potential key players for cellular growth. Moreover, correlation analysis between transcriptome and translatome data sets showed that transcript level and translation efficiency were uncoupled for 95% of investigated genes, suggesting the implication of translational control mechanisms such as the mTOR pathway. Thus, the current translatome analysis platform offers new insights into gene expression in CHO cell cultures by bridging the gap between transcriptome and proteome data, which will enable researchers of the bioprocessing field to prioritize in high-potential candidate genes and to devise optimal strategies for cell engineering toward improving culture performance. PMID:23876478

Courtes, Franck C; Lin, Joyce; Lim, Hsueh Lee; Ng, Sze Wai; Wong, Niki S C; Koh, Geoffrey; Vardy, Leah; Yap, Miranda G S; Loo, Bernard; Lee, Dong-Yup

2013-07-19

147

'Gene shaving' as a method for identifying distinct sets of genes with similar expression patterns  

PubMed Central

Background: Large gene expression studies, such as those conducted using DNA arrays, often provide millions of different pieces of data. To address the problem of analyzing such data, we describe a statistical method, which we have called 'gene shaving'. The method identifies subsets of genes with coherent expression patterns and large variation across conditions. Gene shaving differs from hierarchical clustering and other widely used methods for analyzing gene expression studies in that genes may belong to more than one cluster, and the clustering may be supervised by an outcome measure. The technique can be 'unsupervised', that is, the genes and samples are treated as unlabeled, or partially or fully supervised by using known properties of the genes or samples to assist in finding meaningful groupings. Results: We illustrate the use of the gene shaving method to analyze gene expression measurements made on samples from patients with diffuse large B-cell lymphoma. The method identifies a small cluster of genes whose expression is highly predictive of survival. Conclusions: The gene shaving method is a potentially useful tool for exploration of gene expression data and identification of interesting clusters of genes worth further investigation.

Hastie, Trevor; Tibshirani, Robert; Eisen, Michael B; Alizadeh, Ash; Levy, Ronald; Staudt, Louis; Chan, Wing C; Botstein, David; Brown, Patrick

2000-01-01

148

Beryllium Lymphocyte Proliferation Test Surveillance Identifies Clinically Significant Beryllium Disease  

PubMed Central

Background Workplace surveillance identifies chronic beryllium disease (CBD) but it remains unknown over what time frame mild CBD will progress to a more severe form. Methods We examined physiology and treatment in 229 beryllium sensitization (BeS) and 171 CBD surveillance-identified cases diagnosed from 1982 to 2002. Never smoking CBD cases (81) were compared to never smoking BeS patients (83) to assess disease progression. We compared CBD machinists to non-machinists to examine effects of exposure. Results At baseline, CBD and BeS cases did not differ significantly in exposure time or physiology. CBD patients were more likely to have machined beryllium. Of CBD cases, 19.3% went on to require oral immunosuppressive therapy. At 30 years from first exposure, measures of gas exchange were significantly worse and total lung capacity was lower for CBD subjects. Machinists had faster disease progression as measured by pulmonary function testing and gas exchange. Conclusions Medical surveillance for CBD identifies individuals at significant risk of disease progression and impairment with sufficient time since first exposure.

Mroz, Margaret M.; Maier, Lisa A.; Strand, Matthew; Silviera, Lori; Newman, Lee S.

2011-01-01

149

Improving disease gene prioritization using the semantic similarity of Gene Ontology terms  

PubMed Central

Motivation: Many hereditary human diseases are polygenic, resulting from sequence alterations in multiple genes. Genomic linkage and association studies are commonly performed for identifying disease-related genes. Such studies often yield lists of up to several hundred candidate genes, which have to be prioritized and validated further. Recent studies discovered that genes involved in phenotypically similar diseases are often functionally related on the molecular level. Results: Here, we introduce MedSim, a novel approach for ranking candidate genes for a particular disease based on functional comparisons involving the Gene Ontology. MedSim uses functional annotations of known disease genes for assessing the similarity of diseases as well as the disease relevance of candidate genes. We benchmarked our approach with genes known to be involved in 99 diseases taken from the OMIM database. Using artificial quantitative trait loci, MedSim achieved excellent performance with an area under the ROC curve of up to 0.90 and a sensitivity of over 70% at 90% specificity when classifying gene products according to their disease relatedness. This performance is comparable or even superior to related methods in the field, albeit using less and thus more easily accessible information. Availability: MedSim is offered as part of our FunSimMat web service (http://www.funsimmat.de). Contact: mario.albrecht@mpi-inf.mpg.de Supplementary information: Supplementary data are available at Bioinformatics online.

Schlicker, Andreas; Lengauer, Thomas; Albrecht, Mario

2010-01-01

150

Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma.  

PubMed

Outcome in multiple myeloma is highly variable and a better understanding of the factors that influence disease biology is essential to understand and predict behavior in individual patients. In the present study, we analyzed combined genomewide DNA methylation and gene expression data of patients treated in the Medical Research Council Myeloma IX trial. We used these data to identify epigenetically repressed tumor suppressor genes with prognostic relevance in myeloma. We identified 195 genes with changes in methylation status that were significantly associated with prognosis. Combining DNA methylation and gene expression data led to the identification of the epigenetically regulated tumor modulating genes GPX3, RBP1, SPARC, and TGFBI. Hypermethylation of these genes was associated with significantly shorter overall survival, independent of age, International Staging System score, and adverse cytogenetics. The 4 differentially methylated and expressed genes are known to mediate important tumor suppressive functions including response to chemotherapy (TGFBI), interaction with the microenvironment (SPARC), retinoic acid signaling (RBP1), and the response to oxidative stress (GPX3), which could explain the prognostic impact of their differential methylation. Assessment of the DNA methylation status of the identified genes could contribute to the molecular characterization of myeloma, which is prerequisite for an individualized treatment approach. PMID:23699600

Kaiser, Martin F; Johnson, David C; Wu, Ping; Walker, Brian A; Brioli, Annamaria; Mirabella, Fabio; Wardell, Christopher P; Melchor, Lorenzo; Davies, Faith E; Morgan, Gareth J

2013-05-22

151

Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma  

PubMed Central

Outcome in multiple myeloma is highly variable and a better understanding of the factors that influence disease biology is essential to understand and predict behavior in individual patients. In the present study, we analyzed combined genomewide DNA methylation and gene expression data of patients treated in the Medical Research Council Myeloma IX trial. We used these data to identify epigenetically repressed tumor suppressor genes with prognostic relevance in myeloma. We identified 195 genes with changes in methylation status that were significantly associated with prognosis. Combining DNA methylation and gene expression data led to the identification of the epigenetically regulated tumor modulating genes GPX3, RBP1, SPARC, and TGFBI. Hypermethylation of these genes was associated with significantly shorter overall survival, independent of age, International Staging System score, and adverse cytogenetics. The 4 differentially methylated and expressed genes are known to mediate important tumor suppressive functions including response to chemotherapy (TGFBI), interaction with the microenvironment (SPARC), retinoic acid signaling (RBP1), and the response to oxidative stress (GPX3), which could explain the prognostic impact of their differential methylation. Assessment of the DNA methylation status of the identified genes could contribute to the molecular characterization of myeloma, which is prerequisite for an individualized treatment approach.

Kaiser, Martin F.; Johnson, David C.; Wu, Ping; Walker, Brian A.; Brioli, Annamaria; Mirabella, Fabio; Wardell, Christopher P.; Melchor, Lorenzo; Davies, Faith E.

2013-01-01

152

Modularity-based credible prediction of disease genes and detection of disease subtypes on the phenotype-gene heterogeneous network  

PubMed Central

Background Protein-protein interaction networks and phenotype similarity information have been synthesized together to discover novel disease-causing genes. Genetic or phenotypic similarities are manifested as certain modularity properties in a phenotype-gene heterogeneous network consisting of the phenotype-phenotype similarity network, protein-protein interaction network and gene-disease association network. However, the quantitative analysis of modularity in the heterogeneous network and its influence on disease-gene discovery are still unaddressed. Furthermore, the genetic correspondence of the disease subtypes can be identified by marking the genes and phenotypes in the phenotype-gene network. We present a novel network inference method to measure the network modularity, and in particular to suggest the subtypes of diseases based on the heterogeneous network. Results Based on a measure which is introduced to evaluate the closeness between two nodes in the phenotype-gene heterogeneous network, we developed a Hitting-Time-based method, CIPHER-HIT, for assessing the modularity of disease gene predictions and credibly prioritizing disease-causing genes, and then identifying the genetic modules corresponding to potential subtypes of the queried phenotype. The CIPHER-HIT is free to rely on any preset parameters. We found that when taking into account the modularity levels, the CIPHER-HIT method can significantly improve the performance of disease gene predictions, which demonstrates modularity is one of the key features for credible inference of disease genes on the phenotype-gene heterogeneous network. By applying the CIPHER-HIT to the subtype analysis of Breast cancer, we found that the prioritized genes can be divided into two sub-modules, one contains the members of the Fanconi anemia gene family, and the other contains a reported protein complex MRE11/RAD50/NBN. Conclusions The phenotype-gene heterogeneous network contains abundant information for not only disease genes discovery but also disease subtypes detection. The CIPHER-HIT method presented here is effective for network inference, particularly on credible prediction of disease genes and the subtype analysis of diseases, for example Breast cancer. This method provides a promising way to analyze heterogeneous biological networks, both globally and locally.

2011-01-01

153

Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene.  

PubMed

Through complete sequencing of the protein-coding genes in a patient with familial pancreatic cancer, we identified a germline, truncating mutation in PALB2 that appeared responsible for this patient's predisposition to the disease. Analysis of 96 additional patients with familial pancreatic cancer revealed three distinct protein-truncating mutations, thereby validating the role of PALB2 as a susceptibility gene for pancreatic cancer. PALB2 mutations have been previously reported in patients with familial breast cancer, and the PALB2 protein is a binding partner for BRCA2. These results illustrate that complete, unbiased sequencing of protein-coding genes can lead to the identification of a gene responsible for a hereditary disease. PMID:19264984

Jones, Siân; Hruban, Ralph H; Kamiyama, Mihoko; Borges, Michael; Zhang, Xiaosong; Parsons, D Williams; Lin, Jimmy Cheng-Ho; Palmisano, Emily; Brune, Kieran; Jaffee, Elizabeth M; Iacobuzio-Donahue, Christine A; Maitra, Anirban; Parmigiani, Giovanni; Kern, Scott E; Velculescu, Victor E; Kinzler, Kenneth W; Vogelstein, Bert; Eshleman, James R; Goggins, Michael; Klein, Alison P

2009-03-05

154

Identifying critical transitions and their leading biomolecular networks in complex diseases  

PubMed Central

Identifying a critical transition and its leading biomolecular network during the initiation and progression of a complex disease is a challenging task, but holds the key to early diagnosis and further elucidation of the essential mechanisms of disease deterioration at the network level. In this study, we developed a novel computational method for identifying early-warning signals of the critical transition and its leading network during a disease progression, based on high-throughput data using a small number of samples. The leading network makes the first move from the normal state toward the disease state during a transition, and thus is causally related with disease-driving genes or networks. Specifically, we first define a state-transition-based local network entropy (SNE), and prove that SNE can serve as a general early-warning indicator of any imminent transitions, regardless of specific differences among systems. The effectiveness of this method was validated by functional analysis and experimental data.

Liu, Rui; Li, Meiyi; Liu, Zhi-Ping; Wu, Jiarui; Chen, Luonan; Aihara, Kazuyuki

2012-01-01

155

Identifying critical transitions and their leading biomolecular networks in complex diseases.  

PubMed

Identifying a critical transition and its leading biomolecular network during the initiation and progression of a complex disease is a challenging task, but holds the key to early diagnosis and further elucidation of the essential mechanisms of disease deterioration at the network level. In this study, we developed a novel computational method for identifying early-warning signals of the critical transition and its leading network during a disease progression, based on high-throughput data using a small number of samples. The leading network makes the first move from the normal state toward the disease state during a transition, and thus is causally related with disease-driving genes or networks. Specifically, we first define a state-transition-based local network entropy (SNE), and prove that SNE can serve as a general early-warning indicator of any imminent transitions, regardless of specific differences among systems. The effectiveness of this method was validated by functional analysis and experimental data. PMID:23230504

Liu, Rui; Li, Meiyi; Liu, Zhi-Ping; Wu, Jiarui; Chen, Luonan; Aihara, Kazuyuki

2012-12-10

156

Pathway Correlation Profile of Gene-Gene Co-Expression for Identifying Pathway Perturbation  

PubMed Central

Identifying perturbed or dysregulated pathways is critical to understanding the biological processes that change within an experiment. Previous methods identified important pathways that are significantly enriched among differentially expressed genes; however, these methods cannot account for small, coordinated changes in gene expression that amass across a whole pathway. In order to overcome this limitation, we use microarray gene expression data to identify pathway perturbation based on pathway correlation profiles. By identifying the distribution of gene-gene pair correlations within a pathway, we can rank the pathways based on the level of perturbation and dysregulation. We have shown this successfully for differences between two experimental conditions in Escherichia coli and changes within time series data in Saccharomyces cerevisiae, as well as two estrogen receptor response classes of breast cancer. Overall, our method made significant predictions as to the pathway perturbations that are involved in the experimental conditions.

Tegge, Allison N.; Caldwell, Charles W.; Xu, Dong

2012-01-01

157

Comparative Genomics and Gene Expression Analysis Identifies BBS9, a New Bardet-Biedl Syndrome Gene  

PubMed Central

Bardet-Biedl syndrome (BBS) is an autosomal recessive, genetically heterogeneous, pleiotropic human disorder characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, and hypogenitalism. Eight BBS genes representing all known mapped loci have been identified. Mutation analysis of the known BBS genes in BBS patients indicate that additional BBS genes exist and/or that unidentified mutations exist in the known genes. To identify new BBS genes, we performed homozygosity mapping of small, consanguineous BBS pedigrees, using moderately dense SNP arrays. A bioinformatics approach combining comparative genomic analysis and gene expression studies of a BBS-knockout mouse model was used to prioritize BBS candidate genes within the newly identified loci for mutation screening. By use of this strategy, parathyroid hormone-responsive gene B1 (B1) was found to be a novel BBS gene (BBS9), supported by the identification of homozygous mutations in BBS patients. The identification of BBS9 illustrates the power of using a combination of comparative genomic analysis, gene expression studies, and homozygosity mapping with SNP arrays in small, consanguineous families for the identification of rare autosomal recessive disorders. We also demonstrate that small, consanguineous families are useful in identifying intragenic deletions. This type of mutation is likely to be underreported because of the difficulty of deletion detection in the heterozygous state by the mutation screening methods that are used in many studies.

Nishimura, Darryl Y.; Swiderski, Ruth E.; Searby, Charles C.; Berg, Erik M.; Ferguson, Amanda L.; Hennekam, Raoul; Merin, Saul; Weleber, Richard G.; Biesecker, Leslie G.; Stone, Edwin M.; Sheffield, Val C.

2005-01-01

158

Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene.  

PubMed

Bardet-Biedl syndrome (BBS) is an autosomal recessive, genetically heterogeneous, pleiotropic human disorder characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, and hypogenitalism. Eight BBS genes representing all known mapped loci have been identified. Mutation analysis of the known BBS genes in BBS patients indicate that additional BBS genes exist and/or that unidentified mutations exist in the known genes. To identify new BBS genes, we performed homozygosity mapping of small, consanguineous BBS pedigrees, using moderately dense SNP arrays. A bioinformatics approach combining comparative genomic analysis and gene expression studies of a BBS-knockout mouse model was used to prioritize BBS candidate genes within the newly identified loci for mutation screening. By use of this strategy, parathyroid hormone-responsive gene B1 (B1) was found to be a novel BBS gene (BBS9), supported by the identification of homozygous mutations in BBS patients. The identification of BBS9 illustrates the power of using a combination of comparative genomic analysis, gene expression studies, and homozygosity mapping with SNP arrays in small, consanguineous families for the identification of rare autosomal recessive disorders. We also demonstrate that small, consanguineous families are useful in identifying intragenic deletions. This type of mutation is likely to be underreported because of the difficulty of deletion detection in the heterozygous state by the mutation screening methods that are used in many studies. PMID:16380913

Nishimura, Darryl Y; Swiderski, Ruth E; Searby, Charles C; Berg, Erik M; Ferguson, Amanda L; Hennekam, Raoul; Merin, Saul; Weleber, Richard G; Biesecker, Leslie G; Stone, Edwin M; Sheffield, Val C

2005-10-26

159

Gene Expression Profiles in Cells of Peripheral Blood Identify New Molecular Markers of Acute Pancreatitis  

PubMed Central

Introduction Blood leukocytes play a major role in mediating local and systemic inflammation during acute pancreatitis. We hypothesize that peripheral blood mononuclear cells (PBMC) in circulation exhibit unique changes in gene expression, and could provide a “reporter” function that reflects the inflammatory response in pancreas of acute pancreatitis. Methods To determine specific changes in blood leukocytes during acute pancreatitis, we studied gene transcription profile of in peripheral blood mononuclear cells (PBMC) in a rat model of experimental pancreatitis (sodium taurocholate). Normal rats, saline controls and a model of septic shock were used as a controls. cRNA obtained from PBMC of each group (n = 3) were applied to Affymetrix rat genome DNA Gene Chip Arrays. Results From the 8,799 rat genes analyzed, 140 genes showed unique significant changes in their expression in PBMC during the acute phase of pancreatitis, but not in sepsis. Among the 140 genes, 57 were upregulated, while 69 were downregulated. Platelet-derived growth factor receptor, prostaglandin E2 receptor and phospholipase D1 are among the top upregulated genes. Others include genes involved in G protein-coupled receptor and TGF-?-mediated signaling pathways, while genes associated with apoptosis, glucocorticoid receptors and even the cholecystokinin receptor are downregulated. Conclusions Microarray analysis in transcriptional profiling of PBMC showed that genes that are uniquely related to molecular and pancreatic function display differential expression in acute pancreatitis. Profiling genes obtained from an easily accessible source during severe pancreatitis may identify surrogate markers for disease severity.

Bluth, Martin; Lin, Yin-yao; Zhang, Hong; Viterbo, Dominick; Zenilman, Michael

2009-01-01

160

Harnessing genomics to identify environmental determinants of heritable disease  

PubMed Central

Next-generation sequencing technologies can now be used to directly measure heritable de novo DNA sequence mutations in humans. However, these techniques have not been used to examine environmental factors that induce such mutations and their associated diseases. To address this issue, a working group on environmentally induced germline mutation analysis (ENIGMA) met in October 2011 to propose the necessary foundational studies, which include sequencing of parent–offspring trios from highly exposed human populations, and controlled dose–response experiments in animals. These studies will establish background levels of variability in germline mutation rates and identify environmental agents that influence these rates and heritable disease. Guidance for the types of exposures to examine come from rodent studies that have identified agents such as cancer chemotherapeutic drugs, ionizing radiation, cigarette smoke, and air pollution as germ-cell mutagens. Research is urgently needed to establish the health consequences of parental exposures on subsequent generations.

Yauk, Carole Lyn; Argueso, J. Lucas; Auerbach, Scott S.; Awadalla, Philip; Davis, Sean R.; DeMarini, David M.; Douglas, George R.; Dubrova, Yuri E.; Elespuru, Rosalie K.; Glover, Thomas W.; Hales, Barbara F.; Hurles, Matthew E.; Klein, Catherine B.; Lupski, James R.; Manchester, David K.; Marchetti, Francesco; Montpetit, Alexandre; Mulvihill, John J.; Robaire, Bernard; Robbins, Wendie A.; Rouleau, Guy A.; Shaughnessy, Daniel T.; Somers, Christopher M.; Taylor, James G.; Trasler, Jacquetta; Waters, Michael D.; Wilson, Thomas E.; Witt, Kristine L.; Bishop, Jack B.

2012-01-01

161

Marek's Disease Virus Gene Encoding pp38 Phosphoprotein.  

National Technical Information Service (NTIS)

The Marek's disease virus gene encoding phosphoprotein has been isolated, identified, and sequenced, and the transcriptional unit has been characterized. The gene consists of a DNA fragment about 1.8 kb in size. It is useful as a probe in differential Mar...

L. F. Lee Z. Cui

1991-01-01

162

Genome-wide Expression and Copy Number Analysis Identifies Driver Genes in Gingivobuccal Cancers  

PubMed Central

The molecular mechanisms contributing to the development and progression of gingivobuccal complex (GBC) cancers–a sub-site of oral cancer, comprising the buccal mucosa, the gingivobuccal sulcus, the lower gingival region and the retromolar trigone-remain poorly understood. Identifying the GBC cancer-related gene expression signature and the driver genes residing on the altered chromosomal regions is critical for understanding the molecular basis of its pathogenesis. Genome-wide expression profiling of 27 GBC cancers with known chromosomal alterations was performed to reveal differentially expressed genes. Putative driver genes were identified by integrating copy number and gene expression data. A total of 315 genes were found differentially expressed (P?0.05, logFC>2.0) of which eleven genes were validated by real-time quantitative reverse transcriptase-PCR (qRT-PCR) in tumors (n=57) and normal GBC tissues (n=18). Overexpression of LY6K, in chromosome band 8q24.3, was validated by immunohistochemical (IHC) analysis. We found that 78.5% (2,417/3,079) of the genes located in regions of recurrent chromosomal alterations show copy number dependent expression indicating that copy number alteration has a direct effect on global gene expression. The integrative analysis revealed BIRC3 in 11q22.2 as a candidate driver gene associated with poor clinical outcome. Our study identified previously unreported differentially expressed genes in a homogeneous subtype of oral cancer and the candidate driver genes that may contribute to the development and progression of the disease.

Ambatipudi, Srikant; Gerstung, Moritz; Pandey, Manishkumar; Samant, Tanuja; Patil, Asawari; Kane, Shubhada; Desai, Rajiv S.; Schaffer, Alejandro A.; Beerenwinkel, Niko; Mahimkar, Manoj B.

2011-01-01

163

Identifying sleep regulatory genes using a Drosophila model of insomnia  

PubMed Central

Although it is widely accepted that sleep must serve an essential biological function, little is known about molecules that underlie sleep regulation. Given that insomnia is a common sleep disorder that disrupts the ability to initiate and maintain restorative sleep, a better understanding of its molecular underpinning may provide crucial insights into sleep regulatory processes. Thus, we created a line of flies using laboratory selection that share traits with human insomnia. After 60 generations insomnia-like (ins-l) flies sleep 60 min a day, exhibit difficulty initiating sleep, difficulty maintaining sleep, and show evidence of daytime cognitive impairment. ins-l flies are also hyperactive and hyper responsive to environmental perturbations. In addition they have difficulty maintaining their balance, have elevated levels of dopamine, are short-lived and show increased levels of triglycerides, cholesterol, and free fatty acids. While their core molecular clock remains intact, ins-l flies lose their ability to sleep when placed into constant darkness. Whole genome profiling identified genes that are modified in ins-l flies. Among those differentially expressed transcripts genes involved in metabolism, neuronal activity, and sensory perception constituted over-represented categories. We demonstrate that two of these genes are upregulated in human subjects following acute sleep deprivation. Together these data indicate that the ins-l flies are a useful tool that can be used to identify molecules important for sleep regulation and may provide insights into both the causes and long-term consequences of insomnia.

Seugnet, Laurent; Suzuki, Yasuko; Thimgan, Matthew; Donlea, Jeff; Gimbel, Sarah I.; Gottschalk, Laura; Duntley, Steve P.; Shaw, Paul J.

2009-01-01

164

Analysis of Gene Order Conservation in Eukaryotes Identifies Transcriptionally and Functionally Linked Genes  

PubMed Central

The order of genes in eukaryotes is not entirely random. Studies of gene order conservation are important to understand genome evolution and to reveal mechanisms why certain neighboring genes are more difficult to separate during evolution. Here, genome-wide gene order information was compiled for 64 species, representing a wide variety of eukaryotic phyla. This information is presented in a browser where gene order may be displayed and compared between species. Factors related to non-random gene order in eukaryotes were examined by considering pairs of neighboring genes. The evolutionary conservation of gene pairs was studied with respect to relative transcriptional direction, intergenic distance and functional relationship as inferred by gene ontology. The results show that among gene pairs that are conserved the divergently and co-directionally transcribed genes are much more common than those that are convergently transcribed. Furthermore, highly conserved pairs, in particular those of fungi, are characterized by a short intergenic distance. Finally, gene pairs of metazoa and fungi that are evolutionary conserved and that are divergently transcribed are much more likely to be related by function as compared to poorly conserved gene pairs. One example is the ribosomal protein gene pair L13/S16, which is unusual as it occurs both in fungi and alveolates. A specific functional relationship between these two proteins is also suggested by the fact that they are part of the same operon in both eubacteria and archaea. In conclusion, factors associated with non-random gene order in eukaryotes include relative gene orientation, intergenic distance and functional relationships. It seems likely that certain pairs of genes are conserved because the genes involved have a transcriptional and/or functional relationship. The results also indicate that studies of gene order conservation aid in identifying genes that are related in terms of transcriptional control.

Davila Lopez, Marcela; Martinez Guerra, Juan Jose; Samuelsson, Tore

2010-01-01

165

Lentiviral vector-based insertional mutagenesis identifies genes associated with liver cancer  

PubMed Central

Transposons and ?-retroviruses have been efficiently used as insertional mutagens in different tissues to identify molecular culprits of cancer. However, these systems are characterized by recurring integrations that accumulate in tumor cells, hampering the identification of early cancer-driving events amongst bystander and progression-related events. We developed an insertional mutagenesis platform based on lentiviral vectors (LVV) by which we could efficiently induce hepatocellular carcinoma (HCC) in 3 different mouse models. By virtue of LVV’s replication-deficient nature and broad genome-wide integration pattern, LVV-based insertional mutagenesis allowed identification of 4 new liver cancer genes from a limited number of integrations. We validated the oncogenic potential of all the identified genes in vivo, with different levels of penetrance. Our newly identified cancer genes are likely to play a role in human disease, since they are upregulated and/or amplified/deleted in human HCCs and can predict clinical outcome of patients.

Ranzani, Marco; Cesana, Daniela; Bartholomae, Cynthia C.; Sanvito, Francesca; Pala, Mauro; Benedicenti, Fabrizio; Gallina, Pierangela; Sergi, Lucia Sergi; Merella, Stefania; Bulfone, Alessandro; Doglioni, Claudio; von Kalle, Christof; Kim, Yoon Jun; Schmidt, Manfred; Tonon, Giovanni; Naldini, Luigi; Montini, Eugenio

2013-01-01

166

Prioritizing genes of potential relevance to diseases affected by sex hormones: an example of Myasthenia Gravis  

Microsoft Academic Search

BACKGROUND: About 5% of western populations are afflicted by autoimmune diseases many of which are affected by sex hormones. Autoimmune diseases are complex and involve many genes. Identifying these disease-associated genes contributes to development of more effective therapies. Also, association studies frequently imply genomic regions that contain disease-associated genes but fall short of pinpointing these genes. The identification of disease-associated

Mandeep Kaur; Sebastian Schmeier; Cameron R MacPherson; Oliver Hofmann; Winston A Hide; Stephen Taylor; Nick Willcox; Vladimir B Bajic

2008-01-01

167

Gene regulatory networks elucidating huanglongbing disease mechanisms.  

PubMed

Next-generation sequencing was exploited to gain deeper insight into the response to infection by Candidatus liberibacter asiaticus (CaLas), especially the immune disregulation and metabolic dysfunction caused by source-sink disruption. Previous fruit transcriptome data were compared with additional RNA-Seq data in three tissues: immature fruit, and young and mature leaves. Four categories of orchard trees were studied: symptomatic, asymptomatic, apparently healthy, and healthy. Principal component analysis found distinct expression patterns between immature and mature fruits and leaf samples for all four categories of trees. A predicted protein - protein interaction network identified HLB-regulated genes for sugar transporters playing key roles in the overall plant responses. Gene set and pathway enrichment analyses highlight the role of sucrose and starch metabolism in disease symptom development in all tissues. HLB-regulated genes (glucose-phosphate-transporter, invertase, starch-related genes) would likely determine the source-sink relationship disruption. In infected leaves, transcriptomic changes were observed for light reactions genes (downregulation), sucrose metabolism (upregulation), and starch biosynthesis (upregulation). In parallel, symptomatic fruits over-expressed genes involved in photosynthesis, sucrose and raffinose metabolism, and downregulated starch biosynthesis. We visualized gene networks between tissues inducing a source-sink shift. CaLas alters the hormone crosstalk, resulting in weak and ineffective tissue-specific plant immune responses necessary for bacterial clearance. Accordingly, expression of WRKYs (including WRKY70) was higher in fruits than in leaves. Systemic acquired responses were inadequately activated in young leaves, generally considered the sites where most new infections occur. PMID:24086326

Martinelli, Federico; Reagan, Russell L; Uratsu, Sandra L; Phu, My L; Albrecht, Ute; Zhao, Weixiang; Davis, Cristina E; Bowman, Kim D; Dandekar, Abhaya M

2013-09-25

168

Gene Regulatory Networks Elucidating Huanglongbing Disease Mechanisms  

PubMed Central

Next-generation sequencing was exploited to gain deeper insight into the response to infection by Candidatus liberibacter asiaticus (CaLas), especially the immune disregulation and metabolic dysfunction caused by source-sink disruption. Previous fruit transcriptome data were compared with additional RNA-Seq data in three tissues: immature fruit, and young and mature leaves. Four categories of orchard trees were studied: symptomatic, asymptomatic, apparently healthy, and healthy. Principal component analysis found distinct expression patterns between immature and mature fruits and leaf samples for all four categories of trees. A predicted protein – protein interaction network identified HLB-regulated genes for sugar transporters playing key roles in the overall plant responses. Gene set and pathway enrichment analyses highlight the role of sucrose and starch metabolism in disease symptom development in all tissues. HLB-regulated genes (glucose-phosphate-transporter, invertase, starch-related genes) would likely determine the source-sink relationship disruption. In infected leaves, transcriptomic changes were observed for light reactions genes (downregulation), sucrose metabolism (upregulation), and starch biosynthesis (upregulation). In parallel, symptomatic fruits over-expressed genes involved in photosynthesis, sucrose and raffinose metabolism, and downregulated starch biosynthesis. We visualized gene networks between tissues inducing a source-sink shift. CaLas alters the hormone crosstalk, resulting in weak and ineffective tissue-specific plant immune responses necessary for bacterial clearance. Accordingly, expression of WRKYs (including WRKY70) was higher in fruits than in leaves. Systemic acquired responses were inadequately activated in young leaves, generally considered the sites where most new infections occur.

Martinelli, Federico; Reagan, Russell L.; Uratsu, Sandra L.; Phu, My L.; Albrecht, Ute; Zhao, Weixiang; Davis, Cristina E.; Bowman, Kim D.; Dandekar, Abhaya M.

2013-01-01

169

Gene-For-Gene Disease Resistance without the Hypersensitive Response in Arabidopsis dnd1 Mutant  

Microsoft Academic Search

The cell death response known as the hypersensitive response (HR) is a central feature of gene-for-gene plant disease resistance. A mutant line of Arabidopsis thaliana was identified in which effective gene-for-gene resistance occurs despite the virtual absence of HR cell death. Plants mutated at the DND1 locus are defective in HR cell death but retain characteristic responses to avirulent Pseudomonas

I.-Ching Yu; Jane Parker; Andrew F. Bent

1998-01-01

170

X inactivation testing for identifying a non-syndromic X-linked mental retardation gene.  

PubMed

The purpose of this study was to identify a gene causing non-syndromic X-linked mental retardation in an extended family, taking advantage of the X chromosome inactivation status of the females in order to determine their carrier state. X inactivation in the females was determined with the androgen receptor methylation assay; thereafter, the X chromosome was screened with evenly spaced polymorphic markers. Once initial linkage was identified, the region of interest was saturated with additional markers and the males were added to the analysis. Candidate genes were sequenced. Ten females showed skewed inactivation, while six revealed a normal inactivation pattern. A maximal lod score of 5.54 at ??=?0.00 was obtained with the marker DXS10151. Recombination events mapped the disease gene to a 17.4-Mb interval between the markers DXS10153 and DXS10157. Three candidate genes in the region were sequenced and a previously described missense mutation (P375L) was identified in the ACSL4/FACL4 gene. On the basis of the female X inactivation status, we have mapped and identified the causative mutation in a gene causing non-syndromic X-linked mental retardation. PMID:21584729

Yonath, Hagith; Marek-Yagel, Dina; Resnik-Wolf, Haike; Abu-Horvitz, Almogit; Baris, Hagit N; Shohat, Mordechai; Frydman, Moshe; Pras, Elon

2011-05-17

171

Proteomic analysis of age-dependent changes in protein solubility identifies genes that modulate lifespan  

PubMed Central

While it is generally recognized that misfolding of specific proteins can cause late-onset disease, the contribution of protein aggregation to the normal aging process is less well understood. To address this issue, a mass spectrometry-based proteomic analysis was performed to identify proteins that adopt sodium dodecyl sulfate (SDS)-insoluble conformations during aging in Caenorhabditis elegans. SDS-insoluble proteins extracted from young and aged C. elegans were chemically labeled by isobaric tagging for relative and absolute quantification (iTRAQ) and identified by liquid chromatography and mass spectrometry. Two hundred and three proteins were identified as being significantly enriched in an SDS-insoluble fraction in aged nematodes and were largely absent from a similar protein fraction in young nematodes. The SDS-insoluble fraction in aged animals contains a diverse range of proteins including a large number of ribosomal proteins. Gene ontology analysis revealed highly significant enrichments for energy production and translation functions. Expression of genes encoding insoluble proteins observed in aged nematodes was knocked down using RNAi, and effects on lifespan were measured. 41% of genes tested were shown to extend lifespan after RNAi treatment, compared with 18% in a control group of genes. These data indicate that genes encoding proteins that become insoluble with age are enriched for modifiers of lifespan. This demonstrates that proteomic approaches can be used to identify genes that modify lifespan. Finally, these observations indicate that the accumulation of insoluble proteins with diverse functions may be a general feature of aging.

Reis-Rodrigues, Pedro; Czerwieniec, Gregg; Peters, Theodore W; Evani, Uday S; Alavez, Silvestre; Gaman, Emily A; Vantipalli, Maithili; Mooney, Sean D; Gibson, Bradford W; Lithgow, Gordon J; Hughes, Robert E

2012-01-01

172

Improved human disease candidate gene prioritization using mouse phenotype  

Microsoft Academic Search

Background: The majority of common diseases are multi-factorial and modified by genetically and mechanistically complex polygenic interactions and environmental factors. High-throughput genome-wide studies like linkage analysis and gene expression profiling, tend to be most useful for classification and characterization but do not provide sufficient information to identify or prioritize specific disease causal genes. Results: Extending on an earlier hypothesis that

Jing Chen; Huan Xu; Bruce J. Aronow; Anil G. Jegga

2007-01-01

173

Identifying gene-specific variations in biomedical text.  

PubMed

The influence of genetic variations on diseases or cellular processes is the main focus of many investigations, and results of biomedical studies are often only accessible through scientific publications. Automatic extraction of this information requires recognition of the gene names and the accompanying allelic variant information. In a previous work, the OSIRIS system for the detection of allelic variation in text based on a query expansion approach was communicated. Challenges associated with this system are the relatively low recall for variation mentions and gene name recognition. To tackle this challenge, we integrate the ProMiner system developed for the recognition and normalization of gene and protein names with a conditional random field (CRF)-based recognition of variation terms in biomedical text. Following the newly developed normalization of variation entities, we can link textual entities to Single Nucleotide Polymorphism database (dbSNP) entries. The performance of this novel approach is evaluated, and improved results in comparison to state-of-the-art systems are reported. PMID:18172929

Klinger, Roman; Friedrich, Christoph M; Mevissen, Heinz Theodor; Fluck, Juliane; Hofmann-Apitius, Martin; Furlong, Laura I; Sanz, Ferran

2007-12-01

174

Gene-Environment Interactions in Human Disease: Nuisance or Opportunity?  

PubMed Central

Many environmental risk factors for common, complex human diseases have been revealed by epidemiologic studies, but how genotypes at specific loci modulate individual responses to environmental risk factors is largely unknown. Gene-environment interactions will be missed in genome-wide association studies and may account for some of the ‘missing heritability’ for these diseases. In this review, we focus on asthma as a model disease for studying gene-environment interactions because of relatively large numbers of candidate gene-environment interactions with asthma risk in the literature. Identifying these interactions using genome-wide approaches poses formidable methodological problems and elucidating molecular mechanisms for these interactions has been challenging. We suggest that studying gene-environment interactions in animal models, while more tractable, is not likely to shed light on the genetic architecture of human diseases. Lastly, we propose avenues for future studies to find gene-environment interactions.

Ober, Carole; Vercelli, Donata

2010-01-01

175

The Use of Gene-Expression Profiling to Identify Candidate Genes In Human Sepsis  

Microsoft Academic Search

Rationale: Our understanding of the pathophysiology of sepsis re- mains incomplete. Genomewide study offers an unbiased, system biology approach to examine the expression patterns of circulating leukocytes and may reveal novel insights into the host response to sepsis. Objectives: We examined whether gene-expression profiling of neu- trophils could identify signature genes and important pathways in the clinical syndrome of sepsis.

Benjamin MP Tang; Anthony S McLean; Ian W Dawes; Stephen J Huang; Ruby CY Lin

2007-01-01

176

A stochastic model for identifying differential gene pair co-expression patterns in prostate cancer progression  

PubMed Central

Background The identification of gene differential co-expression patterns between cancer stages is a newly developing method to reveal the underlying molecular mechanisms of carcinogenesis. Most researches of this subject lack an algorithm useful for performing a statistical significance assessment involving cancer progression. Lacking this specific algorithm is apparently absent in identifying precise gene pairs correlating to cancer progression. Results In this investigation we studied gene pair co-expression change by using a stochastic process model for approximating the underlying dynamic procedure of the co-expression change during cancer progression. Also, we presented a novel analytical method named 'Stochastic process model for Identifying differentially co-expressed Gene pair' (SIG method). This method has been applied to two well known prostate cancer data sets: hormone sensitive versus hormone resistant, and healthy versus cancerous. From these data sets, 428,582 gene pairs and 303,992 gene pairs were identified respectively. Afterwards, we used two different current statistical methods to the same data sets, which were developed to identify gene pair differential co-expression and did not consider cancer progression in algorithm. We then compared these results from three different perspectives: progression analysis, gene pair identification effectiveness analysis, and pathway enrichment analysis. Statistical methods were used to quantify the quality and performance of these different perspectives. They included: Re-identification Scale (RS) and Progression Score (PS) in progression analysis, True Positive Rate (TPR) in gene pair analysis, and Pathway Enrichment Score (PES) in pathway analysis. Our results show small values of RS and large values of PS, TPR, and PES; thus, suggesting that gene pairs identified by the SIG method are highly correlated with cancer progression, and highly enriched in disease-specific pathways. From this research, several gene interaction networks inferred could provide clues for the mechanism of prostate cancer progression. Conclusion The SIG method reliably identifies cancer progression correlated gene pairs, and performs well both in gene pair ontology analysis and in pathway enrichment analysis. This method provides an effective means of understanding the molecular mechanism of carcinogenesis by appropriately tracking down the process of cancer progression.

Mo, Wen Juan; Fu, Xu Ping; Han, Xiao Tian; Yang, Guang Yuan; Zhang, Ji Gang; Guo, Feng Hua; Huang, Yan; Mao, Yu Min; Li, Yao; Xie, Yi

2009-01-01

177

Gene therapy for ischemic heart disease  

Microsoft Academic Search

Current pharmacologic therapy for ischemic heart disease suffers multiple limitations such as compliance issues and side effects of medications. Revascularization procedures often end with need for repeat procedures. Patients remain symptomatic despite maximal medical therapy. Gene therapy offers an attractive alternative to current pharmacologic therapies and may be beneficial in refractory disease. Gene therapy with isoforms of growth factors such

Madhav Lavu; Susheel Gundewar; David J. Lefer

2011-01-01

178

An Integrative Genetics Approach to Identify Candidate Genes Regulating BMD: Combining Linkage, Gene Expression, and Association  

PubMed Central

Numerous quantitative trait loci (QTLs) affecting bone traits have been identified in the mouse; however, few of the underlying genes have been discovered. To improve the process of transitioning from QTL to gene, we describe an integrative genetics approach, which combines linkage analysis, expression QTL (eQTL) mapping, causality modeling, and genetic association in outbred mice. In C57BL/6J × C3H/HeJ (BXH) F2 mice, nine QTLs regulating femoral BMD were identified. To select candidate genes from within each QTL region, microarray gene expression profiles from individual F2 mice were used to identify 148 genes whose expression was correlated with BMD and regulated by local eQTLs. Many of the genes that were the most highly correlated with BMD have been previously shown to modulate bone mass or skeletal development. Candidates were further prioritized by determining whether their expression was predicted to underlie variation in BMD. Using network edge orienting (NEO), a causality modeling algorithm, 18 of the 148 candidates were predicted to be causally related to differences in BMD. To fine-map QTLs, markers in outbred MF1 mice were tested for association with BMD. Three chromosome 11 SNPs were identified that were associated with BMD within the Bmd11 QTL. Finally, our approach provides strong support for Wnt9a, Rasd1, or both underlying Bmd11. Integration of multiple genetic and genomic data sets can substantially improve the efficiency of QTL fine-mapping and candidate gene identification.

Farber, Charles R; van Nas, Atila; Ghazalpour, Anatole; Aten, Jason E; Doss, Sudheer; Sos, Brandon; Schadt, Eric E; Ingram-Drake, Leslie; Davis, Richard C; Horvath, Steve; Smith, Desmond J; Drake, Thomas A; Lusis, Aldons J

2009-01-01

179

Transcriptional Profile Analysis of RPGRORF15 Frameshift Mutation Identifies Novel Genes Associated with Retinal Degeneration  

PubMed Central

Purpose. To identify genes and molecular mechanisms associated with photoreceptor degeneration in a canine model of XLRP caused by an RPGR exon ORF15 microdeletion. Methods. Expression profiles of mutant and normal retinas were compared by using canine retinal custom cDNA microarrays. qRT-PCR, Western blot analysis, and immunohistochemistry (IHC) were applied to selected genes, to confirm and expand the microarray results. Results. At 7 and 16 weeks, respectively, 56 and 18 transcripts were downregulated in the mutant retinas, but none were differentially expressed (DE) at both ages, suggesting the involvement of temporally distinct pathways. Downregulated genes included the known retina-relevant genes PAX6, CHML, and RDH11 at 7 weeks and CRX and SAG at 16 weeks. Genes directly or indirectly active in apoptotic processes were altered at 7 weeks (CAMK2G, NTRK2, PRKCB, RALA, RBBP6, RNF41, SMYD3, SPP1, and TUBB2C) and 16 weeks (SLC25A5 and NKAP). Furthermore, the DE genes at 7 weeks (ELOVL6, GLOD4, NDUFS4, and REEP1) and 16 weeks (SLC25A5 and TARS2) are related to mitochondrial functions. qRT-PCR of 18 genes confirmed the microarray results and showed DE of additional genes not on the array. Only GFAP was DE at 3 weeks of age. Western blot and IHC analyses also confirmed the high reliability of the transcriptomic data. Conclusions. Several DE genes were identified in mutant retinas. At 7 weeks, a combination of nonclassic anti- and proapoptosis genes appear to be involved in photoreceptor degeneration, whereas at both 7 and 16 weeks, the expression of mitochondria-related genes indicates that they may play a relevant role in the disease process.

Genini, Sem; Zangerl, Barbara; Slavik, Julianna; Acland, Gregory M.; Beltran, William A.

2010-01-01

180

Finding Cardiovascular Disease Genes in the Dog  

PubMed Central

Recent advances in canine genomics are changing the landscape of veterinary biology, and by default, veterinary medicine. No longer are clinicians locked into traditional methods of diagnoses and therapy. Rather major advances in canine genetics and genomics from the past five years are now changing the way the veterinarian of the 21st century practices medicine. First, the availability of a dense genome map gives canine genetics a much needed foothold in comparative medicine, allowing advances made in human and mouse genetics to be applied to companion animals. Second, the recently released 7.5x whole genome sequence of the dog is facilitating the identification of hereditary disease genes. Finally, development of genetic tools for rapid screening of families and populations at risk for inherited disease means that the cost of identifying and testing for disease loci will significantly decrease in coming years. Out of these advances will come major changes in companion animal diagnostics and therapy. Clinicians will be able to offer their clients genetic testing and counseling for a myriad of disorders. Such advances are certain to generate healthier and more long lived dogs, improving quality of life for owner and pet alike. The clinician of the 21st century, therefore, faces incredible opportunities as well as challenges in the management of genetic disease. In this review we summarize recent findings in canine genomics and discuss their application to the study of canine cardiac health.

Parker, Heidi G.; Meurs, Kathryn M.; Ostrander, Elaine A.

2013-01-01

181

Gene therapy for childhood immunological diseases  

Microsoft Academic Search

Gene therapy using autologous hematopoietic stem cells (HSC) that are corrected with the normal gene may have a beneficial effect on blood cell production or function, without the immunologic complications of allogeneic HSC transplantation. Childhood immunological diseases are highly favorable candidates for responses to gene therapy using HSC. Hemoglobinopathies, lysosomal and metabolic disorders and defects of hematopoietic stem and progenitor

D B Kohn

2008-01-01

182

Gene Therapy for Chronic Granulomatous Disease  

Microsoft Academic Search

Identification of gene mutations responsible for leukocyte dysfunction along with the application of gene transfer technology has made genetic correction of such disorders possible. Much of the research into molecular therapy for inherited disorders of phagocytes has been focused on chronic granulomatous disease (CGD). CGD results from mutations in any one of the four genes encoding essential subunits of respiratory

W. Scott Goebel; Mary C. Dinauer

2003-01-01

183

Identifying gene functions using functional expression profiles obtained by voxelation  

Microsoft Academic Search

Gene expression profiles have been widely used in functional genomic studies. However, not much work in traditional gene expression profiling takes into account the location information of a gene's expressions in the brain. Gene expression maps, which contain spatial information regarding the expression of genes in mice's brain, are obtained by combining voxelation and microarrays. Based on the idea that

Li An; Desmond J. Smith; Hongbo Xie; Vasileios Megalooikonomou; Zoran Obradovic

2010-01-01

184

Diametrical clustering for identifying anti-correlated gene clusters  

Microsoft Academic Search

Motivation: Clustering genes based upon their expres- sion patterns allows us to predict gene function. Most existing clus- tering algorithms cluster genes together when their expression pat- terns show high positive correlation. However, it has been observed that genes whose expression patterns are strongly anti-correlated can also be functionally similar. Biologically, this is not unintuitive ó genes responding to the

Inderjit S. Dhillon; Edward M. Marcotte; Usman Roshan

2003-01-01

185

Identifying overrepresented concepts in gene lists from literature: a statistical approach based on Poisson mixture model  

Microsoft Academic Search

BACKGROUND: Large-scale genomic studies often identify large gene lists, for example, the genes sharing the same expression patterns. The interpretation of these gene lists is generally achieved by extracting concepts overrepresented in the gene lists. This analysis often depends on manual annotation of genes based on controlled vocabularies, in particular, Gene Ontology (GO). However, the annotation of genes is a

Xin He; Moushumi Sen Sarma; Xu Ling; Brant W. Chee; Chengxiang Zhai; Bruce R. Schatz

2010-01-01

186

Microarray Analysis of Pneumococcal Gene Expression during Invasive Disease  

PubMed Central

Streptococcus pneumoniae is a leading cause of invasive bacterial disease. This is the first study to examine the expression of S. pneumoniae genes in vivo by using whole-genome microarrays available from The Institute for Genomic Research. Total RNA was collected from pneumococci isolated from infected blood, infected cerebrospinal fluid, and bacteria attached to a pharyngeal epithelial cell line in vitro. Microarray analysis of pneumococcal genes expressed in these models identified body site-specific patterns of expression for virulence factors, transporters, transcription factors, translation-associated proteins, metabolism, and genes with unknown function. Contributions to virulence predicted for several unknown genes with enhanced expression in vivo were confirmed by insertion duplication mutagenesis and challenge of mice with the mutants. Finally, we cross-referenced our results with previous studies that used signature-tagged mutagenesis and differential fluorescence induction to identify genes that are potentially required by a broad range of pneumococcal strains for invasive disease.

Orihuela, Carlos J.; Radin, Jana N.; Sublett, Jack E.; Gao, Geli; Kaushal, Deepak; Tuomanen, Elaine I.

2004-01-01

187

Recent gene therapy advancements for neurological diseases.  

PubMed

The past few years have seen rapid advancements in vector-mediated gene transfer to the nervous system and modest successes in human gene therapy trials. The purpose of this review is to describe commonly-used viral gene transfer vectors and recent advancements towards producing meaningful gene-based treatments for central nervous system (CNS) disorders. Gene therapy trials for Canavan disease, Batten disease, adrenoleukodystrophy, and Parkinson's disease are discussed to illustrate the current state of clinical gene transfer to the CNS. Preclinical studies are under way for a number of diseases, primarily lysosomal storage disorders, using a newer generation of vectors and delivery strategies. Relevant studies in animal models are highlighted for Mucopolysaccharidosis IIIB and Krabbe disease to provide a prelude for what can be expected in the coming years for human gene transfer trials, using recent advancements in gene transfer technology. In conclusion, recent improvements in CNS gene transfer technology are expected to significantly increase the degree of disease rescue in future CNS-directed clinical trials, exceeding the modest clinical successes that have been observed so far. PMID:23449113

Nagabhushan Kalburgi, Sahana; Khan, Nadia N; Gray, Steven J

2013-02-01

188

SPRIT: Identifying horizontal gene transfer in rooted phylogenetic trees  

PubMed Central

Background Phylogenetic trees based on sequences from a set of taxa can be incongruent due to horizontal gene transfer (HGT). By identifying the HGT events, we can reconcile the gene trees and derive a taxon tree that adequately represents the species' evolutionary history. One HGT can be represented by a rooted Subtree Prune and Regraft (RSPR) operation and the number of RSPRs separating two trees corresponds to the minimum number of HGT events. Identifying the minimum number of RSPRs separating two trees is NP-hard, but the problem can be reduced to fixed parameter tractable. A number of heuristic and two exact approaches to identifying the minimum number of RSPRs have been proposed. This is the first implementation delivering an exact solution as well as the intermediate trees connecting the input trees. Results We present the SPR Identification Tool (SPRIT), a novel algorithm that solves the fixed parameter tractable minimum RSPR problem and its GPL licensed Java implementation. The algorithm can be used in two ways, exhaustive search that guarantees the minimum RSPR distance and a heuristic approach that guarantees finding a solution, but not necessarily the minimum one. We benchmarked SPRIT against other software in two different settings, small to medium sized trees i.e. five to one hundred taxa and large trees i.e. thousands of taxa. In the small to medium tree size setting with random artificial incongruence, SPRIT's heuristic mode outperforms the other software by always delivering a solution with a low overestimation of the RSPR distance. In the large tree setting SPRIT compares well to the alternatives when benchmarked on finding a minimum solution within a reasonable time. SPRIT presents both the minimum RSPR distance and the intermediate trees. Conclusions When used in exhaustive search mode, SPRIT identifies the minimum number of RSPRs needed to reconcile two incongruent rooted trees. SPRIT also performs quick approximations of the minimum RSPR distance, which are comparable to, and often better than, purely heuristic solutions. Put together, SPRIT is an excellent tool for identification of HGT events and pinpointing which taxa have been involved in HGT.

2010-01-01

189

Republished review: Gene therapy for ocular diseases  

PubMed Central

The eye is an easily accessible, highly compartmentalised and immune-privileged organ that offers unique advantages as a gene therapy target. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been implicated as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of-concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis. This review describes current developments and future prospects for ocular gene therapy. Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirus-mediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future.

Liu, Melissa M; Tuo, Jingsheng; Chan, Chi-Chao

2011-01-01

190

Transposon tagging of disease resistance genes  

SciTech Connect

We are developing a transposon mutagenesis system for lettuce to clone genes for resistance to the fungal pathogen, Bremia lactucae. Activity of heterologous transposons is being studied in transgenic plants. Southern analysis of T{sub 1} and T{sub 2} plants containing Tam3 from Antirrhinum provided ambiguous results. Multiple endonuclease digests indicated that transposition had occurred; however, in no plant were all endonuclease digests consistent with a simple excision event. Southern or PCR analysis of over 50 plans containing Ac from maize have also failed to reveal clear evidence of transposition; this is contrast to experiments by others with the same constructs who have observed high rates of Ac excision in other plant species. Nearly all of 65 T{sub 2} families containing Ac interrupting a chimeric streptomycin resistance gene (Courtesy J. Jones, Sainsbury Lab., UK) clearly segregated for streptomycin resistance. Southern analyses, however, showed no evidence of transposition, indicating restoration of a functional message by other mechanisms, possibly mRNA processing. Transgenic plants have also been generated containing CaMV 35S or hsp70 promoters fused to transposase coding sequences or a Ds element interrupting a chimeric GUS gene (Courtesy M. Lassner, UC Davis). F{sub 1} plants containing both constructs were analyzed for transposition. Only two plants containing both constructs were obtained from 48 progeny, far fewer than expected, and neither showed evidence of transposition in Southerns and GUS assays. We are currently constructing further chimeric transposase fusions. To test for the stability of the targeted disease resistance genes, 50,000 F{sub 1} plants heterozygous for three resistance genes were generated; no mutants have been identified in the 5000 so far screened.

Michelmore, R.W. (California Univ., Davis, CA (USA). Dept. of Physics)

1989-01-01

191

Gene expression studies in cells from primary ciliary dyskinesia patients identify 208 potential ciliary genes  

Microsoft Academic Search

Cilia are small cellular projections that either act as sensors (primary cilia) or propel fluid over the epithelia of various\\u000a organs (motile cilia). The organellum has gained much attention lately because of its involvement in a group of human diseases\\u000a called ciliopathies. Primary ciliary dyskinesia (PCD) is an autosomal recessive ciliopathy caused by mutations in cilia motility\\u000a genes. The disease

Maciej Geremek; Marcel Bruinenberg; Ewa Zi?tkiewicz; Andrzej Pogorzelski; Micha? Witt; Cisca Wijmenga

2011-01-01

192

Assessment of gene order computing methods for Alzheimer's disease  

PubMed Central

Background Computational genomics of Alzheimer disease (AD), the most common form of senile dementia, is a nascent field in AD research. The field includes AD gene clustering by computing gene order which generates higher quality gene clustering patterns than most other clustering methods. However, there are few available gene order computing methods such as Genetic Algorithm (GA) and Ant Colony Optimization (ACO). Further, their performance in gene order computation using AD microarray data is not known. We thus set forth to evaluate the performances of current gene order computing methods with different distance formulas, and to identify additional features associated with gene order computation. Methods Using different distance formulas- Pearson distance and Euclidean distance, the squared Euclidean distance, and other conditions, gene orders were calculated by ACO and GA (including standard GA and improved GA) methods, respectively. The qualities of the gene orders were compared, and new features from the calculated gene orders were identified. Results Compared to the GA methods tested in this study, ACO fits the AD microarray data the best when calculating gene order. In addition, the following features were revealed: different distance formulas generated a different quality of gene order, and the commonly used Pearson distance was not the best distance formula when used with both GA and ACO methods for AD microarray data. Conclusion Compared with Pearson distance and Euclidean distance, the squared Euclidean distance generated the best quality gene order computed by GA and ACO methods.

2013-01-01

193

Identifying novel genes for atherosclerosis through mouse-human comparative genetics.  

PubMed

Susceptibility to atherosclerosis is determined by both environmental and genetic factors. Its genetic determinants have been studied by use of quantitative-trait-locus (QTL) analysis. So far, 21 atherosclerosis QTLs have been identified in the mouse: 7 in a high-fat-diet model only, 9 in a sensitized model (apolipoprotein E- or LDL [low-density lipoprotein] receptor-deficient mice) only, and 5 in both models, suggesting that different gene sets operate in each model and that a subset operates in both. Among the 27 human atherosclerosis QTLs reported, 17 (63%) are located in regions homologous (concordant) to mouse QTLs, suggesting that these mouse and human atherosclerosis QTLs have the same underlying genes. Therefore, genes regulating human atherosclerosis will be found most efficiently by first finding their orthologs in concordant mouse QTLs. Novel mouse QTL genes will be found most efficiently by using a combination of the following strategies: identifying QTLs in new crosses performed with previously unused parental strains; inducing mutations in large-scale, high-throughput mutagenesis screens; and using new genomic and bioinformatics tools. Once QTL genes are identified in mice, they can be tested in human association studies for their relevance in human atherosclerotic disease. PMID:15931593

Wang, Xiaosong; Ishimori, Naoki; Korstanje, Ron; Rollins, Jarod; Paigen, Beverly

2005-05-19

194

Identifying Novel Genes for Atherosclerosis through Mouse-Human Comparative Genetics  

PubMed Central

Susceptibility to atherosclerosis is determined by both environmental and genetic factors. Its genetic determinants have been studied by use of quantitative-trait–locus (QTL) analysis. So far, 21 atherosclerosis QTLs have been identified in the mouse: 7 in a high-fat–diet model only, 9 in a sensitized model (apolipoprotein E– or LDL [low-density lipoprotein] receptor–deficient mice) only, and 5 in both models, suggesting that different gene sets operate in each model and that a subset operates in both. Among the 27 human atherosclerosis QTLs reported, 17 (63%) are located in regions homologous (concordant) to mouse QTLs, suggesting that these mouse and human atherosclerosis QTLs have the same underlying genes. Therefore, genes regulating human atherosclerosis will be found most efficiently by first finding their orthologs in concordant mouse QTLs. Novel mouse QTL genes will be found most efficiently by using a combination of the following strategies: identifying QTLs in new crosses performed with previously unused parental strains; inducing mutations in large-scale, high-throughput mutagenesis screens; and using new genomic and bioinformatics tools. Once QTL genes are identified in mice, they can be tested in human association studies for their relevance in human atherosclerotic disease.

Wang, Xiaosong; Ishimori, Naoki; Korstanje, Ron; Rollins, Jarod; Paigen, Beverly

2005-01-01

195

Gene expression profiling of breast cell lines identifies potential new basal markers.  

PubMed

A better molecular characterization of breast cell lines (BCL) may help discover new markers to apply to tumour samples. We performed gene and protein expression profiling of 31 BCL using whole-genome DNA microarrays and immunohistochemistry (IHC) on 'cell microarrays' (CMA), respectively. Global hierarchical clustering discriminated two groups of BCL: group I corresponded to luminal cell lines, group II to basal and mesenchymal cell lines. Correlations with centroids calculated from a published 'intrinsic 500-gene set' assigned 15 cell lines as luminal, eight as basal and four as mesenchymal. A set of 1.233 genes was differentially expressed between basal and luminal samples. Mesenchymal and basal subtypes were rather similar and discriminated by only 227 genes. The expression of 10 proteins (CAV1, CD44, EGFR, MET, ETS1, GATA3, luminal cytokeratin CK19, basal cytokeratin CK5/6, CD10, and ERM protein moesin) encoded by luminal vs basal discriminator genes confirmed the subtype classification and the validity of the identified markers. Our BCL basal/luminal signature correctly re-classified the published series of tumour samples that originally served to identify the molecular subtypes, suggesting that the identified markers should be useful for tumour classification and might represent promising targets for disease management. PMID:16288205

Charafe-Jauffret, E; Ginestier, C; Monville, F; Finetti, P; Adélaïde, J; Cervera, N; Fekairi, S; Xerri, L; Jacquemier, J; Birnbaum, D; Bertucci, F

2006-04-01

196

Match/X, A gene expression pattern recognition algorithm used to identify genes which may be related to CDC2 function and cell cycle regulation.  

PubMed

Large-scale microarray gene expression studies can provide insight into complex genetic networks and biological pathways. A comprehensive gene expression database was constructed using Affymetrix GeneChip microarrays and RNA isolated from more than 6,400 distinct normal and diseased human tissues. These individual patient samples were grouped into over 700 sample sets based on common tissue and disease morphologies, and each set contained averaged expression data for over 45,000 gene probe sets representing more than 33,000 known human genes. Sample sets were compared to each other in more than 750 normal vs. disease pairwise comparisons. Relative up or downregulation patterns of genes across these pairwise comparisons provided unique expression fingerprints that could be compared and matched to a gene of interest using the Match/X trade mark algorithm. This algorithm uses the kappa statistic to compute correlations between genes and calculate a distance score between a gene of interest and all other genes in the database. Using cdc2 as a query gene, we identified several hundred genes that had similar expression patterns and highly correlated distance scores. Most of these genes were known components of the cell cycle involved in G2/M progression, spindle function or chromosome arrangement. Some of the identified genes had unknown biological functions but may be related to cdc2 mediated mechanism based on their closely correlated distance scores. This algorithm may provide novel insights into unknown gene function based on correlation to expression profiles of known genes and can identify elements of cellular pathways and gene interactions in a high throughput fashion. PMID:15136762

Coberley, Carter; Elashoff, Michael; Mertz, Lawrence

2004-06-02

197

Associations between human disease genes and overlapping gene groups and multiple amino acid runs  

PubMed Central

Overlapping gene groups (OGGs) arise when exons of one gene are contained within the introns of another. Typically, the two overlapping genes are encoded on opposite DNA strands. OGGs are often associated with specific disease phenotypes. In this report, we identify genes with OGG architecture and genes encoding multiple long amino acid runs and examine their relations to diseases. OGGs appear to be susceptible to genomic rearrangements as happens commonly with the loci of the DiGeorge syndrome on human chromosome 22. We also examine the degree of conservation of OGGs between human and mouse. Our analyses suggest that (i) a high proportion of genes in OGG regions are disease-associated, (ii) genomic rearrangements are likely to occur within OGGs, possibly as a consequence of anomalous sequence features prevalent in these regions, and (iii) multiple amino acid runs are also frequently associated with pathologies.

Karlin, Samuel; Chen, Chingfer; Gentles, Andrew J.; Cleary, Michael

2002-01-01

198

Gene expression endophenotypes: a novel approach for gene discovery in Alzheimer's disease  

PubMed Central

Uncovering the underlying genetic component of any disease is key to the understanding of its pathophysiology and may open new avenues for development of therapeutic strategies and biomarkers. In the past several years, there has been an explosion of genome-wide association studies (GWAS) resulting in the discovery of novel candidate genes conferring risk for complex diseases, including neurodegenerative diseases. Despite this success, there still remains a substantial genetic component for many complex traits and conditions that is unexplained by the GWAS findings. Additionally, in many cases, the mechanism of action of the newly discovered disease risk variants is not inherently obvious. Furthermore, a genetic region with multiple genes may be identified via GWAS, making it difficult to discern the true disease risk gene. Several alternative approaches are proposed to overcome these potential shortcomings of GWAS, including the use of quantitative, biologically relevant phenotypes. Gene expression levels represent an important class of endophenotypes. Genetic linkage and association studies that utilize gene expression levels as endophenotypes determined that the expression levels of many genes are under genetic influence. This led to the postulate that there may exist many genetic variants that confer disease risk via modifying gene expression levels. Results from the handful of genetic studies which assess gene expression level endophenotypes in conjunction with disease risk suggest that this combined phenotype approach may both increase the power for gene discovery and lead to an enhanced understanding of their mode of action. This review summarizes the evidence in support of gene expression levels as promising endophenotypes in the discovery and characterization of novel candidate genes for complex diseases, which may also represent a novel approach in the genetic studies of Alzheimer's and other neurodegenerative diseases.

2011-01-01

199

Fox Chase researchers identify a gene that predicts recurrence in squamous cell carcinoma of the head and neck  

Cancer.gov

Fox Chase Cancer Center researchers have identified a gene that predicts disease recurrence in individuals with squamous cell carcinoma of the head and neck. The new findings, presented at the American Association for Cancer Research Annual Meeting 2012 on Monday, April 2, show that patients with one common variant of a gene which encodes the cytochrome P450 (CYP1B1) protein are likely to have a longer time-to-recurrence than those with the more typical form of the gene.

200

Brain Expression Genome-Wide Association Study (eGWAS) Identifies Human Disease-Associated Variants  

PubMed Central

Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n?=?197, temporal cortex n?=?202) and with other brain pathologies (non–AD, cerebellar n?=?177, temporal cortex n?=?197). We conducted an expression genome-wide association study (eGWAS) using 213,528 cisSNPs within ±100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs) significant in both ADs and non–ADs (q<0.05, p?=?7.70×10?5–1.67×10?82). Of these, 2,089 were also significant in the temporal cortex (p?=?1.85×10?5–1.70×10?141). The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10?6). We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD) MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9–3.3 fold enrichment (p<10?6) of significant cisSNPs with suggestive AD–risk association (p<10?3) in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS) and non–CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings have implications for the design and interpretation of eGWAS in general and the use of brain expression quantitative trait loci in the study of human disease genetics.

Crook, Julia; Pankratz, V. Shane; Carrasquillo, Minerva M.; Rowley, Christopher N.; Nair, Asha A.; Middha, Sumit; Maharjan, Sooraj; Nguyen, Thuy; Ma, Li; Malphrus, Kimberly G.; Palusak, Ryan; Lincoln, Sarah; Bisceglio, Gina; Georgescu, Constantin; Kouri, Naomi; Kolbert, Christopher P.; Jen, Jin; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Schellenberg, Gerard D.; Petersen, Ronald C.; Graff-Radford, Neill R.; Dickson, Dennis W.; Younkin, Steven G.; Ertekin-Taner, Nilufer

2012-01-01

201

A probabilistic disease-gene finder for personal genomes  

PubMed Central

VAAST (the Variant Annotation, Analysis & Search Tool) is a probabilistic search tool for identifying damaged genes and their disease-causing variants in personal genome sequences. VAAST builds on existing amino acid substitution (AAS) and aggregative approaches to variant prioritization, combining elements of both into a single unified likelihood framework that allows users to identify damaged genes and deleterious variants with greater accuracy, and in an easy-to-use fashion. VAAST can score both coding and noncoding variants, evaluating the cumulative impact of both types of variants simultaneously. VAAST can identify rare variants causing rare genetic diseases, and it can also use both rare and common variants to identify genes responsible for common diseases. VAAST thus has a much greater scope of use than any existing methodology. Here we demonstrate its ability to identify damaged genes using small cohorts (n = 3) of unrelated individuals, wherein no two share the same deleterious variants, and for common, multigenic diseases using as few as 150 cases.

Yandell, Mark; Huff, Chad; Hu, Hao; Singleton, Marc; Moore, Barry; Xing, Jinchuan; Jorde, Lynn B.; Reese, Martin G.

2011-01-01

202

Genetic Mapping and Exome Sequencing Identify Variants Associated with Five Novel Diseases  

PubMed Central

The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean?=?4.4 Mb) that contain many genes (mean?=?79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.

Puffenberger, Erik G.; Jinks, Robert N.; Sougnez, Carrie; Cibulskis, Kristian; Willert, Rebecca A.; Achilly, Nathan P.; Cassidy, Ryan P.; Fiorentini, Christopher J.; Heiken, Kory F.; Lawrence, Johnny J.; Mahoney, Molly H.; Miller, Christopher J.; Nair, Devika T.; Politi, Kristin A.; Worcester, Kimberly N.; Setton, Roni A.; DiPiazza, Rosa; Sherman, Eric A.; Eastman, James T.; Francklyn, Christopher; Robey-Bond, Susan; Rider, Nicholas L.; Gabriel, Stacey; Morton, D. Holmes; Strauss, Kevin A.

2012-01-01

203

Genetic mapping and exome sequencing identify variants associated with five novel diseases.  

PubMed

The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean?=?4.4 Mb) that contain many genes (mean?=?79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data. PMID:22279524

Puffenberger, Erik G; Jinks, Robert N; Sougnez, Carrie; Cibulskis, Kristian; Willert, Rebecca A; Achilly, Nathan P; Cassidy, Ryan P; Fiorentini, Christopher J; Heiken, Kory F; Lawrence, Johnny J; Mahoney, Molly H; Miller, Christopher J; Nair, Devika T; Politi, Kristin A; Worcester, Kimberly N; Setton, Roni A; Dipiazza, Rosa; Sherman, Eric A; Eastman, James T; Francklyn, Christopher; Robey-Bond, Susan; Rider, Nicholas L; Gabriel, Stacey; Morton, D Holmes; Strauss, Kevin A

2012-01-17

204

Combined linkage analysis and exome sequencing identifies novel genes for familial goiter.  

PubMed

Familial goiter is a genetic disease showing heterogeneous expression. To identify causative genes, we investigated three multigenerational goiter families with an autosomal dominant inheritance pattern. We performed genome-wide linkage analysis on all the families, combined with whole-exome sequencing in two affected individuals from each family. For linkage analysis, we considered loci with logarithm of odds (LOD) scores >1.5 as candidate regions for identification of rare variants. In one of the families, we found two rare heterozygous missense variants, p.V56M in RGS12 and p.G37D in GRPEL1, which segregate with goiter and are both located within the same haplotype on 4p16. This haplotype was not observed in 150 controls. In the other two families, we identified two additional rare missense variants segregating with goiter, p.A551T in CLIC6 on 21q22.12 and p.V412A in WFS1 on 4p16. In controls, the minor allele frequency (MAF) of p.V412A in WFS1 was 0.017 while p.A551T in CLIC6 was not detected. All identified genes (RGS12, GRPEL1, CLIC6 and WFS1) show expression in the human thyroid gland, suggesting that they may play a role in thyroid gland function. Moreover, these four genes are novel with regard to their involvement in familial goiter, supporting genetic heterogeneity of this disease. PMID:23535966

Yan, Junxia; Takahashi, Tsutomu; Ohura, Toshihiro; Adachi, Hiroyuki; Takahashi, Ikuko; Ogawa, Eishin; Okuda, Hiroko; Kobayashi, Hatasu; Hitomi, Toshiaki; Liu, Wanyang; Harada, Kouji H; Koizumi, Akio

2013-03-28

205

Hippocampal Gene Expression Meta-Analysis Identifies Aging and Age-Associated Spatial Learning Impairment (ASLI) Genes and Pathways  

PubMed Central

A number of gene expression microarray studies have been carried out in the past, which studied aging and age-associated spatial learning impairment (ASLI) in the hippocampus in animal models, with varying results. Data from such studies were never integrated to identify the most significant ASLI genes and to understand their effect. In this study we integrated these data involving rats using meta-analysis. Our results show that proper removal of batch effects from microarray data generated from different laboratories is necessary before integrating them for meta-analysis. Our meta-analysis has identified a number of significant differentially expressed genes across age or across ASLI. These genes affect many key functions in the aged compared to the young rats, which include viability of neurons, cell-to-cell signalling and interaction, migration of cells, neuronal growth, and synaptic plasticity. These functional changes due to the altered gene expression may manifest into various neurodegenerative diseases and disorders, some of which leading into syndromic memory impairments. While other aging related molecular changes can result into altered synaptic plasticity simply causing normal aging related non-syndromic learning or spatial learning impairments such as ASLI.

Uddin, Raihan K.; Singh, Shiva M.

2013-01-01

206

Functional classification of interferon-stimulated genes identified using microarrays  

Microsoft Academic Search

Interferons (IFNs) are a family of mul- tifunctional cytokines that activate transcription of subsets of genes. The gene products induced by IFNs are responsible for IFN antiviral, antiprolif- erative, and immunomodulatory properties. To obtain a more comprehensive list and a better un- derstanding of the genes regulated by IFNs, we compiled data from many experiments, using two different microarray formats.

Michael J. de Veer; Michelle Holko; Mathias Frevel; Eldon Walker; Sandy Der; Jayashree M. Paranjape; Robert H. Silverman; Bryan R. G. Williams

2001-01-01

207

Identifying biological themes within lists of genes with EASE  

Microsoft Academic Search

EASE is a customizable software application for rapid biological interpretation of gene lists that result from the analysis of microarray, proteomics, SAGE, and other high-throughput genomic data. The biological themes returned by EASE recapitulate manually determined themes in previously published gene lists and are robust to varying methods of normalization, intensity calculation and statistical selection of genes. EASE is a

Douglas A Hosack; Glynn Dennis Jr; Brad T Sherman; Richard A Lempicki

2003-01-01

208

Identifying concerted evolution and gene conversion in mammalian gene pairs lasting over 100 million years  

PubMed Central

Background Concerted evolution occurs in multigene families and is characterized by stretches of homogeneity and higher sequence similarity between paralogues than between orthologues. Here we identify human gene pairs that have undergone concerted evolution, caused by ongoing gene conversion, since at least the human-mouse divergence. Our strategy involved the identification of duplicated genes with greater similarity within a species than between species. These genes were required to be present in multiple mammalian genomes, suggesting duplication early in mammalian divergence. To eliminate genes that have been conserved due to strong purifying selection, our analysis also required at least one intron to have retained high sequence similarity between paralogues. Results We identified three human gene pairs undergoing concerted evolution (BMP8A/B, DDX19A/B, and TUBG1/2). Phylogenetic investigations reveal that in each case the duplication appears to have occurred prior to eutherian mammalian radiation, with exactly two paralogues present in all examined species. This indicates that all three gene duplication events were established over 100 million years ago. Conclusion The extended duration of concerted evolution in multiple distant lineages suggests that there has been prolonged homogenization of specific segments within these gene pairs. Although we speculate that selection for homogenization could have been utilized in order to maintain crucial homo- or hetero- binding domains, it remains unclear why gene conversion has persisted for such extended periods of time. Through these analyses, our results demonstrate additional examples of a process that plays a definite, although unspecified, role in molecular evolution.

Carson, Andrew R; Scherer, Stephen W

2009-01-01

209

A New Strategy to Identify and Annotate Human RPE-Specific Gene Expression  

PubMed Central

Background To identify and functionally annotate cell type-specific gene expression in the human retinal pigment epithelium (RPE), a key tissue involved in age-related macular degeneration and retinitis pigmentosa. Methodology RPE, photoreceptor and choroidal cells were isolated from selected freshly frozen healthy human donor eyes using laser microdissection. RNA isolation, amplification and hybridization to 44 k microarrays was carried out according to Agilent specifications. Bioinformatics was carried out using Rosetta Resolver, David and Ingenuity software. Principal Findings Our previous 22 k analysis of the RPE transcriptome showed that the RPE has high levels of protein synthesis, strong energy demands, is exposed to high levels of oxidative stress and a variable degree of inflammation. We currently use a complementary new strategy aimed at the identification and functional annotation of RPE-specific expressed transcripts. This strategy takes advantage of the multilayered cellular structure of the retina and overcomes a number of limitations of previous studies. In triplicate, we compared the transcriptomes of RPE, photoreceptor and choroidal cells and we deduced RPE specific expression. We identified at least 114 entries with RPE-specific gene expression. Thirty-nine of these 114 genes also show high expression in the RPE, comparison with the literature showed that 85% of these 39 were previously identified to be expressed in the RPE. In the group of 114 RPE specific genes there was an overrepresentation of genes involved in (membrane) transport, vision and ophthalmic disease. More fundamentally, we found RPE-specific involvement in the RAR-activation, retinol metabolism and GABA receptor signaling pathways. Conclusions In this study we provide a further specification and understanding of the RPE transcriptome by identifying and analyzing genes that are specifically expressed in the RPE.

Booij, Judith C.; ten Brink, Jacoline B.; Swagemakers, Sigrid M. A.; Verkerk, Annemieke J. M. H.; Essing, Anke H. W.; van der Spek, Peter J.; Bergen, Arthur A. B.

2010-01-01

210

A Pilot Study of Gene/Gene and Gene/Environment Interactions in Alzheimer Disease  

PubMed Central

Background: Although some genes associated with increased risk of Alzheimer Disease (AD) have been identified, few data exist related to gene/gene and gene/environment risk of AD. The purpose of this pilot study was to explore gene/gene and gene/environment associations in AD and to obtain data for sample size estimates for larger, more definitive studies of AD. Methods: The effect of gene/gene and gene/environment interaction related to late onset Alzheimer Disease (LOAD) was investigated in 153 subjects with LOAD and 302 gender matched controls enrolled in the Personalized Medicine Research Project, a population-based bio-repository. Genetic risk factors examined included APOE, ACE, OLR1,and CYP46 genes, and environmental factors included smoking, total cholesterol, LDL, HDL, triglycerides, C-reactive protein, blood pressure, statin use, and body mass index. Results: The mean age of the cases was 78.2 years and the mean age of the controls was 87.2 years. APOE4 was significantly associated with LOAD (OR=3.55, 95%CL=1.70, 7.45). Cases were significantly more likely to have ever smoked cigarettes during their life (49.3% versus 38.4%, p=0.03). The highest recorded blood pressure and pulse pressure measurements were significantly higher in the controls than the cases (all P<0.005). Although not statistically significant in this pilot study, the relationship of the following factors was associated in opposite directions with LOAD based on the presence of an APOE4 allele: obesity at the age of 50, ACE, OLR1, and CYP46. Conclusions: These pilot data suggest that gene/gene and gene/environment interactions may be important in LOAD, with APOE, a known risk factor for LOAD, affecting the relationship of ACE and OLR1 to LOAD. Replication with a larger sample size and in other racial/ethnic groups is warranted and the allele and risk factor frequencies will assist in choosing an appropriate sample size for a definitive study.

Ghebranious, Nader; Mukesh, Bickol; Giampietro, Philip F.; Glurich, Ingrid; Mickel, Susan F.; Waring, Stephen C.; McCarty, Catherine A.

2011-01-01

211

Integration of text- and data-mining using ontologies successfully selects disease gene candidates  

PubMed Central

Genome-wide techniques such as microarray analysis, Serial Analysis of Gene Expression (SAGE), Massively Parallel Signature Sequencing (MPSS), linkage analysis and association studies are used extensively in the search for genes that cause diseases, and often identify many hundreds of candidate disease genes. Selection of the most probable of these candidate disease genes for further empirical analysis is a significant challenge. Additionally, identifying the genes that cause complex diseases is problematic due to low penetrance of multiple contributing genes. Here, we describe a novel bioinformatic approach that selects candidate disease genes according to their expression profiles. We use the eVOC anatomical ontology to integrate text-mining of biomedical literature and data-mining of available human gene expression data. To demonstrate that our method is successful and widely applicable, we apply it to a database of 417 candidate genes containing 17 known disease genes. We successfully select the known disease gene for 15 out of 17 diseases and reduce the candidate gene set to 63.3% (±18.8%) of its original size. This approach facilitates direct association between genomic data describing gene expression and information from biomedical texts describing disease phenotype, and successfully prioritizes candidate genes according to their expression in disease-affected tissues.

Tiffin, Nicki; Kelso, Janet F.; Powell, Alan R.; Pan, Hong; Bajic, Vladimir B.; Hide, Winston A.

2005-01-01

212

Simulated Search For A Disease Gene  

NSDL National Science Digital Library

This simulation is based on the research of Nancy Wexler and James Gusella on Huntington's disease (see Micklos and Freyer, 1991, DNA Science, pp. 148-155). Plasmid DNA is used to represent human DNA samples from a family affected by a genetic disease. RFLP analysis of the samples reveals a potential marker for the disease gene. A mutation within or near the disease gene has created a new restriction site for the restriction endonuclease Nru1, yielding 2 smaller restriction fragments on electrophoresis instead of a single larger one. The students discover that the disease phenotype is linked to the double-banded allele. They are able to use the information to describe the inheritance of the disease (autosomal, recessive) and to predict that a fetus (#52) will be unaffected by the disease. Through creative writing assignments, students explore personal and societal issues surrounding genetic testing.

BEGIN:VCARD VERSION:2.1 FN:Katharine Noonan N:Noonan;Katharine ORG:Oakland High School REV:2005-04-12 END:VCARD

1995-06-30

213

Identifying the viral genes encoding envelope glycoproteins for differentiation of Cyprinid herpesvirus 3 isolates.  

PubMed

Cyprinid herpes virus 3 (CyHV-3) diseases have been reported around the world and are associated with high mortalities of koi (Cyprinus carpio). Although little work has been conducted on the molecular analysis of this virus, glycoprotein genes identified in the present study seem to be valuable targets for genetic comparison of this virus. Three envelope glycoprotein genes (ORF25, 65 and 116) of the CyHV-3 isolates from the USA, Israel, Japan and Korea were compared, and interestingly, sequence insertions or deletions were observed in these target regions. In addition, polymorphisms were presented in microsatellite zones from two glycoprotein genes (ORF65 and 116). In phylogenetic tree analysis, the Korean isolate was remarkably distinguished from USA, Israel, Japan isolates. These findings may be suitable for many applications including isolates differentiation and phylogeny studies. PMID:23435236

Han, Jee Eun; Kim, Ji Hyung; Renault, Tristan; Jr, Casiano Choresca; Shin, Sang Phil; Jun, Jin Woo; Park, Se Chang

2013-01-31

214

Identifying the Viral Genes Encoding Envelope Glycoproteins for Differentiation of Cyprinid herpesvirus 3 Isolates  

PubMed Central

Cyprinid herpes virus 3 (CyHV-3) diseases have been reported around the world and are associated with high mortalities of koi (Cyprinus carpio). Although little work has been conducted on the molecular analysis of this virus, glycoprotein genes identified in the present study seem to be valuable targets for genetic comparison of this virus. Three envelope glycoprotein genes (ORF25, 65 and 116) of the CyHV-3 isolates from the USA, Israel, Japan and Korea were compared, and interestingly, sequence insertions or deletions were observed in these target regions. In addition, polymorphisms were presented in microsatellite zones from two glycoprotein genes (ORF65 and 116). In phylogenetic tree analysis, the Korean isolate was remarkably distinguished from USA, Israel, Japan isolates. These findings may be suitable for many applications including isolates differentiation and phylogeny studies.

Han, Jee Eun; Kim, Ji Hyung; Renault, Tristan; Choresca, Casiano; Shin, Sang Phil; Jun, Jin Woo; Park, Se Chang

2013-01-01

215

HLA and Other Gene Associations with Dengue Disease Severity  

Microsoft Academic Search

\\u000a Large case control gene association studies have been performed on cohorts of dengue virus (DENV) infected patients identified\\u000a in mainland Southeast Asia, South Asia and the Caribbean. Candidate genes that have shown statistically significant associations\\u000a with DENV disease severity encode HLA molecules, cell receptors for IgG (FcGII), vitamin D and ICAM3 (DCSIGN or CD209), pathogen\\u000a recognition molecules such as mannose

H. A. F. Stephens

216

Comparative genomics and an insect model rapidly identify novel virulence genes of Burkholderia mallei.  

PubMed

Burkholderia pseudomallei and its host-adapted deletion clone Burkholderia mallei cause the potentially fatal human diseases melioidosis and glanders, respectively. The antibiotic resistance profile and ability to infect via aerosol of these organisms and the absence of protective vaccines have led to their classification as major biothreats and select agents. Although documented infections by these bacteria date back over 100 years, relatively little is known about their virulence and pathogenicity mechanisms. We used in silico genomic subtraction to generate their virulome, a set of 650 putative virulence-related genes shared by B. pseudomallei and B. mallei but not present in five closely related nonpathogenic Burkholderia species. Although most of these genes are clustered in putative operons, the number of targets for mutant construction and verification of reduced virulence in animal models is formidable. Therefore, Galleria mellonella (wax moth) larvae were evaluated as a surrogate host; we found that B. pseudomallei and B. mallei, but not other phylogenetically related bacteria, were highly pathogenic for this insect. More importantly, four previously characterized B. mallei mutants with reduced virulence in hamsters or mice had similarly reduced virulence in G. mellonella larvae. Site-specific inactivation of selected genes in the computationally derived virulome identified three new potential virulence genes, each of which was required for rapid and efficient killing of larvae. Thus, this approach may provide a means to quickly identify high-probability virulence genes in B. pseudomallei, B. mallei, and other pathogens. PMID:18223084

Schell, Mark A; Lipscomb, Lyla; DeShazer, David

2008-01-25

217

Expressed sequences tags of the anther smut fungus, Microbotryum violaceum, identify mating and pathogenicity genes  

PubMed Central

Background The basidiomycete fungus Microbotryum violaceum is responsible for the anther-smut disease in many plants of the Caryophyllaceae family and is a model in genetics and evolutionary biology. Infection is initiated by dikaryotic hyphae produced after the conjugation of two haploid sporidia of opposite mating type. This study describes M. violaceum ESTs corresponding to nuclear genes expressed during conjugation and early hyphal production. Results A normalized cDNA library generated 24,128 sequences, which were assembled into 7,765 unique genes; 25.2% of them displayed significant similarity to annotated proteins from other organisms, 74.3% a weak similarity to the same set of known proteins, and 0.5% were orphans. We identified putative pheromone receptors and genes that in other fungi are involved in the mating process. We also identified many sequences similar to genes known to be involved in pathogenicity in other fungi. The M. violaceum EST database, MICROBASE, is available on the Web and provides access to the sequences, assembled contigs, annotations and programs to compare similarities against MICROBASE. Conclusion This study provides a basis for cloning the mating type locus, for further investigation of pathogenicity genes in the anther smut fungi, and for comparative genomics.

Yockteng, Roxana; Marthey, Sylvain; Chiapello, Helene; Gendrault, Annie; Hood, Michael E; Rodolphe, Francois; Devier, Benjamin; Wincker, Patrick; Dossat, Carole; Giraud, Tatiana

2007-01-01

218

Microarray gene expression analysis of the Fob3b obesity QTL identifies positional candidate gene Sqle and perturbed cholesterol and glycolysis pathways  

Microsoft Academic Search

Simon Horvat. Microarray gene expression analysis of the Fob3b obesity QTL identifies positional candidate gene Sqle and perturbed cholesterol and glycolysis pathways. Physiol Genomics 20: 224-232, 2005. First published December 14, 2004; doi:10.1152\\/physiol- genomics.00183.2004.—Obesity-related diseases are poised to be- come the primary cause of death in developed nations. While a number of monogenic causes of obesity have recently been identified,

Ioannis M. Stylianou; Michael Clinton; Peter D. Keightley; Clare Pritchard; Zuzzana Tymowska-Lalanne; Lutz Bunger; Simon Horvat

2004-01-01

219

Gene Expression Analysis of Human Prostate Carcinoma during Hormonal Therapy Identifies Androgen-Responsive Genes and Mechanisms of Therapy Resistance  

PubMed Central

The androgen-signaling pathway is critical to the development and progression of prostate cancer and androgen ablation is a mainstay of therapy for this disease. We performed a genome-wide expression analysis of human prostate cancer during androgen ablation therapy to identify genes regulated by androgen and genes differentially expressed after the development of resistance. Six hundred and fifty-four of 63,175 probe sets detected significant expression changes after 3 months of treatment with goserelin and flutamide. This included 149 genes that were also differentially expressed 36 hours after androgen withdrawal in LNCaP cells. These genes reflect the physiological changes that occur in treated tumors and include potential direct targets of the androgen receptor. Expression profiles of androgen ablation-resistant tumors demonstrated that many of the gene expression changes detected during therapy were no longer present suggesting a reactivation of the androgen response pathway in the absence of exogenous hormone. Therapy resistance was associated with differential expression of a unique set of genes that reflect potential mechanisms of reactivation. Specifically an up-regulation of the androgen receptor and key enzymes for steroid biosynthesis suggest that resistant tumors have increased sensitivity to and endogenous synthesis of androgenic hormones. The specific pathways of reactivation provide opportunities for classification of resistant tumors and targeted therapies.

Holzbeierlein, Jeff; Lal, Priti; LaTulippe, Eva; Smith, Alex; Satagopan, Jaya; Zhang, Liying; Ryan, Charles; Smith, Steve; Scher, Howard; Scardino, Peter; Reuter, Victor; Gerald, William L.

2004-01-01

220

Celiac Disease: a model autoimmune disease with gene therapy applications  

Microsoft Academic Search

Gene therapy (GT) is still at the ‘experimental’ stage and some recent setbacks have cooled the potential use of this therapeutic tool even in life-threatening conditions. However, this therapeutic approach has a potential, which is not limited to disease for which we have not other option. There are increasing evidence that GT will be soon used in diseases that are

M Londei; S Quaratino; L Maiuri

2003-01-01

221

MouseFinder: candidate disease genes from mouse phenotype data  

PubMed Central

Mouse phenotype data represents a valuable resource for the identification of disease-associated genes, especially where the molecular basis is unknown and there is no clue to the candidate gene’s function, pathway involvement or expression pattern. However, until recently these data have not been systematically used due to difficulties in mapping between clinical features observed in humans and mouse phenotype annotations. Here, we describe a semantic approach to solve this problem and demonstrate highly significant recall of known disease-gene associations and orthology relationships. A web application (MouseFinder; www.mousemodels.org) has been developed to allow users to search the results of our whole-phenome comparison of human and mouse. We demonstrate its use in identifying ARTN as a strong candidate gene within the 1p34.1-p32 mapped locus for a hereditary form of ptosis.

Chen, Chao-Kung; Mungall, Christopher J; Gkoutos, Georgios V; Doelken, Sandra C; Kohler, Sebastian; Ruef, Barbara J; Smith, Cynthia; Westerfield, Monte; Robinson, Peter N; Lewis, Suzanna E; Schofield, Paul N; Smedley, Damian

2012-01-01

222

Genetics of Sputum Gene Expression in Chronic Obstructive Pulmonary Disease  

PubMed Central

Previous expression quantitative trait loci (eQTL) studies have performed genetic association studies for gene expression, but most of these studies examined lymphoblastoid cell lines from non-diseased individuals. We examined the genetics of gene expression in a relevant disease tissue from chronic obstructive pulmonary disease (COPD) patients to identify functional effects of known susceptibility genes and to find novel disease genes. By combining gene expression profiling on induced sputum samples from 131 COPD cases from the ECLIPSE Study with genomewide single nucleotide polymorphism (SNP) data, we found 4315 significant cis-eQTL SNP-probe set associations (3309 unique SNPs). The 3309 SNPs were tested for association with COPD in a genomewide association study (GWAS) dataset, which included 2940 COPD cases and 1380 controls. Adjusting for 3309 tests (p<1.5e-5), the two SNPs which were significantly associated with COPD were located in two separate genes in a known COPD locus on chromosome 15: CHRNA5 and IREB2. Detailed analysis of chromosome 15 demonstrated additional eQTLs for IREB2 mapping to that gene. eQTL SNPs for CHRNA5 mapped to multiple linkage disequilibrium (LD) bins. The eQTLs for IREB2 and CHRNA5 were not in LD. Seventy-four additional eQTL SNPs were associated with COPD at p<0.01. These were genotyped in two COPD populations, finding replicated associations with a SNP in PSORS1C1, in the HLA-C region on chromosome 6. Integrative analysis of GWAS and gene expression data from relevant tissue from diseased subjects has located potential functional variants in two known COPD genes and has identified a novel COPD susceptibility locus.

Qiu, Weiliang; Cho, Michael H.; Riley, John H.; Anderson, Wayne H.; Singh, Dave; Bakke, Per; Gulsvik, Amund; Litonjua, Augusto A.; Lomas, David A.; Crapo, James D.; Beaty, Terri H.; Celli, Bartolome R.; Rennard, Stephen; Tal-Singer, Ruth; Fox, Steven M.; Silverman, Edwin K.; Hersh, Craig P.

2011-01-01

223

Evaluation of an efficient approach for identifying genetic disease loci  

SciTech Connect

Identification of disease loci by genetic linkage analysis has been enhanced by the availability of highly polymorphic short tandem repeat polymorphic markers (STRPs). The development of high quality tri- and tetranucleotide STRPs allows new strategies to increase the efficiency of genotyping resulting in streamlined linkage studies. We have tested a strategy using pooled DNA samples from affected individuals from large Bedouin pedigrees segregating recessive disorders. Equal molar amounts of DNA from affected individuals are pooled and used as a template for PCR of STRPs. Pooled DNA from unaffected siblings are used as controls. STRPS linked to the disorder show a shift in allele frequency in the affected compared to the control pool, whereas unlinked markers show an identical allele distribution in affected and control pools. We have demonstrated the sensitivity of this approach for identifying STRPs giving positive lod scores in recessive kindreds. We have also modelled this approach with dominant pedigrees. Application of this approach to polygenic disorders should be possible by using methods to quantitate allele frequencies in pooled samples. The high quality tri- and tetranucleotide repeat markers developed by the Cooperative Human Linkage Center (CHLC) facilitate the use of this method.

Sheffield, V.C.; Kwitek-Black, A.E.; Rokhlina, T. [Univ. of Iowa, Iowa City, IA (United States)] [and others

1994-09-01

224

Patterns of population differentiation of candidate genes for cardiovascular disease  

Microsoft Academic Search

BACKGROUND: The basis for ethnic differences in cardiovascular disease (CVD) susceptibility is not fully understood. We investigated patterns of population differentiation (FST) of a set of genes in etiologic pathways of CVD among 3 ethnic groups: Yoruba in Nigeria (YRI), Utah residents with European ancestry (CEU), and Han Chinese (CHB) + Japanese (JPT). We identified 37 pathways implicated in CVD

Iftikhar J Kullo; Keyue Ding

2007-01-01

225

Modeling Human Disease by Gene Targeting  

Microsoft Academic Search

An accepted practice of studying human disease processes is to establish disease surrogates using model vertebrate and invertebrate species. In many respects, this practice is predicated on the underlying assumption that all species have, to a large extent, the same repertoire of genes, which then leads to the conclusion that model species have common biological pathways. Of importance, mutations in

Andrew Dodd; Stephen P. Chambers; Peter E. Nielsen; Donald R. Love

2004-01-01

226

Genes associated with disc degeneration identified using microarray gene expression profiling and bioinformatics analysis.  

PubMed

Disc degeneration is strongly associated with back or neck pain, sciatica, and disc herniation or prolapse. It places an enormous economic burden on society and can greatly affect quality of life. Alternative treatment approaches, such as genetic therapies, are urgently needed to slow or reverse the disc degeneration process. We downloaded gene expression data from Gene Expression Omnibus during various stages of disc degeneration and identified differentially expressed genes (DEGs) as well as dysfunctional pathways through comparisons with controls. We identified 2 significant DEGs between grade II and III discs and 8 significant DEGs between grade II and IV discs. By constructing an interactive network of the DEGs, we found that mitogen-activated protein family genes and Ras homologous (Rho) family genes - in particular, MAP2K6 and RHOBTB2 - may play important roles in the progression of degeneration of grade III and IV discs, respectively. MAP2K6 and RHOBTB2 may be specific therapeutic molecular targets in the treatment of disc degeneration. However, further experiments are needed to confirm this result. PMID:23661466

Chen, Y; Chen, K; Li, M; Li, C; Ma, H; Bai, Y S; Zhu, X D; Fu, Q

2013-04-26

227

Gene Network Analysis in a Pediatric Cohort Identifies Novel Lung Function Genes  

PubMed Central

Lung function is a heritable trait and serves as an important clinical predictor of morbidity and mortality for pulmonary conditions in adults, however, despite its importance, no studies have focused on uncovering pediatric-specific loci influencing lung function. To identify novel genetic determinants of pediatric lung function, we conducted a genome-wide association study (GWAS) of four pulmonary function traits, including FVC, FEV1, FEV1/FVC and FEF25–75% in 1556 children. Further, we carried out gene network analyses for each trait including all SNPs with a P-value of <1.0×10?3 from the individual GWAS. The GWAS identified SNPs with notable trends towards association with the pulmonary function measures, including the previously described INTS12 locus association with FEV1 (pmeta?=?1.41×10?7). The gene network analyses identified 34 networks of genes associated with pulmonary function variables in Caucasians. Of those, the glycoprotein gene network reached genome-wide significance for all four variables. P-value range pmeta?=?6.29×10?4 - 2.80×10?8 on meta-analysis. In this study, we report on specific pathways that are significantly associated with pediatric lung function at genome-wide significance. In addition, we report the first loci associated with lung function in both pediatric Caucasian and African American populations.

McDonough, Joseph M.; Wei, Zhi; Kim, Cecilia; Chiavacci, Rosetta; Mentch, Frank; Caboot, Jason B.; Spergel, Jonathan; Allen, Julian L.; Sleiman, Patrick M. A.; Hakonarson, Hakon

2013-01-01

228

Identifying essential genes in bacterial metabolic networks with machine learning methods  

Microsoft Academic Search

BACKGROUND: Identifying essential genes in bacteria supports to identify potential drug targets and an understanding of minimal requirements for a synthetic cell. However, experimentally assaying the essentiality of their coding genes is resource intensive and not feasible for all bacterial organisms, in particular if they are infective. RESULTS: We developed a machine learning technique to identify essential genes using the

Kitiporn Plaimas; Roland Eils; Rainer König

2010-01-01

229

Gene Profiling of Mta1 Identifies Novel Gene Targets and Functions  

PubMed Central

Background Metastasis-associated protein 1 (MTA1), a master dual co-regulatory protein is found to be an integral part of NuRD (Nucleosome Remodeling and Histone Deacetylation) complex, which has indispensable transcriptional regulatory functions via histone deacetylation and chromatin remodeling. Emerging literature establishes MTA1 to be a valid DNA-damage responsive protein with a significant role in maintaining the optimum DNA-repair activity in mammalian cells exposed to genotoxic stress. This DNA-damage responsive function of MTA1 was reported to be a P53-dependent and independent function. Here, we investigate the influence of P53 on gene regulation function of Mta1 to identify novel gene targets and functions of Mta1. Methods Gene expression analysis was performed on five different mouse embryonic fibroblasts (MEFs) samples (i) the Mta1 wild type, (ii) Mta1 knock out (iii) Mta1 knock out in which Mta1 was reintroduced (iv) P53 knock out (v) P53 knock out in which Mta1 was over expressed using Affymetrix Mouse Exon 1.0 ST arrays. Further Hierarchical Clustering, Gene Ontology analysis with GO terms satisfying corrected p-value<0.1, and the Ingenuity Pathway Analysis were performed. Finally, RT-qPCR was carried out on selective candidate genes. Significance/Conclusion This study represents a complete genome wide screen for possible target genes of a coregulator, Mta1. The comparative gene profiling of Mta1 wild type, Mta1 knockout and Mta1 re-expression in the Mta1 knockout conditions define “bona fide” Mta1 target genes. Further extensive analyses of the data highlights the influence of P53 on Mta1 gene regulation. In the presence of P53 majority of the genes regulated by Mta1 are related to inflammatory and anti-microbial responses whereas in the absence of P53 the predominant target genes are involved in cancer signaling. Thus, the presented data emphasizes the known functions of Mta1 and serves as a rich resource which could help us identify novel Mta1 functions.

Eswaran, Jeyanthy; Kumar, Rakesh

2011-01-01

230

Viruses, Autophagy Genes, and Crohn's Disease  

PubMed Central

The etiology of the intestinal disease Crohn’s disease involves genetic factors as well as ill-defined environmental agents. Several genetic variants linked to this disease are associated with autophagy, a process that is critical for proper responses to viral infections. While a role for viruses in this disease remains speculative, accumulating evidence indicate that this possibility requires serious consideration. In this review, we will examine the three-way relationship between viruses, autophagy genes, and Crohn’s disease and discuss how host-pathogen interactions can mediate complex inflammatory disorders.

Hubbard, Vanessa M.; Cadwell, Ken

2011-01-01

231

Gene Therapy For Ischemic Heart Disease  

PubMed Central

Current pharmacologic therapy for ischemic heart disease suffers multiple limitations such as compliance issues and side effects of medications. Revascularization procedures often end with need for repeat procedures. Patients remain symptomatic despite maximal medical therapy. Gene therapy offers an attractive alternative to current pharmacologic therapies and may be beneficial in refractory disease. Gene therapy with isoforms of growth factors such as VEGF, FGF and HGF induces angiogenesis, decreases apoptosis and leads to protection in the ischemic heart. Stem cell therapy augmented with gene therapy used for myogenesis has proven to be beneficial in numerous animal models of myocardial ischemia. Gene therapy coding for antioxidants, eNOS, HSP, mitogen-activated protein kinase and numerous other anti apoptotic proteins have demonstrated significant cardioprotection in animal models. Clinical trials have demonstrated safety in humans apart from symptomatic and objective improvements in cardiac function. Current research efforts are aimed at refining various gene transfection techniques and regulation of gene expression in vivo in the heart and circulation to improve clinical outcomes in patients that suffer from ischemic heart disease. In this review article we will attempt to summarize the current state of both preclinical and clinical studies of gene therapy to combat myocardial ischemic disease.

Lavu, Madhav; Gundewar, Susheel; Lefer, David J.

2010-01-01

232

Sleeping Beauty Plays a Significant Role in Identifying Cancer Genes  

Cancer.gov

Researchers at the University of Minnesota Cancer Center and the National Cancer Institute (NCI), part of the National Institutes of Health, have discovered a new method that could accelerate the way cancer-causing genes are found and could lead to a more accurate identification of the genes

233

How to identify essential genes from molecular networks?  

Microsoft Academic Search

BACKGROUND: The prediction of essential genes from molecular networks is a way to test the understanding of essentiality in the context of what is known about the network. However, the current knowledge on molecular network structures is incomplete yet, and consequently the strategies aimed to predict essential genes are prone to uncertain predictions. We propose that simultaneously evaluating different network

Gabriel del Rio; Dirk Koschützki; Gerardo Coello

2009-01-01

234

Gene Expression Profiles Identify Inflammatory Signatures in Dendritic Cells  

Microsoft Academic Search

Dendritic cells (DCs) constitute a heterogeneous group of antigen-presenting leukocytes important in activation of both innate and adaptive immunity. We studied the gene expression patterns of DCs incubated with reagents inducing their activation or inhibition. Total RNA was isolated from DCs and gene expression profiling was performed with oligonucleotide microarrays. Using a supervised learning algorithm based on Random Forest, we

Anna Torri; Ottavio Beretta; Anna Ranghetti; Francesca Granucci; Paola Ricciardi-Castagnoli; Maria Foti; Patricia T. Bozza

2010-01-01

235

DRUMS: a human disease related unique gene mutation search engine.  

PubMed

With the completion of the human genome project and the development of new methods for gene variant detection, the integration of mutation data and its phenotypic consequences has become more important than ever. Among all available resources, locus-specific databases (LSDBs) curate one or more specific genes' mutation data along with high-quality phenotypes. Although some genotype-phenotype data from LSDB have been integrated into central databases little effort has been made to integrate all these data by a search engine approach. In this work, we have developed disease related unique gene mutation search engine (DRUMS), a search engine for human disease related unique gene mutation as a convenient tool for biologists or physicians to retrieve gene variant and related phenotype information. Gene variant and phenotype information were stored in a gene-centred relational database. Moreover, the relationships between mutations and diseases were indexed by the uniform resource identifier from LSDB, or another central database. By querying DRUMS, users can access the most popular mutation databases under one interface. DRUMS could be treated as a domain specific search engine. By using web crawling, indexing, and searching technologies, it provides a competitively efficient interface for searching and retrieving mutation data and their relationships to diseases. The present system is freely accessible at http://www.scbit.org/glif/new/drums/index.html. PMID:21913285

Li, Zuofeng; Liu, Xingnan; Wen, Jingran; Xu, Ye; Zhao, Xin; Li, Xuan; Liu, Lei; Zhang, Xiaoyan

2011-10-01

236

Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia  

PubMed Central

Schizophrenia is a highly heritable disorder with a polygenic pattern of inheritance and a population prevalence of ?1%. Previous studies have implicated synaptic dysfunction in schizophrenia. We tested the accumulated association of genetic variants in expert-curated synaptic gene groups with schizophrenia in 4673 cases and 4965 healthy controls, using functional gene group analysis. Identifying groups of genes with similar cellular function rather than genes in isolation may have clinical implications for finding additional drug targets. We found that a group of 1026 synaptic genes was significantly associated with the risk of schizophrenia (P=7.6 × 10?11) and more strongly associated than 100 randomly drawn, matched control groups of genetic variants (P<0.01). Subsequent analysis of synaptic subgroups suggested that the strongest association signals are derived from three synaptic gene groups: intracellular signal transduction (P=2.0 × 10?4), excitability (P=9.0 × 10?4) and cell adhesion and trans-synaptic signaling (P=2.4 × 10?3). These results are consistent with a role of synaptic dysfunction in schizophrenia and imply that impaired intracellular signal transduction in synapses, synaptic excitability and cell adhesion and trans-synaptic signaling play a role in the pathology of schizophrenia.

Lips, E S; Cornelisse, L N; Toonen, R F; Min, J L; Hultman, C M; Holmans, P A; O'Donovan, M C; Purcell, S M; Smit, A B; Verhage, M; Sullivan, P F; Visscher, P M; Posthuma, D

2012-01-01

237

Link-based quantitative methods to identify differentially coexpressed genes and gene Pairs  

PubMed Central

Background Differential coexpression analysis (DCEA) is increasingly used for investigating the global transcriptional mechanisms underlying phenotypic changes. Current DCEA methods mostly adopt a gene connectivity-based strategy to estimate differential coexpression, which is characterized by comparing the numbers of gene neighbors in different coexpression networks. Although it simplifies the calculation, this strategy mixes up the identities of different coexpression neighbors of a gene, and fails to differentiate significant differential coexpression changes from those trivial ones. Especially, the correlation-reversal is easily missed although it probably indicates remarkable biological significance. Results We developed two link-based quantitative methods, DCp and DCe, to identify differentially coexpressed genes and gene pairs (links). Bearing the uniqueness of exploiting the quantitative coexpression change of each gene pair in the coexpression networks, both methods proved to be superior to currently popular methods in simulation studies. Re-mining of a publicly available type 2 diabetes (T2D) expression dataset from the perspective of differential coexpression analysis led to additional discoveries than those from differential expression analysis. Conclusions This work pointed out the critical weakness of current popular DCEA methods, and proposed two link-based DCEA algorithms that will make contribution to the development of DCEA and help extend it to a broader spectrum.

2011-01-01

238

Prioritization of retinal disease genes: an integrative approach.  

PubMed

The discovery of novel disease-associated variations in genes is often a daunting task in highly heterogeneous disease classes. We seek a generalizable algorithm that integrates multiple publicly available genomic data sources in a machine-learning model for the prioritization of candidates identified in patients with retinal disease. To approach this problem, we generate a set of feature vectors from publicly available microarray, RNA-seq, and ChIP-seq datasets of biological relevance to retinal disease, to observe patterns in gene expression specificity among tissues of the body and the eye, in addition to photoreceptor-specific signals by the CRX transcription factor. Using these features, we describe a novel algorithm, positive and unlabeled learning for prioritization (PULP). This article compares several popular supervised learning techniques as the regression function for PULP. The results demonstrate a highly significant enrichment for previously characterized disease genes using a logistic regression method. Finally, a comparison of PULP with the popular gene prioritization tool ENDEAVOUR shows superior prioritization of retinal disease genes from previous studies. The java source code, compiled binary, assembled feature vectors, and instructions are available online at https://github.com/ahwagner/PULP. PMID:23508994

Wagner, Alex H; Taylor, Kyle R; DeLuca, Adam P; Casavant, Thomas L; Mullins, Robert F; Stone, Edwin M; Scheetz, Todd E; Braun, Terry A

2013-04-12

239

Gene Therapy Techniques for Peripheral Arterial Disease  

Microsoft Academic Search

  Somatic gene therapy is the introduction of new\\u000a genetic material into selective somatic cells with resulting\\u000a therapeutic benefits. Vascular wall and, subsequently, cardiovascular\\u000a diseases have become an interesting target for gene therapy studies.\\u000a Arteries are an attractive target for gene therapy since vascular\\u000a interventions, both open surgical and endovascular, are well suited for\\u000a minimally invasive, easily monitored gene delivery. Promising

Hannu I. Manninen; Kimmo Mäkinen

2002-01-01

240

Discovering disease-genes by topological features in human protein-protein interaction network  

Microsoft Academic Search

Motivation: Mining the hereditary disease-genes from human genome is one of the most important tasks in bioinformatics research. A variety of sequence features and functional similarities between known human hereditary disease-genes and those not known to be involved in disease have been systematically examined and efficient classifiers have been constructed based on the identified common patterns. The availability of human

Jianzhen Xu; Yongjin Li

2006-01-01

241

Gene expression profiling in human neurodegenerative disease.  

PubMed

Transcriptome study in neurodegenerative disease has advanced considerably in the past 5 years. Increasing scientific rigour and improved analytical tools have led to more-reproducible data. Many transcriptome analysis platforms assay the expression of the entire genome, enabling a complete biological context to be captured. Gene expression profiling (GEP) is, therefore, uniquely placed to discover pathways of disease pathogenesis, potential therapeutic targets, and biomarkers. This Review summarizes microarray human GEP studies in the common neurodegenerative diseases amyotrophic lateral sclerosis (ALS), Parkinson disease (PD) and Alzheimer disease (AD). Several interesting reports have compared pathological gene expression in different patient groups, disease stages and anatomical areas. In all three diseases, GEP has revealed dysregulation of genes related to neuroinflammation. In ALS and PD, gene expression related to RNA splicing and protein turnover is disrupted, and several studies in ALS support involvement of the cytoskeleton. GEP studies have implicated the ubiquitin-proteasome system in PD pathogenesis, and have provided evidence of mitochondrial dysfunction in PD and AD. Lastly, in AD, a possible role for dysregulation of intracellular signalling pathways, including calcium signalling, has been highlighted. This Review also provides a discussion of methodological considerations in microarray sample preparation and data analysis. PMID:22890216

Cooper-Knock, Johnathan; Kirby, Janine; Ferraiuolo, Laura; Heath, Paul R; Rattray, Magnus; Shaw, Pamela J

2012-08-14

242

Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomes  

PubMed Central

Background Model organisms have contributed substantially to our understanding of the etiology of human disease as well as having assisted with the development of new treatment modalities. The availability of the human, mouse and, most recently, the rat genome sequences now permit the comprehensive investigation of the rodent orthologs of genes associated with human disease. Here, we investigate whether human disease genes differ significantly from their rodent orthologs with respect to their overall levels of conservation and their rates of evolutionary change. Results Human disease genes are unevenly distributed among human chromosomes and are highly represented (99.5%) among human-rodent ortholog sets. Differences are revealed in evolutionary conservation and selection between different categories of human disease genes. Although selection appears not to have greatly discriminated between disease and non-disease genes, synonymous substitution rates are significantly higher for disease genes. In neurological and malformation syndrome disease systems, associated genes have evolved slowly whereas genes of the immune, hematological and pulmonary disease systems have changed more rapidly. Amino-acid substitutions associated with human inherited disease occur at sites that are more highly conserved than the average; nevertheless, 15 substituting amino acids associated with human disease were identified as wild-type amino acids in the rat. Rodent orthologs of human trinucleotide repeat-expansion disease genes were found to contain substantially fewer of such repeats. Six human genes that share the same characteristics as triplet repeat-expansion disease-associated genes were identified; although four of these genes are expressed in the brain, none is currently known to be associated with disease. Conclusions Most human disease genes have been retained in rodent genomes. Synonymous nucleotide substitutions occur at a higher rate in disease genes, a finding that may reflect increased mutation rates in the chromosomal regions in which disease genes are found. Rodent orthologs associated with neurological function exhibit the greatest evolutionary conservation; this suggests that rodent models of human neurological disease are likely to most faithfully represent human disease processes. However, with regard to neurological triplet repeat expansion-associated human disease genes, the contraction, relative to human, of rodent trinucleotide repeats suggests that rodent loci may not achieve a 'critical repeat threshold' necessary to undergo spontaneous pathological repeat expansions. The identification of six genes in this study that have multiple characteristics associated with repeat expansion-disease genes raises the possibility that not all human loci capable of facilitating neurological disease by repeat expansion have as yet been identified.

Huang, Hui; Winter, Eitan E; Wang, Huajun; Weinstock, Keith G; Xing, Heming; Goodstadt, Leo; Stenson, Peter D; Cooper, David N; Smith, Douglas; Alba, M Mar; Ponting, Chris P; Fechtel, Kim

2004-01-01

243

Gene Therapy for Parkinson's Disease  

Microsoft Academic Search

Background: Parkinson’s disease (PD) is a neurodegenerative disorder of unknown cause. The characteristic motor impairments of PD including resting tremor, rigidity, slowed movement, decreased dexterity, small handwriting, flexed posture, gait disorder, and imbalance predominantly arise from the loss of neurons in the substantia nigra region of the midbrain that produce the neurotransmitter dopamine. Dopamine replacement therapy provides temporary relief of

Kari Andersen

2012-01-01

244

Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry  

PubMed Central

To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of “homozygosity mapping” in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.

Morrow, Eric M.; Yoo, Seung-Yun; Flavell, Steven W.; Kim, Tae-Kyung; Lin, Yingxi; Hill, Robert Sean; Mukaddes, Nahit M.; Balkhy, Soher; Gascon, Generoso; Hashmi, Asif; Al-Saad, Samira; Ware, Janice; Joseph, Robert M.; Greenblatt, Rachel; Gleason, Danielle; Ertelt, Julia A.; Apse, Kira A.; Bodell, Adria; Partlow, Jennifer N.; Barry, Brenda; Yao, Hui; Markianos, Kyriacos; Ferland, Russell J.; Greenberg, Michael E.; Walsh, Christopher A.

2008-01-01

245

Comparative genomics identifies new alpha class genes within the avian glutathione S-transferase gene cluster.  

PubMed

Glutathione S-transferases (GSTs: EC2.5.1.18) are a superfamily of multifunctional dimeric enzymes that catalyze the conjugation of glutathione (GSH) to electrophilic chemicals. In most animals and in humans, GSTs are the principal enzymes responsible for detoxifying the mycotoxin aflatoxin B(1) (AFB(1)) and GST dysfunction is a known risk factor for susceptibility towards AFB(1). Turkeys are one of the most susceptible animals known to AFB(1), which is a common contaminant of poultry feeds. The extreme susceptibility of turkeys is associated with hepatic GSTs unable to detoxify the highly reactive and electrophilic metabolite exo-AFB(1)-8,9-epoxide (AFBO). In this study, comparative genomic approaches were used to amplify and identify the alpha-class tGST genes (tGSTA1.1, tGSTA1.2, tGSTA1.3, tGSTA2, tGSTA3 and tGSTA4) from turkey liver. The conserved GST domains and four alpha-class signature motifs in turkey GSTs (with the exception of tGSTA1.1 which lacked one motif) confirm the presence of hepatic alpha-class GSTs in the turkey. Four signature motifs and conserved residues found in alpha-class tGSTs are (1) xMExxxWLLAAAGVE, (2) YGKDxKERAxIDMYVxG, (3) PVxEKVLKxHGxxxL and (4) PxIKKFLXPGSxxKPxxx. A BAC clone containing the alpha-class GST gene cluster was isolated and sequenced. The turkey alpha-class GTS genes genetically map to chromosome MGA2 with synteny between turkey and human alpha-class GSTs and flanking genes. This study identifies the alpha-class tGST gene cluster and genetic markers (SNPs, single nucleotide polymorphisms) that can be used to further examine AFB(1) susceptibility and resistance in turkeys. Functional characterization of heterologously expressed proteins from these genes is currently underway. PMID:19913078

Kim, Ji Eun; Bauer, Miranda M; Mendoza, Kristelle M; Reed, Kent M; Coulombe, Roger A

2009-11-10

246

Genetics and gene manipulation therapy of premature coronary artery disease.  

PubMed

Despite the notable recent scientific advances, our ability to detect and prevent premature coronary artery disease (CAD) remains limited, and the identification of patients at risk is yet to be based on objective scientific testing. Eliciting a family history of CAD currently remains the only available screening tool to identify patients with a genetic predisposition. The risk of CAD attributable to genes appears to be most significant at younger ages, and this may explain the lack of definite markers for the disease. Candidate gene association studies focusing on young patients with CAD will, therefore, be more likely to identify a true genetic risk. In this report, we review the known genetic risk factors for premature CAD. We also discuss the potential gene manipulation therapy of CAD as well as of vein graft atherosclerosis following coronary artery bypass surgery. PMID:14988634

Chaer, Rabih A; Billeh, Rana; Massad, Malek G

2004-01-01

247

Identifying Novel Target Genes in Psychotic Disorder Network Association Analyses  

Microsoft Academic Search

Many believe that unique genes for schizophrenia (SZ) and bipolar disorder (BD) are associated with the susceptibility for\\u000a the respective illnesses. To explore this idea, gene expression profiling (GEP) studies of “whole” hippocampus (HIPP) have\\u000a been performed on a cohort consisting of SZs, BDs and normal controls and the data have been interrogated using a combination\\u000a of a global functional

Francine M. Benes; Benjamin Lim; David Matzilevich; John Walsh

248

Dissecting the Gene Network of Dietary Restriction to Identify Evolutionarily Conserved Pathways and New Functional Genes  

PubMed Central

Dietary restriction (DR), limiting nutrient intake from diet without causing malnutrition, delays the aging process and extends lifespan in multiple organisms. The conserved life-extending effect of DR suggests the involvement of fundamental mechanisms, although these remain a subject of debate. To help decipher the life-extending mechanisms of DR, we first compiled a list of genes that if genetically altered disrupt or prevent the life-extending effects of DR. We called these DR–essential genes and identified more than 100 in model organisms such as yeast, worms, flies, and mice. In order for other researchers to benefit from this first curated list of genes essential for DR, we established an online database called GenDR (http://genomics.senescence.info/diet/). To dissect the interactions of DR–essential genes and discover the underlying lifespan-extending mechanisms, we then used a variety of network and systems biology approaches to analyze the gene network of DR. We show that DR–essential genes are more conserved at the molecular level and have more molecular interactions than expected by chance. Furthermore, we employed a guilt-by-association method to predict novel DR–essential genes. In budding yeast, we predicted nine genes related to vacuolar functions; we show experimentally that mutations deleting eight of those genes prevent the life-extending effects of DR. Three of these mutants (OPT2, FRE6, and RCR2) had extended lifespan under ad libitum, indicating that the lack of further longevity under DR is not caused by a general compromise of fitness. These results demonstrate how network analyses of DR using GenDR can be used to make phenotypically relevant predictions. Moreover, gene-regulatory circuits reveal that the DR–induced transcriptional signature in yeast involves nutrient-sensing, stress responses and meiotic transcription factors. Finally, comparing the influence of gene expression changes during DR on the interactomes of multiple organisms led us to suggest that DR commonly suppresses translation, while stimulating an ancient reproduction-related process.

Wuttke, Daniel; Connor, Richard; Vora, Chintan; Craig, Thomas; Li, Yang; Wood, Shona; Vasieva, Olga; Shmookler Reis, Robert; Tang, Fusheng; de Magalhaes, Joao Pedro

2012-01-01

249

Dissecting the gene network of dietary restriction to identify evolutionarily conserved pathways and new functional genes.  

PubMed

Dietary restriction (DR), limiting nutrient intake from diet without causing malnutrition, delays the aging process and extends lifespan in multiple organisms. The conserved life-extending effect of DR suggests the involvement of fundamental mechanisms, although these remain a subject of debate. To help decipher the life-extending mechanisms of DR, we first compiled a list of genes that if genetically altered disrupt or prevent the life-extending effects of DR. We called these DR-essential genes and identified more than 100 in model organisms such as yeast, worms, flies, and mice. In order for other researchers to benefit from this first curated list of genes essential for DR, we established an online database called GenDR (http://genomics.senescence.info/diet/). To dissect the interactions of DR-essential genes and discover the underlying lifespan-extending mechanisms, we then used a variety of network and systems biology approaches to analyze the gene network of DR. We show that DR-essential genes are more conserved at the molecular level and have more molecular interactions than expected by chance. Furthermore, we employed a guilt-by-association method to predict novel DR-essential genes. In budding yeast, we predicted nine genes related to vacuolar functions; we show experimentally that mutations deleting eight of those genes prevent the life-extending effects of DR. Three of these mutants (OPT2, FRE6, and RCR2) had extended lifespan under ad libitum, indicating that the lack of further longevity under DR is not caused by a general compromise of fitness. These results demonstrate how network analyses of DR using GenDR can be used to make phenotypically relevant predictions. Moreover, gene-regulatory circuits reveal that the DR-induced transcriptional signature in yeast involves nutrient-sensing, stress responses and meiotic transcription factors. Finally, comparing the influence of gene expression changes during DR on the interactomes of multiple organisms led us to suggest that DR commonly suppresses translation, while stimulating an ancient reproduction-related process. PMID:22912585

Wuttke, Daniel; Connor, Richard; Vora, Chintan; Craig, Thomas; Li, Yang; Wood, Shona; Vasieva, Olga; Shmookler Reis, Robert; Tang, Fusheng; de Magalhães, João Pedro

2012-08-09

250

Gene-expression profiling in rheumatic disease: tools and therapeutic potential  

Microsoft Academic Search

Gene-expression profiling is a powerful tool for the discovery of molecular fingerprints that underlie human disease. Microarray technologies allow the analysis of messenger RNA transcript levels for every gene in the genome. However, gene-expression profiling is best viewed as part of a pipeline that extends from sample collection through clinical application. Key genes and pathways identified by microarray profiling should

Jason W. Bauer; Hatice Bilgic; Emily C. Baechler

2009-01-01

251

Identification of the von Hippel-Lindau Disease Tumor Suppressor Gene  

Microsoft Academic Search

A gene discovered by positional cloning has been identified as the von Hippel-Lindau (VHL) disease tumor suppressor gene. A restriction fragment encompassing the gene showed rearrangements in 28 of 221 VHL kindreds. Eighteen of these rearrangements were due to deletions in the candidate gene, including three large nonoverlapping deletions. Intragenic mutations were detected in cell lines derived from VHL patients

Farida Latif; Kalman Tory; James Gnarra; Masahiro Yao; Fuh-Mei Duh; Mary Lou Orcutt; Thomas Stackhouse; Igor Kuzmin; William Modi; Laura Geil; Laura Schmidt; Fangwei Zhou; Hua Li; Ming Hui Wei; Fan Chen; Gladys Glenn; Peter Choyke; Mcclellan M. Walther; Yongkai Weng; Dah-Shuhn R. Duan; Michael Dean; Damjan Glavac; Frances M. Richards; Paul A. Crossey; Malcolm A. Ferguson-Smith; Denis Le Paslier; Iiya Chumakov; Daniel Cohen; A. Craig Chinault; Eamonn R. Maher; W. Marston Linehan; Berton Zbar; Michael I. Lerman

1993-01-01

252

Seven newly identified loci for autoimmune thyroid disease.  

PubMed

Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), is one of the most common of the immune-mediated diseases. To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism (SNP) array, the ImmunoChip. The SNP array contains all known and genotype-able SNPs across 186 distinct susceptibility loci associated with one or more immune-mediated diseases. After stringent quality control, we analysed 103 875 common SNPs (minor allele frequency >0.05) in 2285 GD and 462 HT patients and 9364 controls. We found evidence for seven new AITD risk loci (P < 1.12 × 10(-6); a permutation test derived significance threshold), five at locations previously associated and two at locations awaiting confirmation, with other immune-mediated diseases. PMID:22922229

Cooper, Jason D; Simmonds, Matthew J; Walker, Neil M; Burren, Oliver; Brand, Oliver J; Guo, Hui; Wallace, Chris; Stevens, Helen; Coleman, Gillian; Franklyn, Jayne A; Todd, John A; Gough, Stephen C L

2012-08-24

253

Gene therapy for Fabry disease  

Microsoft Academic Search

Fabry disease is an X-linked metabolic disorder caused by a deficiency of?-galactosidase A (?-Gal A). Lack of this lysosomal\\u000a hydrolase results in the accumulation of galactose-terminal glycosphingolipids in a number of tissues, including vascular\\u000a endothelial cells. Premature death is predominantly associated with vascular conditions of the heart, kidneys and brain. Historically,\\u000a treatment has largely been palliative. Alternative treatments for many

C. Sitaskas; J. A. Medin

2001-01-01

254

Genome-wide screens to identify genes of human pathogenic Yersinia species that are expressed during host infection.  

PubMed

An obvious goal in the study of bacteria that cause human disease is to identify the bacterial genes required for growth within the host. Historically, this has presented a significant technological challenge. However, with this goal in mind, the in vivo expression technology (IVET) and signature-tagged mutagenesis (STM) techniques were developed during the 1990s. These techniques have been used to identify virulence genes in the three human pathogenic Yersinia species, Y. enterocolitica, Y. pseudotuberculosis and Y. pestis, using variations of their mouse models of infection. In this review, each of these studies is described individually, including the pertinent details of how each was done, and a brief discussion of the genes identified. In addition, the results of these IVET and STM screens are compared, and the striking lack of overlap between the genes identified is discussed. Most of these studies were only recently published, which means that there have been few follow-up studies on some of the novel virulence genes identified. However, the Y. enterocolitica hreP, rscR and psp genes have become the subject of further studies, which are also summarized here. Finally, I briefly describe the use of the genome-wide (but not in vivo) technology, subtractive hybridization, to identify Yersinia virulence genes. PMID:16053247

Darwin, Andrew J

2005-07-01

255

FROM GENES TO PHENOTYPE IN A FLY: A DEFICIENCY SCREEN TO IDENTIFY GENE REGIONS AFFECTING FEMALE FERTILITY IN DROSOPHILA MELANOGASTER  

NSDL National Science Digital Library

This series of laboratory exercises engages students in the scholarship of discovery by having them conduct a deficiency screen to identify genes affecting Drosophila female fertility. Students are also introduced to bioinformatics as they use FlyBase to identify genes within a deficiency region and develop hypotheses regarding specific gene effects on female sperm storage.

PhD Margaret C Bloch-Qazi (Gustavus Adolphus College Biology)

2009-01-28

256

Identification of genes for bone mineral density variation by computational disease gene identification strategy  

Microsoft Academic Search

We previously used five freely available bioinformatics tools (Prioritizer, Geneseeker, PROSPECTR and SUSPECTS, Disease Gene\\u000a Prediction, and Endeavour) to analyze the thirteen well-replicated osteoporosis susceptibility loci and identify a subset\\u000a of most likely candidate osteoporosis susceptibility genes (Huang et al. in J Hum Genet 53:644–655, 2008). In the current study, we experimentally tested the association between bone mineral density (BMD)

Gloria H. Y. LiHong-Wen; Hong-Wen Deng; Annie W. C. Kung; Qing-Yang Huang

257

Identification of the human CYS1 gene and candidate gene analysis in Boichis disease  

Microsoft Academic Search

Recessive mutations cause cystic kidney disease and a variable degree of biliary liver fibrosis in cpk mice. Recently, the responsible murine gene (Cys1) was identified and expression in renal cilia demonstrated. Here we describe the cDNA cloning of the full-length coding region of the orthologous human CYS1 gene. CYS1 is located on Chromosome 2p25. The CYS1 genomic region comprises three

Manfred Fliegauf; Christian Fröhlich; Judit Horvath; Heike Olbrich; Friedhelm Hildebrandt; Heymut Omran

2003-01-01

258

An introduction to genes, genomes and disease.  

PubMed

The human and other genome projects and subsequent resequencing programmes have provided new perspectives on the nature of the gene and how genes function. Understanding the complexity of the eukaryotic nucleus and the diversity of genetic regulatory mechanisms, including the role of non-coding RNAs, translational control mechanisms and the extraordinary prevalence of splicing, will be central to understanding how genes function, as will the recognition of gene dosage issues. This introduction to the 2010 Annual Review Issue, Genes, Genomes and Disease, provides overviews of these areas and then considers their relevance to a range of human diseases, including cardiovascular and renal disease, neural tube defects and cancer. The p53 gene is considered as an example of a massively regulated gene and the genetic perturbations in cancer are considered in a historical perspective. High-throughput genomic and transcriptomic methods have led to a paradigm shift in the way cancers are perceived and have changed the way translational research is performed. The progress in our understanding of chromosomal rearrangements in cancer, once believed to be incredibly rare events in epithelial malignancies, is discussed. The identification of low-penetrance cancer susceptibility genes through genome-wide association studies and their implications are reviewed. The contribution and limitations of expression profiling are discussed. In the last series of reviews, future challenges are addressed: the promise of synthetic lethality strategies in cancer therapy, a case for 'systems' approaches to genetic networks and the potential of single molecule genetic technologies. Finally, the question 'Does massively parallel DNA resequencing signify the end of histopathology as we know it?' is posed. Readers should find that the 2010 Annual Review Issue is an invaluable resource on contemporary genetics and its applications to understanding disease. PMID:19960555

Hall, Peter A; Reis-Filho, Jorge S; Tomlinson, Ian Pm; Poulsom, Richard

2010-01-01

259

Comparative prion disease gene expression profiling using the prion disease mimetic, cuprizone  

PubMed Central

Identification of genes expressed in response to prion infection may elucidate biomarkers for disease, identify factors involved in agent replication, mechanisms of neuropathology and therapeutic targets. Although several groups have sought to identify gene expression changes specific to prion disease, expression profiles rife with cell population changes have consistently been identified. Cuprizone, a neurotoxicant, qualitatively mimics the cell population changes observed in prion disease, resulting in both spongiform change and astrocytosis. The use of cuprizone-treated animals as an experimental control during comparative expression profiling allows for the identification of transcripts whose expression increases during prion disease and remains unchanged during cuprizone-triggered neuropathology. In this study, expression profiles from the brains of mice preclinically and clinically infected with Rocky Mountain Laboratory (RML) mouse-adapted scrapie agent and age-matched controls were profiled using Affymetrix gene arrays. In total, 164 genes were differentially regulated during prion infection. Eighty-three of these transcripts have been previously undescribed as differentially regulated during prion disease. A 0.4% cuprizone diet was utilized as a control for comparative expression profiling. Cuprizone treatment induced spongiosis and astrocyte proliferation as indicated by glial fibrillary acidic protein (Gfap) transcriptional activation and immunohistochemistry. Gene expression profiles from brain tissue obtained from cuprizone-treated mice identified 307 differentially regulated transcript changes. After comparative analysis, 17 transcripts unaffected by cuprizone treatment but increasing in expression from preclinical to clinical prion infection were identified. Here we describe the novel use of the prion disease mimetic, cuprizone, to control for cell population changes in the brain during prion infection.

Moody, Laura R; Herbst, Allen J; Yoo, Han Sang; Vanderloo, Joshua P

2009-01-01

260

An integrative framework for Bayesian variable selection with informative priors for identifying genes and pathways.  

PubMed

The discovery of genetic or genomic markers plays a central role in the development of personalized medicine. A notable challenge exists when dealing with the high dimensionality of the data sets, as thousands of genes or millions of genetic variants are collected on a relatively small number of subjects. Traditional gene-wise selection methods using univariate analyses face difficulty to incorporate correlational, structural, or functional structures amongst the molecular measures. For microarray gene expression data, we first summarize solutions in dealing with 'large p, small n' problems, and then propose an integrative Bayesian variable selection (iBVS) framework for simultaneously identifying causal or marker genes and regulatory pathways. A novel partial least squares (PLS) g-prior for iBVS is developed to allow the incorporation of prior knowledge on gene-gene interactions or functional relationships. From the point view of systems biology, iBVS enables user to directly target the joint effects of multiple genes and pathways in a hierarchical modeling diagram to predict disease status or phenotype. The estimated posterior selection probabilities offer probabilitic and biological interpretations. Both simulated data and a set of microarray data in predicting stroke status are used in validating the performance of iBVS in a Probit model with binary outcomes. iBVS offers a general framework for effective discovery of various molecular biomarkers by combining data-based statistics and knowledge-based priors. Guidelines on making posterior inferences, determining Bayesian significance levels, and improving computational efficiencies are also discussed. PMID:23844055

Peng, Bin; Zhu, Dianwen; Ander, Bradley P; Zhang, Xiaoshuai; Xue, Fuzhong; Sharp, Frank R; Yang, Xiaowei

2013-07-03

261

Genome-wide RNAi screening identifies protein damage as a regulator of osmoprotective gene expression  

PubMed Central

The detection, stabilization, and repair of stress-induced damage are essential requirements for cellular life. All cells respond to osmotic stress-induced water loss with increased expression of genes that mediate accumulation of organic osmolytes, solutes that function as chemical chaperones and restore osmotic homeostasis. The signals and signaling mechanisms that regulate osmoprotective gene expression in animal cells are poorly understood. Here, we show that gpdh-1 and gpdh-2, genes that mediate the accumulation of the organic osmolyte glycerol, are essential for survival of the nematode Caenorhabditis elegans during osmotic stress. Expression of GFP driven by the gpdh-1 promoter (Pgpdh-1::GFP) is detected only during hypertonic stress but is not induced by other stressors. Using Pgpdh-1::GFP expression as a phenotype, we screened ?16,000 genes by RNAi feeding and identified 122 that cause constitutive activation of gpdh-1 expression and glycerol accumulation. Many of these genes function to regulate protein translation and cotranslational protein folding and to target and degrade denatured proteins, suggesting that the accumulation of misfolded proteins functions as a signal to activate osmoprotective gene expression and organic osmolyte accumulation in animal cells. Consistent with this hypothesis, 73% of these protein-homeostasis genes have been shown to slow age-dependent protein aggregation in C. elegans. Because diverse environmental stressors and numerous disease states result in protein misfolding, mechanisms must exist that discriminate between osmotically induced and other forms of stress-induced protein damage. Our findings provide a foundation for understanding how these damage-selectivity mechanisms function.

Lamitina, Todd; Huang, Chunyi George; Strange, Kevin

2006-01-01

262

Moffitt Cancer Center researchers identify unique immune gene signature  

Cancer.gov

Researchers at Moffitt Cancer Center have discovered a unique immune gene signature that can predict the presence of microscopic lymph node-like structures in metastatic melanoma. The presence of these immune structures, the researchers said, appears to be associated with better survival and may indicate the possibility of selecting patients for immunotherapy based solely on the immune-related makeup of their tumors.

263

Virus-induced gene silencing of Arabidopsis thaliana gene homologues in wheat identifies genes conferring improved drought tolerance.  

PubMed

In a non-model staple crop like wheat (Triticum aestivumI L.), functional validation of potential drought stress responsive genes identified in Arabidopsis could provide gene targets for breeding. Virus-induced gene silencing (VIGS) of genes of interest can overcome the inherent problems of polyploidy and limited transformation potential that hamper functional validation studies in wheat. In this study, three potential candidate genes shown to be involved in abiotic stress response pathways in Arabidopsis thaliana were selected for VIGS experiments in wheat. These include Era1 (enhanced response to abscisic acid), Cyp707a (ABA 8'-hydroxylase), and Sal1 (inositol polyphosphate 1-phosphatase). Gene homologues for these three genes were identified in wheat and cloned in the viral vector barley stripe mosaic virus (BSMV) in the antisense direction, followed by rub inoculation of BSMV viral RNA transcripts onto wheat plants. Quantitative real-time PCR showed that VIGS-treated wheat plants had significant reductions in target gene transcripts. When VIGS-treated plants generated for Era1 and Sal1 were subjected to limiting water conditions, they showed increased relative water content, improved water use efficiency, reduced gas exchange, and better vigour compared to water-stressed control plants inoculated with RNA from the empty viral vector (BSMV0). In comparison, the Cyp707a-silenced plants showed no improvement over BSMV0-inoculated plants under limited water condition. These results indicate that Era1 and Sal1 play important roles in conferring drought tolerance in wheat. Other traits affected by Era1 silencing were also studied. Delayed seed germination in Era1-silenced plants suggests this gene may be a useful target for developing resistance to pre-harvest sprouting. PMID:23364940

Manmathan, Harish; Shaner, Dale; Snelling, Jacob; Tisserat, Ned; Lapitan, Nora

2013-01-30

264

Virus-induced gene silencing of Arabidopsis thaliana gene homologues in wheat identifies genes conferring improved drought tolerance  

PubMed Central

In a non-model staple crop like wheat (Triticum aestivumI L.), functional validation of potential drought stress responsive genes identified in Arabidopsis could provide gene targets for breeding. Virus-induced gene silencing (VIGS) of genes of interest can overcome the inherent problems of polyploidy and limited transformation potential that hamper functional validation studies in wheat. In this study, three potential candidate genes shown to be involved in abiotic stress response pathways in Arabidopsis thaliana were selected for VIGS experiments in wheat. These include Era1 (enhanced response to abscisic acid), Cyp707a (ABA 8’-hydroxylase), and Sal1 (inositol polyphosphate 1-phosphatase). Gene homologues for these three genes were identified in wheat and cloned in the viral vector barley stripe mosaic virus (BSMV) in the antisense direction, followed by rub inoculation of BSMV viral RNA transcripts onto wheat plants. Quantitative real-time PCR showed that VIGS-treated wheat plants had significant reductions in target gene transcripts. When VIGS-treated plants generated for Era1 and Sal1 were subjected to limiting water conditions, they showed increased relative water content, improved water use efficiency, reduced gas exchange, and better vigour compared to water-stressed control plants inoculated with RNA from the empty viral vector (BSMV0). In comparison, the Cyp707a-silenced plants showed no improvement over BSMV0-inoculated plants under limited water condition. These results indicate that Era1 and Sal1 play important roles in conferring drought tolerance in wheat. Other traits affected by Era1 silencing were also studied. Delayed seed germination in Era1-silenced plants suggests this gene may be a useful target for developing resistance to pre-harvest sprouting.

Lapitan, Nora

2013-01-01

265

Genome-wide Screens to Identify Genes of Human Pathogenic Yersinia Species that are Expressed during Host Infection  

Microsoft Academic Search

An obvious goal in the study of bacteria that cause human disease is to identify the bacterial genes required for growth within the host. Historically, this has presented a significant technological challenge. However, with this goal in mind, the in vivo expression technology (IVET) and signature-tagged mutagenesis (STM) techniques were developed during the 1990s. These techniques have been used to

Andrew J. Darwin

266

Identifying mechanistic indicators of childhood asthma from blood gene expression  

EPA Science Inventory

Asthmatic individuals have been identified as a susceptible subpopulation for air pollutants. However, asthma represents a syndrome with multiple probable etiologies, and the identification of these asthma endotypes is critical to accurately define the most susceptible subpopula...

267

A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease  

PubMed Central

A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p<5×10?10, PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n?=?399) and methylation (n?=?292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loci.

2011-01-01

268

Hypertrophic cardiomyopathy: from gene defect to clinical disease.  

PubMed

Major advances have been made over the last decade in our understanding of the molecular basis of several cardiac conditions. Hypertrophic cardiomyopathy (HCM) was the first cardiac disorder in which a genetic basis was identified and as such, has acted as a paradigm for the study of an inherited cardiac disorder. HCM can result in clinical symptoms ranging from no symptoms to severe heart failure and premature sudden death. HCM is the commonest cause of sudden death in those aged less than 35 years, including competitive athletes. At least ten genes have now been identified, defects in which cause HCM. All of these genes encode proteins which comprise the basic contractile unit of the heart, i.e. the sarcomere. While much is now known about which genes cause disease and the various clinical presentations, very little is known about how these gene defects cause disease, and what factors modify the expression of the mutant genes. Studies in both cell culture and animal models of HCM are now beginning to shed light on the signalling pathways involved in HCM, and the role of both environmental and genetic modifying factors. Understanding these mechanisms will ultimately improve our knowledge of the basic biology of heart muscle function, and will therefore provide new avenues for treating cardiovascular disease in man. PMID:12643345

Chung, Man-Wei; Tsoutsman, Tatiana; Semsarian, Christopher

2003-02-01

269

Potential new genes for resistance to Mycosphaerella graminicola identified in Triticum aestivum  ×  Lophopyrum elongatum disomic substitution lines  

Microsoft Academic Search

Lophopyrum species carry many desirable agronomic traits, including disease resistance, which can be transferred to wheat by interspecific\\u000a hybridization. To identify potentially new genes for disease and insect resistance carried by individual Lophopyrum chromosomes, 19 of 21 possible wheat cultivar Chinese Spring × Lophopyrum elongatum disomic substitution lines were tested for resistance to barley yellow dwarf virus (BYDV), cereal yellow dwarf virus

Joseph M. Anderson; Dennis L. Bucholtz; Nagesh Sardesai; Judith B. Santini; Gábor Gyulai; Christie E. Williams; Stephen B. Goodwin

2010-01-01

270

Identifying genetic diversity of avirulence genes in Leptosphaeria maculans using whole genome sequencing.  

PubMed

Next generation sequencing technology allows rapid re-sequencing of individuals, as well as the discovery of single nucleotide polymorphisms (SNPs), for genomic diversity and evolutionary analyses. By sequencing two isolates of the fungal plant pathogen Leptosphaeria maculans, the causal agent of blackleg disease in Brassica crops, we have generated a resource of over 76 million sequence reads aligned to the reference genome. We identified over 21,000 SNPs with an overall SNP frequency of one SNP every 2,065 bp. Sequence validation of a selection of these SNPs in additional isolates collected throughout Australia indicates a high degree of polymorphism in the Australian population. In preliminary phylogenetic analysis, isolates from Western Australia clustered together and those collected from Brassica juncea stubble were identical. These SNPs provide a novel marker resource to study the genetic diversity of this pathogen. We demonstrate that re-sequencing provides a method of validating previously characterised SNPs and analysing differences in important genes, such as the disease related avirulence genes of L. maculans. Understanding the genetic characteristics of this devastating pathogen is vital in developing long-term solutions to managing blackleg disease in Brassica crops. PMID:23793572

Zander, Manuel; Patel, Dhwani A; Van de Wouw, Angela; Lai, Kaitao; Lorenc, Michal T; Campbell, Emma; Hayward, Alice; Edwards, David; Raman, Harsh; Batley, Jacqueline

2013-06-21

271

PORCN mutations and variants identified in patients with focal dermal hypoplasia through diagnostic gene sequencing.  

PubMed

Focal dermal hypoplasia (FDH) is an X-linked dominant disorder caused by mutations in the gene PORCN, which encodes a protein required for the secretion and signaling of Wnt proteins. While deletions are responsible for a small percentage of FDH-causing mutations, the vast majority of mutations are single-nucleotide substitutions or small deletions or insertions that can be identified by sequence analysis. In 2007, we implemented a PORCN gene sequencing test for individuals with a clinical diagnosis of FDH. To date, we have detected 12 novel PORCN mutations and 6 previously reported mutations in 53 such unrelated patients. The pathogenic PORCN mutations included nine nonsense mutations, three missense mutations, one small deletion, two small duplications, and three splice-site mutations. Of these mutations, two were found in affected men and were mosaic; one of these was found in three other affected women. The remaining 16 mutations were found only in women. All the mutations detected in women were presumed heterozygous. In addition to the disease-causing mutations, eight nucleotide variants of unknown significance were identified. Further characterization of these variants suggests that four of them are pathogenic mutations. These findings add to the heterogeneity of mutations in the PORCN gene that cause FDH. PMID:20854095

Fernandes, Priscilla H; Wen, Shu; Sutton, Vernon Reid; Ward, Patricia A; Van den Veyver, Ignatia B; Fang, Ping

2010-09-20

272

Newly identified milder phenotype of peroxisome biogenesis disorder caused by mutated PEX3 gene.  

PubMed

We identified the first patient with infantile Refsum disease (IRD), a milder phenotype of peroxisome biogenesis disorder (PBD) caused by a mutated PEX3, and investigated the clinical, molecular and cellular characterization in this patient. The patient presented psychomotor regression, late-onset leukodystrophy, peripheral neuropathy, hearing impairment, a renal cyst, and renal hypertension and survived until the age of 36. Furthermore, fibroblasts from the patient indicated a mosaic pattern of catalase-positive particles (peroxisomes) and numerous peroxisomal membrane structures. Molecular analysis was homozygous for the D347Y mutation and reduced gene expression of PEX3 which encodes a peroxisomal membrane protein, pex3p, involved in peroxisome assembly at the early stage of peroxisomal membrane vesicle formation, therefore, patients with a mutated PEX3 gene have been reported to have only a severe phenotype of Zellweger syndrome and no or less peroxisomal remnant membrane structure. This is not only a newly identified milder PBD caused by a mutated PEX3 gene but also the first report of a Japanese patient with IRD who had not been diagnosed until over 30years of age, which suggests there must be more variant PBD in patients with degenerative neurologic disorder, and to bring them to light is necessary. PMID:23245813

Matsui, Shuji; Funahashi, Masuko; Honda, Ayako; Shimozawa, Nobuyuki

2012-12-14

273

Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles.  

PubMed

Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families. PMID:23028338

Thompson, Ella R; Doyle, Maria A; Ryland, Georgina L; Rowley, Simone M; Choong, David Y H; Tothill, Richard W; Thorne, Heather; Barnes, Daniel R; Li, Jason; Ellul, Jason; Philip, Gayle K; Antill, Yoland C; James, Paul A; Trainer, Alison H; Mitchell, Gillian; Campbell, Ian G

2012-09-27

274

Exome Sequencing Identifies Rare Deleterious Mutations in DNA Repair Genes FANCC and BLM as Potential Breast Cancer Susceptibility Alleles  

PubMed Central

Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families.

Thompson, Ella R.; Doyle, Maria A.; Ryland, Georgina L.; Rowley, Simone M.; Choong, David Y. H.; Tothill, Richard W.; Thorne, Heather; Barnes, Daniel R.; Li, Jason; Ellul, Jason; Philip, Gayle K.; Antill, Yoland C.; James, Paul A.; Trainer, Alison H.; Mitchell, Gillian; Campbell, Ian G.

2012-01-01

275

Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease  

Microsoft Academic Search

Genetic studies of Hirschsprung disease, a common congenital malformation, have identified eight genes with mutations that can be associated with this condition. Mutations at individual loci are, however, neither necessary nor sufficient to cause clinical disease. We conducted a genome-wide association study in 43 Mennonite family trios using 2,083 microsatellites and single-nucleotide polymorphisms and a new multipoint linkage disequilibrium method

Minerva M. Carrasquillo; Andrew S. McCallion; Erik G. Puffenberger; Carl S. Kashuk; Nassim Nouri; Aravinda Chakravarti

2002-01-01

276

Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry  

Microsoft Academic Search

To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, orc3orf58), whose level of expression changes in response to neuronal activity,

Eric M. Morrow; Seung-Yun Yoo; Steven W. Flavell; Tae-Kyung Kim; Yingxi Lin; Robert Sean Hill; Nahit M. Mukaddes; Soher Balkhy; Generoso Gascon; Asif Hashmi; Samira Al-Saad; Janice Ware; Robert M. Joseph; Rachel Greenblatt; Danielle Gleason; Julia A. Ertelt; Kira A. Apse; Adria Bodell; Jennifer N. Partlow; Brenda Barry; Hui Yao; Kyriacos Markianos; Russell J. Ferland; Michael E. Greenberg; Christopher A. Walsh

2008-01-01

277

Deep Sequencing Study of the MTHFR Gene to Identify Variants Associated with Myelomeningocele  

PubMed Central

INTRODUCTION Neural tube defects (NTDs) are congenital anomalies caused by a combination of genetic and environmental influences. A defect below the head region resulting in protuberance of meninges and nervous tissue is termed myelomeningocele (MM). MM, the most common NTD compatible with survival, occurs in approximately 1 in 1,000 births worldwide. Maternal pre- and periconceptional folate supplementation reduces the risk of NTDs by up to 70%. A key enzyme in folate metabolism is 5, 10-methylene-tetrahydrofolate reductase (MTHFR). OBJECTIVES Sequence the 12 exons of the MTHFR gene among 96 subjects with MM to identify variants potentially contributing to the disease trait. METHODS Exons were amplified by polymerase chain reaction and the products were sequenced by Sanger method to reveal sequence variants compared to MTHFR reference sequences. Association of variants was examined by Fisher’s test. RESULTS A novel variant c.171+3G>T was identified in intron 1 in one affected subject. The variant was not found in the subject’s unaffected mother’s DNA and the unaffected father’s DNA was unavailable. We found significant differences in allele frequencies for seven SNPs in MM subjects compared to ethnically matched reference populations reported in the single nucleotide polymorphism (SNP) database (dbSNP). CONCLUSION We identified a novel variant c.171+3G>T in the MTHFR gene that potentially affects splicing in an affected subject. Also, we observed five SNPs (rs13306561, rs2274976, rs2066462, rs12121543, and rs1476413) in the MTHFR gene not previously shown to associate with MM. The current study provides additional evidence that multiple variations in the MTHFR gene are associated with MM.

Aneji, Chiamaka U; Northrup, Hope; Au, Kit Sing

2012-01-01

278

Linkage Analysis of Candidate Genes in Autoimmune Thyroid Disease. II. Selected Gender-Related Genes and the X-Chromosome  

Microsoft Academic Search

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are auto- immune thyroid diseases (AITD) in which multiple genetic factors are suspected to play an important role. Until now, only a few minor risk factors for these diseases have been identified. Susceptibility seems to be stronger in women, pointing toward a possible role for genes related to sex steroid action or mechanisms

GIUSEPPE BARBESINO; YARON TOMER; ERLINDA S. CONCEPCION; TERRY F. DAVIES; DAVID A. GREENBERG

279

Identification of Sequence Variants in Genetic Disease-Causing Genes Using Targeted Next-Generation Sequencing  

Microsoft Academic Search

BackgroundIdentification of gene variants plays an important role in research on and diagnosis of genetic diseases. A combination of enrichment of targeted genes and next-generation sequencing (targeted DNA-HiSeq) results in both high efficiency and low cost for targeted sequencing of genes of interest.Methodology\\/Principal FindingsTo identify mutations associated with genetic diseases, we designed an array-based gene chip to capture all of

Xiaoming Wei; Xiangchun Ju; Xin Yi; Qian Zhu; Ning Qu; Tengfei Liu; Yang Chen; Hui Jiang; Guanghui Yang; Ruan Zhen; Zhangzhang Lan; Ming Qi; Jinming Wang; Yi Yang; Yuxing Chu; Xiaoyan Li; Yanfang Guang; Jian Huang

2011-01-01

280

Prion disease induced alterations in gene expression in spleen and brain prior to clinical symptoms  

Microsoft Academic Search

Prion diseases are fatal neurodegenerative disorders that affect animals and humans. There is a need to gain understanding of prion disease pathogenesis and to develop diagnostic assays to detect prion diseases prior to the onset of clinical symptoms. The goal of this study was to identify genes that show altered expression early in the disease process in the spleen and

Hyeon O Kim; Greg P Snyder; Tyler M Blazey; Richard E Race; Bruce Chesebro; Pamela J Skinner

281

Screening for Single Gene Genetic Disease  

Microsoft Academic Search

The screening and directed testing for genetic disease caused by single gene mutations is an expanding part of the overall scheme of prenatal care. In addition to reproductive choice, carrier screening and fetal diagnostic testing afford the important opportunity for preparation of the family and the delivery site for the birth of a fetus with a known genetic disorder. Increasingly

Thomas J. Musci

2005-01-01

282

Gene therapy for autoimmune diseases: quo vadis?  

Microsoft Academic Search

Biological therapies using antibodies and cytokines are becoming widespread for the treatment of chronic inflammatory autoimmune diseases. However, these treatments have several limitations — such as expense, the need for repeated injections and unwanted side-effects — that can be overcome by genetic delivery. This review summarizes the ingenuity, sophistication and variety of gene-therapy approaches that have been taken in the

David J. Gould; Osvaldo L. Podhajcer; Yuti Chernajovsky

2004-01-01

283

Gene Therapy for Lysosomal Storage Diseases  

Microsoft Academic Search

Lysosomal storage diseases (LSDs) comprise a diverse group of monogenetic disorders with complex clinical phenotypes that include both systemic and central nervous system pathologies. In recent years, the identification or development of mouse models recapitulating the clinical course of the LSDs has been instrumental in evaluating therapeutic strategies. Here, we review the various gene replacement strategies for target organs affected

Mark S. Sands; Beverly L. Davidson

2006-01-01

284

Model-based methods for identifying periodically expressed genes based on time course microarray gene expression data  

Microsoft Academic Search

Motivation: The expressions of many genes associated with certain periodic biological and cell cycle processes such as circadian rhythm regulation are known to be rhythmic. Iden- tification of the genes whose time course expressions are synchronized to certain periodic biological process may help to elucidate the molecular basis of many diseases, and these gene products may in turn represent drug

Yihui Luan; Hongzhe Li

2004-01-01

285

Using registries to identify adverse events in rheumatic diseases.  

PubMed

The proven effectiveness of biologics and other immunomodulatory products in inflammatory rheumatic diseases has resulted in their widespread use as well as reports of potential short- and long-term complications such as infection and malignancy. These complications are especially worrisome in children who often have serial exposures to multiple immunomodulatory products. Post-marketing surveillance of immunomodulatory products in juvenile idiopathic arthritis (JIA) and pediatric systemic lupus erythematosus is currently based on product-specific registries and passive surveillance, which may not accurately reflect the safety risks for children owing to low numbers, poor long-term retention, and inadequate comparators. In collaboration with the US Food and Drug Administration (FDA), patient and family advocacy groups, biopharmaceutical industry representatives and other stakeholders, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the Duke Clinical Research Institute (DCRI) have developed a novel pharmacosurveillance model (CARRA Consolidated Safety Registry [CoRe]) based on a multicenter longitudinal pediatric rheumatic diseases registry with over 8000 participants. The existing CARRA infrastructure provides access to much larger numbers of subjects than is feasible in single-product registries. Enrollment regardless of medication exposure allows more accurate detection and evaluation of safety signals. Flexibility built into the model allows the addition of specific data elements and safety outcomes, and designation of appropriate disease comparator groups relevant to each product, fulfilling post-marketing requirements and commitments. The proposed model can be applied to other pediatric and adult diseases, potentially transforming the paradigm of pharmacosurveillance in response to the growing public mandate for rigorous post-marketing safety monitoring. PMID:24144710

Lionetti, Geraldina; Kimura, Yukiko; Schanberg, Laura E; Beukelman, Timothy; Wallace, Carol A; Ilowite, Norman T; Winsor, Jane; Fox, Kathleen; Natter, Marc; Sundy, John S; Brodsky, Eric; Curtis, Jeffrey R; Del Gaizo, Vincent; Iyasu, Solomon; Jahreis, Angelika; Meeker-O'Connell, Ann; Mittleman, Barbara B; Murphy, Bernard M; Peterson, Eric D; Raymond, Sandra C; Setoguchi, Soko; Siegel, Jeffrey N; Sobel, Rachel E; Solomon, Daniel; Southwood, Taunton R; Vesely, Richard; White, Patience H; Wulffraat, Nico M; Sandborg, Christy I

2013-10-21

286

Transposon-tagging identifies novel pathogenicity genes in Fusarium graminearum.  

PubMed

With the increase of sequenced fungal genomes, high-throughput methods for functional analyses of genes are needed. We assessed the potential of a new transposon mutagenesis tool deploying a Fusarium oxysporum miniature inverted-repeat transposable element mimp1, mobilized by the transposase of impala, a Tc1-like transposon, to obtain knock-out mutants in Fusarium graminearum. We localized 91 mimp1 insertions which showed good distribution over the entire genome. The main exception was a major hotspot on chromosome 2 where independent insertions occurred at exactly the same nucleotide position. Furthermore insertions in promoter regions were over-represented. Screening 331 mutants for sexual development, radial growth and pathogenicity on wheat resulted in 19 mutants (5.7%) with altered phenotypes. Complementation with the original gene restored the wild-type phenotype in two selected mutants demonstrating the high tagging efficiency. This is the first report of a MITE transposon tagging system as an efficient mutagenesis tool in F. graminearum. PMID:18926918

Dufresne, Marie; van der Lee, Theo; Ben M'barek, Sarrah; Xu, Xiude; Zhang, Xu; Liu, Taiguo; Waalwijk, Cees; Zhang, Wenwei; Kema, Gert H J; Daboussi, Marie-Josée

2008-09-23

287

Post Hoc Parkinson's Disease: Identifying an Uncommon Disease in the Cardiovascular Health Study  

PubMed Central

Background Although ongoing cohort studies offer a unique opportunity to apply existing information collected prospectively to further the scientific understanding of Parkinson's disease (PD), they typically have limited information for clinical diagnosis. Methods We used combinations of self-report, International Classification of Diseases ? 9th edition codes and antiparkinsonian medications to identify PD in the Cardiovascular Health Study. To determine whether the expected inverse association between smoking and PD is evident using our outcome definitions, we assessed baseline smoking characteristics for various definitions of PD. Results We identified 60 cases with prevalent PD (1.0%; 95% confidence interval, CI = 0.8–1.3%) and 154 with incident PD by year 14. Clear associations were observed for current smokers (odds ratio, OR = 0.50; 95% CI = 0.26–0.95) and for those who smoked ?50 pack-years (OR = 0.53; 95% CI = 0.29–0.96). Estimates for smoking were similar when ?2 data sources were required. Estimates for self-report alone were attenuated towards null. Conclusions Using multiple data sources to identify PD represents an alternative method of outcome identification in a cohort that would otherwise not be possible for PD research. Ongoing cohort studies can provide settings in which rapid replication and explorations of new hypotheses for PD are possible.

Ton, T.G.; Jain, S.; Boudreau, R.; Thacker, E.L.; Strotmeyer, E.S.; Newman, A.B.; Longstreth, W.T.; Checkoway, H.

2010-01-01

288

Gene-Environment Interactions and Epigenetic Basis of Human Diseases  

Microsoft Academic Search

Most human diseases are related in some way to the loss or gain in gene functions. Regulation of gene expression is a complex process. In addition to genetic mechanisms, epigenetic causes are gaining new perspectives in human diseases related to gene deregulation. Most eukaryotic genes are packed into chromatin structures, which lead to high condensations of the genes that require

Liang Liu; Yuanyuan Li; Trygve O. Tollefsbol

289

Identifying Genes Responsible for Tamoxifen Resistance in Breast Cancer  

Microsoft Academic Search

Breast cancer is one of the leading causes of death of women in western countries.\\u000aIt affects one out of eight females in the USA (1) and one out of nine females in The\\u000aNetherlands (www.kankerregistratie.nl) during their lifetime. Many risk factors for breast\\u000acancer have been identified including gender, familial susceptibility, age, and exposure\\u000ato hormones i.e. use of

D. Meijer

2008-01-01

290

Accurate breast cancer diagnosis through real-time PCR her-2 gene quantification using immunohistochemically-identified biopsies  

PubMed Central

her-2 gene amplification and its overexpression in breast cancer cells is directly associated with aggressive clinical behavior. The her-2 gene and its Her-2 protein have been utilized for disease diagnosis and as a predictive marker for treatment response to the antibody herceptin. Fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) are the most common FDA-approved methodologies involving gene and protein quantification, respectively. False positive or negative her-2/Her-2 patient results may result in inappropriate treatment administration. To support accurate quantification and interpretation of results, in this study we have standardized qPCR analysis using previously identified IHC samples, obtaining very significant and clinically useful results.

MENDOZA, GRETEL; PORTILLO, AMELIA; OLMOS-SOTO, JORGE

2013-01-01

291

Gene expression profiling in whole blood identifies distinct biological pathways associated with obesity  

Microsoft Academic Search

BACKGROUND: Obesity is reaching epidemic proportions and represents a significant risk factor for cardiovascular disease, diabetes, and cancer. METHODS: To explore the relationship between increased body mass and gene expression in blood, we conducted whole-genome expression profiling of whole blood from seventeen obese and seventeen well matched lean subjects. Gene expression data was analyzed at the individual gene and pathway

Sujoy Ghosh; Robert Dent; Mary-Ellen Harper; Shelby A Gorman; Joan S Stuart; Ruth McPherson

2010-01-01

292

Identification of dysfunctional modules and disease genes in congenital heart disease by a network-based approach  

PubMed Central

Background The incidence of congenital heart disease (CHD) is continuously increasing among infants born alive nowadays, making it one of the leading causes of infant morbidity worldwide. Various studies suggest that both genetic and environmental factors lead to CHD, and therefore identifying its candidate genes and disease-markers has been one of the central topics in CHD research. By using the high-throughput genomic data of CHD which are available recently, network-based methods provide powerful alternatives of systematic analysis of complex diseases and identification of dysfunctional modules and candidate disease genes. Results In this paper, by modeling the information flow from source disease genes to targets of differentially expressed genes via a context-specific protein-protein interaction network, we extracted dysfunctional modules which were then validated by various types of measurements and independent datasets. Network topology analysis of these modules revealed major and auxiliary pathways and cellular processes in CHD, demonstrating the biological usefulness of the identified modules. We also prioritized a list of candidate CHD genes from these modules using a guilt-by-association approach, which are well supported by various kinds of literature and experimental evidence. Conclusions We provided a network-based analysis to detect dysfunctional modules and disease genes of CHD by modeling the information transmission from source disease genes to targets of differentially expressed genes. Our method resulted in 12 modules from the constructed CHD subnetwork. We further identified and prioritized candidate disease genes of CHD from these dysfunctional modules. In conclusion, module analysis not only revealed several important findings with regard to the underlying molecular mechanisms of CHD, but also suggested the distinct network properties of causal disease genes which lead to identification of candidate CHD genes.

2011-01-01

293

Type 1 Gaucher Disease: Significant disease manifestations in "asymptomatic" homozygotes identified by prenatal carrier screening  

PubMed Central

Background Type 1 Gaucher Disease (GD), an autosomal recessive lysosomal storage disease, is most prevalent in the Ashkenazi Jewish (AJ) population. Experts have suggested that up to two-thirds of AJ homozygotes for the common mutation (N370S) are asymptomatic throughout life and never come to medical attention. However, there are no systematic studies of N370S homozygotes to support this presumption. Methods Prenatal carrier screening of 8069 AJ adults for six common GD mutations was performed. GD manifestations in 37 previously unrecognized homozygotes were assessed by clinical, laboratory and imaging studies. Results Among the 8069 AJ screenees, 524 GD carriers (1:15.4) and nine previously unrecognized GD homozygotes (1:897) were identified, consistent with that expected (1:949, p=1.0). Six of these homozygotes, and 31 AJ GD homozygotes identified by other prenatal carrier screening programs in the New York metropolitan area were evaluated (aged 17-40 years). Of these, 84% were N370S homozygotes, others being heteroallelic for N370S and V394L, L444P or R496H. Notably, 65% reported no GD medical complaints. However, 49% had anemia and/or thrombocytopenia. Among the 29 who had imaging studies, 97% had mild to moderate splenomegaly and 55% had hepatomegaly; skeletal imaging revealed marrow infiltration (100%), Erlenmeyer flask deformities (43%), lucencies (22%) and bone infarcts (14%). DEXA studies of 25 homozygotes found 60% osteopenic or osteoporotic. Conclusions Contrary to previous discussions, almost all asymptomatic GD homozygotes serendipitously diagnosed by prenatal carrier screening had disease manifestations and should be followed for disease progression and institution of appropriate medical management.

Balwani, Manisha; Fuerstman, Laura; Kornreich, Ruth; Edelmann, Lisa; Desnick, Robert J.

2011-01-01

294

Genome-Wide Association Analyses Identify SPOCK as a Key Novel Gene Underlying Age at Menarche  

PubMed Central

For females, menarche is a most significant physiological event. Age at menarche (AAM) is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largely unknown. To identify genetic factors underlying AAM variation, a genome-wide association study (GWAS) examining about 380,000 SNPs was conducted in 477 Caucasian women. A follow-up replication study was performed to validate our major GWAS findings using two independent Caucasian cohorts with 854 siblings and 762 unrelated subjects, respectively, and one Chinese cohort of 1,387 unrelated subjects—all females. Our GWAS identified a novel gene, SPOCK (Sparc/Osteonectin, CWCV, and Kazal-like domains proteoglycan), which had seven SNPs associated with AAM with genome-wide false discovery rate (FDR) q<0.05. Six most significant SNPs of the gene were selected for validation in three independent replication cohorts. All of the six SNPs were replicated in at least one cohort. In particular, SNPs rs13357391 and rs1859345 were replicated both within and across different ethnic groups in all three cohorts, with p values of 5.09×10?3 and 4.37×10?3, respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19×10?5 and 1.02×10?4, respectively, in all three replication cohorts. Interestingly, SPOCK can inhibit activation of MMP-2 (matrix metalloproteinase-2), a key factor promoting endometrial menstrual breakdown and onset of menstrual bleeding. Our findings, together with the functional relevance, strongly supported that the SPOCK gene underlies variation of AAM.

Liu, Yao-Zhong; Guo, Yan-Fang; Wang, Liang; Tan, Li-Jun; Liu, Xiao-Gang; Pei, Yu-Fang; Yan, Han; Xiong, Dong-Hai; Deng, Fei-Yan; Yu, Na; Zhang, Yin-Ping; Zhang, Lei; Lei, Shu-Feng; Chen, Xiang-Ding; Liu, Hong-Bin; Zhu, Xue-Zhen; Levy, Shawn; Papasian, Christopher J.; Drees, Betty M.; Hamilton, James J.; Recker, Robert R.; Deng, Hong-Wen

2009-01-01

295

The HOX genes network in metabolic diseases.  

PubMed

Fat distribution is associated with metabolic risk. Differences in cellular characteristics and metabolic functions of these depots have been described, but the molecular mechanisms involved are not understood. The pathogenesis and pathophysiology of metabolic disease can be better understood by studying the molecular mechanisms that control the development and function of adipose tissue (adipogenesis). Homeobox genes are transcription factors that act during normal development and contain the homeobox, a 183bp DNA sequence coding for a 61 amino acid domain defined as homeodomain (HD). Class 1 homeobox genes (Hox genes) have a critical role in controlling positional information and tissue patterning during development. The expression of the whole HOX gene network in different deposits of normal adult human white adipose tissue (intraperitoneal, extra-peritoneal and dermis) indicate a marked expression in adipose tissue. Furthermore, this expression seems to vary in different bodily deposits of white adipose tissue and between white and brown adipose tissue. The purpose of this mini-review is to discuss the role of HOX genes in metabolic diseases. PMID:23765685

Procino, Alfredo; Cillo, Clemente

2013-07-23

296

A search engine to identify pathway genes from expression data on multiple organisms  

PubMed Central

Background The completion of several genome projects showed that most genes have not yet been characterized, especially in multicellular organisms. Although most genes have unknown functions, a large collection of data is available describing their transcriptional activities under many different experimental conditions. In many cases, the coregulatation of a set of genes across a set of conditions can be used to infer roles for genes of unknown function. Results We developed a search engine, the Multiple-Species Gene Recommender (MSGR), which scans gene expression datasets from multiple organisms to identify genes that participate in a genetic pathway. The MSGR takes a query consisting of a list of genes that function together in a genetic pathway from one of six organisms: Homo sapiens, Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, Arabidopsis thaliana, and Helicobacter pylori. Using a probabilistic method to merge searches, the MSGR identifies genes that are significantly coregulated with the query genes in one or more of those organisms. The MSGR achieves its highest accuracy for many human pathways when searches are combined across species. We describe specific examples in which new genes were identified to be involved in a neuromuscular signaling pathway and a cell-adhesion pathway. Conclusion The search engine can scan large collections of gene expression data for new genes that are significantly coregulated with a pathway of interest. By integrating searches across organisms, the MSGR can identify pathway members whose coregulation is either ancient or newly evolved.

Chen, Chunnuan; Weirauch, Matthew T; Powell, Corey C; Zambon, Alexander C; Stuart, Joshua M

2007-01-01

297

Linkage, Association, and Gene-Expression Analyses Identify CNTNAP2 as an Autism-Susceptibility Gene  

PubMed Central

Autism is a genetically complex neurodevelopmental syndrome in which language deficits are a core feature. We describe results from two complimentary approaches used to identify risk variants on chromosome 7 that likely contribute to the etiology of autism. A two-stage association study tested 2758 SNPs across a 10 Mb 7q35 language-related autism QTL in AGRE (Autism Genetic Resource Exchange) trios1,2 and found significant association with Contactin Associated Protein-Like 2 (CNTNAP2), a strong a priori candidate. Male-only containing families were identified as primarily responsible for this association signal, consistent with the strong male affection bias in ASD and other language-based disorders. Gene-expression analyses in developing human brain further identified CNTNAP2 as enriched in circuits important for language development. Together, these results provide convergent evidence for involvement of CNTNAP2, a Neurexin family member, in autism, and demonstrate a connection between genetic risk for autism and specific brain structures.

Alarcon, Maricela; Abrahams, Brett S.; Stone, Jennifer L.; Duvall, Jacqueline A.; Perederiy, Julia V.; Bomar, Jamee M.; Sebat, Jonathan; Wigler, Michael; Martin, Christa L.; Ledbetter, David H.; Nelson, Stanley F.; Cantor, Rita M.; Geschwind, Daniel H.

2008-01-01

298

Whole exome sequencing identifies a novel mutation in the transglutaminase 6 gene for spinocerebellar ataxia in a Chinese family.  

PubMed

Autosomal dominant spinocerebellar ataxias (SCA) constitute a heterogeneous group of inherited disorders. The transglutaminase 6 (TGM6) gene was recently suggested as a SCA causative gene in Chinese SCA families. In this study, two affected members of a three-generation Chinese family with SCA characterized by progressive cerebellar ataxia and lower limb pyramidal signs were subjected to whole exome sequencing. Through bioinformatics analysis of the sequence variants in these two individuals, we identified a novel mutation in the TGM6 gene (c.1528G>C) which showed perfect co-segregation with disease phenotype in all nine members of this family. This finding confirms that mutations in TGM6 gene represent an important cause of SCA in Chinese. This study also shows that whole exome sequencing of a small number of affected individuals, leveraged on bioinformatics analysis, can be an efficient strategy for identifying causative mutations in rare Mendelian disorders. PMID:22554020

Li, M; Pang, S Y Y; Song, Y; Kung, M H W; Ho, S-L; Sham, P-C

2012-05-29

299

PTEN IDENTIFIED AS IMPORTANT RISK FACTOR OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE  

PubMed Central

Common genetic variation may play an important role in altering chronic obstructive pulmonary disease (COPD) risk. In Xuanwei, China, the COPD rate is more than twice the Chinese national average, and COPD is strongly associated with in-home coal use. To identify genetic variation that may be associated with COPD in a population with substantial in-home coal smoke exposures, we evaluated 1,261 single nucleotide polymorphisms (SNPs) in 380 candidate genes potentially relevant for cancer and other human diseases in a population-based case-control study in Xuanwei (53 cases; 107 controls). PTEN was the most significantly associated gene with COPD in a minP analysis using 20,000 permutations (P = 0.00005). SNP-based analyses found that homozygote variant carriers of PTEN rs701848 (ORTT = 0.12, 95%CI = 0.03 - 0.47) had a significant decreased risk of COPD. PTEN, or phosphatase and tensin homolog, is an important regulator of cell cycle progression and cellular survival via the AKT signaling pathway. Our exploratory analysis suggests that genetic variation in PTEN may be an important risk factor of COPD in Xuanwei. However, due to the small sample size, additional studies are needed to evaluate these associations within Xuanwei and other populations with coal smoke exposures.

Hosgood, H Dean; Menashe, Idan; He, Xingzhou; Chanock, Stephen; Lan, Qing

2009-01-01

300

Identification of susceptibility genes and genetic modifiers of human diseases  

NASA Astrophysics Data System (ADS)

The completion of the human genome sequence enables the discovery of genes involved in common human disorders. The successful identification of these genes is dependent on the availability of informative sample sets, validated marker panels, a high-throughput scoring technology, and a strategy for combining these resources. We have developed a universal platform technology based on mass spectrometry (MassARRAY) for analyzing nucleic acids with high precision and accuracy. To fuel this technology, we generated more than 100,000 validated assays for single nucleotide polymorphisms (SNPs) covering virtually all known and predicted human genes. We also established a large DNA sample bank comprised of more than 50,000 consented healthy and diseased individuals. This combination of reagents and technology allows the execution of large-scale genome-wide association studies. Taking advantage of MassARRAY"s capability for quantitative analysis of nucleic acids, allele frequencies are estimated in sample pools containing large numbers of individual DNAs. To compare pools as a first-pass "filtering" step is a tremendous advantage in throughput and cost over individual genotyping. We employed this approach in numerous genome-wide, hypothesis-free searches to identify genes associated with common complex diseases, such as breast cancer, osteoporosis, and osteoarthritis, and genes involved in quantitative traits like high density lipoproteins cholesterol (HDL-c) levels and central fat. Access to additional well-characterized patient samples through collaborations allows us to conduct replication studies that validate true disease genes. These discoveries will expand our understanding of genetic disease predisposition, and our ability for early diagnosis and determination of specific disease subtype or progression stage.

Abel, Kenneth; Kammerer, Stefan; Hoyal, Carolyn; Reneland, Rikard; Marnellos, George; Nelson, Matthew R.; Braun, Andreas

2005-03-01

301

Circulating RNA Transcripts Identify Therapeutic Response in Cystic Fibrosis Lung Disease  

PubMed Central

Rationale: Circulating leukocyte RNA transcripts are systemic markers of inflammation, which have not been studied in cystic fibrosis (CF) lung disease. Although the standard assessment of pulmonary treatment response is FEV1, a measure of airflow limitation, the lack of systemic markers to reflect changes in lung inflammation critically limits the testing of proposed therapeutics. Objectives: We sought to prospectively identify and validate peripheral blood leukocyte genes that could mark resolution of pulmonary infection and inflammation using a model by which RNA transcripts could increase the predictive value of spirometry. Methods: Peripheral blood mononuclear cells were isolated from 10 patients with CF and acute pulmonary exacerbations before and after therapy. RNA expression profiling revealed that 10 genes significantly changed with treatment when compared with matched non-CF and control subjects with stable CF to establish baseline transcript abundance. Peripheral blood mononuclear cell RNA transcripts were prospectively validated, using real-time polymerase chain reaction amplification, in an independent cohort of acutely ill patients with CF (n = 14). Patients who responded to therapy were analyzed using general estimating equations and multiple logistic regression, such that changes in FEV1% predicted were regressed with transcript changes. Measurements and Main Results: Three genes, CD64, ADAM9, and CD36, were significant and independent predictors of a therapeutic response beyond that of FEV1 alone (P < 0.05). In both cohorts, receiver operating characteristic analysis revealed greater accuracy when genes were combined with FEV1. Conclusions: Circulating mononuclear cell transcripts characterize a response to the treatment of pulmonary exacerbations. Even in small patient cohorts, changes in gene expression in conjunction with FEV1 may enhance current outcomes measures for treatment response.

Saavedra, Milene T.; Hughes, Grant J.; Sanders, Linda A.; Carr, Michelle; Rodman, David M.; Coldren, Christopher D.; Geraci, Mark W.; Sagel, Scott D.; Accurso, Frank J.; West, James; Nick, Jerry A.

2008-01-01

302

Gene expression profiling defines molecular subtypes of classical Hodgkin's disease.  

PubMed

Although the prognosis of Hodgkin's disease is relatively good, around 20% of patients do not benefit from current therapies and succumb to their disease. A large-scale molecular characterization of disease might help improve HD management. Using cDNA arrays, we studied the mRNA expression levels of approximately 1000 selected genes in 34 benign and malignant lymphoid samples including 21 classical Hodgkin's disease (HD) tissue samples. Hierarchical clustering identified three main molecular groups of HD tumours relevant with respect to histology and clinical outcome (response to therapy and survival). Samples from all bad outcome HD (BOHD) patients clustered in one group whereas the two other groups contained most good outcome HD (GOHD) cases. The nodular sclerosis GOHD samples overexpressed genes involved in apoptotic induction and cell signalling, including cytokines, while the BOHD samples were characterized by the upregulation of genes involved in fibroblast activation, angiogenesis, extracellular matrix remodelling, cell proliferation, and the downregulation of tumour suppressor genes. Our results establish a molecular taxonomy of HD correlating with response to therapy and clinical outcome, thereby suggesting the possibility of improving the current prognostic classification. PMID:12082542

Devilard, Elisabeth; Bertucci, François; Trempat, Pascal; Bouabdallah, Reda; Loriod, Béatrice; Giaconia, Aurélia; Brousset, Pierre; Granjeaud, Samuel; Nguyen, Catherine; Birnbaum, Daniel; Birg, Françoise; Houlgatte, Remi; Xerri, Luc

2002-05-01

303

Novel variants identified in methyl-CpG-binding domain genes in autistic individuals  

PubMed Central

Misregulation of the methyl-CpG-binding protein 2 (MECP2) gene has been found to cause a myriad of neurological disorders including autism, mental retardation, seizures, learning disabilities, and Rett syndrome. We hypothesized that mutations in other members of the methyl-CpG-binding domain (MBD) family may also cause autistic features in individuals. We evaluated 226 autistic individuals for alterations in the four genes most homologous to MECP2: MBD1, MBD2, MBD3, and MBD4. A total of 46 alterations were identified in the four genes, including ten missense changes and two deletions that alter coding sequence. Several are either unique to our autistic population or cosegregate with affected individuals within a family, suggesting a possible relation of these variations to disease etiology. Variants include a R23M alteration in two affected half brothers which falls within the MBD domain of the MBD3 protein, as well as a frameshift in MBD4 that is predicted to truncate almost half of the protein. These results suggest that rare cases of autism may be influenced by mutations in members of the dynamic MBD protein family.

Cukier, Holly N.; Rabionet, Raquel; Konidari, Ioanna; Rayner-Evans, Melissa Y.; Baltos, Mary L.; Wright, Harry H.; Abramson, Ruth K.; Martin, Eden R.; Cuccaro, Michael L.; Pericak-Vance, Margaret A.

2010-01-01

304

Novel variants identified in methyl-CpG-binding domain genes in autistic individuals.  

PubMed

Misregulation of the methyl-CpG-binding protein 2 (MECP2) gene has been found to cause a myriad of neurological disorders including autism, mental retardation, seizures, learning disabilities, and Rett syndrome. We hypothesized that mutations in other members of the methyl-CpG-binding domain (MBD) family may also cause autistic features in individuals. We evaluated 226 autistic individuals for alterations in the four genes most homologous to MECP2: MBD1, MBD2, MBD3, and MBD4. A total of 46 alterations were identified in the four genes, including ten missense changes and two deletions that alter coding sequence. Several are either unique to our autistic population or cosegregate with affected individuals within a family, suggesting a possible relation of these variations to disease etiology. Variants include a R23M alteration in two affected half brothers which falls within the MBD domain of the MBD3 protein, as well as a frameshift in MBD4 that is predicted to truncate almost half of the protein. These results suggest that rare cases of autism may be influenced by mutations in members of the dynamic MBD protein family. PMID:19921286

Cukier, Holly N; Rabionet, Raquel; Konidari, Ioanna; Rayner-Evans, Melissa Y; Baltos, Mary L; Wright, Harry H; Abramson, Ruth K; Martin, Eden R; Cuccaro, Michael L; Pericak-Vance, Margaret A; Gilbert, John R

2009-11-18

305

An integrative genomics approach to infer causal associations between gene expression and disease  

Microsoft Academic Search

A key goal of biomedical research is to elucidate the complex network of gene interactions underlying complex traits such as common human diseases. Here we detail a multistep procedure for identifying potential key drivers of complex traits that integrates DNA-variation and gene-expression data with other complex trait data in segregating mouse populations. Ordering gene expression traits relative to one another

John Lamb; Xia Yang; Jun Zhu; Steve Edwards; Debraj GuhaThakurta; Solveig K Sieberts; Stephanie Monks; Marc Reitman; Chunsheng Zhang; Pek Yee Lum; Amy Leonardson; Rolf Thieringer; Joseph M Metzger; Liming Yang; John Castle; Haoyuan Zhu; Shera F Kash; Thomas A Drake; Alan Sachs; Aldons J Lusis; Eric E Schadt

2005-01-01

306

Meta-Analysis Approach identifies Candidate Genes and associated Molecular Networks for Type2 Diabetes Mellitus  

Microsoft Academic Search

BACKGROUND: Multiple functional genomics data for complex human diseases have been published and made available by researchers worldwide. The main goal of these studies is the detailed analysis of a particular aspect of the disease. Complementary, meta-analysis approaches try to extract supersets of disease genes and interaction networks by integrating and combining these individual studies using statistical approaches. RESULTS: Here

Axel Rasche; Hadi Al-Hasani; Ralf Herwig

2008-01-01

307

Using BLAST for identifying gene and protein names in journal articles  

Microsoft Academic Search

We describe a system which automatically identifies gene and protein names in journal articles, an important and non-trivial first step in knowledge extraction of protein and gene actions. Our system uses a database of gene and protein names and is based on BLAST [Altschul et al., Nucleic Acids Res. 25 (1997) 3389–3402], a popular tool for DNA and protein sequence

Michael Krauthammer; Andrey Rzhetsky; Pavel Morozov; Carol Friedman

2000-01-01

308

Decreased NURR1 gene expression in patients with Parkinson's disease  

PubMed Central

NURR1 is a transcription factor essential for the development, survival, and functional maintenance of midbrain dopaminergic (DAergic) neurons and NURR1 is a potential susceptibility gene for Parkinson’s disease (PD). To determine whether NURR1 gene expression is altered in patients with PD we measured its expression in human peripheral blood lymphocytes (PBL) in 278 patients with PD, 166 healthy controls (HC), and 256 neurological disease controls (NDC) by quantitative real-time PCR. NURR1 gene expression was significantly decreased in patients with PD (particularly those with family history of PD) as compared with HC (p < 0.01) and also as compared with NDC (p < 0.05). There was no significant difference in NURR1 gene expression among PD patients with or without anti-PD medications. When adjusted for gender, age, and ethnicity, lower levels of NURR1 gene expression were associated with significantly increased risk for PD in women, in patients 60 years old or older, and in patients of Caucasian origin. The observed reduction in PBL NURR1 gene expression indicates possible systemic involvement in PD, and the finding may help identify individuals with PD and other disorders associated with impaired central DAergic system.

Le, Weidong; Pan, Tianhong; Huang, Maosheng; Xu, Pingyi; Xie, Wenjie; Zhu, Wen; Zhang, Xiong; Deng, Hao; Jankovic, Joseph

2008-01-01

309

Gene therapy: progress in childhood disease.  

PubMed

The recent sequencing of the human genome combined with the development of massively high throughput genetic analysis technologies is driving unprecedented growth in our knowledge of the molecular basis of disease. While this has already had a major impact on our diagnostic power, the therapeutic benefits remain largely unrealised. This review examines progress in the exciting and challenging field of gene therapy. In particular we focus on the treatment of genetic disease in infants and children where the most significant successes have been observed to date, despite the majority of trial participants being adults. Notably, gene transfer to the haematopoietic compartment has provided the clearest examples of therapeutic benefit, particularly in the context of primary immunodeficiencies. The triumphs and tribulations of these successes are explored, and the key challenges confronting researchers as they seek to further advance the field are defined and discussed. PMID:22017270

Ginn, Samantha L; Alexander, Ian E

2011-10-21

310

Signature-Tagged Mutagenesis to Identify Virulence Genes in Salmonella choleraesuis  

Microsoft Academic Search

Signature-tagged mutagenesis is a functional genomics approach to identify bacterial virulence genes by simultaneously screening multiple mutants in a single host animal. Avirulent (attenuated) mutants are identified by negative selection (failure to colonize the host). The method was recently developed to investigate Salmonella typhimurium in a mouse model of human typhoid fever. We modified the protocol to investigate virulence genes

Carol A. Lichtensteiger; Eric R. Vimr

311

PCR-Based Strategy To Detect and Identify Species of Phaeoacremonium Causing Grapevine Diseases?  

PubMed Central

Species of Phaeoacremonium (especially Phaeoacremonium aleophilum) are associated with two severe diseases in grapevines, Petri disease in young plants and Esca disease in adult plants. Phaeoacremonium species grow slowly on culture medium, and it is difficult to identify these species on the basis of morphological characteristics. Primers Pm1 and Pm2 were designed in the ribosomal DNA internal transcribed spacer (ITS) regions ITS1 and ITS2, respectively. They yielded a single amplicon of 415 bp for nine species of Phaeoacremonium that may occur in grapevines. A nested PCR (using general fungal primers ITS1F/ITS4 in the primary reaction) was developed to detect Phaeoacremonium directly in grapevine wood. Molecular detection was more sensitive than the traditional method of culturing in growth medium was. Identification of Phaeoacremonium species was achieved by digesting the PCR-amplified fragment with the restriction enzymes BssKI, EcoO109I, and HhaI. It was possible to distinguish these species by their restriction fragment length polymorphism patterns, except for Phaeoacremonium viticola and Phaeoacremonium angustius, which had 100% similarity in their ITS region sequences. A species-specific PCR amplification of the partial ?-tubulin gene using the primer pair Pbr4_1/T1 and Pbr8/T1 was necessary to differentiate P. angustius from P. viticola, respectively. An easy and fast protocol was developed to detect and identify species of Phaeoacremonium in a few hours. Primers defined here can be used in a plant nursery sanitation program to produce plants free of Phaeoacremonium spp. Use of healthy grapevine plants in new plantations is the most effective measure to manage Petri disease.

Aroca, Angeles; Raposo, Rosa

2007-01-01

312

Disease-Specific Gene Expression Profiling in Multiple Models of Lung Disease  

PubMed Central

Rationale: Microarray technology is widely employed for studying the molecular mechanisms underlying complex diseases. However, analyses of individual diseases or models of diseases frequently yield extensive lists of differentially expressed genes with uncertain relationships to disease pathogenesis. Objectives: To compare gene expression changes in a heterogeneous set of lung disease models in order to identify common gene expression changes seen in diverse forms of lung pathology, as well as relatively small subsets of genes likely to be involved in specific pathophysiological processes. Methods: We profiled lung gene expression in 12 mouse models of infection, allergy, and lung injury. A linear model was used to estimate transcript expression changes for each model, and hierarchical clustering was used to compare expression patterns between models. Selected expression changes were verified by quantitative polymerase chain reaction. Measurements and Main Results: A total of 24 transcripts, including many involved in inflammation and immune activation, were differentially expressed in a substantial majority (9 or more) of the models. Expression patterns distinguished three groups of models: (1) bacterial infection (n = 5), with changes in 89 transcripts, including many related to nuclear factor-?B signaling, cytokines, chemokines, and their receptors; (2) bleomycin-induced diseases (n = 2), with changes in 53 transcripts, including many related to matrix remodeling and Wnt signaling; and (3) T helper cell type 2 (allergic) inflammation (n = 5), with changes in 26 transcripts, including many encoding epithelial secreted molecules, ion channels, and transporters. Conclusions: This multimodel dataset highlights novel genes likely involved in various pathophysiological processes and will be a valuable resource for the investigation of molecular mechanisms underlying lung disease pathogenesis.

Lewis, Christina C.; Yang, Jean Yee Hwa; Huang, Xiaozhu; Banerjee, Suman K.; Blackburn, Michael R.; Baluk, Peter; McDonald, Donald M.; Blackwell, Timothy S.; Nagabhushanam, Vijaya; Peters, Wendy; Voehringer, David; Erle, David J.

2008-01-01

313

Mouse Huntington's disease gene homolog ( Hdh )  

Microsoft Academic Search

The incurable neurodegenerative disorder, Huntington's disease (HD), is caused by an expanded, unstable CAG repeat encoding a stretch of polyglutamine in a 4p16.3 gene (HD) of unknown function. Near the CAG repeat is a polyproline-encoding CCG repeat that shows more limited allelic variation. The mouse homologue,Hdh, has been mapped to chromosome 5, in a region devoid of mutations causing any

Glenn T. Barnes; Mabel P. Duyao; Christine M. Ambrose; Sandra McNeil; Francesca Persichetti; Jayalakshmi Srinidhi; James F. Gusella; Marcy E. MacDonald

1994-01-01

314

Exome-based linkage disequilibrium maps of individual genes: functional clustering and relationship to disease.  

PubMed

Exome sequencing identifies thousands of DNA variants and a proportion of these are involved in disease. Genotypes derived from exome sequences provide particularly high-resolution coverage enabling study of the linkage disequilibrium structure of individual genes. The extent and strength of linkage disequilibrium reflects the combined influences of mutation, recombination, selection and population history. By constructing linkage disequilibrium maps of individual genes, we show that genes containing OMIM-listed disease variants are significantly under-represented amongst genes with complete or very strong linkage disequilibrium (P = 0.0004). In contrast, genes with disease variants are significantly over-represented amongst genes with levels of linkage disequilibrium close to the average for genes not known to contain disease variants (P = 0.0038). Functional clustering reveals, amongst genes with particularly strong linkage disequilibrium, significant enrichment of essential biological functions (e.g. phosphorylation, cell division, cellular transport and metabolic processes). Strong linkage disequilibrium, corresponding to reduced haplotype diversity, may reflect selection in utero against deleterious mutations which have profound impact on the function of essential genes. Genes with very weak linkage disequilibrium show enrichment of functions requiring greater allelic diversity (e.g. sensory perception and immune response). This category is not enriched for genes containing disease variation. In contrast, there is significant enrichment of genes containing disease variants amongst genes with more average levels of linkage disequilibrium. Mutations in these genes may less likely lead to in utero lethality and be subject to less intense selection. PMID:23124193

Gibson, Jane; Tapper, William; Ennis, Sarah; Collins, Andrew

2012-11-04

315

Synthetic lethal analysis of Caenorhabditis elegans posterior embryonic patterning genes identifies conserved genetic interactions  

Microsoft Academic Search

Phenotypic robustness is evidenced when single-gene mutations do not result in an obvious phenotype. It has been suggested\\u000a that such phenotypic stability results from 'buffering' activities of homologous genes as well as non-homologous genes acting\\u000a in parallel pathways. One approach to characterizing mechanisms of phenotypic robustness is to identify genetic interactions,\\u000a specifically, double mutants where buffering is compromised. To identify

L Ryan Baugh; Joanne C Wen; Andrew A Hill; Donna K Slonim; Eugene L Brown; Craig P Hunter

2005-01-01

316

Retinitis Pigmentosa: Genes and Disease Mechanisms  

PubMed Central

Retinitis pigmentosa (RP) is a group of inherited disorders affecting 1 in 3000-7000 people and characterized by abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium of the retina which lead to progressive visual loss. RP can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. While usually limited to the eye, RP may also occur as part of a syndrome as in the Usher syndrome and Bardet-Biedl syndrome. Over 40 genes have been associated with RP so far, with the majority of them expressed in either the photoreceptors or the retinal pigment epithelium. The tremendous heterogeneity of the disease makes the genetics of RP complicated, thus rendering genotype-phenotype correlations not fully applicable yet. In addition to the multiplicity of mutations, in fact, different mutations in the same gene may cause different diseases. We will here review which genes are involved in the genesis of RP and how mutations can lead to retinal degeneration. In the future, a more thorough analysis of genetic and clinical data together with a better understanding of the genotype-phenotype correlation might allow to reveal important information with respect to the likelihood of disease development and choices of therapy.

Ferrari, Stefano; Di Iorio, Enzo; Barbaro, Vanessa; Ponzin, Diego; Sorrentino, Francesco S; Parmeggiani, Francesco

2011-01-01

317

Loci influencing blood pressure identified using a cardiovascular gene-centric array.  

PubMed

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ?50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ?2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention. PMID:23303523

Ganesh, Santhi K; Tragante, Vinicius; Guo, Wei; Guo, Yiran; Lanktree, Matthew B; Smith, Erin N; Johnson, Toby; Castillo, Berta Almoguera; Barnard, John; Baumert, Jens; Chang, Yen-Pei Christy; Elbers, Clara C; Farrall, Martin; Fischer, Mary E; Franceschini, Nora; Gaunt, Tom R; Gho, Johannes M I H; Gieger, Christian; Gong, Yan; Isaacs, Aaron; Kleber, Marcus E; Mateo Leach, Irene; McDonough, Caitrin W; Meijs, Matthijs F L; Mellander, Olle; Molony, Cliona M; Nolte, Ilja M; Padmanabhan, Sandosh; Price, Tom S; Rajagopalan, Ramakrishnan; Shaffer, Jonathan; Shah, Sonia; Shen, Haiqing; Soranzo, Nicole; van der Most, Peter J; Van Iperen, Erik P A; Van Setten, Jessica; Van Setten, Jessic A; Vonk, Judith M; Zhang, Li; Beitelshees, Amber L; Berenson, Gerald S; Bhatt, Deepak L; Boer, Jolanda M A; Boerwinkle, Eric; Burkley, Ben; Burt, Amber; Chakravarti, Aravinda; Chen, Wei; Cooper-Dehoff, Rhonda M; Curtis, Sean P; Dreisbach, Albert; Duggan, David; Ehret, Georg B; Fabsitz, Richard R; Fornage, Myriam; Fox, Ervin; Furlong, Clement E; Gansevoort, Ron T; Hofker, Marten H; Hovingh, G Kees; Kirkland, Susan A; Kottke-Marchant, Kandice; Kutlar, Abdullah; Lacroix, Andrea Z; Langaee, Taimour Y; Li, Yun R; Lin, Honghuang; Liu, Kiang; Maiwald, Steffi; Malik, Rainer; Murugesan, Gurunathan; Newton-Cheh, Christopher; O'Connell, Jeffery R; Onland-Moret, N Charlotte; Ouwehand, Willem H; Palmas, Walter; Penninx, Brenda W; Pepine, Carl J; Pettinger, Mary; Polak, Joseph F; Ramachandran, Vasan S; Ranchalis, Jane; Redline, Susan; Ridker, Paul M; Rose, Lynda M; Scharnag, Hubert; Schork, Nicholas J; Shimbo, Daichi; Shuldiner, Alan R; Srinivasan, Sathanur R; Stolk, Ronald P; Taylor, Herman A; Thorand, Barbara; Trip, Mieke D; van Duijn, Cornelia M; Verschuren, W Monique; Wijmenga, Cisca; Winkelmann, Bernhard R; Wyatt, Sharon; Young, J Hunter; Boehm, Bernhard O; Caulfield, Mark J; Chasman, Daniel I; Davidson, Karina W; Doevendans, Pieter A; Fitzgerald, Garret A; Gums, John G; Hakonarson, Hakon; Hillege, Hans L; Illig, Thomas; Jarvik, Gail P; Johnson, Julie A; Kastelein, John J P; Koenig, Wolfgang; März, Winfried; Mitchell, Braxton D; Murray, Sarah S; Oldehinkel, Albertine J; Rader, Daniel J; Reilly, Muredach P; Reiner, Alex P; Schadt, Eric E; Silverstein, Roy L; Snieder, Harold; Stanton, Alice V; Uitterlinden, André G; van der Harst, Pim; van der Schouw, Yvonne T; Samani, Nilesh J; Johnson, Andrew D; Munroe, Patricia B; de Bakker, Paul I W; Zhu, Xiaofeng; Levy, Daniel; Keating, Brendan J; Asselbergs, Folkert W

2013-01-08

318

Identification of disease-causing genes using microarray data mining and Gene Ontology  

PubMed Central

Background One of the best and most accurate methods for identifying disease-causing genes is monitoring gene expression values in different samples using microarray technology. One of the shortcomings of microarray data is that they provide a small quantity of samples with respect to the number of genes. This problem reduces the classification accuracy of the methods, so gene selection is essential to improve the predictive accuracy and to identify potential marker genes for a disease. Among numerous existing methods for gene selection, support vector machine-based recursive feature elimination (SVMRFE) has become one of the leading methods, but its performance can be reduced because of the small sample size, noisy data and the fact that the method does not remove redundant genes. Methods We propose a novel framework for gene selection which uses the advantageous features of conventional methods and addresses their weaknesses. In fact, we have combined the Fisher method and SVMRFE to utilize the advantages of a filtering method as well as an embedded method. Furthermore, we have added a redundancy reduction stage to address the weakness of the Fisher method and SVMRFE. In addition to gene expression values, the proposed method uses Gene Ontology which is a reliable source of information on genes. The use of Gene Ontology can compensate, in part, for the limitations of microarrays, such as having a small number of samples and erroneous measurement results. Results The proposed method has been applied to colon, Diffuse Large B-Cell Lymphoma (DLBCL) and prostate cancer datasets. The empirical results show that our method has improved classification performance in terms of accuracy, sensitivity and specificity. In addition, the study of the molecular function of selected genes strengthened the hypothesis that these genes are involved in the process of cancer growth. Conclusions The proposed method addresses the weakness of conventional methods by adding a redundancy reduction stage and utilizing Gene Ontology information. It predicts marker genes for colon, DLBCL and prostate cancer with a high accuracy. The predictions made in this study can serve as a list of candidates for subsequent wet-lab verification and might help in the search for a cure for cancers.

2011-01-01

319

Interlocus gene conversion events introduce deleterious mutations into at least 1% of human genes associated with inherited disease  

PubMed Central

Establishing the molecular basis of DNA mutations that cause inherited disease is of fundamental importance to understanding the origin, nature, and clinical sequelae of genetic disorders in humans. The majority of disease-associated mutations constitute single-base substitutions and short deletions and/or insertions resulting from DNA replication errors and the repair of damaged bases. However, pathological mutations can also be introduced by nonreciprocal recombination events between paralogous sequences, a phenomenon known as interlocus gene conversion (IGC). IGC events have thus far been linked to pathology in more than 20 human genes. However, the large number of duplicated gene sequences in the human genome implies that many more disease-associated mutations could originate via IGC. Here, we have used a genome-wide computational approach to identify disease-associated mutations derived from IGC events. Our approach revealed hundreds of known pathological mutations that could have been caused by IGC. Further, we identified several dozen high-confidence cases of inherited disease mutations resulting from IGC in ?1% of all genes analyzed. About half of the donor sequences associated with such mutations are functional paralogous genes, suggesting that epistatic interactions or differential expression patterns will determine the impact upon fitness of specific substitutions between duplicated genes. In addition, we identified thousands of hitherto undescribed and potentially deleterious mutations that could arise via IGC. Our findings reveal the extent of the impact of interlocus gene conversion upon the spectrum of human inherited disease.

Casola, Claudio; Zekonyte, Ugne; Phillips, Andrew D.; Cooper, David N.; Hahn, Matthew W.

2012-01-01

320

Functional Genomics Approach to Identifying Genes Required for Biofilm Development by Streptococcus mutans  

Microsoft Academic Search

Streptococcus mutans, the primary etiological agent of human dental caries, is an obligate biofilm-forming bacterium. The goals of this study were to identify the gene(s) required for biofilm formation by this organism and to elucidate the role(s) that some of the known global regulators of gene expression play in controlling biofilm formation. In S. mutans UA159, the brpA gene (for

Zezhang T. Wen; Robert A. Burne

2002-01-01

321

Limits of resolution of genetic linkage studies: implications for the positional cloning of human disease genes.  

PubMed Central

Positional cloning studies to identify disease genes are being carried out for many human genetic diseases. Such studies often include a genome-scan linkage analysis to identify the rough chromosomal location of a disease gene, fine structure genetic mapping to define and narrow the chromosomal interval in which the disease gene may be located, and physical mapping and gene identification in the genetically defined interval to clone the disease gene. During the planning of a positional cloning study, it is important to know that, if linkage is found, the genetic interval identified is likely to be sufficiently narrow to be dissected efficiently by methods of physical mapping and gene identification. Thus, we wish to know the limits of resolution of a genetic linkage study. In this paper, I determine for Mendelian diseases the distributions and moments of three measures of linkage resolution: (1) in a set of N chromosomes, the distance between the nearest crossovers that flank a disease locus, (2) the distance between the nearest genetic markers that flank the pair of flanking crossovers after a genome scan, and (3) the distance between the nearest flanking markers after additional randomly placed markers are generated and typed in an identified interval. These results provide explicit sample-size guidelines for future positional cloning studies of Mendelian diseases and make possible a more objective evaluation of whether a proposed positional cloning study is likely to be successful. I also briefly discuss the more difficult problem of linkage resolution for complex genetic diseases.

Boehnke, M.

1994-01-01

322

Prion disease induced alterations in gene expression in spleen and brain prior to clinical symptoms  

PubMed Central

Prion diseases are fatal neurodegenerative disorders that affect animals and humans. There is a need to gain understanding of prion disease pathogenesis and to develop diagnostic assays to detect prion diseases prior to the onset of clinical symptoms. The goal of this study was to identify genes that show altered expression early in the disease process in the spleen and brain of prion disease-infected mice. Using Affymetrix microarrays, we identified 67 genes that showed increased expression in the brains of prion disease-infected mice prior to the onset of clinical symptoms. These genes function in many cellular processes including immunity, the endosome/lysosome system, hormone activity, and the cytoskeleton. We confirmed a subset of these gene expression alterations using other methods and determined the time course in which these changes occur. We also identified 14 genes showing altered expression prior to the onset of clinical symptoms in spleens of prion disease infected mice. Interestingly, four genes, Atp1b1, Gh, Anp32a, and Grn, were altered at the very early time of 46 days post-infection. These gene expression alterations provide insights into the molecular mechanisms underlying prion disease pathogenesis and may serve as surrogate markers for the early detection and diagnosis of prion disease.

Kim, Hyeon O; Snyder, Greg P; Blazey, Tyler M; Race, Richard E; Chesebro, Bruce; Skinner, Pamela J

2008-01-01

323

Using functional genomics to identify drug targets: a Dupuytren's disease example.  

PubMed

Research into the molecular mechanism of Dupuytren's disease (DD) illustrates all the problems common to drug discovery in orphan diseases, but also in more commonly investigated ailments. Current findings characterize DD as a disease with complex molecular pathology, with changes in expression of multiple genes and proteins as well as many contributing risk factors. Some of the observed changes include genes and proteins that have been identified in a number of other pathological processes, such as TGF-?, some which may be more specific to DD, such as ADAM12, and undoubtedly also some that have yet to be discovered in future studies. When all these results are taken into consideration, it can be deduced that DD is an end result of several pathological processes that can have many points of origin, and probably involves several subtypes that give rise to sufficiently similar clinical symptoms to be unified under a single medical term. Such breadth of view has become possible with the advent of functional genomics methods and system-wide overview of the molecular processes, which highlight molecular players and processes that might not be intuitively obvious from symptoms, as is the case with the observed parallels with wound-healing processes. As functional genomics methods allow researchers to compile a more complete image of the molecular mechanisms involved in DD pathogenesis, they also help to propose new drug targets that can be employed to develop an effective pharmacological treatment for DD. Identification of key molecular players in DD has already benefited from the integration of functional genomics and biocomputational methods, and such approach may reveal new ways how we can interfere with the emergence of the DD phenotype. PMID:22821590

Sedic, Mirela; Pavelic, Sandra Kraljevic; Hock, Karlo

2012-01-01

324

Plant disease resistance genes: recent insights and potential applications  

Microsoft Academic Search

Plant disease resistance genes (R genes) encode proteins that detect pathogens. R genes have been used in resistance breeding programs for decades, with varying degrees of success. Recent molecular research on R proteins and downstream signal transduction networks has provided exciting insights, which will enhance the use of R genes for disease control. Definition of conserved structural motifs in R

John M. McDowell; Bonnie J. Woffenden

2003-01-01

325

PKD2, a Gene for Polycystic Kidney Disease That Encodes an Integral Membrane Protein  

Microsoft Academic Search

A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning. Nonsense mutations in this gene (PKD2) segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis elegans homolog

Toshio Mochizuki; Guanqing Wu; Tomohito Hayashi; Stavroulla L. Xenophontos; Barbera Veldhuisen; Jasper J. Saris; David M. Reynolds; Yiqiang Cai; Patricia A. Gabow; Alkis Pierides; William J. Kimberling; Martijn H. Breuning; C. Constantinou Deltas; Dorien J. M. Peters; Stefan Somlo

1996-01-01

326

The KM-Algorithm Identifies Regulated Genes in Time Series Expression Data  

PubMed Central

We present a statistical method to rank observed genes in gene expression time series experiments according to their degree of regulation in a biological process. The ranking may be used to focus on specific genes or to select meaningful subsets of genes from which gene regulatory networks can be built. Our approach is based on a state space model that incorporates hidden regulators of gene expression. Kalman (K) smoothing and maximum (M) likelihood estimation techniques are used to derive optimal estimates of the model parameters upon which a proposed regulation criterion is based. The statistical power of the proposed algorithm is investigated, and a real data set is analyzed for the purpose of identifying regulated genes in time dependent gene expression data. This statistical approach supports the concept that meaningful biological conclusions can be drawn from gene expression time series experiments by focusing on strong regulation rather than large expression values.

Bremer, Martina; Doerge, R. W.

2009-01-01

327

A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci.  

PubMed

A genome-wide association study was performed to identify genetic factors involved in susceptibility to psoriasis (PS) and psoriatic arthritis (PSA), inflammatory diseases of the skin and joints in humans. 223 PS cases (including 91 with PSA) were genotyped with 311,398 single nucleotide polymorphisms (SNPs), and results were compared with those from 519 Northern European controls. Replications were performed with an independent cohort of 577 PS cases and 737 controls from the U.S., and 576 PSA patients and 480 controls from the U.K.. Strongest associations were with the class I region of the major histocompatibility complex (MHC). The most highly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C (P = 7.8x10(-11), GWA scan; P = 1.8x10(-30), replication; P = 1.8x10(-39), combined; U.K. PSA: P = 6.9x10(-11)). However, rs2395029 encoding the G2V polymorphism within the class I gene HCP5 (combined P = 2.13x10(-26) in U.S. cases) yielded the highest ORs with both PS and PSA (4.1 and 3.2 respectively). This variant is associated with low viral set point following HIV infection and its effect is independent of rs10484554. We replicated the previously reported association with interleukin 23 receptor and interleukin 12B (IL12B) polymorphisms in PS and PSA cohorts (IL23R: rs11209026, U.S. PS, P = 1.4x10(-4); U.K. PSA: P = 8.0x10(-4); IL12B:rs6887695, U.S. PS, P = 5x10(-5) and U.K. PSA, P = 1.3x10(-3)) and detected an independent association in the IL23R region with a SNP 4 kb upstream from IL12RB2 (P = 0.001). Novel associations replicated in the U.S. PS cohort included the region harboring lipoma HMGIC fusion partner (LHFP) and conserved oligomeric golgi complex component 6 (COG6) genes on chromosome 13q13 (combined P = 2x10(-6) for rs7993214; OR = 0.71), the late cornified envelope gene cluster (LCE) from the Epidermal Differentiation Complex (PSORS4) (combined P = 6.2x10(-5) for rs6701216; OR 1.45) and a region of LD at 15q21 (combined P = 2.9x10(-5) for rs3803369; OR = 1.43). This region is of interest because it harbors ubiquitin-specific protease-8 whose processed pseudogene lies upstream from HLA-C. This region of 15q21 also harbors the gene for SPPL2A (signal peptide peptidase like 2a) which activates tumor necrosis factor alpha by cleavage, triggering the expression of IL12 in human dendritic cells. We also identified a novel PSA (and potentially PS) locus on chromosome 4q27. This region harbors the interleukin 2 (IL2) and interleukin 21 (IL21) genes and was recently shown to be associated with four autoimmune diseases (Celiac disease, Type 1 diabetes, Grave's disease and Rheumatoid Arthritis). PMID:18369459

Liu, Ying; Helms, Cynthia; Liao, Wilson; Zaba, Lisa C; Duan, Shenghui; Gardner, Jennifer; Wise, Carol; Miner, Andrew; Malloy, M J; Pullinger, Clive R; Kane, John P; Saccone, Scott; Worthington, Jane; Bruce, Ian; Kwok, Pui-Yan; Menter, Alan; Krueger, James; Barton, Anne; Saccone, Nancy L; Bowcock, Anne M

2008-03-28

328

CFTR gene mutations in isolated chronic obstructive pulmonary disease  

SciTech Connect

In order to identify a possible hereditary predisposition to the development of chronic obstructive pulmonary disease (COPD), we have looked for the presence of cystic fibrosis transmembrane regulator (CFTR) gene DNA sequence modifications in 28 unrelated patients with no signs of cystic fibrosis. The known mutations in Italian CF patients, as well as the most frequent worldwide CF mutations, were investigated. In addition, a denaturing gradient gel electrophoresis analysis of about half of the coding sequence of the gene in 56 chromosomes from the patients and in 102 chromosomes from control individuals affected by other pulmonary diseases and from normal controls was performed. Nine different CFTR gene mutations and polymorphisms were found in seven patients, a highly significant increase over controls. Two of the patients were compound heterozygotes. Two frequent CF mutations were detected: deletion F508 and R117H; two rare CF mutations: R1066C and 3667ins4; and five CF sequence variants: R75Q (which was also described as a disease-causing mutation in male sterility cases due to the absence of the vasa deferentia), G576A, 2736 A{r_arrow}G, L997F, and 3271+18C{r_arrow}T. Seven (78%) of the mutations are localized in transmembrane domains. Six (86%) of the patients with defined mutations and polymorphisms had bronchiectasis. These results indicate that CFTR gene mutations and sequence alterations may be involved in the etiopathogenesis of some cases of COPD.

Pignatti, P.F.; Bombien, C.; Marigo, C. [and others

1994-09-01

329

The impact of self-identified race on epidemiologic studies of gene expression.  

PubMed

Although population differences in gene expression have been established, the impact on differential gene expression studies in large populations is not well understood. We describe the effect of self-reported race on a gene expression study of lung function in asthma. We generated gene expression profiles for 254 young adults (205 non-Hispanic whites and 49 African Americans) with asthma on whom concurrent total RNA derived from peripheral blood CD4(+) lymphocytes and lung function measurements were obtained. We identified four principal components that explained 62% of the variance in gene expression. The dominant principal component, which explained 29% of the total variance in gene expression, was strongly associated with self-identified race (P<10(-16)). The impact of these racial differences was observed when we performed differential gene expression analysis of lung function. Using multivariate linear models, we tested whether gene expression was associated with a quantitative measure of lung function: pre-bronchodilator forced expiratory volume in one second (FEV(1)). Though unadjusted linear models of FEV(1) identified several genes strongly correlated with lung function, these correlations were due to racial differences in the distribution of both FEV(1) and gene expression, and were no longer statistically significant following adjustment for self-identified race. These results suggest that self-identified race is a critical confounding covariate in epidemiologic studies of gene expression and that, similar to genetic studies, careful consideration of self-identified race in gene expression profiling studies is needed to avoid spurious association. PMID:21254216

Sharma, Sunita; Murphy, Amy; Howrylak, Judie; Himes, Blanca; Cho, Michael H; Chu, Jen-Hwa; Hunninghake, Gary M; Fuhlbrigge, Anne; Klanderman, Barbara; Ziniti, John; Senter-Sylvia, Jody; Liu, Andy; Szefler, Stanley J; Strunk, Robert; Castro, Mario; Hansel, Nadia N; Diette, Gregory B; Vonakis, Becky M; Adkinson, N Franklin; Carey, Vincent J; Raby, Benjamin A

2011-02-01

330

Gene, pathway and network frameworks to identify epistatic interactions of single nucleotide polymorphisms derived from GWAS data  

PubMed Central

Background Interactions among genomic loci (also known as epistasis) have been suggested as one of the potential sources of missing heritability in single locus analysis of genome-wide association studies (GWAS). The computational burden of searching for interactions is compounded by the extremely low threshold for identifying significant p-values due to multiple hypothesis testing corrections. Utilizing prior biological knowledge to restrict the set of candidate SNP pairs to be tested can alleviate this problem, but systematic studies that investigate the relative merits of integrating different biological frameworks and GWAS data have not been conducted. Results We developed four biologically based frameworks to identify pairwise interactions among candidate SNP pairs as follows: (1) for each human protein-coding gene, a set of SNPs associated with that gene was constructed providing a gene-based interaction model, (2) for each known biological pathway, a set of SNPs associated with the genes in the pathway was constructed providing a pathway-based interaction model, (3) a set of SNPs associated with genes in a disease-related subnetwork provides a network-based interaction model, and (4) a framework is based on the function of SNPs. The last approach uses expression SNPs (eSNPs or eQTLs), which are SNPs or loci that have defined effects on the abundance of transcripts of other genes. We constructed pairs of eSNPs and SNPs located in the target genes whose expression is regulated by eSNPs. For all four frameworks the SNP sets were exhaustively tested for pairwise interactions within the sets using a traditional logistic regression model after excluding genes that were previously identified to associate with the trait. Using previously published GWAS data for type 2 diabetes (T2D) and the biologically based pair-wise interaction modeling, we identify twelve genes not seen in the previous single locus analysis. Conclusion We present four approaches to detect interactions associated with complex diseases. The results show our approaches outperform the traditional single locus approaches in detecting genes that previously did not reach significance; the results also provide novel drug targets and biomarkers relevant to the underlying mechanisms of disease.

2012-01-01

331

Current Status of Gene Therapy for Inherited Lung Diseases  

PubMed Central

Gene therapy as a treatment modality for pulmonary disorders has attracted significant interest over the past decade. Since the initiation of the first clinical trials for cystic fibrosis lung disease using recombinant adenovirus in the early 1990s, the field has encountered numerous obstacles including vector inflammation, inefficient delivery, and vector production. Despite these obstacles, enthusiasm for lung gene therapy remains high. In part, this enthusiasm is fueled through the diligence of numerous researchers whose studies continue to reveal great potential of new gene transfer vectors that demonstrate increased tropism for airway epithelia. Several newly identified serotypes of adeno-associated virus have demonstrated substantial promise in animal models and will likely surface soon in clinical trials. Furthermore, an increased understanding of vector biology has also led to the development of new technologies to enhance the efficiency and selectivity of gene delivery to the lung. Although the promise of gene therapy to the lung has yet to be realized, the recent concentrated efforts in the field that focus on the basic virology of vector development will undoubtedly reap great rewards over the next decade in treating lung diseases.

Driskell, Ryan R.; Engelhardt, John F.

2007-01-01

332

Gene Expression Signature-Based Screening Identifies New Broadly Effective Influenza A Antivirals  

PubMed Central

Classical antiviral therapies target viral proteins and are consequently subject to resistance. To counteract this limitation, alternative strategies have been developed that target cellular factors. We hypothesized that such an approach could also be useful to identify broad-spectrum antivirals. The influenza A virus was used as a model for its viral diversity and because of the need to develop therapies against unpredictable viruses as recently underlined by the H1N1 pandemic. We proposed to identify a gene-expression signature associated with infection by different influenza A virus subtypes which would allow the identification of potential antiviral drugs with a broad anti-influenza spectrum of activity. We analyzed the cellular gene expression response to infection with five different human and avian influenza A virus strains and identified 300 genes as differentially expressed between infected and non-infected samples. The most 20 dysregulated genes were used to screen the connectivity map, a database of drug-associated gene expression profiles. Candidate antivirals were then identified by their inverse correlation to the query signature. We hypothesized that such molecules would induce an unfavorable cellular environment for influenza virus replication. Eight potential antivirals including ribavirin were identified and their effects were tested in vitro on five influenza A strains. Six of the molecules inhibited influenza viral growth. The new pandemic H1N1 virus, which was not used to define the gene expression signature of infection, was inhibited by five out of the eight identified molecules, demonstrating that this strategy could contribute to identifying new broad anti-influenza agents acting on cellular gene expression. The identified infection signature genes, the expression of which are modified upon infection, could encode cellular proteins involved in the viral life cycle. This is the first study showing that gene expression-based screening can be used to identify antivirals. Such an approach could accelerate drug discovery and be extended to other pathogens.

Josset, Laurence; Textoris, Julien; Loriod, Beatrice; Ferraris, Olivier; Moules, Vincent; Lina, Bruno; N'Guyen, Catherine; Diaz, Jean-Jacques; Rosa-Calatrava, Manuel

2010-01-01

333

Detecting gene-gene interactions that underlie human diseases  

PubMed Central

Following the identification of several disease-associated polymorphisms by whole genome association analysis, interest is now focussing on the detection of effects that, due to their interaction with other genetic (or environmental) factors, may not be identified by using standard single-locus tests. In addition to increasing power to detect association, there is also a hope detecting interactions between loci will allow us to elucidate the biological and biochemical pathways underpinning disease. Here I provide a critical survey of the current methodological approaches (and related software packages) used to detect interactions between genetic loci that contribute to human genetic disease. I also discuss the difficulties in determining the biologcal relevance of statistical interactions.

Cordell, Heather J.

2010-01-01

334

A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model.  

PubMed

Elevations of circulating Fibroblast growth factor 23 (FGF23) are associated with adverse cardiovascular outcomes and progression of renal failure in chronic kidney disease (CKD). Efforts to identify gene products whose transcription is directly regulated by FGF23 stimulation of fibroblast growth factor receptors (FGFR)/?-Klotho complexes in the kidney is confounded by both systemic alterations in calcium, phosphorus and vitamin D metabolism and intrinsic alterations caused by the underlying renal pathology in CKD. To identify FGF23 responsive genes in the kidney that might explain the association between FGF23 and adverse outcomes in CKD, we performed comparative genome wide analysis of gene expression profiles in the kidney of the Collagen 4 alpha 3 null mice (Col4a3(-/-)) model of progressive kidney disease with kidney expression profiles of Hypophosphatemic (Hyp) and FGF23 transgenic mouse models of elevated FGF23. The different complement of potentially confounding factors in these models allowed us to identify genes that are directly targeted by FGF23. This analysis found that ?-Klotho, an anti-aging hormone and FGF23 co-receptor, was decreased by FGF23. We also identified additional FGF23-responsive transcripts and activation of networks associated with renal damage and chronic inflammation, including lipocalin 2 (Lcn2), transforming growth factor beta (TGF-?) and tumor necrosis factor-alpha (TNF-?) signaling pathways. Finally, we found that FGF23 suppresses angiotensin-converting enzyme 2 (ACE2) expression in the kidney, thereby providing a pathway for FGF23 regulation of the renin-angiotensin system. These gene products provide a possible mechanistic links between elevated FGF23 and pathways responsible for renal failure progression and cardiovascular diseases. PMID:22970174

Dai, Bing; David, Valentin; Martin, Aline; Huang, Jinsong; Li, Hua; Jiao, Yan; Gu, Weikuan; Quarles, L Darryl

2012-09-06

335

Caenorhabditis elegans as a model system for identifying effectors of ?-synuclein misfolding and dopaminergic cell death associated with Parkinson's disease.  

PubMed

Protein misfolding and aggregation are key pathological features observed in numerous neurodegenerative diseases, including the misfolding of ?-synuclein (?-syn) in Parkinson's disease (PD) and ?-amyloid in Alzheimer's disease. While this phenomenon is widely observed, the etiology and progression of these diseases is not fully understood. Furthermore, there is a lack of therapeutic treatments directed at halting the progression and neurodegeneration associated with these diseases. This demands a need for an inexpensive, easy to manipulate multicellular organism to conduct both genetic and chemical screens within to identify factors that may play a pivotal role in the pathology of these diseases. Herein, we describe methodology involved in identifying genetic modifiers of ?-syn misfolding and toxicity in the nematode roundworm, Caenorhabditis elegans. Transgenic nematodes engineered to express human ?-syn in the body wall muscles or dopaminergic (DA) neurons result in formation of cytoplasmic puncta or DA neurodegeneration, respectively. Using these models, we describe the use of RNA interference (RNAi) and transgenic gene expression to functionally elucidate potential therapeutic gene targets that alter ?-syn misfolding and DA neurotoxicity. PMID:21195766

Harrington, Adam J; Knight, Adam L; Caldwell, Guy A; Caldwell, Kim A

2010-12-31

336

Systematic 16S rRNA Gene Sequencing of Atypical Clinical Isolates Identified 27 New Bacterial Species Associated with Humans  

PubMed Central

Clinical microorganisms isolated during a 5-year study in our hospital that could not be identified by conventional criteria were studied by 16S rRNA gene sequence analysis. Each isolate yielded a ?1,400-bp sequence containing <5 ambiguities which was compared with the GenBank 16S rRNA gene library; 1,404 such isolates were tested, and 120 were considered unique (27 isolates) or rare (?10 cases reported in the literature) human pathogens. Eleven new species, “Actinobaculum massiliae,” “Candidatus Actinobaculum timonae,” Paenibacillus sanguinis, “Candidatus Bacteroides massiliae,” Chryseobacterium massiliae, “Candidatus Chryseobacterium timonae,” Paenibacillus massiliensis, “Candidatus Peptostreptococcus massiliae,” “Candidatus Prevotella massiliensis,” Rhodobacter massiliensis, and “Candidatus Veillonella atypica” were identified. Sixteen species were obtained from humans for the first time. Our results show the important role that 16S rRNA gene sequence-based bacterial identification currently plays in recognizing unusual and emerging bacterial diseases.

Drancourt, M.; Berger, P.; Raoult, D.

2004-01-01

337

Association study of cholesterol-related genes in Alzheimer's disease.  

PubMed

Alzheimer's disease (AD) is a genetically complex disorder, and several genes related to cholesterol metabolism have been reported to contribute to AD risk. To identify further AD susceptibility genes, we have screened genes that map to chromosomal regions with high logarithm of the odds scores for AD in full genome scans and are related to cholesterol metabolism. In a European screening sample of 115 sporadic AD patients and 191 healthy control subjects, we analyzed single nucleotide polymorphisms in 28 cholesterol-related genes for association with AD. The genes HMGCS2, FDPS, RAFTLIN, ACAD8, NPC2, and ABCG1 were associated with AD at a significance level of P < or = 0.05 in this sample. Replication trials in five independent European samples detected associations of variants within HMGCS2, FDPS, NPC2, or ABCG1 with AD in some samples (P = 0.05 to P = 0.005). We did not identify a marker that was significantly associated with AD in the pooled sample (n = 2864). Stratification of this sample revealed an APOE-dependent association of HMGCS2 with AD (P = 0.004). We conclude that genetic variants investigated in this study may be associated with a moderate modification of the risk for AD in some samples. PMID:17387528

Wollmer, M Axel; Sleegers, Kristel; Ingelsson, Martin; Zekanowski, Cezary; Brouwers, Nathalie; Maruszak, Aleksandra; Brunner, Fabienne; Huynh, Kim-Dung; Kilander, Lena; Brundin, Rose-Marie; Hedlund, Marie; Giedraitis, Vilmantas; Glaser, Anna; Engelborghs, Sebastiaan; De Deyn, Peter P; Kapaki, Elisabeth; Tsolaki, Magdalini; Daniilidou, Makrina; Molyva, Dimitra; Paraskevas, George P; Thal, Dietmar R; Barcikowska, Maria; Kuznicki, Jacek; Lannfelt, Lars; Van Broeckhoven, Christine; Nitsch, Roger M; Hock, Christoph; Papassotiropoulos, Andreas

2007-03-27

338

Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease.  

PubMed

Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most ?20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease. PMID:21151126

Momozawa, Yukihide; Mni, Myriam; Nakamura, Kayo; Coppieters, Wouter; Almer, Sven; Amininejad, Leila; Cleynen, Isabelle; Colombel, Jean-Frédéric; de Rijk, Peter; Dewit, Olivier; Finkel, Yigael; Gassull, Miquel A; Goossens, Dirk; Laukens, Debby; Lémann, Marc; Libioulle, Cécile; O'Morain, Colm; Reenaers, Catherine; Rutgeerts, Paul; Tysk, Curt; Zelenika, Diana; Lathrop, Mark; Del-Favero, Jurgen; Hugot, Jean-Pierre; de Vos, Martine; Franchimont, Denis; Vermeire, Severine; Louis, Edouard; Georges, Michel

2010-12-12

339

Identifying the susceptibility gene(s) in a set of trait-linked genes using genotype data.  

PubMed Central

There are generally three steps to isolate a disease linkage-susceptibility gene: genome-wide scan, fine mapping, and, last, positional cloning. The last step is time consuming and involves intensive laboratory work. In some cases, fine mapping cannot proceed further on a set of markers because they are tightly linked. For years, genetic statisticians have been trying different ways to narrow the fine-mapping results to provide some guidance for the next step of laboratory work. Although these methods are practical and efficient, most of them are based on IBD data, which usually can be inferred only from the genotype data with some uncertainty. The corresponding methods thus have no greater power than one using genotype data directly. Also, IBD-based methods apply only to relative pair data. Here, using genotype data, we have developed a statistical hypothesis-testing method to pinpoint a SNP, or SNPs, suspected of responsibility for a disease trait linkage among a set of SNPs tightly linked in a region. Our method uses genotype data of affected individuals or case-control studies, which are widely available in the laboratory. The testing statistic can be constructed using any genotype-based disease-marker disequilibrium measure and is asymptotically distributed as a chi-square mixture. This method can be used for singleton data, relative pair data, or general pedigree data. We have applied the method to simulated data as well as a real data set; it gives satisfactory results.

Yuan, Ao; Chen, Guanjie; Chen, Yuanxiu; Rotimi, Charles; Bonney, George E

2004-01-01

340

Systems Biology Approach to Identify Gene Network Signatures for Colorectal Cancer  

PubMed Central

In this work, we integrated prior knowledge from gene signatures and protein interactions with gene set enrichment analysis (GSEA), and gene/protein network modeling together to identify gene network signatures from gene expression microarray data. We demonstrated how to apply this approach into discovering gene network signatures for colorectal cancer (CRC) from microarray datasets. First, we used GSEA to analyze the microarray data through enriching differential genes in different CRC-related gene sets from two publicly available up-to-date gene set databases – Molecular Signatures Database (MSigDB) and Gene Signatures Database (GeneSigDB). Second, we compared the enriched gene sets through enrichment score, false-discovery rate, and nominal p-value. Third, we constructed an integrated protein–protein interaction (PPI) network through connecting these enriched genes by high-quality interactions from a human annotated and predicted protein interaction database, with a confidence score labeled for each interaction. Finally, we mapped differential gene expressions onto the constructed network to build a comprehensive network model containing visualized transcriptome and proteome data. The results show that although MSigDB has more CRC-relevant gene sets than GeneSigDB, the integrated PPI network connecting the enriched genes from both MSigDB and GeneSigDB can provide a more complete view for discovering gene network signatures. We also found several important sub-network signatures for CRC, such as TP53 sub-network, PCNA sub-network, and IL8 sub-network, corresponding to apoptosis, DNA repair, and immune response, respectively.

Sonachalam, Madhankumar; Shen, Jeffrey; Huang, Hui; Wu, Xiaogang

2012-01-01

341

A vertex similarity-based framework to discover and rank orphan disease-related genes  

PubMed Central

Background A rare or orphan disease (OD) is any disease that affects a small percentage of the population. While opportunities now exist to accelerate progress toward understanding the basis for many more ODs, the prioritization of candidate genes is still a critical step for disease-gene identification. Several network-based frameworks have been developed to address this problem with varied results. Result We have developed a novel vertex similarity (VS) based parameter-free prioritizing framework to identify and rank orphan disease candidate genes. We validate our approach by using 1598 known orphan disease-causing genes (ODGs) representing 172 orphan diseases (ODs). We compare our approach with a state-of-art parameter-based approach (PageRank with Priors or PRP) and with another parameter-free method (Interconnectedness or ICN). Our results show that VS-based approach outperforms ICN and is comparable to PRP. We further apply VS-based ranking to identify and rank potential novel candidate genes for several ODs. Conclusion We demonstrate that VS-based parameter-free ranking approach can be successfully used for disease candidate gene prioritization and can complement other network-based methods for candidate disease gene ranking. Importantly, our VS-ranked top candidate genes for the ODs match the known literature, suggesting several novel causal relationships for further investigation.

2012-01-01

342

Gene expression profiling and candidate gene resequencing identifies pathways and mutations important for malignant transformation caused by leukemogenic fusion genes.  

PubMed

NUP98-HOXD13 (NHD13) and CALM-AF10 (CA10) are oncogenic fusion proteins produced by recurrent chromosomal translocations in patients with acute myeloid leukemia (AML). Transgenic mice that express these fusions develop AML with a long latency and incomplete penetrance, suggesting that collaborating genetic events are required for leukemic transformation. We employed genetic techniques to identify both preleukemic abnormalities in healthy transgenic mice as well as collaborating events leading to leukemic transformation. Candidate gene resequencing revealed that 6 of 27 (22%) CA10 AMLs spontaneously acquired a Ras pathway mutation and 8 of 27 (30%) acquired an Flt3 mutation. Two CA10 AMLs acquired an Flt3 internal-tandem duplication, demonstrating that these mutations can be acquired in murine as well as human AML. Gene expression profiles revealed a marked upregulation of Hox genes, particularly Hoxa5, Hoxa9, and Hoxa10 in both NHD13 and CA10 mice. Furthermore, mir196b, which is embedded within the Hoxa locus, was overexpressed in both CA10 and NHD13 samples. In contrast, the Hox cofactors Meis1 and Pbx3 were differentially expressed; Meis1 was increased in CA10 AMLs but not NHD13 AMLs, whereas Pbx3 was consistently increased in NHD13 but not CA10 AMLs. Silencing of Pbx3 in NHD13 cells led to decreased proliferation, increased apoptosis, and decreased colony formation in vitro, suggesting a previously unexpected role for Pbx3 in leukemic transformation. PMID:22885519

Novak, Rachel L; Harper, David P; Caudell, David; Slape, Christopher; Beachy, Sarah H; Aplan, Peter D

2012-08-08

343

Genes identified by visible mutant phenotypes show increased bias toward one of two subgenomes of maize.  

PubMed

Not all genes are created equal. Despite being supported by sequence conservation and expression data, knockout homozygotes of many genes show no visible effects, at least under laboratory conditions. We have identified a set of maize (Zea mays L.) genes which have been the subject of a disproportionate share of publications recorded at MaizeGDB. We manually anchored these "classical" maize genes to gene models in the B73 reference genome, and identified syntenic orthologs in other grass genomes. In addition to proofing the most recent version 2 maize gene models, we show that a subset of these genes, those that were identified by morphological phenotype prior to cloning, are retained at syntenic locations throughout the grasses at much higher levels than the average expressed maize gene, and are preferentially found on the maize1 subgenome even with a duplicate copy is still retained on the opposite subgenome. Maize1 is the subgenome that experienced less gene loss following the whole genome duplication in maize lineage 5-12 million years ago and genes located on this subgenome tend to be expressed at higher levels in modern maize. Links to the web based software that supported our syntenic analyses in the grasses should empower further research and support teaching involving the history of maize genetic research. Our findings exemplify the concept of "grasses as a single genetic system," where what is learned in one grass may be applied to another. PMID:21423772

Schnable, James C; Freeling, Michael

2011-03-10

344

ALK1 signalling analysis identifies angiogenesis related genes and reveals disparity between TGF-? and constitutively active receptor induced gene expression  

PubMed Central

Background TGF-?1 is an important angiogenic factor involved in the different aspects of angiogenesis and vessel maintenance. TGF-? signalling is mediated by the T?RII/ALK5 receptor complex activating the Smad2/Smad3 pathway. In endothelial cells TGF-? utilizes a second type I receptor, ALK1, activating the Smad1/Smad5 pathway. Consequently, a perturbance of ALK1, ALK5 or T?RII activity leads to vascular defects. Mutations in ALK1 cause the vascular disorder hereditary hemorrhagic telangiectasia (HHT). Methods The identification of ALK1 and not ALK5 regulated genes in endothelial cells, might help to better understand the development of HHT. Therefore, the human microvascular endothelial cell line HMEC-1 was infected with a recombinant constitutively active ALK1 adenovirus, and gene expression was studied by using gene arrays and quantitative real-time PCR analysis. Results After 24 hours, 34 genes were identified to be up-regulated by ALK1 signalling. Analysing ALK1 regulated gene expression after 4 hours revealed 13 genes to be up- and 2 to be down-regulated. Several of these genes, including IL-8, ET-1, ID1, HPTP? and TEAD4 are reported to be involved in angiogenesis. Evaluation of ALK1 regulated gene expression in different human endothelial cell types was not in complete agreement. Further on, disparity between constitutively active ALK1 and TGF-?1 induced gene expression in HMEC-1 cells and primary HUVECs was observed. Conclusion Gene array analysis identified 49 genes to be regulated by ALK1 signalling and at least 14 genes are reported to be involved in angiogenesis. There was substantial agreement between the gene array and quantitative real-time PCR data. The angiogenesis related genes might be potential HHT modifier genes. In addition, the results suggest endothelial cell type specific ALK1 and TGF-? signalling.

Lux, Andreas; Salway, Fiona; Dressman, Holly K; Kroner-Lux, Gabriele; Hafner, Mathias; Day, Philip JR; Marchuk, Douglas A; Garland, John

2006-01-01

345

POCUS: mining genomic sequence annotation to predict disease genes  

Microsoft Academic Search

Here we present POCUS (prioritization of candidate genes using statistics), a novel computational approach to prioritize candidate disease genes that is based on over-representation of functional annotation between loci for the same disease. We show that POCUS can provide high (up to 81-fold) enrichment of real disease genes in the candidate-gene shortlists it produces compared with the original large sets

Frances S Turner; Daniel R Clutterbuckand Colin; Colin AM Semple

2003-01-01

346

Large-scale association analyses identifies 13 new susceptibility loci for coronary artery disease  

PubMed Central

We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 cases and 64,762 controls of European descent, followed by genotyping of top association signals in 60,738 additional individuals. This genomic analysis identified 13 novel loci harboring one or more SNPs that were associated with CAD at P<5×10?8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 novel loci displayed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6 to 17 percent increase in the risk of CAD per allele. Notably, only three of the novel loci displayed significant association with traditional CAD risk factors, while the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the novel CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

Schunkert, Heribert; Konig, Inke R.; Kathiresan, Sekar; Reilly, Muredach P.; Assimes, Themistocles L.; Holm, Hilma; Preuss, Michael; Stewart, Alexandre F. R.; Barbalic, Maja; Gieger, Christian; Absher, Devin; Aherrahrou, Zouhair; Allayee, Hooman; Altshuler, David; Anand, Sonia S.; Andersen, Karl; Anderson, Jeffrey L.; Ardissino, Diego; Ball, Stephen G.; Balmforth, Anthony J.; Barnes, Timothy A.; Becker, Diane M.; Becker, Lewis C.; Berger, Klaus; Bis, Joshua C.; Boekholdt, S. Matthijs; Boerwinkle, Eric; Braund, Peter S.; Brown, Morris J.; Burnett, Mary Susan; Buysschaert, Ian; Carlquist, Cardiogenics, John F.; Chen, Li; Cichon, Sven; Codd, Veryan; Davies, Robert W.; Dedoussis, George; Dehghan, Abbas; Demissie, Serkalem; Devaney, Joseph M.; Do, Ron; Doering, Angela; Eifert, Sandra; El Mokhtari, Nour Eddine; Ellis, Stephen G.; Elosua, Roberto; Engert, James C.; Epstein, Stephen E.; Faire, Ulf de; Fischer, Marcus; Folsom, Aaron R.; Freyer, Jennifer; Gigante, Bruna; Girelli, Domenico; Gretarsdottir, Solveig; Gudnason, Vilmundur; Gulcher, Jeffrey R.; Halperin, Eran; Hammond, Naomi; Hazen, Stanley L.; Hofman, Albert; Horne, Benjamin D.; Illig, Thomas; Iribarren, Carlos; Jones, Gregory T.; Jukema, J.Wouter; Kaiser, Michael A.; Kaplan, Lee M.; Kastelein, John J.P.; Khaw, Kay-Tee; Knowles, Joshua W.; Kolovou, Genovefa; Kong, Augustine; Laaksonen, Reijo; Lambrechts, Diether; Leander, Karin; Lettre, Guillaume; Li, Mingyao; Lieb, Wolfgang; Linsel-Nitschke, Patrick; Loley, Christina; Lotery, Andrew J.; Mannucci, Pier M.; Maouche, Seraya; Martinelli, Nicola; McKeown, Pascal P.; Meisinger, Christa; Meitinger, Thomas; Melander, Olle; Merlini, Pier Angelica; Mooser, Vincent; Morgan, Thomas; Muhleisen, Thomas W.; Muhlestein, Joseph B.; Munzel, Thomas; Musunuru, Kiran; Nahrstaedt, Janja; Nelson, Christopher P.; Nothen, Markus M.; Olivieri, Oliviero; Patel, Riyaz S.; Patterson, Chris C.; Peters, Annette; Peyvandi, Flora; Qu, Liming; Quyyumi, Arshed A.; Rader, Daniel J.; Rallidis, Loukianos S.; Rice, Catherine; Rosendaal, Frits R.; Rubin, Diana; Salomaa, Veikko; Sampietro, M. Lourdes; Sandhu, Manj S.; Schadt, Eric; Schafer, Arne; Schillert, Arne; Schreiber, Stefan; Schrezenmeir, Jurgen; Schwartz, Stephen M.; Siscovick, David S.; Sivananthan, Mohan; Sivapalaratnam, Suthesh; Smith, Albert; Smith, Tamara B.; Snoep, Jaapjan D.; Soranzo, Nicole; Spertus, John A.; Stark, Klaus; Stirrups, Kathy; Stoll, Monika; Tang, W. H. Wilson; Tennstedt, Stephanie; Thorgeirsson, Gudmundur; Thorleifsson, Gudmar; Tomaszewski, Maciej; Uitterlinden, Andre G.; van Rij, Andre M.; Voight, Benjamin F.; Wareham, Nick J.; Wells, George A.; Wichmann, H.-Erich; Wild, Philipp S.; Willenborg, Christina; Witteman, Jaqueline C. M.; Wright, Benjamin J.; Ye, Shu; Zeller, Tanja; Ziegler, Andreas; Cambien, Francois; Goodall, Alison H.; Cupples, L. Adrienne; Quertermous, Thomas; Marz, Winfried; Hengstenberg, Christian; Blankenberg, Stefan; Ouwehand, Willem H.; Hall, Alistair S.; Deloukas, Panos; Thompson, John R.; Stefansson, Kari; Roberts, Robert; Thorsteinsdottir, Unnur; O'Donnell, Christopher J.; McPherson, Ruth; Erdmann, Jeanette; Samani, Nilesh J.

2011-01-01

347

Brain Expression Genome-Wide Association Study (eGWAS) Identifies Human Disease-Associated Variants  

Microsoft Academic Search

Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n = 197, temporal cortex n = 202) and with other brain pathologies (non–AD, cerebellar n = 177, temporal cortex n =

Fanggeng Zou; High Seng Chai; Curtis S. Younkin; Mariet Allen; Julia Crook; V. Shane Pankratz; Minerva M. Carrasquillo; Christopher N. Rowley; Asha A. Nair; Sumit Middha; Sooraj Maharjan; Thuy Nguyen; Li Ma; Kimberly G. Malphrus; Ryan Palusak; Sarah Lincoln; Gina Bisceglio; Constantin Georgescu; Naomi Kouri; Christopher P. Kolbert; Jin Jen; Jonathan L. Haines; Richard Mayeux; Margaret A. Pericak-Vance; Lindsay A. Farrer; Gerard D. Schellenberg; Ronald C. Petersen; Neill R. Graff-Radford; Dennis W. Dickson; Steven G. Younkin; Nilüfer Ertekin-Taner

2012-01-01

348

Systematic enrichment analysis of gene expression profiling studies identifies consensus pathways implicated in colorectal cancer development  

PubMed Central

Background: A large number of gene expression profiling (GEP) studies on colorectal carcinogenesis have been performed but no reliable gene signature has been identified so far due to the lack of reproducibility in the reported genes. There is growing evidence that functionally related genes, rather than individual genes, contribute to the etiology of complex traits. We used, as a novel approach, pathway enrichment tools to define functionally related genes that are consistently up- or down-regulated in colorectal carcinogenesis. Materials and Methods: We started the analysis with 242 unique annotated genes that had been reported by any of three recent meta-analyses covering GEP studies on genes differentially expressed in carcinoma vs normal mucosa. Most of these genes (218, 91.9%) had been reported in at least three GEP studies. These 242 genes were submitted to bioinformatic analysis using a total of nine tools to detect enrichment of Gene Ontology (GO) categories or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. As a final consistency criterion the pathway categories had to be enriched by several tools to be taken into consideration. Results: Our pathway-based enrichment analysis identified the categories of ribosomal protein constituents, extracellular matrix receptor interaction, carbonic anhydrase isozymes, and a general category related to inflammation and cellular response as significantly and consistently overrepresented entities. Conclusions: We triaged the genes covered by the published GEP literature on colorectal carcinogenesis and subjected them to multiple enrichment tools in order to identify the consistently enriched gene categories. These turned out to have known functional relationships to cancer development and thus deserve further investigation.

Lascorz, Jesus; Hemminki, Kari; Forsti, Asta

2011-01-01

349

Hashimoto's Thyroiditis: From Genes to the Disease  

PubMed Central

Hashimoto’s thyroiditis (HT) is the most prevalent autoimmune thyroid disorder. Intrathyroidal lymphocytic infiltration is followed by a gradual destruction of the thyroid gland which may lead to subclinical or overt hypothyroidism. Biochemical markers of the disease are thyroid peroxidase and/or thyroglobulin autoantibodies in the serum which are present with a higher prevalence in females than in males and increase with age. Although exact mechanisms of aetiology and pathogenesis of the disorder are not completely understood, a strong genetic susceptibility to the disease has been confirmed predominantly by family and twin studies. Several genes were shown to be associated with the disease occurrence, progression, and severity. Genes for human leukocyte antigen, cytotoxic T lymphocyte antigen-4, protein tyrosine phosphatase nonreceptor-type 22, thyroglobulin, vitamin D receptor, and cytokines are considered to be of utmost importance. Amongst endogenous factors for the disease development, the attention is focused predominantly on female sex, pregnancy with postpartum period and fetal microchimerism. Environmental factors influencing HT development are iodine intake, drugs, infections and different chemicals. Disturbed self-tolerance accompanied by the increased antigen presentation is a prerequisite for the HT occurrence, whereas proper interaction of thyroid cells, antigen presenting cells, and T cells are necessary for the initiation of thyroid autoimmunity. Secreted cytokines lead predominantly to T-helper type 1 (Th1) response as well as to Th 17 response which has only recently been implicated. Final outcome of HT is thyroid destruction which is mostly a consequence of the apoptotic processes combined with T-cell mediated cytotoxicity.

Zaletel, Katja; Gaberscek, Simona

2011-01-01

350

Gene Prospector: An evidence gateway for evaluating potential susceptibility genes and interacting risk factors for human diseases  

PubMed Central

Background Millions of single nucleotide polymorphisms have been identified as a result of the human genome project and the rapid advance of high throughput genotyping technology. Genetic association studies, such as recent genome-wide association studies (GWAS), have provided a springboard for exploring the contribution of inherited genetic variation and gene/environment interactions in relation to disease. Given the capacity of such studies to produce a plethora of information that may then be described in a number of publications, selecting possible disease susceptibility genes and identifying related modifiable risk factors is a major challenge. A Web-based application for finding evidence of such relationships is key to the development of follow-up studies and evidence for translational research. We developed a Web-based application that selects and prioritizes potential disease-related genes by using a highly curated and updated literature database of genetic association studies. The application, called Gene Prospector, also provides a comprehensive set of links to additional data sources. Results We compared Gene Prospector results for the query "Parkinson" with a list of 13 leading candidate genes (Top Results) from a curated, specialty database for genetic associations with Parkinson disease (PDGene). Nine of the thirteen leading candidate genes from PDGene were in the top 10th percentile of the ranked list from Gene Prospector. In fact, Gene Prospector included more published genetic association studies for the 13 leading candidate genes than PDGene did. Conclusion Gene Prospector provides an online gateway for searching for evidence about human genes in relation to diseases, other phenotypes, and risk factors, and provides links to published literature and other online data sources. Gene Prospector can be accessed via .

Yu, Wei; Wulf, Anja; Liu, Tiebin; Khoury, Muin J; Gwinn, Marta

2008-01-01

351

Gene patents related to common diseases of the eye.  

PubMed

Visual impairment and blindness impose substantial morbidity and premature mortality on the population. The direct costs for vision disorders have been shown to be more than the cost of coronary heart disease, stroke, arthritis or depression and were estimated to be $9.85 billion in 2004 in Australia. Hence it is important to identify the causes of common eye diseases and understand their aetiology which in turn would allow determination of better management strategies and treatment options. Age related Macular Degeneration, Cataract, Diabetic Retinopathy, Glaucoma and uncorrected refractive errors represent the majority of the visual impairment and blindness in Australia and various parts of the world. This article reviews the gene patents available for these eye conditions and highlights the important discoveries that have so far contributed to our understanding of these diseases and provides valuable information as to where research will be heading in the future. PMID:21867478

Sahebjada, Srujana; Cantsileris, Stuart; Baird, Paul N

2011-12-01

352

Rationale, methods, and assays for identifying human and non-human primate taste specific genes and use thereof in taste modulator and therapeutic screening assays  

US Patent & Trademark Office Database

This invention relates to novel rationale and methods for identifying human and primate taste-specific genes, including genes involved in salty taste perception, especially human salty taste perception, but also genes involved in sweet, bitter, umami, and sour taste perception, and genes involved in other taste cell or taste receptor related activities such as digestive function and digestive related diseases, taste cell turnover, immunoregulation of the oral and digestive tract, and metabolic regulation such as in diabetes and obesity, the genes identified using these methods, and assays for identifying taste modulators (enhancers or blockers) and potential therapeutics using these genes. These compounds have potential application in modulating (enhancing or blocking) taste perception, especially salty taste perception and as potential therapeutics. In addition, this invention relates to novel methods for identifying taste-specific genes that can be used as markers for different taste cell types, including sweet, bitter, umami, sour, salty, and other taste cells in mammals as well as assays that measure the activity of the sweet, bitter, umami, or sour receptor in the presence of these genes to identify modulators of sweet, bitter, umami, and sour taste and to identify therapeutics especially for treating digestive or metabolic disorders, taste loss, and oral infections. Particularly, the genes identified herein and antibodies or oligos thereto can be used as markers to identify and/or purify specific taste cells e.g., from taste cell suspensions by use of FACS or magnetic bead cell selection or other known cell purification and isolation procedures.

2011-04-26

353

Genome-wide association identifies ATOH7 as a major gene determining human optic disc size  

PubMed Central

Optic nerve assessment is important for many blinding diseases, with cup-to-disc ratio (CDR) assessments commonly used in both diagnosis and progression monitoring of glaucoma patients. Optic disc, cup, rim area and CDR measurements all show substantial variation between human populations and high heritability estimates within populations. To identify loci underlying these quantitative traits, we performed a genome-wide association study in two Australian twin cohorts and identified rs3858145, P = 6.2 × 10?10, near the ATOH7 gene as associated with the mean disc area. ATOH7 is known from studies in model organisms to play a key role in retinal ganglion cell formation. The association with rs3858145 was replicated in a cohort of UK twins, with a meta-analysis of the combined data yielding P = 3.4 × 10?10. Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P = 1.3 × 10?10 to 4.3 × 10?11, top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P = 1.5 × 10?7, in the gene RFTN1. Direct sequencing of ATOH7 in 12 patients with optic nerve hypoplasia, one of the leading causes of blindness in children, revealed two novel non-synonymous mutations (Arg65Gly, Ala47Thr) which were not found in 90 unrelated controls (combined Fisher's exact P = 0.0136). Furthermore, the Arg65Gly variant was found to have very low frequency (0.00066) in an additional set of 672 controls.

Macgregor, Stuart; Hewitt, Alex W.; Hysi, Pirro G.; Ruddle, Jonathan B.; Medland, Sarah E.; Henders, Anjali K.; Gordon, Scott D.; Andrew, Toby; McEvoy, Brian; Sanfilippo, Paul G.; Carbonaro, Francis; Tah, Vikas; Li, Yi Ju; Bennett, Sonya L.; Craig, Jamie E.; Montgomery, Grant W.; Tran-Viet, Khanh-Nhat; Brown, Nadean L.; Spector, Timothy D.; Martin, Nicholas G.; Young, Terri L.; Hammond, Christopher J.; Mackey, David A.

2010-01-01

354

The compact Selaginella genome identifies changes in gene content associated with the evolution of vascular plants  

SciTech Connect

We report the genome sequence of the nonseed vascular plant, Selaginella moellendorffii, and by comparative genomics identify genes that likely played important roles in the early evolution of vascular plants and their subsequent evolution

Grigoriev, Igor V.; Banks, Jo Ann; Nishiyama, Tomoaki; Hasebe, Mitsuyasu; Bowman, John L.; Gribskov, Michael; dePamphilis, Claude; Albert, Victor A.; Aono, Naoki; Aoyama, Tsuyoshi; Ambrose, Barbara A.; Ashton, Neil W.; Axtell, Michael J.; Barker, Elizabeth; Barker, Michael S.; Bennetzen, Jeffrey L.; Bonawitz, Nicholas D.; Chapple, Clint; Cheng, Chaoyang; Correa, Luiz Gustavo Guedes; Dacre, Michael; DeBarry, Jeremy; Dreyer, Ingo; Elias, Marek; Engstrom, Eric M.; Estelle, Mark; Feng, Liang; Finet, Cedric; Floyd, Sandra K.; Frommer, Wolf B.; Fujita, Tomomichi; Gramzow, Lydia; Gutensohn, Michael; Harholt, Jesper; Hattori, Mitsuru; Heyl, Alexander; Hirai, Tadayoshi; Hiwatashi, Yuji; Ishikawa, Masaki; Iwata, Mineko; Karol, Kenneth G.; Koehler, Barbara; Kolukisaoglu, Uener; Kubo, Minoru; Kurata, Tetsuya; Lalonde, Sylvie; Li, Kejie; Li, Ying; Litt, Amy; Lyons, Eric; Manning, Gerard; Maruyama, Takeshi; Michael, Todd P.; Mikami, Koji; Miyazaki, Saori; Morinaga, Shin-ichi; Murata, Takashi; Mueller-Roeber, Bernd; Nelson, David R.; Obara, Mari; Oguri, Yasuko; Olmstead, Richard G.; Onodera, Naoko; Petersen, Bent Larsen; Pils, Birgit; Prigge, Michael; Rensing, Stefan A.; Riano-Pachon, Diego Mauricio; Roberts, Alison W.; Sato, Yoshikatsu; Scheller, Henrik Vibe; Schulz, Burkhard; Schulz, Christian; Shakirov, Eugene V.; Shibagaki, Nakako; Shinohara, Naoki; Shippen, Dorothy E.; Sorensen, Iben; Sotooka, Ryo; Sugimoto, Nagisa; Sugita, Mamoru; Sumikawa, Naomi; Tanurdzic, Milos; Theilsen, Gunter; Ulvskov, Peter; Wakazuki, Sachiko; Weng, Jing-Ke; Willats, William W.G.T.; Wipf, Daniel; Wolf, Paul G.; Yang, Lixing; Zimmer, Andreas D.; Zhu, Qihui; Mitros, Therese; Hellsten, Uffe; Loque, Dominique; Otillar, Robert; Salamov, Asaf; Schmutz, Jeremy; Shapiro, Harris; Lindquist, Erika; Lucas, Susan; Rokhsar, Daniel

2011-04-28

355

Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis. GRP78/BiP and novel genes.  

PubMed

An elevated blood level of homocysteine is associated with arteriosclerosis and thrombosis. The mechanisms by which homocysteine may promote vascular diseases have not been elucidated yet. In the present study, we have applied a modified nonradioactive differential display analysis to evaluate changes in gene expression induced by homocysteine treatment of cultured human umbilical vein endothelial cells (HUVEC). We identified six up-regulated and one down-regulated genes. One up-regulated gene was GRP78/BiP, a stress protein, suggesting that misfolded proteins would accumulate in the endoplasmic reticulum because of redox potential changes caused by homocysteine. Another up-regulated gene encoded a bifunctional enzyme with activities of methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase, which is involved in a homocysteine metabolism. A third up-regulated gene encoded activating transcription factor 4, and a fourth was a gene whose function is not identified yet. The remaining three were novel genes. We isolated a full-length cDNA of one of the up-regulated genes from a HUVEC library. It encoded a novel protein with 394 amino acids, which was termed reducing agents and tunicamycin-responsive protein (RTP). Northern blot analysis revealed that RTP gene expression was induced in HUVEC after 4 h incubation with homocysteine. RTP mRNA was also observed in unstimulated cells and induced by not only homocysteine but also 2-mercaptoethanol and tunicamycin. The mRNA was ubiquitously expressed in human tissues. These observations indicate that homocysteine can alter the expressivity of multiple genes, including a stress protein and several novel genes. These responses may contribute to atherogenesis. PMID:8939898

Kokame, K; Kato, H; Miyata, T

1996-11-22

356

GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease.  

PubMed

Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and A??? are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10?? for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10?? and p = 3.22 × 10?? for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10?? for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10??, 0.039, 4.86 × 10??, respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci. PMID:23562540

Cruchaga, Carlos; Kauwe, John S K; Harari, Oscar; Jin, Sheng Chih; Cai, Yefei; Karch, Celeste M; Benitez, Bruno A; Jeng, Amanda T; Skorupa, Tara; Carrell, David; Bertelsen, Sarah; Bailey, Matthew; McKean, David; Shulman, Joshua M; De Jager, Philip L; Chibnik, Lori; Bennett, David A; Arnold, Steve E; Harold, Denise; Sims, Rebecca; Gerrish, Amy; Williams, Julie; Van Deerlin, Vivianna M; Lee, Virginia M-Y; Shaw, Leslie M; Trojanowski, John Q; Haines, Jonathan L; Mayeux, Richard; Pericak-Vance, Margaret A; Farrer, Lindsay A; Schellenberg, Gerard D; Peskind, Elaine R; Galasko, Douglas; Fagan, Anne M; Holtzman, David M; Morris, John C; Goate, Alison M

2013-04-04

357

Microarray analysis identifies distinct gene expression profiles associated with histological subtype in human osteosarcoma  

Microsoft Academic Search

Osteosarcoma is the most common primary malignant bone tumour. Currently osteosarcoma classification is based on histological\\u000a appearance. It was the aim of this study to use a more systematic approach to osteosarcoma classification based on gene expression\\u000a analysis and to identify subtype specific differentially expressed genes. We analysed the global gene expression profiles\\u000a of ten osteosarcoma samples using Affymetrix U133A

Bernd Kubista; Florian Klinglmueller; Martin Bilban; Martin Pfeiffer; Richard Lass; Alexander Giurea; Phillipp T. Funovics; Cyril Toma; Martin Dominkus; Rainer Kotz; Theresia Thalhammer; Klemens Trieb; Teresa Zettl; Christian F. Singer

2011-01-01

358

Insertional mutagenesis in zebrafish rapidly identifies genes essential for early vertebrate development  

Microsoft Academic Search

To rapidly identify genes required for early vertebrate development, we are carrying out a large-scale, insertional mutagenesis screen in zebrafish, using mouse retroviral vectors as the mutagen. We will obtain mutations in 450 to 500 different genes—roughly 20% of the genes that can be mutated to produce a visible embryonic phenotype in this species—and will clone the majority of the

Gregory Golling; Adam Amsterdam; Zhaoxia Sun; Marcelo Antonelli; Ernesto Maldonado; Wenbiao Chen; Shawn Burgess; Maryann Haldi; Karen Artzt; Sarah Farrington; Shuh-Yow Lin; Robert M. Nissen; Nancy Hopkins

2002-01-01

359

A stochastic model for identifying differential gene pair co-expression patterns in prostate cancer progression  

Microsoft Academic Search

BACKGROUND: The identification of gene differential co-expression patterns between cancer stages is a newly developing method to reveal the underlying molecular mechanisms of carcinogenesis. Most researches of this subject lack an algorithm useful for performing a statistical significance assessment involving cancer progression. Lacking this specific algorithm is apparently absent in identifying precise gene pairs correlating to cancer progression. RESULTS: In

Wen Juan Mo; Xu Ping Fu; Xiao Tian Han; Guang Yuan Yang; Ji Gang Zhang; Feng Hua Guo; Yan Huang; Yu Min Mao; Yao Li; Yi Xie

2009-01-01

360

Method to identify specific alleles of a Phanerochaete chrysosporium gene encoding lignin peroxidase  

SciTech Connect

A method to identify and differentiate allelic variants of the gene encoding lignin peroxidase isozyme H8 is presented. The strategy involves amplifying a variable region of the gene's carboxy terminus by use of the polymerase chain reaction and then probing with allele-specific oligonucleotides.

Gaskell, J.; Wymelenberg, A.V.; Cullen, D. (Dept of Agriculture, Madison, WI (United States)); Stewart, P. (Univ. of Wisconsin, Madison (United States))

1992-04-01

361

Stress-Inducible Gene of Salmonella typhimurium Identified by Arbitrarily Primed PCR of RNA  

Microsoft Academic Search

Fingerprinting of RNA by arbitrarily primed PCR (RAP) can be used to identify conditionally expressed genes in prokaryotes. Differential gene expression in Salmonella typhimurium LT2 in re