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Improved human disease candidate gene prioritization using mouse phenotype
Jing Chen, Huan Xu, Bruce J Aronow, Anil G Jegga
BMC Bioinformatics , 2007, DOI: 10.1186/1471-2105-8-392
Abstract: 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 http://toppgene.cchmc.org webcite, outperforms two of the existing candidate gene prioritization methods, SUSPECTS and ENDEAVOUR.The incorporation of phenotype information for mouse orthologs of human genes greatly improves the human disease candidate gene analysis and prioritization.Although the availability of complete genome sequences and the wealth of large-scale biological data sets opened up unprecedented opportunities to elucidate the genetic basis of rare and common human diseases [1], comprehending the underlying pathophysiological mechanisms continues to be challenging. Majority of the common diseases are genetically intricate, polygenic and multifactorial, and frequently manifest as different clinical phenotypes. Additionally, these complex conditions are often triggered by an interaction of genetic, environmental, and physiological factors, making it difficult for researchers to narrow their focus to a single or few genes. High-throughput genome-wide studies like linkage analysis and gene expression profiling although useful for classification and characterization do not provide sufficient information to identify specific disease causal genes. Both of these approaches typically result in hundreds of potential candidate genes, failing to help the researchers in reducing the target genes to a manageable number for further validation.Functional enrichment approaches [2-4] focusing on gene sets that share common biological function, chromosomal location, or regulation although successful in identifying enriched biological themes are not suitable for gene prioritization. To overco
Gene Network Analysis of Candidate Loci for Human Anorectal Malformations  [PDF]
Emily H. M. Wong, Chun-Laam Ng, Vincent Chi-Hang Lui, Man-ting So, Stacey S. Cherny, Pak-Chung Sham, Paul Kwong-Hang Tam, Maria-Mercè Garcia-Barceló
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069142
Abstract: Anorectal malformations (ARMs) are birth defects that require surgery and carry significant chronic morbidity. Our earlier genome-wide copy number variation (CNV) study had provided a wealth of candidate loci. To find out whether these candidate loci are related to important developmental pathways, we have performed an extensive literature search coupled with the currently available bioinformatics tools. This has allowed us to assign both genic and non-genic CNVs to interrelated pathways known to govern the development of the anorectal region. We have linked 11 candidate genes to the WNT signalling pathway and 17 genes to the cytoskeletal network. Interestingly, candidate genes with similar functions are disrupted by the same type of CNV. The gene network we discovered provides evidence that rare mutations in different interrelated genes may lead to similar phenotypes, accounting for genetic heterogeneity in ARMs. Classification of patients according to the affected pathway and lesion type should eventually improve the diagnosis and the identification of common genes/molecules as therapeutic targets.
High-throughput analysis of candidate imprinted genes and allele-specific gene expression in the human term placenta
Caroline Daelemans, Matthew E Ritchie, Guillaume Smits, Sayeda Abu-Amero, Ian M Sudbery, Matthew S Forrest, Susana Campino, Taane G Clark, Philip Stanier, Dominic Kwiatkowski, Panos Deloukas, Emmanouil T Dermitzakis, Simon Tavaré, Gudrun E Moore, Ian Dunham
BMC Genetics , 2010, DOI: 10.1186/1471-2156-11-25
Abstract: Twenty-three family trios of placental cDNA, placental genomic DNA (gDNA) and gDNA from both parents were tested for 130 candidate genes with the Sequenom MassArray system. Six genes were found differentially expressed but none imprinted. The Illumina ASE BeadArray platform was then used to test 1536 SNPs in 932 genes. The array was enriched for the human orthologues of 124 mouse candidate genes from bioinformatics predictions and 10 human candidate imprinted genes from EST database mining. After quality control pruning, a total of 261 informative SNPs (214 genes) remained for analysis. Imprinting with maternal expression was demonstrated for the lymphocyte imprinted gene ZNF331 in human placenta. Two potential differentially methylated regions (DMRs) were found in the vicinity of ZNF331. None of the bioinformatically predicted candidates tested showed imprinting except for a skewed allelic expression in a parent-specific manner observed for PHACTR2, a neighbour of the imprinted PLAGL1 gene. ASE was detected for two or more individuals in 39 candidate genes (18%).Both Sequenom and Illumina assays were sensitive enough to study imprinting and strong allelic bias. Previous bioinformatics approaches were not predictive of new imprinted genes in the human term placenta. ZNF331 is imprinted in human term placenta and might be a new ubiquitously imprinted gene, part of a primate-specific locus. Demonstration of partial imprinting of PHACTR2 calls for re-evaluation of the allelic pattern of expression for the PHACTR2-PLAGL1 locus. ASE was common in human term placenta.Although diploid organisms have two copies of each gene, they are not always equally expressed. For some genes, only one allele is active while the other is almost completely silenced. Two different groups of genes fall into this category: genes that exhibit random monoallelic expression, e.g. the odorant receptor genes and genes coding for immunoglobulins [1,2]; and imprinted genes that exhibit monoallelic e
Evaluation of Candidate Genes from Orphan FEB and GEFS+ Loci by Analysis of Human Brain Gene Expression Atlases  [PDF]
Rosario M. Piro, Ivan Molineris, Ugo Ala, Ferdinando Di Cunto
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023149
Abstract: Febrile seizures, or febrile convulsions (FEB), represent the most common form of childhood seizures and are believed to be influenced by variations in several susceptibility genes. Most of the associated loci, however, remain ‘orphan’, i.e. the susceptibility genes they contain still remain to be identified. Further orphan loci have been mapped for a related disorder, genetic (generalized) epilepsy with febrile seizures plus (GEFS+). We show that both spatially mapped and ‘traditional’ gene expression data from the human brain can be successfully employed to predict the most promising candidate genes for FEB and GEFS+, apply our prediction method to the remaining orphan loci and discuss the validity of the predictions. For several of the orphan FEB/GEFS+ loci we propose excellent, and not always obvious, candidates for mutation screening in order to aid in gaining a better understanding of the genetic origin of the susceptibility to seizures.
Identification of a candidate alternative promoter region of the human Bcl2L11 (Bim) gene
Margherita Gaviraghi, Andrea Caricasole, Chiara Costanzo, Daniela Diamanti, Mario Dandrea, Massimo Donadelli, Aldo Scarpa, Marta Palmieri
BMC Molecular Biology , 2008, DOI: 10.1186/1471-2199-9-56
Abstract: In the search for novel promoter sequences in the human BCL2L11 locus, we have identified previously unrecognized genomic sequences displaying promoter activity and E2F responsiveness, and driving the expression of BCL2L11 coding transcripts. In man, transcripts originating from this novel putative promoter contribute significantly to total BCL2L11 mRNA expression in testis, heart and liver. In HEK293 cells, this novel candidate promoter originates BCL2L11 transcripts whose expression can be modulated by a known modulator of BCL2L11 expression (Trichostatin A) and by E2F, a characterized transcriptional regulator of BCL2L11 expression.The identification of a novel putative human BCL2L11 promoter provides new insights into the structure and regulation of the BCL2L11 locus.The human BCL2L11 locus, located on chromosome 2q13, encodes a protein of 198 amino acids structurally and functionally related to the BH3-only group of pro-apoptotic BCL2 family members [3]. The gene is frequently mutated in diverse human tumours leading to loss of BCL2L11 activity [14,21]. Expression of BCL2L11 is induced by a diverse range of apoptotic stimuli such as deprivation of growth factors/cytokines, ionizing radiation, and cytotoxic peptides [2,6,14,22]. Although the regulation of BCL2L11 activity is highly complex and is cell context-dependent, studies aimed at identifying the molecular mechanisms underlying BCL2L11 activation during apoptosis have revealed an important role for the transcriptional regulation of BCL2L11 gene expression [1,6,9,12,13,22,23]. A genomic region displaying promoter activity has been characterized for the human BCL2L11 locus [13], while in the rat the existence of three alternative promoter sequences has been postulated, the most upstream of which corresponds to the promoter described for the human BCL2L11 gene [2,3]. Regulation of this conserved BCL2L11 promoter by FOXO and E2F has been described using rat BCL2L11 genomic constructs, thus providing a likely m
RAI , one candidate gene associated with differentiation of human lung adenocarcinoma cells
RAI, one candidate gene associated with differentiation of human lung adenocarcinoma cells

WANG Xuejiao ZHANG Rui LIU Zhihua,WANG Xiuqin DING Fang GUO Mingzhou WU Min,
王雪皎
,张睿,刘芝华,王秀琴,丁芳,郭明洲,吴旻

中国科学C辑(英文版) , 2000,
Abstract: From all-trans retinoic acid (ATRA)-treated human lung adenocarcinoma GLC-82 cells and control, subtractive cDNA library has been constructed using subtractive hybridization technique in our laboratory. The screening of the cDNA subtractive library resulted in identification of a clone containing cDNA fragment of one ATRA-induced gene (RAI) in GLC-82 cells. The positive clone with full-length cDNA of RAI was identified by screening fetal brain cDNA library using colony hybridization technique, and then sequenced. RT-PCR results showed that RAI was expressed in many different human fetal tissues. These results suggest that RAI may be involved in cell differentiation and play an important role in vital activities of cells.
Identification of MSRA gene on chromosome 8p as a candidate metastasis suppressor for human hepatitis B virus-positive hepatocellular carcinoma
Ke-Feng Lei, Yan-Fang Wang, Xiao-Qun Zhu, Peng-Cheng Lu, Bing-Sheng Sun, Hu-Liang Jia, Ning Ren, Qing-Hai Ye, Hui-Chuan Sun, Lu Wang, Zhao-You Tang, Lun-Xiu Qin
BMC Cancer , 2007, DOI: 10.1186/1471-2407-7-172
Abstract: Oligo-nucleotide microarrays which included 322 genes on human chromosome 8p were constructed to analyze the difference in gene expression profiles between HCC tissues with and without metastasis. The leading differentially expressed genes were identified and selected for further analysis by real-time PCR and Western blotting. Recombinant expression plasmid vectors for each target gene were constructed and transfected into HCC cells and its in vitro effects on proliferation and invasion of HCC cells were also investigated.Sixteen leading differentially expressed genes were identified from the HCC tissues with metastasis compared with those without metastasis (p < 0.01, q < 16 %). Among of the 10 significantly down-regulated genes in HCC with metastasis, methionine sulfoxide reductase A (MSRA) had the lowest p value and false discovery rate (FDR), and was considered as a potential candidate for metastasis suppressor gene. Real-time PCR and Western blotting confirmed that the mRNA and protein expression levels of MSRA were significantly decreased in HCC with metastasis compared with those without metastasis (p < 0.001), and MSRA mRNA level in HCCLM6 cells (with high metastatic potential) was also much lower than that of other HCC cell lines. Transfection of a recombinant expression plasmid vector and overexpression of MSRA gene could obviously inhibit cell colony formation (4.33 ± 2.92 vs. 9.17 ± 3.38, p = 0.008) and invasion (7.40 ± 1.67 vs. 17.20 ± 2.59, p= 0.0001) of HCCLM6 cell line.MSRA gene on chromosome 8p might possess metastasis suppressor activity in HCC.Primary liver cancer (mainly hepatocellular carcinoma, HCC) is one of the most frequent human cancers worldwide. The number of deaths from liver cancer is very similar to that of new cancer cases (598,000 and 626,000 respectively) and the liver cancer mortality rate is the third highest in the world [1]. In China, liver cancer kills 54.7 people out of one-hundred-thousand per year [2]. Although many advances
GAD2 on Chromosome 10p12 Is a Candidate Gene for Human Obesity  [PDF]
Philippe Boutin,Christian Dina,Francis Vasseur,Séverine Dubois,Laetitia Corset,Karin Séron,Lynn Bekris,Janice Cabellon,Bernadette Neve,Valérie Vasseur-Delannoy,Mohamed Chikri,M. Aline Charles,Karine Clement,Ake Lernmark,Philippe Froguel
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0000068
Abstract: The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11–12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of γ-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681–0.972], p = 0.0049) and an at-risk SNP (?243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053–1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (χ2 = 7.637, p = 0.02). In the murine insulinoma cell line βTC3, the G at-risk allele of SNP ?243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The ?243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic β cells, we analyzed GAD65 antibody level as a marker of β-cell activity and of insulin secretion. In the control group, ?243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of β-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.
GAD2 on Chromosome 10p12 Is a Candidate Gene for Human Obesity  [PDF]
Philippe Boutin equal contributor,Christian Dina equal contributor,Francis Vasseur equal contributor,Séverine Dubois,Laetitia Corset,Karin Séron,Lynn Bekris,Janice Cabellon,Bernadette Neve,Valérie Vasseur-Delannoy,Mohamed Chikri,M. Aline Charles,Karine Clement,Ake Lernmark,Philippe Froguel
PLOS Biology , 2003, DOI: 10.1371/journal.pbio.0000068
Abstract: The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11–12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of γ-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681–0.972], p = 0.0049) and an at-risk SNP (?243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053–1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (χ2 = 7.637, p = 0.02). In the murine insulinoma cell line βTC3, the G at-risk allele of SNP ?243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The ?243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic β cells, we analyzed GAD65 antibody level as a marker of β-cell activity and of insulin secretion. In the control group, ?243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of β-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.
Frequent loss of heterozygosity and altered expression of the candidate tumor suppressor gene 'FAT' in human astrocytic tumors
Kunzang Chosdol, Anjan Misra, Sachin Puri, Tapasya Srivastava, Parthaprasad Chattopadhyay, Chitra Sarkar, Ashok K Mahapatra, Subrata Sinha
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-5
Abstract: In this study we used RAPD-PCR to identify novel genomic alterations in the astrocytic tumors of WHO grade II (Low Grade Diffuse Astrocytoma) and WHO Grade IV (Glioblastoma Multiforme). Loss of heterozygosity (LOH) of the altered region was studied by microsatellite and Single Nucleotide Polymorphism (SNP) markers. Expression study of the gene identified at the altered locus was done by semi-quantitative reverse-transcriptase-PCR (RT-PCR).Bands consistently altered in the RAPD profile of tumor DNA in a significant proportion of tumors were identified. One such 500 bp band, that was absent in the RAPD profile of 33% (4/12) of the grade II astrocytic tumors, was selected for further study. Its sequence corresponded with a region of FAT, a putative tumor suppressor gene initially identified in Drosophila. Fifty percent of a set of 40 tumors, both grade II and IV, were shown to have Loss of Heterozygosity (LOH) at this locus by microsatellite (intragenic) and by SNP markers. Semi-quantitative RT-PCR showed low FAT mRNA levels in a major subset of tumors.These results point to a role of the FAT in astrocytic tumorigenesis and demonstrate the use of RAPD analysis in identifying specific alterations in astrocytic tumors.Astrocytic tumors are the most frequent human gliomas; they are the second most common cause of cancer mortality in young adults after leukemia. WHO has classified astrocytic tumors into 4 grades [1]. Grade I (Pilocytic Astrocytomas) have a benign outcome and have genetic pathways that differ from the three higher grades. However Grades II to IV follow the same lineage of progression and Grade II (Low-grade Diffuse Astrocytomas, DA) have an inherent tendency to progress to grade III (Anaplastic Astrocytoma, AA) and grade IV (Glioblastoma Multiforme, GBM)[2,3]. Molecular alterations associated with these histopathological classes have also been identified and studied extensively. The median survival time of Grade II and IV tumors is 6 years and 1 year respec
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