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1

Single Nucleotide Deletion Mutation of KCNH2 Gene is Responsible for LQT Syndrome in a 3-Generation Korean Family  

PubMed Central

Long QT syndrome (LQTS) is characterized by the prolongation of the QT interval in ECG and manifests predisposition to life threatening arrhythmia which often leads to sudden cardiac death. We encountered a 3-generation family with 5 affected family members in which LQTS was inherited in autosomal dominant manner. The LQTS is considered an ion channel disorder in which the type and location of the genetic mutation determines to a large extent the expression of the clinical syndrome. Upon screening of the genomic sequences of cardiac potassium ion channel genes, we found a single nucleotide C deletion mutation in the exon 3 of KCNH2 gene that co-segregates with the LQTS in this family. This mutation presumably resulted in a frameshift mutation, P151fs+15X. This study added a new genetic cause to the pool of mutations that lead to defected potassium ion channels in the heart.

Park, Jong Keun; Oh, Yong-Seog; Choi, Jee-hyun

2013-01-01

2

Single nucleotide deletion mutation of KCNH2 gene is responsible for LQT syndrome in a 3-generation Korean family.  

PubMed

Long QT syndrome (LQTS) is characterized by the prolongation of the QT interval in ECG and manifests predisposition to life threatening arrhythmia which often leads to sudden cardiac death. We encountered a 3-generation family with 5 affected family members in which LQTS was inherited in autosomal dominant manner. The LQTS is considered an ion channel disorder in which the type and location of the genetic mutation determines to a large extent the expression of the clinical syndrome. Upon screening of the genomic sequences of cardiac potassium ion channel genes, we found a single nucleotide C deletion mutation in the exon 3 of KCNH2 gene that co-segregates with the LQTS in this family. This mutation presumably resulted in a frameshift mutation, P151fs+15X. This study added a new genetic cause to the pool of mutations that lead to defected potassium ion channels in the heart. PMID:24015048

Park, Jong Keun; Oh, Yong-Seog; Choi, Jee-hyun; Yoon, Sungjoo Kim

2013-09-01

3

Postmortem molecular analysis of KCNQ1, KCNH2, KCNE1 and KCNE2 genes in sudden unexplained nocturnal death syndrome in the Chinese Han population.  

PubMed

The etiology of sudden unexplained nocturnal death syndrome (SUNDS) remains unclear. Previous studies have implicated that SUNDS is probably allelic to cardiac sodium channel diseases such as Brugada syndrome. The variation in cardiac potassium channels is the main genetic cause of inherited long QT syndrome (LQTS), which may manifest as syncope and sudden cardiac death without structural disease. We hypothesized that cardiac potassium channel disease may be responsible for certain Chinese SUNDS cases. Genotyping of 4 main LQTS-susceptibility genes (KCNQ1, KCNH2, KCNE1, and KCNE2) was performed here for the first time in SUNDS victims from the Chinese Han population to address the pathogenic cause of some SUNDS using polymerase chain reaction and direct DNA sequencing. 120 sporadic SUNDS cases were enrolled. Genomic DNA was extracted from blood samples. A total of 2 novel non-synonymous mutations and 3 previously reported arrhythmia susceptibility polymorphisms were identified in KCNQ1, KCNH2, KCNE1, and KCNE2. We concluded that the variants in KCNQ1, KCNH2, KCNE1 and KCNE2 genes may be correlated with the occurrence of part of SUNDS cases in southern China. PMID:23890619

Liu, Chao; Zhao, Qianhao; Su, Terry; Tang, Shuangbo; Lv, Guoli; Liu, Hong; Quan, Li; Cheng, Jianding

2013-09-10

4

Long-Term Channel Block Is Required to Inhibit Cellular Transformation by Human Ether-à-Go-Go-Related Gene (hERG1) Potassium Channels.  

PubMed

Both human ether-à-go-go-related gene (hERG1) and the closely related human ether-à-go-go (hEAG1) channel are aberrantly expressed in a large proportion of human cancers. In the present study, we demonstrate that transfection of hERG1 into mouse fibroblasts is sufficient to induce many features characteristic of malignant transformation. An important finding of this work is that this transformation could be reversed by chronic incubation (for 2-3 weeks) with the hERG channel blocker dofetilide (100 nM), whereas more acute applications (for 1-2 days) were ineffective. The hERG1 expression resulted in a profound loss of cell contact inhibition, multiple layers of overgrowing cells, and high saturation densities. Cells also changed from fibroblast-like to a more spindle-shaped morphology, which was associated with a smaller cell size, a dramatic increase in cell polarization, a reduction in the number of actin stress fibers, and less punctate labeling of focal adhesions. Analysis of single-cell migration and scratch-wound closure clearly demonstrated that hERG1-expressing cells migrated more rapidly than vector-transfected control cells. In contrast to previous studies on hEAG1, there were no increases in rates of proliferation, or loss of growth factor dependency; however, hERG1-expressing cells were capable of substrate-independent growth. Allogeneic transplantation of hERG1-expressing cells into nude mice resulted in an increased incidence of tumors. In contrast to hEAG1, the mechanism of cellular transformation is dependent on ion conduction. Trafficking-deficient and conduction-deficient hERG1 mutants also prevented cellular transformation. These results provide evidence that hERG1 expression is sufficient to induce cellular transformation by a mechanism distinct from hEAG1. The most important conclusion of this study is that selective hERG1 channel blockers have therapeutic potential in the treatment of hERG1-expressing cancers. PMID:24830940

Pier, David M; Shehatou, George S G; Giblett, Susan; Pullar, Christine E; Trezise, Derek J; Pritchard, Catrin A; Challiss, R A John; Mitcheson, John S

2014-08-01

5

Molecular Coupling in the Human ether-a-go-go-related gene-1 (hERG1) K+ Channel Inactivation Pathway  

PubMed Central

Emerging evidence suggests that K+ channel inactivation involves coupling between residues in adjacent regions of the channel. Human ether-a-go-go-related gene-1 (hERG1) K+ channels undergo a fast inactivation gating process that is crucial for maintaining electrical stability in the heart. The molecular mechanisms that drive inactivation in hERG1 channels are unknown. Using alanine scanning mutagenesis, we show that a pore helix residue (Thr-618) that points toward the S5 segment is critical for normal inactivation gating. Amino acid substitutions at position 618 modulate the free energy of inactivation gating, causing enhanced or reduced inactivation. Mutation of an S5 residue that is predicted to be adjacent to Thr-618 (W568L) abolishes inactivation and alters ion selectivity. The introduction of the Thr-618-equivalent residue in Kv1.5 enhances inactivation. Molecular dynamic simulations of the Kv1.2 tetramer reveal van der Waals coupling between hERG1 618- and 568-equivalent residues and a significant increase in interaction energies when threonine is introduced at the 618-equivalent position. We propose that coupling between the S5 segment and pore helix may participate in the inactivation process in hERG1 channels.

Ferrer, Tania; Cordero-Morales, Julio F.; Arias, Marcelo; Ficker, Eckhard; Medovoy, David; Perozo, Eduardo; Tristani-Firouzi, Martin

2011-01-01

6

Characterization of hERG1 channel role in mouse colorectal carcinogenesis  

PubMed Central

The human ether-à-go-go-related gene (hERG)1 K+ channel is upregulated in human colorectal cancer cells and primary samples. In this study, we examined the role of hERG1 in colorectal carcinogenesis using two mouse models: adenomatous polyposis coli (Apcmin/+) and azoxymethane (AOM)-treated mice. Colonic polyps of Apcmin/+ mice overexpressed mERG1 and their formation was reverted by the hERG1 blocker E4031. AOM was applied to either hERG1-transgenic (TG) mice, which overexpress hERG1 in the mucosa of the large intestine, or wild-type mice. A significant increase of both mucin-depleted foci and polyps in the colon of hERG1-TG mice was detected. Both the intestine of TG mice and colonic polyps of Apcmin/+ showed an upregulation of phospho-Protein Kinase B (pAkt)/vascular endothelial growth factor (VEGF-A) and an increased angiogenesis, which were reverted by treatment with E4031. On the whole, this article assigns a relevant role to hERG1 in the process of in vivo colorectal carcinogenesis.

Fiore, Antonella; Carraresi, Laura; Morabito, Angela; Polvani, Simone; Fortunato, Angelo; Lastraioli, Elena; Femia, Angelo P; Lorenzo, Emanuele; Caderni, Giovanna; Arcangeli, Annarosa

2013-01-01

7

Characterization of hERG1 channel role in mouse colorectal carcinogenesis.  

PubMed

The human ether-à-go-go-related gene (hERG)1 K(+) channel is upregulated in human colorectal cancer cells and primary samples. In this study, we examined the role of hERG1 in colorectal carcinogenesis using two mouse models: adenomatous polyposis coli (Apc(min/+) ) and azoxymethane (AOM)-treated mice. Colonic polyps of Apc(min/+) mice overexpressed mERG1 and their formation was reverted by the hERG1 blocker E4031. AOM was applied to either hERG1-transgenic (TG) mice, which overexpress hERG1 in the mucosa of the large intestine, or wild-type mice. A significant increase of both mucin-depleted foci and polyps in the colon of hERG1-TG mice was detected. Both the intestine of TG mice and colonic polyps of Apc(min/+) showed an upregulation of phospho-Protein Kinase B (pAkt)/vascular endothelial growth factor (VEGF-A) and an increased angiogenesis, which were reverted by treatment with E4031. On the whole, this article assigns a relevant role to hERG1 in the process of in vivo colorectal carcinogenesis. PMID:24403225

Fiore, Antonella; Carraresi, Laura; Morabito, Angela; Polvani, Simone; Fortunato, Angelo; Lastraioli, Elena; Femia, Angelo P; De Lorenzo, Emanuele; Caderni, Giovanna; Arcangeli, Annarosa

2013-10-01

8

Isoform-Specific Dominant-Negative Effects Associated with hERG1 G628S Mutation in Long QT Syndrome  

PubMed Central

Background Mutations in the human ether-a-go-go-related gene 1 (hERG1) cause type 2 long QT syndrome (LQT2). The hERG1 gene encodes a K+ channel with properties similar to the rapidly activating delayed rectifying K+ current in the heart. Several hERG1 isoforms with unique structural and functional properties have been identified. To date, the pathogenic mechanisms of LQT2 mutations have been predominantly described in the context of the hERG1a isoform. In the present study, we investigated the functional consequences of the LQT2 mutation G628S in the hERG1b and hERG1aUSO isoforms. Methods A double-stable, mammalian expression system was developed to characterize isoform-specific dominant-negative effects of G628S-containing channels when co-expressed at equivalent levels with wild-type hERG1a. Western blot and co-immunoprecipitation studies were performed to study the trafficking and co-assembly of wild-type and mutant hERG1 isoforms. Patch-clamp electrophysiology was performed to characterize hERG1 channel function and the isoform-specific dominant-negative effects associated with the G628S mutation. Conclusions The non-functional hERG1a-G628S and hERG1b-G628S channels co-assembled with wild-type hERG1a and dominantly suppressed hERG1 current. In contrast, G628S-induced dominant-negative effects were absent in the context of the hERG1aUSO isoform. hERG1aUSO-G628S channels did not appreciably associate with hERG1a and did not significantly suppress hERG1 current when co-expressed at equivalent ratios or at ratios that approximate those found in cardiac tissue. These results suggest that the dominant-negative effects of LQT2 mutations may primarily occur in the context of the hERG1a and hERG1b isoforms.

Stump, Matthew R.; Gong, Qiuming; Zhou, Zhengfeng

2012-01-01

9

The amiodarone derivative KB130015 activates hERG1 potassium channels via a novel mechanism  

PubMed Central

Human ether à go-go related gene (hERG1) potassium channels underlie the repolarizing IKr current in the heart. Since they are targets of various drugs with cardiac side effects we tested whether the amiodarone derivative 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015) blocks hERG1 channels like its parent compound. Using patch-clamp and two-electrode voltage-clamp techniques we found that KB130015 blocks native and recombinant hERG1 channels at high voltages, but it activates them at low voltages. The activating effect has an apparent EC50 value of 12 ?M and is brought about by an about 4-fold acceleration of activation kinetics and a shift in voltage-dependent activation by ?16 mV. Channel activation was not use-dependent and was independent of inactivation gating. KB130015 presumably binds to the hERG1 pore from the cytosolic side and functionally competes with hERG1 block by amiodarone, E4031 (N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl] -4-piperidinyl] carbonyl] phenyl] methanesulfonamide dihydrochloride), and sertindole. Vice versa, amiodarone attenuates hERG1 activation by KB130015. Based on synergic channel activation by mallotoxin and KB130015 we conclude that the hERG1 pore contains at least two sites for activators that are functionally coupled among each other and to the cavity-blocker site. KB130015 and amiodarone may serve as lead structures for the identification of hERG1 pore-interacting drugs favoring channel activation vs. block.

Gessner, Guido; Macianskiene, Regina; Starkus, John G.; Schonherr, Roland; Heinemann, Stefan H.

2010-01-01

10

Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2  

PubMed Central

Background Long QT syndrome (LQTS) is a cardiac ion channelopathy which presents clinically with palpitations, syncope or sudden death. More than 700 LQTS-causing mutations have been identified in 13 genes, all of which encode proteins involved in the execution of the cardiac action potential. The most frequently affected genes, covering?>?90% of cases, are KCNQ1, KCNH2 and SCN5A. Methods We describe 64 different mutations in 70 unrelated Danish families using a routine five-gene screen, comprising KCNQ1, KCNH2 and SCN5A as well as KCNE1 and KCNE2. Results Twenty-two mutations were found in KCNQ1, 28 in KCNH2, 9 in SCN5A, 3 in KCNE1 and 2 in KCNE2. Twenty-six of these have only been described in the Danish population and 18 are novel. One double heterozygote (1.4% of families) was found. A founder mutation, p.F29L in KCNH2, was identified in 5 “unrelated” families. Disease association, in 31.2% of cases, was based on the type of mutation identified (nonsense, insertion/deletion, frameshift or splice-site). Functional data was available for 22.7% of the missense mutations. None of the mutations were found in 364 Danish alleles and only three, all functionally characterised, were recorded in the Exome Variation Server, albeit at a frequency of?KCNH2 was identified. In 48.4% of the mutations disease causation was based on mutation type or functional analysis.

2014-01-01

11

Circulating KCNH2 Current-Activating Factor in Patients with Heart Failure and Ventricular Tachyarrhythmia  

PubMed Central

Background It is estimated that approximately half of the deaths in patients with HF are sudden and that the most likely causes of sudden death are lethal ventricular tachyarrhythmias such as ventricular tachycardia (VT) or fibrillation (VF). However, the precise mechanism of ventricular tachyarrhythmias remains unknown. The KCNH2 channel conducting the delayed rectifier K+ current (IKr) is recognized as the most susceptible channel in acquired long QT syndrome. Recent findings have revealed that not only suppression but also enhancement of IKr increase vulnerability to major arrhythmic events, as seen in short QT syndrome. Therefore, we investigated the existence of a circulating KCNH2 current-modifying factor in patients with HF. Methodology/Principal Findings We examined the effects of serum of HF patients on recombinant IKr recorded from HEK 293 cells stably expressing KCNH2 by using the whole-cell patch-clamp technique. Study subjects were 14 patients with non-ischemic HF and 6 normal controls. Seven patients had a history of documented ventricular tachyarrhythmias (VT: 7 and VF: 1). Overnight treatment with 2% serum obtained from HF patients with ventricular arrhythmia resulted in a significant enhancement in the peaks of IKr tail currents compared to the serum from normal controls and HF patients without ventricular arrhythmia. Conclusions/Significance Here we provide the first evidence for the presence of a circulating KCNH2 channel activator in patients with HF and ventricular tachyarrhythmias. This factor may be responsible for arhythmogenesis in patients with HF.

Morita, Hiroshi; Akagi, Satoshi; Tani, Yoshinori; Katayama, Yusuke; Nishii, Nobuhiro; Miyoshi, Toru; Nagase, Satoshi; Kohno, Kunihisa; Kusano, Kengo Fukushima; Ohe, Tohru; Kurokawa, Junko; Furukawa, Tetsushi; Ito, Hiroshi

2011-01-01

12

hERG1 Channels and Glut-1 as Independent Prognostic Indicators of Worse Outcome in Stage I and II Colorectal Cancer: A Pilot Study1  

PubMed Central

BACKGROUND: There is a need to identify new markers to assess recurrence risk in early-stage colorectal cancer (CRC) patients. We explored the prognostic impact of ether-a-gò-gò-related gene 1 channels and some hypoxia markers, in patients with nonmetastatic (stage I, II, and III) CRC. METHODS: The expression of hERG1, vascular endothelial growth factor A (VEGF-A), glucose transporter 1, carbonic anhydrase IX (CA-IX), epidermal growth factor receptor (EGF-R), and p53 was tested by immunohistochemistry in 135 patients. The median follow-up was 35 months. Clinicopathologic parameters and overall survival were evaluated. RESULTS: hERG1 displayed a statistically significant association with Glut-1, VEGF-A, CA-IX, and EGF-R; p53 with VEGF-A and CA-IX; Glut-1 with the age of the patients; and EGF-R with TNM and mucin content. TNM and CA-IX were prognostic factors at the univariate analysis; TNM, hERG1, and Glut-1, at the multivariate analysis. Risk scores calculated from the final multivariate model allowed to stratify patients into four different risk groups: A) stage I–II, Glut-1 positivity, any hERG1; B) stage I–II, Glut-1 and hERG1 negativity; C) stage I–II, Glut-1 negativity, hERG1 positivity; D) stage III, any Glut-1 and any hERG1. CONCLUSIONS: hERG1 positivity with Glut-1 negativity identifies a patient group with poor prognosis within stage I–II CRC. The possibility that these patients might benefit from adjuvant therapy, independently from the TNM stage, is discussed. IMPACT: More robust prognostic and predictive markers, supplementing standard clinical and pathologic staging, are needed for node-negative patients.

Lastraioli, Elena; Bencini, Lapo; Bianchini, Elisa; Romoli, Maria Raffaella; Crociani, Olivia; Giommoni, Elisa; Messerini, Luca; Gasperoni, Silvia; Moretti, Renato; Di Costanzo, Francesco; Boni, Luca; Arcangeli, Annarosa

2012-01-01

13

Peripartum cardiomyopathy presenting with syncope due to Torsades de pointes: a case of long QT syndrome with a novel KCNH2 mutation.  

PubMed

Peripartum cardiomyopathy (PPCM) is a cardiomyopathy of unknown cause that occurs in the peripartum period. We report a case of PPCM presenting with syncope 1 month after an uncomplicated delivery. Electrocardiography showed Torsades de pointes (TdP) and QT interval prolongation. Echocardiography showed left ventricular systolic dysfunction and endomyocardial biopsy showed myocyte degeneration and fibrosis. Administration of magnesium sulfate and temporary pacing eliminated recurrent TdP. Genetic analyses revealed that recurrent TdP occurred via electrolyte disturbance and cardiac failure due to PPCM on the basis of a novel mutation in KCNH2, a gene responsible for inherited type 2 long QT syndrome. PMID:22382559

Nishimoto, Orie; Matsuda, Morihiro; Nakamoto, Kei; Nishiyama, Hirohiko; Kuraoka, Kazuya; Taniyama, Kiyomi; Tamura, Ritsu; Shimizu, Wataru; Kawamoto, Toshiharu

2012-01-01

14

hERG1 channels modulate integrin signaling to trigger angiogenesis and tumor progression in colorectal cancer  

PubMed Central

Angiogenesis is a potential target for cancer therapy. We identified a novel signaling pathway that sustains angiogenesis and progression in colorectal cancer (CRC). This pathway is triggered by ?1 integrin-mediated adhesion and leads to VEGF-A secretion. The effect is modulated by the human ether-à-go-go related gene 1 (hERG1) K+ channel. hERG1 recruits and activates PI3K and Akt. This in turn increases the Hypoxia Inducible Factor (HIF)-dependent transcription of VEGF-A and other tumour progression genes. This signaling pathway has novel features in that the integrin- and hERG1-dependent activation of HIF (i) is triggered in normoxia, especially after CRC cells have experienced a hypoxic stage, (ii) involves NF-kB and (iii) is counteracted by an active p53. Blocking hERG1 switches this pathway off also in vivo, by inhibiting cell growth, angiogenesis and metastatic spread. This suggests that non-cardiotoxic anti-hERG1 drugs might be a fruitful therapeutic strategy to prevent the failure of anti-VEGF therapy.

Crociani, Olivia; Zanieri, Francesca; Pillozzi, Serena; Lastraioli, Elena; Stefanini, Matteo; Fiore, Antonella; Fortunato, Angelo; D'Amico, Massimo; Masselli, Marika; De Lorenzo, Emanuele; Gasparoli, Luca; Chiu, Martina; Bussolati, Ovidio; Becchetti, Andrea; Arcangeli, Annarosa

2013-01-01

15

The KCNH2 Genetic Polymorphism (1956, C>T) Is a Novel Biomarker That Is Associated with CCB and ?,?-ADR Blocker Response in EH Patients in China  

PubMed Central

Background KCNH2 (hERG) potassium channels have an integral role in regulating the excitability of smooth muscle cells. Some pathways driven by angiotensin II, nitric oxide and adrenergic receptors blocker are involved in modulating the properties of KCNH2 potassium channels. And these pathways are closely related to blood pressure regulation. Therefore, we hypothesized that KCNH2 genetic polymorphisms may affect blood pressure response to the antihypertensive drug therapies. Materials and Methods To evaluate the interactions between KCNH2 genetic polymorphisms and individual blood pressure response to antihypertensive drugs, 370 subjects with essential hypertension (EH) were studied. In evaluating the interactions between KCNH2 genetic polymorphisms and drug response to blood pressure, multivariable ANOVA analysis followed by Bonferroni correction were carried out. Results There were statistically significant interactions between KCNH2 (1956, C>T) polymorphism and DBP change (P?=?0.010), MAP change (P?=?0.014) on azelnidipine or nitrendipine therapy patients at the end of 6 weeks. We found that the KCNH2 (1956,C>T) polymorphism was associated with the hypotensive effects of ?,?-ADR blockers of DBP change at the end of 4 and 6 weeks' treatment in an age- and gender-dependent manner (P?=?0.007 and 0.019, respectively). Similar results were also observed for changes in MAP at the end of 4 and 6 weeks (P-values were 0.035 and 0.078, respectively). While patients who received imidapril, candesartan and irbesartan therapy, no significant difference in drug response among KCNH2(1956,C>T) genotype was observed. Conclusion We have reported for the first time that KCNH2 (1956, C>T) polymorphism is associated with efficacy of antihypertensive drugs CCBs and ADR blockers, and may serve as a novel biomarker for individualized therapy for certain antihypertensive drugs.

He, Fazhong; Luo, Jianquan; Luo, Zhiying; Fan, Lan; He, Yijing; Zhu, Dingliang; Gao, Jinping; Deng, Sheng; Wang, Yan; Qian, Yuesheng; Zhou, Honghao; Chen, Xiaoping; Zhang, Wei

2013-01-01

16

Modification of hERG1 channel gating by Cd2+  

PubMed Central

Each of the four subunits in a voltage-gated potassium channel has a voltage sensor domain (VSD) that is formed by four transmembrane helical segments (S1–S4). In response to changes in membrane potential, intramembrane displacement of basic residues in S4 produces a gating current. As S4 moves through the membrane, its basic residues also form sequential electrostatic interactions with acidic residues in immobile regions of the S2 and S3 segments. Transition metal cations interact with these same acidic residues and modify channel gating. In human ether-á-go-go–related gene type 1 (hERG1) channels, Cd2+ coordinated by D456 and D460 in S2 and D509 in S3 induces a positive shift in the voltage dependence of activation of ionic currents. Here, we characterize the effects of Cd2+ on hERG1 gating currents in Xenopus oocytes using the cut-open Vaseline gap technique. Cd2+ shifted the half-point (V1/2) for the voltage dependence of the OFF gating charge–voltage (QOFF-V) relationship with an EC50 of 171 µM; at 0.3 mM, V1/2 was shifted by +50 mV. Cd2+ also induced an as of yet unrecognized small outward current (ICd-out) upon repolarization in a concentration- and voltage-dependent manner. We propose that Cd2+ and Arg residues in the S4 segment compete for interaction with acidic residues in S2 and S3 segments, and that the initial inward movement of S4 associated with membrane repolarization displaces Cd2+ in an outward direction to produce ICd-out. Co2+, Zn2+, and La3+ at concentrations that caused ?+35-mV shifts in the QOFF-V relationship did not induce a current similar to ICd-out, suggesting that the binding site for these cations or their competition with basic residues in S4 differs from Cd2+. New Markov models of hERG1 channels were developed that describe gating currents as a noncooperative two-phase process of the VSD and can account for changes in these currents caused by extracellular Cd2+.

Abbruzzese, Jennifer; Sachse, Frank B.; Tristani-Firouzi, Martin

2010-01-01

17

Interacting sites of scorpion toxin ErgTx1 with hERG1 K+ channels.  

PubMed

Peptides purified from scorpion venoms were shown to interact with specific amino acid residues present in the outer vestibule of various sub-types of potassium channels, occluding the pore and causing a decrement of K(+) permeability through the membrane of excitable and non excitable cells. This communication describes the identification of several interacting sites of toxin ErgTx1, a toxin purified from the venom of the scorpion Centruroides noxius, with the human ERG1 K(+) channels, by means of site-directed mutagenesis of specific residues of the toxin. Recombinant mutants of the gene coding for ErgTx1 were expressed heterologously in Escherichia coli, properly folded and their affinities and interactions with hERG1 channels were determined by patch-clamp techniques. Residues in position Y14, Y17 and F37 of the solvent exposed hydrophobic surface, and charged residues at the position K13 and K38 of ErgTx1 were shown to cause a decrement of the affinity from 20 folds to 3 orders of magnitude, thus suggesting that they are certainly participating on the binding surface of this toxin towards the hERG1 channels. Double mutants at positions K13 and F37, Y14 and F37, Y17 and F37 and K13 and K38 were also prepared and assayed, but the results obtained are not much different from the single point mutants of ErgTx1. The results of the present work indicate the most probable surface area of ErgTx1 that makes contact with the hERG channels. PMID:22366117

Jimenez-Vargas, J M; Restano-Cassulini, R; Possani, L D

2012-05-01

18

Long QT syndrome with nocturnal cardiac events caused by a KCNH2 missense mutation (G604S).  

PubMed

An 8-year-old boy suffered from an unconsciousness attack and torsade de pointes arrhythmia during sleep or at rest. His electrocardiogram showed prolonged QT intervals, but the T wave morphology was atypical for type 1, 2 or 3 congenital long-QT syndrome (LQTS). Intravenous epinephrine slightly prolonged the QT interval whereas mexiletine infusion shortened the QT interval. Although these clinical characteristics might suggest type 3 LQTS, a genetic analysis identified the G604S-KCNH2 mutation (type 2 LQTS). Because mismatches between the genotype and phenotype of LQTS are possible, genetic analysis of LQTS is important to identify the most appropriate therapeutic option and risk stratification. PMID:22821100

Sato, Akinori; Chinushi, Masaomi; Suzuki, Hiroshi; Numano, Fujito; Hanyu, Takanori; Iijima, Kenichi; Watanabe, Hiroshi; Furushima, Hiroshi

2012-01-01

19

Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome.  

PubMed

Patient-specific induced pluripotent stem cells (iPSCs) will assist research on genetic cardiac maladies if the disease phenotype is recapitulated in vitro. However, genetic background variations may confound disease traits, especially for disorders with incomplete penetrance, such as long-QT syndromes (LQTS). To study the LQT2-associated c.A2987T (N996I) KCNH2 mutation under genetically defined conditions, we derived iPSCs from a patient carrying this mutation and corrected it. Furthermore, we introduced the same point mutation in human embryonic stem cells (hESCs), generating two genetically distinct isogenic pairs of LQTS and control lines. Correction of the mutation normalized the current (IKr) conducted by the HERG channel and the action potential (AP) duration in iPSC-derived cardiomyocytes (CMs). Introduction of the same mutation reduced IKr and prolonged the AP duration in hESC-derived CMs. Further characterization of N996I-HERG pathogenesis revealed a trafficking defect. Our results demonstrated that the c.A2987T KCNH2 mutation is the primary cause of the LQTS phenotype. Precise genetic modification of pluripotent stem cells provided a physiologically and functionally relevant human cellular context to reveal the pathogenic mechanism underlying this specific disease phenotype. PMID:24213244

Bellin, Milena; Casini, Simona; Davis, Richard P; D'Aniello, Cristina; Haas, Jessica; Ward-van Oostwaard, Dorien; Tertoolen, Leon G J; Jung, Christian B; Elliott, David A; Welling, Andrea; Laugwitz, Karl-Ludwig; Moretti, Alessandra; Mummery, Christine L

2013-12-11

20

Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome  

PubMed Central

Patient-specific induced pluripotent stem cells (iPSCs) will assist research on genetic cardiac maladies if the disease phenotype is recapitulated in vitro. However, genetic background variations may confound disease traits, especially for disorders with incomplete penetrance, such as long-QT syndromes (LQTS). To study the LQT2-associated c.A2987T (N996I) KCNH2 mutation under genetically defined conditions, we derived iPSCs from a patient carrying this mutation and corrected it. Furthermore, we introduced the same point mutation in human embryonic stem cells (hESCs), generating two genetically distinct isogenic pairs of LQTS and control lines. Correction of the mutation normalized the current (IKr) conducted by the HERG channel and the action potential (AP) duration in iPSC-derived cardiomyocytes (CMs). Introduction of the same mutation reduced IKr and prolonged the AP duration in hESC-derived CMs. Further characterization of N996I-HERG pathogenesis revealed a trafficking defect. Our results demonstrated that the c.A2987T KCNH2 mutation is the primary cause of the LQTS phenotype. Precise genetic modification of pluripotent stem cells provided a physiologically and functionally relevant human cellular context to reveal the pathogenic mechanism underlying this specific disease phenotype.

Bellin, Milena; Casini, Simona; Davis, Richard P; D'Aniello, Cristina; Haas, Jessica; Ward-van Oostwaard, Dorien; Tertoolen, Leon G J; Jung, Christian B; Elliott, David A; Welling, Andrea; Laugwitz, Karl-Ludwig; Moretti, Alessandra; Mummery, Christine L

2013-01-01

21

Cooperative Interactions Between R531 and Acidic Residues in the Voltage Sensing Module of hERG1 Channels  

Microsoft Academic Search

HERG1 K+ channels are critical for modulating the duration of the cardiac action potential. The role of hERG1 channels in maintaining electrical stability in the heart derives from their unusual gating properties: slow activation and fast inactivation. HERG1 channel inactivation is intrinsically voltage sensitive and is not coupled to activation in the same way as in the Shaker family of

David R. Piper; Jason Rupp; Frank B. Sachse; Michael C. Sanguinetti; Martin Tristani-Firouzi

2008-01-01

22

herg1 Gene and HERG1 Protein Are Overexpressed in Colorectal Cancers and Regulate Cell Invasion of Tumor Cells  

Microsoft Academic Search

The acquisition of the capacity to invade surrounding tissues confers a more malignant phenotype to tumor cells and is necessary for the estab- lishment of metastases. The understanding of the molecular mechanisms underlying cell invasion in human solid tumors such as colorectal cancers could provide not only more sensitive prognostic analyses but also novel molecular targets for cancer therapy. We

Elena Lastraioli; Leonardo Guasti; Olivia Crociani; Simone Polvani; Giovanna Hofmann; Harry Witchel; Lapo Bencini; Massimo Calistri; Luca Messerini; Marco Scatizzi; Renato Moretti; Enzo Wanke; Massimo Olivotto; Gabriele Mugnai; Annarosa Arcangeli

23

The generation of induced pluripotent stem cells from a patient with KCNH2 G603D, without LQT2 disease associated symptom.  

PubMed

The long QT syndrome type 2 (LQT2) is inheritable life threatening arrhythmic disorder and one of the most common genetic variants in long QT syndrome. There are some indications for treatment of the patients with LQT2 but it is impossible to completely prevent fatal arrhythmia. To develop novel therapy for the patients with LQT2, it has been desired to generate diseasespecific and patient-specific disease model. Human induced pluripotent stem (iPS) cells are somatic cell-derived pluripotent stem cells with infinite proliferation ability and multipotency. Patient-specific iPS cells can be derived from patient somatic cells, have all genomic information encoded in patient's genome including mutation and all SNPs, and can be ideal disease models of the patients. To generate disease model for LQT2 by iPS cells, we should firstly generate iPS cells from the patient with LQT2 and confirm the genomic mutation in iPS cells. In this study, we showed the successful generation of iPS cells from a patient with KCNH2 G603D mutation. The patient specific iPS cells properly expressed stem cell markers, such as NANOG and OCT3/4. We also confirmed that the KCNH2 G603D (G1808A) mutation was taken over in patient specific iPS cells. These patient-specific iPS cells may contribute to the future analysis for disease pathogenesis and drug innovation. PMID:23917959

Okata, Shinichiro; Yuasa, Shinsuke; Yamane, Teiichi; Furukawa, Tetsushi; Fukuda, Keiichi

2013-01-01

24

Mechanistic Basis for Type 2 Long QT Syndrome Caused by KCNH2 Mutations that Disrupt Conserved Arginine Residue in the Voltage Sensor  

PubMed Central

KCNH2 encodes the Kv11.1 channel, which conducts the rapidly activating delayed rectifier K+ current (IKr) in the heart. KCNH2 mutations cause type 2 long QT syndrome (LQT2), which increases the risk for life-threatening ventricular arrhythmias. LQT2 mutations are predicted to prolong the cardiac action potential (AP) by reducing IKr during repolarization. Kv11.1 contains several conserved basic amino acids in the fourth transmembrane segment (S4) of the voltage sensor that are important for normal channel trafficking and gating. This study sought to determine the mechanism(s) by which LQT2 mutations at conserved arginine residues in S4 (R531Q, R531W or R534L) alter Kv11.1 function. Western blot analyses of HEK293 cells transiently expressing R531Q, R531W or R534L suggested that only R534L inhibited Kv11.1 trafficking. Voltage-clamping experiments showed that R531Q or R531W dramatically altered Kv11.1 current (IKv11.1) activation, inactivation, recovery from inactivation and deactivation. Coexpression of wild type (to mimic the patients’ genotypes) mostly corrected the changes in IKv11.1 activation and inactivation, but deactivation kinetics were still faster. Computational simulations using a human ventricular AP model showed that accelerating deactivation rates was sufficient to prolong the AP, but these effects were minimal compared to simply reducing IKr. These are the first data to demonstrate that coexpressing wild type can correct activation and inactivation dysfunction caused by mutations at a critical voltage-sensing residue in Kv11.1. We conclude that some Kv11.1 mutations might accelerate deactivation to cause LQT2 but that the ventricular AP duration is much more sensitive to mutations that decrease IKr. This likely explains why most LQT2 mutations are nonsense or trafficking-deficient.

McBride, Christie M.; Smith, Ashley M.; Smith, Jennifer L.; Reloj, Allison R.; Velasco, Ellyn J.; Powell, Jonathan; Elayi, Claude S.; Bartos, Daniel C.; Burgess, Don E.

2013-01-01

25

Molecular Determinants for Activation of Human Ether-à-go-go-related Gene 1 Potassium Channels by 3-Nitro-N-(4-phenoxyphenyl) BenzamideS?  

PubMed Central

Human ether-à-go-go-related gene 1 (hERG1) channels mediate repolarization of cardiac action potentials. Inherited long QT syndrome (LQTS) caused by loss-of-function mutations, or unintended blockade of hERG1 channels by many drugs, can lead to severe arrhythmia and sudden death. Drugs that activate hERG1 are a novel pharmacological approach to treat LQTS. 3-Nitro-n-(4-phenoxyphenyl) benzamide [ICA-105574 (ICA)] has been discovered to activate hERG1 by strong attenuation of pore-type inactivation. Here, we used scanning mutagenesis of hERG1 to identify the molecular determinants of ICA action. Three mutations abolished the activator effects of 30 ?M ICA, including L622C in the pore helix, F557L in the S5 segment, and Y652A in the S6 segment. One mutation in S6 (A653M) switched the activity of ICA from an activator to an inhibitor, revealing its partial agonist activity. This was confirmed by showing that the noninactivating mutant hERG1 channel (G628C/S631C) was inhibited by ICA and that the addition of the F557L mutation rendered the channel drug-insensitive. Simulated molecular docking of ICA to homology models of hERG1 corroborated the scanning mutagenesis findings. Together, our findings indicate that ICA is a mixed agonist of hERG1 channels. Activation or inhibition of currents is mediated by the same or overlapping binding site located in the pore module between two adjacent subunits of the homotetrameric channel.

Garg, Vivek; Stary-Weinzinger, Anna; Sachse, Frank

2011-01-01

26

Molecular analysis of potassium ion channel genes in sudden death cases among patients administered psychotropic drug therapy: are polymorphisms in LQT genes a potential risk factor?  

PubMed

Psychotropic drugs can pose the risk of acquired long QT syndrome (LQTS). Unexpected autopsy-negative sudden death in patients taking psychotropic drugs may be associated with prolonged QT intervals and life-threatening arrhythmias. We analyzed genes that encode for cardiac ion channels and potentially associated with LQTS, examining specifically the potassium channel genes KCNQ1 and KCNH2 in 10 cases of sudden death involving patients administered psychotropic medication in which autopsy findings identified no clear cause of death. We amplified and sequenced all exons of KCNQ1 and KCNH2, identifying G643S, missense polymorphism in KCNQ1, in 6 of the 10 cases. A study analysis indicated that only 11% of 381 healthy Japanese individuals carry this polymorphism. Reports of previous functional analyses indicate that the G643S polymorphism in the KCNQ1 potassium channel protein causes mild I(Ks) channel dysfunction. Our present study suggests that administering psychotropic drug therapy to individuals carrying the G643S polymorphism may heighten the risk of prolonged QT intervals and life-threatening arrhythmias. Thus, screening for the G643S polymorphism before prescribing psychotropic drugs may help reduce the risk of unexpected sudden death. PMID:24284363

Kamei, Sayako; Sato, Noriko; Harayama, Yuta; Nunotani, Miyako; Takatsu, Kanae; Shiozaki, Tetsuya; Hayashi, Tokutaro; Asamura, Hideki

2014-02-01

27

Identification of Highly Methylated Genes across Various Types of B-Cell Non-Hodgkin Lymphoma  

PubMed Central

Epigenetic alterations of gene expression are important in the development of cancer. In this study, we identified genes which are epigenetically altered in major lymphoma types. We used DNA microarray technology to assess changes in gene expression after treatment of 11 lymphoma cell lines with epigenetic drugs. We identified 233 genes with upregulated expression in treated cell lines and with downregulated expression in B-cell lymphoma patient samples (n?=?480) when compared to normal B cells (n?=?5). The top 30 genes were further analyzed by methylation specific PCR (MSP) in 18 lymphoma cell lines. Seven of the genes were methylated in more than 70% of the cell lines and were further subjected to quantitative MSP in 37 B-cell lymphoma patient samples (diffuse large B-cell lymphoma (activated B-cell like and germinal center B-cell like subtypes), follicular lymphoma and Burkitt`s lymphoma) and normal B lymphocytes from 10 healthy donors. The promoters of DSP, FZD8, KCNH2, and PPP1R14A were methylated in 28%, 67%, 22%, and 78% of the 36 tumor samples, respectively, but not in control samples. Validation using a second series of healthy donor controls (n?=?42; normal B cells, peripheral blood mononuclear cells, bone marrow, tonsils and follicular hyperplasia) and fresh-frozen lymphoma biopsies (n?=?25), confirmed the results. The DNA methylation biomarker panel consisting of DSP, FZD8, KCNH2, and PPP1R14A was positive in 89% (54/61) of all lymphomas. Receiver operating characteristic analysis to determine the discriminative power between lymphoma and healthy control samples showed a c-statistic of 0.96, indicating a possible role for the biomarker panel in monitoring of lymphoma patients.

Bethge, Nicole; Honne, Hilde; Hilden, Vera; Tr?en, Gunhild; Eknaes, Mette; Liest?l, Knut; Holte, Harald; Delabie, Jan; Smeland, Erlend B.; Lind, Guro E.

2013-01-01

28

Identification of highly methylated genes across various types of B-cell non-hodgkin lymphoma.  

PubMed

Epigenetic alterations of gene expression are important in the development of cancer. In this study, we identified genes which are epigenetically altered in major lymphoma types. We used DNA microarray technology to assess changes in gene expression after treatment of 11 lymphoma cell lines with epigenetic drugs. We identified 233 genes with upregulated expression in treated cell lines and with downregulated expression in B-cell lymphoma patient samples (n?=?480) when compared to normal B cells (n?=?5). The top 30 genes were further analyzed by methylation specific PCR (MSP) in 18 lymphoma cell lines. Seven of the genes were methylated in more than 70% of the cell lines and were further subjected to quantitative MSP in 37 B-cell lymphoma patient samples (diffuse large B-cell lymphoma (activated B-cell like and germinal center B-cell like subtypes), follicular lymphoma and Burkitt`s lymphoma) and normal B lymphocytes from 10 healthy donors. The promoters of DSP, FZD8, KCNH2, and PPP1R14A were methylated in 28%, 67%, 22%, and 78% of the 36 tumor samples, respectively, but not in control samples. Validation using a second series of healthy donor controls (n?=?42; normal B cells, peripheral blood mononuclear cells, bone marrow, tonsils and follicular hyperplasia) and fresh-frozen lymphoma biopsies (n?=?25), confirmed the results. The DNA methylation biomarker panel consisting of DSP, FZD8, KCNH2, and PPP1R14A was positive in 89% (54/61) of all lymphomas. Receiver operating characteristic analysis to determine the discriminative power between lymphoma and healthy control samples showed a c-statistic of 0.96, indicating a possible role for the biomarker panel in monitoring of lymphoma patients. PMID:24260260

Bethge, Nicole; Honne, Hilde; Hilden, Vera; Trøen, Gunhild; Eknæs, Mette; Liestøl, Knut; Holte, Harald; Delabie, Jan; Smeland, Erlend B; Lind, Guro E

2013-01-01

29

Altered Gene Expression by Low-Dose Arsenic Exposure in Humans and Cultured Cardiomyocytes: Assessment by Real-Time PCR Arrays  

PubMed Central

Chronic arsenic exposure results in higher risk of skin, lung, and bladder cancer, as well as cardiovascular disease and diabetes. The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT-PCR TaqMan low-density array (TLDA). We found that expression of tumor necrosis factor-? (TNF-?), which activates both inflammation and NF-?B-dependent survival pathways, was strongly associated with water and urinary arsenic levels. Expression of KCNA5, which encodes a potassium ion channel protein, was positively associated with water and toe nail arsenic levels. Expression of 2 and 11 genes were positively associated with nail and urinary arsenic, respectively. Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans, we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro. Expression of the ion-channel genes CACNA1, KCNH2, KCNQ1 and KCNE1 were down-regulated by 1-?M arsenic. Alteration of some common pathways, including those involved in oxidative stress, inflammatory signaling, and ion-channel function, may underlay the seemingly disparate array of arsenic-associated diseases, such as cancer, cardiovascular disease, and diabetes.

Mo, Jinyao; Xia, Yajuan; Wade, Timothy J.; DeMarini, David M.; Davidson, Mercy; Mumford, Judy

2011-01-01

30

Long QT Syndrome-Associated Mutations in Intrauterine Fetal Death  

PubMed Central

Importance Intrauterine fetal death or stillbirth occurs in approximately 1 out of every 160 pregnancies and accounts for 50% of all perinatal deaths. Postmortem evaluation fails to elucidate an underlying cause in many cases. Long QT syndrome (LQTS) may contribute to this problem. Objective To determine the spectrum and prevalence of mutations in the 3 most common LQTS susceptible genes (KCNQ1, KCNH2, and SCN5A) for a cohort of unexplained cases. Design, Setting, and Patients In this case series, retrospective postmortem genetic testing was conducted on a convenience sample of 91 unexplained intrauterine fetal deaths (mean [SD] estimated gestational age at fetal death, 26.3 [8.7] weeks) that were collected from 2006-2012 by the Mayo Clinic, Rochester, Minnesota, or the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. More than 1300 ostensibly healthy individuals served as controls. In addition, publicly available exome databases were assessed for the general population frequency of identified genetic variants. Main Outcomes and Measures Comprehensive mutational analyses of KCNQ1 (KV7.1, LQTS type 1), KCNH2 (HERG/KV11.1, LQTS type 2), and SCN5A (NaV1.5, LQTS type 3) were performed using denaturing high-performance liquid chromatography and direct DNA sequencing on genomic DNA extracted from decedent tissue. Functional analyses of novel mutations were performed using heterologous expression and patch-clamp recording. Results The 3 putative LQTS susceptibility missense mutations (KCNQ1, p.A283T; KCNQ1, p.R397W; and KCNH2[1b], p.R25W), with a heterozygous frequency of less than 0.05% in more than 10000 publicly available exomes and absent in more than 1000 ethnically similar control patients, were discovered in 3 intrauterine fetal deaths (3.3% [95% CI, 0.68%-9.3%]). Both KV7.1-A283T (16-week male) and KV7.1-R397W (16-week female) mutations were associated with marked KV7.1 loss-of-function consistent with in utero LQTS type 1, whereas the HERG1b-R25W mutation (33.2-week male) exhibited a loss of function consistent with in utero LQTS type 2. In addition, 5 intrauterine fetal deaths hosted SCN5A rare nonsynonymous genetic variants (p.T220I, p.R1193Q, involving 2 cases, and p.P2006A, involving 2 cases) that conferred in vitro electrophysiological characteristics consistent with potentially proarrhythmic phenotypes. Conclusions and Relevance In this molecular genetic evaluation of 91 cases of intrauterine fetal death, missense mutations associated with LQTS susceptibility were discovered in 3 cases (3.3%) and overall, genetic variants leading to dysfunctional LQTS-associated ion channels in vitro were discovered in 8 cases (8.8%). These preliminary findings may provide insights into mechanisms of some cases of stillbirth.

Crotti, Lia; Tester, David J.; White, Wendy M.; Bartos, Daniel C.; Insolia, Roberto; Besana, Alessandra; Kunic, Jennifer D.; Will, Melissa L.; Velasco, Ellyn J.; Bair, Jennifer J.; Ghidoni, Alice; Cetin, Irene; Van Dyke, Daniel L.; Wick, Myra J.; Brost, Brian; Delisle, Brian P.; Facchinetti, Fabio; George, Alfred L.; Schwartz, Peter J.; Ackerman, Michael J.

2013-01-01

31

Sphingosine 1-phosphate and human ether-a'-go-go-related gene potassium channels modulate migration in human anaplastic thyroid cancer cells.  

PubMed

Anaplastic thyroid cancer (ATC) is the most aggressive form of human thyroid cancer, lacking any effective treatment. Sphingosine 1-phosphate (S1P) receptors and human ether-a'-go-go-related gene (HERG (KCNH2)) potassium channels are important modulators of cell migration. In this study, we have shown that the S1P(1-3) receptors are expressed in C643 and THJ-16T human ATC cell lines, both at mRNA and protein level. S1P inhibited migration of these cells and of follicular FTC-133 thyroid cancer cells. Using the S1P(1,3) inhibitor VPC-23019, the S1P(2) inhibitor JTE-013, and the S1P(2) receptor siRNA, we showed that the effect was mediated through S1P(2). Treatment of the cells with the Rho inhibitor C3 transferase abolished the effect of S1P on migration. S1P attenuated Rac activity, and inhibiting Rac decreased migration. Sphingosine kinase inhibitor enhanced basal migration of cells, and addition of exogenous S1P inhibited migration. C643 cells expressed a nonconducting HERG protein, and S1P decreased HERG protein expression. The HERG blocker E-4031 decreased migration. Interestingly, downregulating HERG protein with siRNA decreased the basal migration. In experiments using HEK cells overexpressing HERG, we showed that S1P decreased channel protein expression and current and that S1P attenuated migration of the cells. We conclude that S1P attenuates migration of C643 ATC cells by activating S1P(2) and the Rho pathway. The attenuated migration is also, in part, dependent on a S1P-induced decrease of HERG protein. PMID:22889737

Asghar, Muhammad Yasir; Viitanen, Tero; Kemppainen, Kati; Törnquist, Kid

2012-10-01

32

Long QT Interval in Turner Syndrome - A High Prevalence of LQTS Gene Mutations  

PubMed Central

Objectives QT-interval prolongation of unknown aetiology is common in Turner syndrome. This study set out to explore the presence of known long QT mutations in Turner syndrome and to examine the corrected QT-interval (QTc) over time and relate the findings to the Turner syndrome phenotype. Methods Adult women with Turner syndrome (n?=?88) were examined thrice and 68 age-matched healthy controls were examined once. QTc was measured by one blinded reader (intra-reader variability: 0.7%), and adjusted for influence of heart rate by Bazett’s (bQTc) and Hodges’s formula (hQTc). The prevalence of mutations in genes related to Long QT syndrome was determined in women with Turner syndrome and a QTc >432.0 milliseconds (ms). Echocardiographic assessment of aortic valve morphology, 24-hour blood pressures and blood samples were done. Results The mean hQTc in women with Turner syndrome (414.0±25.5 ms) compared to controls (390.4±17.8 ms) was prolonged (p<0.001) and did not change over time (416.9±22.6 vs. 415.6±25.5 ms; p?=?0.4). 45,X karyotype was associated with increased hQTc prolongation compared to other Turner syndrome karyotypes (418.2±24.8 vs. 407.6±25.5 ms; p?=?0.055). In women with Turner syndrome and a bQTc >432 ms, 7 had mutations in major Long QT syndrome genes (SCN5A and KCNH2) and one in a minor Long QT syndrome gene (KCNE2). Conclusion There is a high prevalence of mutations in the major LQTS genes in women with TS and prolonged QTc. It remains to be settled, whether these findings are related to the unexplained excess mortality in Turner women. Clinical Trial Registration NCT00624949. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol/sid/S0001FLI/selectaction/View/ts/3/uid/U000099E.

Trolle, Christian; Mortensen, Kristian H.; Pedersen, Lisbeth N.; Berglund, Agnethe; Jensen, Henrik K.; Andersen, Niels H.; Gravholt, Claus H.

2013-01-01

33

Species diversity and peptide toxins blocking selectivity of ether-a-go-go-related gene subfamily K+ channels in the central nervous system.  

PubMed

The ether-à-go-go-related gene (erg) K+ channels are known to be crucial for life in Caenorhabditis elegans (mating), Drosophila melanogaster (seizure), and humans (LQT syndrome). The erg genes known to date (erg1, erg2, and erg3) are highly expressed in various areas of the rat and mouse central nervous system (CNS), and ERG channel blockers alter firing accommodation. To assign physiological roles to each isoform, it is necessary to design pharmacological strategies to distinguish individual currents. To this purpose, we have investigated the blocking properties of specific peptide inhibitors of hERG1 channels on the human and rat isoforms. In particular, we have tested ErgTx1 (from the scorpion Centruroides noxious), BeKm-1 (from the scorpion Buthus eupeus), and APETx1 (from the sea anemone Anthopleura elegantissima). Because these peptides had different species-specific effects on the six different channels, we have also carried out a biophysical characterization of hERG2 and hERG3 channels that turned out to be different from the rat homologs. It emerged that APETx1 is exquisitely selective for ERG1 and does not compete with the other two toxins. BeKm-1 discriminates well among the three rat members. ErgTx1 is unable to block hERG2, but blocks rERG2 and has the lowest KD for hERG3. BeKm-1 and ErgTx1 compete for hERG3 but not for rERG2 blockade. Our findings should be helpful for structure-function studies and for novel CNS ERG-specific drug design. PMID:16497878

Restano-Cassulini, Rita; Korolkova, Yuliya V; Diochot, Sylvie; Gurrola, Georgina; Guasti, Leonardo; Possani, Lourival D; Lazdunski, Michel; Grishin, Eugene V; Arcangeli, Annarosa; Wanke, Enzo

2006-05-01

34

Rehabilitating drug-induced long-QT promoters: In-silico design of hERG-neutral cisapride analogues with retained pharmacological activity  

PubMed Central

Background The human ether-a-go-go related gene 1 (hERG1), which codes for a potassium ion channel, is a key element in the cardiac delayed rectified potassium current, IKr, and plays an important role in the normal repolarization of the heart’s action potential. Many approved drugs have been withdrawn from the market due to their prolongation of the QT interval. Most of these drugs have high potencies for their principal targets and are often irreplaceable, thus “rehabilitation” studies for decreasing their high hERG1 blocking affinities, while keeping them active at the binding sites of their targets, have been proposed to enable these drugs to re-enter the market. Methods In this proof-of-principle study, we focus on cisapride, a gastroprokinetic agent withdrawn from the market due to its high hERG1 blocking affinity. Here we tested an a priori strategy to predict a compound’s cardiotoxicity using de novo drug design with molecular docking and Molecular Dynamics (MD) simulations to generate a strategy for the rehabilitation of cisapride. Results We focused on two key receptors, a target interaction with the (adenosine) receptor and an off-target interaction with hERG1 channels. An analysis of the fragment interactions of cisapride at human A2A adenosine receptors and hERG1 central cavities helped us to identify the key chemical groups responsible for the drug activity and hERG1 blockade. A set of cisapride derivatives with reduced cardiotoxicity was then proposed using an in-silico two-tier approach. This set was compared against a large dataset of commercially available cisapride analogs and derivatives. Conclusions An interaction decomposition of cisapride and cisapride derivatives allowed for the identification of key active scaffolds and functional groups that may be responsible for the unwanted blockade of hERG1.

2014-01-01

35

Prevalence of arrhythmia-associated gene mutations and risk of sudden cardiac death in the Finnish population  

PubMed Central

Background Sudden cardiac death (SCD) remains a major cause of death in Western Countries. It has a heritable component, but previous molecular studies have mainly focused on common genetic variants. We studied the prevalence, clinical phenotypes, and risk of SCD presented by ten rare mutations previously associated with arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, or catecholaminergic polymorphic ventricular tachycardia. Methods The occurrence of ten arrhythmia-associated mutations was determined in four large prospective population cohorts (FINRISK 1992, 1997, 2002, and Health 2000, n = 28,465) and two series of forensic autopsies (The Helsinki Sudden Death Study and The Tampere Autopsy Study, n = 825). Follow-up data was collected from national registries. Results The ten mutations showed a combined prevalence of 79 per 10,000 individuals in Finland and six of them showed remarkable geographic clustering. Of a total of 715 SCD cases, seven (1.0%) carried one of the ten mutations assayed: three carried KCNH2 R176W, one KCNH2 L552S, two PKP2 Q59L, and one RYR2 R3570W. Conclusions Arrhythmia-associated mutations are prevalent in the general Finnish population but do not seem to present a major risk factor for SCD, at least during a mean of 10-year follow-up of a random adult population sample.

Lahtinen, Annukka M.; Havulinna, Aki S.; Noseworthy, Peter A.; Jula, Antti; Karhunen, Pekka J.; Perola, Markus; Newton-Cheh, Christopher; Salomaa, Veikko; Kontula, Kimmo

2013-01-01

36

Phylogenetic and Physicochemical Analyses Enhance the Classification of Rare Non-Synonymous Single Nucleotide Variants in Type 1 and 2 Long QT Syndrome  

PubMed Central

Background Hundreds of non-synonymous single nucleotide variants (nsSNVs) have been identified in the two most common LQTS-susceptibility genes (KCNQ1 and KCNH2). Unfortunately, a ~3% background rate of rare KCNQ1 and KCNH2 nsSNVs amongst healthy individuals complicates the ability to distinguish rare pathogenic mutations from similarly rare yet presumably innocuous variants. Methods and Results In this study, 4 tools [1) conservation across species, 2) Grantham values, 3) SIFT, and 4) PolyPhen] were used to predict “pathogenic” or “benign” status for nsSNVs identified across 388 clinically “definite” LQTS cases and 1344 ostensibly healthy controls. From these data, estimated predictive values (EPVs) were determined for each tool independently, in concert with previously published protein topology-derived EPVs, and synergistically when ? 3 tools were in agreement. Overall, all 4 tools displayed a statistically significant ability to distinguish between case-derived and control-derived nsSNVs in KCNQ1, whereas each tool, except Grantham values, displayed a similar ability to differentiate KCNH2 nsSNVs. Collectively, when at least 3 of the 4 tools agreed on the “pathogenic” status of C-terminal nsSNVs located outside the KCNH2/Kv11.1 cyclic nucleotide binding domain, the topology-specific EPV improved from 56% to 91%. Conclusions While in silico prediction tools should not be used to predict independently the pathogenicity of a novel, rare nSNV, our results support the potential clinical utility of the synergistic use of these tools to enhance the classification of nsSNVs, particularly for Kv11.1’s difficult to interpret C-terminal region.

Giudicessi, John R.; Kapplinger, Jamie D.; Tester, David J.; Alders, Marielle; Salisbury, Benjamin A.; Wilde, Arthur A.M.; Ackerman, Michael J.

2013-01-01

37

Selective acquired long QT syndrome (saLQTS) upon risperidone treatment  

PubMed Central

Background Numerous structurally unrelated drugs, including antipsychotics, can prolong QT interval and trigger the acquired long QT syndrome (aLQTS). All of them are thought to act at the level of KCNH2, a subunit of the potassium channel. Although the QT-prolonging drugs are proscribed in the subjects with aLQTS, the individual response to diverse QT-prolonging drugs may vary substantially. Case presentation We report here a case of aLQTS in response to small doses of risperidone that was confirmed at three independent drug challenges in the absence of other QT-prolonging drugs. On the other hand, the patient did not respond with QT prolongation to some other antipsychotics. In particular, the administration of clozapine, known to be associated with higher QT-prolongation risk than risperidone, had no effect on QT-length. A detailed genetic analysis revealed no mutations or polymorphisms in KCNH2, KCNE1, KCNE2, SCN5A and KCNQ1 genes. Conclusions Our observation suggests that some patients may display a selective aLQTS to a single antipsychotic, without a potassium channel-related genetic substrate. Contrasting with the idea of a common target of the aLQTS-triggerring drugs, our data suggests existence of an alternative target protein, which unlike the KCNH2 would be drug-selective.

2012-01-01

38

Synthetic Genes.  

National Technical Information Service (NTIS)

The invention provides strategies, methods, vectors, reagents, and systems for production of synthetic genes, production of libraries of such genes, and manipulation and characterization of the genes and corresponding encoded polypeptides. In one aspect, ...

D. Sand K. G. Patel R. C. Reid S. J. Kodunal

2004-01-01

39

Endocrine genes  

SciTech Connect

This book contains 13 chapters. Some of the titles are: Gene Transfer and Expression of Mammalian Cell Receptors; Mapping Endocrine Genes with Sorted Human Chromosomes; Structure, Function, Hormonal Regulation of Steroidogenic Enzyme Genes; Molecular Analysis of Steroid Hormone Action Using the Human Metallothionein Genes as a Model.

Lau, Y.F.

1988-01-01

40

Gene Therapy  

PubMed Central

Gene therapy is defined as the treatment of disease by transfer of genetic material into cells. This review will explore methods available for gene transfer as well as current and potential applications for craniofacial regeneration, with emphasis on future development and design. Though non-viral gene delivery methods are limited by low gene transfer efficiency, they benefit from relative safety, low immunogenicity, ease of manufacture, and lack of DNA insert size limitation. In contrast, viral vectors are nature’s gene delivery machines that can be optimized to allow for tissue-specific targeting, site-specific chromosomal integration, and efficient long-term infection of dividing and non-dividing cells. In contrast to traditional replacement gene therapy, craniofacial regeneration seeks to use genetic vectors as supplemental building blocks for tissue growth and repair. Synergistic combination of viral gene therapy with craniofacial tissue engineering will significantly enhance our ability to repair and replace tissues in vivo.

Scheller, E.L.; Krebsbach, P.H.

2009-01-01

41

Molecular autopsy in the sudden cardiac death of a young woman: a first Canadian report.  

PubMed

Standard autopsy of young victims with sudden cardiac death commonly does not identify a specific pathological diagnosis. In such cases, sudden cardiac death may be secondary to a genetic condition predisposing the patient to ventricular arrhythmias. Failure to identify a genetic etiology for an unexpected sudden death may leave surviving family members at risk for a similar tragedy. The case of a 21-year-old woman who died suddenly while at rest is presented. Molecular genetic analysis of tissue retrieved from the regional coroner's office identified a novel missense mutation in the KCNH2 gene, a gene known to cause the long QT syndrome. PMID:17876385

Rutberg, Julie; Green, Martin S; Gow, Robert M; Geraghty, Michael T; Honeywell, Christina; Ewen, John; Birnie, David H; Tang, Anthony; Lemery, Robert; Gollob, Michael H

2007-09-01

42

Genetic Mutation in Korean Patients of Sudden Cardiac Arrest as a Surrogating Marker of Idiopathic Ventricular Arrhythmia  

PubMed Central

Mutation or common intronic variants in cardiac ion channel genes have been suggested to be associated with sudden cardiac death caused by idiopathic ventricular tachyarrhythmia. This study aimed to find mutations in cardiac ion channel genes of Korean sudden cardiac arrest patients with structurally normal heart and to verify association between common genetic variation in cardiac ion channel and sudden cardiac arrest by idiopathic ventricular tachyarrhythmia in Koreans. Study participants were Korean survivors of sudden cardiac arrest caused by idiopathic ventricular tachycardia or fibrillation. All coding exons of the SCN5A, KCNQ1, and KCNH2 genes were analyzed by Sanger sequencing. Fifteen survivors of sudden cardiac arrest were included. Three male patients had mutations in SCN5A gene and none in KCNQ1 and KCNH2 genes. Intronic variant (rs2283222) in KCNQ1 gene showed significant association with sudden cardiac arrest (OR 4.05). Four male sudden cardiac arrest survivors had intronic variant (rs11720524) in SCN5A gene. None of female survivors of sudden cardiac arrest had SCN5A gene mutations despite similar frequencies of intronic variants between males and females in 55 normal controls. Common intronic variant in KCNQ1 gene is associated with sudden cardiac arrest caused by idiopathic ventricular tachyarrhythmia in Koreans.

Son, Myoung Kyun; Ki, Chang-Seok; Park, Seung-Jung; Huh, June; Kim, June Soo

2013-01-01

43

Gene Identification  

NSDL National Science Digital Library

This module will examine the "Language" of genes and illustrate how basic statistical methods can be applied to the problem of gene prediction. The merger of computational sciences with biology, and the challenges facing BioinFormatics, will also be explored through the use of analysis tools available at the National Center for Biotechnology InFormation (NCBI).

Daniels, Chuck

44

Epigenome-wide ovarian cancer analysis identifies a methylation profile differentiating clear-cell histology with epigenetic silencing of the HERG K+ channel.  

PubMed

Ovarian cancer remains the leading cause of death in women with gynecologic malignancies, despite surgical advances and the development of more effective chemotherapeutics. As increasing evidence indicates that clear-cell ovarian cancer may have unique pathogenesis, further understanding of molecular features may enable us to begin to understand the underlying biology and histology-specific information for improved outcomes. To study epigenetics in clear-cell ovarian cancer, fresh frozen tumor DNA (n = 485) was assayed on Illumina Infinium HumanMethylation450 BeadChips. We identified a clear-cell ovarian cancer tumor methylation profile (n = 163) which we validated in two independent replication sets (set 1, n = 163; set 2, n = 159), highlighting 22 CpG loci associated with nine genes (VWA1, FOXP1, FGFRL1, LINC00340, KCNH2, ANK1, ATXN2, NDRG21 and SLC16A11). Nearly all of the differentially methylated CpGs showed a propensity toward hypermethylation among clear-cell cases. Several loci methylation inversely correlated with tumor gene expression, most notably KCNH2 (HERG, a potassium channel) (P = 9.5 × 10(-7)), indicating epigenetic silencing. In addition, a predicted methylation class mainly represented by the clear-cell cases (20 clear cell out of 23 cases) had improved survival time. Although these analyses included only 30 clear-cell carcinomas, results suggest that loss of expression of KCNH2 (HERG) by methylation could be a good prognostic marker, given that overexpression of the potassium (K(+)) channel Eag family members promotes increased proliferation and results in poor prognosis. Validation in a bigger cohort of clear-cell tumors of the ovary is warranted. PMID:23571109

Cicek, Mine S; Koestler, Devin C; Fridley, Brooke L; Kalli, Kimberly R; Armasu, Sebastian M; Larson, Melissa C; Wang, Chen; Winham, Stacey J; Vierkant, Robert A; Rider, David N; Block, Matthew S; Klotzle, Brandy; Konecny, Gottfried; Winterhoff, Boris J; Hamidi, Habib; Shridhar, Viji; Fan, Jian-Bing; Visscher, Daniel W; Olson, Janet E; Hartmann, Lynn C; Bibikova, Marina; Chien, Jeremy; Cunningham, Julie M; Goode, Ellen L

2013-08-01

45

Genes V.  

SciTech Connect

This fifth edition book encompasses a wide range of topics covering 1,272 pages. The book is arranged into nine parts with a total of 36 chapters. These nine parts include Introduction; DNA as a Store of Information; Translation; Constructing Cells; Control of Prokaryotypic Gene Expression; Perpetuation of DNA; Organization of the Eukaryotypic Genome; Eukaryotypic Transcription and RNA Processing; The Dynamic Genome; and Genes in Development.

Lewin, B.

1994-12-31

46

Glucose and arginine-induced insulin secretion by human pancreatic b-cells: the role of HERG K1 channels in firing and release  

Microsoft Academic Search

The human ether-a-go-go-related genes (herg) are expressed in tissues other than heart and brain where the HERG K1 channels are known to regulate the repolarization of the heart action poten- tial and the neuronal spike-frequency accommoda- tion. We provide evidence that herg1 transcripts are present in human pancreatic islets that were used to study both insulin secretion and electrical activity

BARBARA ROSATI; PIERO MARCHETTI; OLIVIA CROCIANI; MARZIA LECCHI; ROBERTO LUPI; ANNAROSA ARCANGELI; MASSIMO OLIVOTTO; ENZO WANKE

47

Quantitative PCR as an Alternative in the Diagnosis of Long-QT Syndrome  

PubMed Central

Congenital long-QT syndrome is a genetic disorder associated with abnormalities in the function and/or structure of cardiac ion channels. Up to the present, 13 types of the disease have been described (LQTS1-13) which result from the fact that 13 genes of which mutations can have an influence on the occurrence of the disease have been identified. Characteristic symptoms of the disease include the changes in the ECG (QT interval prolonged above 450?ms), “torsade de pointes,” fainting, and even sudden cardiac death. The present study has been focused on two types of the disease, namely, LQTS1 and LQTS2. The examination of two appropriate genes expression (KCNQ1; KCNH2) at the transcription level by QRT-PCR in a group of LQTS patients and a healthy control group showed different transcriptional activities of KCNH2 gene in LQTS2 patients compared to the control individuals. KCNQ1 gene expression study did not reveal such differences between both groups. The results indicate that QRT-PCR may serve as a complimentary method to the identification of molecular alterations in genetic determinants of LQTS2 only, but it cannot be used as a sole diagnostic criterion.

Weglarz, Ludmila; Szczurko, Magdalena

2013-01-01

48

Gene Cloning  

NSDL National Science Digital Library

Teachers' Domain presents this interactive, adapted from the University of Nebraska's Library of Crop Technologies, with reading material and animations to help students learn the basics of gene cloning. Following an introduction, the lesson is divided two parts: Making a Recombinant Plasmid and Bacteria Transformation. On the site, visitors will also find a supplemental background essay, discussion questions, and standards alignment from Teachers' Domain.

2010-10-05

49

Attention Genes  

ERIC Educational Resources Information Center

A major problem for developmental science is understanding how the cognitive and emotional networks important in carrying out mental processes can be related to individual differences. The last five years have seen major advances in establishing links between alleles of specific genes and the neural networks underlying aspects of attention. These…

Posner, Michael I.; Rothbart, Mary K.; Sheese, Brad E.

2007-01-01

50

Designer Genes.  

ERIC Educational Resources Information Center

Genetic technologies may soon help fill some of the most important needs of humanity from food to energy to health care. The research of major designer genes companies and reasons why the initial mad rush for biotechnology has slowed are reviewed. (SR)

Miller, Judith; Miller, Mark

1983-01-01

51

Analysis of Gene-Gene Interactions  

PubMed Central

The goal of this unit is to introduce gene-gene interactions (epistasis) as a significant complicating factor in the search for disease susceptibility genes. This unit begins with an overview of gene-gene interactions and why they are likely to be common. Then, it reviews several statistical and computational methods for detecting and characterizing genes with effects that are dependent on other genes. The focus of this unit is genetic association studies of discrete and quantitative traits because most of the methods for detecting gene-gene interactions have been developed specifically for these study designs.

Gilbert-Diamond, Diane; Moore, Jason H.

2014-01-01

52

Gene Switches  

NSDL National Science Digital Library

In this activity, learners explore how genetic switches function and the role of genetic switches in the process of evolution. To make these concepts less abstract and more understandable, learners first view a series of video clips and animations from the HHMI DVD (or online) "Evolution: Constant Change and Common Threads." Then, learners construct a model of a gene switch using craft materials or FridgiGears (magnetic gears). This activity can be done as a demonstration, a student inquiry activity, or a combination of the two.

Colvard, Mary

2010-01-01

53

QT Is Longer in Drug-Free Patients with Schizophrenia Compared with Age-Matched Healthy Subjects  

PubMed Central

The potassium voltage-gated channel KCNH2 is a well-known gene in which mutations induce familial QT interval prolongation. KCNH2 is suggested to be a risk gene for schizophrenia. Additionally, the disturbance of autonomic control, which affects the QT interval, is known in schizophrenia. Therefore, we speculate that schizophrenic patients have characteristic features in terms of the QT interval in addition to the effect of antipsychotic medication. The QT interval of patients with schizophrenia not receiving antipsychotics (n?=?85) was compared with that of patients with schizophrenia receiving relatively large doses of antipsychotics (n?=?85) and healthy volunteers (n?=?85). The QT interval was corrected using four methods (Bazett, Fridericia, Framingham or Hodges method). In ANCOVA with age and heart rate as covariates, patients not receiving antipsychotic treatment had longer QT intervals than did the healthy volunteers, but antipsychotics prolonged the QT interval regardless of the correction method used (P<0.01). Schizophrenic patients with and without medication had a significantly higher mean heart rate than did the healthy volunteers, with no obvious sex-related differences in the QT interval. The QT interval prolongation may be manifestation of a certain biological feature of schizophrenia.

Fujii, Kumiko; Ozeki, Yuji; Okayasu, Hiroaki; Takano, Yumiko; Shinozaki, Takahiro; Hori, Hiroaki; Orui, Masami; Horie, Minoru; Kunugi, Hiroshi; Shimoda, Kazutaka

2014-01-01

54

Gene - Gene Interactions Among MCP Genes Polymorphisms in Asthma  

PubMed Central

Purpose Monocyte chemoattractant proteins (MCPs) are important cytokines that involved in cellular activation and releasing of inflammatoy mediators by basophils and eosinophils in allergic disease. Some MCP gene variants implicate in asthma and monoclonal antibody for MCP-3 blocks allergic inflammations in the patients with asthma. Detection of interactions between gene and environment or between genes for complex disease such as asthma is important. We searched for an evidence of genetic effect of single nucleotide polymorphisms (SNPs) of MCP genes as well as gene - gene interactions involved in asthma. Methods Four hundreds asthmatics and four hundreds normal controls were enrolled. Asthma was defined as a positive bronchodilator response or positive methacholine provocation test with compatible clinical symptoms. Seven MCP gene SNPs (2 SNPs in MCP-1, 1 in MCP-2, and 4 in MCP-3) were included. Association analyses between SNP and asthma, and the tests for gene - gene interaction were performed. Results Strong linkage disequilibria were found among 7 MCP gene polymorphisms. There was no SNP that showed a significant association with asthma among 7 SNPs of 3 MCP genes. No haplotype was associated with asthma, either. The combination of MCP1-2518G>A, MCP2+46A>C, and MCP3+563C>T was the best predictive model for asthma as compared to the control in tests for gene - gene interaction. The MCP1-2518G>A and MCP2+46A>C was the second best predictive combination and this had the highest synergistic interaction effect on the subject's status than any other combination of polymorphisms. Complete linkages were not associated with the gene - gene interactions models. Conclusions MCP gene polymorphisms probably interact with each other; thus, these findings may help in developing a possible genetic marker to predict asthma.

Lee, June-Hyuk

2014-01-01

55

GENES 2000  

NSDL National Science Digital Library

Benjamin Lewin provides this detailed educational site as the online (and continuously updated) version of the printed resource, GENES. Designed as a pilot project "for building an online site that will develop into a general resource for the life sciences, including molecular biology, cell biology, development, immunology, and neurobiology, at levels varying from introductory to advanced," this impressive site is intended to be useful to students at the undergraduate level (or above). First-time users must register (access is free, "at least temporarily") to gain access to chapters; registered users may conduct searches, build references, write notes, highlight specified information, or browse the full resource. Future plans include "better (and faster) searches on the text, searches on figures, identification of new material and recently added references, printing by chapter or by section, more animations, on line tests and problem sets." Content is detailed, well illustrated, and thorough; this looks to be an exceptional resource.

56

Bayesian Gene Set Analysis  

Microsoft Academic Search

Gene expression microarray technologies provide the simultaneous measurements of a large number of genes. Typical analyses of such data focus on the individual genes, but recent work has demonstrated that evaluating changes in expression across predefined sets of genes often increases statistical power and produces more robust results. We introduce a new methodology for identifying gene sets that are differentially

Babak Shahbaba; Robert Tibshirani; Catherine M. Shachaf; Sylvia K. Plevritis

2010-01-01

57

Zebrafish model for human long QT syndrome  

PubMed Central

Long QT syndrome (LQTS) is a disorder of ventricular repolarization that predisposes affected individuals to lethal cardiac arrhythmias. To date, an appropriate animal model of inherited LQTS does not exist. The zebrafish is a powerful vertebrate model used to dissect molecular pathways of cardiovascular development and disease. Because fundamental electrical properties of the zebrafish heart are remarkably similar to those of the human heart, the zebrafish may be an appropriate model for studying human inherited arrhythmias. Here we describe the molecular, cellular, and electrophysiological basis of a zebrafish mutant characterized by ventricular asystole. Genetic mapping and direct sequencing identify the affected gene as kcnh2, which encodes the channel responsible for the rapidly activating delayed rectifier K+ current (IKr). We show that complete loss of functional IKr in embryonic hearts leads to ventricular cell membrane depolarization, inability to generate action potentials (APs), and disrupted calcium release. A small hyperpolarizing current restores spontaneous APs, implying wild-type function of other ionic currents critical for AP generation. Heterozygous fish manifest overt cellular and electrocardiographic evidence for delayed ventricular repolarization. Our findings provide insight into the pathogenesis of homozygous kcnh2 mutations and expand the use of zebrafish mutants as a model system to study human arrhythmias.

Arnaout, Rima; Ferrer, Tania; Huisken, Jan; Spitzer, Kenneth; Stainier, Didier Y. R.; Tristani-Firouzi, Martin; Chi, Neil C.

2007-01-01

58

Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes  

PubMed Central

Aims Long-QT syndromes (LQTS) are mostly autosomal-dominant congenital disorders associated with a 1:1000 mutation frequency, cardiac arrest, and sudden death. We sought to use cardiomyocytes derived from human-induced pluripotency stem cells (hiPSCs) as an in vitro model to develop and evaluate gene-based therapeutics for the treatment of LQTS. Methods and results We produced LQTS-type 2 (LQT2) hiPSC cardiomyocytes carrying a KCNH2 c.G1681A mutation in a IKr ion-channel pore, which caused impaired glycosylation and channel transport to cell surface. Allele-specific RNA interference (RNAi) directed towards the mutated KCNH2 mRNA caused knockdown, while leaving the wild-type mRNA unaffected. Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K+ currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations). Conclusions These findings provide in vitro evidence that allele-specific RNAi can rescue diseased phenotype in LQTS cardiomyocytes. This is a potentially novel route for the treatment of many autosomal-dominant-negative disorders, including those of the heart.

Matsa, Elena; Dixon, James E.; Medway, Christopher; Georgiou, Orestis; Patel, Minal J.; Morgan, Kevin; Kemp, Paul J.; Staniforth, Andrew; Mellor, Ian; Denning, Chris

2014-01-01

59

Chromatin loops, gene positioning, and gene expression  

PubMed Central

Technological developments and intense research over the last years have led to a better understanding of the 3D structure of the genome and its influence on genome function inside the cell nucleus. We will summarize topological studies performed on four model gene loci: the ?- and ?-globin gene loci, the antigen receptor loci, the imprinted H19–Igf2 locus and the Hox gene clusters. Collectively, these studies show that regulatory DNA sequences physically contact genes to control their transcription. Proteins set up the 3D configuration of the genome and we will discuss the roles of the key structural organizers CTCF and cohesin, the nuclear lamina and the transcription machinery. Finally, genes adopt non-random positions in the nuclear interior. We will review studies on gene positioning and propose that cell-specific genome conformations can juxtapose a regulatory sequence on one chromosome to a responsive gene on another chromosome to cause altered gene expression in subpopulations of cells.

Holwerda, Sjoerd; de Laat, Wouter

2012-01-01

60

Genes and Hearing Loss  

MedlinePLUS

... mutation may only have dystopia canthorum. How Do Genes Work? Genes are a road map for the synthesis of ... lung, etc. Every child inherits half of its genes from one parent and half from the other ...

61

Gene conversion in steroid 21-hydroxylase genes.  

PubMed Central

The steroid 21-hydroxylase gene, CYP21B, encodes cytochrome P450c21, which mediates 21-hydroxylation. The gene is located about 30 kb downstream from pseudogene CYP21A. The CYP21A gene is homologous to the CYP21B gene but contains some mutations, including a C----T change which leads a termination codon, TAG, in the eighth exon. We found the same change in a mutant CYP21B gene isolated from a patient with 21-hydroxylase deficiency. Furthermore, a reciprocal change--i.e., a T----C change in the eighth exon of the CYP21A gene--was observed in the Japanese population and was associated with the two HLA haplotypes, HLA-B44-DRw13 and HLA-Bw46-DRw8. These changes may be considered the result of gene conversion-like events. Images Figure 1 Figure 3 Figure 5 Figure 6

Urabe, K; Kimura, A; Harada, F; Iwanaga, T; Sasazuki, T

1990-01-01

62

Gene conversion in steroid 21-hydroxylase genes.  

PubMed

The steroid 21-hydroxylase gene, CYP21B, encodes cytochrome P450c21, which mediates 21-hydroxylation. The gene is located about 30 kb downstream from pseudogene CYP21A. The CYP21A gene is homologous to the CYP21B gene but contains some mutations, including a C----T change which leads a termination codon, TAG, in the eighth exon. We found the same change in a mutant CYP21B gene isolated from a patient with 21-hydroxylase deficiency. Furthermore, a reciprocal change--i.e., a T----C change in the eighth exon of the CYP21A gene--was observed in the Japanese population and was associated with the two HLA haplotypes, HLA-B44-DRw13 and HLA-Bw46-DRw8. These changes may be considered the result of gene conversion-like events. PMID:1971153

Urabe, K; Kimura, A; Harada, F; Iwanaga, T; Sasazuki, T

1990-06-01

63

Autism and Genes  

ERIC Educational Resources Information Center

This document defines and discusses autism and how genes play a role in the condition. Answers to the following questions are covered: (1) What are genes? (2) What is autism? (3) What causes autism? (4) Why study genes to learn about autism? (5) How do researchers look for the genes involved in autism? (screen the whole genome; conduct cytogenetic…

National Institutes of Health, 2005

2005-01-01

64

Clustering gene expression patterns  

Microsoft Academic Search

Recent advances in biotechnology allow researchers to measure expression levels for thousands of genes simultaneously, across different conditions and over time. Analysis of data produced by such experiments offers potential insight into gene function and regulatory mechanisms. A key step in the analysis of gene expression data is the detection of groups of genes that manifest similar expression patterns. The

Amir Ben-Dor; Zohar Yakhinit; Zohar Yakhini

1999-01-01

65

Conditional gene targeting  

Microsoft Academic Search

Gene targeting: The classical approach Central to an understanding of the in vivo function of genes is their analysis by mutation, that is, inactivation or modification of a gene by mutation and the study of the consequences of the mutation in the mutant organism. In mammals, before gene targeting, this approach was limited to the rare spontaneous mutations reflected in

Klaus Rajewsky; Hua Gu; Ralf Kühn; Ulrich A. K. Betz; Werner Müller; Jürgen Roes; Frieder Schwenk

1996-01-01

66

Gene–environment interdependence  

Microsoft Academic Search

The modern understanding of genetic influences, of environmental effects, of mental disorder, and of heritabilities is noted. The practical utility of finding susceptibility genes with a very small effect is questioned. The empirical findings and implications of developmental perturbations, epigenetics, gene–environment correlations and interactions are then discussed. It is noted that the genes involved in gene–environment interactions may be concerned

Michael Rutter

2012-01-01

67

Bayesian Gene Set Analysis  

Microsoft Academic Search

Gene expression microarray technologies provide the simultaneous measurements\\u000aof a large number of genes. Typical analyses of such data focus on the\\u000aindividual genes, but recent work has demonstrated that evaluating changes in\\u000aexpression across predefined sets of genes often increases statistical power\\u000aand produces more robust results. We introduce a new methodology for\\u000aidentifying gene sets that are differentially

Babak Shahbaba; Robert Tibshirani; Catherine M. Shachaf; Sylvia K. Plevritis

2010-01-01

68

Novel gene delivery systems  

PubMed Central

Gene therapy is an emerging field in medical and pharmaceutical sciences because of its potential in treating chronic diseases like cancer, viral infections, myocardial infarctions, and genetic disorders. Application of gene therapy is limited because of lack of suitable methods for proper introduction of genes into cells and therefore, this is an area of interest for most of the researchers. To achieve successful gene therapy, development of proper gene delivery systems could be one of the most important factors. Several nonviral and viral gene transfer methods have been developed. Even though the viral agents have a high transferring efficiency, they are difficult to handle due to their toxicity. To overcome the safety problems of the viral counterpart, several nonviral in vitro and in vivo gene delivery systems are developed. Out of these, the most promising and latest systems include polymer-based nonviral gene carriers, dendrimers, and physical means like electroporation, microinjection, etc., Shunning of possible immunogenicity and toxicity, and the feasibility of repeated administration are some of the merits of nonviral gene delivery systems over viral gene delivery. An ideal nonviral gene carrying system should possess all these merits without any compromise to its gene transferring efficiency. The viral gene delivery systems include lytic and nonlytic vectors for drug delivery. Inspite of its toxicity they are still preferred because of their long term expression, stability, and integrity. This review explores the recent developments and relevancy of the novel gene delivery systems in gene therapy.

Manjila, Steffy B; Baby, Jomon N; Bijin, Elambilan N; Constantine, Icey; Pramod, Kannissery; Valsalakumari, Janardhanan

2013-01-01

69

Speciation genes in plants  

PubMed Central

Background Analyses of speciation genesgenes that contribute to the cessation of gene flow between populations – can offer clues regarding the ecological settings, evolutionary forces and molecular mechanisms that drive the divergence of populations and species. This review discusses the identities and attributes of genes that contribute to reproductive isolation (RI) in plants, compares them with animal speciation genes and investigates what these genes can tell us about speciation. Scope Forty-one candidate speciation genes were identified in the plant literature. Of these, seven contributed to pre-pollination RI, one to post-pollination, prezygotic RI, eight to hybrid inviability, and 25 to hybrid sterility. Genes, gene families and genetic pathways that were frequently found to underlie the evolution of RI in different plant groups include the anthocyanin pathway and its regulators (pollinator isolation), S RNase-SI genes (unilateral incompatibility), disease resistance genes (hybrid necrosis), chimeric mitochondrial genes (cytoplasmic male sterility), and pentatricopeptide repeat family genes (cytoplasmic male sterility). Conclusions The most surprising conclusion from this review is that identities of genes underlying both prezygotic and postzygotic RI are often predictable in a broad sense from the phenotype of the reproductive barrier. Regulatory changes (both cis and trans) dominate the evolution of pre-pollination RI in plants, whereas a mix of regulatory mutations and changes in protein-coding genes underlie intrinsic postzygotic barriers. Also, loss-of-function mutations and copy number variation frequently contribute to RI. Although direct evidence of positive selection on speciation genes is surprisingly scarce in plants, analyses of gene family evolution, along with theoretical considerations, imply an important role for diversifying selection and genetic conflict in the evolution of RI. Unlike in animals, however, most candidate speciation genes in plants exhibit intraspecific polymorphism, consistent with an important role for stochastic forces and/or balancing selection in development of RI in plants.

Rieseberg, Loren H.; Blackman, Benjamin K.

2010-01-01

70

Gene therapy for arthritis  

Microsoft Academic Search

\\u000a Gene therapy has a potential for effective therapeutic intervention in rheumatoid arthritis (RA). Proof of concept has been\\u000a demonstrated in animal models, either through local gene delivery to the joint space or through systemic gene delivery for\\u000a immune intervention. This chapter reviews how certain clinical applications of gene therapy would be beneficial for RA patients\\u000a and discusses the roadblocks that

Florence Apparailly; Paul Peter Tak; Christian Jorgensen

71

Myocardial gene therapy  

NASA Astrophysics Data System (ADS)

Gene therapy is proving likely to be a viable alternative to conventional therapies in coronary artery disease and heart failure. Phase 1 clinical trials indicate high levels of safety and clinical benefits with gene therapy using angiogenic growth factors in myocardial ischaemia. Although gene therapy for heart failure is still at the pre-clinical stage, experimental data indicate that therapeutic angiogenesis using short-term gene expression may elicit functional improvement in affected individuals.

Isner, Jeffrey M.

2002-01-01

72

Cyanobacterial signature genes  

Microsoft Academic Search

A comparison of 8 cyanobacterial genomes reveals that there are 181 shared genes that do not have obvious orthologs in other\\u000a bacteria. These signature genes define aspects of the genotype that are uniquely cyanobacterial. Approximately 25% of these\\u000a genes have been associated with some function. These signature genes may or may not be involved in photosynthesis but likely\\u000a they will

Kirt A. Martin; Janet L. Siefert; Sailaja Yerrapragada; Yue Lu; Thomas Z. McNeill; Pedro A. Moreno; George M. Weinstock; William R. Widger; George E. Fox

2003-01-01

73

Schizophrenia: genes at last?  

Microsoft Academic Search

Genetic epidemiological studies suggest that individual variation in susceptibility to schizophrenia is largely genetic, reflecting alleles of moderate to small effect in multiple genes. Molecular genetic studies have identi- fied several potential regions of linkage and two associated chromosomal abnormalities, and evidence is accumulating in favour of several positional candidate genes. Currently, the positional candidate genes for which we consider

M. J. Owen; N. Craddock; M. C. O'Donovan

2005-01-01

74

Dopamine genes and ADHD  

Microsoft Academic Search

Family, twin, and adoption studies have documented a strong genetic basis for ADHD\\/HKD, but these studies do not identify specific genes linked to the disorder. Molecular genetic studies can identify allelic variations of specific genes that are functionally associated with ADHD\\/HKD, and dopamine genes have been the initial candidates based on the site of action of the stimulants drugs, which

J. M Swanson; Pamela Flodman; James Kennedy; M. Anne Spence; Robert Moyzis; Sabrina Schuck; Michael Murias; Joan Moriarity; Cathy Barr; Moyra Smith; Michael Posner

2000-01-01

75

Reading and Generalist Genes  

ERIC Educational Resources Information Center

Twin-study research suggests that many (but not all) of the same genes contribute to genetic influence on diverse learning abilities and disabilities, a hypothesis called "generalist genes". This generalist genes hypothesis was tested using a set of 10 DNA markers (single nucleotide polymorphisms [SNPs]) found to be associated with early reading…

Haworth, Claire M. A.; Meaburn, Emma L.; Harlaar, Nicole; Plomin, Robert

2007-01-01

76

Noncoding RNA genes  

Microsoft Academic Search

Some genes produce RNAs that are functional instead of encoding proteins. Noncoding RNA genes are surprisingly numerous. Recently, active research areas include small nucleolar RNAs, antisense riboregulator RNAs, and RNAs involved in X-dosage compensation. Genome sequences and new algorithms have begun to make systematic computational screens for noncoding RNA genes possible.

Sean R. Eddy

1999-01-01

77

Cloning Human Chromosome 17 Genes: Candidate Genes for BRCA1.  

National Technical Information Service (NTIS)

Our research interest is focused on the identification of genes from chromosome 17. The isolation of genes transcribed from chromosome 17 will provide candidates for the proposed sporadic breast cancer genes and genes for other human disorders.The ability...

C. Lee

1998-01-01

78

Cloning Human Chromosome 17 Genes: Candidate Genes for BRCA1.  

National Technical Information Service (NTIS)

Our research interest is focused on the identification of genes from chromosome 17. The isolation of genes transcribed from chromosome 17 will provide candidates for the proposed sporadic breast cancer genes and genes for other human disorders. The abilit...

C. C. Lee

1997-01-01

79

Gene Gateway: Exploring Genes and Genetic Disorders  

NSDL National Science Digital Library

This collection of guides and tutorials is intended to help users take advantage of of online data sources from the Human Genome Project for learning about genetic disorders, genes, and proteins. Resources include the Gene Gateway Workbook, a downloadable tutorial consisting of activities with screenshots and instructions, that helps new users locate and use genetic-disorder and bioinformatics resources on the web. There are also resources for learning about genes and the proteins they encode; tips, tutorials, and terminology for using selected resources in the Genome Database Guide; a guide to nontechnical resources on genetic disorder descriptions and treatments; a human genome landmarks poster; and others.

80

Phosphinothricin-resistance gene  

US Patent & Trademark Office Database

Phosphinothricin (PTC) selection of bacteria which are not fungus-like yields PTC-resistant selectants. The DNA fragment which carries the resistance gene is obtained from the complete DNA of these selectants by constructing a gene bank and screening for chemical modification of PTC. The resistance gene can be localized to a fragment which is 2 kb in size, and selection for PTC resistance. This gene is suitable for producing PTC-resistant plants and propagation material thereof, and as a resistance marker as well. Microorganisms which contain this PTC-resistance gene can be used in sewage treatment plants.

1991-12-31

81

Understanding Cancer Series: Gene Testing  

MedlinePLUS

... Dictionary Search for Clinical Trials NCI Publications Español Gene Testing Slide Number and Title Genes in the News DNA Chemical Bases in DNA DNA Molecules Gene Subunits DNA->RNA->Protein Different Genes - Different Functions ...

82

Essential Bacillus subtilis genes  

PubMed Central

To estimate the minimal gene set required to sustain bacterial life in nutritious conditions, we carried out a systematic inactivation of Bacillus subtilis genes. Among ?4,100 genes of the organism, only 192 were shown to be indispensable by this or previous work. Another 79 genes were predicted to be essential. The vast majority of essential genes were categorized in relatively few domains of cell metabolism, with about half involved in information processing, one-fifth involved in the synthesis of cell envelope and the determination of cell shape and division, and one-tenth related to cell energetics. Only 4% of essential genes encode unknown functions. Most essential genes are present throughout a wide range of Bacteria, and almost 70% can also be found in Archaea and Eucarya. However, essential genes related to cell envelope, shape, division, and respiration tend to be lost from bacteria with small genomes. Unexpectedly, most genes involved in the Embden–Meyerhof–Parnas pathway are essential. Identification of unknown and unexpected essential genes opens research avenues to better understanding of processes that sustain bacterial life.

Kobayashi, K.; Ehrlich, S. D.; Albertini, A.; Amati, G.; Andersen, K. K.; Arnaud, M.; Asai, K.; Ashikaga, S.; Aymerich, S.; Bessieres, P.; Boland, F.; Brignell, S. C.; Bron, S.; Bunai, K.; Chapuis, J.; Christiansen, L. C.; Danchin, A.; Debarbouille, M.; Dervyn, E.; Deuerling, E.; Devine, K.; Devine, S. K.; Dreesen, O.; Errington, J.; Fillinger, S.; Foster, S. J.; Fujita, Y.; Galizzi, A.; Gardan, R.; Eschevins, C.; Fukushima, T.; Haga, K.; Harwood, C. R.; Hecker, M.; Hosoya, D.; Hullo, M. F.; Kakeshita, H.; Karamata, D.; Kasahara, Y.; Kawamura, F.; Koga, K.; Koski, P.; Kuwana, R.; Imamura, D.; Ishimaru, M.; Ishikawa, S.; Ishio, I.; Le Coq, D.; Masson, A.; Mauel, C.; Meima, R.; Mellado, R. P.; Moir, A.; Moriya, S.; Nagakawa, E.; Nanamiya, H.; Nakai, S.; Nygaard, P.; Ogura, M.; Ohanan, T.; O'Reilly, M.; O'Rourke, M.; Pragai, Z.; Pooley, H. M.; Rapoport, G.; Rawlins, J. P.; Rivas, L. A.; Rivolta, C.; Sadaie, A.; Sadaie, Y.; Sarvas, M.; Sato, T.; Saxild, H. H.; Scanlan, E.; Schumann, W.; Seegers, J. F. M. L.; Sekiguchi, J.; Sekowska, A.; Seror, S. J.; Simon, M.; Stragier, P.; Studer, R.; Takamatsu, H.; Tanaka, T.; Takeuchi, M.; Thomaides, H. B.; Vagner, V.; van Dijl, J. M.; Watabe, K.; Wipat, A.; Yamamoto, H.; Yamamoto, M.; Yamamoto, Y.; Yamane, K.; Yata, K.; Yoshida, K.; Yoshikawa, H.; Zuber, U.; Ogasawara, N.

2003-01-01

83

Parkinson's Disease: Gene Therapies  

PubMed Central

With the recent development of effective gene delivery systems, gene therapy for the central nervous system is finding novel applications. Here, we review existing viral vectors and discuss gene therapy strategies that have been proposed for Parkinson’s disease. To date, most of the clinical trials were based on viral vectors to deliver therapeutic transgenes to neurons within the basal ganglia. Initial trials used genes to relieve the major motor symptoms caused by nigrostriatal degeneration. Although these new genetic approaches still need to prove more effective than existing symptomatic treatments, there is a need for disease-modifying strategies. The investigation of the genetic factors implicated in Parkinson’s disease is providing precious insights in disease pathology that, combined with innovative gene delivery systems, will hopefully offer novel opportunities for gene therapy interventions to slow down, or even halt disease progression.

Coune, Philippe G.; Schneider, Bernard L.; Aebischer, Patrick

2012-01-01

84

The gap gene network  

PubMed Central

Gap genes are involved in segment determination during the early development of the fruit fly Drosophila melanogaster as well as in other insects. This review attempts to synthesize the current knowledge of the gap gene network through a comprehensive survey of the experimental literature. I focus on genetic and molecular evidence, which provides us with an almost-complete picture of the regulatory interactions responsible for trunk gap gene expression. I discuss the regulatory mechanisms involved, and highlight the remaining ambiguities and gaps in the evidence. This is followed by a brief discussion of molecular regulatory mechanisms for transcriptional regulation, as well as precision and size-regulation provided by the system. Finally, I discuss evidence on the evolution of gap gene expression from species other than Drosophila. My survey concludes that studies of the gap gene system continue to reveal interesting and important new insights into the role of gene regulatory networks in development and evolution.

2010-01-01

85

DNA, Genes and Chromosomes  

NSDL National Science Digital Library

Today you will learn about the parts of DNA and what DNA, genes and chromosomes are. Today you will learn what DNA, genes and chromosomes are and the parts of the DNA molecule. Look at all of the websites, take whatever notes you need to. At the end of the assignment, be able to describle DNA, the parts of DNA, genes and chromosomes. Covers Biology Core Curriculum, ...

Fomby, Mrs.

2007-11-07

86

Gene therapy for arthritis  

PubMed Central

Arthritis is among the leading causes of disability in the developed world. There remains no cure for this disease and the current treatments are only modestly effective at slowing the disease's progression and providing symptomatic relief. The clinical effectiveness of current treatment regimens has been limited by short half-lives of the drugs and the requirement for repeated systemic administration. Utilizing gene transfer approaches for the treatment of arthritis may overcome some of the obstacles associated with current treatment strategies. The present review examines recent developments in gene therapy for arthritis. Delivery strategies, gene transfer vectors, candidate genes, and safety are also discussed.

Traister, Russell S.

2008-01-01

87

Genes Involved in Atherosclerosis  

Microsoft Academic Search

Atherosclerosis is a multifactorial disease that involves several genes and proteins. The purpose of this article is to focus on the arterial wall and to review lipoprotein receptors, growth factors, cytokines, chemokines, matrix metalloproteinases, adhesion molecules, and apoptosis genes and their involvement in atherogenesis.

Johanna Laukkanen; Seppo Ylä-Herttuala

2002-01-01

88

TIGR Tomato Gene Index  

NSDL National Science Digital Library

The Institute for Genomic Resources (TIGR) placed online the Tomato Gene Index (version 1.2) in 1999. The index is searchable by nucleotide or protein sequence, identifier (TC, ET, EST, GB), tissue, or gene product name. Note that this resource is available free of charge "only to researchers at non-profit institutions using it for non-commercial purposes."

89

One Gene, Many Proteins  

Microsoft Academic Search

The release of the sequence of the human genome in early 2000 generated enormous excitement with the promise of rapid identification of the gene products responsible for cellular function. What has become apparent is that knowledge of the DNA sequence of the gene that is involved in a particular metabolic process is insufficient to predict its function, expression and activity.

NICOLLE H. PACKER; ANDREW A. GOOLEY; MARC R. WILKINS

90

Gene Expression Mural: Visualizing Gene Expression Databases  

Microsoft Academic Search

The Gene Expression Mural is a tool designed for managing the vast amount of information produced by the rapidly growing field of Bioinformatics. The advantages of this tool are that it not only provides an overview of many experiments for an entire genome, but also promotes discovery with its zooming and navigation capabilities. A \\

Mathew Clement; Margaret Ellis; Josh Steele; Yuying Tian; Chris North

91

GeneEd: Genetics, Education, Discovery  

NSDL National Science Digital Library

The GeneEd website was created by the National Library of Medicine (NLM), the National Human Genome Research Institute (NHGRI), and the National Institutes of Health (NIH) as a helpful resource for the teaching and learning of genetics. On the site, visitors can find labs and experiments, fact sheets, and teacher resources on topics including DNA forensics, genetic conditions, evolution, and biostatistics. First-time visitors will want to start their journey by looking over the Topics tab at the top of the page. There are 40 different thematic areas here consisting of articles, video clips, webcasts, and links to additional quality resources vetted by the GeneEd web team. The Labs & Experiments section includes virtual labs that explore the genetics of different organisms as well as links to resources provided by the Howard Hughes Medical Institute and Cold Spring Harbor Laboratory. Young people may also wish to take a look at the Careers in Genetics section as it features interviews with scientists that will inspire and delight.

92

Autophagy genes in immunity  

PubMed Central

In its classical form, autophagy is a pathway by which cytoplasmic constituents, including intracellular pathogens, are sequestered in a double-membrane–bound autophagosome and delivered to the lysosome for degradation. This pathway has been linked to diverse aspects of innate and adaptive immunity, including pathogen resistance, production of type I interferon, antigen presentation, tolerance and lymphocyte development, as well as the negative regulation of cytokine signaling and inflammation. Most of these links have emerged from studies in which genes encoding molecules involved in autophagy are inactivated in immune effector cells. However, it is not yet known whether all of the critical functions of such genes in immunity represent ‘classical autophagy’ or possible as-yet-undefined autophagolysosome-independent functions of these genes. This review summarizes phenotypes that result from the inactivation of autophagy genes in the immune system and discusses the pleiotropic functions of autophagy genes in immunity.

Virgin, Herbert W; Levine, Beth

2009-01-01

93

Engineered gene circuits.  

PubMed

A central focus of postgenomic research will be to understand how cellular phenomena arise from the connectivity of genes and proteins. This connectivity generates molecular network diagrams that resemble complex electrical circuits, and a systematic understanding will require the development of a mathematical framework for describing the circuitry. From an engineering perspective, the natural path towards such a framework is the construction and analysis of the underlying submodules that constitute the network. Recent experimental advances in both sequencing and genetic engineering have made this approach feasible through the design and implementation of synthetic gene networks amenable to mathematical modelling and quantitative analysis. These developments have signalled the emergence of a gene circuit discipline, which provides a framework for predicting and evaluating the dynamics of cellular processes. Synthetic gene networks will also lead to new logical forms of cellular control, which could have important applications in functional genomics, nanotechnology, and gene and cell therapy. PMID:12432407

Hasty, Jeff; McMillen, David; Collins, J J

2002-11-14

94

Retinoblastoma family genes  

PubMed Central

The retinoblastoma gene Rb was the first tumor suppressor gene cloned, and it is well known as a negative regulator of the cell cycle through its ability to bind the transcription factor E2Fand repress transcription of genes required for S phase. Although over 100 other proteins have been reported to interact with Rb, in most cases these interactions are much less well characterized. Therefore, this review will primarily focus on Rb and E2F interactions. In addition to cell cycle regulation, studies of Rb and E2Fproteins in animal models have revealed important roles for these proteins in apoptosis and differentiation. Recent screens of Rb/E2Ftarget genes have identified new targets in all these areas. In addition, the mechanisms determining how different subsets of target genes are regulated under different conditions have only begun to be addressed and offer exciting possibilities for future research.

Du, W; Pogoriler, J

2007-01-01

95

Gene therapy for haemophilia  

PubMed Central

The ultimate goal of gene therapy is the replacement of a defective gene sequence with a corrected version to eliminate disease for the lifetime of the patient. This challenging task is not yet accomplished, however significant progress is evident. An initial spate of clinical trials attempting the treatment of haemophilia with gene transfer primarily resulted in the demonstration of good safety profiles, but without efficacy. Subsequent reengineering of vector plasmids and delivery systems resulted in markedly improved outcomes in animal models of the disease. The most recent clinical trial for the treatment of haemophilia B with gene transfer showed transient achievement of efficacy in the highest dose cohort tested, but also exposed a previously hidden barrier to the future success of these treatments. The progress and problems of gene therapies for haemorrhagic disorders will be discussed. This review will concentrate on approaches in or near clinical application.

Murphy, Samuel L; High, Katherine A

2008-01-01

96

4. AERIAL VIEW OF GENE WASH RESERVOIR AND GENE CAMP ...  

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

4. AERIAL VIEW OF GENE WASH RESERVOIR AND GENE CAMP LOOKING SOUTHWEST. DAM AND SPILLWAY VISIBLE IN BOTTOM OF PHOTO. - Gene Wash Reservoir & Dam, 2 miles west of Parker Dam, Parker Dam, San Bernardino County, CA

97

Gene–gene effects on central processing of aversive stimuli  

Microsoft Academic Search

Emotional reactivity and regulation are fundamental to human behavior. As inter-individual behavioral variation is affected by a multitude of different genes, there is intense interest to investigate gene–gene effects. Functional sequence variation at two genes has been associated with response and resiliency to emotionally unpleasant stimuli. These genes are the catechol-O-methyltransferase gene (COMT Val158Met) and the regulatory region (5-HTTLPR) of

M N Smolka; M Bühler; G Schumann; S Klein; X-Z Hu; M Moayer; A Zimmer; J Wrase; H Flor; K Mann; D F Braus; D Goldman; A Heinz

2007-01-01

98

Sudden Cardiac Arrest during Anesthesia in a 30-Month-Old Boy with Syndactyly: A Case of Genetically Proven Timothy Syndrome  

PubMed Central

Timothy syndrome, long QT syndrome type 8, is highly malignant with ventricular tachyarrhythmia. A 30-month-old boy had sudden cardiac arrest during anesthesia induction before plastic surgery for bilateral cutaneous syndactyly. After successful resuscitation, prolonged QT interval (QTc, 0.58-0.60 sec) and T-wave alternans were found in his electrocardiogram. Starting ?-blocker to prevent further tachycardia and collapse event, then there were no more arrhythmic events. The genes KCNQ1, KCNH2, KCNE1 and 2, and SCN5A were negative for long QT syndrome. The mutation p.Gly406Arg was confirmed in CACNA1C, which maintains L-type calcium channel depolarization in the heart and other systems.

An, Hyo Soon; Choi, Eun Young; Kwon, Bo Sang; Kim, Gi Beom; Noh, Chung Il; Choi, Jung Yun; Park, Sung Sup

2013-01-01

99

Classification of the long-QT syndrome based on discriminant analysis of T-wave morphology.  

PubMed

The long QT syndrome (LQTS) is a genetic disorder, typically characterized by a prolonged QT interval in the ECG due to abnormal cardiac repolarization. LQTS may lead to syncopal episodes and sudden cardiac death. Various parameters based on T-wave morphology, as well as the QT interval itself have been shown to be useful discriminators, but no single ECG parameter has been sufficient to solve the diagnostic problem. In this study we present a method for discrimination among persons with a normal genotype and those with mutations in the KCNQ1 (KvLQT1 or LQT1) and KCNH2 (HERG or LQT2) genes on the basis of parameters describing T-wave morphology in terms of duration, asymmetry, flatness and amplitude. Discriminant analyses based on 4 or 5 parameters both resulted in perfect discrimination in a learning set of 36 subjects. In both cases cross-validation of the resulting classifiers showed no misclassifications either. PMID:16937190

Struijk, J J; Kanters, J K; Andersen, M P; Hardahl, T; Graff, C; Christiansen, M; Toft, E

2006-07-01

100

Genes, dreams, and cancer.  

PubMed Central

There have been tremendous advances in our understanding of cancer from the application of molecular biology over the past decade. The disease is caused by a series of defects in the genes that accelerate growth--oncogenes--and those that slow down cellular turnover--tumour suppressor genes. The proteins they encode provide a promising hunting ground in which to design and test new anticancer drugs. Several treatment strategies are now under clinical trial entailing direct gene transfer. These include the use of gene marking to detect minimal residual disease, the production of novel cancer vaccines by the insertion of genes which uncloak cancer cells so making them visible to the host's immune system, the isolation and coupling of cancer specific molecular switches upstream of drug activating genes, and the correction of aberrant oncogenes or tumour suppressor genes. The issues in these approaches are likely to have a profound impact on the management of cancer patients as we enter the next century. Images p1221-a

Sikora, K.

1994-01-01

101

CARTaGENE Project  

Cancer.gov

Launched in October 2009, the CARTaGENE project is the largest prospective longitudinal cohort of Québec. CARTaGENE's distinguishing features are that it is a quantitative prospective cohort that has deeply phenotyped 20,000 individuals aged 40-69, the age most individuals will develop chronic disease. 37,000 individuals will be enrolled by 2014. It is an open-access infrastructure enabling researchers to investigate the genetic, environmental, and lifestyle determinants of disease in the French Canadian population. CARTaGENE has collected whole blood for DNA from 30,000 individuals.

102

Drug-induced torsades de pointes: the evolving role of pharmacogenetics.  

PubMed

Drug-induced torsades de pointes (TdP) is a rare, but potentially lethal, unwanted effect of drugs, including many commonly prescribed noncardiac drugs. Despite its low frequency, drug-induced TdP has generated a great deal of angst among physicians and pharmaceutical companies as well as tragedy, albeit rare, among patients. Although in retrospect many patients who died suddenly as a result of drug-induced TdP had identifiable risk factors, prediction in individual cases remains problematic. Over the past decade, tremendous progress has been made with respect to elucidating the fundamental pathogenic mechanisms that underlie drug-induced TdP. The vast majority of drugs associated with "QT liability" and the potential for drug-induced TdP, including all of the drugs removed from the market because of this side effect, are "HERG (human ether-á-go-go-related gene) blockers." These drugs inhibit the KCNH2-encoded HERG potassium channel, which is one of the critical repolarizing forces involved in the exquisite orchestration of the heart's action potential. Consequently, myocyte repolarization is potentially delayed as evidenced by prolongation of the QT interval, thus providing the substrate for drug-induced TdP. Rare mutations in KCNH2 provide the pathogenic substrate for type 2 congenital long QT syndrome (LQTS), thus placing this cardiac potassium channel squarely in the intersection between congenital LQTS (the "Rosetta stone" of the heritable channelopathies) and acquired LQTS (drug-induced TdP). In addition, common polymorphisms residing in the LQTS-causing channel genes may confer heightened arrhythmogenic susceptibility and contribute to the makings of a vulnerable host. This review focuses on the present strategy of identifying "at-risk compounds" and the potential future strategy involving pharmacogenetics to pinpoint "at-risk hosts" in an effort to curb this rare, unintended, but potentially life-threatening side effect. PMID:16253929

Fitzgerald, Patrick T; Ackerman, Michael J

2005-11-01

103

Genes and Psoriasis  

MedlinePLUS

... Francisco, Dr. Wilson Liao is using new genetic sequencing technology to find rare "trigger genes" that may ... and therefore never developed the disease. Working with DNA samples from a large family that includes many ...

104

Ring around the genes.  

PubMed

How is RNA Polymerase II (RNAP) regulated at poised loci in embryonic stem cells? Recent work provides new insights into Ring1-mediated transcriptional control of this important subset of developmental regulatory genes. PMID:18059356

Spektor, Tanya M; Rice, Judd C

2007-12-01

105

Some Genes Are Dominant  

NSDL National Science Digital Library

This interactive activity, adapted from the Dolan DNA Learning Center, illustrates how Gregor Mendel used pure-bred yellow and green peas to show that some genes are dominant and others are recessive.

Foundation, Wgbh E.

2007-04-19

106

Gene Toxicity and Cancer  

MedlinePLUS

... as a major cause of cancer. This knowledge led to some of the most effective early screening ... gene toxicity in human health and disease and led to new treatments for cancer. NIH-funded research ...

107

glucose-repressible gene  

Microsoft Academic Search

Eucaryotic gene expression requires chromatin-remodel- ing activities. We show by time-course studies that trans- criptional induction of the yeast glucose-regulated SUC2 gene is rapid and shows a striking biphasic pattern, the first phase of which is partly mediated by the general stress transcription factors Msn2p\\/Msn4p. The SWI\\/SNF ATP-dependent chromatin-remodeling complex associates with the promoter in a similar biphasic manner and

Fuqiang Geng; Brehon C Laurent

108

Interkingdom gene fusions  

PubMed Central

Background: Genome comparisons have revealed major lateral gene transfer between the three primary kingdoms of life - Bacteria, Archaea, and Eukarya. Another important evolutionary phenomenon involves the evolutionary mobility of protein domains that form versatile multidomain architectures. We were interested in investigating the possibility of a combination of these phenomena, with an invading gene merging with a pre-existing gene in the recipient genome. Results: Complete genomes of fifteen bacteria, four archaea and one eukaryote were searched for interkingdom gene fusions (IKFs); that is, genes coding for proteins that apparently consist of domains originating from different primary kingdoms. Phylogenetic analysis supported 37 cases of IKF, each of which includes a 'native' domain and a horizontally acquired 'alien' domain. IKFs could have evolved via lateral transfer of a gene coding for the alien domain (or a larger protein containing this domain) followed by recombination with a native gene. For several IKFs, this scenario is supported by the presence of a gene coding for a second, stand-alone version of the alien domain in the recipient genome. Among the genomes investigated, the greatest number of IKFs has been detected in Mycobacterium tuberculosis, where they are almost always accompanied by a stand-alone alien domain. For most of the IKF cases detected in other genomes, the stand-alone counterpart is missing. Conclusions: The results of comparative genome analysis show that IKF formation is a real, but relatively rare, evolutionary phenomenon. We hypothesize that IKFs are formed primarily via the proposed two-stage mechanism, but other than in the Actinomycetes, in which IKF generation seems to be an active, ongoing process, most of the stand-alone intermediates have been eliminated, perhaps because of functional redundancy.

Wolf, Yuri I; Kondrashov, Alexey S; Koonin, Eugene V

2000-01-01

109

GeneCards Version 3: the human gene integrator  

PubMed Central

GeneCards (www.genecards.org) is a comprehensive, authoritative compendium of annotative information about human genes, widely used for nearly 15 years. Its gene-centric content is automatically mined and integrated from over 80 digital sources, resulting in a web-based deep-linked card for each of >73 000 human gene entries, encompassing the following categories: protein coding, pseudogene, RNA gene, genetic locus, cluster and uncategorized. We now introduce GeneCards Version 3, featuring a speedy and sophisticated search engine and a revamped, technologically enabling infrastructure, catering to the expanding needs of biomedical researchers. A key focus is on gene-set analyses, which leverage GeneCards’ unique wealth of combinatorial annotations. These include the GeneALaCart batch query facility, which tabulates user-selected annotations for multiple genes and GeneDecks, which identifies similar genes with shared annotations, and finds set-shared annotations by descriptor enrichment analysis. Such set-centric features address a host of applications, including microarray data analysis, cross-database annotation mapping and gene-disorder associations for drug targeting. We highlight the new Version 3 database architecture, its multi-faceted search engine, and its semi-automated quality assurance system. Data enhancements include an expanded visualization of gene expression patterns in normal and cancer tissues, an integrated alternative splicing pattern display, and augmented multi-source SNPs and pathways sections. GeneCards now provides direct links to gene-related research reagents such as antibodies, recombinant proteins, DNA clones and inhibitory RNAs and features gene-related drugs and compounds lists. We also portray the GeneCards Inferred Functionality Score annotation landscape tool for scoring a gene’s functional information status. Finally, we delineate examples of applications and collaborations that have benefited from the GeneCards suite. Database URL: www.genecards.org

Safran, Marilyn; Dalah, Irina; Alexander, Justin; Rosen, Naomi; Iny Stein, Tsippi; Shmoish, Michael; Nativ, Noam; Bahir, Iris; Doniger, Tirza; Krug, Hagit; Sirota-Madi, Alexandra; Olender, Tsviya; Golan, Yaron; Stelzer, Gil; Harel, Arye; Lancet, Doron

2010-01-01

110

Harnessing Gene Expression Networks to Prioritize Candidate Epileptic Encephalopathy Genes  

PubMed Central

We apply a novel gene expression network analysis to a cohort of 182 recently reported candidate Epileptic Encephalopathy genes to identify those most likely to be true Epileptic Encephalopathy genes. These candidate genes were identified as having single variants of likely pathogenic significance discovered in a large-scale massively parallel sequencing study. Candidate Epileptic Encephalopathy genes were prioritized according to their co-expression with 29 known Epileptic Encephalopathy genes. We utilized developing brain and adult brain gene expression data from the Allen Human Brain Atlas (AHBA) and compared this to data from Celsius: a large, heterogeneous gene expression data warehouse. We show replicable prioritization results using these three independent gene expression resources, two of which are brain-specific, with small sample size, and the third derived from a heterogeneous collection of tissues with large sample size. Of the nineteen genes that we predicted with the highest likelihood to be true Epileptic Encephalopathy genes, two (GNAO1 and GRIN2B) have recently been independently reported and confirmed. We compare our results to those produced by an established in silico prioritization approach called Endeavour, and finally present gene expression networks for the known and candidate Epileptic Encephalopathy genes. This highlights sub-networks of gene expression, particularly in the network derived from the adult AHBA gene expression dataset. These networks give clues to the likely biological interactions between Epileptic Encephalopathy genes, potentially highlighting underlying mechanisms and avenues for therapeutic targets.

Oliver, Karen L.; Lukic, Vesna; Thorne, Natalie P.; Berkovic, Samuel F.; Scheffer, Ingrid E.; Bahlo, Melanie

2014-01-01

111

Gene discovery and gene function assignment in filamentous fungi  

Microsoft Academic Search

Filamentous fungi are a large group of diverse and economically important microorganisms. Large-scale gene disruption strategies developed in budding yeast are not applicable to these organisms because of their larger genomes and lower rate of targeted integration (TI) during transformation. We developed transposon-arrayed gene knockouts (TAGKO) to discover genes and simultaneously create gene disruption cassettes for subsequent transformation and mutant

Lisbeth Hamer; Kiichi Adachi; Maria V. Montenegro-Chamorro; Matthew M. Tanzer; Sanjoy K. Mahanty; Clive Lo; Rex W. Tarpey; Amy R. Skalchunes; Ryan W. Heiniger; Sheryl A. Frank; Blaise A. Darveaux; David J. Lampe; Ted M. Slater; Lakshman Ramamurthy; Todd M. Dezwaan; Grant H. Nelson; Jeffrey R. Shuster; Jeffrey Woessner; John E. Hamer

2001-01-01

112

Positive Darwinian Selection after Gene Duplication in Primate Ribonuclease Genes  

Microsoft Academic Search

Evolutionary mechanisms of origins of new gene function have been a subject of long-standing debate. Here we report a convincing case in which positive Darwinian selection operated at the molecular level during the evolution of novel function by gene duplication. The genes for eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) in primates belong to the ribonuclease gene family, and

Jianzhi Zhang; Helene F. Rosenberg; Masatoshi Nei

1998-01-01

113

5. OVERHEAD VIEW OF GENE CAMP LOOKING SOUTH. GENE PUMP ...  

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

5. OVERHEAD VIEW OF GENE CAMP LOOKING SOUTH. GENE PUMP PLANT IS AT CENTER WITH ADMINISTRATIVE COMPLEX IN FOREGROUND AND RESIDENTIAL AREA BEYOND PLANT. - Gene Pump Plant, South of Gene Wash Reservoir, 2 miles west of Whitsett Pump Plant, Parker Dam, San Bernardino County, CA

114

Classification of genes based on gene expression analysis  

SciTech Connect

Systems biology and bioinformatics are now major fields for productive research. DNA microarrays and other array technologies and genome sequencing have advanced to the point that it is now possible to monitor gene expression on a genomic scale. Gene expression analysis is discussed and some important clustering techniques are considered. The patterns identified in the data suggest similarities in the gene behavior, which provides useful information for the gene functionalities. We discuss measures for investigating the homogeneity of gene expression data in order to optimize the clustering process. We contribute to the knowledge of functional roles and regulation of E. coli genes by proposing a classification of these genes based on consistently correlated genes in expression data and similarities of gene expression patterns. A new visualization tool for targeted projection pursuit and dimensionality reduction of gene expression data is demonstrated.

Angelova, M., E-mail: maia.angelova@unn.ac.uk; Myers, C., E-mail: chris.myers@unn.ac.uk; Faith, J., E-mail: joe.faith@unn.ac.u [Northumbria University (United Kingdom)

2008-05-15

115

Classification of genes based on gene expression analysis  

NASA Astrophysics Data System (ADS)

Systems biology and bioinformatics are now major fields for productive research. DNA microarrays and other array technologies and genome sequencing have advanced to the point that it is now possible to monitor gene expression on a genomic scale. Gene expression analysis is discussed and some important clustering techniques are considered. The patterns identified in the data suggest similarities in the gene behavior, which provides useful information for the gene functionalities. We discuss measures for investigating the homogeneity of gene expression data in order to optimize the clustering process. We contribute to the knowledge of functional roles and regulation of E. coli genes by proposing a classification of these genes based on consistently correlated genes in expression data and similarities of gene expression patterns. A new visualization tool for targeted projection pursuit and dimensionality reduction of gene expression data is demonstrated.

Angelova, M.; Myers, C.; Faith, J.

2008-05-01

116

Stochastic Gene Expression Model Base Gene Regulatory Networks  

NASA Astrophysics Data System (ADS)

Gene regulatory networks consist of a number of genes and their interactions which regulate expressions of the genes. Along with the development of gene regulatory network studies, computer simulations have become a valuable tool to evaluate complex relationships between genes. Due to the stochastic nature of gene expressions, various stochastic approaches have attracted increasing interest. In this study, we build gene regulatory networks based on a stochastic gene expression model with delicate assumptions such as transcription, translation, DNA-protein, protein-protein associations and time delay for protein activation. Two simple in-silico gene regulatory network models are constructed and monitored their expression profiles reflecting the inhibition and activation of the gene regulations.

Kim, Haseong; Gelenbe, Erol

117

GeneCards Version 3: the human gene integrator.  

PubMed

GeneCards (www.genecards.org) is a comprehensive, authoritative compendium of annotative information about human genes, widely used for nearly 15 years. Its gene-centric content is automatically mined and integrated from over 80 digital sources, resulting in a web-based deep-linked card for each of >73,000 human gene entries, encompassing the following categories: protein coding, pseudogene, RNA gene, genetic locus, cluster and uncategorized. We now introduce GeneCards Version 3, featuring a speedy and sophisticated search engine and a revamped, technologically enabling infrastructure, catering to the expanding needs of biomedical researchers. A key focus is on gene-set analyses, which leverage GeneCards' unique wealth of combinatorial annotations. These include the GeneALaCart batch query facility, which tabulates user-selected annotations for multiple genes and GeneDecks, which identifies similar genes with shared annotations, and finds set-shared annotations by descriptor enrichment analysis. Such set-centric features address a host of applications, including microarray data analysis, cross-database annotation mapping and gene-disorder associations for drug targeting. We highlight the new Version 3 database architecture, its multi-faceted search engine, and its semi-automated quality assurance system. Data enhancements include an expanded visualization of gene expression patterns in normal and cancer tissues, an integrated alternative splicing pattern display, and augmented multi-source SNPs and pathways sections. GeneCards now provides direct links to gene-related research reagents such as antibodies, recombinant proteins, DNA clones and inhibitory RNAs and features gene-related drugs and compounds lists. We also portray the GeneCards Inferred Functionality Score annotation landscape tool for scoring a gene's functional information status. Finally, we delineate examples of applications and collaborations that have benefited from the GeneCards suite. Database URL: www.genecards.org. PMID:20689021

Safran, Marilyn; Dalah, Irina; Alexander, Justin; Rosen, Naomi; Iny Stein, Tsippi; Shmoish, Michael; Nativ, Noam; Bahir, Iris; Doniger, Tirza; Krug, Hagit; Sirota-Madi, Alexandra; Olender, Tsviya; Golan, Yaron; Stelzer, Gil; Harel, Arye; Lancet, Doron

2010-01-01

118

How old is my gene?  

PubMed

Gene functions, interactions, disease associations, and ecological distributions are all correlated with gene age. However, it is challenging to estimate the intricate series of evolutionary events leading to a modern-day gene and then to reduce this history to a single age estimate. Focusing on eukaryotic gene families, we introduce a framework that can be used to compare current strategies for quantifying gene age, discuss key differences between these methods, and highlight several common problems. We argue that genes with complex evolutionary histories do not have a single well-defined age. As a result, care must be taken to articulate the goals and assumptions of any analysis that uses gene age estimates. Recent algorithmic advances offer the promise of gene age estimates that are fast, accurate, and consistent across gene families. This will enable a shift to integrated genome-wide analyses of all events in gene evolutionary histories in the near future. PMID:23915718

Capra, John A; Stolzer, Maureen; Durand, Dannie; Pollard, Katherine S

2013-11-01

119

FunGene: the functional gene pipeline and repository.  

PubMed

Ribosomal RNA genes have become the standard molecular markers for microbial community analysis for good reasons, including universal occurrence in cellular organisms, availability of large databases, and ease of rRNA gene region amplification and analysis. As markers, however, rRNA genes have some significant limitations. The rRNA genes are often present in multiple copies, unlike most protein-coding genes. The slow rate of change in rRNA genes means that multiple species sometimes share identical 16S rRNA gene sequences, while many more species share identical sequences in the short 16S rRNA regions commonly analyzed. In addition, the genes involved in many important processes are not distributed in a phylogenetically coherent manner, potentially due to gene loss or horizontal gene transfer. While rRNA genes remain the most commonly used markers, key genes in ecologically important pathways, e.g., those involved in carbon and nitrogen cycling, can provide important insights into community composition and function not obtainable through rRNA analysis. However, working with ecofunctional gene data requires some tools beyond those required for rRNA analysis. To address this, our Functional Gene Pipeline and Repository (FunGene; http://fungene.cme.msu.edu/) offers databases of many common ecofunctional genes and proteins, as well as integrated tools that allow researchers to browse these collections and choose subsets for further analysis, build phylogenetic trees, test primers and probes for coverage, and download aligned sequences. Additional FunGene tools are specialized to process coding gene amplicon data. For example, FrameBot produces frameshift-corrected protein and DNA sequences from raw reads while finding the most closely related protein reference sequence. These tools can help provide better insight into microbial communities by directly studying key genes involved in important ecological processes. PMID:24101916

Fish, Jordan A; Chai, Benli; Wang, Qiong; Sun, Yanni; Brown, C Titus; Tiedje, James M; Cole, James R

2013-01-01

120

Eukaryotic Genes Involved in Adult Lifespan Regulation.  

National Technical Information Service (NTIS)

The present invention relates to regulation of adult lifespan in eukaryotes. More particularly, the present invention is directed to methods of assaying for genes, gene products, and genes in pathways controlled by such genes and gene products, using RNAi...

A. Dillin A. L. A. Hsu C. Kenyon D. Garigan J. Apfeld

2005-01-01

121

Integrated Analysis of Gene Expression and Gene Copy Number for Gene Shaving Based on ICA Approach  

Microsoft Academic Search

Microarray gene expression and array CGH (aCGH) are two genomic approaches, which are widely used for biomedical discovery. While microarray gene expression analysis provides functional information, the aCGH analysis provides structural variations of genome using gene copy number analysis. The integration of this complementary information is challenging. We proposed a method, named as “gene shaving”, to identify subsets of the

Yu-Ping Wang

2011-01-01

122

Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions  

Microsoft Academic Search

Motivation: Polymorphisms in human genes are being described in remarkable numbers. Determining which polymorphisms and which environmental factors are associated with common, complex diseases has become a daunting task. This is partly because the effect of any single genetic variation will likely be dependent on other genetic variations (gene-gene interaction or epistasis) and environmental factors (gene-environment interac- tion). Detecting and

Lance W. Hahn; Marylyn D. Ritchie; Jason H. Moore

2003-01-01

123

Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics  

PubMed Central

Understanding the basis for differential responses to drug therapies remains a challenge despite advances in genetics and genomics. Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to investigate the pharmacology of disease processes in therapeutically and genetically relevant primary cell types in vitro and to interweave clinical and basic molecular data. We report here the derivation of iPSCs from a long QT syndrome patient with complex genetics. The proband was found to have a de novo SCN5A LQT-3 mutation (F1473C) and a polymorphism (K897T) in KCNH2, the gene for LQT-2. Analysis of the biophysics and molecular pharmacology of ion channels expressed in cardiomyocytes (CMs) differentiated from these iPSCs (iPSC-CMs) demonstrates a primary LQT-3 (Na+ channel) defect responsible for the arrhythmias not influenced by the KCNH2 polymorphism. The F1473C mutation occurs in the channel inactivation gate and enhances late Na+ channel current (INaL) that is carried by channels that fail to inactivate completely and conduct increased inward current during prolonged depolarization, resulting in delayed repolarization, a prolonged QT interval, and increased risk of fatal arrhythmia. We find a very pronounced rate dependence of INaL such that increasing the pacing rate markedly reduces INaL and, in addition, increases its inhibition by the Na+ channel blocker mexiletine. These rate-dependent properties and drug interactions, unique to the proband’s iPSC-CMs, correlate with improved management of arrhythmias in the patient and provide support for this approach in developing patient-specific clinical regimens.

Terrenoire, Cecile; Wang, Kai; Chan Tung, Kelvin W.; Chung, Wendy K.; Pass, Robert H.; Jean, Jyh-Chang; Omari, Amel; Sampson, Kevin J.; Kotton, Darrell N.; Keller, Gordon

2013-01-01

124

Characterizing gene family evolution  

PubMed Central

Gene families are widely used in comparative genomics, molecular evolution, and in systematics. However, they are constructed in different manners, their data analyzed and interpreted differently, with different underlying assumptions, leading to sometimes divergent conclusions. In systematics, concepts like monophyly and the dichotomy between homoplasy and homology have been central to the analysis of phylogenies. We critique the traditional use of such concepts as applied to gene families and give examples of incorrect inferences they may lead to. Operational definitions that have emerged within functional genomics are contrasted with the common formal definitions derived from systematics. Lastly, we question the utility of layers of homology and the meaning of homology at the character state level in the context of sequence evolution. From this, we move forward to present an idealized strategy for characterizing gene family evolution for both systematic and functional purposes, including recent methodological improvements.

Liberles, David A.

2008-01-01

125

XLMR genes: Update 1994  

SciTech Connect

We provide a comprehensive list of all known forms of X-linked mental retardation. It comprises 127 entries, subdivided into 5 categories (syndromes, dominant disorders, and nonspecific mental retardation). Map location of 69 putative loci demonstrates several overlaps, which will only be resolved by more refined mapping or cloning of the respective genes. The ultimate goal of identifying all the genes on the X chromosome whose mutations cause mental retardation will require a concerted effort between clinical and molecular investigators. 74 refs., 2 figs., 5 tabs.

Neri, G.; Chiurazzi, P. [Universita Cattolica del Sacro Cuore, Rome (Italy); Arena, J.F.; Lubs, H.A. [Univ. of Miami School of Medicine, FL (United States)

1994-07-15

126

BBC: Gene Stories  

NSDL National Science Digital Library

This site comes from the BBC's "Gene Stories...The Basics of Being," a Web feature that explores in great depth the field of genetics and how it relates to our everyday lives. In Genes and History, visitors can "find out how science can help solve historical riddles that have long perplexed historians, and how history can offer cautionary tales about the promise of science." The site also includes some interactive features like How Viking Are You?, a fun way to find out if Viking blood runs through your veins.

127

Phospholipid - Driven gene regulation  

PubMed Central

Phospholipids (PLs), well known for their fundamental role in cellular structure, play critical signaling roles via their derivatives and cleavage products acting as second messengers in signaling cascades. Recent work has shown that intact PLs act as signaling molecules in their own right by modulating the activity of nuclear hormone transcription factors responsible for tuning genes involved in metabolism, lipid flux, steroid synthesis and inflammation. As such, PLs have been classified as novel hormones. This review highlights recent work in PL-driven gene regulation with a focus on the unique structural features of phospholipid-sensing transcription factors and what sets them apart from well known soluble phospholipid transporters.

Musille, Paul M.; Kohn, Jeffrey A.; Ortlund, Eric A.

2013-01-01

128

Genes2FANs: connecting genes through functional association networks  

PubMed Central

Background Protein-protein, cell signaling, metabolic, and transcriptional interaction networks are useful for identifying connections between lists of experimentally identified genes/proteins. However, besides physical or co-expression interactions there are many ways in which pairs of genes, or their protein products, can be associated. By systematically incorporating knowledge on shared properties of genes from diverse sources to build functional association networks (FANs), researchers may be able to identify additional functional interactions between groups of genes that are not readily apparent. Results Genes2FANs is a web based tool and a database that utilizes 14 carefully constructed FANs and a large-scale protein-protein interaction (PPI) network to build subnetworks that connect lists of human and mouse genes. The FANs are created from mammalian gene set libraries where mouse genes are converted to their human orthologs. The tool takes as input a list of human or mouse Entrez gene symbols to produce a subnetwork and a ranked list of intermediate genes that are used to connect the query input list. In addition, users can enter any PubMed search term and then the system automatically converts the returned results to gene lists using GeneRIF. This gene list is then used as input to generate a subnetwork from the user’s PubMed query. As a case study, we applied Genes2FANs to connect disease genes from 90 well-studied disorders. We find an inverse correlation between the counts of links connecting disease genes through PPI and links connecting diseases genes through FANs, separating diseases into two categories. Conclusions Genes2FANs is a useful tool for interpreting the relationships between gene/protein lists in the context of their various functions and networks. Combining functional association interactions with physical PPIs can be useful for revealing new biology and help form hypotheses for further experimentation. Our finding that disease genes in many cancers are mostly connected through PPIs whereas other complex diseases, such as autism and type-2 diabetes, are mostly connected through FANs without PPIs, can guide better strategies for disease gene discovery. Genes2FANs is available at: http://actin.pharm.mssm.edu/genes2FANs.

2012-01-01

129

Gene therapy in diabetes  

PubMed Central

Type 1 diabetes (T1D) is a chronic autoimmune disease, whereby auto-reactive cytotoxic T cells target and destroy insulin-secreting ?-cells in pancreatic islets leading to insulin deficiency and subsequent hyperglycemia. These individuals require multiple daily insulin injections every day of their life without which they will develop life-threatening diabetic ketoacidosis (DKA) and die. Gene therapy by viral vector and non-viral transduction may be useful techniques to treat T1D as it can be applied from many different angles; such as the suppression of autoreactive T cells to prevent islet destruction (prophylactic) or the replacement of the insulin gene (post-disease). The need for a better method for providing euglycemia arose from insufficient numbers of cadaver islets for transplantation and the immunosuppression required post-transplant. Ectopic expression of insulin or islet modification have been examined, but not perfected. This review examines the various gene transfer methods, gene therapy techniques used to date and promising novel techniques for the maintenance of euglycemia in the treatment of T1D.

Wong, Mary S; Hawthorne, Wayne J

2010-01-01

130

Engineering prokaryotic gene circuits  

PubMed Central

Engineering of synthetic gene circuits is a rapidly growing discipline, currently dominated by prokaryotic transcription networks, which can be easily rearranged or rewired to give different output behaviours. In this review, we examine both a rational and a combinatorial design of such networks and discuss progress on using in vitro evolution techniques to obtain functional systems. Moving beyond pure transcription networks, more and more networks are being implemented at the level of RNA, taking advantage of mechanisms of translational control and aptamer–small molecule complex formation. Unlike gene expression systems, metabolic components are generally not as interconnectable in any combination, and so engineering of metabolic circuits is a particularly challenging field. Nonetheless, metabolic engineering has immense potential to provide useful biosynthesis tools for biotechnology applications. Finally, although prokaryotes are mostly studied as single cell systems, cell–cell communication networks are now being developed that result in spatial pattern formation in multicellular prokaryote colonies. This represents a crossover with multicellular organisms, showing that prokaryotic systems have the potential to tackle questions traditionally associated with developmental biology. Overall, the current advances in synthetic gene synthesis, ultra-high-throughput DNA sequencing and computation are synergizing to drive synthetic gene network design at an unprecedented pace.

Michalodimitrakis, Konstantinos; Isalan, Mark

2009-01-01

131

Exploring Genes & Genetic Disorders  

NSDL National Science Digital Library

More and more excellent data continues to be produced by the Human Genome Project, and a number of government organizations have created top-notch educational resources based on this information. The Gene Gateway website was originally produced as a companion to the Human Genome Landmarks poster and has evolved into a "collection of guides and tutorials designed to help students and other novice users get started with some of the resources that make these data available to the public." Here visitors are introduced to various Internet tools that anyone can use to investigate "genetic disorders, chromosomes, genome maps, genes, sequence data, genetic variants, and molecular structures." Visitors can download the Gene Gateway workbook, which contains five activities, complete with screenshots and step-by-step instructions "designed to introduce new users to genetic disorder and bioinformatics resources on the Web". Moving down the homepage, visitors can look into sections such as "Bioinformatics Tools", the "Genetic Disorder Guide", and an outstanding "Chromosome Viewer". The viewer provides a great backdrop for those seeking to understand the physical makeup of human chromosomes. Also, visitors can order a free copy of the wall poster "Human Genome Landmarks: Selected Genes, Traits, and Disorders".

132

Genes and Vocal Learning  

ERIC Educational Resources Information Center

Could a mutation in a single gene be the evolutionary lynchpin supporting the development of human language? A rare mutation in the molecule known as FOXP2 discovered in a human family seemed to suggest so, and its sequence phylogeny reinforced a Chomskian view that language emerged wholesale in humans. Spurred by this discovery, research in…

White, Stephanie A.

2010-01-01

133

Gene Therapy for Hypertension  

Microsoft Academic Search

Despite several drugs for the treatment of hypertension, there are many patients with poorly controlled high blood pressure. This is partly because all of the available drugs are short-lasting ( #24 hours), have side effects, and are not highly specific. Gene therapy offers a possibility of producing longer-lasting effects with precise specificity based on the genetic design. Preclinical studies on

M. Ian Phillips

2010-01-01

134

Gene Trap Mutagenesis  

Microsoft Academic Search

Our ability to genetically manipulate the mouse has had a great impact on medical research over the last few decades. Mouse genetics has developed into a powerful tool for dissecting the genetic causes of human disease and identifying potential targets for pharmaceutical intervention. With the recent sequencing of the human and mouse genomes, a large number of novel genes have

A. Abuin; G. Hansen; B. Zambrowicz

135

Ultrasound mediated gene transfection  

NASA Astrophysics Data System (ADS)

Gene therapy is a promising modality for the treatment of a variety of human diseases both inherited and acquired, such as cystic fibrosis and cancer. The lack of an effective, safe method for the delivery of foreign genes into the cells, a process known as transfection, limits this effort. Ultrasound mediated gene transfection is an attractive method for gene delivery since it is a noninvasive technique, does not introduce any viral particles into the host and can offer very good temporal and spatial control. Previous investigators have shown that sonication increases transfection efficiency with and without ultrasound contrast agents. The mechanism is believed to be via a cavitation process where collapsing bubble nuclei permeabilize the cell membrane leading to increased DNA transfer. The research is focused on the use of pulsed wave high frequency focused ultrasound to transfect DNA into mammalian cells in vitro and in vivo. A better understanding of the mechanism behind the transfection process is also sought. A summary of some in vitro results to date will be presented, which includes the design of a sonication chamber that allows us to model the in vivo case more accurately.

Williamson, Rene G.; Apfel, Robert E.; Brandsma, Janet L.

2002-05-01

136

GeneTrail--advanced gene set enrichment analysis  

PubMed Central

We present a comprehensive and efficient gene set analysis tool, called ‘GeneTrail’ that offers a rich functionality and is easy to use. Our web-based application facilitates the statistical evaluation of high-throughput genomic or proteomic data sets with respect to enrichment of functional categories. GeneTrail covers a wide variety of biological categories and pathways, among others KEGG, TRANSPATH, TRANSFAC, and GO. Our web server provides two common statistical approaches, ‘Over-Representation Analysis’ (ORA) comparing a reference set of genes to a test set, and ‘Gene Set Enrichment Analysis’ (GSEA) scoring sorted lists of genes. Besides other newly developed features, GeneTrail's statistics module includes a novel dynamic-programming algorithm that improves the P-value computation of GSEA methods considerably. GeneTrail is freely accessible at http://genetrail.bioinf.uni-sb.de

Backes, Christina; Keller, Andreas; Kuentzer, Jan; Kneissl, Benny; Comtesse, Nicole; Elnakady, Yasser A.; Muller, Rolf; Meese, Eckart; Lenhof, Hans-Peter

2007-01-01

137

Evolution of teleostean hatching enzyme genes and their paralogous genes  

Microsoft Academic Search

We isolated genes for hatching enzymes and their paralogs having two cysteine residues at their N-terminal regions in addition to four cysteines conserved in all the astacin family proteases. Genes for such six-cysteine-containing astacin proteases (C6AST) were searched out in the medaka genome database. Five genes for MC6AST1 to 5 were found in addition to embryo-specific hatching enzyme genes. RT-PCR

Mari Kawaguchi; Shigeki Yasumasu; Junya Hiroi; Kiyoshi Naruse; Masayuki Inoue; Ichiro Iuchi

2006-01-01

138

Identification of Genes and Gene Products Necessary for Bacterial Bioluminescence  

Microsoft Academic Search

Expression of luminescence in Escherichia coli was recently achieved by cloning genes from the marine bacterium Vibrio fischeri. One DNA fragment on a hybrid plasmid encoded regulatory functions and enzymatic activities necessary for light production. We report the results of a genetic analysis to identify the luminescence genes (lux) that reside on this recombinant plasmid. lux gene mutations were generated

Joanne Engebrecht; Michael Silverman

1984-01-01

139

GENE METHYLATION CHANGES IN TUMOR SUPPRESSOR GENES INDUCED BY ARSENIC  

EPA Science Inventory

The choice of a dose-response model used for extrapolation can be influenced by knowledge of mechanism of action. We have already showed that arsenic affects methylation of the human p53 gene promoter. Evidence that genes other than the p53 tumor suppressor gene are affected woul...

140

Proto-genes and de novo gene birth  

PubMed Central

Novel protein-coding genes can arise either through re-organization of pre-existing genes or de novo1,2. Processes involving re-organization of pre-existing genes, notably following gene duplication, have been extensively described1,2. In contrast, de novo gene birth remains poorly understood, mainly because translation of sequences devoid of genes, or “non-genic” sequences, is expected to produce insignificant polypeptides rather than proteins with specific biological functions1,3-6. Here, we formalize an evolutionary model according to which functional genes evolve de novo through transitory proto-genes4 generated by widespread translational activity in non-genic sequences. Testing this model at genome-scale in Saccharomyces cerevisiae, we detect translation of hundreds of short species-specific open reading frames (ORFs) located in non-genic sequences. These translation events appear to provide adaptive potential7, as suggested by their differential regulation upon stress and by signatures of retention by natural selection. In line with our model, we establish that S. cerevisiae ORFs can be placed within an evolutionary continuum ranging from non-genic sequences to genes. We identify ~1,900 candidate proto-genes among S. cerevisiae ORFs and find that de novo gene birth from such a reservoir may be more prevalent than sporadic gene duplication. Our work illustrates that evolution exploits seemingly dispensable sequences to generate adaptive functional innovation.

Carvunis, Anne-Ruxandra; Rolland, Thomas; Wapinski, Ilan; Calderwood, Michael A.; Yildirim, Muhammed A.; Simonis, Nicolas; Charloteaux, Benoit; Hidalgo, Cesar A.; Barbette, Justin; Santhanam, Balaji; Brar, Gloria A.; Weissman, Jonathan S.; Regev, Aviv; Thierry-Mieg, Nicolas; Cusick, Michael E.; Vidal, Marc

2012-01-01

141

Interactive Fly: Maternally transcribed genes  

NSDL National Science Digital Library

The maternally transcribed genes section of the award-winning and comprehensive site: Interactive fly. It thoroughly discusses genes, tissues, biochemical paths, and developmental processes in the fruit fly, Drosophila.

PhD Thomas B Brody (NIH Laboratory of Neurochemistry)

2006-11-13

142

Using Genes to Guide Prescriptions  

MedlinePLUS

... role in how your body responds to medicines. Credit: Stock image. Your genes determine the color of ... of them, and genes might make the difference. Credit: Stock image. For people who have had a ...

143

Interactive Fly: Genes involved in Malpighian Tubules  

NSDL National Science Digital Library

A list and description of Drosophila genes involved in malpigian tubule formation, highlighting transcription factors, ATPase genes, and surface protein genes. A subset of the Interactive Fly collection.

PhD Thomas B Brody (NIH Laboratory of Neurochemistry)

2006-12-14

144

Hematopoietic Stem Cell Gene Therapy  

Microsoft Academic Search

Gene therapy applications that target hematopoietic stem cells (HSCs) offer great potential for the treatment of hematologic\\u000a disease. Despite this promise, clinical success has been limited by poor rates of gene transfer, poor engraftment of modified\\u000a cells, and poor levels of gene expression. We describe here the basic approach used for HSC gene therapy, briefly review some\\u000a of the seminal

David W. Emery; Tamon Nishino; Ken Murata; Michalis Fragkos; George Stamatoyannopoulos

2002-01-01

145

The Human Gene Mutation Database  

NSDL National Science Digital Library

The Human Gene Mutation Database from the Institute of Medical Genetics at Cardiff provides practical information for researchers, physicians, and genetic counselors. The database is currently undergoing some reorganization, but information can be searched by "disease, gene name, or gene symbol." Search results are well organized and easy to navigate, linking directly to results from external Web databases without requiring that the user perform additional searches. Frequent users may also appreciate the listing of genes recently added to the database.

2008-09-09

146

The Human Gene Mutation Database  

NSDL National Science Digital Library

The Human Gene Mutation Database from the Institute of Medical Genetics at Cardiff provides practical information for researchers, physicians, and genetic counselors. The database is currently undergoing some reorganization, but information can be searched by "disease, gene name, or gene symbol." Search results are well organized and easy to navigate, linking directly to results from external Web databases without requiring that the user perform additional searches. Frequent users may also appreciate the listing of genes recently added to the database.

1997-01-01

147

The Family of Connexin Genes  

Microsoft Academic Search

\\u000a The connexin genes code for a family of proteins that form intercellular gap junction channels. There are 21 connexin genes\\u000a in the human genome and 20 in the mouse genome. Most connexin genes contain the protein coding region in a single exon. Variations\\u000a in promoter usage and splicing of 5’-untranslated exons contribute to regulation of connexin expression. Connexin gene promoters

Eric C. Beyer; Viviana M. Berthoud

148

Regulatory Protein Coordinating Gene Expression  

NSDL National Science Digital Library

The action of the glucocorticoid receptor is illustrated. On the left is shown a series of genes, each of which has various gene activator proteins bound to its regulatory region. However, these bound proteins are not sufficient on their own to activate transcription efficiently. On the right is shown the effects of adding an additional gene regulatory protein

BEGIN:VCARD VERSION:2.1 FN:Bruce Alberts N:Alberts;Bruce REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Dennis Bray N:Bray;Dennis REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Alexander Johnson N:Johnson;Alexander REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Julian Lewis N:Lewis;Julian REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Martin Raff N:Raff;Martin REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Keith Roberts N:Roberts;Keith REV:2005-04-16 END:VCARD

1998-07-01

149

Gene regulation in physiological stress  

Microsoft Academic Search

A range of new tools in molecular biology are now available to allow the comparative biochemist to explore animal responses to environmental stress at multiple levels. In particular, new techniques of gene discovery, such as cDNA array screening, allow broad assessment of the responses of thousands of genes to a stress. This approach frequently identifies genes (and their associated metabolic

Kenneth B. Storey

2004-01-01

150

Homologous Recombination Based Gene Therapy  

Microsoft Academic Search

Background\\/Aims: Most of the current expression vector based gene therapy protocols fail to achieve clinically significant transgene expression required for treating genetic diseases. Homologous recombination, initially considered to be of limited use for gene therapy because of its low frequency in mammalian cells, has recently emerged as a potential strategy for developing gene therapy. Methods: Six recent studies of homologous

Li-Wen Lai; Yeong-Hau H. Lien

1999-01-01

151

Male Germ Cell Gene Expression  

Microsoft Academic Search

Formation of the male gamete occurs in sequential mitotic, meiotic, and postmeiotic phases. Many germ cell-specific transcripts are produced during this process. Their expression is develop- mentally regulated and stage specific. Some of these transcripts are product of genes that are male germ cell-specific homologs of genes expressed in somatic cells, while some are expressed from unique genes unlike any

EDWARD M. EDDY

2010-01-01

152

Prospects for Human Gene Therapy  

Microsoft Academic Search

Procedures have now been developed for inserting functional genes into the bone marrow of mice. The most effective delivery system at present uses retroviral-based vectors to transfer a gene into murine bone marrow cells in culture. The genetically altered bone marrow is then implanted into recipient animals. These somatic cell gene therapy techniques are becoming increasingly efficient. Their future application

W. French Anderson

1984-01-01

153

Inducible Gene Targeting in Mice  

Microsoft Academic Search

A method of gene targeting that allows the inducible inactivation of a target gene in mice is presented. The method uses an interferon-responsive promoter to control the expression of Cre recombinase. Here, Cre was used to delete a segment of the DNA polymerase beta gene flanked by loxP recombinase recognition sites. Deletion was complete in liver and nearly complete in

Ralf Kuhn; Frieder Schwenk; Michel Aguet; Klaus Rajewsky

1995-01-01

154

Generalist Genes and Learning Disabilities  

Microsoft Academic Search

The authors reviewed recent quantitative genetic research on learning disabilities that led to the conclusion that genetic diagnoses differ from traditional diagnoses in that the effects of relevant genes are largely general rather than specific. This research suggests that most genes associated with common learning disabilities—language impairment, reading disability, and mathematics disability—are generalists in 3 ways. First, genes that affect

Robert Plomin; Yulia Kovas

2005-01-01

155

The Merck Gene Index project  

Microsoft Academic Search

The Merck Gene Index project (MGIP) fills an important niche in the Human Genome Project by directly identifying genes through sequences of their transcripts and placing in the public domain a set of EST sequences and associated clones for the uniquely expressed human genes. The MGIP promotes the unrestricted exchange of human genomic data, and facilitates progress in biomedical research

Alan R. Williamson

1999-01-01

156

Analyses of Gene Frequencies  

PubMed Central

Models of variance components and their intraclass correlational equivalences are developed for genes falling into various categories of subdivisions within a population. Estimable functions are elaborated demonstrating that intraclass correlations can be estimated only relative to that for the least related genes in the informational system. The effects of different types of subdivisions—and of ignoring them—on the parameters are demonstrated. Small sample estimators are formulated for all of the parameters by three different methods, including both a weighted and an unweighted method of analysis of the variation among subpopulations. How estimators change with assumptions about the parameters is illustrated. Various tests of hypotheses are outlined in ?2 and F-test terminology. Discussed are factors which may affect the correlations and the manner in which their effects are manifest, hopefully in clarification of some of the misconceptions that have arisen in this connection.

Cockerham, C. Clark

1973-01-01

157

Myc Cancer Gene  

NSDL National Science Digital Library

This Web site, offered through Johns Hopkins University School of Medicine and Johns Hopkins Health System, aims to "provide a hub for the integration of information on Myc target genes, the role of Myc in human cancers, and proteins that interact with the Myc transcription factors." Users will find a well-organized collection of resources relating to Myc, such as an extensive set of links to PubMed articles, related databases, and some original data. The Web site's introduction provides a very readable explanation of Myc gene function and its role in tumor formation. Researchers working with Myc are encouraged to submit data to the site, which also offers a Myc-related listserve for convenient email updates.

158

PRRT2 gene mutations  

PubMed Central

ABSTRACT Objective: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM). Methods: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. Results: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. Conclusions: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders.

Gardiner, Alice R.; Bhatia, Kailash P.; Stamelou, Maria; Dale, Russell C.; Kurian, Manju A.; Schneider, Susanne A.; Wali, G.M.; Counihan, Tim; Schapira, Anthony H.; Spacey, Sian D.; Valente, Enza-Maria; Silveira-Moriyama, Laura; Teive, Helio A.G.; Raskin, Salmo; Sander, Josemir W.; Lees, Andrew; Warner, Tom; Kullmann, Dimitri M.; Wood, Nicholas W.; Hanna, Michael

2012-01-01

159

Basic Sciences - Gene Regulation  

Cancer.gov

Currently, Dr. Levens's research is focusing on the transcriptional regulation of c-myc and the elucidation of the roles of conformation and topology-selective, sequence-specific DNA binding transcription factors. The c-myc gene employs multiple cis-elements, upstream and downstream of its promoters, P1 and P2. The goal is to illuminate the mechanisms through which the input of multiple factors sets the expression level of this critical proto-oncogene.

160

Single Gene Disease Risk  

Microsoft Academic Search

\\u000a The diagnosis of a child with a single gene disorder can take on different meanings for different families. It is not uncommon\\u000a for some families to arrive at a pediatric genetics clinic after months or years of searching for an underlying reason for\\u000a their child’s symptoms. The fact that, through genetic testing, clinicians can put a name to the collection

Tricia See; Cynthia J. Tifft

161

Clock genes and sleep  

Microsoft Academic Search

In most species—from cyanobacteria to humans—endogenous clocks have evolved that drive 24-h rhythms of behavior and physiology.\\u000a In mammals, these circadian rhythms are regulated by a hierarchical network of cellular oscillators controlled by a set of\\u000a clock genes organized in a system of interlocked transcriptional feedback loops. One of the most prominent outputs of the\\u000a circadian system is the synchronization

Dominic Landgraf; Anton Shostak; Henrik Oster

162

Explore IT Gene Hunter  

NSDL National Science Digital Library

In this exploration, we'll take a look at how DNA stores information and how scientists identify what particular genes do. DNA is a very, very long molecule. To find out what a particular piece is for, a person (most often a scientist) must search -- or rather hunt-- for the genetic meaning. At the end, we examine how you can use the DNA code yourself.

Nickle, Todd

2010-06-01

163

GENE DELIVERY TO BONE  

PubMed Central

Gene delivery to bone is useful both as an experimental tool and as a potential therapeutic strategy. Among its advantages over protein delivery are the potential for directed, sustained and regulated expression of authentically processed, nascent proteins. Although no clinical trials have been initiated, there is a substantial pre-clinical literature documenting the successful transfer of genes to bone, and their intraosseous expression. Recombinant vectors derived from adenovirus, retrovirus and lentivirus, as well as non-viral vectors, have been used for this purpose. Both ex vivo and in vivo strategies, including gene-activated matrices, have been explored. Ex vivo delivery has often employed mesenchymal stem cells (MSCs), partly because of their ability to differentiate into osteoblasts. MSCs also have the potential to home to bone after systemic administration, which could serve as a useful way to deliver transgenes in a disseminated fashion for the treatment of diseases affecting the whole skeleton, such as osteoporosis or osteogenesis imperfecta. Local delivery of osteogenic transgenes, particularly those encoding bone morphogenetic proteins, has shown great promise in a number of applications where it is necessary to regenerate bone. These include healing large segmental defects in long bones and the cranium, as well as spinal fusion and treating avascular necrosis.

Evans, C. H.

2012-01-01

164

Design of polyketide synthase genes  

US Patent & Trademark Office Database

Methods for the computational analysis of polyketides and the computer-assisted design of PKS genes are facilitated by representing the structure of a polyketide and/or a PKS gene that encodes the PKS that produces the polyketide by alphanumeric symbols that facilitates computer assisted analysis. A database of polyketides and corresponding PKS genes that can be rapidly searched and information extracted for a variety of applications, including the design and specification of PKS genes via the recombining of modules or portions of modules or sets of modules from already known and available PKS genes.

2010-03-16

165

Gene-Gene, Gene-Environment & Multiple Interactions in Colorectal Cancer  

Microsoft Academic Search

This review comprehensively evaluates the influence of gene-gene, gene-environment and multiple interactions on the risk of colorectal cancer (CRC). Methods of studying these interactions and their limitations have been discussed herein. There is a need to develop biomarkers of exposure and of risk that are sensitive, specific, present in the pathway of the disease, and that have been clinically tested

FARID E. AHMED

2006-01-01

166

Same Genes May Influence Reading, Math Skills  

MedlinePLUS

... Preidt Wednesday, July 9, 2014 Related MedlinePlus Pages Children's Health Genes and Gene Therapy WEDNESDAY, July 9, 2014 ( ... HealthDay . All rights reserved. More Health News on: Children's Health Genes and Gene Therapy Recent Health News Page ...

167

Horizontal gene transfer in choanoflagellates.  

PubMed

Horizontal gene transfer (HGT), also known as lateral gene transfer, results in the rapid acquisition of genes from another organism. HGT has long been known to be a driving force in speciation in prokaryotes, and there is evidence for HGT from symbiotic and infectious bacteria to metazoans, as well as from protists to bacteria. Recently, it has become clear that as many as a 1,000 genes in the genome of the choanoflagellate Monosiga brevicollis may have been acquired by HGT. Interestingly, these genes reportedly come from algae, bacteria, and other choanoflagellate prey. Some of these genes appear to have allowed an ancestral choanoflagellate to exploit nutrient-poor environments and were not passed on to metazoan descendents. However, some of these genes are also found in animal genomes, suggesting that HGT into a common ancestor of choanozoans and animals may have contributed to metazoan evolution. PMID:22997182

Tucker, Richard P

2013-01-01

168

The Gene Wiki: community intelligence applied to human gene annotation.  

PubMed

Annotating the function of all human genes is a critical, yet formidable, challenge. Current gene annotation efforts focus on centralized curation resources, but it is increasingly clear that this approach does not scale with the rapid growth of the biomedical literature. The Gene Wiki utilizes an alternative and complementary model based on the principle of community intelligence. Directly integrated within the online encyclopedia, Wikipedia, the goal of this effort is to build a gene-specific review article for every gene in the human genome, where each article is collaboratively written, continuously updated and community reviewed. Previously, we described the creation of Gene Wiki 'stubs' for approximately 9000 human genes. Here, we describe ongoing systematic improvements to these articles to increase their utility. Moreover, we retrospectively examine the community usage and improvement of the Gene Wiki, providing evidence of a critical mass of users and editors. Gene Wiki articles are freely accessible within the Wikipedia web site, and additional links and information are available at http://en.wikipedia.org/wiki/Portal:Gene_Wiki. PMID:19755503

Huss, Jon W; Lindenbaum, Pierre; Martone, Michael; Roberts, Donabel; Pizarro, Angel; Valafar, Faramarz; Hogenesch, John B; Su, Andrew I

2010-01-01

169

From gene expression to gene regulatory networks in Arabidopsis thaliana  

PubMed Central

Background The elucidation of networks from a compendium of gene expression data is one of the goals of systems biology and can be a valuable source of new hypotheses for experimental researchers. For Arabidopsis, there exist several thousand microarrays which form a valuable resource from which to learn. Results A novel Bayesian network-based algorithm to infer gene regulatory networks from gene expression data is introduced and applied to learn parts of the transcriptomic network in Arabidopsis thaliana from a large number (thousands) of separate microarray experiments. Starting from an initial set of genes of interest, a network is grown by iterative addition to the model of the gene, from another defined set of genes, which gives the 'best' learned network structure. The gene set for iterative growth can be as large as the entire genome. A number of networks are inferred and analysed; these show (i) an agreement with the current literature on the circadian clock network, (ii) the ability to model other networks, and (iii) that the learned network hypotheses can suggest new roles for poorly characterized genes, through addition of relevant genes from an unconstrained list of over 15,000 possible genes. To demonstrate the latter point, the method is used to suggest that particular GATA transcription factors are regulators of photosynthetic genes. Additionally, the performance in recovering a known network from different amounts of synthetically generated data is evaluated. Conclusion Our results show that plausible regulatory networks can be learned from such gene expression data alone. This work demonstrates that network hypotheses can be generated from existing gene expression data for use by experimental biologists.

Needham, Chris J; Manfield, Iain W; Bulpitt, Andrew J; Gilmartin, Philip M; Westhead, David R

2009-01-01

170

Gene Circuit Analysis of the Terminal Gap Gene huckebein  

PubMed Central

The early embryo of Drosophila melanogaster provides a powerful model system to study the role of genes in pattern formation. The gap gene network constitutes the first zygotic regulatory tier in the hierarchy of the segmentation genes involved in specifying the position of body segments. Here, we use an integrative, systems-level approach to investigate the regulatory effect of the terminal gap gene huckebein (hkb) on gap gene expression. We present quantitative expression data for the Hkb protein, which enable us to include hkb in gap gene circuit models. Gap gene circuits are mathematical models of gene networks used as computational tools to extract regulatory information from spatial expression data. This is achieved by fitting the model to gap gene expression patterns, in order to obtain estimates for regulatory parameters which predict a specific network topology. We show how considering variability in the data combined with analysis of parameter determinability significantly improves the biological relevance and consistency of the approach. Our models are in agreement with earlier results, which they extend in two important respects: First, we show that Hkb is involved in the regulation of the posterior hunchback (hb) domain, but does not have any other essential function. Specifically, Hkb is required for the anterior shift in the posterior border of this domain, which is now reproduced correctly in our models. Second, gap gene circuits presented here are able to reproduce mutants of terminal gap genes, while previously published models were unable to reproduce any null mutants correctly. As a consequence, our models now capture the expression dynamics of all posterior gap genes and some variational properties of the system correctly. This is an important step towards a better, quantitative understanding of the developmental and evolutionary dynamics of the gap gene network.

Ashyraliyev, Maksat; Siggens, Ken; Janssens, Hilde; Blom, Joke; Akam, Michael; Jaeger, Johannes

2009-01-01

171

Complex gene-gene interactions in multiple sclerosis: a multifactorial approach reveals associations with inflammatory genes.  

PubMed

The complex inheritance involved in multiple sclerosis (MS) risk has been extensively investigated, but our understanding of MS genetics remains rudimentary. In this study, we explore 51 single nucleotide polymorphisms (SNPs) in 36 candidate genes from the inflammatory pathway and test for gene-gene interactions using complementary case-control, discordant sibling pair, and trio family study designs. We used a sample of 421 carefully diagnosed MS cases and 96 unrelated, healthy controls; discordant sibling pairs from 146 multiplex families; and 275 trio families. We used multifactor dimensionality reduction to explore gene-gene interactions. Based on our analyses, we have identified several statistically significant models including both main effect models and two-locus, three-locus, and four-locus epistasis models that predict MS disease risk with between approximately 61% and 85% accuracy. These results suggest that significant epistasis, or gene-gene interactions, may exist even in the absence of statistically significant individual main effects. PMID:17024427

Motsinger, Alison A; Brassat, David; Caillier, Stacy J; Erlich, Henry A; Walker, Karen; Steiner, Lori L; Barcellos, Lisa F; Pericak-Vance, Margaret A; Schmidt, Silke; Gregory, Simon; Hauser, Stephen L; Haines, Jonathan L; Oksenberg, Jorge R; Ritchie, Marylyn D

2007-01-01

172

Gene delivery and gene therapy of prostate cancer.  

PubMed

Surgery, radiation or hormonal therapy are not adequate to control prostate cancer. Clearly, other novel treatment approaches, such as gene therapy, for advanced/recurrent disease are desperately needed to achieve long-term local control and particularly to develop effective systemic therapy for metastatic prostate cancer. In the last decade, significant progress in gene therapy for the treatment of localised prostate cancer has been demonstrated. A broad range of different gene therapy approaches, including cytolytic, immunological and corrective gene therapy, have been successfully applied for prostate cancer treatment in animal models, with translation into early clinical trials. In addition, a wide variety of viral and nonbiological gene delivery systems are available for basic and clinical research. Gene therapy approaches that have been developed for the treatment of prostate cancer are summarised. PMID:16370939

Kaliberov, Sergey A; Buchsbaum, Donald J

2006-01-01

173

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

174

Gene transfer in experimental medicine.  

PubMed

Gene transfer technology has many potential applications in medicine. Phase I and phase II gene-based clinical trials have been conducted for the treatment of cancer, monogenic disorders, some neurodegenerative illnesses, cardiopathies and infectious diseases. A phase I gene therapy clinical trial has recently been approved for the treatment of Parkinson's disease, while preclinical studies are in progress to develop gene-based interventions for the treatment of Alzheimer's disease and Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and diabetes type 1 and type 2. A number of gene transfer models have been generated for gene therapy and genetic immunization programs. Vector design is addressing several pressing issues in the matter of gene delivery improvement, stabilization of transgene expression and safety. This is necessary in order to achieve efficient gene-based therapeutic interventions. Indeed, considerable progress has been reported in the field of vector design, which has produced some encouraging results in clinical trials and preclinical studies. However, vector design should be further developed to allow for the successful application of gene transfer technology in therapy. This review summarizes the latest achievements and controversies in clinical trials and preclinical studies in the field of gene therapy. PMID:12942157

Romano, Gaetano

2003-06-01

175

ZC88, a novel 4-amino piperidine analog, inhibits the growth of neuroblastoma cells through blocking hERG potassium channel  

PubMed Central

Many studies have provided convincing evidence for hERG as an important diagnostic and prognostic factor in human cancers, as well as a useful target for antineoplastic therapy. Our previous study also revealed that knockdown of herg gene expression by shRNA interference inhibited the growth of neuroblastoma cells in vitro and in vivo. In the experiment, a novel 4-amino piperidine analog, ZC88, was examined for its effect on hERG potassium channels and its antitumor potency was observed in vitro and in vivo. The results showed that ZC88 could block hERG1 and hERG1b channels expressed in Xenopus oocytes in a concentration-dependent manner. ZC88 displayed significant antiproliferative activity in several tumor cell lines and the tumor cells with higher expression of hERG presented higher sensitivity to ZC88. The mitotic progression of tumor cells was markedly suppressed in the presence of ZC88 through arresting cells in G0/G1 phase. ZC88 significantly inhibited the tumor growth in nude mice at a dosage with slight influence on the cardiac QT interval. The antitumor effect of ZC88 was correlated at least partly with its blockage of hERG channels, which implicated a positive role of hERG potassium channel in tumor cell proliferation.

Wei, Xiaoli; Sun, Hongliang; Yan, Haitao; Zhang, Cheng; Zhang, Shuzhuo; Liu, Xiaoyan; Hua, Nan; Ma, Xiaoyun; Zheng, Jianquan

2013-01-01

176

Statistics for approximate gene clusters  

PubMed Central

Background Genes occurring co-localized in multiple genomes can be strong indicators for either functional constraints on the genome organization or remnant ancestral gene order. The computational detection of these patterns, which are usually referred to as gene clusters, has become increasingly sensitive over the past decade. The most powerful approaches allow for various types of imperfect cluster conservation: Cluster locations may be internally rearranged. The individual cluster locations may contain only a subset of the cluster genes and may be disrupted by uninvolved genes. Moreover cluster locations may not at all occur in some or even most of the studied genomes. The detection of such low quality clusters increases the risk of mistaking faint patterns that occur merely by chance for genuine findings. Therefore, it is crucial to estimate the significance of computational gene cluster predictions and discriminate between true conservation and coincidental clustering. Results In this paper, we present an efficient and accurate approach to estimate the significance of gene cluster predictions under the approximate common intervals model. Given a single gene cluster prediction, we calculate the probability to observe it with the same or a higher degree of conservation under the null hypothesis of random gene order, and add a correction factor to account for multiple testing. Our approach considers all parameters that define the quality of gene cluster conservation: the number of genomes in which the cluster occurs, the number of involved genes, the degree of conservation in the different genomes, as well as the frequency of the clustered genes within each genome. We apply our approach to evaluate gene cluster predictions in a large set of well annotated genomes.

2013-01-01

177

Frequent gene conversion between human red and green opsin genes  

Microsoft Academic Search

To study the evolution of human X-linked red and green opsin genes, genomic sequences in large regions of the two genes were\\u000a compared. The divergences in introns 3, 4, and 5 and the 3? flanking sequence of the two genes are significantly lower than\\u000a those in exons 4 and 5. The homogenization mechanism of introns and the 3? flanking sequence

Zhongming Zhao; David Hewett-Emmett; Wen-Hsiung Li

1998-01-01

178

GeneMark.hmm: new solutions for gene finding.  

PubMed Central

The number of completely sequenced bacterial genomes has been growing fast. There are computer methods available for finding genes but yet there is a need for more accurate algorithms. The GeneMark. hmm algorithm presented here was designed to improve the gene prediction quality in terms of finding exact gene boundaries. The idea was to embed the GeneMark models into naturally derived hidden Markov model framework with gene boundaries modeled as transitions between hidden states. We also used the specially derived ribosome binding site pattern to refine predictions of translation initiation codons. The algorithm was evaluated on several test sets including 10 complete bacterial genomes. It was shown that the new algorithm is significantly more accurate than GeneMark in exact gene prediction. Interestingly, the high gene finding accuracy was observed even in the case when Markov models of order zero, one and two were used. We present the analysis of false positive and false negative predictions with the caution that these categories are not precisely defined if the public database annotation is used as a control.

Lukashin, A V; Borodovsky, M

1998-01-01

179

Identification of additional genes that influence baculovirus late gene expression.  

PubMed

We were unable to confirm transient late gene expression using constructs of 18 genes that had been reported to support Autographa californica multinucleocapsid nucleopolyhedrovirus (AcMNPV) late gene expression when transfected into Spodoptera frugiperda cells [Lu, A., and Miller, L. K. (1995). J. Virol. 69, 975-982]. Three genes (orf66, orf68, and orf41) were included, all or in part, in the constructs used in that study, but they had not been independently tested. Therefore we investigated these and neighboring orfs for their influence on late gene expression. We found that orf41 was required for late gene expression and that sequences within orf45 appeared to be required for the expression of orf41. Although orf66 and orf68 did not appear to affect late gene expression, orf69 stimulated expression. orf69 was found to have high homology to recent entries in GenBank from a variety of organisms. In addition, it was found that orf121, which was shown to be involved in early gene expression, and the viral homolog of pcna did not influence late gene expression. PMID:10049816

Li, L; Harwood, S H; Rohrmann, G F

1999-03-01

180

XLMR genes: Update 1996  

SciTech Connect

A current list of all known forms of X-linked mental retardation (XLMR) and a slightly revised classification are presented. The number of known disorders has not increased because 6 disorders have been combined based on new molecular data or on clinical grounds and only 6 newly described XLMR disorders have been reported. Of the current 105 XLMR disorders, 34 have been mapped, and 18 disorders and 1 non-specific XLMR (FRAXE) have been cloned. The number of families with nonspecific XLMR with a LOD score of {ge}2.0 has more than doubled, with 42 (including FRAXE) now being known. A summary of the localization of presumed nonspecific mental retardation (MR) genes from well-studied X-chromosomal translocations and deletions is also included. Only 10-12 nonoverlapping loci are required to explain all localizations of non-specific MR from both approaches. These new trends mark the beginning of a significantly improved understanding of the role of genes on the X chromosome in producing MR. Continued close collaboration between clinical and molecular investigators will be required to complete the process. 105 refs., 2 figs., 6 tabs.

Lubs, H.A.; Tranebjaerg, L. [Univ. Hospital of Tromso (Norway)] [Univ. Hospital of Tromso (Norway); Arena, J.F. [Univ. of Miami School of Medicine, FL (United States)] [and others] [Univ. of Miami School of Medicine, FL (United States); and others

1996-07-12

181

The human loricrin gene.  

PubMed

Loricrin is the major protein component of the cornified cell envelope of terminally differentiated mammalian epidermal (stratum corneum) cells. Using a specific human cDNA clone, we have isolated and characterized the human loricrin gene. We show that it has a very simple structure of a single intron of 1188 base pairs (bp) in the 5'-untranslated region; there are no introns in coding sequences. By use of rodent-human somatic cell hybrids, followed by in situ hybridization with a biotin-labeled genomic DNA clone, the single-copy gene maps to chromosome location 1q21. Polymerase chain reaction analyses of genomic DNAs from different individuals show that human loricrin consists of two allelic size variants, due to sequence variations in its second glycine loop domain, and these variants segregate in the human population by normal Mendelian mechanisms. Furthermore, there are multiple sequence variants within these two size class alleles due to various deletions of 12 bp (4 amino acids) in the major loop of this glycine loop domain. By use of a specific loricrin antibody, we show by immunogold electron microscopy that loricrin initially appears in the granular layer of human epidermis and forms composite keratohyalin granules with profilaggrin, but localizes to the cell periphery (cell envelope) of fully differentiated stratum corneum cells. PMID:1355480

Yoneda, K; Hohl, D; McBride, O W; Wang, M; Cehrs, K U; Idler, W W; Steinert, P M

1992-09-01

182

Endothelin-1 gene regulation  

PubMed Central

Over two decades of research have demonstrated that the peptide hormone endothelin-1 (ET-1) plays multiple, complex roles in cardiovascular, neural, pulmonary, reproductive, and renal physiology. Differential and tissue-specific production of ET-1 must be tightly regulated in order to preserve these biologically diverse actions. The primary mechanism thought to control ET-1 bioavailability is the rate of transcription from the ET-1 gene (edn1). Studies conducted on a variety of cell types have identified key transcription factors that govern edn1 expression. With few exceptions, the cis-acting elements bound by these factors have been mapped in the edn1 regulatory region. Recent evidence has revealed new roles for some factors originally believed to regulate edn1 in a tissue or hormone-specific manner. In addition, other mechanisms involved in epigenetic regulation and mRNA stability have emerged as important processes for regulated edn1 expression. The goal of this review is to provide a comprehensive overview of the specific factors and signaling systems that govern edn1 activity at the molecular level.—Stow, L. R., Jacobs, M. E., Wingo, C. S., Cain, B. D. Endothelin-1 gene regulation.

Stow, Lisa R.; Jacobs, Mollie E.; Wingo, Charles S.; Cain, Brian D.

2011-01-01

183

Introns in gene evolution.  

PubMed

Introns are integral elements of eukaryotic genomes that perform various important functions and actively participate in gene evolution. We review six distinct roles of spliceosomal introns: (1) sources of non-coding RNA; (2) carriers of transcription regulatory elements; (3) actors in alternative and trans-splicing; (4) enhancers of meiotic crossing over within coding sequences; (5) substrates for exon shuffling; and (6) signals for mRNA export from the nucleus and nonsense-mediated decay. We consider transposable capacities of introns and the current state of the long-lasting debate on the 'early-or-late' origin of introns. Cumulative data on known types of contemporary exon shuffling and the estimation of the size of the underlying exon universe are also discussed. We argue that the processes central to introns-early (exon shuffling) and introns-late (intron insertion) theories are entirely compatible. Each has provided insight: the latter through elucidating the transposon capabilities of introns, and the former through understanding the importance of introns in genomic recombination leading to gene rearrangements and evolution. PMID:12868603

Fedorova, Larisa; Fedorov, Alexei

2003-07-01

184

Gene therapy for psychiatric disorders.  

PubMed

Gene therapy has become of increasing interest in clinical neurosurgery with the completion of numerous clinical trials for Parkinson disease, Alzheimer disease, and pediatric genetic disorders. With improved understanding of the dysfunctional circuitry mediating various psychiatric disorders, deep brain stimulation for refractory psychiatric diseases is being increasingly explored in human patients. These factors are likely to facilitate development of gene therapy for psychiatric diseases. Because delivery of gene therapy agents would require the same surgical techniques currently being employed for deep brain stimulation, neurosurgeons are likely to lead the development of this field, as has occurred in other areas of clinical gene therapy for neurologic disorders. We review the current state of gene therapy for psychiatric disorders and focus specifically on particular areas of promising research that may translate into human trials for depression, drug addiction, obsessive-compulsive disorder, and schizophrenia. Issues that are relatively unique to psychiatric gene therapy are also discussed. PMID:23268195

Gelfand, Yaroslav; Kaplitt, Michael G

2013-01-01

185

Evolutionary biclustering of gene expressions  

Microsoft Academic Search

With the advent of microarray technology it has been possible to measure thousands of expression values of genes in a single experiment. Biclustering or simultaneous clustering of both genes and conditions is challenging particularly for the analysis of high-dimensional gene expression data in information retrieval, knowledge discovery, and data mining. The objective here is to find sub-matrices, i.e., maximal subgroups

Haider Banka; Sushmita Mitra

2006-01-01

186

Combinatorial Approaches to Gene Recognition  

Microsoft Academic Search

Recognition of genes via exon assembly approaches leads naturally to the use of dynamic programming. We consider the general graph-theoretical formulation of the exon assembly problem and analyze in detail some specific variants: multicriterial optimization in the case of non-linear gene-scoring functions; context-dependent schemes for scoring exons and related procedures for exon filtering; and highly specific recognition of arbitrary gene

Mikhail A. Roytberg; Tatiana V. Astakhova; Mikhail S. Gelfand

1997-01-01

187

AMIGene: Annotation of MIcrobial Genes  

Microsoft Academic Search

AMIGene (Annotation of MIcrobial Genes) is an application for automatically identifying the most likely coding sequences (CDSs) in a large contig or a complete bacterial genome sequence. The first step in AMIGene is dedicated to the construction of Markov models that fit the input genomic data (i.e. the gene model), followed by the combination of well-known gene-finding methods and an

Stéphanie Bocs; Stéphane Cruveiller; David Vallenet; Grégory Nuel; Claudine Médigue

2003-01-01

188

Understanding Cancer Series: Gene Testing  

Cancer.gov

Lydia Schindler Donna Kerrigan, M.S. Jeanne Kelly Brian Hollen Illustrates what genes are, explains how mutations occur and are identified within genes, and discusses the benefits and limitations of gene testing for cancer and other disorders. These PowerPoint slides are not locked files. You can mix and match slides from different tutorials as you prepare your own lectures. In the Notes section, you will find explanations of the graphics.

189

Gene Therapy for Chronic Pain  

Microsoft Academic Search

\\u000a Gene therapy shows great potential to assist numerous patients with inadequate relief of inflammatory or neuropathic pain,\\u000a or intractable pain associated with advanced cancer. A brief overview is provided of the methods of gene therapy and of preclinical\\u000a findings in animal models of prolonged inflammatory, neuropathic and cancer pain. Preclinical findings demonstrate no efficacy\\u000a of gene therapy on basal thermal

William R. Lariviere; Doris K. Cope

190

Gene and Genome Parameters of Mammalian Liver Circadian Genes (LCGs)  

PubMed Central

The mammalian circadian system controls various physiology processes and behavior responses by regulating thousands of circadian genes with rhythmic expressions. In this study, we redefined circadian-regulated genes based on published results in the mouse liver and compared them with other gene groups defined relative to circadian regulations, especially the non-circadian-regulated genes expressed in liver at multiple molecular levels from gene position to protein expression based on integrative analyses of different datasets from the literature. Based on the intra-tissue analysis, the liver circadian genes or LCGs show unique features when compared to other gene groups. First, LCGs in general have less neighboring genes and larger in both genomic and 3?-UTR lengths but shorter in CDS (coding sequence) lengths. Second, LCGs have higher mRNA and protein abundance, higher temporal expression variations, and shorter mRNA half-life. Third, more than 60% of LCGs form major co-expression clusters centered in four temporal windows: dawn, day, dusk, and night. In addition, larger and smaller LCGs are found mainly expressed in the day and night temporal windows, respectively, and we believe that LCGs are well-partitioned into the gene expression regulatory network that takes advantage of gene size, expression constraint, and chromosomal architecture. Based on inter-tissue analysis, more than half of LCGs are ubiquitously expressed in multiple tissues but only show rhythmical expression in one or limited number of tissues. LCGs show at least three-fold lower expression variations across the temporal windows than those among different tissues, and this observation suggests that temporal expression variations regulated by the circadian system is relatively subtle as compared with the tissue expression variations formed during development. Taken together, we suggest that the circadian system selects gene parameters in a cost effective way to improve tissue-specific functions by adapting temporal variations from the environment over evolutionary time scales.

Wu, Gang; Zhu, Jiang; He, Fuhong; Wang, Weiwei; Hu, Songnian; Yu, Jun

2012-01-01

191

GENE THERAPY FOR LUNG NEOPLASMS  

PubMed Central

SYNOPSIS Both advanced stage lung cancer and malignant pleural mesothelioma are associated with a poor prognosis. Although there have been advances in treatment regimens for both diseases, these have had only a modest effect on their progressive course. Gene therapy for thoracic malignancies represents a novel therapeutic approach and has been evaluated in a number of clinical trials over the last two decades. Strategies have included induction of apoptosis, tumor suppressor gene replacement, suicide gene expression, cytokine based therapy, various vaccination approaches, and adoptive transfer of modified immune cells. This review will consider the clinical results, limitations, and future directions of gene therapy trials for thoracic malignancies.

Vachani, Anil; Moon, Edmund; Wakeam, Elliot; Haas, Andrew R.; Sterman, Daniel H.; Albelda, Steven M.

2011-01-01

192

Importance of Combinatorial Gene Control  

NSDL National Science Digital Library

A hypothetical scheme illustrating how combinations of a few gene regulatory proteins can generate many different cell types during development. In this simple scheme a "decision" to make a new gene regulatory protein (shown as a numbered circle) is made after each cell division. Repetition of this simple rule enables eight cell types (A through H) to be created using only three different regulatory proteins. Each of these hypothetical cell types would then express different genes, as dictated by the combination of gene regulatory proteins that are present within it.

BEGIN:VCARD VERSION:2.1 FN:Bruce Alberts N:Alberts;Bruce REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Dennis Bray N:Bray;Dennis REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Alexander Johnson N:Johnson;Alexander REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Julian Lewis N:Lewis;Julian REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Martin Raff N:Raff;Martin REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Keith Roberts N:Roberts;Keith REV:2005-04-16 END:VCARD

1998-07-01

193

Genes don't count.  

PubMed

It is the regulation of gene expression that determines phenotype and cellular response. Several families of proteins control gene expression in cells and influence the pathogenesis of multiple organ failure, the acute phase response, atherosclerosis, and graft-vs-host disease. Understanding the basics of the regulation of gene transcription will allow the knowledgeable surgeon to target gene expression as a therapeutic modality in multiple diseases. We examine nuclear factor kappa B as an example of a transcription factor that is involved in multiple surgical diseases and has pharmacological inhibitors available to knowledgeable surgeons. PMID:9637469

Shames, B D; Selzman, C H; Meng, X; Meldrum, D R; Cain, B S; Harken, A H

1998-06-01

194

Selector Genes, Polymorphisms, and Evolution  

NSDL National Science Digital Library

Access to the article is free, however registration and sign-in are required. Evolution has been thought to act on small changes in the characteristics of organisms coded by genes called realizator genes. D. Tautz explains how a new result in this issue of Science by Gibson and Hogness (p. 200) shows that this may not always be true. A small phenotypic variation in Drosophila (sensitivity to ether), apparent only under environmental stress, turns out to be coded by a polymorphism in a selector gene, Ultrabithorax, a member of a class of genes that specifies whole body parts and anatomical regions.

Diethard Tautz (Zoologisches Institut der Universität München;)

1996-01-12

195

Fuzzy measures on the Gene Ontology for gene product similarity.  

PubMed

One of the most important objects in bioinformatics is a gene product (protein or RNA). For many gene products, functional information is summarized in a set of Gene Ontology (GO) annotations. For these genes, it is reasonable to include similarity measures based on the terms found in the GO or other taxonomy. In this paper, we introduce several novel measures for computing the similarity of two gene products annotated with GO terms. The fuzzy measure similarity (FMS) has the advantage that it takes into consideration the context of both complete sets of annotation terms when computing the similarity between two gene products. When the two gene products are not annotated by common taxonomy terms, we propose a method that avoids a zero similarity result. To account for the variations in the annotation reliability, we propose a similarity measure based on the Choquet integral. These similarity measures provide extra tools for the biologist in search of functional information for gene products. The initial testing on a group of 194 sequences representing three proteins families shows a higher correlation of the FMS and Choquet similarities to the BLAST sequence similarities than the traditional similarity measures such as pairwise average or pairwise maximum. PMID:17048464

Popescu, Mihail; Keller, James M; Mitchell, Joyce A

2006-01-01

196

Gene structure conservation aids similarity based gene prediction  

Microsoft Academic Search

One of the primary tasks in deciphering the func- tional contents of a newly sequenced genome is the identification of its protein coding genes. Existing computational methods for gene prediction include ab initio methods which use the DNA sequence itself as the only source of information, comparative methods using multiple genomic sequences, and similarity based methods which employ the cDNA

Irmtraud M. Meyer; Richard Durbin

2004-01-01

197

Targeted gene alteration in Caenorhabditis elegans by gene conversion  

Microsoft Academic Search

Now that some genomes have been completely sequenced, the ability to direct specific mutations into genomes is particularly desirable. Here we present a method to create mutations in the Caenorhabditis elegans genome efficiently through transgene-directed, transposon-mediated gene conversion. Engineered deletions targeted into two genes show that the frequency of obtaining the desired mutation was higher using this approach than using

Peter L Barrett; John T Fleming; Verena Göbel

2004-01-01

198

Antigen receptor gene rearrangement.  

PubMed

Two specialized forms of site-directed double-strand (ds) DNA breakage and rejoining are part of the physiologic program of lymphocytes. One is recombination of the V, D and J gene sequences, termed V(D)J recombination, occurring during early B- and T-cell development, and the other is class-switch recombination occurring exclusively in mature B cells. For V(D)J recombination significant progress has been made recently elucidating the biochemistry of the reaction. In particular our understanding of how DNA ds breaks are both generated and rejoined has increased. For class-switch recombination no definitive information is known about the nucleases required for making the ds breaks, but recent evidence suggests that the joining phase shares activities also required for V(D)J recombination and general DNA ds break repair. PMID:9602306

Grawunder, U; West, R B; Lieber, M R

1998-04-01

199

Cardiac Gene Therapy  

PubMed Central

Heart failure is a chronic progressive disorder where frequent and recurrent hospitalizations are associated with high mortality and morbidity. The incidence and the prevalence of this disease will increase with the increase in the number of the aging population of the United States. Understanding the molecular pathology and pathophysiology of this disease will uncover novel targets and therapies that can restore the function or attenuate the damage of malfunctioning cardiomyocytes by gene therapy that becomes an interesting and a promising field for the treatment of heart failure as well as other diseases in the future. Of equal importance is developing vectors and delivery methods that can efficiently transduce the majority of the cardiomyocytes, that can offer a long term expression and that can escape the host immune response. Recombinant adeno-associated virus vectors have the potential to become a promising novel therapeutic vehicles for molecular medicine in the future.

Chaanine, Antoine H.; Kalman, Jill; Hajjar, Roger J.

2010-01-01

200

Gene therapy for Deafness  

PubMed Central

Hearing loss is the most common sensory deficit in humans and can result from genetic, environmental, or combined etiologies that prevent normal function of the cochlea, the peripheral sensory organ. Recent advances in understanding the genetic pathways that are critical for the development and maintenance of cochlear function, as well as the molecular mechanisms that underlie cell trauma and death have provided exciting opportunities for modulating these pathways to correct genetic mutations, to enhance endogenous protective pathways for hearing preservation and to regenerate lost sensory cells with the possibility of ameliorating hearing loss. A number of recent animal studies have used gene-based therapies in innovative ways toward realizing these goals. With further refinement, some of the protective and regenerative approaches reviewed here may become clinically applicable.

Kohrman, David C.; Raphael, Yehoash

2014-01-01

201

See the Genes  

NSDL National Science Digital Library

Through this concluding lesson and its associated activity, students experience one valuable and often overlooked skill of successful scientists and engineersâcommunicating your work and ideas. They explore the importance of scientific communication, including the basic, essential elements of communicating new information to the public and pitfalls to avoid. In the associated activity, student groups create posters depicting their solutions to the unit's challenge questionâaccurate, efficient methods for detecting cancer-causing genes using optical biosensorsâwhich includes providing a specific example with relevant equations. Students are also individually assessed on their understanding of refraction via a short quiz. This lesson and its associated activity conclude the unit and serve as the culminating Go Public phase of the Legacy Cycle, providing unit review and summative assessment.

Vu Bioengineering Ret Program

202

Information-theoretic gene-gene and gene-environment interaction analysis of quantitative traits  

Microsoft Academic Search

BACKGROUND: The purpose of this research was to develop a novel information theoretic method and an efficient algorithm for analyzing the gene-gene (GGI) and gene-environmental interactions (GEI) associated with quantitative traits (QT). The method is built on two information-theoretic metrics, the k-way interaction information (KWII) and phenotype-associated information (PAI). The PAI is a novel information theoretic metric that is obtained

Pritam Chanda; Lara Sucheston; Song Liu; Aidong Zhang; Murali Ramanathan

2009-01-01

203

Uncovering trends in gene naming  

PubMed Central

We take stock of current genetic nomenclature and attempt to organize strange and notable gene names. We categorize, for instance, those that involve a naming system transferred from another context (for example, Pavlov’s dogs). We hope this analysis provides clues to better steer gene naming in the future.

Seringhaus, Michael R; Cayting, Philip D; Gerstein, Mark B

2008-01-01

204

The Meaning of Gene Positioning  

PubMed Central

There is no doubt that genomes are organized nonrandomly in the nucleus of higher eukaryotes. But what is the functional relevance of this nonrandomness? In this Essay, we explore the biological meaning of spatial gene positioning by examining the functional link between the activity of a gene and its radial position in the nucleus.

Takizawa, Takumi; Meaburn, Karen J.; Misteli, Tom

2012-01-01

205

HOX genes in ovarian cancer  

PubMed Central

The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development. Here we review a number of recent studies showing that HOX genes are strongly expressed in ovarian cancer, and that in some cases the expression of specific HOX genes is sufficient to confer a particular identity and phenotype upon cancer cells. We also review the recent advances in elucidating the different functions of HOX genes in ovarian cancer. A literature search was performed using the search terms HOX genes (including specific HOX genes), ovarian cancer and oncogenesis. Articles were accessed through searches performed in ISI Web of Knowledge, PubMed and ScienceDirect. Taken together, these studies have shown that HOX genes play a role in the oncogenesis of ovarian cancer and function in the inhibition of apoptosis, DNA repair and enhanced cell motility. The function of HOX genes in ovarian cancer oncogenesis supports their potential role as prognostic and diagnostic markers, and as therapeutic targets in this disease.

2011-01-01

206

Gene therapy on the move  

PubMed Central

The first gene therapy clinical trials were initiated more than two decades ago. In the early days, gene therapy shared the fate of many experimental medicine approaches and was impeded by the occurrence of severe side effects in a few treated patients. The understanding of the molecular and cellular mechanisms leading to treatment- and/or vector-associated setbacks has resulted in the development of highly sophisticated gene transfer tools with improved safety and therapeutic efficacy. Employing these advanced tools, a series of Phase I/II trials were started in the past few years with excellent clinical results and no side effects reported so far. Moreover, highly efficient gene targeting strategies and site-directed gene editing technologies have been developed and applied clinically. With more than 1900 clinical trials to date, gene therapy has moved from a vision to clinical reality. This review focuses on the application of gene therapy for the correction of inherited diseases, the limitations and drawbacks encountered in some of the early clinical trials and the revival of gene therapy as a powerful treatment option for the correction of monogenic disorders.

Kaufmann, Kerstin B; Buning, Hildegard; Galy, Anne; Schambach, Axel; Grez, Manuel

2013-01-01

207

for Hemophilia B Gene Therapy  

Microsoft Academic Search

Adeno-associated viral (AAV) vector is attracting significant interest for use in gene therapy for genetic diseases, because of its unique and advantageous characteristics, compared to other currently available viral vectors. Eight natural serotypes of AAV have been identified, of which AAV serotype 2 is the one best characterized and most widely used in current gene delivery studies. The application of

HENGJUN CHAO; CHRISTOPHER E. WALSH

208

Gene Therapy for Liver Disease  

Microsoft Academic Search

With major advances in biomedical science over the last 2 decades, the possibility of treating human disease at a genetic level has become a tantalizing possibility. As a result, a growing number of investigators are focusing on the development of techniques to deliver therapeutic genes into cells. The liver has been a model organ in the development of this gene

Timothy J. Davern II; Bruce F. Scharschmidt

1998-01-01

209

Gene targeting in Physcomitrella patens  

Microsoft Academic Search

Gene-targeting efficiency in the land plant Physcomitrella patens (Bryophyta) can only be compared with that observed in Saccharomyces cerevisiae. Sequencing programs and microbiological molecular genetic approaches are now being developed to unravel the precise function of plant genes. Physcomitrella patens, as the new ‘green yeast’, might well become a major tool for functional genomic studies of multicellular eukaryotes.

Didier G Schaefer

2001-01-01

210

Multifunctional nanorods for gene delivery  

NASA Astrophysics Data System (ADS)

The goal of gene therapy is to introduce foreign genes into somatic cells to supplement defective genes or provide additional biological functions, and can be achieved using either viral or synthetic non-viral delivery systems. Compared with viral vectors, synthetic gene-delivery systems, such as liposomes and polymers, offer several advantages including ease of production and reduced risk of cytotoxicity and immunogenicity, but their use has been limited by the relatively low transfection efficiency. This problem mainly stems from the difficulty in controlling their properties at the nanoscale. Synthetic inorganic gene carriers have received limited attention in the gene-therapy community, the only notable example being gold nanoparticles with surface-immobilized DNA applied to intradermal genetic immunization by particle bombardment. Here we present a non-viral gene-delivery system based on multisegment bimetallic nanorods that can simultaneously bind compacted DNA plasmids and targeting ligands in a spatially defined manner. This approach allows precise control of composition, size and multifunctionality of the gene-delivery system. Transfection experiments performed in vitro and in vivo provide promising results that suggest potential in genetic vaccination applications.

Salem, Aliasger K.; Searson, Peter C.; Leong, Kam W.

2003-10-01

211

Aerosol Gene Delivery in vivo  

Microsoft Academic Search

The ability to express transgenes selectively within the lung will greatly facilitate the development of gene therapy for a variety of human diseases. We have demonstrated that aerosol administration of a chloramphenicol acetyltransferase (CAT) expression plasmid complexed to cationic liposomes produces high-level, lung-specific CAT gene expression in mice in vivo. Significant levels of CAT activity are seen in the lungs

Roscoe Stribling; Elisa Brunette; Denny Liggitt; Karin Gaensler; Robert Debs

1992-01-01

212

LKB1 gene knockout mice  

US Patent & Trademark Office Database

A mammal is provided, in which the LKB1 gene can be deleted phase-specifically and tissue-specifically. These mammals are highly useful as tools to reveal the onset mechanism for diseases caused by LKB1 gene deficiency, such as Peutz-Jeghers syndrome and cancers, as well as to develop therapeutic agents, methods, and so on for the diseases.

2004-09-14

213

On meme--gene coevolution.  

PubMed

In this article we examine the effects of the emergence of a new replicator, memes, on the evolution of a pre-existing replicator, genes. Using a version of the NKCS model we examine the effects of increasing the rate of meme evolution in relation to the rate of gene evolution, for various degrees of interdependence between the two replicators. That is, the effects of memes' (suggested) more rapid rate of evolution in comparison to that of genes is investigated using a tunable model of coevolution. It is found that, for almost any degree of interdependence between the two replicators, as the rate of meme evolution increases, a phase transition-like dynamic occurs under which memes have a significantly detrimental effect on the evolution of genes, quickly resulting in the cessation of effective gene evolution. Conversely, the memes experience a sharp increase in benefit from increasing their rate of evolution. We then examine the effects of enabling genes to reduce the percentage of gene-detrimental evolutionary steps taken by memes. Here a critical region emerges as the comparative rate of meme evolution increases, such that if genes cannot effectively select memes a high percentage of the time, they suffer from meme evolution as if they had almost no selective capability. PMID:11224917

Bull, L; Holland, O; Blackmore, S

2000-01-01

214

Expression divergence between duplicate genes  

Microsoft Academic Search

A general picture of the role of expression divergence in the evolution of duplicate genes is emerging, thanks to the availability of completely sequenced genomes and functional genomic data, such as microarray data. It is now clear that expression divergence, regulatory-motif divergence and coding-sequence divergence all increase with the age of duplicate genes, although their exact interrelationships remain to be

Wen-Hsiung Li; Jing Yang; Xun Gu

2005-01-01

215

Molecular Clock and Gene Function  

Microsoft Academic Search

Molecular phylogenies based on the molecular clock require the comparison of orthologous genes. Orthologous and paralogous genes usually have very different evolutionary fates. In general, orthologs keep the same functions in species, whereas, particularly over a long time span, paralogs diverge functionally and may become pseudogenes or get lost. In eukaryotic genomes, because of the degree of redundancy of genetic

Cecilia Saccone; Corrado Caggese; Anna Maria D’Erchia; Cecilia Lanave; Marta Oliva; Graziano Pesole

2003-01-01

216

Control of expression of silk protein genes  

Microsoft Academic Search

At least three silk genes are specifically expressed in the posterior, and five other genes in middle, silk glands. The products of genes active in PSG include fibroin, L-chain fibroin and P25 protein. PSG genes as well as the Ser-1 gene, differing in structure, exhibit a striking degree of homology of their 5? flanking sequences. This suggests the presence of

Krystyna Grzelak

1995-01-01

217

PAGE: Parametric Analysis of Gene Set Enrichment  

Microsoft Academic Search

Background: Gene set enrichment analysis (GSEA) is a microarray data analysis method that uses predefined gene sets and ranks of genes to identify significant biological changes in microarray data sets. GSEA is especially useful when gene expression changes in a given microarray data set is minimal or moderate. Results: We developed a modified gene set enrichment analysis method based on

Seon-young Kim; David J. Volsky

2005-01-01

218

Discovering Connected Patterns in Gene Expression Arrays  

Microsoft Academic Search

Clustering methods have been extensively used for gene expression data analysis to detect groups of related genes. The clusters provide useful information to analyze gene function, gene regulation and cellular patterns. Most existing clustering algorithms, though, discover only coherent gene expression patterns, and do not handle connected patterns. Coherent and connected patterns correspond to globular and arbitrary shaped clusters, respectively,

Noha A. Yousri; Mohamed A. Ismail; Mohamed S. Kamel

2007-01-01

219

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

220

New colon cancer gene discovered  

SciTech Connect

A new gene has been discovered, by genetic linkage studies, that predisposes to colon cancer. The gene was discovered by linkage to a microsatellite marker on human chromosome 2. The microsatellite DNA shows a high degree of variation in colon cancers, varying in length from tumor to tumor. The gene may act by destabilizing the genome. Different groups looking at different satellite markers saw thousands of microsatellite instabilities throughout the genome, raising the possibility that the DNA as a whole is not being copied correctly, apparently due to a gene mutation that causes wholesale errors during DNA replication. Researchers hope to use the gene as a screening tool for screening individuals susceptible to colon cancer.

Marx, J.

1993-05-07

221

Systems Biophysics of Gene Expression  

PubMed Central

Gene expression is a process central to any form of life. It involves multiple temporal and functional scales that extend from specific protein-DNA interactions to the coordinated regulation of multiple genes in response to intracellular and extracellular changes. This diversity in scales poses fundamental challenges to the use of traditional approaches to fully understand even the simplest gene expression systems. Recent advances in computational systems biophysics have provided promising avenues to reliably integrate the molecular detail of biophysical process into the system behavior. Here, we review recent advances in the description of gene regulation as a system of biophysical processes that extend from specific protein-DNA interactions to the combinatorial assembly of nucleoprotein complexes. There is now basic mechanistic understanding on how promoters controlled by multiple, local and distal, DNA binding sites for transcription factors can actively control transcriptional noise, cell-to-cell variability, and other properties of gene regulation, including precision and flexibility of the transcriptional responses.

Vilar, Jose M.G.; Saiz, Leonor

2013-01-01

222

Nuclear Neighborhoods and Gene Expression  

PubMed Central

Summary The eukaryotic nucleus is a highly compartmentalized and dynamic environment. Chromosome territories are arranged non-randomly within the nucleus and numerous studies have indicated that a gene’s position in the nucleus can impact its transcriptional activity. Here, we focus on recent advances in our understanding of the influence of specific nuclear neighborhoods on gene expression or repression. Nuclear neighborhoods associated with transcriptional repression include the inner nuclear membrane/nuclear lamina and peri-nucleolar chromatin, whereas neighborhoods surrounding the nuclear pore complex, PML nuclear bodies, and nuclear speckles seem to be transcriptionally permissive. While nuclear position appears to play an important role in gene expression, it is likely to be only one piece of a flexible puzzle that incorporates numerous parameters. We are still at a very early, yet exciting stage in our journey toward deciphering the mechanism(s) that govern the permissiveness of gene expression/repression within different nuclear neighborhoods.

Zhao, Rui; Bodnar, Megan S.; Spector, David L.

2009-01-01

223

Fast parsers for Entrez Gene.  

PubMed

NCBI completed the transition of its main genome annotation database from Locuslink to Entrez Gene in Spring 2005. However, to this date few parsers exist for the Entrez Gene annotation file. Owing to the widespread use of Locuslink and the popularity of Perl programming language in bioinformatics, a publicly available high performance Entrez Gene parser in Perl is urgently needed. We present four such parsers that were developed using several parsing approaches (Parse::RecDescent, Parse::Yapp, Perl-byacc and Perl 5 regular expressions) and provide the first in-depth comparison of these sophisticated Perl tools. Our fastest parser processes the entire human Entrez Gene annotation file in under 12 min on one Intel Xeon 2.4 GHz CPU and can be of help to the bioinformatics community during and after the transition from Locuslink to Entrez Gene. PMID:15879451

Liu, Mingyi; Grigoriev, Andrei

2005-07-15

224

Delivery systems for gene therapy  

PubMed Central

The structure of DNA was unraveled by Watson and Crick in 1953, and two decades later Arber, Nathans and Smith discovered DNA restriction enzymes, which led to the rapid growth in the field of recombinant DNA technology. From expressing cloned genes in bacteria to expressing foreign DNA in transgenic animals, DNA is now slated to be used as a therapeutic agent to replace defective genes in patients suffering from genetic disorders or to kill tumor cells in cancer patients. Gene therapy provides modern medicine with new perspectives that were unthinkable two decades ago. Progress in molecular biology and especially, molecular medicine is now changing the basics of clinical medicine. A variety of viral and non-viral possibilities are available for basic and clinical research. This review summarizes the delivery routes and methods for gene transfer used in gene therapy.

Mali, Shrikant

2013-01-01

225

Gene therapy in cystic fibrosis.  

PubMed

The principal cause of morbidity and mortality in cystic fibrosis (CF) is pulmonary disease, so the focus of new treatments in this condition is primarily targeted at the lungs. Since the cloning of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene in 1989, there has been significant interest in the possibility of gene therapy as a treatment for CF. Early studies using viral vectors carrying a healthy CFTR plasmid highlighted the difficulties with overcoming the body's host defences. This article reviews the work on gene therapy in CF to date and describes the ongoing work of the UK CF Gene Therapy Consortium in investigating the potential of gene therapy as a treatment for patients with CF. PMID:24464978

Armstrong, David K; Cunningham, Steve; Davies, Jane C; Alton, Eric W F W

2014-05-01

226

Phylogenetic analysis of gene expression.  

PubMed

Phylogenetic analyses of gene expression have great potential for addressing a wide range of questions. These analyses will, for example, identify genes that have evolutionary shifts in expression that are correlated with evolutionary changes in morphological, physiological, and developmental characters of interest. This will provide entirely new opportunities to identify genes related to particular phenotypes. There are, however, 3 key challenges that must be addressed for such studies to realize their potential. First, data on gene expression must be measured from multiple species, some of which may be field-collected, and parameterized in such a way that they can be compared across species. Second, it will be necessary to develop comparative phylogenetic methods suitable for large multidimensional datasets. In most phylogenetic comparative studies to date, the number n of independent observations (independent contrasts) has been greater than the number p of variables (characters). The behavior of comparative methods for these classic problems is now well understood under a wide variety of conditions. In studies of gene expression, and in studies based on other high-throughput tools, the number n of samples is dwarfed by the number p of variables. The estimated covariance matrices will be singular, complicating their analysis and interpretation, and prone to spurious results. Third, new approaches are needed to investigate the expression of the many genes whose phylogenies are not congruent with species phylogenies due to gene loss, gene duplication, and incomplete lineage sorting. Here we outline general considerations of project design for phylogenetic analyses of gene expression and suggest solutions to these three categories of challenges. These topics are relevant to high-throughput phenotypic data well beyond gene expression. PMID:23748631

Dunn, Casey W; Luo, Xi; Wu, Zhijin

2013-11-01

227

Quantitative set analysis for gene expression: a method to quantify gene set differential expression including gene-gene correlations  

PubMed Central

Enrichment analysis of gene sets is a popular approach that provides a functional interpretation of genome-wide expression data. Existing tests are affected by inter-gene correlations, resulting in a high Type I error. The most widely used test, Gene Set Enrichment Analysis, relies on computationally intensive permutations of sample labels to generate a null distribution that preserves gene–gene correlations. A more recent approach, CAMERA, attempts to correct for these correlations by estimating a variance inflation factor directly from the data. Although these methods generate P-values for detecting gene set activity, they are unable to produce confidence intervals or allow for post hoc comparisons. We have developed a new computational framework for Quantitative Set Analysis of Gene Expression (QuSAGE). QuSAGE accounts for inter-gene correlations, improves the estimation of the variance inflation factor and, rather than evaluating the deviation from a null hypothesis with a P-value, it quantifies gene-set activity with a complete probability density function. From this probability density function, P-values and confidence intervals can be extracted and post hoc analysis can be carried out while maintaining statistical traceability. Compared with Gene Set Enrichment Analysis and CAMERA, QuSAGE exhibits better sensitivity and specificity on real data profiling the response to interferon therapy (in chronic Hepatitis C virus patients) and Influenza A virus infection. QuSAGE is available as an R package, which includes the core functions for the method as well as functions to plot and visualize the results.

Yaari, Gur; Bolen, Christopher R.; Thakar, Juilee; Kleinstein, Steven H.

2013-01-01

228

Reference Gene Screening for Analyzing Gene Expression Across Goat Tissue  

PubMed Central

Real-time quantitative PCR (qRT-PCR) is one of the important methods for investigating the changes in mRNA expression levels in cells and tissues. Selection of the proper reference genes is very important when calibrating the results of real-time quantitative PCR. Studies on the selection of reference genes in goat tissues are limited, despite the economic importance of their meat and dairy products. We used real-time quantitative PCR to detect the expression levels of eight reference gene candidates (18S, TBP, HMBS, YWHAZ, ACTB, HPRT1, GAPDH and EEF1A2) in ten tissues types sourced from Boer goats. The optimal reference gene combination was selected according to the results determined by geNorm, NormFinder and Bestkeeper software packages. The analyses showed that tissue is an important variability factor in genes expression stability. When all tissues were considered, 18S, TBP and HMBS is the optimal reference combination for calibrating quantitative PCR analysis of gene expression from goat tissues. Dividing data set by tissues, ACTB was the most stable in stomach, small intestine and ovary, 18S in heart and spleen, HMBS in uterus and lung, TBP in liver, HPRT1 in kidney and GAPDH in muscle. Overall, this study provided valuable information about the goat reference genes that can be used in order to perform a proper normalisation when relative quantification by qRT-PCR studies is undertaken.

Zhang, Yu; Zhang, Xiao-Dong; Liu, Xing; Li, Yun-Sheng; Ding, Jian-Ping; Zhang, Xiao-Rong; Zhang, Yun-Hai

2013-01-01

229

Imprinted genes and regulation of gene expression by epigenetic inheritance.  

PubMed

Six new imprinted genes have recently been identified by association with established imprinted regions, in systematic screens or by serendipity. This brings the total to seventeen imprinted genes, which display a wide variety of functions. Some imprinted genes have been shown to be both physically and mechanistically linked within domains that are under the control of an imprinting centre. Others may apparently undergo imprinting independently. Methylation is clearly required for maintenance of mono-allelic expression while chromatin structure and non-coding RNAs may also play a role. PMID:8743885

John, R M; Surani, M A

1996-06-01

230

GenePRIMP: A GENE PRediction IMprovement Pipeline for Prokaryotic genomes  

SciTech Connect

We present 'gene prediction improvement pipeline' (GenePRIMP; http://geneprimp.jgi-psf.org/), a computational process that performs evidence-based evaluation of gene models in prokaryotic genomes and reports anomalies including inconsistent start sites, missed genes and split genes. We found that manual curation of gene models using the anomaly reports generated by GenePRIMP improved their quality, and demonstrate the applicability of GenePRIMP in improving finishing quality and comparing different genome-sequencing and annotation technologies.

Pati, Amrita; Ivanova, Natalia N.; Mikhailova, Natalia; Ovchinnikova, Galina; Hooper, Sean D.; Lykidis, Athanasios; Kyrpides, Nikos C.

2010-04-01

231

Genes, Economics, and Happiness *  

PubMed Central

We explore the influence of genetic variation on subjective well-being by employing a twin design and genetic association study. In a nationally-representative twin sample, we first show that about 33% of the variation in life satisfaction is explained by genetic variation. Although previous studies have shown that baseline happiness is significantly heritable, little research has considered molecular genetic associations with subjective well-being. We study the relationship between a functional polymorphism on the serotonin transporter gene (5-HTTLPR) and life satisfaction. We initially find that individuals with the longer, transcriptionally more efficient variant of this genotype report greater life satisfaction (n=2,545, p=0.012). However, our replication attempts on independent samples produce mixed results indicating that more work needs to be done to better understand the relationship between this genotype and subjective well-being. This work has implications for how economists think about the determinants of utility, and the extent to which exogenous shocks might affect individual well-being.

De Neve, Jan-Emmanuel; Christakis, Nicholas A.; Fowler, James H.; Frey, Bruno S.

2012-01-01

232

Genes to Cognition Online  

NSDL National Science Digital Library

The Dolan DNA Learning Center at Cold Spring Harbor, NY has created this fantastic website to explore neuroscience, and it is focused on cognitive disorders, cognitive processes, and research approaches. There are many activities on the site, and each is broken down into six categories of analysis, "Genes", "Biochemicals", "Cells", "Brain Anatomy", "Cognition", and "Environment". Thus, clicking on "Bipolar Disorder" under the "Disorders" tab at the top of the page, will take the visitor to a "subway line" at the top of the page. There are several "stops" on the line, and each allows the visitor to learn about the key areas of bipolar disorder research. Scrolling over the stops opens up a small window with a blurb about the content to view. The blurb also shows whether the content is a video, an application, animation, etc. Visitors wishing to see all the research available, should click on the network map, which is the screen behind the smaller "subway line" page. The "Teacher Feature", under the "Targeted Content" tab, and next to the small model of the brain, offers lessons on such topics as autism, memory, and ethical decision-making. "Teacher Pages," "Student Worksheets", and "Test Items" are offered in PDF form.

233

Environment, genes, and cancer  

SciTech Connect

In January, comedian George Burns turned 100 years old. In recent appearances in the media, he still seems sharp as a tack, and is still seen smoking his trademark cigars. Others of us, however, were never very funny, and would die of cancer at age 60 if we continuously smoked cigars or cigarettes. Burns presents a common but perplexing paradox; some people are able to tolerate at least moderate exposure to toxins such as cigarette smoke with little adverse affect, while others develop cancer, emphysema, or heart disease. New studies support the idea that there is an interaction between genes and the environment, and that this interaction may be an important determinant of cancer risk. To understand such risks, it is essential to look at both an individual`s genetic makeup and environmental exposures. Such studies require the collaboration of molecular epidemiologists and molecular biologists. At the NIEHS, Jack A. Taylor, a lead clinical investigator in the Epidemiology Branch, and Douglas A. Bell, an investigator with the Genetic Risk Group of the Laboratory of Biochemical Risk Analysis, have worked together and with other scientists to uncover new information in this area.

Manuel, J.

1996-03-01

234

Longevity Gene May Boost Brain Power  

MedlinePLUS

... Friday, May 9, 2014 Longevity gene may boost brain power NIH-funded researchers discover the gene may ... of a longevity gene, called KLOTHO, have improved brain skills such as thinking, learning and memory regardless ...

235

Your Genes May Help Pick Your Friends  

MedlinePLUS

... features on this page, please enable JavaScript. Your Genes May Help Pick Your Friends Study says DNA ... Preidt Monday, July 14, 2014 Related MedlinePlus Page Genes and Gene Therapy MONDAY, July 14, 2014 (HealthDay ...

236

New Gene 'Atlas' Maps Human DNA Activity  

MedlinePLUS

... please enable JavaScript. New Gene 'Atlas' Maps Human DNA Activity Knowing the 'on/off' switches for genes ... The map includes switches -- which are regions of DNA that manage gene activity -- across a wide range ...

237

IGF-Regulated Genes in Prostate Cancer.  

National Technical Information Service (NTIS)

We hypothesized that genes that are differentially expressed as a result of the decreased IGF-I receptor gene expression seen in metastatic prostate cancer contribute to prostate cancer progression, and include metastasis-regulating genes that could const...

C. T. Roberts

2005-01-01

238

Gene function prediction with gene interaction networks: a context graph kernel approach  

Microsoft Academic Search

Predicting gene functions is a challenge for biologists in the postgenomic era. Interactions among genes and their products compose networks that can be used to infer gene functions. Most previous studies adopt a linkage assumption, i.e., they assume that gene interactions indicate functional similarities between connected genes. In this study, we propose to use a gene's context graph, i.e., the

Xin Li; Hsinchun Chen; Jiexun Li; Zhu Zhang

2010-01-01

239

Selection of housekeeping genes for gene expression studies in human reticulocytes using real-time PCR  

Microsoft Academic Search

BACKGROUND: Control genes, which are often referred to as housekeeping genes, are frequently used to normalise mRNA levels between different samples. However, the expression level of these genes may vary among tissues or cells and may change under certain circumstances. Thus, the selection of housekeeping genes is critical for gene expression studies. To address this issue, 7 candidate housekeeping genes

Nicholas Silver; Steve Best; Jie Jiang; Swee Lay Thein

2006-01-01

240

A WIDE TOMATO DISEASE GENES SCANNING FOR R GENE MARKERS DEVELOPMENT  

Microsoft Academic Search

in silico analysis resistance gene, tomato genome, SNPs, multiplex Plant disease resistance genes (R-Genes) are an important class of genes from which a subset are well characterized at the molecular level. These genes play a key role in the recognition of the products of avirulence (Avr) genes from pathogens and in the activation of plant defence responses. In the Solanaceae

241

Mining gene-chip data  

NASA Astrophysics Data System (ADS)

DNA microarray (``gene chip'') technology has enabled a rapid accumulation of gene-expression data for model organisms such as S. cerevisiae and C. elegans, as well as for H. sapiens, raising the issue of how best to extract information about the gene regulatory networks of these organisms from this data. While basic clustering algorithms have been successful at finding genes that are coregulated for a small, specific set of experimental conditions, these algorithms are less effective when applied to large, varied data sets. One of the major challenges in analyzing the data is the diversity in both size and signal strength of the various transcriptional modules, i.e. sets of coregulated genes along with the sets of conditions for which the genes are strongly coregulated. One method that has proven successful at identifying large and/or strong modules is the Iterative Signature Algorithm (ISA) [1]. A modified version of the ISA algorithm, the Progressive Iterative Signature Algorithm (PISA), is also able to identify smaller, weaker modules by sequentially eliminating transcriptional modules as they are identified. Applying these algorithms to a large set of yeast gene expression data illustrates the strengths and weaknesses of each approach. [1] Bergmann, S., Ihmels, J., and Barkai, N., Phys. Rev. E 67, 031902 (2002).

Kloster, Morten

2005-03-01

242

GENES IN SPORT AND DOPING  

PubMed Central

Genes control biological processes such as muscle production of energy, mitochondria biogenesis, bone formation, erythropoiesis, angiogenesis, vasodilation, neurogenesis, etc. DNA profiling for athletes reveals genetic variations that may be associated with endurance ability, muscle performance and power exercise, tendon susceptibility to injuries and psychological aptitude. Already, over 200 genes relating to physical performance have been identified by several research groups. Athletes’ genotyping is developing as a tool for the formulation of personalized training and nutritional programmes to optimize sport training as well as for the prediction of exercise-related injuries. On the other hand, development of molecular technology and gene therapy creates a risk of non-therapeutic use of cells, genes and genetic elements to improve athletic performance. Therefore, the World Anti-Doping Agency decided to include prohibition of gene doping within their World Anti-Doping Code in 2003. In this review article, we will provide a current overview of genes for use in athletes’ genotyping and gene doping possibilities, including their development and detection techniques.

Kaliszewski, P.; Majorczyk, E.; Zembron-Lacny, A.

2013-01-01

243

The Gene Resource Locator: gene locus maps for transcriptome analysis  

PubMed Central

Since the advent of the draft human genome sequence there has been growing interest in transcriptome analysis based on genomic data. The Gene Resource Locator (GRL) assembles gene maps that include information on gene-expression patterns, cis-elements in regulatory regions and alternatively spliced transcripts. The database was constructed using customized software, and currently contains 2.2 million alignments (exon–intron structures). The alignments have been annotated and integrated into a system that encompasses approximately 90 000 EST loci sharing common exons, 8091 alternatively spliced transcript groups, 10 801 expression-profile groups, 8066 candidate regulatory regions in full-length cDNAs, and 1 million SNP loci. We have used Flash technology to build a dynamic web viewer that facilitates browsing through the millions of alignments. All of the information is available through the World Wide Web at the Gene Resource Locator web site (http://grl.gi.k.u-tokyo.ac.jp).

Honkura, Toshihiko; Ogasawara, Jun; Yamada, Tomoyuki; Morishita, Shinichi

2002-01-01

244

COMPARISON OF THE METHYL REDUCTASE GENES AND GENE PRODUCTS  

EPA Science Inventory

The DNA sequences encoding component C of methyl coenzyme M reductase (mcr genes) in Methanothermus fervidus, Methanobacterium thermoautotrophicum, Methanococcus vannielii, and Methanosarcina barkeri have been published. omparisons of transcription initiation and termination site...

245

GeneTRACE-reconstruction of gene content of ancestral species.  

PubMed

While current computational methods allow the reconstruction of individual ancestral protein sequences, reconstruction of complete gene content of ancestral species is not yet an established task. In this paper, we describe GENETRACE, an efficient linear-time algorithm that allows the reconstruction of evolutionary history of individual protein families as well as the complete gene content of ancestral species. The performance of the method was validated with a simulated evolution program called SimulEv. Our results indicate that given a set of correct phylogenetic profiles and a correct species tree, ancestral gene content can be reconstructed with sensitivity and selectivity of more than 90%. SimulEv simulations were also used to evaluate performance of the reconstruction of gene content-based phylogenetic trees, suggesting that these trees may be accurate at the terminal branches but suffer from long branch attraction near the root of the tree. PMID:12874054

Kunin, Victor; Ouzounis, Christos A

2003-07-22

246

Regulation of Primary Response Genes  

PubMed Central

Primary response genes (PRGs) are a set of genes that are induced in response to both cell-extrinsic and cell-intrinsic signals and do not require de novo protein synthesis for their expression. These 'first responders' in the waves of transcription of signal responsive genes play pivotal roles in a wide rage of biological responses, including neuronal survival and plasticity, cardiac stress response, innate and adaptive immune responses, glucose metabolism and oncogeneic transformation. Here we bring together recent advances and our current understanding of the signal-induced transcriptional and epigenetic regulation of PRGs.

Fowler, Trent; Sen, Ranjan; Roy, Ananda L

2011-01-01

247

Genomics screens for metastasis genes  

PubMed Central

Metastasis is responsible for most cancer mortality. The process of metastasis is complex, requiring the coordinated expression and fine regulation of many genes in multiple pathways in both the tumor and host tissues. Identification and characterization of the genetic programs that regulate metastasis is critical to understanding the metastatic process and discovering molecular targets for the prevention and treatment of metastasis. Genomic approaches and functional genomic analyses can systemically discover metastasis genes. In this review, we summarize the genetic tools and methods that have been used to identify and characterize the genes that play critical roles in metastasis.

Yan, Jinchun; Huang, Qihong

2014-01-01

248

Prospects for human gene therapy.  

PubMed

Procedures have now been developed for inserting functional genes into the bone marrow of mice. The most effective delivery system at present uses retroviral-based vectors to transfer a gene into murine bone marrow cells in culture. The genetically altered bone marrow is then implanted into recipient animals. These somatic cell gene therapy techniques are becoming increasingly efficient. Their future application in humans should result in at least partial correction of a number of genetic disorders. However, the safety of the procedures must still be established by further animal studies before human clinical trials would be ethical. PMID:6093246

Anderson, W F

1984-10-26

249

Gene Delivery to the Airway  

PubMed Central

This unit describes generation of and gene transfer to several commonly used airway models. Isolation and transduction of primary airway epithelial cells are first described. Next, the preparation of polarized airway epithelial monolayers is outlined. Transduction of these polarized cells is also described. Methods are presented for generation of tracheal xenografts as well as both ex vivo and in vivo gene transfer to these xenografts. Finally, a method for in vivo gene delivery to the lungs of rodents is included. Methods for evaluating transgene expression are given in the support protocols.

Keiser, Nicholas W.; Engelhardt, John F.

2013-01-01

250

Cationic liposomes for gene delivery.  

PubMed

Cationic liposome-DNA complexes (lipoplexes) constitute a potentially viable alternative to viral vectors for the delivery of therapeutic genes. This review will focus on various parameters governing lipoplex biological activity, from their mode of formation to in vivo behaviour. Particular emphasis is given to the mechanism of interaction of lipoplexes with cells, in an attempt to dissect the different barriers that need to be surpassed for efficient gene expression to occur. Aspects related to new trends in the formulation of lipid-based gene delivery systems aiming at overcoming some of their limitations will be covered. Finally, examples illustrating the potential of cationic liposomes in clinical applications will be provided. PMID:16296751

Simões, Sérgio; Filipe, Ana; Faneca, Henrique; Mano, Miguel; Penacho, Nuno; Düzgünes, Nejat; de Lima, Maria Pedroso

2005-03-01

251

FYN Kinase Gene: Another Glutamatergic Gene Associated with Bipolar Disorder?  

Microsoft Academic Search

Several genes of the glutamatergic system have been implicated in both schizophrenia and bipolar disorder. The Src family tyrosine kinase FYN plays a key role in the interaction between brain-derived neurotrophic factor and glutamatergic receptor N-methyl-D-aspartate. Although no association between FYN gene polymorphisms and schizophrenia has been demonstrated, in our previous paper we found an association between FYN polymorphisms and

Aleksandra Szczepankiewicz; Janusz K. Rybakowski; Maria Skibinska; Monika Dmitrzak-Weglarz; Anna Leszczynska-Rodziewicz; Monika Wilkosc; Joanna Hauser

2009-01-01

252

THE REX GENE OF BACTERIOPHAGE h IS REALLY TWO GENES  

Microsoft Academic Search

Complementation tests among previously isolated rex- mutants of bacterio- phage A reveal that the mutants comprise two complementation groups, desig- nate,d rexA and rexB. Because rexB- mutants complement prm- mutants, but rexA- mutants do not, it appears that the rexA gene is coordinately controlled with the cI (repressor) gene under the direction of the PW promoter, but that some other

KAREN MATZ; MARGARET SCHMANDT; GARY N. GUSSIN

253

Gene-gene interaction filtering with ensemble of filters  

PubMed Central

Background Complex diseases are commonly caused by multiple genes and their interactions with each other. Genome-wide association (GWA) studies provide us the opportunity to capture those disease associated genes and gene-gene interactions through panels of SNP markers. However, a proper filtering procedure is critical to reduce the search space prior to the computationally intensive gene-gene interaction identification step. In this study, we show that two commonly used SNP-SNP interaction filtering algorithms, ReliefF and tuned ReliefF (TuRF), are sensitive to the order of the samples in the dataset, giving rise to unstable and suboptimal results. However, we observe that the ‘unstable’ results from multiple runs of these algorithms can provide valuable information about the dataset. We therefore hypothesize that aggregating results from multiple runs of the algorithm may improve the filtering performance. Results We propose a simple and effective ensemble approach in which the results from multiple runs of an unstable filter are aggregated based on the general theory of ensemble learning. The ensemble versions of the ReliefF and TuRF algorithms, referred to as ReliefF-E and TuRF-E, are robust to sample order dependency and enable a more informative investigation of data characteristics. Using simulated and real datasets, we demonstrate that both the ensemble of ReliefF and the ensemble of TuRF can generate a much more stable SNP ranking than the original algorithms. Furthermore, the ensemble of TuRF achieved the highest success rate in comparison to many state-of-the-art algorithms as well as traditional ?2-test and odds ratio methods in terms of retaining gene-gene interactions.

2011-01-01

254

Antivirulence genes: insights into pathogen evolution through gene loss.  

PubMed

The emergence of new pathogens and the exploitation of novel pathogenic niches by bacteria typically require the horizontal transfer of virulence factors and subsequent adaptation--a "fine-tuning" process--for the successful incorporation of these factors into the microbe's genome. The function of newly acquired virulence factors may be hindered by the expression of genes already present in the bacterium. Occasionally, certain genes must be inactivated or deleted for full expression of the pathogen phenotype to occur. These genes are known as antivirulence genes (AVGs). Originally identified in Shigella, AVGs have improved our understanding of pathogen evolution and provided a novel approach to drug and vaccine development. In this review, we revisit the AVG definition and update the list of known AVGs, which now includes genes from pathogens such as Salmonella, Yersinia pestis, and the virulent Francisella tularensis subspecies. AVGs encompass a wide variety of different roles within the microbe, including genes involved in metabolism, biofilm synthesis, lipopolysaccharide modification, and host vasoconstriction. More recently, the use of one of these AVGs (lpxL) as a potential vaccine candidate highlights the practical application of studying AVG inactivation in microbial pathogens. PMID:23045475

Bliven, Kimberly A; Maurelli, Anthony T

2012-12-01

255

Gene discovery and gene function assignment in filamentous fungi.  

PubMed

Filamentous fungi are a large group of diverse and economically important microorganisms. Large-scale gene disruption strategies developed in budding yeast are not applicable to these organisms because of their larger genomes and lower rate of targeted integration (TI) during transformation. We developed transposon-arrayed gene knockouts (TAGKO) to discover genes and simultaneously create gene disruption cassettes for subsequent transformation and mutant analysis. Transposons carrying a bacterial and fungal drug resistance marker are used to mutagenize individual cosmids or entire libraries in vitro. Cosmids are annotated by DNA sequence analysis at the transposon insertion sites, and cosmid inserts are liberated to direct insertional mutagenesis events in the genome. Based on saturation analysis of a cosmid insert and insertions in a fungal cosmid library, we show that TAGKO can be used to rapidly identify and mutate genes. We further show that insertions can create alterations in gene expression, and we have used this approach to investigate an amino acid oxidation pathway in two important fungal phytopathogens. PMID:11296265

Hamer, L; Adachi, K; Montenegro-Chamorro, M V; Tanzer, M M; Mahanty, S K; Lo, C; Tarpey, R W; Skalchunes, A R; Heiniger, R W; Frank, S A; Darveaux, B A; Lampe, D J; Slater, T M; Ramamurthy, L; DeZwaan, T M; Nelson, G H; Shuster, J R; Woessner, J; Hamer, J E

2001-04-24

256

Gene discovery and gene function assignment in filamentous fungi  

PubMed Central

Filamentous fungi are a large group of diverse and economically important microorganisms. Large-scale gene disruption strategies developed in budding yeast are not applicable to these organisms because of their larger genomes and lower rate of targeted integration (TI) during transformation. We developed transposon-arrayed gene knockouts (TAGKO) to discover genes and simultaneously create gene disruption cassettes for subsequent transformation and mutant analysis. Transposons carrying a bacterial and fungal drug resistance marker are used to mutagenize individual cosmids or entire libraries in vitro. Cosmids are annotated by DNA sequence analysis at the transposon insertion sites, and cosmid inserts are liberated to direct insertional mutagenesis events in the genome. Based on saturation analysis of a cosmid insert and insertions in a fungal cosmid library, we show that TAGKO can be used to rapidly identify and mutate genes. We further show that insertions can create alterations in gene expression, and we have used this approach to investigate an amino acid oxidation pathway in two important fungal phytopathogens.

Hamer, Lisbeth; Adachi, Kiichi; Montenegro-Chamorro, Maria V.; Tanzer, Matthew M.; Mahanty, Sanjoy K.; Lo, Clive; Tarpey, Rex W.; Skalchunes, Amy R.; Heiniger, Ryan W.; Frank, Sheryl A.; Darveaux, Blaise A.; Lampe, David J.; Slater, Ted M.; Ramamurthy, Lakshman; DeZwaan, Todd M.; Nelson, Grant H.; Shuster, Jeffrey R.; Woessner, Jeffrey; Hamer, John E.

2001-01-01

257

Microarray analysis of genes and gene functions in disc degeneration  

PubMed Central

The aim of the present study was to screen differentially expressed genes (DEGs) in human degenerative intervertebral discs (IVDs), and to perform functional analysis on these DEGs. The gene expression profile was downloaded from the Gene Expression Omnibus database (GSE34095)and included six human IVD samples: three degenerative and three non-degenerative. The DEGs between the normal and disease samples were identified using R packages. The online software WebGestalt was used to perform the functional analysis of the DEGs, followed by Osprey software to search for interactions between the DEGs. The Database for Annotation, Visualization and Integrated Discovery was utilized to annotate the DEGs in the interaction network and then the DEGs were uploaded to the Connectivity Map database to search for small molecules. In addition, the active binding sites for the hub genes in the network were obtained, based on the Universal Protein database. By comparing the gene expression profiles of the non-degenerative and degenerative IVDs, the DEGs between the samples were identified. The DEGs were significantly associated with transforming growth factor ? and the extracellular matrix. Matrix metalloproteinase 2 (MMP2) was identified as the hub gene of the interaction network of DEGs. In addition, MMP2 was found to be upregulated in degenerative IVDs. The screened small molecules and the active binding sites of MMP2 may facilitate the development of methods to inhibit overexpression of MMP2.

TANG, YANCHUN; WANG, SHAOKUN; LIU, YING; WANG, XUYUN

2014-01-01

258

Gene Therapy for Parkinson's Disease  

PubMed Central

Current pharmacological and surgical treatments for Parkinson's disease offer symptomatic improvements to those suffering from this incurable degenerative neurological disorder, but none of these has convincingly shown effects on disease progression. Novel approaches based on gene therapy have several potential advantages over conventional treatment modalities. These could be used to provide more consistent dopamine supplementation, potentially providing superior symptomatic relief with fewer side effects. More radically, gene therapy could be used to correct the imbalances in basal ganglia circuitry associated with the symptoms of Parkinson's disease, or to preserve or restore dopaminergic neurons lost during the disease process itself. The latter neuroprotective approach is the most exciting, as it could theoretically be disease modifying rather than simply symptom alleviating. Gene therapy agents using these approaches are currently making the transition from the laboratory to the bedside. This paper summarises the theoretical approaches to gene therapy for Parkinson's disease and the findings of clinical trials in this rapidly changing field.

Denyer, Rachel; Douglas, Michael R.

2012-01-01

259

Gene regulatory networks for development  

PubMed Central

The genomic program for development operates primarily by the regulated expression of genes encoding transcription factors and components of cell signaling pathways. This program is executed by cis-regulatory DNAs (e.g., enhancers and silencers) that control gene expression. The regulatory inputs and functional outputs of developmental control genes constitute network-like architectures. In this PNAS Special Feature are assembled papers on developmental gene regulatory networks governing the formation of various tissues and organs in nematodes, flies, sea urchins, frogs, and mammals. Here, we survey salient points of these networks, by using as reference those governing specification of the endomesoderm in sea urchin embryos and dorsal–ventral patterning in the Drosophila embryo.

Levine, Michael; Davidson, Eric H.

2005-01-01

260

Autophagy Genes as Tumor Suppressors  

PubMed Central

Autophagy, originally described as a universal lysosome-dependent bulk degradation of cytoplasmic components upon nutrient deprivation, has since been shown to influence diverse aspects of homeostasis and is implicated in a wide variety of pathological conditions, including cancer. The list of autophagy-related (Atg) genes associated with the initiation and progression of human cancer as well as with responses to cancer therapy continues to grow as these genes are being discovered. However, whether Atg genes work through their expected mechanisms of autophagy regulation and/or through as-yet-undefined functions in the development of cancer remains to be further clarified. Here we review recent advances in the knowledge of the molecular basis of autophagy genes and their biological outputs during tumor development. A better understanding of the mechanistic link between cellular autophagy and tumor growth control may ultimately better human cancer treatments.

Liang, Chengyu; Jung, Jae U.

2009-01-01

261

Gene Therapy for Heart Failure  

PubMed Central

Congestive heart failure accounts for half a million deaths per year in the US. Despite its place among the leading causes of morbidity, pharmcalogical and mechanic remedies have been able to slow the progression of the disease, today’s science has yet to provide a cure and there are few therapeutic modalities available for patients with advanced heart failure. There is a critical need to explore new therapeutic approaches in heart failure and gene therapy has emerged as a viable alternative. Recent advances in understanding of the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, has placed heart failure within reach of gene-based therapy. The recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) along with the start of more recent phase 1 trials opens a new era for gene therapy for the treatment of heart failure.

Tilemann, Lisa; Ishikawa, Kiyotake; Weber, Thomas; Hajjar, Roger J.

2012-01-01

262

Gene discovery in Triatoma infestans  

PubMed Central

Background Triatoma infestans is the most relevant vector of Chagas disease in the southern cone of South America. Since its genome has not yet been studied, sequencing of Expressed Sequence Tags (ESTs) is one of the most powerful tools for efficiently identifying large numbers of expressed genes in this insect vector. Results In this work, we generated 826 ESTs, resulting in an increase of 47% in the number of ESTs available for T. infestans. These ESTs were assembled in 471 unique sequences, 151 of which represent 136 new genes for the Reduviidae family. Conclusions Among the putative new genes for the Reduviidae family, we identified and described an interesting subset of genes involved in development and reproduction, which constitute potential targets for insecticide development.

2011-01-01

263

Vibrio Fischeri Symbiosis Gene Regulation.  

National Technical Information Service (NTIS)

The goals of this project were to investigate the molecular mechanisms controlling luminescence gene expression of the symbiotic bioluminescent bacterium Vibrio fischeri; and to identify and investigate the regulation of other symbiosis functions in this ...

P. V. Dunlap

1989-01-01

264

Prospects for Human Gene Therapy.  

National Technical Information Service (NTIS)

In this taped lecture Dr. Anderson reviews the currently most promising means for using gene therapy in managing various disease states. He outlines a technique by which genetically modified calls can be used in a specific cancer chemotherapy protocol, an...

1994-01-01

265

Gene Cloning, Transfection, and Mutagenesis  

Microsoft Academic Search

\\u000a Mutagenesis is a change or alteration in the DNA sequences of a gene. Mutagenic events may occur spontaneously within the\\u000a genome of an organism and many times do not lead to functional consequences or an altered phenotype. However, at times a change\\u000a in the coding sequence of a gene manifests itself as a dysfunctional phenotypic trait or predisposes an individual

Ellen C. Breen; Jason X.-J. Yuan

266

Monoallelic gene expression in mammals  

Microsoft Academic Search

Three systems of monoallelic gene expression in mammals are known, namely, X-chromosome inactivation, imprinting, and allelic\\u000a exclusion. In all three systems, monoallelic expression is regulated epigenetically and is frequently directed by long non-coding\\u000a RNAs (ncRNAs). This review briefs all three systems of monoallelic gene expression in mammals focusing on chromatin modifications,\\u000a spatial chromosome organization in the nucleus, and the functioning

Irina S. Zakharova; Alexander I. Shevchenko; Suren M. Zakian

2009-01-01

267

Arthritis gene therapy's first death  

PubMed Central

In July 2007 a subject died while enrolled in an arthritis gene therapy trial. The study was placed on clinical hold while the circumstances surrounding this tragedy were investigated. Early in December 2007 the Food and Drug Administration removed the clinical hold, allowing the study to resume with minor changes to the protocol. In the present article we collate the information we were able to obtain about this clinical trial and discuss it in the wider context of arthritis gene therapy.

Evans, Christopher H; Ghivizzani, Steven C; Robbins, Paul D

2008-01-01

268

More options for gene editing.  

PubMed

Engineering precise genetic changes in a genome is powerful way to study gene function, and several recent papers describe new applications of gene-editing tools. Working with researchers at Sangamo BioSciences, Howard Hughes Medical Institute investigator Barbara Meyer and her colleagues at the University of California, Berkeley, described the first systems for making targeted genomic modifications in the roundworm Caenorhabditis elegans, a valuable model organism (Wood et al., 2011). PMID:21985000

Baker, Monya

2011-09-01

269

RNA-triggered gene silencing  

Microsoft Academic Search

Double-stranded RNA (dsRNA) has recently been shown to trigger sequence-specific gene silencing in a wide variety of organisms, including nematodes, plants, trypanosomes, fruit flies and planaria; meanwhile an as yet uncharacterized RNA trigger has been shown to induce DNA methylation in several different plant systems. In addition to providing a surprisingly effective set of tools to interfere selectively with gene

Andrew Fire

1999-01-01

270

Gene Therapy for Erectile Dysfunction  

Microsoft Academic Search

Our current understanding of the underlying mechanisms of erectile dysfunction suggests that gene therapy will become a therapeutic\\u000a treatment in the near future. Over the past decade, erectile dysfunction has been ameliorated in animal models using viral-and\\u000a plasmid-based vectors. Genes that stimulate smooth muscle cell relaxation, such as neuronal, inducible, and endothelial nitric\\u000a oxide synthase, or that inhibit smooth muscle

Thomas R. Magee; Jacob Rajfer; Nestor F. Gonzalez-Cadavid

271

Methylated genes in breast cancer  

PubMed Central

Background Hundreds of hypermethylated genes have been described in breast cancer, yet the nature and contribution of these genes in their methylated state to overall risk and prognosis is under-characterized in non-sporadic breast cancers. We therefore compared associations of DNA methylation with tumor stage, hormone/growth receptor status and clinical outcomes in a familial breast cancer cohort. Because few previous methylation studies have considered the oncogenic or tumor suppressor properties of their gene sets, this functional status was included as part of our correlative analysis. Results We found methylation of oncogenes was associated with better prognostic indicators, whereas tumor suppressor gene methylation was associated with a more severe phenotype in women that were either HER2+ or lymph node positive at diagnosis, and/or tended to recur or develop distant metastases. For example, the methylation of the tumor suppressor gene APC was strongly associated with a specific subset of tumors that were both ER+ and HER2+, while methylation of the TWIST oncogene was associated with breast cancers that did not metastasize. Methods This was a retrospective, hospital-based study of n = 99 archival breast tumors derived from women with a germline genetic BRCA1 or BRCA2 mutation and/or familial breast cancer history. DNA methylation was quantified from formalin fixed, paraffin embedded tumors using the established protocol of quantitative multiplex-methylation specific PCR (QM-MSP). Non-parametric statistics were used to analyze candidate gene methylation in association with clinical outcomes. Conclusion We report several novel, positive associations between percent methylation of the APC, RASSF1A, TWIST, ER?, CDH1 and Cyclin D2 genes and key variables such as tumor stage, hormone and growth receptor status, and a history of recurrent or metastatic disease. Our data suggest the potential utility of parsing gene methylation by functional status and breast tumor subtype.

Vang, Russell; Blackford, Amanda; Fackler, Mary Jo

2011-01-01

272

Transgenic Arabidopsis Gene Expression System  

NASA Technical Reports Server (NTRS)

The Transgenic Arabidopsis Gene Expression System (TAGES) investigation is one in a pair of investigations that use the Advanced Biological Research System (ABRS) facility. TAGES uses Arabidopsis thaliana, thale cress, with sensor promoter-reporter gene constructs that render the plants as biomonitors (an organism used to determine the quality of the surrounding environment) of their environment using real-time nondestructive Green Fluorescent Protein (GFP) imagery and traditional postflight analyses.

Ferl, Robert; Paul, Anna-Lisa

2009-01-01

273

Hydrogels for Lentiviral Gene Delivery  

PubMed Central

Introduction Gene delivery from hydrogel biomaterials provides a fundamental tool for a variety of clinical applications including regenerative medicine, gene therapy for inherited disorders and drug delivery. The high water content and mild gelation conditions of hydrogels support their use for gene delivery by preserving activity of lentiviral vectors and acting to shield vectors from any host immune response. Areas Covered Strategies to control lentiviral entrapment within and retention/release from hydrogels are reviewed. We discuss the ability of hydrogel design parameters to control the transgene expression profile and the capacity of hydrogels to protect vectors from (and even modulate) the host immune response. Expert Opinion Delivery of genetic vectors from scaffolds provides a unique opportunity to capitalize on the potential synergy between the biomaterial design for cell processes and gene delivery. Hydrogel properties can be tuned to directly control the events that determine the tissue response to controlled gene delivery, which include the extent of cell infiltration, preservation of vector activity and vector retention. While some design parameters have been identified, numerous opportunities for investigation are available in order to develop a complete model relating the biomaterial properties and host response to gene delivery.

Seidlits, Stephanie K.; Gower, R. Michael; Shepard, Jaclyn A.; Shea, Lonnie D.

2013-01-01

274

DNA methylation and gene expression.  

PubMed

A large body of evidence demonstrates that DNA methylation plays a role in gene regulation in animal cells. Not only is there a correlation between gene transcription and undermethylation, but also transfection experiments clearly show that the presence of methyl moieties inhibits gene expression in vivo. Furthermore, gene activation can be induced by treatment of cells with 5-azacytidine, a potent demethylating agent. Methylation appears to influence gene expression by affecting the interactions with DNA of both chromatin proteins and specific transcription factors. Although methylation patterns are very stable in somatic cells, the early embryo is characterized by large alterations in DNA modification. New methodologies are now becoming available for studying methylation at this stage and in the germ line. During development, tissue-specific genes undergo demethylation in their tissue of expression. In tissue culture cells this process is highly specific and appears to involve an active mechanism which takes place in the absence of DNA replication. The X chromosome undergoes inactivation during development; this is accompanied by de novo methylation, which appears necessary to stably maintain its silent state. As opposed to the programmed changes in DNA methylation which occur in vivo, immortalized tissue culture cells demonstrate alterations in DNA modification which take place over a long time scale and which appear to be the result of selective pressures present during the growth of these cells in culture. PMID:1943996

Razin, A; Cedar, H

1991-09-01

275

Homologous Gene Replacement in Physarum  

PubMed Central

The protist Physarum polycephalum is useful for analysis of several aspects of cellular and developmental biology. To expand the opportunities for experimental analysis of this organism, we have developed a method for gene replacement. We transformed Physarum amoebae with plasmid DNA carrying a mutant allele, ardD?1, of the ardD actin gene; ardD?1 mutates the critical carboxy-terminal region of the gene product. Because ardD is not expressed in the amoeba, replacement of ardD(+) with ardD?1 should not be lethal for this cell type. Transformants were obtained only when linear plasmid DNA was used. Most transformants carried one copy of ardD?1 in addition to ardD(+), but in two (5%), ardD(+) was replaced by a single copy of ardD?1. This is the first example of homologous gene replacement in Physarum. ardD?1 was stably maintained in the genome through growth, development and meiosis. We found no effect of ardD?1 on viability, growth, or development of any of the various cell types of Physarum. Thus, the carboxy-terminal region of the ardD product appears not to perform a unique essential role in growth or development. Nevertheless, this method for homologous gene replacement can be applied to analyze the function of any cloned gene.

Burland, T. G.; Pallotta, D.

1995-01-01

276

Book Review: Plant Gene Expression  

NSDL National Science Digital Library

Whereas many important biological discoveries have been made using plants, subsequent progress in some areas of plant research has fallen behind that in other organisms for which funding and in vitro assays are more readily available. Gene expression is one such field in which importance continues to grow because many potential plant biotechnology–based solutions to global problems depend on regulating the expression of specific genes. Previous limitations to exploring gene expression in plants have been partially mitigated by recent advances in genomics, genetics, and transformation techniques. The book Regulation of Gene Expression in Plants: The Role of Transcript Structure and Processing, edited by Carole L. Bassett, summarizes our current understanding of plant gene expression, with an emphasis on transcriptional and posttranscriptional regulation. The topics covered in six chapters include differences in messenger RNA (mRNA) structure caused by variations in transcription start and polyadenylation sites, alternative splicing, regulation by small RNAs, and mRNA transport and degradation. The chapters vary in depth, quality, and the degree to which the emphasis is placed on plants rather than eukaryotes in general. However, this slim volume is a useful review of gene expression in plants. The question of whether or not all differences in mRNA structure have functional importance remains open.

Alan Rose (University of California Davis;Molecular and Cellular Biology REV)

2007-05-22

277

Gene therapy in status epilepticus.  

PubMed

Gene therapy in human disease has expanded rapidly in recent years with the development of safer and more effective viral vectors, and presents a novel approach to the treatment of epilepsy. Studies in animals models have demonstrated that overexpression of inhibitory peptides can modify seizure threshold, prevent the development of epilepsy, and modify established epilepsy. More recently there has been a flurry of studies using optogenetics in which light-activated channels expressed in neurons can transiently change neuronal excitability on exposure to light, thereby enabling the development of closed loop systems to detect and stop seizure activity. The treatment of status epilepticus presents its own challenges. Because of both the delay in gene expression following transfection and also the necessity of using focal transfection, there are a limited number of situations in which gene therapy can be used in status epilepticus. One such condition is epilepsia partialis continua (EPC). We have used gene therapy in a model of EPC and have shown that we can "cure" the condition. Recent evidence suggesting that gene therapy targeting subcortical regions can modify generalized or more diffuse epilepsies, indicates that the range of situations in status epilepticus in which gene therapy could be used will expand. PMID:24001071

Walker, Matthew C; Schorge, Stephanie; Kullmann, Dimitri M; Wykes, Robert C; Heeroma, Joost H; Mantoan, Laura

2013-09-01

278

Shared gene expression in distinct neurons expressing common selector genes  

PubMed Central

Expression of the mec-3/unc-86 selector gene complex induces the differentiation of the touch receptor neurons (TRNs) of Caenorhabditis elegans. These genes are also expressed in another set of embryonically derived mechanosensory neurons, the FLP neurons, but these cells do not share obvious TRN traits or proteins. We have identified ?300 genes in each cell type that are up-regulated at least threefold using DNA microarrays. Twenty-three percent of these genes are up-regulated in both cells. Surprisingly, some of the common genes had previously been identified as TRN-specific. Although the FLP neurons contain low amounts of the mRNAs for these TRN genes, they do not have detectable proteins. These results suggest that transcription control is relatively inexact but that these apparent errors of transcription are tolerated and do not alter cell fate. Previous studies showed that loss of the EGL-44 and EGL-46 transcription factors cause the FLP neurons to acquire TRN-like traits. Here, we show that similar changes occur (e.g., the expression of both the TRN mRNAs and proteins) when the FLP neurons ectopically express the auxiliary transcription factor ALR-1 (Aristaless related), which ensures, but does not direct, TRN differentiation. Thus, the FLP neurons can acquire a TRN-like fate but use multiple levels of regulation to ensure they do not. Our data indicate that expression of common master regulators in different cell types can result in inappropriate expression of effector genes. This misexpression makes these cells vulnerable to influences that could cause them to acquire alternative fates.

Topalidou, Irini; Chalfie, Martin

2011-01-01

279

Combining Hierarchical and Associative Gene Ontology Relations with Textual Evidence in Estimating Gene and Gene Product Similarity  

SciTech Connect

Gene and gene product similarity is a fundamental diagnostic measure in analyzing biological data and constructing predictive models for functional genomics. With the rising influence of the Gene Ontology, two complementary approaches have emerged where the similarity between two genes or gene products is obtained by comparing Gene Ontology (GO) annotations associated with the genes or gene products. One approach captures GO-based similarity in terms of hierarchical relations within each gene subontology. The other approach identifies GO-based similarity in terms of associative relations across the three gene subontologies. We propose a novel methodology where the two approaches can be merged with ensuing benefits in coverage and accuracy, and demonstrate that further improvements can be obtained by integrating textual evidence extracted from relevant biomedical literature.

Sanfilippo, Antonio P.; Posse, Christian; Gopalan, Banu; Riensche, Roderick M.; Beagley, Nathaniel; Baddeley, Bob L.; Tratz, Stephen C.; Gregory, Michelle L.

2007-03-01

280

Use of Gene Replacement Transformation to Elucidate Gene Function in the Qa Gene Cluster of Neurospora Crassa  

PubMed Central

Gene replacement by transformation, employing selective genetic recombination techniques, has been used to delete or disrupt the qa-x, qa-y and qa-1S genes of the qa gene cluster of Neurospora crassa. The growth characteristics of the strain carrying the deletion of the qa-y gene support earlier evidence that this gene encodes a quinic acid permease. The strain containing the deletion of the qa-1S gene (?qa-1S) was examined with respect to quinic acid induction and carbon catabolite repression. The ?qa-1S strain exhibits constitutive expression of the qa genes supporting earlier evidence that the qa-1S gene codes for a repressor. Several of the qa genes continued to be expressed at high levels even in the presence of glucose in the ?qa-1S strain, which indicates that transcription of these genes is not being affected directly by a repressor molecule in the presence of glucose.

Case, M. E.; Geever, R. F.; Asch, D. K.

1992-01-01

281

Aphids acquired symbiotic genes via lateral gene transfer  

PubMed Central

Background Aphids possess bacteriocytes, which are cells specifically differentiated to harbour the obligate mutualist Buchnera aphidicola (?-Proteobacteria). Buchnera has lost many of the genes that appear to be essential for bacterial life. From the bacteriocyte of the pea aphid Acyrthosiphon pisum, we previously identified two clusters of expressed sequence tags that display similarity only to bacterial genes. Southern blot analysis demonstrated that they are encoded in the aphid genome. In this study, in order to assess the possibility of lateral gene transfer, we determined the full-length sequences of these transcripts, and performed detailed structural and phylogenetic analyses. We further examined their expression levels in the bacteriocyte using real-time quantitative RT-PCR. Results Sequence similarity searches demonstrated that these fully sequenced transcripts are significantly similar to the bacterial genes ldcA (product, LD-carboxypeptidase) and rlpA (product, rare lipoprotein A), respectively. Buchnera lacks these genes, whereas many other bacteria, including Escherichia coli, a close relative of Buchnera, possess both ldcA and rlpA. Molecular phylogenetic analysis clearly demonstrated that the aphid ldcA was derived from a rickettsial bacterium closely related to the extant Wolbachia spp. (?-Proteobacteria, Rickettsiales), which are intracellular symbionts of various lineages of arthropods. The evolutionary origin of rlpA was not fully resolved, but it was clearly demonstrated that its double-? ?-barrel domain is of bacterial origin. Real-time quantitative RT-PCR demonstrated that ldcA and rlpA are expressed 11.6 and 154-fold higher in the bacteriocyte than in the whole body, respectively. LdcA is an enzyme required for recycling murein (peptidoglycan), which is a component of the bacterial cell wall. As Buchnera possesses a cell wall composed of murein but lacks ldcA, a high level of expression of the aphid ldcA in the bacteriocyte may be essential to maintain Buchnera. Although the function of RlpA is not well known, conspicuous up-regulation of the aphid rlpA in the bacteriocyte implies that this gene is also essential for Buchnera. Conclusion In this study, we obtained several lines of evidence indicating that aphids acquired genes from bacteria via lateral gene transfer and that these genes are used to maintain the obligately mutualistic bacterium, Buchnera.

Nikoh, Naruo; Nakabachi, Atsushi

2009-01-01

282

The biology of novel animal genes: Mouse APEX gene knockout  

SciTech Connect

This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The controlled breeding of novel genes into mice, including the gene knockout (KO), or conversely by adding back transgenes provide powerful genetic technologies that together suffice to determine in large part the biological role(s) of novel genes. Inbred mouse remains the best understood and most useful mammalian experimental system available for tackling the biology of novel genes. The major mammalian apurinic/apyrimidinic (AP) endonuclease (APE), is involved in a key step in the repair of spontaneous and induced AP sites in DNA. Efficient repair of these lesions is imperative to prevent the stable incorporation of mutations into the cellular genome which may lead to cell death or transformation. Loss or modulation of base excison repair activity in vivo may elevate the spontaneous mutation rate in cells, and may lead to a substantial increase in the incidence of cancer. Despite extensive biochemical analysis, however, the significance of these individual APE functions in vivo has not been elucidated. Mouse embryonic stem (ES) cells heterozygous for a deletion mutation in APE have been generated and whole animals containing the APE mutation have been derived from these ES cells. Animals homozygous for the APE null mutation die early in gestation, underscoring the biological significance of this DNA repair gene.

MacInnes, M.; Altherr, M.R.; Ludwig, D. [Los Alamos National Lab., NM (United States); Pedersen, R.; Mold, C. [Univ. of California, San Francisco, CA (United States)

1997-07-01

283

Newer Gene Editing Technologies toward HIV Gene Therapy  

PubMed Central

Despite the great success of highly active antiretroviral therapy (HAART) in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called “Berlin patient” who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realistic possibility with recent advances in understanding the DNA repair mechanisms, DNA interaction with transcription factors and bacterial defense mechanisms. Within the past few years, four novel technologies have emerged that can be engineered for recognition of specific DNA target sequences to enable site-specific gene editing: Homing Endonuclease, ZFN, TALEN, and CRISPR/Cas9 system. The most recent CRISPR/Cas9 system uses a short stretch of complementary RNA bound to Cas9 nuclease to recognize and cleave target DNA, as opposed to the previous technologies that use DNA binding motifs of either zinc finger proteins or transcription activator-like effector molecules fused to an endonuclease to mediate sequence-specific DNA cleavage. Unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, the newer technologies allow permanent disruption of the targeted gene after a single treatment. Here, we review the applications, limitations and future prospects of novel gene-editing strategies for use as HIV therapy.

Manjunath, N.; Yi, Guohua; Dang, Ying; Shankar, Premlata

2013-01-01

284

Restricted parameter space models for testing gene-gene interaction  

PubMed Central

There is a growing recognition that interactions (gene-gene and gene-environment) can play an important role in common disease etiology. The development of cost-effective genotyping technologies has made genome-wide association studies the preferred tool for searching for loci affecting disease risk. These studies are characterized by a large number of investigated SNPs, and efficient statistical methods are even more important than in classical association studies that are done with a small number of markers. In this paper we propose a novel gene-gene interaction test that is more powerful than classical methods. The increase in power is due to the fact that the proposed method incorporates reasonable constraints in the parameter space. The test for both association and interaction is based on a likelihood ratio statistic that has a chi-bar-squared distribution asymptotically. We also discuss the definitions used for “no interaction” and argue that tests for pure interaction are useful in genome-wide studies, especially when using two stage strategies where the analyses in the second stage are done on pairs of loci for which at least one is associated with the trait.

Song, Minsun; Nicolae, Dan L.

2014-01-01

285

Fetal muscle gene therapy/gene delivery in large animals.  

PubMed

Gene delivery to the fetal muscles is a potential strategy for the early treatment of muscular dystrophies. In utero muscle gene therapy can also be used to treat other genetic disorders such as hemophilia, where the missing clotting proteins may be secreted from the treated muscle. In the past few years, studies in small animal models have raised the hopes that a phenotypic cure can be obtained after fetal application of gene therapy. Studies of efficacy and safety in large animals are, however, essential before clinical application can be considered in the human fetus. For this reason, the development of clinically applicable strategies for the delivery of gene therapy to the fetal muscles is of prime importance. In this chapter, we describe the protocols for in utero ultrasound-guided gene delivery to the ovine fetal muscle in early gestation. In particular, procedures to inject skeletal muscle groups such as the thigh and thoracic musculature and targeting the diaphragm in the fetus are described in detail. PMID:21194032

Abi-Nader, Khalil N; David, Anna L

2011-01-01

286

Molecular Evolution of Human Visual Pigment Genes  

Microsoft Academic Search

By comparing the published DNA sequences for (a) the genes encoding the human visual color pigments (red, green, and blue) with (b) the genes encoding human, bovine, and Drosophila rhodopsins, a phylogenetic tree for the mammalian pigment genes has been constructed. This evolutionary tree shows that the common ancestor of the visual color pigment genes diverged first from that of

Shozo Yokoyama; Ruth Yokoyama

1989-01-01

287

Polymers for gene delivery across length scales  

Microsoft Academic Search

A number of human diseases stem from defective genes. One approach to treating such diseases is to replace, or override, the defective genes with normal genes, an approach called 'gene therapy'. However, the introduction of correctly functioning DNA into cells is a non-trivial matter, and cells must be coaxed to internalize, and then use, the DNA in the desired manner.

David Putnam

2006-01-01

288

Environmentally Induced Gene Silencing in Breast Cancer.  

National Technical Information Service (NTIS)

The main goal of the study was to test the hypothesis that a reduction in gene expression could induce gene silencing (i.e. relatively stable loss of gene expression) in breast cells. Silencing of a variety of tumor suppressor genes plays a major role in ...

M. Turker

2008-01-01

289

Common Genes Implicated in Autism Study  

MedlinePLUS

... Preidt Monday, July 21, 2014 Related MedlinePlus Pages Autism Genes and Gene Therapy SUNDAY, July 20, 2014 (HealthDay News) -- Most of ... HealthDay . All rights reserved. More Health News on: Autism Genes and Gene Therapy Recent Health News Page last updated on 21 ...

290

Comparative Gene Prediction in Human and Mouse  

Microsoft Academic Search

The completion of the sequencing of the mouse genome promises to help predict human genes with greater accuracy. While current ab initio gene prediction programs are remarkably sensitive (i.e., they predict at least a fragment of most genes), their specificity is often low, predicting a large number of false-positive genes in the human genome. Sequence conservation at the protein level

Genis Parra; Pankaj Agarwal; Josep F. Abril; Thomas Wiehe; James W. Fickett; Roderic Guigo

2003-01-01

291

Markov process modelling of gene regulation  

Microsoft Academic Search

This paper discusses the mathematical modelling of gene regulation with emphasis on the bottom-up modelling of genetic componentry rather than the reverse-engineering of networks from gene expression data. Reflecting the stochastic nature of gene regulation, the chemical master equation is used as a tool to study Markovian models of networks of gene states between which probabilistic transitions occur. These states

Hilary S. Booth; Conrad J. Burden; Markus Hegland; Lucia Santoso

292

Evolution by gene duplication: an update  

Microsoft Academic Search

The importance of gene duplication in supplying raw genetic material to biological evolution has been recognized since the 1930s. Recent genomic sequence data provide substantial evidence for the abundance of duplicated genes in all organisms surveyed. But how do newly duplicated genes survive and acquire novel functions, and what role does gene duplication play in the evolution of genomes and

Jianzhi Zhang

2003-01-01

293

Analysis of Microarray Gene Expression Data  

Microsoft Academic Search

Microarrays provide the biological research community with tremendously rich, sensitive and detailed information on gene expression profiles. Gene expression profiling and gene expression patterns have been found useful for solving a wide variety of important biological and biomedical problems, including the study of metabolic pathways, inference of the functions of unknown genes, diagnosis of diseased states, as well as facilitating

Tuan D. Pham; Christine Wells; Denis I. Crane

2006-01-01

294

Accessory Gene Regulator Locus of Staphylococcus intermedius  

Microsoft Academic Search

The accessory gene regulator (agr) locus, a candidate system for the regulation of the production of virulence factors in Staphylococcus intermedius, has been characterized. Using PCR-based genome walking, we have obtained the first complete sequence (3,436 bp) of the accessory gene regulator (agr) gene in this organism. Sequence analysis of the agr gene has identified five open reading frames (ORFs),

Julia M. L. Sung; Peter D. Chantler; David H. Lloyd

2006-01-01

295

Gene Therapy of Brain and Endocrine Tumors  

Microsoft Academic Search

Gene therapy of cancer has become a major interest of medical research since more than 60% of the ongoing gene therapy protocols today involve cancer patients. To increase the therapeutic index of cancer gene therapy, targeting strategies have been developed to ensure that the expression of therapeutic genes is restricted exclusively to the tissue of interest. An attractive approach lies

Giorgio Palù; Roberta Bonaguro; Elisa Gnatta; Elisa Franchin; Luisa Barzon

296

Tissue engineering via local gene delivery  

Microsoft Academic Search

The first goal of this review is to describe a local plasmid gene transfer technology known as the gene activated matrix (GAM). GAM was the first gene therapy designed specifically for tissue engineering applications, and the mechanism of action of plasmid gene transfer is closely tied to the normal sequence of events associated with wound healing. The normal sequence of

Jeffrey Bonadio

2000-01-01

297

Locating Multiple Gene Duplications through Reconciled Trees  

Microsoft Academic Search

We introduce the first exact and efficient algorithm for Guig´ o et al.'s problem that, given a collection of rooted, binary gene trees and a rooted, binary species tree, determines a minimum number of locations for gene duplication events from the gene trees on the species tree. We examined the performance of our algorithm using a set of 85 gene

J. Gordon Burleigh; Mukul S. Bansal; André Wehe; Oliver Eulenstein

2008-01-01

298

EMF Genes Regulate Arabidopsis Inflorescence Development  

Microsoft Academic Search

Mutations in EMBRYONlC FLOWER (EMF) genes EMFl and EMf2 abolish rosette development, and the mutants pro- duce either a much reduced inflorescence or a transformed flower. These mutant characteristics suggest a repressive effect of EMF activities on reproductive development. To investigate the role of EMf genes in regulating reproductive development, we studied the relationship between EMf genes and the genes

Lingjing Chen; Jin-Chen Cheng; Linda Castle; Renee Sung

1997-01-01

299

From circadian clock gene expression to pathologies  

Microsoft Academic Search

In most organisms, circadian rhythms are generated by a molecular clockwork involving so-called clock genes. These circadian clock genes participate in regulatory feedback loops, in which proteins regulate their own expression. The outcome is that ribonucleic acids (RNAs) and proteins produced from many of these genes oscillate with a circadian rhythm. Here, we describe the regulation of clock genes and

Elaine Waddington Lamont; Francine O. James; Diane B. Boivin; Nicolas Cermakian

2007-01-01

300

Genes and Abdominal Aortic Aneurysm  

PubMed Central

Abdominal aortic aneurysm (AAA) is a multifactorial disease with a strong genetic component. Since first candidate gene studies were published 20 years ago, nearly 100 genetic association studies using single nucleotide polymorphisms (SNPs) in biologically relevant genes have been reported on AAA. The studies investigated SNPs in genes of the extracellular matrix, the cardiovascular system, the immune system, and signaling pathways. Very few studies were large enough to draw firm conclusions and very few results could be replicated in another sample set. The more recent unbiased approaches are family-based DNA linkage studies and genome-wide genetic association studies, which have the potential of identifying the genetic basis for AAA, if appropriately powered and well-characterized large AAA cohorts are used. SNPs associated with AAA have already been identified in these large multicenter studies. One significant association was of a variant in a gene called CNTN3 which is located on chromosome 3p12.3. Two follow-up studies, however, could not replicate the association. Two other SNPs, which are located on chromosome 9p21 and 9q33 were replicated in other samples. The two genes with the strongest supporting evidence of contribution to the genetic risk for AAA are the CDKN2BAS gene, also known as ANRIL, which encodes an antisense RNA that regulates expression of the cyclin-dependent kinase inhibitors CDKN2A and CDKN2B, and DAB2IP, which encodes an inhibitor of cell growth and survival. Functional studies are now needed to establish the mechanisms by which these genes contribute to AAA pathogenesis.

Hinterseher, Irene; Tromp, Gerard; Kuivaniemi, Helena

2010-01-01

301

The aristaless (Arx) gene: one gene for many "interneuronopathies".  

PubMed

The ARX (Aristaless-related (X-linked) homeobox) gene is not only present in arthropods and their ancestors, but also in vertebrates including humans (ARX orthologs). The gene is composed of 5 coding exons and it is expressed predominantly in foetal and adult brain and skeletal muscle. In this review we report on our experience and review the existing literature on the genotype and phenotype heterogeneity associated with ARX abnormalities in humans ranging from severe neuronal migration defects (e.g., lissencephaly), to mild forms of X-linked mental retardation without apparent brain abnormalities. The ARX-related disorders are reviewed focusing on their clinical features and on the role of the ARX gene. It has yet to be established whether the molecular defect alone could cause a given cerebral abnormality and/or malformation or an additional or related molecular or environmental event could contribute to a given phenotype in molecularly. PMID:20036914

Ruggieri, Martino; Pavone, Piero; Scapagnini, Giovanni; Romeo, Loriana; Lombardo, Ilaria; Li Volti, Giovanni; Corsello, Giovanni; Pavone, Lorenzo

2010-01-01

302

CONTEXT-SPECIFIC GENE REGULATIONS IN CANCER GENE EXPRESSION DATA*  

PubMed Central

Learning or inferring networks of genomic regulation specific to a cellular state, such as a subtype of tumor, can yield insight above and beyond that resulting from network learning-techniques which do not acknowledge the adaptive nature of the cellular system. In this study we show that Cellular Context Mining, which is based on a mathematical model of contextual genomic regulation, produces gene regulatory networks (GRNs) from steady-state expression microarray data which are specific to the varying cellular contexts hidden in the data; we show that these GRNs not only model gene interactions, but that they are also readily annotated with context-specific genomic information. We propose that these context-specific GRNs provide advantages over other techniques, such as clustering and Bayesian networks, when applied to gene expression data of cancer patients.

Sen, Ina; Verdicchio, Michael P.; Jung, Sungwon; Trevino, Robert; Bittner, Michael; Kim, Seungchan

2009-01-01

303

Advancement and prospects of tumor gene therapy  

PubMed Central

Gene therapy is one of the most attractive fields in tumor therapy. In past decades, significant progress has been achieved. Various approaches, such as viral and non-viral vectors and physical methods, have been developed to make gene delivery safer and more efficient. Several therapeutic strategies have evolved, including gene-based (tumor suppressor genes, suicide genes, antiangiogenic genes, cytokine and oxidative stress-based genes) and RNA-based (antisense oligonucleotides and RNA interference) approaches. In addition, immune response-based strategies (dendritic cell– and T cell–based therapy) are also under investigation in tumor gene therapy. This review highlights the progress and recent developments in gene delivery systems, therapeutic strategies, and possible clinical directions for gene therapy.

Zhang, Chao; Wang, Qing-Tao; Liu, He; Zhang, Zhen-Zhu; Huang, Wen-Lin

2011-01-01

304

Activities of Human Gene Nomenclature Committee  

SciTech Connect

The objective of this project, shared between NIH and DOE, has been and remains to enable the medical genetics communities to use common names for genes that are discovered by different gene hunting groups, in different species. This effort provides consistent gene nomenclature and approved gene symbols to the community at large. This contributes to a uniform and consistent understanding of genomes, particularly the human as well as functional genomics based on comparisons between homologous genes in related species (human and mice).

NONE

2002-07-16

305

Combination of Gene Therapy with Radiation  

Microsoft Academic Search

To date tremendous progress has been made in the field of cancer gene therapy. Strategies have been explored for achieving\\u000a therapeutic benefit using various genes and several clinical trials for cancer gene therapy have been carried out demonstrating\\u000a that gene therapy is well tolerated. However, in most cases the efficacy of gene transfer has been very limited. As an alternative,

Anupama Munshi; Raymond E. Meyn

306

Update on acquired tetracycline resistance genes  

Microsoft Academic Search

This mini-review summarizes the changes in the field of bacterial acquired tetracycline resistance (tet) and oxytetracycline (otr) genes identified since the last major review in 2001. Thirty-eight acquired tetracycline resistant (Tcr) genes are known of which nine are new and include five genes coding for energy-dependent efflux proteins, two genes coding for ribosomal protection proteins, and two genes coding for

Marilyn C. Roberts

2005-01-01

307

Gene Therapy for Pituitary Tumors  

PubMed Central

Pituitary tumors are the most common primary intracranial neoplasms. Although most pituitary tumors are considered typically benign, others can cause severe and progressive disease. The principal aims of pituitary tumor treatment are the elimination or reduction of the tumor mass, normalization of hormone secretion and preservation of remaining pituitary function. In spite of major advances in the therapy of pituitary tumors, for some of the most difficult tumors, current therapies that include medical, surgical and radiotherapeutic methods are often unsatisfactory and there is a need to develop new treatment strategies. Gene therapy, which uses nucleic acids as drugs, has emerged as an attractive therapeutic option for the treatment of pituitary tumors that do not respond to classical treatment strategies if the patients become intolerant to the therapy. The development of animal models for pituitary tumors and hormone hypersecretion has proven to be critical for the implementation of novel treatment strategies and gene therapy approaches. Preclinical trials using several gene therapy approaches for the treatment of anterior pituitary diseases have been successfully implemented. Several issues need to be addressed before clinical implementation becomes a reality, including the development of more effective and safer viral vectors, uncovering novel therapeutic targets and development of targeted expression of therapeutic transgenes. With the development of efficient gene delivery vectors allowing long-term transgene expression with minimal toxicity, gene therapy will become one of the most promising approaches for treating pituitary adenomas.

Seilicovich, Adriana; Pisera, Daniel; Sciascia, Sandra A.; Candolfi, Marianela; Puntel, Mariana; Xiong, Weidong; Jaita, Gabriela; Castro, Maria G.

2009-01-01

308

Ontogeny of erythroid gene expression  

PubMed Central

Erythroid ontogeny is characterized by overlapping waves of primitive and definitive erythroid lineages that share many morphologic features during terminal maturation but have marked differences in cell size and globin expression. In the present study, we compared global gene expression in primitive, fetal definitive, and adult definitive erythroid cells at morphologically equivalent stages of maturation purified from embryonic, fetal, and adult mice. Surprisingly, most transcriptional complexity in erythroid precursors is already present by the proerythroblast stage. Transcript levels are markedly modulated during terminal erythroid maturation, but housekeeping genes are not preferentially lost. Although primitive and definitive erythroid lineages share a large set of nonhousekeeping genes, annotation of lineage-restricted genes shows that alternate gene usage occurs within shared functional categories, as exemplified by the selective expression of aquaporins 3 and 8 in primitive erythroblasts and aquaporins 1 and 9 in adult definitive erythroblasts. Consistent with the known functions of Aqp3 and Aqp8 as H2O2 transporters, primitive, but not definitive, erythroblasts preferentially accumulate reactive oxygen species after exogenous H2O2 exposure. We have created a user-friendly Web site (http://www.cbil.upenn.edu/ErythronDB) to make these global expression data readily accessible and amenable to complex search strategies by the scientific community.

Kingsley, Paul D.; Greenfest-Allen, Emily; Frame, Jenna M.; Bushnell, Timothy P.; Malik, Jeffrey; McGrath, Kathleen E.; Stoeckert, Christian J.

2013-01-01

309

Metazoan Gene Families from Metazome  

DOE Data Explorer

Metazome is a joint project of the Department of Energy's Joint Genome Institute and the Center for Integrative Genomics to facilitate comparative genomic studies amongst metazoans. Clusters of orthologous and paralogous genes that represent the modern descendents of ancestral gene sets are constructed at key phylogenetic nodes. These clusters allow easy access to clade specific orthology/paralogy relationships as well as clade specific genes and gene expansions. As of version 2.0.4, Metazome provides access to twenty-four sequenced and annotated metazoan genomes, clustered at nine evolutionarily significant nodes. Where possible, each gene has been annotated with PFAM, KOG, KEGG, and PANTHER assignments, and publicly available annotations from RefSeq, UniProt, Ensembl, and JGI are hyper-linked and searchable. The included organisms (by common name) are: Human, Mouse, Rat, Dog, Opossum, Chicken, Frog, Stickleback, Medaka, Fugu pufferfish; Zebrafish, Seasquirt - savignyi, Seasquirt - intestinalis, Amphioxus, Sea Urchin, Fruitfly, Mosquite, Yellow Fever Mosquito, Silkworm, Red Flour Beetle, Worm, Briggsae Worm, Owl limpet (snail), and Sea anemone. [Copied from Metazome Overview at http://www.metazome.net/Metazome_info.php

310

Melatonin receptor genes in vertebrates.  

PubMed

Melatonin receptors are members of the G protein-coupled receptor (GPCR) family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A) and MT2 (or Mel1b or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C), has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor. PMID:23712359

Li, Di Yan; Smith, David Glenn; Hardeland, Rüdiger; Yang, Ming Yao; Xu, Huai Liang; Zhang, Long; Yin, Hua Dong; Zhu, Qing

2013-01-01

311

Improved Algorithms for Finding Gene Teams and Constructing Gene Team Trees  

Microsoft Academic Search

A gene team is a set of genes that appear in two or more species, possibly in a different order yet with the distance between adjacent genes in the team for each chromosome always no more than a certain threshold ? . A gene team tree is a succinct way to represent all gene teams for every possible value of

Biing-Feng Wang; Chien-Hsin Lin

2011-01-01

312

Gene expression studies in prostate cancer tissue: which reference gene should be selected for normalization?  

Microsoft Academic Search

Using quantitative reverse transcription–polymerase chain reaction (RT-PCR), reference genes are utilized as endogenous controls for relative quantification of target genes in gene profiling studies. The suitability of housekeeping genes for that purpose in prostate cancer tissue has not been sufficiently investigated so far. The objective of this study was to select from a panel of 16 potential candidate reference genes

Falk Ohl; Monika Jung; Chuanliang Xu; Carsten Stephan; Anja Rabien; Mick Burkhardt; Andreas Nitsche; Glen Kristiansen; Stefan A. Loening; Aleksandar Radoni?; Klaus Jung

2005-01-01

313

GOToolBox: functional analysis of gene datasets based on Gene Ontology  

Microsoft Academic Search

We have developed methods and tools based on the Gene Ontology (GO) resource allowing the identification of statistically over- or under-represented terms in a gene dataset; the clustering of functionally related genes within a set; and the retrieval of genes sharing annotations with a query gene. GO annotations can also be constrained to a slim hierarchy or a given level

David Martin; Christine Brun; Elisabeth Remy; Pierre Mouren; Denis Thieffry; Bernard Jacq

2004-01-01

314

Graph Kernel-Based Learning for Gene Function Prediction from Gene Interaction Network  

Microsoft Academic Search

Prediction of gene functions is a major challenge to biologists in the post-genomic era. Interactions between genes and their products compose networks and can be used to infer gene functions. Most previous studies used heuristic approaches based on either local or global information of gene interaction networks to assign unknown gene functions. In this study, we propose a graph kernel-based

Xin Li; Zhu Zhang; Hsinchun Chen; Jiexun Li

2007-01-01

315

Graph Kernel-Based Learning for Gene Function Prediction from Gene Interaction Network  

Microsoft Academic Search

Prediction of gene functions is a major challenge to biol- ogists in the post-genomic era. Interactions between genes and their products compose networks and can be used to infer gene functions. Most previous studies used heuris- tic approaches based on either local or global informa- tion of gene interaction networks to assign unknown gene functions. In this study, we propose

Xin Li; Zhu Zhang; Hsinchun Chen; Jiexun Li

2007-01-01

316

GeneMANIA Prediction Server 2013 Update  

PubMed Central

GeneMANIA (http://www.genemania.org) is a flexible user-friendly web interface for generating hypotheses about gene function, analyzing gene lists and prioritizing genes for functional assays. Given a query gene list, GeneMANIA extends the list with functionally similar genes that it identifies using available genomics and proteomics data. GeneMANIA also reports weights that indicate the predictive value of each selected data set for the query. GeneMANIA can also be used in a function prediction setting: given a query gene, GeneMANIA finds a small set of genes that are most likely to share function with that gene based on their interactions with it. Enriched Gene Ontology categories among this set can sometimes point to the function of the gene. Seven organisms are currently supported (Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Mus musculus, Homo sapiens, Rattus norvegicus and Saccharomyces cerevisiae), and hundreds of data sets have been collected from GEO, BioGRID, IRefIndex and I2D, as well as organism-specific functional genomics data sets. Users can customize their search by selecting specific data sets to query and by uploading their own data sets to analyze.

Zuberi, Khalid; Franz, Max; Rodriguez, Harold; Montojo, Jason; Lopes, Christian Tannus; Bader, Gary D.; Morris, Quaid

2013-01-01

317

Gene expression throughout a vertebrate's embryogenesis  

PubMed Central

Background Describing the patterns of gene expression during embryonic development has broadened our understanding of the processes and patterns that define morphogenesis. Yet gene expression patterns have not been described throughout vertebrate embryogenesis. This study presents statistical analyses of gene expression during all 40 developmental stages in the teleost Fundulus heteroclitus using four biological replicates per stage. Results Patterns of gene expression for 7,000 genes appear to be important as they recapitulate developmental timing. Among the 45% of genes with significant expression differences between pairs of temporally adjacent stages, significant differences in gene expression vary from as few as five to more than 660. Five adjacent stages have disproportionately more significant changes in gene expression (> 200 genes) relative to other stages: four to eight and eight to sixteen cell stages, onset of circulation, pre and post-hatch, and during complete yolk absorption. The fewest differences among adjacent stages occur during gastrulation. Yet, at stage 16, (pre-mid-gastrulation) the largest number of genes has peak expression. This stage has an over representation of genes in oxidative respiration and protein expression (ribosomes, translational genes and proteases). Unexpectedly, among all ribosomal genes, both strong positive and negative correlations occur. Similar correlated patterns of expression occur among all significant genes. Conclusions These data provide statistical support for the temporal dynamics of developmental gene expression during all stages of vertebrate development.

2011-01-01

318

Nonviral gene therapy targeting cardiovascular system.  

PubMed

The goal of gene therapy is either to introduce a therapeutic gene into or replace a defective gene in an individual's cells and tissues. Gene therapy has been urged as a potential method to induce therapeutic angiogenesis in ischemic myocardium and peripheral tissues after extensive investigation in recent preclinical and clinical studies. A successful gene therapy mainly relies on the development of the gene delivery vector. Developments in viral and nonviral vector technology including cell-based gene transfer will further improve transgene delivery and expression efficiency. Nonviral approaches as alternative gene delivery vehicles to viral vectors have received significant attention. Recently, a simple and safe approach of gene delivery into target cells using naked DNA has been improved by combining several techniques. Among the physical approaches, ultrasonic microbubble gene delivery, with its high safety profile, low costs, and repeatable applicability, can increase the permeability of cell membrane to macromolecules such as plasmid DNA by its bioeffects and can provide as a feasible tool in gene delivery. On the other hand, among the promising areas for gene therapy in acquired diseases, ischemic cardiovascular diseases have been widely studied. As a result, gene therapy using advanced technology may play an important role in this regard. The aims of this review focus on understanding the cellular and in vivo barriers in gene transfer and provide an overview of currently used chemical vectors and physical tools that are applied in nonviral cardiovascular gene transfer. PMID:22821991

Su, Cheng-Huang; Wu, Yih-Jer; Wang, Hsueh-Hsiao; Yeh, Hung-I

2012-09-15

319

Gene-gene and gene-environment interactions in ulcerative colitis.  

PubMed

Genome-wide association studies (GWAS) have identified at least 133 ulcerative colitis (UC) associated loci. The role of genetic factors in clinical practice is not clearly defined. The relevance of genetic variants to disease pathogenesis is still uncertain because of not characterized gene-gene and gene-environment interactions. We examined the predictive value of combining the 133 UC risk loci with genetic interactions in an ongoing inflammatory bowel disease (IBD) GWAS. The Wellcome Trust Case-Control Consortium (WTCCC) IBD GWAS was used as a replication cohort. We applied logic regression (LR), a novel adaptive regression methodology, to search for high-order interactions. Exploratory genotype correlations with UC sub-phenotypes [extent of disease, need of surgery, age of onset, extra-intestinal manifestations and primary sclerosing cholangitis (PSC)] were conducted. The combination of 133 UC loci yielded good UC risk predictability [area under the curve (AUC) of 0.86]. A higher cumulative allele score predicted higher UC risk. Through LR, several lines of evidence for genetic interactions were identified and successfully replicated in the WTCCC cohort. The genetic interactions combined with the gene-smoking interaction significantly improved predictability in the model (AUC, from 0.86 to 0.89, P = 3.26E-05). Explained UC variance increased from 37 to 42 % after adding the interaction terms. A within case analysis found suggested genetic association with PSC. Our study demonstrates that the LR methodology allows the identification and replication of high-order genetic interactions in UC GWAS datasets. UC risk can be predicted by a 133 loci and improved by adding gene-gene and gene-environment interactions. PMID:24241240

Wang, Ming-Hsi; Fiocchi, Claudio; Zhu, Xiaofeng; Ripke, Stephan; Kamboh, M Ilyas; Rebert, Nancy; Duerr, Richard H; Achkar, Jean-Paul

2014-05-01

320

Gene Expression Studies in Mosquitoes  

PubMed Central

Research on gene expression in mosquitoes is motivated by both basic and applied interests. Studies of genes involved in hematophagy, reproduction, olfaction, and immune responses reveal an exquisite confluence of biological adaptations that result in these highly-successful life forms. The requirement of female mosquitoes for a bloodmeal for propagation has been exploited by a wide diversity of viral, protozoan and metazoan pathogens as part of their life cycles. Identifying genes involved in host-seeking, blood feeding and digestion, reproduction, insecticide resistance and susceptibility/refractoriness to pathogen development is expected to provide the bases for the development of novel methods to control mosquito-borne diseases. Advances in mosquito transgenesis technologies, the availability of whole genome sequence information, mass sequencing and analyses of transcriptomes and RNAi techniques will assist development of these tools as well as deepen the understanding of the underlying genetic components for biological phenomena characteristic of these insect species.

Chen, Xlao-Guang; Mathur, Geetika; James, Anthony A.

2009-01-01

321

Gene therapy in Parkinson's disease.  

PubMed

Gene therapy in Parkinson's disease appears to be at the brink of the clinical study phase. Future gene therapy protocols will be based on a substantial amount of preclinical data regarding the use of ex vivo and in vivo genetic modifications with the help of viral or non-viral vectors. To date, the supplementation of neurotrophic factors and substitution for the dopaminergic deficit have formed the focus of trials to achieve relief in animal models of Parkinson's disease. Newer approaches include attempts to influence detrimental cell signalling pathways and to inhibit overactive basal ganglia structures. Nevertheless, current models of Parkinson's disease do not mirror all aspects of the human disease, and important issues with respect to long-term protein expression, choice of target structures and transgenes and safety remain to be solved. Here, we thoroughly review available animal data of gene transfer in models of Parkinson's disease. PMID:15322915

Eberhardt, O; Schulz, J B

2004-10-01

322

Epigenetic manipulation of gene expression  

PubMed Central

Cell biologists have been afforded extraordinary new opportunities for experimentation by the emergence of powerful technologies that allow the selective manipulation of gene expression. Currently, RNA interference is very much in the limelight; however, significant progress has also been made with two other approaches. Thus, antisense oligonucleotide technology is undergoing a resurgence as a result of improvements in the chemistry of these molecules, whereas designed transcription factors offer a powerful and increasingly convenient strategy for either up- or down-regulation of targeted genes. This mini-review will highlight some of the key features of these three approaches to gene regulation, as well as provide pragmatic guidance concerning their use in cell biological experimentation based on our direct experience with each of these technologies. The approaches discussed here are being intensely pursued in terms of possible therapeutic applications. However, we will restrict our comments primarily to the cell culture situation, only briefly alluding to fundamental differences between utilization in animals versus cells.

Juliano, Rudy L.; Dixit, Vidula R.; Kang, Hyunmin; Kim, Tai Young; Miyamoto, Yuko; Xu, Dong

2005-01-01

323

Transients in chloroplast gene transcription  

SciTech Connect

Transcriptional regulation of chloroplast genes is demonstrated by Quantitative Polymerase Chain Reaction (qPCR). These genes encode apoproteins of the reaction centres of photosystem I and photosystem II. Their transcription is regulated by changes in wavelength of light selectively absorbed by photosystem I and photosystem II, and therefore by the redox state of an electron carrier located between the two photosystems. Chloroplast transcriptional redox regulation is shown to have greater amplitude, and the kinetics of transcriptional changes are more complex, than suggested by previous experiments using only DNA probes in Northern blot experiments. Redox effects on chloroplast transcription appear to be superimposed on an endogenous rhythm of mRNA abundance. The functional significance of these transients in chloroplast gene transcription is discussed.

Puthiyaveetil, Sujith [School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS (United Kingdom); Allen, John F. [School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS (United Kingdom)], E-mail: j.f.allen@qmul.ac.uk

2008-04-18

324

Gene encoding plant asparagine synthetase  

DOEpatents

The identification and cloning of the gene(s) for plant asparagine synthetase (AS), an important enzyme involved in the formation of asparagine, a major nitrogen transport compound of higher plants is described. Expression vectors constructed with the AS coding sequence may be utilized to produce plant AS; to engineer herbicide resistant plants, salt/drought tolerant plants or pathogen resistant plants; as a dominant selectable marker; or to select for novel herbicides or compounds useful as agents that synchronize plant cells in culture. The promoter for plant AS, which directs high levels of gene expression and is induced in an organ specific manner and by darkness, is also described. The AS promoter may be used to direct the expression of heterologous coding sequences in appropriate hosts.

Coruzzi, Gloria M. (New York, NY); Tsai, Fong-Ying (New York, NY)

1993-10-26

325

Human height genes and cancer.  

PubMed

Body development requires the ability to control cell proliferation and metabolism, together with selective 'invasive' cell migration for organogenesis. These requirements are shared with cancer. Human height-associated loci have been recently identified by genome-wide SNP-association studies. Strikingly, most of the more than 100 genes found associated to height appear linked to neoplastic growth, and impose a higher risk for cancer. Height-associated genes drive the HH/PTCH and BMP/TGF? pathways, with p53, c-Myc, ER?, HNF4A and SMADs as central network nodes. Genetic analysis of body-size-affecting diseases and evidence from genetically-modified animals support this model. The finding that cancer is deeply linked to normal, body-plan master genes may profoundly affect current paradigms on tumor development. PMID:23428607

Tripaldi, Romina; Stuppia, Liborio; Alberti, Saverio

2013-08-01

326

GENE THERAPY FOR VENTRICULAR TACHYARRHYTHMIAS  

PubMed Central

Cardiac arrest is the leading cause of death in the United States and other developed countries. Ventricular tachyarrhythmias are the most prominent cause of cardiac arrest, and patients with structural heart disease are at increased risk for these abnormal heart rhythms. Drug and device therapy have important limitations that make them inadequate to meet this challenge. We and others have proposed development of arrhythmia gene therapy as an alternative to current treatment methods. In this review, I discuss the basic mechanisms of ventricular arrhythmias and summarize the literature on the use of gene therapy for ventricular tachyarrhythmias.

Donahue, J. Kevin

2013-01-01

327

Leukemogenesis: More Than Mutant Genes  

PubMed Central

Acute leukemias are characterized by recurring chromosomal aberrations and gene mutations which are critical to disease pathogenesis. It is now evident that epigenetic modifications including DNA methylation and histone modifications contribute significantly to the leukemogenic phenotype. An additional layer of epigenetic complexity is the pathogenetic role of microRNAs in leukemias, and their key role in the transcriptional regulation of tumor suppressor genes and oncogenes. The genetic heterogeneity of acute leukemias poses therapeutic challenges, but pharmacologic agents that target components of the epigenetic machinery hold promise as a part of the therapeutic arsenal for this group of diseases.

Chen, Jianjun; Odenike, Olatoyosi; Rowley, Janet D.

2010-01-01

328

Gene therapy in clinical medicine  

PubMed Central

Although the field of gene therapy has experienced significant setbacks and limited success, it is one of the most promising and active research fields in medicine. Interest in this therapeutic modality is based on the potential for treatment and cure of some of the most malignant and devastating diseases affecting humans. Over the next decade, the relevance of gene therapy to medical practices will increase and it will become important for physicians to understand the basic principles and strategies that underlie the therapeutic intervention. This report reviews the history, basic strategies, tools, and several current clinical paradigms for application.

Selkirk, S

2004-01-01

329

Zipf's Law in Gene Expression  

NASA Astrophysics Data System (ADS)

Using data from gene expression databases on various organisms and tissues, including yeast, nematodes, human normal and cancer tissues, and embryonic stem cells, we found that the abundances of expressed genes exhibit a power-law distribution with an exponent close to -1; i.e., they obey Zipf’s law. Furthermore, by simulations of a simple model with an intracellular reaction network, we found that Zipf’s law of chemical abundance is a universal feature of cells where such a network optimizes the efficiency and faithfulness of self-reproduction. These findings provide novel insights into the nature of the organization of reaction dynamics in living cells.

Furusawa, Chikara; Kaneko, Kunihiko

2003-02-01

330

GenePRIMP: Improving Microbial Gene Prediction Quality  

SciTech Connect

Amrita Pati of the DOE Joint Genome Institute's Genome Biology group talks about a computational pipeline that evaluates the accuracy of gene models in genomes and metagenomes at different stages of finishing at the "Sequencing, Finishing, Analysis in the Future" meeting in Santa Fe, NM

Pati, Amrita [DOE Joint Genome Institute's Genome Biology group

2009-05-29

331

Machine Learning for Detecting Gene-Gene Interactions  

PubMed Central

Complex interactions among genes and environmental factors are known to play a role in common human disease aetiology. There is a growing body of evidence to suggest that complex interactions are ‘the norm’ and, rather than amounting to a small perturbation to classical Mendelian genetics, interactions may be the predominant effect. Traditional statistical methods are not well suited for detecting such interactions, especially when the data are high dimensional (many attributes or independent variables) or when interactions occur between more than two polymorphisms. In this review, we discuss machine-learning models and algorithms for identifying and characterising susceptibility genes in common, complex, multifactorial human diseases. We focus on the following machine-learning methods that have been used to detect gene-gene interactions: neural networks, cellular automata, random forests, and multifactor dimensionality reduction. We conclude with some ideas about how these methods and others can be integrated into a comprehensive and flexible framework for data mining and knowledge discovery in human genetics.

McKinney, Brett A.; Reif, David M.; Ritchie, Marylyn D.; Moore, Jason H.

2011-01-01

332

Many ribosomal protein genes are cancer genes in zebrafish  

Microsoft Academic Search

We have generated several hundred lines of zebrafish (Danio rerio), each heterozygous for a recessive embryonic lethal mutation. Since many tumor suppressor genes are recessive lethals, we screened our colony for lines that display early mortality and\\/or gross evidence of tumors. We identified 12 lines with elevated cancer incidence. Fish from these lines develop malignant peripheral nerve sheath tumors, and

Adam Amsterdam; Kirsten C. Sadler; Kevin Lai; Sarah Farrington; Roderick T. Bronson; Jacqueline A. Lees; Nancy Hopkins

2004-01-01

333

Gene-Environment Interaction in Yeast Gene Expression  

PubMed Central

The effects of genetic variants on phenotypic traits often depend on environmental and physiological conditions, but such gene–environment interactions are poorly understood. Recently developed approaches that treat transcript abundances of thousands of genes as quantitative traits offer the opportunity to broadly characterize the architecture of gene–environment interactions. We examined the genetic and molecular basis of variation in gene expression between two yeast strains (BY and RM) grown in two different conditions (glucose and ethanol as carbon sources). We observed that most transcripts vary by strain and condition, with 2,996, 3,448, and 2,037 transcripts showing significant strain, condition, and strain–condition interaction effects, respectively. We expression profiled over 100 segregants derived from a cross between BY and RM in both growth conditions, and identified 1,555 linkages for 1,382 transcripts that show significant gene–environment interaction. At the locus level, local linkages, which usually correspond to polymorphisms in cis-regulatory elements, tend to be more stable across conditions, such that they are more likely to show the same effect or the same direction of effect across conditions. Distant linkages, which usually correspond to polymorphisms influencing trans-acting factors, are more condition-dependent, and often show effects in different directions in the two conditions. We characterized a locus that influences expression of many growth-related transcripts, and showed that the majority of the variation is explained by polymorphism in the gene IRA2. The RM allele of IRA2 appears to inhibit Ras/PKA signaling more strongly than the BY allele, and has undergone a change in selective pressure. Our results provide a broad overview of the genetic architecture of gene–environment interactions, as well as a detailed molecular example, and lead to key insights into how the effects of different classes of regulatory variants are modulated by the environment. These observations will guide the design of studies aimed at understanding the genetic basis of complex traits.

Smith, Erin N; Kruglyak, Leonid

2008-01-01

334

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

PubMed

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 apply them in concert to the analysis of 9556 positional candidate genes for type 2 diabetes (T2D) and the related trait obesity. We generate and analyse a list of nine primary candidate genes for T2D genes and five for obesity. Two genes, LPL and BCKDHA, are common to these two sets. We also present a set of secondary candidates for T2D (94 genes) and for obesity (116 genes) with 58 genes in common to both diseases. PMID:16757574

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

2006-01-01

335

Amplification of kinetic oscillations in gene expression  

NASA Astrophysics Data System (ADS)

Because of the feedbacks between the DNA transcription and mRNA translation, the gene expression in cells may exhibit bistability and oscillations. The deterministic and stochastic calculations presented illustrate how the bistable kinetics of expression of one gene in a cell can be influenced by the kinetic oscillations in the expression of another gene. Due to stability of the states of the bistable kinetics of gene 1 and the relatively small difference between the maximum and minimum protein amounts during the oscillations of gene 2, the induced oscillations of gene 1 are found to typically be related either to the low-or high-reactive state of this gene. The quality of the induced oscillations may be appreciably better than that of the inducing oscillations. This means that gene 1 can serve as an amplifier of the kinetic oscillations of gene 2.

Zhdanov, V. P.

2008-10-01

336

Gene therapy on demand: site specific regulation of gene therapy.  

PubMed

Since 1990 when the first clinical gene therapy trial was conducted, much attention and considerable promise have been given to this form of treatment. Gene therapy has been used with success in patients suffering from severe combined immunodeficiency syndromes (X-SCID and ADA-deficiency), Leber's congenital amaurosis, hemophilia, ?-thalassemia and adrenoleukodystrophy. Last year, the first therapeutic vector (Glybera) for treatment of lipoprotein lipase deficiency has been registered in the European Union. Nevertheless, there are still several numerous issues that need to be improved to make this technique more safe, effective and easily accessible for patients. Introduction of the therapeutic gene to the given cells should provide the level of expression which will restore the production of therapeutic protein to normal values or will provide therapeutic efficacy despite not fully physiological expression. However, in numerous diseases the expression of therapeutic genes has to be kept at certain level for some time, and then might be required to be switched off to be activated again when worsening of the symptoms may aggravate the risk of disease relapse. In such cases the promoters which are regulated by local conditions may be more required. In this article the special emphasis is to discuss the strategies of regulation of gene expression by endogenous stimuli. Particularly, the hypoxia- or miRNA-regulated vectors offer the possibilities of tight but, at the same time, condition-dependent and cell-specific expression. Such means have been already tested in certain pathophysiological conditions. This creates the chance for the translational approaches required for development of effective treatments of so far incurable diseases. PMID:23566848

Jazwa, Agnieszka; Florczyk, Urszula; Jozkowicz, Alicja; Dulak, Jozef

2013-08-10

337

Identification of 10 murine homeobox genes.  

PubMed Central

In Drosophila a number of genes important in establishing segmentation patterns and in determining segment identities have been shown to carry the homeobox sequence. Over 30 murine homeobox genes have been cloned, many on the basis of sequence homology to Drosophila prototypes. Here we report the cloning and sequencing of 10 new and 6 previously known homeobox genes by screening a murine genomic library with a 768-fold degenerate oligonucleotide corresponding to the most conserved 8-amino acid motif in the recognition helix of the homeodomain. Eight of these new homeobox genes have been chromosomally mapped. Four genes do not belong to any of the known homeobox gene clusters but instead map to new locations on chromosome 1 (single gene) and chromosome 5 (three genes). Sequence comparisons indicate that two of these are very closely related and represent a distinct new category of homeobox genes. The remaining four mapped genes reside in previously established murine homeobox gene clusters. Specifically, two map to the cluster HOX-1 on chromosome 6 and one each to HOX-3 and HOX-4 on chromosome 15 and 2, respectively. The ratio of newly identified homeobox genes to the previously characterized murine homeobox genes suggests that there remain several uncharacterized homeobox genes in the murine genome. Images

Singh, G; Kaur, S; Stock, J L; Jenkins, N A; Gilbert, D J; Copeland, N G; Potter, S S

1991-01-01

338

Identifying disease feature genes based on cellular localized gene functional modules and regulation networks  

Microsoft Academic Search

Identifying disease-relevant genes and functional modules, based on gene expression profiles and gene functional knowledge,\\u000a is of high importance for studying disease mechanisms and subtyping disease phenotypes. Using gene categories of biological\\u000a process and cellular component in Gene Ontology, we propose an approach to selecting functional modules enriched with differentially\\u000a expressed genes, and identifying the feature functional modules of high

Min Zhang; Jing Zhu; Zheng Guo; Xia Li; Da Yang; Lei Wang; Shaoqi Rao

2006-01-01

339

Rapid Concerted Evolution via Gene Conversion at the Drosophila hsp70 Genes  

Microsoft Academic Search

.   We analyzed nucleotide variation in the hsp70 genes of Drosophila melanogaster (five genes) and D. simulans (four genes) to characterize the homogenizing and diversifying roles of gene conversion in their evolution. Gene conversion\\u000a within and between the 87A7 and 87C1 gene clusters homogenize the hsp70 coding regions; in both D. melanogaster and D. simulans, same-cluster paralogues are virtually identical,

Brian R. Bettencourt; Martin E. Feder

2002-01-01

340

Evolution of the chicken Toll-like receptor gene family: A story of gene gain and gene loss  

PubMed Central

Background Toll-like receptors (TLRs) perform a vital role in disease resistance through their recognition of pathogen associated molecular patterns (PAMPs). Recent advances in genomics allow comparison of TLR genes within and between many species. This study takes advantage of the recently sequenced chicken genome to determine the complete chicken TLR repertoire and place it in context of vertebrate genomic evolution. Results The chicken TLR repertoire consists of ten genes. Phylogenetic analyses show that six of these genes have orthologs in mammals and fish, while one is only shared by fish and three appear to be unique to birds. Furthermore the phylogeny shows that TLR1-like genes arose independently in fish, birds and mammals from an ancestral gene also shared by TLR6 and TLR10. All other TLRs were already present prior to the divergence of major vertebrate lineages 550 Mya (million years ago) and have since been lost in certain lineages. Phylogenetic analysis shows the absence of TLRs 8 and 9 in chicken to be the result of gene loss. The notable exception to the tendency of gene loss in TLR evolution is found in chicken TLRs 1 and 2, each of which underwent gene duplication about 147 and 65 Mya, respectively. Conclusion Comparative phylogenetic analysis of vertebrate TLR genes provides insight into their patterns and processes of gene evolution, with examples of both gene gain and gene loss. In addition, these comparisons clarify the nomenclature of TLR genes in vertebrates.

Temperley, Nicholas D; Berlin, Sofia; Paton, Ian R; Griffin, Darren K; Burt, David W

2008-01-01

341

The mammalian RPS6 gene, homolog of the Drosophila air8 tumor suppressor gene: is it an oncosuppressor gene?  

PubMed

The mammalian gene encoding the S6 ribosomal protein is the homolog of the Drosophila air8 tumor suppressor gene. We assigned the rat Rps6 gene to chromosome 5q22-33. The rat 5q22-33 chromosome region, previously shown to bear a malignant transformation suppressor gene, is homologous to the human 9p2l region, frequently deleted in various kinds of cancers and also containing at least one tumor suppressor (oncosuppressor) gene. To test the possibility that the Rps6 gene could be an oncosuppressor gene in mammals, we analysed its sequence and expression in normal and malignantly transformed cells. In mouse hepatoma cells (BWTG3), the Rps6 gene is hemizygously deleted but the remaining copy shows no sequence anomaly in the coding region, indicating that Rps6 is not oncosuppressor and that another gene acting as an oncosuppressor is located in its vicinity. In human tumor cells, the RPS6 gene is retained in cells showing deletion of the near-by gene, IFNB. Our results do not support the possibility that the RPS6 gene acts as an oncosuppressor gene in mammalian cells. PMID:8600571

Lecomte, F; Champagne, B; Dasnoy, J F; Szpirer, J; Szpirer, C

1995-11-01

342

Gene therapy and its implications in Periodontics  

PubMed Central

Gene therapy is a field of Biomedicine. With the advent of gene therapy in dentistry, significant progress has been made in the control of periodontal diseases and reconstruction of dento-alveolar apparatus. Implementation in periodontics include: -As a mode of tissue engineering with three approaches: cell, protein-based and gene delivery approach. -Genetic approach to Biofilm Antibiotic Resistance. Future strategies of gene therapy in preventing periodontal diseases: -Enhances host defense mechanism against infection by transfecting host cells with an antimicrobial peptide protein-encoding gene. -Periodontal vaccination. Gene therapy is one of the recent entrants and its applications in the field of periodontics are reviewed in general here.

Mahale, Swapna; Dani, Nitin; Ansari, Shumaila S.; Kale, Triveni

2009-01-01

343

Gene transfer: anything goes in plant mitochondria  

PubMed Central

Parasitic plants and their hosts have proven remarkably adept at exchanging fragments of mitochondrial DNA. Two recent studies provide important mechanistic insights into the pattern, process and consequences of horizontal gene transfer, demonstrating that genes can be transferred in large chunks and that gene conversion between foreign and native genes leads to intragenic mosaicism. A model involving duplicative horizontal gene transfer and differential gene conversion is proposed as a hitherto unrecognized source of genetic diversity. See research article: http://www.biomedcentral.com/1741-7007/8/150

2010-01-01

344

GenePRIMP: a gene prediction improvement pipeline for prokaryotic genomes.  

PubMed

We present 'gene prediction improvement pipeline' (GenePRIMP; http://geneprimp.jgi-psf.org/), a computational process that performs evidence-based evaluation of gene models in prokaryotic genomes and reports anomalies including inconsistent start sites, missed genes and split genes. We found that manual curation of gene models using the anomaly reports generated by GenePRIMP improved their quality, and demonstrate the applicability of GenePRIMP in improving finishing quality and comparing different genome-sequencing and annotation technologies. PMID:20436475

Pati, Amrita; Ivanova, Natalia N; Mikhailova, Natalia; Ovchinnikova, Galina; Hooper, Sean D; Lykidis, Athanasios; Kyrpides, Nikos C

2010-06-01

345

Ancient genes of Saccharomyces cerevisiae.  

PubMed

Amber is a plant resin mainly produced by coniferous trees that, after entrapping a variety of living beings, was subjected to a process of fossilization until it turned into yellowish, translucent stones. It is also one of the best sources of ancient DNA on which to perform studies on evolution. Here a method for the sterilization of amber that allows reliable ancient DNA extraction with no actual DNA contamination is described. Working with insects taken from amber, it was possible to amplify the ATP9, PGU1 and rRNA18S ancient genes of Saccharomyces cerevisiae corresponding to samples from the Miocene and Oligocene. After comparison of the current genes with their ancient (up to 35-40 million years) counterparts it was concluded that essential genes such as rRNA18S are highly conserved and that even normal 'house-keeping' genes, such as PGU1, are strikingly conserved along the millions of years that S. cerevisiae has evolved. PMID:15256564

Veiga-Crespo, P; Poza, M; Prieto-Alcedo, M; Villa, T G

2004-07-01

346

The dps Gene of Symbiotic \\  

Microsoft Academic Search

To survive in host cells, intracellular pathogens or symbiotic bacteria require protective mechanisms to overcome the oxidative stress generated by phagocytic activities of the host. By genomic library tagging, we cloned a dps (stands for DNA-binding protein from starved cells) gene of the symbiotic \\

Seong Tae Yun; Sue-Yun Hwang; Choong-Ill Chun; Tae In Ahn

2006-01-01

347

Dock 3 Tumor Suppressor Gene.  

National Technical Information Service (NTIS)

The invention relates to a newly identified tumor suppressor gene, designated DOS (for Deleted in Osteosarcoma and alternatively referred to herein as DOCK 3) which has been cloned from human and mouse cells. The DOS nucleic acid and protein molecules and...

A. McClatchey C. Paulding D. Haber V. Yajnik

2002-01-01

348

DNA Methylation and Gene Function  

Microsoft Academic Search

In most higher organisms, DNA is modified after synthesis by the enzymatic conversion of many cytosine residues to 5-methylcytosine. For several years, control of gene activity by DNA methylation has been recognized as a logically attractive possibility, but experimental support has proved elusive. However, there is now reason to believe, from recent studies, that DNA methylation is a key element

Aharon Razin; Arthur D. Riggs

1980-01-01

349

Orthopedic Gene Therapy in 2008  

Microsoft Academic Search

Orthopedic disorders, although rarely fatal, are the leading cause of morbidity and impose a huge socioeconomic burden. Their prevalence will increase dramatically as populations age and gain weight. Many orthopedic conditions are difficult to treat by conventional means; however, they are good candidates for gene therapy. Clinical trials have already been initiated for arthritis and the aseptic loosening of prosthetic

Christopher H Evans; Steven C Ghivizzani; Paul D Robbins

2009-01-01

350

Gene therapy for pancreatitis pain.  

PubMed

Pancreatic cancer and chronic pancreatitis are clinical syndromes associated with severe pain that is difficult to manage. Thus, seeking additional pain reduction therapies is warranted. Excessive alcohol consumption over an extended period of time is the primary causal agent in pancreatitis. The efficacy of a replication defective Herpes (HSV-1, DPE) viral vector construct encoding the human preproenkephalin gene (HSV-Enk), used as a molecular therapy for alleviation of pancreatitis pain, is reviewed here. The characteristics of the gene therapy treatment for inflammation and pain-related behavior in two alcoholic pancreatitis animal models is described. Significant analgesia and protection of pancreatic tissue was provided for the duration of the transgene expression (approximately 4-6 weeks). These studies establish a basis for use of HSV-based gene therapy for chronic visceral pain. Targeted enkephalin gene therapy approaches are providing clear promise for pain control. As innovative means of significantly reducing pancreatic inflammation and preserving tissue architecture, they may extend their clinical usefulness for pancreatitis and pancreatic cancer pain patients. PMID:19262610

Westlund, K N

2009-04-01

351

Ethics of Gene Therapy Debated.  

ERIC Educational Resources Information Center

Presented are the highlights of a press conference featuring biomedical ethicist LeRoy Walters of Georgetown University and attorney Andrew Kimbrell of the Foundation on Economic Trends. The opposing points of view of these two speakers serve to outline the pros and cons of the gene therapy issue. (CW)

Borman, Stu

1991-01-01

352

Gene Loss in Human Teratomas  

Microsoft Academic Search

If benign cystic teratomas (dermoid cysts) of the ovary arise from a germ cell that has undergone meiosis, they should be missing genes which are present in the person. Three independently segregating allelic isozymes in 11 benign cystic teratomas of the human female ovary were compared with normal tissue of the same case. Dermoid cysts from persons heterozygous for these

David Linder

1969-01-01

353

Gene Expression in Trypanosomatid Parasites  

PubMed Central

The parasites Leishmania spp., Trypanosoma brucei, and Trypanosoma cruzi are the trypanosomatid protozoa that cause the deadly human diseases leishmaniasis, African sleeping sickness, and Chagas disease, respectively. These organisms possess unique mechanisms for gene expression such as constitutive polycistronic transcription of protein-coding genes and trans-splicing. Little is known about either the DNA sequences or the proteins that are involved in the initiation and termination of transcription in trypanosomatids. In silico analyses of the genome databases of these parasites led to the identification of a small number of proteins involved in gene expression. However, functional studies have revealed that trypanosomatids have more general transcription factors than originally estimated. Many posttranslational histone modifications, histone variants, and chromatin modifying enzymes have been identified in trypanosomatids, and recent genome-wide studies showed that epigenetic regulation might play a very important role in gene expression in this group of parasites. Here, we review and comment on the most recent findings related to transcription initiation and termination in trypanosomatid protozoa.

Martinez-Calvillo, Santiago; Vizuet-de-Rueda, Juan C.; Florencio-Martinez, Luis E.; Manning-Cela, Rebeca G.; Figueroa-Angulo, Elisa E.

2010-01-01

354

Gene expression in trypanosomatid parasites.  

PubMed

The parasites Leishmania spp., Trypanosoma brucei, and Trypanosoma cruzi are the trypanosomatid protozoa that cause the deadly human diseases leishmaniasis, African sleeping sickness, and Chagas disease, respectively. These organisms possess unique mechanisms for gene expression such as constitutive polycistronic transcription of protein-coding genes and trans-splicing. Little is known about either the DNA sequences or the proteins that are involved in the initiation and termination of transcription in trypanosomatids. In silico analyses of the genome databases of these parasites led to the identification of a small number of proteins involved in gene expression. However, functional studies have revealed that trypanosomatids have more general transcription factors than originally estimated. Many posttranslational histone modifications, histone variants, and chromatin modifying enzymes have been identified in trypanosomatids, and recent genome-wide studies showed that epigenetic regulation might play a very important role in gene expression in this group of parasites. Here, we review and comment on the most recent findings related to transcription initiation and termination in trypanosomatid protozoa. PMID:20169133

Martínez-Calvillo, Santiago; Vizuet-de-Rueda, Juan C; Florencio-Martínez, Luis E; Manning-Cela, Rebeca G; Figueroa-Angulo, Elisa E

2010-01-01

355

Circadian gene variants in cancer.  

PubMed

Abstract Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostasis leading to increased risk of various diseases including cancer. The clock is operated by the feedback loops of circadian genes and controls daily physiology by coupling cell proliferation and metabolism, DNA damage repair, and apoptosis in peripheral tissues with physical activity, energy homeostasis, immune and neuroendocrine functions at the organismal level. Recent studies have revealed that defects in circadian genes due to targeted gene ablation in animal models or single nucleotide polymorphism, deletion, deregulation and/or epigenetic silencing in humans are closely associated with increased risk of cancer. In addition, disruption of circadian rhythm can disrupt the molecular clock in peripheral tissues in the absence of circadian gene mutations. Circadian disruption has recently been recognized as an independent cancer risk factor. Further study of the mechanism of clock-controlled tumor suppression will have a significant impact on human health by improving the efficiencies of cancer prevention and treatment. PMID:24901356

Kettner, Nicole M; Katchy, Chinenye A; Fu, Loning

2014-06-01

356

Genes and Syndromic Hearing Loss.  

ERIC Educational Resources Information Center

This article provides a description of the human genome and patterns of inheritance and discusses genes that are associated with some of the syndromes for which hearing loss is a common finding, including: Waardenburg, Stickler, Jervell and Lange-Neilsen, Usher, Alport, mitochondrial encephalomyopathy, and sensorineural hearing loss. (Contains…

Keats, Bronya J. B.

2002-01-01

357

ACTH resistance: genes and mechanisms.  

PubMed

ACTH resistance is a rare disorder typified by familial glucocorticoid deficiency (FGD), a genetically heterogeneous disease. Previously, genetic defects in FGD have been identified in the ACTH receptor gene (MC2R), its accessory protein (MRAP) and the steroidogenic acute regulatory protein gene (STAR). The defective mechanisms here are failures in ACTH ligand binding and/or receptor trafficking for MC2R and MRAP and, in the case of STAR mutations, inefficient cholesterol transport to allow steroidogenesis to proceed. Novel gene defects in FGD have recently been recognised in mini-chromosome maintenance-deficient 4 homologue (MCM4) and nicotinamide nucleotide transhydrogenase (NNT). MCM4 is one part of a DNA repair complex essential for DNA replication and genome stability, whilst NNT is involved in the glutathione redox system that protects cells against reactive oxygen species. The finding of mutations in these two genes implicates new pathogenetic mechanisms at play in FGD, and implies that the adrenal cortex is exquisitely sensitive to replicative and oxidative stresses. PMID:23392095

Meimaridou, E; Hughes, C R; Kowalczyk, J; Chan, L F; Clark, A J L; Metherell, L A

2013-01-01

358

The Caenorhabditis chemoreceptor gene families  

Microsoft Academic Search

BACKGROUND: Chemoreceptor proteins mediate the first step in the transduction of environmental chemical stimuli, defining the breadth of detection and conferring stimulus specificity. Animal genomes contain families of genes encoding chemoreceptors that mediate taste, olfaction, and pheromone responses. The size and diversity of these families reflect the biology of chemoperception in specific species. RESULTS: Based on manual curation and sequence

James H Thomas; Hugh M Robertson

2008-01-01

359

Molecular biology of epilepsy genes.  

PubMed

Multifactorial inheritance is the most important model accounting for the genetic behavior of the common epilepsies. Important to this model is the concept that many cumulative or synergistic risk genes ultimately lead to a threshold effect. Sophisticated molecular testing indicates that the common epilepsies are very polygenic without evidence of any single gene having even a mild-to-modest risk effect. However, enrichment of copy number variants in cohorts of individuals with epilepsy indicates that certain structural changes in the genome can confer significant risk for epilepsy. The mechanisms whereby copy number variants confer this effect are not yet known. The study of epilepsy due to single gene defects however has helped clarify certain seizure mechanisms. For example, discoveries using animal models of SCN1A or ARX mutations implicate a predominant role for interneurons due to disturbed GABAergic function. It is hoped that future genetic and neurobiological studies will provide better insight into how multiple genes contribute to the common epilepsies. PMID:22178301

Williams, Charles A; Battaglia, Agatino

2013-06-01

360

Gene-Culture Coevolutionary Games  

ERIC Educational Resources Information Center

Gene-culture interactions have largely been modelled employing population genetic-type models. Moreover, in the most notable application to date, the "interactive" modes have been one way rather than bidirectional. This paper suggests using game theoretic, fully interactive models. Employing the logic utilized in population ecology for coevolution…

Blute, Marion

2006-01-01

361

Molecular Genetics: Proteins and Genes  

NSDL National Science Digital Library

In this chapter, the authors focus conceptually on the connection between genotype and phenotype, specifically the role of genes and proteins in that connection. They also consider the importance of proteins to the work of cells and the impact of proteins

Tweed, Susan K.

2009-05-22

362

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

363

MGC: a metagenomic gene caller  

PubMed Central

Background Computational gene finding algorithms have proven their robustness in identifying genes in complete genomes. However, metagenomic sequencing has presented new challenges due to the incomplete and fragmented nature of the data. During the last few years, attempts have been made to extract complete and incomplete open reading frames (ORFs) directly from short reads and identify the coding ORFs, bypassing other challenging tasks such as the assembly of the metagenome. Results In this paper we introduce a metagenomics gene caller (MGC) which is an improvement over the state-of-the-art prediction algorithm Orphelia. Orphelia uses a two-stage machine learning approach and computes a model that classifies extracted ORFs from fragmented sequences. We hypothesise and demonstrate evidence that sequences need separate models based on their local GC-content in order to avoid the noise introduced to a single model computed with sequences from the entire GC spectrum. We have also added two amino-acid features based on the benefit of amino-acid usage shown in our previous research. Our algorithm is able to predict genes and translation initiation sites (TIS) more accurately than Orphelia which uses a single model. Conclusions Learning separate models for several pre-defined GC-content regions as opposed to a single model approach improves the performance of the neural network as demonstrated by the experimental results presented in this paper. The inclusion of amino-acid usage features also helps improve the overall accuracy of our algorithm. MGC's improvement sets the ground for further investigation into the use of GC-content to separate data for training models in machine learning based gene finders.

2013-01-01

364

Vascular gene expression: a hypothesis  

PubMed Central

The phloem is the conduit through which photoassimilates are distributed from autotrophic to heterotrophic tissues and is involved in the distribution of signaling molecules that coordinate plant growth and responses to the environment. Phloem function depends on the coordinate expression of a large array of genes. We have previously identified conserved motifs in upstream regions of the Arabidopsis genes, encoding the homologs of pumpkin phloem sap mRNAs, displaying expression in vascular tissues. This tissue-specific expression in Arabidopsis is predicted by the overrepresentation of GA/CT-rich motifs in gene promoters. In this work we have searched for common motifs in upstream regions of the homologous genes from plants considered to possess a “primitive” vascular tissue (a lycophyte), as well as from others that lack a true vascular tissue (a bryophyte), and finally from chlorophytes. Both lycophyte and bryophyte display motifs similar to those found in Arabidopsis with a significantly low E-value, while the chlorophytes showed either a different conserved motif or no conserved motif at all. These results suggest that these same genes are expressed coordinately in non-vascular plants; this coordinate expression may have been one of the prerequisites for the development of conducting tissues in plants. We have also analyzed the phylogeny of conserved proteins that may be involved in phloem function and development. The presence of CmPP16, APL, FT, and YDA in chlorophytes suggests the recruitment of ancient regulatory networks for the development of the vascular tissue during evolution while OPS is a novel protein specific to vascular plants.

Martinez-Navarro, Angelica C.; Galvan-Gordillo, Santiago V.; Xoconostle-Cazares, Beatriz; Ruiz-Medrano, Roberto

2013-01-01

365

Small genes/gene-products in Escherichia coli K-12.  

PubMed

Forty-two protein spots of observed M(r) 6-15 kDa were resolved by two-dimensional gel electrophoresis, stained by Coomassie blue and subjected to Edman microsequencing. All of the proteins could be related back to their encoding open reading frames, thereby vindicating the bioinformatic tools currently utilised in their identification. However, only 14/42 gene-products were expressed as annotated. Translation was confirmed for 14 open reading frames with no attributed function (EcoGene Y-entries), while N-terminal sequence allowed the start codon to be accurately annotated for the genes yigF, yccU, yqiC, ynfD, and yeeX. The methionine start codon was cleaved in 11 gene-products (AtpE, Hns, RpoZ, RplL, CspC, YccJ, YggX, YjgF, HimA, InfA, RpsQ) and a further five showed loss of a signal peptide (PspE, HdeB, HdeA, YnfD, YkfE). Internal (Tig, AtpA, TufA) and N-terminal fragmentation (CspD, RpsF, AtcU) of much larger proteins was also detected, which may have resulted from physiological or translational processes. M(r) and pI isoforms were detected respectively for PtsH and GatB, each being phosphoproteins, as well as RplY which manifested differences with respect to predicted M(r) and pI. In addition, YjgF was shown to belong to a small gene family of unknown function with ancient conserved regions across procaryotes and eucaryotes. YgiN was revealed to have a paralogue and orthologues in Bacillus subtilis, Synechocystis sp., Mycobacterium tuberculosis, Neisseria gonorrhoea, and Rhodococcus erythropolis. Orthologues are also reported for YihD, YccU and YeeX. Of the 14 Y-genes, only YkfE possessed no detectable orthologues. These results highlight the need to complement genomic analysis with detailed proteomics in order to gain a better understanding of cellular molecular biology, while the confirmation of the open reading frame start codon using Edman degradation protein microsequencing has yet to be superseded by recent advances in mass spectrometry. PMID:9868784

Wasinger, V C; Humphery-Smith, I

1998-12-15

366

Simultaneous Identification of Duplications and Lateral Gene Transfers  

Microsoft Academic Search

The incongruency between a gene tree and a corresponding species tree can be attributed to evolutionary events such as gene duplication and gene loss. This paper describes a combinatorial model where so-called DTL-scenarios are used to explain the differences between a gene tree and a corresponding species tree taking into account gene duplications, gene losses, and lateral gene transfers (also

Ali Tofigh; Michael T. Hallett; Jens Lagergren

2011-01-01

367

Homeobox genes in normal hematopoiesis and leukemogenesis.  

PubMed

Homeobox genes are broadly classified into two subclasses: HOX and non-HOX homeobox genes. A number of genes in both classes are expressed in a variety of hematopoietic cells. Two major categories of evidence implying the involvement of these genes in normal hematopoiesis have been demonstrated. First, the expression pattern of the homeobox genes in hematopoietic cells is lineage- and differentiation-stage specific. Second, enforced and suppressed expression of various homeobox genes cause defects in the hematopoietic cells of specific lineages. The reduction in myeloid, erythroid and B cell progenitors is found in mice with a disrupted HOXA9 gene. The thymuses of HOXB3-overexpressed marrow recipients contain a markedly decreased number of CD4/CD8 double-positive T cells. These examples suggest that the proper level of expression and timely down-regulation of some homeobox genes are necessary for normal hematopoiesis. Homeobox genes are also implicated in human and mouse leukemias. In human leukemias, a HOX gene (HOXA9) and two non-HOX homeobox genes (PBX1 and HOX11) are involved in chromosomal translocations. In mouse leukemias, provirus integrations cause aberrant expression of several HOX and non-HOX genes. Currently available information will be discussed separately on HOX and non-HOX genes, in normal and leukemic hematopoiesis, respectively. PMID:9885434

Chiba, S

1998-12-01

368

Nucleotide sequence of Klebsiella pneumoniae lac genes.  

PubMed Central

The nucleotide sequences of the Klebsiella pneumoniae lacI and lacZ genes and part of the lacY gene were determined, and these genes were located and oriented relative to one another. The K. pneumoniae lac operon is divergent in that the lacI and lacZ genes are oriented head to head, and complementary strands are transcribed. Besides base substitutions, the lacZ genes of K. pneumoniae and Escherichia coli have suffered short distance shifts of reading frame caused by additions or deletions or both during evolutionary divergence from a common ancestral gene. Relative to corresponding E. coli sequences, the nucleotide sequences of the lacZ and lacY genes are 61 and 67% conserved, and the lacI genes are 49% conserved. A comparison of both nucleotide and amino acid sequences revealed that the K. pneumoniae and E. coli lacI genes and lac repressor proteins each are related to the galR gene and gal repressor of E. coli to about the same extent. In terms of evolutionary relationships, the divergence of the forerunner of the galR gene from an ancestral lac repressor gene preceded separation and differentiation of the K. pneumoniae and E. coli lac repressor genes.

Buvinger, W E; Riley, M

1985-01-01

369

Thesaurus-based disambiguation of gene symbols  

PubMed Central

Background Massive text mining of the biological literature holds great promise of relating disparate information and discovering new knowledge. However, disambiguation of gene symbols is a major bottleneck. Results We developed a simple thesaurus-based disambiguation algorithm that can operate with very little training data. The thesaurus comprises the information from five human genetic databases and MeSH. The extent of the homonym problem for human gene symbols is shown to be substantial (33% of the genes in our combined thesaurus had one or more ambiguous symbols), not only because one symbol can refer to multiple genes, but also because a gene symbol can have many non-gene meanings. A test set of 52,529 Medline abstracts, containing 690 ambiguous human gene symbols taken from OMIM, was automatically generated. Overall accuracy of the disambiguation algorithm was up to 92.7% on the test set. Conclusion The ambiguity of human gene symbols is substantial, not only because one symbol may denote multiple genes but particularly because many symbols have other, non-gene meanings. The proposed disambiguation approach resolves most ambiguities in our test set with high accuracy, including the important gene/not a gene decisions. The algorithm is fast and scalable, enabling gene-symbol disambiguation in massive text mining applications.

Schijvenaars, Bob JA; Mons, Barend; Weeber, Marc; Schuemie, Martijn J; van Mulligen, Erik M; Wain, Hester M; Kors, Jan A

2005-01-01

370

Wistar Institute study finds multiple 'siblings' from every gene: Alternate gene reading leads to alternate gene products:  

Cancer.gov

A genome-wide survey by researchers at The Wistar Institute shows how our cells create alternate versions of mRNA transcripts by altering how they "read" DNA. Many genes are associated with multiple gene promoters, the researchers say, which is the predominant way multiple variants of a given gene, for example, can be made with the same genetic instructions.

371

GENETICS OF LONG QT SYNDROME  

PubMed Central

Long QT syndrome (LQTS) is a potentially life-threatening cardiac arrhythmia characterized by delayed myocardial repolarization that produces QT prolongation and increased risk for torsades des pointes (TdP)-triggered syncope, seizures, and sudden cardiac death (SCD) in an otherwise healthy young individual with a structurally normal heart. Currently, there are three major LQTS genes (KCNQ1, KCNH2, and SCN5A) that account for approximately 75% of the disorder. For the major LQTS genotypes, genotype-phenotype correlations have yielded gene-specific arrhythmogenic triggers, electrocardiogram (ECG) patterns, response to therapies, and intragenic and increasingly mutation-specific risk stratification. The 10 minor LQTS-susceptibility genes collectively account for less than 5% of LQTS cases. In addition, three atypical LQTS or multisystem syndromic disorders that have been associated with QT prolongation have been described, including ankyrin-B syndrome, Anderson-Tawil syndrome (ATS), and Timothy syndrome (TS). Genetic testing for LQTS is recommended in patients with either a strong clinical index of suspicion or persistent QT prolongation despite their asymptomatic state. However, genetic test results must be interpreted carefully.

2014-01-01

372

Gene Therapy Progress and Prospects: cancer gene therapy using tumour suppressor genes  

Microsoft Academic Search

Targeting tumour suppressor gene pathways is an attractive therapeutic strategy in cancer. Since the first clinical trial took place in 1996, at least 20 other trials have investigated the possibility of restoring p53 function, either alone or in combination with chemotherapy, but with limited success. Other recent clinical trials have sought to harness abnormalities in the p53 pathway to permit

IA McNeish; SJ Bell; NR Lemoine

2004-01-01

373

Bayesian Mixture Modeling of Gene-Environment and Gene-Gene Interactions  

PubMed Central

With the advent of rapid and relatively cheap genotyping technologies there is now the opportunity to attempt to identify gene-environment and gene-gene interactions when the number of genes and environmental factors is potentially large. Unfortunately the dimensionality of the parameter space leads to a computational explosion in the number of possible interactions that may be investigated. The full model that includes all interactions and main effects can be unstable, with wide confidence intervals arising from the large number of estimated parameters. We describe a hierarchical mixture model that allows all interactions to be investigated simultaneously, but assumes the effects come from a mixture prior with two components, one that reflects small null effects and the second for epidemiologically significant effects. Effects from the former are effectively set to zero, hence increasing the power for the detection of real signals. The prior framework is very flexible, which allows substantive information to be incorporated into the analysis. We illustrate the methods first using simulation, and then on data from a case-control study of lung cancer in Central and Eastern Europe.

Wakefield, Jon; De Vocht, Frank; Hung, Rayjean J.

2009-01-01

374

A combinatorial approach to detecting gene-gene and gene-environment interactions in family studies.  

PubMed

Widespread multifactor interactions present a significant challenge in determining risk factors of complex diseases. Several combinatorial approaches, such as the multifactor dimensionality reduction (MDR) method, have emerged as a promising tool for better detecting gene-gene (G x G) and gene-environment (G x E) interactions. We recently developed a general combinatorial approach, namely the generalized multifactor dimensionality reduction (GMDR) method, which can entertain both qualitative and quantitative phenotypes and allows for both discrete and continuous covariates to detect G x G and G x E interactions in a sample of unrelated individuals. In this article, we report the development of an algorithm that can be used to study G x G and G x E interactions for family-based designs, called pedigree-based GMDR (PGMDR). Compared to the available method, our proposed method has several major improvements, including allowing for covariate adjustments and being applicable to arbitrary phenotypes, arbitrary pedigree structures, and arbitrary patterns of missing marker genotypes. Our Monte Carlo simulations provide evidence that the PGMDR method is superior in performance to identify epistatic loci compared to the MDR-pedigree disequilibrium test (PDT). Finally, we applied our proposed approach to a genetic data set on tobacco dependence and found a significant interaction between two taste receptor genes (i.e., TAS2R16 and TAS2R38) in affecting nicotine dependence. PMID:18834969

Lou, Xiang-Yang; Chen, Guo-Bo; Yan, Lei; Ma, Jennie Z; Mangold, Jamie E; Zhu, Jun; Elston, Robert C; Li, Ming D

2008-10-01

375

Small genes\\/gene-products in Escherichia coli K-12  

Microsoft Academic Search

Forty-two protein spots of observed Mr 6–15 kDa were resolved by two-dimensional gel electrophoresis, stained by Coomassie blue and subjected to Edman microsequencing. All of the proteins could be related back to their encoding open reading frames, thereby vindicating the bioinformatic tools currently utilised in their identification. However, only 14\\/42 gene-products were expressed as annotated. Translation was confirmed for 14

Valerie C Wasinger; Ian Humphery-Smith

1998-01-01

376

Gene conversions may obscure actin gene family relationships.  

PubMed

Phylogenetic hypotheses of muscle actin evolution are significantly different when a sea urchin is used as a representative echinoderm than when a sea star is used. While sea urchin muscle actins support an echinoderm-chordate sister relationship, sea star sequences suggest that echinoderm muscle actins are convergent with chordate muscle actins. Our results suggest that gene conversion in the sea star muscle actin may be responsible for these discordant results. PMID:10684350

White, M E; Crother, B I

2000-02-01

377

Identification of genes responsive to PFOS using gene expression profiling  

Microsoft Academic Search

Perfluorooctane sulfonic acid (PFOS) is widely distributed in the environment including in the tissues of wildlife and humans, however, its mechanism of action remains unclear. Here, the Affymetrix rat genome U34A genechip was used to identify alterations in gene expression due to PFOS exposure. Rat hepatoma cells were treated with PFOS at 2–50mg\\/L (4–100?M) for 96h. Sprague-Dawley rats were orally

Wenyue Hu; Paul D. Jones; Trine Celius; John P. Giesy

2005-01-01

378

Interactive Fly: Early Zygotic Gene Expression Images  

NSDL National Science Digital Library

In situ images from an award-winning and comprehensive site, The Interactive Fly. Entering through an expression pattern, this site thoroughly discusses each genes and shows its expression relative to other genes at this stage.

PhD Thomas B Brody (NIH Laboratory of Neurochemistry)

2006-12-12

379

Towards integrative gene functional similarity measurement  

PubMed Central

Background In Gene Ontology, the "Molecular Function" (MF) categorization is a widely used knowledge framework for gene function comparison and prediction. Its structure and annotation provide a convenient way to compare gene functional similarities at the molecular level. The existing gene similarity measures, however, solely rely on one or few aspects of MF without utilizing all the rich information available including structure, annotation, common terms, lowest common parents. Results We introduce a rank-based gene semantic similarity measure called InteGO by synergistically integrating the state-of-the-art gene-to-gene similarity measures. By integrating three GO based seed measures, InteGO significantly improves the performance by about two-fold in all the three species studied (yeast, Arabidopsis and human). Conclusions InteGO is a systematic and novel method to study gene functional associations. The software and description are available at http://www.msu.edu/~jinchen/InteGO.

2014-01-01

380

PAX Genes in Cancer; Friends or Foes?  

PubMed Central

PAX genes have been shown to be critically required for the development of specific tissues and organs during embryogenesis. In addition, PAX genes are expressed in a handful of adult tissues where they are thought to play important roles, usually different from those in embryogenesis. A common theme in adult tissues is a requirement for PAX gene expression in adult stem cell maintenance or tissue regeneration. The connections between adult stem cell PAX gene expression and cancer are intriguing, and the literature is replete with examples of PAX gene expression in either situation. Here we systematically review the literature and present an overview of postnatal PAX gene expression in normal and cancerous tissue. We discuss the potential link between PAX gene expression in adult tissue and cancer. In addition, we discuss whether persistent PAX gene expression in cancer is favorable or unfavorable.

Li, Caiyun G.; Eccles, Michael R.

2012-01-01

381

Human fibroblast interferon gene lacks introns  

PubMed Central

A recombinant ? bacteriophage isolated from a human genome library contains the gene for fibroblast interferon (IFN-?1). The DNA sequence of this gene is identical to the sequence of its mRNA and is devoid of introns.

Lawn, Richard M.; Adelman, John; Franke, Arthur E.; Houck, Catherine M.; Gross, Mitchell; Najarian, Richard; Goeddel, David V.

1981-01-01

382

Potato Genes for Resistance to Late Blight.  

National Technical Information Service (NTIS)

Resistance genes and their encoded proteins from the wild potato, Solanum bulbocastanum, are disclosed. The genes and proteins are useful for conferring disease resistance to plants, particularly solanaceous species such as potato and tomato. In particula...

J. Jiang J. Song J. P. Helgeson S. Austin-Phillips S. K. Naess

2004-01-01

383

NIH Researchers Identify OCD Risk Gene  

MedlinePLUS

... News From NIH NIH Researchers Identify OCD Risk Gene Past Issues / Summer 2006 Table of Contents For ... and Alcoholism (NIAAA) have identified a previously unknown gene variant that doubles an individual's risk for obsessive- ...

384

Physical Characterization of Clostridium Botulinum Neurotoxin Genes.  

National Technical Information Service (NTIS)

DNA fragments encompassing the neurotoxin genes of Clostridium botulinum types B and E have been cloned and their entire nucleotide sequences determined. Similarly, recombinant clones carrying all but the extreme 51 end of the type F gene have been obtain...

N. P. Minton

1992-01-01

385

Diacylglycerol Acyltransferase Genes, Proteins, and Uses Thereof.  

National Technical Information Service (NTIS)

The present invention relates to diacylglycerol acyltransferase genes and proteins, and methods of their use. In particular, the invention describes genes and proteins that exhibit both long-chain acyltransferase and acetyltransferase activity. The presen...

A. Milcamps D. A. Pan M. R. Pollard

2004-01-01

386

IGF-Regulated Genes in Prostate Cancer.  

National Technical Information Service (NTIS)

We hypothesize that genes that are differentially expressed as a result of the decreased IGF-I receptor gene expression seen in metastatic prostate cancer contribute to prostate cancer progression, and include metastasis-regulating genensthat could consti...

C. Roberts

2004-01-01

387

Gene-gene interactions in breast cancer susceptibility.  

PubMed

There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10(-4); ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 × 10(-4); CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation. PMID:22072393

Turnbull, Clare; Seal, Sheila; Renwick, Anthony; Warren-Perry, Margaret; Hughes, Deborah; Elliott, Anna; Pernet, David; Peock, Susan; Adlard, Julian W; Barwell, Julian; Berg, Jonathan; Brady, Angela F; Brewer, Carole; Brice, Glen; Chapman, Cyril; Cook, Jackie; Davidson, Rosemarie; Donaldson, Alan; Douglas, Fiona; Greenhalgh, Lynn; Henderson, Alex; Izatt, Louise; Kumar, Ajith; Lalloo, Fiona; Miedzybrodzka, Zosia; Morrison, Patrick J; Paterson, Joan; Porteous, Mary; Rogers, Mark T; Shanley, Susan; Walker, Lisa; Ahmed, Munaza; Eccles, Diana; Evans, D Gareth; Donnelly, Peter; Easton, Douglas F; Stratton, Michael R; Rahman, Nazneen

2012-02-15

388

Polymer Design for Nonviral Gene Delivery  

Microsoft Academic Search

Gene therapy continues to hold promise in treating a variety of inherited and acquired diseases. The great majority of gene\\u000a therapy trials rely on viral vectors for gene transduction because of their high efficiency. Viruses remain the vectors of\\u000a choice in achieving high efficiency of gene transfer in vivo. Viral vectors, however, pose safety concerns unlikely to abate\\u000a in the

Kam W. Leong

389

Evolutionary Dynamics of Overlapped Genes in Salmonella  

PubMed Central

Presence of overlapping genes (OGs) is a common phenomenon in bacterial genomes. Most frequently, overlapping genes share coding regions with as few as one nucleotide to as many as thousands of nucleotides. Overlapping genes are often co-regulated, transcriptionally and translationally. Overlapping genes are also subject to the whims of evolution, as the gene overlap is known to be disrupted in some species/strains and participating genes are sometimes lost in independent lineages. Therefore, a better understanding of evolutionary patterns and rates of the disruption of overlapping genes is an important component of genome structure and evolution of gene function. In this study, we investigate the fate of ancestrally overlapping genes in complete genomes from 15 contemporary strains of Salmonella species. We find that the fates of overlapping genes inside and outside operons are distinctly different. A larger fraction of overlapping genes inside operons conserves their overlap as compared to gene pairs outside of the operons (average 0.89 vs. 0.83 per genome). However, when overlapping genes in the operons separate, one partner is lost more frequently than in those separated genes outside of operons (average 0.02 vs. 0.01 per genome). We also investigate the fate of a pan set of overlapping genes at the present and ancestral nodes over a phylogenetic tree based on genome sequence data, respectively. We propose that co-regulation plays important roles on the fates of genes. Furthermore, a vast majority of disruptions occurred prior to the common ancestor of all 15 Salmonella strains, which enables us to obtain an estimate of disruptions between Salmonella and E. coli.

Luo, Yingqin; Battistuzzi, Fabia; Lin, Kui

2013-01-01

390

Evolution of Exceptionally Large Genes in Prokaryotes  

Microsoft Academic Search

Analysis of bacterial genomic sequences revealed an average bacterial gene size of approximately 1 kb. However, genes with\\u000a a size >10 kb were also noted. This study investigates the prevalence, possible function, and origin of exceptionally large-size\\u000a genes (ELSGs; >10 kb) in prokaryotes. Forty-two ELSGs (0.03%) were identified after searching more than 170,000 genes in 46\\u000a bacterial and 11 archaeal species. These

Min-Chieh Kuo; Li-Fang Chou; Hwan-You Chang

2008-01-01

391

The HUGO Gene Nomenclature Database, 2006 updates  

Microsoft Academic Search

The HUGO Gene Nomenclature Committee (HGNC) aims to give every human gene a unique and ideally meaningful name and symbol. The HGNC database, previously known as Genew, contains over 22000 public records with approved human gene nomen- clature and associated information. The database has undergone major improvements throughout the last year, is publicly available for online searching at http:\\/\\/www.gene.ucl.ac.uk\\/cgi-bin\\/nomenclature\\/ searchgenes.pl

Tina A. Eyre; Fabrice Ducluzeau; Tam P. Sneddon; Sue Povey; Elspeth A. Bruford; Michael J. Lush

2006-01-01

392

Polycystic kidney disease - where gene dosage counts  

PubMed Central

Gene dosage effects have emerged as playing a central role in the pathogenesis of polycystic kidney disease. Yet, how gene dosage can ultimately have an impact on the formation of kidney cysts remains unknown. In this commentary we review the evidence for the role of gene dosage effects versus the “2-hit” mutation model in polycystic kidney disease (PKD), and also discuss how gene networks may potentially make intertwined contributions to PKD.

Stayner, Cherie A.

2014-01-01

393

Identifying Antimicrobial Resistance Genes with DNA Microarrays  

Microsoft Academic Search

We developed and tested a glass-based microarray suitable for detecting multiple tetracycline (tet) resistance genes. Microarray probes for 17 tet genes, the -lactamase blaTEM-1 gene, and a 16S ribosomal DNA gene (Escherichia coli) were generated from known controls by PCR. The resulting products (ca. 550 bp) were applied as spots onto epoxy-silane-derivatized, Teflon-masked slides by using a robotic spotter. DNA

Douglas R. Call; Marlene K. Bakko; Melissa J. Krug; Marilyn C. Roberts

2003-01-01

394

Plant nitrogen regulatory P-PII genes  

DOEpatents

The present invention generally relates to plant nitrogen regulatory PII gene (hereinafter P-PII gene), a gene involved in regulating plant nitrogen metabolism. The invention provides P-PII nucleotide sequences, expression constructs comprising said nucleotide sequences, and host cells and plants having said constructs and, optionally expressing the P-PII gene from said constructs. The invention also provides substantially pure P-PII proteins. The P-PII nucleotide sequences and constructs of the

Coruzzi, Gloria M. (New York, NY); Lam, Hon-Ming (Hong Kong, HK); Hsieh, Ming-Hsiun (Woodside, NY)

2001-01-01

395

Serotonergic genes and suicide: a systematic review.  

PubMed

Suicide is one of the leading causes of death in the world. Its aetiology is complex and diverse, however, epidemiological studies show that suicidal behavior is partly heritable. Neurobiological evidence implicates serotonergic dysfunction in suicidality, stimulating genetic research to focus on genes related to the serotonergic system. In this paper, we review evidence from studies examining the association between various serotonergic genes (Tryptophan Hydroxylase genes: TPH1; TPH2, Serotonin Transporter gene: 5-HTTLPR in SLC6A4, Serotonin Receptor genes: HTR1A, HTR2A, HTR1B, HTR2C and Monoamine Oxidase A gene: MAOA) and suicidal behavior. The data show associations between variation on the TPH1 gene and 5-HTTLPR gene and violent suicidal behavior in Caucasian populations, with the least inconsistencies. Results are mixed for the TPH2 gene and serotonin receptor genes, but for some genes, studies that include haplotypic analyses or that examine a larger coding region of the genes tend to provide more reliable results. Findings on endophenotypes of suicidality, such as aggression and impulsivity traits, show positive associations for the TPH1, HTR2A, and MAOA genes, but need further replication, since negative associations are also occasionally reported. Since genes can only partially explain suicidal risk, several studies during the past decade have tried to incorporate environmental factors in the susceptibility model. Studies to date show that variation on the 5-HTTLPR, MAOA and HTR2A gene can interact with stressful life events to increase risk for suicidal behavior. Limitations of case-control studies are discussed and future considerations are put forward with regard to endophenotypic measurements and gene-environment interactions. PMID:23742855

Antypa, Niki; Serretti, Alessandro; Rujescu, Dan

2013-10-01

396

ETS gene fusions in prostate cancer  

Microsoft Academic Search

Chromosomal rearrangements that result in high level expression of ETS gene family members are common events in human prostate cancer. Most frequently, the androgen-activated gene TMPRSS2 is found fused to the ERG gene. Fusions involving ETV1, ETV4 and ETV5 occur less frequently but exhibit greater variability in fusion structure with 12 unique 5? fusion partners identified so far. ETS gene

Colin S. Cooper; Jeremy P. Clark

2009-01-01

397

Regulation of the genes involved in nitrification.  

SciTech Connect

OAK-B135 This project focuses on the characterization of the regulation of the genes involved in nitrification in the bacterium Nitrosomonas europaea. The key genes in the nitrification pathway, amo and hao, are present in multiple copies in the genome. The promoters for these genes were identified and characterized. It was shown that there were some differences in the transcriptional regulation of the copies of these genes.

Arp, D.J.; Sayavedra-Soto, L.A.

2003-08-14

398

Function of the DISC1 Gene  

NSDL National Science Digital Library

As a result of the human genome project, we now know largely where our genes are, and what structure they have. The search to uncover each gene's function, on the other hand, is only in its infancy. Functional genomics is an area of research dedicated to studying what protein is produced by a gene, and what happens in the body when it is activated. Understanding gene function is the next major hurdle in genomic research, which holds the key to developing revolutionary therapeutics.

2009-04-14

399

Fungal avirulence genes: structure and possible functions.  

PubMed

Avirulence (Avr) genes exist in many fungi that share a gene-for-gene relationship with their host plant. They represent unique genetic determinants that prevent fungi from causing disease on plants that possess matching resistance (R) genes. Interaction between elicitors (primary or secondary products of Avr genes) and host receptors in resistant plants causes induction of various defense responses often involving a hypersensitive response. Avr genes have been successfully isolated by reverse genetics and positional cloning. Five cultivar-specific Avr genes (Avr4, Avr9, and Ecp2 from Cladosporium fulvum; nip1 from Rhynchosporium secalis; and Avr2-YAMO from Magnaporthe grisea) and three species-specific Avr genes (PWL1 and PWL2 from M. grisea and inf1 from Phytophthora infestans) have been cloned. Isolation of additional Avr genes from these fungi, but also from other fungi such as Uromyces vignae, Melampsora lini, Phytophthora sojae, and Leptosphaeria maculans, is in progress. Molecular analyses of nonfunctional Avr gene alleles show that these originate from deletions or mutations in the open reading frame or the promoter sequence of an Avr gene. Although intrinsic biological functions of most Avr gene products are still unknown, recent studies have shown that two Avr genes, nip1 and Ecp2, encode products that are important pathogenicity factors. All fungal Avr genes cloned so far have been demonstrated or predicted to encode extracellular proteins. Current studies focus on unraveling the mechanisms of perception of avirulence factors by plant receptors. The exploitation of Avr genes and the matching R genes in engineered resistance is also discussed. PMID:9756710

Laugé, R; De Wit, P J

1998-08-01

400

Positive selection-guided mutational analysis revealing two key functional sites of scorpion ERG K(+) channel toxins.  

PubMed

Scorpion ?-KTx toxins are important molecular tools for studying physiological and pharmacological functions of human ether-á-go-go related gene (hERG) K(+) channels. To pinpoint functional residues of this class of toxins involved in channel binding, we employed a combined approach that integrates evolutionary information and site-directed mutagenesis. Among three positively selected sites (PSSs) identified here, two (Gln18 and Met35) were found to be associated with the toxin's function because their changes significantly decreased the potency of ErgTx1 (also called CnErg1) on hERG1 channel. On the contrary, no potency alteration was observed at the third PSS (Ala42) when the mutation was introduced, which could be due to its location far from the functional surface of the toxin. Our strategy will accelerate the research of structure-function relationship of scorpion K(+) channel toxins. PMID:23103547

Wang, Xueli; Jimenez-Vargas, Juana Maria; Xu, Chenqi; Possani, Lourival D; Zhu, Shunyi

2012-12-01

401

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

402

Basics on Genes and Genetic Disorders  

MedlinePLUS

The Basics on Genes and Genetic Disorders KidsHealth > Teens > Body > Health Basics > The Basics on Genes and Genetic Disorders Print A A A Text Size What's in ... repair" the gene change. Back Continue What Are Genetic Disorders? Researchers have identified more than 4,000 ...

403

Mining gene expression databases for association rules  

Microsoft Academic Search

Motivation: Global gene expression profiling, both at the transcript level and at the protein level, can be a valuable tool in the understanding of genes, biological networks, and cellular states. As larger and larger gene expression data sets become available, data mining techniques can be applied to identify patterns of interest in the data. As- sociation rules, used widely in

Chad Creighton; Samir Hanash

2003-01-01

404

Recurrent gene fusions in prostate cancer  

Microsoft Academic Search

The discovery of recurrent gene fusions in a majority of prostate cancers has important clinical and biological implications in the study of common epithelial tumours. Gene fusion and chromosomal rearrangements were previously thought to be primarily the oncogenic mechanism of haematological malignancies and sarcomas. The prostate cancer gene fusions that have been identified thus far are characterized by 5? genomic

Chandan Kumar-Sinha; Scott A. Tomlins; Arul M. Chinnaiyan

2008-01-01

405

Comparative Gene Prediction in Human and Mouse  

PubMed Central

The completion of the sequencing of the mouse genome promises to help predict human genes with greater accuracy. While current ab initio gene prediction programs are remarkably sensitive (i.e., they predict at least a fragment of most genes), their specificity is often low, predicting a large number of false-positive genes in the human genome. Sequence conservation at the protein level with the mouse genome can help eliminate some of those false positives. Here we describe SGP2, a gene prediction program that combines ab initio gene prediction with TBLASTX searches between two genome sequences to provide both sensitive and specific gene predictions. The accuracy of SGP2 when used to predict genes by comparing the human and mouse genomes is assessed on a number of data sets, including single-gene data sets, the highly curated human chromosome 22 predictions, and entire genome predictions from ENSEMBL. Results indicate that SGP2 outperforms purely ab initio gene prediction methods. Results also indicate that SGP2 works about as well with 3x shotgun data as it does with fully assembled genomes. SGP2 provides a high enough specificity that its predictions can be experimentally verified at a reasonable cost. SGP2 was used to generate a complete set of gene predictions on both the human and mouse by comparing the genomes of these two species. Our results suggest that another few thousand human and mouse genes currently not in ENSEMBL are worth verifying experimentally.

Parra, Genis; Agarwal, Pankaj; Abril, Josep F.; Wiehe, Thomas; Fickett, James W.; Guigo, Roderic

2003-01-01

406

Dynamic modeling of gene expression data  

Microsoft Academic Search

We describe the time evolution of gene expression levels by using a time translational matrix to predict future expression levels of genes based on their expression levels at some initial time. We deduce the time translational matrix for previously published DNA microarray gene expression data sets by modeling them within a linear framework by using the characteristic modes obtained by

Neal S. Holter; Amos Maritan; Marek Cieplak; Nina V. Fedoroff; Jayanth R. Banavar

2001-01-01

407

Recent Patents Relating to Tumor Suppressor Genes  

Microsoft Academic Search

Researchers in the field of tumor suppressor genes are actively attempting to discover new tumor suppressor genes and\\/or characterize known tumor suppressor genes with the intention of treating and diagnosing cancers. A number of recent patents and patent applications have been published that discuss some of these discoveries. Some of the patents and patent applications discuss newly discovered tumor suppressor

Jason J. Derry; Yijan E. Chang

2007-01-01

408

Environmental and Behavioral Influences on Gene Activity  

Microsoft Academic Search

The central dogma of molecular biology holds that “information” flows from the genes to the structure of the proteins that the genes bring about through the formula DNA ? RNA ? protein. In this view, a set of master genes activates the DNA necessary to produce the appropriate proteins that the organism needs during development. In contrast to this view,

Gilbert Gottlieb

2000-01-01

409

Evolution of Mitochondrial Gene Orders in Echinoderms  

Microsoft Academic Search

A comprehensive analysis of the mitochondrial gene orders of all previously pub- lished and two novel Antedon mediterranea (Crinoidea) and Ophiura albida (Ophi- uroidea) complete echinoderm mitochondrial genomes shows that all major types of rearrangement operations are necessary to explain the evolution of mitochondrial genomes. In addition to protein coding genes we include all tRNA genes as well as the

Marleen Perseke; Guido Fritzsch; Kai Ramsch; Matthias Bernt; Daniel Merkle; Martin Middendorf; Detlef Bernhard; Peter F. Stadler; Martin Schlegel

2007-01-01

410

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

411

Uses of antimicrobial genes from microbial genome  

DOEpatents

We describe a method for mining microbial genomes to discover antimicrobial genes and proteins having broad spectrum of activity. Also described are antimicrobial genes and their expression products from various microbial genomes that were found using this method. The products of such genes can be used as antimicrobial agents or as tools for molecular biology.

Sorek, Rotem; Rubin, Edward M.

2013-08-20

412

Network topology reveals key cardiovascular disease genes.  

PubMed

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. PMID:23977067

Sarajli?, Anida; Janji?, Vuk; Stojkovi?, Neda; Radak, Djordje; Pržulj, Nataša

2013-01-01

413

Gene prioritization through genomic data fusion  

Microsoft Academic Search

The identification of genes involved in health and disease remains a challenge. We describe a bioinformatics approach, together with a freely accessible, interactive and flexible software termed Endeavour, to prioritize candidate genes underlying biological processes or diseases, based on their similarity to known genes involved in these phenomena. Unlike previous approaches, ours generates distinct prioritizations for multiple heterogeneous data sources,

Diether Lambrechts; Sunit Maity; Peter Van Loo; Bert Coessens; Frederik De Smet; Leon-Charles Tranchevent; Bart De Moor; Peter Marynen; Bassem Hassan; Peter Carmeliet; Yves Moreau; Stein Aerts

2006-01-01

414

Rough Overlapping Biclustering of Gene Expression Data  

Microsoft Academic Search

A great number of biclustering algorithms have been proposed for analyzing gene expression data. Many of them assume to find exclusive biclusters whose subsets of genes are co-regulated under subsets of conditions without intersection. This is not consistent with a general understanding of biological processes that many genes participate in multiple different processes. Therefore nonexclusive biclustering algorithms are required. In

Ruizhi Wang; Duoqian Miao; Gang Li; Hongyun Zhang

2007-01-01

415

Jumping Genes: The Transposable DNAs of Bacteria.  

ERIC Educational Resources Information Center

Transposons are transposable elements that carry genes for antibiotic resistance. Provides background information on the structure and organization of these "jumping genes" in bacteria. Also describes the use of transposons in tagging genes and lists pertinent references and resource materials. (DH)

Berg, Claire M.; Berg, Douglas E.

1984-01-01

416

The evolutionary demography of duplicate genes  

Microsoft Academic Search

Although gene duplication has generally been viewed as a necessary source of material for the origin of evolu- tionary novelties, the rates of origin, loss, and preservation of gene duplicates are not well understood. Applying steady-state demographic techniques to the age distributions of duplicate genes censused in seven completely sequenced genomes, we estimate the average rate of duplication of a

Michael Lynch; John S. Conery

2003-01-01

417

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

418

Sample size for gene expression microarray experiments  

Microsoft Academic Search

Motivation: Microarray experiments often involve hundreds or thou- sands of genes. In a typical experiment, only a fraction of genes are expected to be differentially expressed; in addition, the measured intensities among different genes may be correlated. Depending on the experimental objectives, sample size calculations can be based on one of the three specified measures: sensitivity, true discovery and accuracy

Chen-an Tsai; Sue-jane Wang; Dung-tsa Chen; James J. Chen

2005-01-01

419

Gene therapy for the regeneration of bone  

Microsoft Academic Search

Gene transfer technologies offer the prospect of enhancing bone regeneration by delivering osteogenic gene products locally to osseous defects. In most cases the gene product will be a protein, which will be synthesized endogenously within and around the lesion in a sustained fashion. It will have undergone authentic post-translational processing and lack the alterations that occur when recombinant proteins are

Christopher Evans

2011-01-01

420

Discovery of Tumor Suppressor Gene Function.  

ERIC Educational Resources Information Center

This is an update of a 1991 review on tumor suppressor genes written at a time when understanding of how the genes work was limited. A recent major breakthrough in the understanding of the function of tumor suppressor genes is discussed. (LZ)

Oppenheimer, Steven B.

1995-01-01

421

Human gene therapy and imaging: cardiology  

Microsoft Academic Search

This review discusses the basics of cardiovascular gene therapy, the results of recent human clinical trials, and the rapid progress in imaging techniques in cardiology. Improved understanding of the molecular and genetic basis of coronary heart disease has made gene therapy a potential new alternative for the treatment of cardiovascular diseases. Experimental studies have established the proof-of-principle that gene transfer

Joseph C. Wu; Seppo Yla-Herttuala

2005-01-01

422

KEGG: Kyoto Encyclopedia of Genes and Genomes  

Microsoft Academic Search

Kyoto Encyclopedia of Genes and Genomes (KEGG) is a knowledge base for systematic analysis of gene functions in terms of the networks of genes and molecules. The major component of KEGG is the PATHWAY database that consists of graphical dia- grams of biochemical pathways including most of the known metabolic pathways and some of the known regulatory pathways. The pathway

Hiroyuki Ogata; Susumu Goto; Kazushige Sato; Wataru Fujibuchi; Hidemasa Bono; Minoru Kanehisa

1999-01-01

423

IGF-Regulated Genes in Prostate Cancer.  

National Technical Information Service (NTIS)

We hypothesized that genes that are differentially expressed as a result of the decreased IGF-I receptor gene expression seen in metastatic prostate cancer contribute to prostate cancer progression. IGF-I receptor target genes may include metastasis-promo...

C. T. Roberts

2003-01-01

424

Muscle Gene Therapy for Hemophilia  

PubMed Central

Muscle-directed gene therapy for hemophilia is an attractive strategy for expression of therapeutic levels of clotting factor as evident from preclinical studies and an early phase clinical trial. Notably, local FIX expression by AAV-mediated direct intramuscular injection to skeletal muscle persists for years. Development of intravascular delivery of AAV vector approaches to skeletal muscle resulted in vector in widespread areas of the limb and increased expression of FIX in hemophilia B dogs. The use of FIX variants with improved biological activity may provide the opportunity to increase the efficacy of these approaches. Studies for hemophilia A are less developed at this point, but utilizing transgenes that improve hemostasis independent of FIX and FVIII has potential therapeutic application for both hemophilia A and B. Continuous monitoring of humoral and T cell responses to the transgene and AAV capsid in human trials will be critical for the translation of these promising approaches for muscle gene therapy for hemophilia.

Sabatino, Denise E.; Arruda, Valder R.

2013-01-01

425

Gene Therapy for Primary Immunodeficiencies  

PubMed Central

Abstract For over 40 years, primary immunodeficiencies (PIDs) have featured prominently in the development and refinement of human allogeneic hematopoietic stem cell transplantation. More recently, ex vivo somatic gene therapy using autologous cells has provided remarkable evidence of clinical efficacy in patients without HLA-matched stem cell donors and in whom toxicity of allogeneic procedures is likely to be high. Together with improved preclinical models, a wealth of information has accumulated that has allowed development of safer, more sophisticated technologies and protocols that are applicable to a much broader range of diseases. In this review we summarize the status of these gene therapy trials and discuss the emerging application of similar strategies to other PIDs.

Rivat, Christine; Santilli, Giorgia; Gaspar, H. Bobby

2012-01-01

426

Ikaros gene expression and leukemia.  

PubMed

The Ikaros (Ik) protein, or LyF1, was initially described as a protein binding to regulatory sequences of a number of genes expressed in murine lymphoid cells. Ikaros is a critical regulator of normal hematopoietic stem cell differentiation, as evidenced by dramatic defects in the lymphoid compartments, in homozygous animals with gene inactivation. Because differential splicing produces multiple isoforms with potentially different functions, Ikaros provides a unique model to study how post-transcriptional mechanisms may be involved in neoplastic processes. Indeed, several groups including ours have underlined evidences that expression of different Ikaros isoforms vary among different types of leukemias. The predominance of short isoforms in certain subsets is intriguing. Here, additional observations reinforced the hypothesis that Ikaros expression may be deregulated in human leukemias. Whether this is a cause or a consequence of the leukemic process remains speculative. Other human diseases however, provide examples of abnormal post-transcriptional regulations that have been further characterized. PMID:11908734

Tonnelle, Cécile; Calmels, Boris; Maroc, Christine; Gabert, Jean; Chabannon, Christian

2002-01-01

427

Nickel and epigenetic gene silencing.  

PubMed

Insoluble nickel compounds are well-established human carcinogens. Occupational exposure to these compounds leads to increased incidence of lung and nasal cancer in nickel refinery workers. Apart from its weak mutagenic activity and hypoxia mimicking effect there is mounting experimental evidence indicating that epigenetic alteration plays an important role in nickel-induced carcinogenesis. Multiple epigenetic mechanisms have been identified to mediate nickel-induced gene silencing. Nickel ion is able to induce heterochromatinization by binding to DNA-histone complexes and initiating chromatin condensation. The enzymes required for establishing or removing epigenetic marks can be targeted by nickel, leading to altered DNA methylation and histone modification landscapes. The current review will focus on the epigenetic changes that contribute to nickel-induced gene silencing. PMID:24705264

Sun, Hong; Shamy, Magdy; Costa, Max

2013-01-01

428

Nickel and Epigenetic Gene Silencing  

PubMed Central

Insoluble nickel compounds are well-established human carcinogens. Occupational exposure to these compounds leads to increased incidence of lung and nasal cancer in nickel refinery workers. Apart from its weak mutagenic activity and hypoxia mimicking effect there is mounting experimental evidence indicating that epigenetic alteration plays an important role in nickel-induced carcinogenesis. Multiple epigenetic mechanisms have been identified to mediate nickel-induced gene silencing. Nickel ion is able to induce heterochromatinization by binding to DNA-histone complexes and initiating chromatin condensation. The enzymes required for establishing or removing epigenetic marks can be targeted by nickel, leading to altered DNA methylation and histone modification landscapes. The current review will focus on the epigenetic changes that contribute to nickel-induced gene silencing.

Sun, Hong; Shamy, Magdy; Costa, Max

2013-01-01

429

RGST - Rat Gene Symbol Tracker, a database for defining official rat gene symbols  

Microsoft Academic Search

BACKGROUND: The names of genes are central in describing their function and relationship. However, gene symbols are often a subject of controversy. In addition, the discovery of mammalian genes is now so rapid that a proper use of gene symbol nomenclature rules tends to be overlooked. This is currently the situation in the rat and there is a need for

Greta Petersen; Fredrik Ståhl

2008-01-01

430

Bystander effect caused by suicide gene expression indicates the feasibility of gene therapy for hepatocellular carcinoma  

Microsoft Academic Search

In the field of gene therapy using retroviral vectors, it appears impossible to introduce a foreign gene into all target cells. Therefore adjacent cell killing, the so-called bystander effect, caused by genetically modified cells provides therapeutic advantages for gene therapy against cancers. We retrovirally transduced the herpes simplex virus thymidine kinase (HSV-tk) gene into murine and rat hepatocellular carcinoma (HCC)

Shigeki Kuriyama; Toshiya Nakatani; Kazuhiro Masui; Takemi Sakamoto; Kentarou Tominaga; Masahide Yoshikawa; Hiroshi Fukui; Kazuhiro Ikenaka; Tadasu Tsujii

1995-01-01

431

Reranking candidate gene models with cross-species comparison for improved gene prediction  

PubMed Central

Background Most gene finders score candidate gene models with state-based methods, typically HMMs, by combining local properties (coding potential, splice donor and acceptor patterns, etc). Competing models with similar state-based scores may be distinguishable with additional information. In particular, functional and comparative genomics datasets may help to select among competing models of comparable probability by exploiting features likely to be associated with the correct gene models, such as conserved exon/intron structure or protein sequence features. Results We have investigated the utility of a simple post-processing step for selecting among a set of alternative gene models, using global scoring rules to rerank competing models for more accurate prediction. For each gene locus, we first generate the K best candidate gene models using the gene finder Evigan, and then rerank these models using comparisons with putative orthologous genes from closely-related species. Candidate gene models with lower scores in the original gene finder may be selected if they exhibit strong similarity to probable orthologs in coding sequence, splice site location, or signal peptide occurrence. Experiments on Drosophila melanogaster demonstrate that reranking based on cross-species comparison outperforms the best gene models identified by Evigan alone, and also outperforms the comparative gene finders GeneWise and Augustus+. Conclusion Reranking gene models with cross-species comparison improves gene prediction accuracy. This straightforward method can be readily adapted to incorporate additional lines of evidence, as it requires only a ranked source of candidate gene models.

Liu, Qian; Crammer, Koby; Pereira, Fernando CN; Roos, David S

2008-01-01

432

The Homeobox Gene Caudal Regulates Constitutive Local Expression of Antimicrobial Peptide Genes in Drosophila Epithelia  

Microsoft Academic Search

In Drosophila melanogaster, although the NF-B transcription factors play a pivotal role in the inducible expression of innate immune genes, such as antimicrobial peptide genes, the exact regulatory mechanism of the tissue-specific constitutive expression of these genes in barrier epithelia is largely unknown. Here, we show that the Drosophila homeobox gene product Caudal functions as the innate immune transcription modulator

Ji-Hwan Ryu; Ki-Bum Nam; Chun-Taek Oh; Hyuck-Jin Nam; Sung-Hee Kim; Joo-Heon Yoon; Je-Kyeong Seong; Mi-Ae Yoo; In-Hwan Jang; Paul T. Brey; Won-Jae Lee

2004-01-01

433

Detection of gene orthology from gene co-expression and protein interaction networks  

Microsoft Academic Search

BACKGROUND: Ortholog detection methods present a powerful approach for finding genes that participate in similar biological processes across different organisms, extending our understanding of interactions between genes across different pathways, and understanding the evolution of gene families. RESULTS: We exploit features derived from the alignment of protein-protein interaction networks and gene-coexpression networks to reconstruct KEGG orthologs for Drosophila melanogaster, Saccharomyces

Fadi Towfic; Susan VanderPlas; Casey A. Oliver; Oliver Couture; Christopher K. Tuggle; M. Heather West Greenlee; Vasant Honavar

2010-01-01

434

Expression of a truncated tomato polygalacturonase gene inhibits expression of the endogenous gene in transgenic plants  

Microsoft Academic Search

Tomato plants were transformed with a chimaeric polygalacturonase (PG) gene, designed to produce a truncated PG transcript constitutively. In these plants expression of the endogenous PG gene was inhibited during ripening, resulting in a substantial reduction in PG mRNA and enzyme accumulation. This inhibition was comparable to that achieved previously using antisense genes. The expression of the truncated gene in

C. J. S. Smith; C. F. Watson; C. R. Bird; J. Ray; W. Schuch; D. Grierson

1990-01-01

435

Associating Genes with Gene Ontology Codes Using a Maximum Entropy Analysis of Biomedical Literature  

Microsoft Academic Search

Functional characterizations of thousands of gene products from many species are described in the published literature. These discussions are extremely valuable for characterizing the functions not only of these gene products, but also of their homologs in other organisms. The Gene Ontology (GO) is an effort to create a controlled terminology for labeling gene functions in a more precise, reliable,

Soumya Raychaudhuri; Jeffrey T. Chang; Patrick D. Sutphin; Russ B. Altman

2002-01-01

436

GENE-FOR-GENE DISEASE RESISTANCE: BRIDGING INSECT PEST AND PATHOGEN DEFENSE  

Microsoft Academic Search

Active plant defense, also known as gene-for-gene resistance, is triggered when a plant resistance (R) gene recognizes the intrusion of a specific insect pest or pathogen. Activation of plant defense includes an array of physiological and transcriptional reprogramming. During the past decade, a large number of plant R genes that confer resistance to diverse group of pathogens have been cloned

ISGOUHI KALOSHIAN

2004-01-01

437

Evaluating reference genes to normalize gene expression in human epileptogenic brain tissues  

Microsoft Academic Search

Several reference genes have been used to quantify gene expression in human epilepsy surgery tissue. However, their reliability has not been validated in detail, although this is crucial in interpreting epilepsy-related changes of gene expression. We evaluated 12 potential reference genes in neocortical tissues resected from patients with temporal lobe epilepsy (TLE) with either few or many seizures (n=6 each)

Stephan Wierschke; Sylvain Gigout; Peter Horn; Thomas-Nicolas Lehmann; Christoph Dehnicke; Anja U. Bräuer; Rudolf A. Deisz

2010-01-01

438

Identification and validation of suitable endogenous reference genes for gene expression studies in human peripheral blood  

Microsoft Academic Search

BACKGROUND: Gene expression studies require appropriate normalization methods. One such method uses stably expressed reference genes. Since suitable reference genes appear to be unique for each tissue, we have identified an optimal set of the most stably expressed genes in human blood that can be used for normalization. METHODS: Whole-genome Affymetrix Human 2.0 Plus arrays were examined from 526 samples

Boryana S Stamova; Michelle Apperson; Wynn L Walker; Yingfang Tian; Huichun Xu; Peter Adamczy; Xinhua Zhan; Da-Zhi Liu; Bradley P Ander; Isaac H Liao; Jeffrey P Gregg; Renee J Turner; Glen Jickling; Lisa Lit; Frank R Sharp

2009-01-01

439

Reference genes for normalising gene expression data in collagenase-induced rat intracerebral haemorrhage  

Microsoft Academic Search

BACKGROUND: The mechanisms of brain injury following intracerebral haemorrhage (ICH) are incompletely understood. Gene expression studies using quantitative real-time RT-PCR following ICH have increased our understanding of these mechanisms, however the inconsistent results observed may be related to inappropriate reference gene selection. Reference genes should be stably expressed across different experimental conditions, however, transcript levels of common reference genes have

Naomi L Cook; Timothy J Kleinig; Corinna van den Heuvel; Robert Vink

2010-01-01

440

Reconstruction of Ancestral Gene Order Following Large Scale Genome Duplication and Gene Loss  

Microsoft Academic Search

Gene order evolves through gross chromosomal rearrangements, small scale inversions and transpo- sitions, gene duplication, and gene loss. Much research has been done on the calculation of edit distance and on sorting algorithms under a variety of rearrangement models in which the genome may be repre- sented as conserved segments with permuted order and orientation. However, gene loss within otherwise

Jun Huan; Jan F. Prins; Wei Wang; Todd J. Vision

441

Ranking differentially expressed genes from Affymetrix gene expression data: methods with reproducibility, sensitivity, and specificity  

Microsoft Academic Search

BACKGROUND: To identify differentially expressed genes (DEGs) from microarray data, users of the Affymetrix GeneChip system need to select both a preprocessing algorithm to obtain expression-level measurements and a way of ranking genes to obtain the most plausible candidates. We recently recommended suitable combinations of a preprocessing algorithm and gene ranking method that can be used to identify DEGs with

Koji Kadota; Yuji Nakai; Kentaro Shimizu

2009-01-01

442

Gene Expression Omnibus: NCBI gene expression and hybridization array data repository  

Microsoft Academic Search

The Gene Expression Omnibus (GEO) project was initiated in response to the growing demand for a public repository for high-throughput gene expression data. GEO provides a flexible and open design that facilitates submission, storage and retrieval of heterogeneous data sets from high-throughput gene expression and genomic hybridization experiments. GEO is not intended to replace in house gene expres- sion databases

Ron Edgar; Michael Domrachev; Alex E. Lash

2002-01-01

443

Gene teams: a new formalization of gene clusters for comparative genomics  

Microsoft Academic Search

This paper describes an efficient algorithm based on a new concept called gene team for detecting conserved gene clusters among an arbitrary number of chromosomes. Within the clusters, neither the order of the genes nor their orientation need be conserved. In addition, insertion of foreign genes within the clusters are permitted to a user-defined extent. This algorithm has been implemented

Nicolas Luc; Jean-loup Risler; Anne Bergeron; Mathieu Raffinot

2003-01-01

444

Indexing TNF-? gene expression using a gene-targeted reporter cell line  

Microsoft Academic Search

BACKGROUND: Current cell-based drug screening technologies utilize randomly integrated reporter genes to index transcriptional activity of an endogenous gene of interest. In this context, reporter expression is controlled by known genetic elements that may only partially capture gene regulation and by unknown features of chromatin specific to the integration site. As an alternative technology, we applied highly efficient gene-targeting with

Ziying Yan; Diana Lei-Butters; John F Engelhardt; Gregory H Leno

2009-01-01

445

Reshaping of global gene expression networks and sex-biased gene expression by integration of a young gene  

PubMed Central

New genes originate frequently across diverse taxa. Given that genetic networks are typically comprised of robust, co-evolved interactions, the emergence of new genes raises an intriguing question: how do new genes interact with pre-existing genes? Here, we show that a recently originated gene rapidly evolved new gene networks and impacted sex-biased gene expression in Drosophila. This 4–6 million-year-old factor, named Zeus for its role in male fecundity, originated through retroposition of a highly conserved housekeeping gene, Caf40. Zeus acquired male reproductive organ expression patterns and phenotypes. Comparative expression profiling of mutants and closely related species revealed that Zeus has recruited a new set of downstream genes, and shaped the evolution of gene expression in germline. Comparative ChIP-chip revealed that the genomic binding profile of Zeus diverged rapidly from Caf40. These data demonstrate, for the first time, how a new gene quickly evolved novel networks governing essential biological processes at the genomic level.

Chen, Sidi; Ni, Xiaochun; Krinsky, Benjamin H; Zhang, Yong E; Vibranovski, Maria D; White, Kevin P; Long, Manyuan

2012-01-01

446

Gene expression in diabetic nephropathy  

Microsoft Academic Search

Diabetic nephropathy (DN) is a common complication of diabetes types 1 and 2. One of the hallmarks of DN is the development\\u000a of mesangial expansion, which occurs through accumulation of extracellular matrix (ECM) components. Altered local gene expression\\u000a of humoral factors (eg, transforming growth factor-â, connective tissue growth factor, and platelet-derived growth factor) can lead to increased\\u000a production of ECM

Daniela Hohenadel; Fokko J. van der Woude

2004-01-01

447

PPAR?, the ultimate thrifty gene  

Microsoft Academic Search

\\u000a \\u000a Abstract\\u000a \\u000a    The peroxisome proliferator-activated receptor gamma (PPAR?) quickly evolved over the last decade from a new orphan receptor to one of the best characterized nuclear receptors. This\\u000a fast pace in PPAR? research was triggered by two main discoveries. Firstly, that PPAR? was shown to have a key role in adipogenesis and be a master controller of the “thrifty gene

J. Auwerx

1999-01-01

448

Active Gene Sequences are Undermethylated  

Microsoft Academic Search

The degree of methylation of active regions of the chromosome has been investigated by several techniques. DNase I (deoxyribonuclease I, EC 3.1.21.1) was used to introduce nicks in the active regions of the nucleus and thereby specifically label these areas. By using the methylation-specific restriction enzymes Hpa II and Hha I it could be shown that active genes are more

Tally Naveh-Many; Howard Cedar

1981-01-01

449

Method for determining gene knockouts  

SciTech Connect

A method for determining candidates for gene deletions and additions using a model of a metabolic network associated with an organism, the model includes a plurality of metabolic reactions defining metabolite relationships, the method includes selecting a bioengineering objective for the organism, selecting at least one cellular objective, forming an optimization problem that couples the at least one cellular objective with the bioengineering objective, and solving the optimization problem to yield at least one candidate.

Maranas, Costa D; Burgard, Anthony R; Pharkya, Priti

2013-06-04

450

Gene expression in Chromobacterium violaceum  

Microsoft Academic Search

The repertoire of 4,431 open reading frames (ORFs), eight rRNA operons and 98 tRNA genes of Chromobacterium viola- ceum must be expressed in a regulated manner for successful adapta- tion to a wide variety of environmental conditions. To accomplish this feat, the organism relies on protein machineries involved in transcription, RNA processing and translation. Analysis of the C. violaceum genome

Rosane Silva; Júlia R. Araripe; Edson Rondinelli; Turán P. Ürményi

2004-01-01

451

Transgenic plants with cyanobacterial genes  

Microsoft Academic Search

Over the years, cyanobacteria have been regarded as ideal model systems for studying fundamental biochemical processes like\\u000a oxygenic photosynthesis and carbon and nitrogen assimilation. Additionally, they have been used as human foods, sources for\\u000a vitamins, proteins, fine chemicals, and bioactive compounds. Aiming to increase plant productivity as well as nutritional\\u000a values, cyanobacterial genes involved in carbon metabolism, fatty acid biosynthesis,

Youn-Il Park; Sang-Bong Choi; Jang R. Liu

2009-01-01

452

Chromosomal destabilization during gene amplification.  

PubMed Central

Acentric extrachromosomal elements, such as submicroscopic autonomously replicating circular molecules (episomes) and double minute chromosomes, are common early, and in some cases initial, intermediates of gene amplification in many drug-resistant and tumor cell lines. In order to gain a more complete understanding of the amplification process, we investigated the molecular mechanisms by which such extrachromosomal elements are generated and we traced the fate of these amplification intermediates over time. The model system consists of a Chinese hamster cell line (L46) created by gene transfer in which the initial amplification product was shown previously to be an unstable extrachromosomal element containing an inverted duplication spanning more than 160 kilobases (J. C. Ruiz and G. M. Wahl, Mol. Cell. Biol. 8:4302-4313, 1988). In this study, we show that these molecules were formed by a process involving chromosomal deletion. Fluorescence in situ hybridization was performed at multiple time points on cells with amplified sequences. These studies reveal that the extrachromosomal molecules rapidly integrate into chromosomes, often near or at telomeres, and once integrated, the amplified sequences are themselves unstable. These data provide a molecular and cytogenetic chronology for gene amplification in this model system; an early event involves deletion to generate extrachromosomal elements, and subsequent integration of these elements precipitates a cascade of chromosome instability. Images

Ruiz, J C; Wahl, G M

1990-01-01

453

Liver Damage using Suicide Genes  

PubMed Central

Liver regeneration from the facultative hepatic stem cells, the oval cells, takes place in situations in which liver regeneration from pre-existing hepatocytes is prevented. Different models have been used to stimulate oval cell response. Many of them involve the use of carcinogenic agents with or without partial hepatectomy. In this study we show that adenovirus-mediated gene transfer of the suicide gene thymidine kinase followed by ganciclovir administration caused hepatotoxicity of variable intensity. Rats with moderate elevation in serum transaminases recovered normal liver architecture few weeks after adenovirus injection. In contrast, rats with severe liver damage exhibited a marked and persisting activation of oval cells accompanied by ductular hyperplasia. In some rats, such lesion eventually evolved to cholangiofibrosis and in one rat to cholangiocarcinoma. Deposition of fibronectin and increased number of hepatic stellate cells were found in association with oval cells and cholangiofibrotic lesions. Hepatocyte growth factor was hyperexpressed in the livers with intense oval cell response or ductular proliferation, suggesting a participation of this factor in those lesions. In summary, our data demonstrate activation of oval cell response after gene transfer of thymidine kinase followed by ganciclovir administration. These findings indicate that high doses of this therapy causes liver damage together with an impairment in hepatocellular regeneration.

Bustos, Matilde; Sangro, Bruno; Alzuguren, Pilar; Gil, Ana Gloria; Ruiz, Juan; Beraza, Naiara; Qian, Chen; Garcia-Pardo, Angeles; Prieto, Jesus

2000-01-01

454

Collaborative computing for gene mapping  

SciTech Connect

The authors are investigating mechanisms for utilizing advances in high performance computing and alignment algorithm development which will allow the analysis of newly acquired sequence data in real time and eliminate the global alignments problems associated with existing datasets. The presence of repetitive DNA sequences in the human genome complicates the process of homology comparisons. Three approaches have been used to address this problem. Two of the approaches involve elimination of the repetitive elements either by removing the repetitive element from the query or scoring words due to the repetitive elements poorly or not at all during the alignment process. The approach involves identification of the repetitive element in the query by comparison to a known repeat set prior to comparison to the large database. Any homologies returned which are contained within a previously identified repeat are ignored unless the homology exceeds set quality parameters. The homologies which extend outside the bounds of the repetitive element are reported. Using this approach the repeat is not eliminated from larger homologous units which may exist, and is returned as part of the overall homology result. The method the authors utilize in the laboratory for gene mapping is fluorescent in situ hybridization (FISH). This approach involves labelling a gene segment with a fluorescent molecule and then mixing the labeled gene segment (probe) with chromosomes.

Gatewood, J.M.

1993-12-01

455

Duplications in the DMD gene.  

PubMed

The detection of duplications in Duchenne (DMD)/Becker Muscular Dystrophy (BMD) has long been a neglected issue. However, recent technological advancements have significantly simplified screening for such rearrang