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Sample records for agt gene m235t

  1. Angiotensinogen (AGT) M235T, AGT T174M and Angiotensin-1-Converting Enzyme (ACE) I/D Gene Polymorphisms in Essential Hypertension: Effects on Ramipril Efficacy

    PubMed Central

    Kolovou, Vana; Lagou, Evangelia; Mihas, Constantinos; Vasiliki, Giannakopoulou; Katsiki, Niki; Kollia, Aikaterini; Triposkiadis, Filippos; Degiannis, Dimitris; Mavrogeni, Sophie; Kolovou, Genovefa

    2015-01-01

    Background: Hypertension, one of the most important risk factors for premature cardiovascular disease, is a major worldwide public health problem. Angiotensin-1-converting enzyme (ACE) and angiotensinogen (AGT) gene polymorphisms are thought to be associated with primary hypertension. In the present study, we examined the frequency of these gene polymorphisms in an adult population with and without essential hypertension. Furthermore, we evaluated the effect of ACE and AGT gene polymorphisms on ramipril treatment efficacy in the hypertensive patients. Methods: A total of 166 adults (83 hypertensives and 83 normotensives) were involved in the study and genotyped for AGTM235T (rs699), AGTT174M (rs4762) and ACEI/D (rs1799752) gene polymorphisms. Results: The genotype and allele distribution of the AGTM235T variant significantly differed between hypertensives and normotensives [odds ratio (OR) = 1.57% (T vs M allele), 95% confidence intervals (CIs): 1.01 - 2.44; p=0.045 for hypertensives]. However, none of the 3 studied Simple Nucleotide Polymorphisms were associated with the blood pressure-lowering response to ramipril. Conclusion: These results suggest that AGTM235T gene polymorphism is associated with essential hypertension. However, none of the AGTM235T, AGTT174M and ACEI/D gene polymorphisms influenced ramipril effectiveness. PMID:27006715

  2. A polymorphism in AGT and AGTR1 gene is associated with lead-related high blood pressure.

    PubMed

    Kim, Hyung-Ki; Lee, Hwayoung; Kwon, Jun-Tack; Kim, Hak-Jae

    2015-12-01

    We investigated the association of polymorphisms in two renin-angiotensin system-related genes, expressed as angiotensinogen (AGT) and angiotensin II type 1 receptor (AGTR1), with blood lead levels and lead-related blood pressure in lead-exposed male workers in Korea. A cross-sectional study involving 808 lead-exposed male workers in Korea was conducted using a restriction fragment length polymorphism-based strategy to differentiate the various genotypes of polymorphisms in the AGT and AGTR1 genes. The association of clinical characteristics with genotypes as modifiers was estimated after adjustment for age, smoking status, drinking status, body mass index and job duration of each subject. Genotype and allele frequencies of the M235T polymorphism in AGT were associated with lead-related high blood pressure status. Moreover, blood lead levels were associated with allele frequencies of the AGT M235T polymorphism. These results suggested that the M/M genotype and M allele of AGT are risk factors for lead-related high blood pressure.

  3. Correlation of M235T DNA polymorphism with cardiovascular and endocrine responses during physical exercise in healthy subjects.

    PubMed

    Krizanová, O; Koska, J; Vigas, M; Kvetnanský, R

    1998-01-01

    In our experiments, we evaluated the possible effect of M235T molecular variant of the angiotensinogen gene on the response to a physical workload. A group of volunteers was composed of healthy male subjects, approximately of the same weight and height, same age and not actively trained. None of these subjects was under any medication. Blood sampling was carried out via an indwelling catheter. Besides blood pressure and heart rate, angiotensin I, angiotensin II, epinephrine and norepinephrine concentrations were measured in the blood. Our results suggest that only the response of diastolic blood pressure during submaximal exercise corresponded to the presence of M235T molecular variant. In all other parameters we found no significant correlation of the response with the M235T molecular variant. PMID:9706989

  4. Angiotensinogen-M235T as a risk factor for myocardial infarction in Asian populations: a genetic association study and a bioinformatics approach

    PubMed Central

    Raygan, Fariba; Karimian, Mohammad; Rezaeian, Atefeh; Bahmani, Bahareh; Behjati, Mohaddeseh

    2016-01-01

    Aim To investigate if there is an association between M235T polymorphism of angiotensinogen gene and myocardial infarction (MI) risk and perform a meta-analysis and an in silico approach. Methods This case-control study included 340 participants (155 MI patients and 185 controls) examined at Kashan University of Medical Sciences (Kashan, Iran) between 2013 and 2015. Meta-analysis included 25 studies with 6334 MI patients and 6711 controls. Bioinformatics tools were applied to evaluate the impact of M235T polymorphism on angiotensinogen function and structure. Results Genetic association study revealed a significant association between TT genotype (odds ratio [OR] 2.08, 95% confidence interval [CI] 1.08-4.00, P = 0.029) and T allele (OR 1.45, 95% CI 1.06-1.99, P = 0.021) and MI risk. Meta-analysis also revealed a significant association between M235T polymorphism and MI risk in allelic (OR 1.55, 95% CI 1.10-2.18, P = 0.012) and recessive (OR 1.69, 95% CI 1.13-2.53, P = 0.010) models within Asian population. In silico-analysis revealed that M235T fundamentally changed the function of angiotensinogen (score 32; expected accuracy 66%). Conclusions Our study suggests that M235T polymorphism might be a helpful biomarker for screening of susceptible individuals for MI in Asian population. PMID:27586550

  5. CYP1A1, GCLC, AGT, AGTR1 gene-gene interactions in community-acquired pneumonia pulmonary complications.

    PubMed

    Salnikova, Lyubov E; Smelaya, Tamara V; Golubev, Arkadiy M; Rubanovich, Alexander V; Moroz, Viktor V

    2013-11-01

    This study was conducted to establish the possible contribution of functional gene polymorphisms in detoxification/oxidative stress and vascular remodeling pathways to community-acquired pneumonia (CAP) susceptibility in the case-control study (350 CAP patients, 432 control subjects) and to predisposition to the development of CAP complications in the prospective study. All subjects were genotyped for 16 polymorphic variants in the 14 genes of xenobiotics detoxification CYP1A1, AhR, GSTM1, GSTT1, ABCB1, redox-status SOD2, CAT, GCLC, and vascular homeostasis ACE, AGT, AGTR1, NOS3, MTHFR, VEGFα. Risk of pulmonary complications (PC) in the single locus analysis was associated with CYP1A1, GCLC and AGTR1 genes. Extra PC (toxic shock syndrome and myocarditis) were not associated with these genes. We evaluated gene-gene interactions using multi-factor dimensionality reduction, and cumulative gene risk score approaches. The final model which included >5 risk alleles in the CYP1A1 (rs2606345, rs4646903, rs1048943), GCLC, AGT, and AGTR1 genes was associated with pleuritis, empyema, acute respiratory distress syndrome, all PC and acute respiratory failure (ARF). We considered CYP1A1, GCLC, AGT, AGTR1 gene set using Set Distiller mode implemented in GeneDecks for discovering gene-set relations via the degree of sharing descriptors within a given gene set. N-acetylcysteine and oxygen were defined by Set Distiller as the best descriptors for the gene set associated in the present study with PC and ARF. Results of the study are in line with literature data and suggest that genetically determined oxidative stress exacerbation may contribute to the progression of lung inflammation.

  6. Role of ACE and AGT gene polymorphisms in genetic susceptibility to diabetes mellitus type 2 in a Brazilian sample.

    PubMed

    Wollinger, L M; Dal Bosco, S M; Rempe, C; Almeida, S E M; Berlese, D B; Castoldi, R P; Arndt, M E; Contini, V; Genro, J P

    2015-12-29

    The aim of the current study was to investigate the association between the InDel polymorphism in the angiotensin I-converting enzyme gene (ACE) and the rs699 polymorphism in the angiotensinogen gene (AGT) and diabetes mellitus type 2 (DM2) in a sample population from Southern Brazil. A case-control study was conducted with 228 patients with DM2 and 183 controls without DM2. The ACE InDel polymorphism was genotyped by polymerase chain reaction (PCR) with specific primers, followed by electrophoresis on 1.5% agarose gel. The AGT rs699 polymorphism was genotyped using a real-time PCR assay. No significant association between the ACE InDel polymorphism and DM2 was detected (P = 0.97). However, regarding the AGT rs699 polymorphism, DM2 patients had a significantly higher frequency of the AG genotype and lower frequency of the GG genotype when compared to the controls (P = 0.03). Our results suggest that there is an association between the AGT rs699 polymorphism and DM2 in a Brazilian sample.

  7. Analysis of Polymorphisms in Genes (AGT, MTHFR, GPIIIa, and GSTP1) Associated with Hypertension, Thrombophilia and Oxidative Stress in Mestizo and Amerindian Populations of México

    PubMed Central

    Juárez-Velázquez, Rocio; Canto, Patricia; Canto-Cetina, Thelma; Rangel-Villalobos, Hector; Rosas-Vargas, Haydee; Rodríguez, Maricela; Canizales-Quinteros, Samuel; Velázquez Wong, Ana Claudia; Ordoñez-Razo, Rosa María; Vilchis-Dorantes, Guadalupe; Coral-Vázquez, Ramón Mauricio

    2010-01-01

    Several polymorphisms related to hypertension, thrombophilia, and oxidative stress has been associated with the development of cardiovascular disease. We analyzed the frequency of M235T angiotensinogen (AGT), A222V 5,10 methylenete-trahydrofolate reductase (MTHFR), L33P glycoprotein IIIa (GPIIIa), and I105V glutathione S-transferase P1 (GSTP1) polymorphisms in 285 individuals belonging to Mexican-Mestizo and five Amerindian population from México, by real time PCR allelic discrimination. Allele and genotype frequencies were compared using χ2 tests. All populations followed the Hardy Weinberg equilibrium for assay markers with the exception of the Triki, whose were in Hardy Weinberg dysequilibrium for the glutathione S-transferase P1 polymorphism. Interestingly, according to all the analyzed single nucleotide polymorphisms (SNPs), the Triki population was the most differentiated and homogeneous group of the six populations analyzed. A comparison of our data with those previously published for some Caucasian, Asian and Black populations showed quite significant differences. These differences were remarkable with all the Mexican populations having a lower frequency of the 105V allele of the glutathione S-transferase P1 and reduced occurrence of the 222A allele of the 5,10 methylenetetrahydrofolate reductase. Our results show the genetic diversity among different Mexican populations and with other racial groups. PMID:20592457

  8. The interaction of AGT and NOS3 gene polymorphisms with conventional risk factors increases predisposition to hypertension.

    PubMed

    Gatti, Renata R; Santos, Paula S; Sena, Angela A S; Marangoni, Karina; Araújo, Messias A; Goulart, Luiz R

    2013-12-01

    Renin-angiotensin and kallikrein-kinin systems are interconnected, regulating blood pressure homeostasis. We have demonstrated the interactions among polymorphisms of the angiotensinogen (AGT) and endothelial nitric oxide synthase (NOS3) genes and conventional risk factors affecting the hypertension occurrence. Individuals were recruited (n=192) and classified into hypertensive (HG; n=140) and normotensive (NG; n=52) groups. The genotypic distribution of the Met235Thr (AGT) and Glu298Asp (NOS3) polymorphisms demonstrated that both are independent risk factors of hypertension (p=0.02 and p=0.008, respectively). The concomitant presence of these polymorphisms in the HG group was significantly different (p=0.001) from the NG. Both gene polymorphisms presented an additive effect for the unfavourable alleles T and A, respectively, and 95% of the double mutant homozygotes were classified into the HG. Specific interactions among certain conventional factors and the presence of at least one unfavourable allele presented significant odds towards hypertension. Blood pressure homeostasis was affected by genetic polymorphisms conditioned by the T and A alleles of the AGT and NOS3 genes, respectively, which acted independently. However, their interaction with smoking, sedentariness, age and total cholesterol may have increased the predisposition to hypertension, which may explain most of the hypertension cases. PMID:22791701

  9. Angiotensinogen gene polymorphism (Met235Thr) influences visceral obesity and insulin resistance in obese Japanese women.

    PubMed

    Takakura, Yasuto; Yoshida, Toshihide; Yoshioka, Keiji; Umekawa, Tsunekazu; Kogure, Akinori; Toda, Hitoshi; Kagawa, Keizo; Fukui, Susumu; Yoshikawa, Toshikazu

    2006-06-01

    M235T polymorphism. After the diet and exercise therapy, the blood pressure in the T/T group tended to be higher than that in the M/T group, but the difference was not significant. We demonstrated that the T/T genotype of the AGT M235T gene polymorphism was positively related to visceral obesity and hyperinsulinemia in obese Japanese women. Blood pressure did not show genotype-specific differences before or after the treatment. Further studies of the association between obesity and this gene polymorphism should contribute to understanding and treating obesity-related diseases. PMID:16713443

  10. AGT100 turbomachinery. [for automobiles

    NASA Technical Reports Server (NTRS)

    Tipton, D. L.; Mckain, T. F.

    1982-01-01

    High-performance turbomachinery components have been designed and tested for the AGT100 automotive engine. The required wide range of operation coupled with the small component size, compact packaging, and low cost of production provide significant aerodynamic challenges. Aerodynamic design and development testing of the centrifugal compressor and two radial turbines are described. The compressor achieved design flow, pressure ratio, and surge margin on the initial build. Variable inlet guide vanes have proven effective in modulating flow capacity and in improving part-speed efficiency. With optimum use of the variable inlet guide vanes, the initial efficiency goals have been demonstrated in the critical idle-to-70% gasifier speed range. The gasifier turbine exceeded initial performance goals and demonstrated good performance over a wide range. The radial power turbine achieved 'developed' efficiency goals on the first build.

  11. Identification of regulatory elements in the AGT1 promoter of ale and lager strains of brewer's yeast.

    PubMed

    Vidgren, Virve; Kankainen, Matti; Londesborough, John; Ruohonen, Laura

    2011-08-01

    Agt1 is an interesting α-glucoside transporter for the brewing industry, as it efficiently transports maltotriose, a sugar often remaining partly unused during beer fermentation. It has been shown that on maltose the expression level of AGT1 is much higher in ale strains than in lager strains, and that glucose represses the expression, particularly in the ale strains. In the present study the regulatory elements of the AGT1 promoter of one ale and two lager strains were identified by computational methods. Promoter regions up to 1.9 kbp upstream of the AGT1 gene were sequenced from the three brewer's yeast strains and the laboratory yeast strain CEN.PK-1D. The promoter sequence of the laboratory strain was identical to the AGT1 promoter of strain S288c of the Saccharomyces Genome Database, whereas the promoter sequences of the industrial strains diverged markedly from the S288c strain. The AGT1 promoter regions of the ale and lager strains were for the most part identical to each other, except for one 22 bp deletion and two 94 and 95 bp insertions in the ale strain. Computational analyses of promoter elements revealed that the promoter sequences contained several Mig1- and MAL-activator binding sites, as was expected. However, some of the Mig1 and MAL-activator binding sites were located on the two insertions of the ale strain, and thus offered a plausible explanation for the different expression pattern of the AGT1 gene in the ale strains. Accordingly, functional analysis of A60 ale and A15 lager strain AGT1 promoters fused to GFP (encoding the green fluorescent protein) showed a significant difference in the ability of these two promoters to drive GFP expression. Under the control of the AGT1 promoter of the ale strain the emergence of GFP was strongly induced by maltose, whereas only a low level of GFP was detected with the construct carrying the AGT1 promoter of the lager strain. Thus, the extra MAL-activator binding element, present in the AGT1 promoter of

  12. Advanced Gas Turbine (AGT) technology development project

    NASA Technical Reports Server (NTRS)

    1987-01-01

    This report is the final in a series of Technical Summary Reports for the Advanced Gas Turbine (AGT) Technology Development Project, authorizrd under NASA Contract DEN3-167 and sponsored by the DOE. The project was administered by NASA-Lewis Research Center of Cleveland, Ohio. Plans and progress are summarized for the period October 1979 through June 1987. This program aims to provide the US automotive industry the high risk, long range technology necessary to produce gas turbine engines for automobiles that will reduce fuel consumption and reduce environmental impact. The intent is that this technology will reach the marketplace by the 1990s. The Garrett/Ford automotive AGT was designated AGT101. The AGT101 is a 74.5 kW (100 shp) engine, capable of speeds to 100,000 rpm, and operates at turbine inlet temperatures to 1370 C (2500 F) with a specific fuel consumption level of 0.18 kg/kW-hr (0.3 lbs/hp-hr) over most of the operating range. This final report summarizes the powertrain design, power section development and component/ceramic technology development.

  13. Polymorphisms of the renin-angiotensin system genes predict progression of subclinical coronary atherosclerosis.

    PubMed

    Kretowski, Adam; McFann, Kim; Hokanson, John E; Maahs, David; Kinney, Gregory; Snell-Bergeon, Janet K; Wadwa, R Paul; Eckel, Robert H; Ogden, Lorraine; Garg, Satish; Li, Jia; Cheng, Suzanne; Erlich, Henry A; Rewers, Marian

    2007-03-01

    Premature coronary artery disease (CAD) in subjects with type 1 diabetes dramatically affects quality of life and morbidity and leads to premature death, but there is still little known about the mechanisms and predictors of this complication. In the present study, we explored the role of genetic variants of angiotensinogen (AGT, M235T), ACE (I/D), and angiotensin type 1 receptor (ATR1, A1166C) as predictors of rapid progression of subclinical coronary atherosclerosis. Five-hundred eighty-five type 1 diabetic patients and 592 similar age and sex control subjects were evaluated for progression of coronary artery calcification (CAC), a marker of subclinical CAD, before and after a 2.5-year follow-up. In logistic regression analysis, CAC progression was dramatically more likely in type 1 diabetic subjects not treated with ACE inhibitor/angiotensin receptor blocker who had the TT-ID-AA/AC genotype combination than in those with other genotypes (odds ratio 11.6 [95%CI 4.5-29.6], P < 0.0001) and was even stronger when adjusted for cardiovascular disease risk factors and the mean A1C (37.5 [3.6-388], P = 0.002). In conclusion, a combination of genotype variants of the renin-angiotensin system genes is a powerful determinant of subclinical progression of coronary artery atherosclerosis in type 1 diabetic patients and may partially explain accelerated CAD in type 1 diabetes. PMID:17327458

  14. Improved Fermentation Performance of a Lager Yeast after Repair of Its AGT1 Maltose and Maltotriose Transporter Genes▿ †

    PubMed Central

    Vidgren, Virve; Huuskonen, Anne; Virtanen, Hannele; Ruohonen, Laura; Londesborough, John

    2009-01-01

    The use of more concentrated, so-called high-gravity and very-high-gravity (VHG) brewer's worts for the manufacture of beer has economic and environmental advantages. However, many current strains of brewer's yeasts ferment VHG worts slowly and incompletely, leaving undesirably large amounts of maltose and especially maltotriose in the final beers. α-Glucosides are transported into Saccharomyces yeasts by several transporters, including Agt1, which is a good carrier of both maltose and maltotriose. The AGT1 genes of brewer's ale yeast strains encode functional transporters, but the AGT1 genes of the lager strains studied contain a premature stop codon and do not encode functional transporters. In the present work, one or more copies of the AGT1 gene of a lager strain were repaired with DNA sequence from an ale strain and put under the control of a constitutive promoter. Compared to the untransformed strain, the transformants with repaired AGT1 had higher maltose transport activity, especially after growth on glucose (which represses endogenous α-glucoside transporter genes) and higher ratios of maltotriose transport activity to maltose transport activity. They fermented VHG (24° Plato) wort faster and more completely, producing beers containing more ethanol and less residual maltose and maltotriose. The growth and sedimentation behaviors of the transformants were similar to those of the untransformed strain, as were the profiles of yeast-derived volatile aroma compounds in the beers. PMID:19181838

  15. Selberg integral and SU( N) AGT conjecture

    NASA Astrophysics Data System (ADS)

    Zhang, Hong; Matsuo, Yutaka

    2011-12-01

    An intriguing coincidence between the partition function of super Yang-Mills theory and correlation functions of 2d Toda system has been heavily studied recently. While the partition function of gauge theory was explored by Nekrasov, the correlation functions of Toda equation have not been completely understood. In this paper, we study the latter in the form of Dotsenko-Fateev integral and reduce it in the form of Selberg integral of several Jack polynomials. We conjecture a formula for such Selberg average which satisfies some consistency conditions and show that it reproduces the SU( N) version of AGT conjecture.

  16. Advanced Gas Turbine (AGT) powertrain system development for automotive applications

    NASA Technical Reports Server (NTRS)

    1982-01-01

    Topics covered include the AGT 101 engine test; compressor design modification; cold air turbine testing; Mod 1 alloy turbine rotor fabrication; combustion aspects; regenerator development; and thermal screening tests for ceramic materials. The foil gas bearings, rotor dynamics, and AGT controls and accessories are also considered.

  17. Advanced Gas Turbine (AGT) technology report

    NASA Technical Reports Server (NTRS)

    1985-01-01

    Engine testing, ceramic component fabrication and evaluation, component performance rig testing, and producibility experiments at Pontiac comprised AGT 100 activities of this period, January to December 1984. Two experimental engines were available and allowed the evaluation of eight experimental assemblies. Operating time accumulated was 115 hr of burning and 156 hr total. Total cumulative engine operating time is now 225 hr. Build number 11 and 12 of engine S/N 1 totaled 28 burning hours and constituted a single assembly of the engine core--the compressor, both turbines, and the gearbox. Build number 11 of engine S/N 1 included a 1:07 hr continuous test at 100% gasifier speed (86,000 rpm). Build number 8 of engine S/N 2 was the first engine test with a ceramic turbine rotor. A mechanical loss test of an engine assembly revealed the actual losses to be near the original design allowance. Component development activity included rig testing of the compressor, combustor, and regenerator. Compressor testing was initiated on a rig modified to control the transfer of heat between flow path, lubricating oil, and structure. Results show successful thermal decoupling of the rig and lubricating/cooling oil. Rig evaluation of a reduced-friction compressor was initiated. Combustor testing covered qualification of ceramic parts for engine use, mapping of operating range limits, and evaluation of a relocated igniter plug. Several seal refinements were tested on the hot regenerator rig. An alternate regenerator disk, extruded MAS, was examined and found to be currently inadequate for the AGT 100 application. Also, a new technique for measuring leakage was explored on the regenerator rig. Ceramic component activity has focused on the development of state-of-the-art material strength characteristics in full-scale hardware. Injection-molded sintered alpha-SiC rotors were produced at Carborundum in an extensive process and tool optimization study.

  18. AGT (Advanced Gas Turbine) technology project

    NASA Technical Reports Server (NTRS)

    1988-01-01

    An overall summary documentation is provided for the Advanced Gas Turbine Technology Project conducted by the Allison Gas Turbine Division of General Motors. This advanced, high risk work was initiated in October 1979 under charter from the U.S. Congress to promote an engine for transportation that would provide an alternate to reciprocating spark ignition (SI) engines for the U.S. automotive industry and simultaneously establish the feasibility of advanced ceramic materials for hot section components to be used in an automotive gas turbine. As this program evolved, dictates of available funding, Government charter, and technical developments caused program emphases to focus on the development and demonstration of the ceramic turbine hot section and away from the development of engine and powertrain technologies and subsequent vehicular demonstrations. Program technical performance concluded in June 1987. The AGT 100 program successfully achieved project objectives with significant technology advances. Specific AGT 100 program achievements are: (1) Ceramic component feasibility for use in gas turbine engines has been demonstrated; (2) A new, 100 hp engine was designed, fabricated, and tested for 572 hour at operating temperatures to 2200 F, uncooled; (3) Statistical design methodology has been applied and correlated to experimental data acquired from over 5500 hour of rig and engine testing; (4) Ceramic component processing capability has progressed from a rudimentary level able to fabricate simple parts to a sophisticated level able to provide complex geometries such as rotors and scrolls; (5) Required improvements for monolithic and composite ceramic gas turbine components to meet automotive reliability, performance, and cost goals have been identified; (6) The combustor design demonstrated lower emissions than 1986 Federal Standards on methanol, JP-5, and diesel fuel. Thus, the potential for meeting emission standards and multifuel capability has been initiated

  19. Advanced Gas Turbine (AGT) Technology Project

    NASA Technical Reports Server (NTRS)

    1986-01-01

    Engine testing, ceramic component fabrication and evaluation, component performance rig testing, and analytical studies comprised AGT 100 activities during the 1985 year. Ten experimental assemblies (builds) were evaluated using two engines. Accrued operating time was 120 hr of burning and 170 hr total, bringing cumulative total operating time to 395 hr, all devoid of major failures. Tests identified the generator seals as the primary working fluid leakage sources. Power transfer clutch operation was demonstrated. An alpha SiC gasifier rotor engine test resulted in blade tip failures. Recurring case vibration and shaft whip have limited gasifier shaft speeds to 84%. Ceramic components successfully engine tested now include the SiC scroll assembly, Si3N3 turbine rotor, combustor assembly, regenerator disk bulkhead, turbine vanes, piston rings, and couplings. A compressor shroud design change to reduce heat recirculation back to the inlet was executed. Ceramic components activity continues to focus on the development of state-of-the-art material strength characteristics in full-scale engine hardware. Fiber reinforced glass-ceramic composite turbine (inner) backplates were fabricated by Corning Glass Works. The BMAS/III material performed well in engine testing. Backplates of MAS material have not been engine tested.

  20. Advanced Gas Turbine (AGT) Technology Development Project

    NASA Technical Reports Server (NTRS)

    1987-01-01

    This report is the eleventh in the series of Technical Summary reports for the Advanced Gas Turbine (AGT) Technology Development Project, authorized under NASA Contract DEN3-167, and sponsored by the Department of Energy (DOE). This report was prepared by Garrett Turbine Engine Company, A Division of the Garrett Corporation, and includes information provided by Ford Motor Company, the Standard Oil Company, and AiResearch Casting Company. This report covers plans and progress for the period July 1, 1985 through June 30, 1986. Technical progress during the reported period was highlighted by the 85-hour endurance run of an all-ceramic engine operating in the 2000 to 2250 F temperature regime. Component development continued in the areas of the combustion/fuel injection system, regenerator and seals system, and ceramic turbine rotor attachment design. Component rig testing saw further refinements. Ceramic materials showed continued improvements in required properties for gas turbine applications; however, continued development is needed before performance and reliability goals can be set.

  1. Advanced Gas Turbine (AGT) Technology Development Project, ceramic component developments

    NASA Technical Reports Server (NTRS)

    Teneyck, M. O.; Macbeth, J. W.; Sweeting, T. B.

    1987-01-01

    The ceramic component technology development activity conducted by Standard Oil Engineered Materials Company while performing as a principal subcontractor to the Garrett Auxiliary Power Division for the Advanced Gas Turbine (AGT) Technology Development Project (NASA Contract DEN3-167) is summarized. The report covers the period October 1979 through July 1987, and includes information concerning ceramic technology work categorized as common and unique. The former pertains to ceramic development applicable to two parallel AGT projects established by NASA contracts DEN3-168 (AGT100) and DEN3-167 (AGT101), whereas the unique work solely pertains to Garrett directed activity under the latter contract. The AGT101 Technology Development Project is sponsored by DOE and administered by NASA-Lewis. Standard Oil directed its efforts toward the development of ceramic materials in the silicon-carbide family. Various shape forming and fabrication methods, and nondestructive evaluation techniques were explored to produce the static structural components for the ceramic engine. This permitted engine testing to proceed without program slippage.

  2. Novel regulation of Skp1 by the Dictyostelium AgtA α-galactosyltransferase involves the Skp1-binding activity of its WD40 repeat domain.

    PubMed

    Schafer, Christopher M; Sheikh, M Osman; Zhang, Dongmei; West, Christopher M

    2014-03-28

    The role of Skp1 as an adaptor protein that links Cullin-1 to F-box proteins in E3 Skp1/Cullin-1/F-box protein (SCF) ubiquitin ligases is well characterized. In the social amoeba Dictyostelium and probably many other unicellular eukaryotes, Skp1 is modified by a pentasaccharide attached to a hydroxyproline near its C terminus. This modification is important for oxygen-sensing during Dictyostelium development and is mediated by a HIF-α type prolyl 4-hydroxylase and five sequentially acting cytoplasmic glycosyltransferase activities. Gene disruption studies show that AgtA, the enzyme responsible for addition of the final two galactose residues, in α-linkages to the Skp1 core trisaccharide, is unexpectedly critical for oxygen-dependent terminal development. AgtA possesses a WD40 repeat domain C-terminal to its single catalytic domain and, by use of domain deletions, binding studies, and enzyme assays, we find that the WD40 repeats confer a salt-sensitive second-site binding interaction with Skp1 that mediates novel catalytic activation in addition to simple substrate recognition. In addition, AgtA binds similarly well to precursor isoforms of Skp1 by a salt-sensitive mechanism that competes with binding to an F-box protein and recognition by early modification enzymes, and the effect of binding is diminished when AgtA modifies Skp1. Genetic studies show that loss of AgtA is more severe when an earlier glycosylation step is blocked, and overexpressed AgtA is deleterious if catalytically inactivated. Together, the findings suggest that AgtA mediates non-enzymatic control of unmodified and substrate precursor forms of Skp1 by a binding mechanism that is normally relieved by switch-like activation of its glycosylation function. PMID:24550398

  3. Renin–angiotensin system gene polymorphisms and endometrial cancer

    PubMed Central

    Delforce, Sarah J; Wang, Yu; Ashton, Katie A; Proietto, Anthony; Otton, Geoffrey; Blackwell, C Caroline; Scott, Rodney J; Lumbers, Eugenie R

    2016-01-01

    Endometrial cancer (EC) is the most common gynaecological malignancy and its incidence is increasing. Dysregulation of the endometrial renin–angiotensin system (RAS) could predispose to EC; therefore, we studied the prevalence of RAS single nucleotide polymorphisms (SNPs) in Australian women with EC. SNPs assessed were AGT M235T (rs699); AGTR1 A1166C (rs5186); ACE A240T and T93C (rs4291, rs4292) and ATP6AP2 (rs2968915). They were identified using TaqMan SNP Genotyping Assays. The C allele of the AGTR1 SNP (rs5186) was more prevalent in women with EC (odds ratio (OR) 1.7, 95% confidence interval (CI) (1.2–2.3), P=0.002). The CC genotype of this SNP is associated with upregulation of the angiotensin II type 1 receptor (AGTR1). The G allele of AGT rs699, which is associated with higher angiotensinogen (AGT) levels, was less prevalent in women with EC (OR 0.54, 95% CI (0.39–0.74), P<0.001) compared with controls. AGT and AGT formed by removal of angiotensin I (des(Ang I)AGT) are both anti-angiogenic. In women with EC who had had hormone replacement therapy (HRT), the prevalence of the AGTR1 SNP (rs5186) and the ACE SNPs (rs4291 and rs4292) was greater than in women who had no record of HRT; SNP rs4291 is associated with increased plasma ACE activity. These data suggest there is an interaction between genotype, oestrogen replacement therapy and EC. In conclusion, the prevalence of two SNPs that enhance RAS activity was different in women with EC compared with healthy controls. These genetic factors may interact with obesity and hyperoestrogenism, predisposing ageing, obese women to EC. PMID:27068935

  4. Renin-angiotensin system gene polymorphisms and endometrial cancer.

    PubMed

    Pringle, Kirsty G; Delforce, Sarah J; Wang, Yu; Ashton, Katie A; Proietto, Anthony; Otton, Geoffrey; Blackwell, C Caroline; Scott, Rodney J; Lumbers, Eugenie R

    2016-05-01

    Endometrial cancer (EC) is the most common gynaecological malignancy and its incidence is increasing. Dysregulation of the endometrial renin-angiotensin system (RAS) could predispose to EC; therefore, we studied the prevalence of RAS single nucleotide polymorphisms (SNPs) in Australian women with EC. SNPs assessed were AGT M235T (rs699); AGTR1 A1166C (rs5186); ACE A240T and T93C (rs4291, rs4292) and ATP6AP2 (rs2968915). They were identified using TaqMan SNP Genotyping Assays. The C allele of the AGTR1 SNP (rs5186) was more prevalent in women with EC (odds ratio (OR) 1.7, 95% confidence interval (CI) (1.2-2.3), P=0.002). The CC genotype of this SNP is associated with upregulation of the angiotensin II type 1 receptor (AGTR1). The G allele of AGT rs699, which is associated with higher angiotensinogen (AGT) levels, was less prevalent in women with EC (OR 0.54, 95% CI (0.39-0.74), P<0.001) compared with controls. AGT and AGT formed by removal of angiotensin I (des(Ang I)AGT) are both anti-angiogenic. In women with EC who had had hormone replacement therapy (HRT), the prevalence of the AGTR1 SNP (rs5186) and the ACE SNPs (rs4291 and rs4292) was greater than in women who had no record of HRT; SNP rs4291 is associated with increased plasma ACE activity. These data suggest there is an interaction between genotype, oestrogen replacement therapy and EC. In conclusion, the prevalence of two SNPs that enhance RAS activity was different in women with EC compared with healthy controls. These genetic factors may interact with obesity and hyperoestrogenism, predisposing ageing, obese women to EC.

  5. Field testing advanced geothermal turbodrill (AGT). Phase 1 final report

    SciTech Connect

    Maurer, W.C.; Cohen, J.H.

    1999-06-01

    Maurer Engineering developed special high-temperature geothermal turbodrills for LANL in the 1970s to overcome motor temperature limitations. These turbodrills were used to drill the directional portions of LANL`s Hot Dry Rock Geothermal Wells at Fenton Hill, New Mexico. The Hot Dry Rock concept is to drill parallel inclined wells (35-degree inclination), hydraulically fracture between these wells, and then circulate cold water down one well and through the fractures and produce hot water out of the second well. At the time LANL drilled the Fenton Hill wells, the LANL turbodrill was the only motor in the world that would drill at the high temperatures encountered in these wells. It was difficult to operate the turbodrills continuously at low speed due to the low torque output of the LANL turbodrills. The turbodrills would stall frequently and could only be restarted by lifting the bit off bottom. This allowed the bit to rotate at very high speeds, and as a result, there was excessive wear in the bearings and on the gauge of insert roller bits due to these high rotary speeds. In 1998, Maurer Engineering developed an Advanced Geothermal Turbodrill (AGT) for the National Advanced Drilling and Excavation Technology (NADET) at MIT by adding a planetary speed reducer to the LANL turbodrill to increase its torque and reduce its rotary speed. Drilling tests were conducted with the AGT using 12 1/2-inch insert roller bits in Texas Pink Granite. The drilling tests were very successful, with the AGT drilling 94 ft/hr in Texas Pink Granite compared to 45 ft/hr with the LANL turbodrill and 42 ft/hr with a rotary drill. Field tests are currently being planned in Mexico and in geothermal wells in California to demonstrate the ability of the AGT to increase drilling rates and reduce drilling costs.

  6. Advanced Gas Turbine (AGT) Technology Development Project annual report

    NASA Technical Reports Server (NTRS)

    1986-01-01

    This report is the tenth in a series of Technical Summary reports for the Advanced Gas Turbine (AGT) Technology Development Project, authorized under NASA Contract DEN3-167, and sponsored by the Department of Energy (DOE). This report was prepared by Garrett Turbine Engine Company, A Division of the Garrett Corporation, and includes information provided by Ford Motor Company, the Carborundum Company, and AiResearch Casting Company. The Project is administered by Mr. Thomas N. Strom, Project Manager, NASA-Lewis Research Center, Cleveland, Ohio. This report covers plans and progress for the period July 1, 1984 through June 30, 1985.

  7. Advanced Gas Turbine (AGT) powertrain system development for automotive applications

    NASA Technical Reports Server (NTRS)

    1982-01-01

    A gas turbine powertrain for automobiles with reduced fuel consumption and reduced environmental impact is investigated. The automotive gas turbine, when installed in an automobile (3000 pounds inertia weight), provides a CFDC fuel economy of 42.8 miles per gallon based on EPA test procedures and diesel No. 2 fuel. The AGT powered vehicle substantially gives the same overall vehicle driveability and performance as a comparable production vehicle powered by a conventional spark ignition powertrain system. The emissions are less than federal standards, and a variety of fuels can be used.

  8. AGT relations for abelian quiver gauge theories on ALE spaces

    NASA Astrophysics Data System (ADS)

    Pedrini, Mattia; Sala, Francesco; Szabo, Richard J.

    2016-05-01

    We construct level one dominant representations of the affine Kac-Moody algebra gl̂k on the equivariant cohomology groups of moduli spaces of rank one framed sheaves on the orbifold compactification of the minimal resolution Xk of the Ak-1 toric singularity C2 /Zk. We show that the direct sum of the fundamental classes of these moduli spaces is a Whittaker vector for gl̂k, which proves the AGT correspondence for pure N = 2 U(1) gauge theory on Xk. We consider Carlsson-Okounkov type Ext-bundles over products of the moduli spaces and use their Euler classes to define vertex operators. Under the decomposition gl̂k ≃ h ⊕sl̂k, these vertex operators decompose as products of bosonic exponentials associated to the Heisenberg algebra h and primary fields of sl̂k. We use these operators to prove the AGT correspondence for N = 2 superconformal abelian quiver gauge theories on Xk.

  9. Advanced Gas Turbine (AGT) powertrain system development for automotive applications

    NASA Technical Reports Server (NTRS)

    1980-01-01

    Progress in the development of a gas turbine engine to improve fuel economy, reduce gaseous emissions and particulate levels, and compatible with a variety of alternate fuels is reported. The powertrain is designated AGT101 and consists of a regenerated single shaft gas turbine engine, a split differential gearbox and a Ford Automatic Overdrive production transmission. The powertrain is controlled by an electronic digital microprocessor and associated actuators, instrumentation, and sensors. Standard automotive accessories are driven by engine power provided by an accessory pad on the gearbox. Component/subsystem development progress is reported in the following areas: compressor, turbine, combustion system, regenerator, gearbox/transmission, structures, ceramic components, foil gas bearing, bearings and seals, rotor dynamics, and controls and accessories.

  10. Advanced Gas Turbine (AGT) powertrain system development for automotive applications

    NASA Technical Reports Server (NTRS)

    1981-01-01

    An automotive gas turbine powertrain system which, when installed in a 1985 production vehicle (3000 pounds inertia weight), is being developed with a CFDC fuel economy of 42.8 miles per gallon based on Environmental Protection Agency (EPA) test procedures and diesel No. 2 fuel. The AGT-powered vehicle shall give substantially the same overall vehicle driveability and performance as a comparable 1985 production vehicle powered by a conventional spark ignition powertrain system (baseline system). Gaseous emissions and particulate levels less than: NOx = 0.4 gm/mile, HC = 0.41 gm/mile, and CO = 3.4 gm/mile, and a total particulate of 0.2 gm/mile, using the same fuel as used for fuel economy measurements is expected, along with the ability to use a variety of alternate fuels.

  11. Angiotensinogen and Plasminogen Activator Inhibitor-1 Gene Polymorphism in Relation to Renovascular Disease

    SciTech Connect

    Reis, Kadriye Altok Onal, Baran; Gonen, Sevim; Arinsoy, Turgay; Erten, Yasemin; Ilgit, Erhan; Soylemezoglu, Oguz; Derici, Ulver; Guz, Galip; Bali, Musa; Sindel, Sukru

    2006-02-15

    The present study was designed to evaluate angiotensinogen (AGT) M235T and plasminogen activator inhibitor-1 (PAI-1) (4G/5G) polymorphisims in relation to the occurrence of atherosclerotic renal artery stenosis (ARAS) and recurrent stenosis. In this study, 30 patients were enrolled after angiographic demonstration of ARAS; 100 healthy subjects for AGT polymorphism and 80 healthy subjects for PAI-1 polymorphism were considered the control group. The patients were followed for a mean 46.1 {+-} 9.2 months. The patients had significantly higher frequencies of the MT genotype and the T allele than control group ({chi}{sup 2} = 18.2, p < 0.001 and {chi}{sup 2} = 11.5 p < 0.001). There were no significant differences in the PAI-1 genotype and allele findings when the data for all patients were compared with that for the controls ({chi}{sup 2}= 2.45, p = 0.29 and {chi}{sup 2} = 0.019, p = 0.89). There were no significant differences in the genotype and allele findings for the patients with and without restenosis (p > 0.05). The C-reactive protein (CRP) level was higher in the patients with restenosis than in the patients without restenosis (7.694 {+-} 0.39 mg/L and 1.56 {+-} 1.08 mg/L) (p = 0.001). Our results suggest that the M235T MT genotype and T allele might be associated with increased risk of atherosclerotic renal artery stenosis. The CRP level might be an independent predictor for recurrent stenosis.

  12. Angiotensinogen Gene Transcription in Pulmonary Fibrosis

    PubMed Central

    Uhal, Bruce D.; Dang, My-Trang T.; Li, Xiaopeng; Abdul-Hafez, Amal

    2012-01-01

    An established body of literature supports the hypothesis that activation of a local tissue angiotensin (ANG) system in the extravascular tissue compartment of the lungs is required for lung fibrogenesis. Transcriptional activation of the angiotensinogen (AGT) gene is believed to be a critical and necessary step in this activation. This paper summarizes the data in support of this theory and discusses transcriptional regulation of AGT, with an emphasis on lung AGT synthesis as a determinant of fibrosis severity. Genetic data linking AGT polymorphisms to the severity of disease in Idiopathic Pulmonary Fibrosis are also discussed. PMID:22500179

  13. Towards the Proof of AGT Relations with the Help of the Generalized Jack Polynomials

    NASA Astrophysics Data System (ADS)

    Morozov, Alexei; Smirnov, Andrey

    2014-05-01

    Original proofs of the AGT relations with the help of the Hubbard-Stratanovich duality of the modified Dotsenko-Fateev matrix model did not work for β ≠ 1, because Nekrasov functions were not properly reproduced by Selberg-Kadell integrals of Jack polynomials. We demonstrate that if the generalized Jack polynomials, depending on the N-ples of Young diagrams from the very beginning, are used instead of the N-linear combinations of ordinary Jacks, this resolves the problem. Such polynomials naturally arise as special elements in the equivariant cohomologies of the GL( N)-instanton moduli spaces, and this also establishes connection to alternative ABBFLT approach to the AGT relations, studying the action of chiral algebras on the instanton moduli spaces. In this paper, we describe a complete proof of AGT in the simple case of GL(2) ( N = 2) Yang-Mills theory, i.e., the 4-point spherical conformal block of the Virasoro algebra.

  14. Variants and Haplotypes in Angiotensinogen Gene Are Associated With Plasmatic Angiotensinogen Level in Mexican Population

    PubMed Central

    Balam-Ortiz, Eros; Esquivel-Villarreal, Adolfo; Alfaro-Ruiz, Luis; Carrillo, Karol; Elizalde, Adela; Gil, Trinidad; Urushihara, Maki; Kobori, Hiroyuki; Jimenez-Sanchez, Gerardo

    2011-01-01

    Introduction The plasmatic angiotensinogen (AGT) level has been associated with essential hypertension. Linkage analysis has found a relationship between the AGT gene locus and hypertension in the Mexican-American population, but studies have failed to identify genetic variants associated with hypertension or plasma AGT levels. This study analyzes the relationship between polymorphisms in the AGT gene and plasmatic AGT levels in Mexican population. Methods Nine polymorphisms in AGT gene were genotyped, and plasma AGT level was determined by enzyme-linked immunosorbent assay. Results Differences in AGT plasma levels were associated with 2 polymorphisms: T-20G, TT = 25.3 ± 8.3 versus TG + GG = 21.6 ± 8.8 μg/mL; P = 0.008 and C3389T (T174M), CC = 25.8 ± 9.9 versus TC + TT = 20.5 ± 5.4 μg/mL; P = 0.0002. Haplotype 2 was associated with low plasma AGT (−5.1 μg/mL [95% confidence interval: −8.6 to −1.6], P = 0.004) and Haplotype 8 was associated with high plasma AGT (6.5 μg/mL [95% confidence interval: 2.5 to 10.6], P = 0.001). This association remained after adjustment for covariates. A Likelihood Ratio Test for haplotype-phenotype association adjusted for covariates resulted in χ2 = 38.9, P = 0.0005. The total effect of the haplotypes on plasma AGT level variance was 19.5%. No association was identified between haplotypes and quantitative traits of blood pressure. Conclusions Two polymorphisms (T-20G and C3389T) and 2 haplotypes (H2 and H8) showed an association with plasma AGT levels in Mexican population. PMID:21629041

  15. Resolving the contributions of two cooperative mechanisms to the DNA binding of AGT.

    PubMed

    Melikishvili, Manana; Fried, Michael G

    2015-09-01

    The O(6)-alkylguanine DNA alkyltransferase (AGT) is a DNA repair enzyme that binds DNA with moderate cooperativity. This cooperativity is important for its search for alkylated bases. A structural model of the cooperative complex of AGT with DNA predicts short-range interactions between nearest protein neighbors and long-range interactions between proteins separated in the array. DNA substrates ranging from 11bp to 30bp allowed us to use differences in binding stoichiometry to resolve short- and long-range protein contributions to the stability of AGT complexes. We found that the short-range component of ΔG°(coop) was nearly independent of DNA length and protein packing density. In contrast the long-range component oscillated with DNA length, with a period equal to the occluded binding site size (4bp). The amplitude of the long-range component decayed from ∼-4 kcal/mole of interaction to ∼-1.2 kcal/mol of interaction as the size of cooperative unit increased from 4 to 7 proteins, suggesting a mechanism to limit the size of cooperative clusters. These features allow us to make testable predictions about AGT distributions and interactions with chromatin structures in vivo. PMID:26017689

  16. Resolving the contributions of two cooperative mechanisms to the DNA Binding of AGT

    PubMed Central

    Melikishvili, Manana

    2015-01-01

    ABSTRACT The O6‐alkylguanine DNA alkyltransferase (AGT) is a DNA repair enzyme that binds DNA with moderate cooperativity. This cooperativity is important for its search for alkylated bases. A structural model of the cooperative complex of AGT with DNA predicts short‐range interactions between nearest protein neighbors and long‐range interactions between proteins separated in the array. DNA substrates ranging from 11bp to 30bp allowed us to use differences in binding stoichiometry to resolve short‐ and long‐range protein contributions to the stability of AGT complexes. We found that the short‐range component of ΔG°coop was nearly independent of DNA length and protein packing density. In contrast the long‐range component oscillated with DNA length, with a period equal to the occluded binding site size (4bp). The amplitude of the long‐range component decayed from ∼−4 kcal/mole of interaction to ∼−1.2 kcal/mol of interaction as the size of cooperative unit increased from 4 to 7 proteins, suggesting a mechanism to limit the size of cooperative clusters. These features allow us to make testable predictions about AGT distributions and interactions with chromatin structures in vivo. © 2015 The Authors Biopolymers Published by Wiley Periodicals, Inc. Biopolymers 103: 509–516, 2015. PMID:26017689

  17. Inconsistency Across Time and Situations: A Decade of Research Using the Adjective Generation Technique (AGT).

    ERIC Educational Resources Information Center

    Allen, Bem P.; Potkay, Charles R.

    The Adjective Generation Technique (AGT) has been used in studies to demonstrate that subjects' responses show variations from one point in time to the next. To examine this hypothesis, longitudinal studies were undertaken where subjects were asked to generate five words to describe themselves on each of 29 days. Some conclusions drawn were that:…

  18. Epistatic interaction between common AGT G(-6)A (rs5051) and AGTR1 A1166C (rs5186) variants contributes to variation in kidney size at birth.

    PubMed

    Kaczmarczyk, Mariusz; Kuprjanowicz, Anna; Łoniewska, Beata; Gorący, Iwona; Taryma-Leśniak, Olga; Skonieczna-Żydecka, Karolina; Ciechanowicz, Andrzej

    2015-11-01

    Low nephron number has been recognised as an important cardiovascular risk factor and recently a strong correlation between renal mass and nephron number has been demonstrated in newborns. The aim of this study was to investigate individual, as well as combined, effects of common variants of genes which encode for major components of the renin-angiotensin system (REN G10601A, AGT G(-6)A, ACE I/D, AGTR1 A1166C) on kidney size in healthy, full-term newborns. A significant additive main effect of the ACE I/D polymorphism, as well as an additive-by-additive interaction between AGT G(-6)A and AGTR1 A1166C variants, were found. The variance attributed to the epistatic effect was 27.9 ml(2)/m(4), which accounted for 73.8% of the interaction variance (37.8 ml(2)/m(4)), 66.4% of the genetic variance (42.0 ml(2)/m(4)) and 4.4% to the total phenotypic variance (628 ml(2)/m(4)). No other statistically significant main or epistatic effects were detected. Our results highlight the importance of considering gene-gene interactions as part of the genetic architecture of congenital nephron number, even when the loci do not show significant single locus effects. Unravelling the genetic determinants of low nephron number, along with early molecular screening, may well help to identify children at risk for cardiovascular disease.

  19. Three Agt1 transporters from brewer's yeasts exhibit different temperature dependencies for maltose transport over the range of brewery temperatures (0–20 °C).

    PubMed

    Vidgren, Virve; Viljanen, Kaarina; Mattinen, Laura; Rautio, Jari; Londesborough, John

    2014-06-01

    Zero-trans rates of maltose transport by brewer's yeasts exert strong control over fermentation rates and are strongly temperature-dependent over the temperature range (20–0 °C) of brewery fermentations. Three α-glucoside transporters, ScAgt1(A60) (a Saccharomyces cerevisiae version of Agt1 from an ale strain), ScAgt1-A548V (a variant of ScAgt1(A60) with a single amino acid change in a transmembrane domain), and SbAgt1 (a Saccharomyces (eu)bayanus version from a lager strain), were compared. When expressed in the same laboratory yeast, grown at 24 °C and assayed at 0, 10, and 20 °C, SbAgt1 had the lowest absolute maltose uptake activity at 20 °C but smallest temperature dependence, ScAgt1-A548V had the highest activity but greatest temperature dependence, and ScAgt1(A60) had intermediate properties. ScAgt1(A60) exhibited higher absolute rates and smaller temperature dependencies when expressed in laboratory rather than brewer's strains. Absolute rates closely reflected the amounts of GFP-tagged ScAgt1(A60) transporter in each host's plasma membrane. Growth at 15 °C instead of 24 °C decreased the absolute activities of strains expressing ScAgt1(A60) by two- to threefold. Evidently, the kinetic characteristics of at least ScAgt1(A60) depended on the nature of the host plasma membrane. However, no consistent correlation was observed between transport activities and fatty acid or ergosterol compositions. PMID:25035870

  20. Renin–angiotensin–aldosterone system related gene polymorphisms and urinary total arsenic is related to chronic kidney disease

    SciTech Connect

    Chen, Wei-Jen; Huang, Ya-Li; Shiue, Horng-Sheng; Chen, Tzen-Wen; Lin, Yuh-Feng; Huang, Chao-Yuan; Lin, Ying-Chin; Han, Bor-Cheng; Hsueh, Yu-Mei

    2014-09-01

    A recent study demonstrated that an increased risk of chronic kidney disease (CKD) was associated with high urinary total arsenic levels. However, whether genomic instability is related to CKD remains unclear. An association between CKD and genetic polymorphisms of regulation enzymes of the renin–angiotensin–aldosterone system (RAAS), such as angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II type I receptor (AT1R), and aldosterone synthase (CYP11B2) has not been shown. The aim of the present study was to investigate the relationship between arsenic, genetic polymorphisms of RAAS enzymes and CKD. A total of 233 patients and 449 age- and gender-matched controls were recruited from the Taipei Medical University Hospital, Taipei Municipal Wan Fang Hospital and the Shin Kong Wu Ho-Su Memorial Hospital. Concentrations of urinary arsenic were determined by a high-performance liquid chromatography-linked hydride generator, and atomic absorption spectrometry. Polymorphisms of ACE(I/D), AGT(A[− 20]C), (T174M), (M235T), AT1R(A1166C) and CYP11B2(C[− 344]T) were examined by polymerase chain reaction and restriction fragment length polymorphism. Subjects carrying the CYP11B2 TT genotype had a higher odds ratio (OR), 1.39 (0.96–2.01), of CKD; while those with the AGT(A[− 20]C) CC genotype had an inverse OR of CKD (0.20 (0.05–0.81)), and a high-risk genotype was defined as A/A + A/C for AGT(A[− 20C]) and T/T for CYP11B2(C[− 344]T). The trend test showed a higher OR for CKD in patients who had either high urinary total arsenic levels or carried the high-risk genotype, or both, compared to patients with low urinary total arsenic levels, who carried the low-risk genotype, and could also be affected by the hypertension or diabetes status. - Highlights: • AGT(− 20 C) and CYP11B2(− 344 T) genotypes were significantly associated with CKD. • Combined effect of high-risk genotypes and high urinary total arsenic on OR of CKD. • Combined

  1. Oligodeoxynucleotides as substrates for O/sup 6/-alkylguanine-DNA alkyltransferase (AGT)

    SciTech Connect

    Scicchitano, D.; Jones, R.A.; Kuzmich, S.; Gaffney, B.; Lasko, D.; Essigmann, J.; Pegg, A.E.

    1986-05-01

    AGT is a DNA repair protein which is known to catalyze the transfer of alkyl groups from the O/sup 6/-position of guanine in alkylated DNA to a cysteine acceptor site contained within its own protein sequence. The authors have examined the ability of this protein isolated from both E. coli and mammalian cells to carry out this reaction using oligodeoxynucleotides containing O/sup 6/-methylguanine (m/sup 6/G). Dodecadeoxynucleotides of the sequence 5'-dCGBGAATTCm/sup 6/GCG-3' where B is any one of the normal 4 bases were all repaired very rapidly with 50% repair in less than 15 sec at 0/sup 0/C. The hexadeoxynucleotide 5'-dCGCm/sup 6/GCG-3' was repaired slightly more slowly with 50% removal requiring 7 min at 0/sup 0/C and 1.5 min at 37/sup 0/C. The tetradeoxynucleotide 5'-dTm/sup 6/GCA-3' was also a substrate for the protein but was repaired much more slowly requiring 45 min for 50% repair at 37/sup 0/C. These results indicate that (a) the AGT has a strong but not absolute preference for double stranded DNA substrates; (b) the repair of m/sup 6/G is independent of the base opposite the lesion; and (c) that very short oligodeoxynucleotides are substrates for repair by this protein. The latter property was used to set up a very sensitive assay procedure for the AGT. The 5' end of the 5'-dTm/sup 6/GCA-3' was labeled with /sup 32/P by use of polynucleotide kinase and the formation of (/sup 32/P)-5'-dTGACA-3' monitored by separating the methylated form from the unmethylated form by HPLC.

  2. Advanced Gas Turbine (AGT) powertrain system development for automotive applications report

    NASA Technical Reports Server (NTRS)

    1984-01-01

    This report describes progress and work performed during January through June 1984 to develop technology for an Advanced Gas Turbine (AGT) engine for automotive applications. Work performed during the first eight periods initiated design and analysis, ceramic development, component testing, and test bed evaluation. Project effort conducted under this contract is part of the DOE Gas Turbine Highway Vehicle System Program. This program is oriented at providing the United States automotive industry the high-risk long-range techology necessary to produce gas turbine engines for automobiles with reduced fuel consumption and reduced environmental impact. Technology resulting from this program is intended to reach the marketplace by the early 1990s.

  3. Cardiac angiotensin-(1-12) expression and systemic hypertension in rats expressing the human angiotensinogen gene.

    PubMed

    Ferrario, Carlos M; VonCannon, Jessica; Jiao, Yan; Ahmad, Sarfaraz; Bader, Michael; Dell'Italia, Louis J; Groban, Leanne; Varagic, Jasmina

    2016-04-15

    Angiotensin-(1-12) [ANG-(1-12)] is processed into ANG II by chymase in rodent and human heart tissue. Differences in the amino acid sequence of rat and human ANG-(1-12) render the human angiotensinogen (hAGT) protein refractory to cleavage by renin. We used transgenic rats harboring the hAGT gene [TGR(hAGT)L1623] to assess the non-renin-dependent effects of increased hAGT expression on heart function and arterial pressure. Compared with Sprague-Dawley (SD) control rats (n= 11), male homozygous TGR(hAGT)L1623 (n= 9) demonstrated sustained daytime and nighttime hypertension associated with no changes in heart rate but increased heart rate lability. Increased heart weight/tibial length ratio and echocardiographic indexes of cardiac hypertrophy were associated with modest reduction of systolic function in hAGT rats. Robust human ANG-(1-12) immunofluorescence within myocytes of TGR(hAGT)L1623 rats was associated with a fourfold increase in cardiac ANG II content. Chymase enzymatic activity, using the rat or human ANG-(1-12) as a substrate, was not different in the cardiac tissue of SD and hAGT rats. Since both cardiac angiotensin-converting enzyme (ACE) and ACE2 activities were not different among the two strains, the changes in cardiac structure and function, blood pressure, and left ventricular ANG II content might be a product of an increased cardiac expression of ANG II generated through a non-renin-dependent mechanism. The data also underscore the existence in the rat of alternate enzymes capable of acting on hAGT protein. Homozygous transgenic rats expressing the hAGT gene represent a novel tool to investigate the contribution of human relevant renin-independent cardiac ANG II formation and function. PMID:26873967

  4. Renin-Angiotensin System Genes and Exercise Training-Induced Changes in Sodium Excretion in African American Hypertensives

    PubMed Central

    Jones, Jennifer M.; Park, Jung-Jun; Johnson, Jennifer; Vizcaino, Dave; Hand, Brian; Ferrell, Robert; Weir, Matthew; Dowling, Thomas; Obisesan, Thomas; Brown, Michael

    2008-01-01

    Objective To determine whether angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) genotypes could predict changes in urinary sodium excretion in response to short-term aerobic exercise training (AEX). Design Longitudinal intervention. Setting The study was conducted at the University of Maryland at College Park and at Baltimore, and the University of Pittsburgh General Clinical Research Center. Participants 31 (age 53 ± 2 years) sedentary, hypertensive (146 ± 2/88 ± 2 mm Hg) African Americans. Intervention Aerobic exercise training (AEX) consisted of seven or eight consecutive days, 50 minutes per day, at 65% of heart rate reserve. Participants underwent a 24-hour period of ambulatory blood pressure (BP) monitoring and urine collection at baseline and 14–18 hours after the last exercise session. Main Outcome Measures Angiotensiongen (AGT) M235T and ACE I/D genotype and sodium excretion and ambulatory BP. Results Average sodium excretion for the entire group independent of genotype increased after AEX (108 ± 9 vs 143 ± 12 mEq/day, P=.003). Sodium excretion significantly increased after exercise training in the ACE II (114 ± 22 vs 169 ± 39 mEq/day, P=.04), but not in the ID (100 ± 8 vs 133 ± 17 mEq/day, P=.12) or DD (113 ± 18 vs 138 ± 11 mEq/day, P=.13) genotype groups. In the II genotype group, the increase in sodium excretion was significantly and inversely correlated with decreases in 24-hour diastolic (r=−.88, P=.02) and mean (r=−.95, P=.004) BP. The AGT TT and MT+MM genotype groups similarly increased their sodium excretion by 34 ± 16 (P=.05) and 37 ± 17 (P=.05) mEq/day respectively. Conclusions These results suggest that African American hypertensives with the ACE II genotype may be more susceptible to sodium balance and BP changes with exercise training compared with those with the ID and DD genotypes. PMID:16937603

  5. Caenorhabditis elegans AGXT-1 is a mitochondrial and temperature-adapted ortholog of peroxisomal human AGT1: New insights into between-species divergence in glyoxylate metabolism.

    PubMed

    Mesa-Torres, Noel; Calvo, Ana C; Oppici, Elisa; Titelbaum, Nicholas; Montioli, Riccardo; Miranda-Vizuete, Antonio; Cellini, Barbara; Salido, Eduardo; Pey, Angel L

    2016-09-01

    In humans, glyoxylate is an intermediary product of metabolism, whose concentration is finely balanced. Mutations in peroxisomal alanine:glyoxylate aminotransferase (hAGT1) cause primary hyperoxaluria type 1 (PH1), which results in glyoxylate accumulation that is converted to toxic oxalate. In contrast, glyoxylate is used by the nematode Caenorhabditis elegans through a glyoxylate cycle to by-pass the decarboxylation steps of the tricarboxylic acid cycle and thus contributing to energy production and gluconeogenesis from stored lipids. To investigate the differences in glyoxylate metabolism between humans and C. elegans and to determine whether the nematode might be a suitable model for PH1, we have characterized here the predicted nematode ortholog of hAGT1 (AGXT-1) and compared its molecular properties with those of the human enzyme. Both enzymes form active PLP-dependent dimers with high specificity towards alanine and glyoxylate, and display similar three-dimensional structures. Interestingly, AGXT-1 shows 5-fold higher activity towards the alanine/glyoxylate pair than hAGT1. Thermal and chemical stability of AGXT-1 is lower than that of hAGT1, suggesting temperature-adaptation of the nematode enzyme linked to the lower optimal growth temperature of C. elegans. Remarkably, in vivo experiments demonstrate the mitochondrial localization of AGXT-1 in contrast to the peroxisomal compartmentalization of hAGT1. Our results support the view that the different glyoxylate metabolism in the nematode is associated with the divergent molecular properties and subcellular localization of the alanine:glyoxylate aminotransferase activity.

  6. Caenorhabditis elegans AGXT-1 is a mitochondrial and temperature-adapted ortholog of peroxisomal human AGT1: New insights into between-species divergence in glyoxylate metabolism.

    PubMed

    Mesa-Torres, Noel; Calvo, Ana C; Oppici, Elisa; Titelbaum, Nicholas; Montioli, Riccardo; Miranda-Vizuete, Antonio; Cellini, Barbara; Salido, Eduardo; Pey, Angel L

    2016-09-01

    In humans, glyoxylate is an intermediary product of metabolism, whose concentration is finely balanced. Mutations in peroxisomal alanine:glyoxylate aminotransferase (hAGT1) cause primary hyperoxaluria type 1 (PH1), which results in glyoxylate accumulation that is converted to toxic oxalate. In contrast, glyoxylate is used by the nematode Caenorhabditis elegans through a glyoxylate cycle to by-pass the decarboxylation steps of the tricarboxylic acid cycle and thus contributing to energy production and gluconeogenesis from stored lipids. To investigate the differences in glyoxylate metabolism between humans and C. elegans and to determine whether the nematode might be a suitable model for PH1, we have characterized here the predicted nematode ortholog of hAGT1 (AGXT-1) and compared its molecular properties with those of the human enzyme. Both enzymes form active PLP-dependent dimers with high specificity towards alanine and glyoxylate, and display similar three-dimensional structures. Interestingly, AGXT-1 shows 5-fold higher activity towards the alanine/glyoxylate pair than hAGT1. Thermal and chemical stability of AGXT-1 is lower than that of hAGT1, suggesting temperature-adaptation of the nematode enzyme linked to the lower optimal growth temperature of C. elegans. Remarkably, in vivo experiments demonstrate the mitochondrial localization of AGXT-1 in contrast to the peroxisomal compartmentalization of hAGT1. Our results support the view that the different glyoxylate metabolism in the nematode is associated with the divergent molecular properties and subcellular localization of the alanine:glyoxylate aminotransferase activity. PMID:27179589

  7. Renin-Angiotensin System Gene Variants and Type 2 Diabetes Mellitus: Influence of Angiotensinogen

    PubMed Central

    Joyce-Tan, Siew Mei; Zain, Shamsul Mohd; Abdul Sattar, Munavvar Zubaid; Abdullah, Nor Azizan

    2016-01-01

    Genome-wide association studies (GWAS) have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM). However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS) and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AGTR1). There were significant differences in allele frequencies between cases and controls for AGT variants (P = 0.05) but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15–3.20, permuted P = 0.012); however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk. PMID:26682227

  8. Retroviral expression of the hepatitis B virus x gene promotes liver cell susceptibility to carcinogen-induced site specific mutagenesis.

    PubMed

    Sohn, S; Jaitovitch-Groisman, I; Benlimame, N; Galipeau, J; Batist, G; Alaoui-Jamali, M A

    2000-06-30

    Mutational inactivation of the tumor suppressor gene p53 is common in hepatocellular carcinomas (HCC). AGG to AGT transversion in codon 249 of exon 7 of the p53 gene occurs in over 50% of HCC from endemic regions, where both chronic infection with the hepatitis B virus (HBV) and exposure to carcinogens such as aflatoxin B1 (AFB1) prevail. In this study, we report the effect of the HBV x protein (HBx) on carcinogen-induced cytotoxicity and AGG to AGT mutation in codon 249 of the p53 gene in the human liver cell line CCL13. Expression of HBx, as revealed by its transactivation function, results in enhanced cell susceptibility to cytotoxicity induced by the AFB1 active metabolite, AFB1-8,9-epoxide, and benzo(a)pyrene diol-epoxide. Under similar conditions, expression of HBx promotes apoptosis in a subset of cell population. Exposure to AFB1-8, 9-epoxide alone induces a low frequency of AGG to AGT mutation in codon 249 of the p53 gene, as determined by an allele-specific polymerase chain reaction (AS-PCR) assay. However, expression of HBx enhances the frequency of AFB1-epoxide-induced AGG to AGT mutation compared to control cells. In summary, this study demonstrates that expression of HBx enhances liver cell susceptibility to carcinogen-induced mutagenesis, possibly through alteration of the balance between DNA repair and apoptosis, two cellular defense mechanisms against genotoxic stress. PMID:10856831

  9. Bacteria in gene therapy: bactofection versus alternative gene therapy.

    PubMed

    Pálffy, R; Gardlík, R; Hodosy, J; Behuliak, M; Resko, P; Radvánský, J; Celec, P

    2006-01-01

    Recent advances in gene therapy can be attributed to improvements of gene delivery vectors. New viral and nonviral transport vehicles that considerably increase the efficiency of transfection have been prepared. However, these vectors still have many disadvantages that are difficult to overcome, thus, a new approach is needed. The approach of bacterial delivery could in the future be important for gene therapy applications. In this article we try to summarize the most important modifications that are used for the preparation of applied strains, difficulties that are related with bacterial gene delivery and the current use of bactofection in animal experiments and clinical trials. Important differences to the alternative gene therapy (AGT) are discussed. AGT resembles bacteria-mediated protein delivery, as the therapeutical proteins are produced not by host cells but by the bacteria in situ and the expression can be regulated exogenously. Although the procedure of bacterial gene delivery is far from being definitely solved, bactofection remains a promising technique for transfection in human gene therapy.

  10. Advanced Gas Turbine (AGT)

    NASA Technical Reports Server (NTRS)

    1983-01-01

    The development and progress of the Advanced Gas Turbine engine program is examined. An analysis of the role of ceramics in the design and major engine components is included. Projected fuel economy, emissions and performance standards, and versatility in fuel use are also discussed.

  11. Neighboring genes for DNA-binding proteins rescue male sterility in Drosophila hybrids.

    PubMed

    Liénard, Marjorie A; Araripe, Luciana O; Hartl, Daniel L

    2016-07-19

    Crosses between closely related animal species often result in male hybrids that are sterile, and the molecular and functional basis of genetic factors for hybrid male sterility is of great interest. Here, we report a molecular and functional analysis of HMS1, a region of 9.2 kb in chromosome 3 of Drosophila mauritiana, which results in virtually complete hybrid male sterility when homozygous in the genetic background of sibling species Drosophila simulans. The HMS1 region contains two strong candidate genes for the genetic incompatibility, agt and Taf1 Both encode unrelated DNA-binding proteins, agt for an alkyl-cysteine-S-alkyltransferase and Taf1 for a subunit of transcription factor TFIID that serves as a multifunctional transcriptional regulator. The contribution of each gene to hybrid male sterility was assessed by means of germ-line transformation, with constructs containing complete agt and Taf1 genomic sequences as well as various chimeric constructs. Both agt and Taf1 contribute about equally to HMS1 hybrid male sterility. Transgenes containing either locus rescue sterility in about one-half of the males, and among fertile males the number of offspring is in the normal range. This finding suggests compensatory proliferation of the rescued, nondysfunctional germ cells. Results with chimeric transgenes imply that the hybrid incompatibilities result from interactions among nucleotide differences residing along both agt and Taf1 Our results challenge a number of preliminary generalizations about the molecular and functional basis of hybrid male sterility, and strongly reinforce the role of DNA-binding proteins as a class of genes contributing to the maintenance of postzygotic reproductive isolation.

  12. Molecular characterization and transcriptional regulation of the renin-angiotensin system genes in Senegalese sole (Solea senegalensis Kaup, 1858): differential gene regulation by salinity.

    PubMed

    Armesto, Paula; Cousin, Xavier; Salas-Leiton, Emilio; Asensio, Esther; Manchado, Manuel; Infante, Carlos

    2015-06-01

    In this work, the complete cDNA sequence encoding angiotensinogen (agt) in the euryhaline flatfish Senegalese sole was obtained. Additionally, putative coding sequences belonging to other renin-angiotensin system (RAS) genes including renin (ren), angiotensin-converting enzyme (ace), angiotensin-converting enzyme 2 (ace2), as well as angiotensin II receptor type I (agtr1) and type II (agtr2), were also identified. In juvenile tissues, agt transcripts were mainly detected in liver, ren in kidney, ace and ace2 in intestine, agtr1 in kidney and brain, and agtr2 in liver and kidney. Expression analysis of the six RAS genes after a salinity shift revealed a clear increase of agt mRNA abundance in liver just after transferring soles to high salinity water (60 ppt) with a peak at 48 h. Moreover, gene expression analysis in gills showed transcriptional regulation of ace and agtr1 at 48 h and agtr2 at 96 h after transferring soles to 60 ppt. Incubation of larvae before mouth opening (until 3 days post hatch; dph) at low salinity (10 ppt) resulted in a coordinated transcriptional up-regulation of RAS genes. Nevertheless, no differences in mRNA abundance between salinities were observed when larvae were cultivated to low salinity after mouth opening. Whole-mount in situ hybridization (WISH) signal for agt and ace in 3 dph larvae incubated at 10 ppt and 35 ppt confirmed that the former gene was mainly expressed in liver whereas the later gene was mainly located in pharynx and posterior gut, without pronounced differences in intensity between salinities. Possible physiological significance of all these results is discussed.

  13. Renin-angiotensin system genes polymorphism in Egyptians with premature coronary artery disease.

    PubMed

    Abd El-Aziz, Tarek A; Hussein, Yousri M; Mohamed, Randa H; Shalaby, Sally M

    2012-05-01

    Genetics polymorphism of the renin-angiotensin system (RAS) affects the pathogenesis of atherosclerosis and associated with coronary artery disease (CAD). We aimed to investigate the association between the RAS genes and premature CAD (PCAD) in Egyptians. 116 patients with PCAD, 114 patients with late onset CAD and 119 controls were included in the study. Angiotensin converting enzyme (ACE), angiotensin II receptor type 1 (ATR1) and angiotensinogen (AGT) genes polymorphisms were analyzed by polymerase chain reaction (PCR). We found that ACE DD, AGT TT and ATR1 CC increased the risk of PCAD by 2.7, 2.8 and 2.86 respectively). Smoking, hypertension, diabetes, total cholesterol, triglycerides and LDL cholesterol were independent risk factors for the development of PCAD. We conclude that the ACE DD, AGT TT and ATR1 CC genotypes may increase the susceptibility of an individual to have PCAD. The coexistence of CAD risk factors with these risky RAS genotypes may lead to the development of PCAD in Egyptian patients. PMID:22387727

  14. Exts and the AGT Relations

    NASA Astrophysics Data System (ADS)

    Neguţ, Andrei

    2016-09-01

    We prove the connection between the Nekrasov partition function of {N=2} super-symmetric U(2) gauge theory with adjoint matter and conformal blocks for the Virasoro algebra, as predicted by the Alday-Gaiotto-Tachikawa relations. Mathematically, this is achieved by relating the Carlsson-Okounkov Ext vector bundle on the moduli space of rank 2 sheaves with Liouville vertex operators. Our approach is geometric in nature, and uses a new method for intersection-theoretic computations of the Ext operator.

  15. AGT-102 automotive gas turbine

    NASA Technical Reports Server (NTRS)

    1981-01-01

    Development of a gas turbine powertrain with a 30% fuel economy improvement over a comparable S1 reciprocating engine, operation within 0.41 HC, 3.4 CO, and 0.40 NOx grams per mile emissions levels, and ability to use a variety of alternate fuels is summarized. The powertrain concept consists of a single-shaft engine with a ceramic inner shell for containment of hot gasses and support of twin regenerators. It uses a fixed-geometry, lean, premixed, prevaporized combustor, and a ceramic radial turbine rotor supported by an air-lubricated journal bearing. The engine is coupled to the vehicle through a widerange continuously variable transmission, which utilizes gearing and a variable-ratio metal compression belt. A response assist flywheel is used to achieve acceptable levels of engine response. The package offers a 100 lb weight advantage in a Chrysler K Car front-wheel-drive installation. Initial layout studies, preliminary transient thermal analysis, ceramic inner housing structural analysis, and detailed performance analysis were carried out for the basic engine.

  16. Endothelial nitric oxide synthase, angiotensin-converting enzyme and angiotensinogen gene polymorphisms in hypertensive disorders of pregnancy.

    PubMed

    Aggarwal, Pardeep Kumar; Jain, Vanita; Jha, Vivekanand

    2010-05-01

    We investigated the variations in genes encoding endothelial nitric oxide synthase (NOS3), angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) in hypertensive disorders of pregnancy and the relationship between the polymorphisms and circulating nitric oxide (NO) and ACE levels in pregnant north Indian women. Frequencies of NOS3 G894T, 4b/a and T(-786) --> C, AGT T704C and ACE ins/del polymorphisms were studied in 342 subjects: 120 with preeclampsia (PE), 104 with gestational hypertension and 118 normotensive pregnant women. Variations were evaluated by polymerase chain reaction-restriction fragment length polymorphism. NO and ACE levels were determined using ELISA. There was no difference in the distribution of individual NOS3 and ACE polymorphisms in the study groups. Haplotype analysis showed a global difference in the NOS3 haplotype distribution between the PE and non-PE subjects (P=0.03). The presence of AGT 704C allele was associated with a reduced risk of developing PE (odds ratio: 0.33, 95% CI: 0.19-0.59 in recessive mode). Circulating total NO and ACE levels were similar in three groups. No relationship was found between circulating NO levels and any of the NOS3 polymorphisms, but the circulating ACE levels were higher in those with DD genotype (P<0.05). In conclusion, there was no association between individual NOS3 and the ACE gene polymorphisms and hypertensive disorders of pregnancy in north Indian women. The presence of minor alleles at all the three sites in NOS3 seemed to increase the risk of PE, and AGT 704C allele was associated with a reduced PE risk. The complexity of interaction between these genetic abnormalities requires further studies. PMID:20186148

  17. Genetic variant of the renin-angiotensin system and prevalence of type 2 diabetes mellitus: a modest but significant effect of aldosterone synthase.

    PubMed

    Ichikawa, Mai; Konoshita, Tadashi; Nakaya, Takahiro; Yamamoto, Katsushi; Yamada, Mika; Sato, Satsuki; Imagawa, Michiko; Makino, Yasukazu; Fujii, Miki; Zenimaru, Yasuo; Arakawa, Kenichiro; Suzuki, Jinya; Ishizuka, Tamotsu; Nakamura, Hiroyuki

    2014-08-01

    Recent genome-wide association studies have identified multiple variants that confer risk of type 2 diabetes mellitus (DM). However, established associations explain only a part of the heritability. Thus, even at the genome-wide association studies era, candidate gene approach should be still useful. Recent interventional studies against the renin-angiotensin system (RAS) showed reduction in new onset of DM, implying the system is involved in the onset. We substantiated the hypothesis that genetic variants of RAS have significant association with prevalence of DM. We enrolled to the study consecutive 782 subjects who had consulted our hospitals for mainly lifestyle related diseases. They consisted of 282 (36.1 %) diabetes cases. Genotypes were assayed with genomic DNA for conventional four genes of the RAS, i.e., angiotensin converting enzyme (ACE) insertion/deletion variant, angiotensinogen (AGT) M235T variant, angiotensin II type I receptor (AT1) A1166C variant, and aldosterone synthase (CYP11B2) C-344T variant. Association between the genetic variants of the RAS and prevalence of type 2 DM was tested. A significant association of DM and CYP11B2 genotype was obtained. There was no significant association between DM and ACE, AGT and AT1 variants. A multivariate logistic regression showed that age, gender, and CYP11B2 genotype were independent factors for association to diabetes, the DM risk of CC/CT to TT being 1.40 (95 % CI 1.04-1.90, p = 0.029). Thus, it is concluded that a genetic variant of the RAS should have a modest but significant impact on the onset of type 2 diabetes mellitus.

  18. Association Between Gene Polymorphisms on Chromosome 1 and Susceptibility to Pre-Eclampsia: An Updated Meta-Analysis

    PubMed Central

    Zhang, Guixin; Zhao, Jinheng; Yi, Jianping; Luan, Yuanyuan; Wang, Qian

    2016-01-01

    Background This meta-analysis enabled us to obtain a precise estimation of the association between gene polymorphisms on chromosome 1 (MTHFR, AGT, F5, IL-10, LEPR) and the susceptibility to pre-eclampsia (PE) in order to reach a uniform conclusion. Material/Methods Web of Science, PubMed, EMBASE, Cochran Library (CENTRAL), and Chinese databases (Chinese National Knowledge Infrastructure-CNKI and Wan Fang) were electronically searched to select relevant studies for this meta-analysis. We selected 95 case-control studies investigating 5 genes (MTHFR, AGT, F5, IL-10, and LEPR) with 8 SNPs. Odds ratios (OR) with their 95% confidence intervals (CI) were used for estimating the association. Results A total of 16 646 PE patients and 28 901 normal-pregnancy patients were included in this meta-analysis. The overall results suggested that rs1801133 of MTHFR (OR=1.17, 95% CI: 1.05–1.13) and rs6025 of F5 (OR=1.53, 95%CI: 1.07–2.20) are significantly associated with PE, whereas rs1801131 of MTHFR, rs699 and rs4762 of AGT, rs1800896 and rs1800871 of IL-10, and rs1137101 of LEPR have no significant association with PE. Subgroup analysis by ethnicity revealed that, except for MTHFR rs1801133 and F5 rs6025 in Caucasians, which were significantly associated with an increased risk of PE, none of these SNPs were significantly associated with PE. As suggested by a symmetric funnel plot in conjunction with the Egger’s test, there was no significant publication bias in MTHFR rs1801133 (P=0.318) and rs1801131 (P=0.204), F5 rs6025 (P=0.511), LEPR rs1137101 (P=0.511), AGT rs4762 (P=0.215) and rs699 (P=0.482), IL-10 rs1800871 (P=0.955), and rs1800896 (P=0.144). Conclusions This meta-analysis provides evidence that MTHFR rs1801133 and F5 rs6025 are associated with an increased risk of PE, especially in Caucasians. However, we do not have sufficient evidence to conclude there is a significant association between other gene polymorphisms and PE. PMID:27348238

  19. Phenotypic correction of a mouse model for primary hyperoxaluria with adeno-associated virus gene transfer.

    PubMed

    Salido, Eduardo; Rodriguez-Pena, Marisol; Santana, Alfredo; Beattie, Stuart G; Petry, Harald; Torres, Armando

    2011-05-01

    Primary hyperoxaluria type I (PH1) is an inborn error of metabolism caused by deficiency of the hepatic enzyme alanine-glyoxylate aminotransferase (AGXT or AGT) which leads to overproduction of oxalate by the liver and subsequent urolithiasis and renal failure. The current therapy largely depends on liver transplantation, which is associated with significant morbidity and mortality. To explore an alternative treatment, we used somatic gene transfer in a mouse genetic model for PH1 (Agxt1KO). Recombinant adeno-associated virus (AAV) vectors containing the human AGXT complementary DNA (cDNA) were pseudotyped with capsids from either serotype 8 or 5, and delivered to the livers of Agxt1KO mice via the tail vein. Both AAV8-AGXT and AAV5-AGXT vectors were able to reduce oxaluria to normal levels. In addition, treated mice showed blunted increase of oxaluria after challenge with ethylene glycol (EG), a glyoxylate precursor. In mice, AGT enzyme activity in whole liver extracts were restored to normal without hepatic toxicity nor immunogenicity for the 50 day follow-up. In summary, this study demonstrates the correction of primary hyperoxaluria in mice treated with either AAV5 or AAV8 vectors. PMID:21119625

  20. Adaptive evolution of the osmoregulation-related genes in cetaceans during secondary aquatic adaptation

    PubMed Central

    2013-01-01

    Background Osmoregulation was a primary challenge for cetaceans during the evolutionary transition from a terrestrial to a mainly hyperosmotic environment. Several physiological mechanisms have been suggested to maintain the water and salt balance in cetaceans, but their genetic and evolutionary bases remain poorly explored. The current study investigated the genes involved in osmoregulation in cetaceans and compared them with their counterparts in terrestrial mammals to test whether adaptive evolution occurred during secondary aquatic adaptation. Results The present study analyzed the molecular evolution of 11 osmoregulation-related genes in 11 cetacean species, which represented all of the major cetacean clades. The results demonstrated positive selection acting on angiotensin converting enzyme (ACE), angiotensinogen (AGT), SLC14A2, and aquaporin 2 (AQP2). This evidence for the positive selection of AQP2 and SLC14A2 suggests that the adaptive evolution of these genes has helped to enhance the capacity for water and urea transport, thereby leading to the concentration of urine, which is an efficient mechanism for maintaining the water balance. By contrast, a series of positively selected amino acid residues identified in the ACE and AGT (two key members of the renin-angiotensin-aldosterone system, RAAS) proteins of cetaceans suggests that RAAS might have been adapted to maintain the water and salt balance in response to a hyperosmotic environment. Radical amino acid changes in positively selected sites were distributed among most internal and terminal branches of the cetacean phylogeny, which suggests the pervasively adaptive evolution of osmoregulation since the origin of cetaceans and their subsequent diversification. Conclusions This is the first comprehensive analysis of the molecular evolution of osmoregulation-related genes in cetaceans in response to selection pressure from a generally hyperosmotic environment. Four genes, i.e., AQP2, SLC14A2, ACE, and AGT

  1. Advanced Gas Turbine (AGT) Technology Project

    NASA Technical Reports Server (NTRS)

    1984-01-01

    Technical work on the design and effort leading to the testing of a 74.5 kW (100 hp) automotive gas turbine engine is reviewed. Development of the engine compressor, gasifier turbine, power turbine, combustor, regenerator, and secondary system is discussed. Ceramic materials development and the application of such materials in the gas turbine engine components is described.

  2. Advanced Gas Turbine (AGT) powertrain system

    NASA Technical Reports Server (NTRS)

    Helms, H. E.; Kaufeld, J.; Kordes, R.

    1981-01-01

    A 74.5 kW(100 hp) advanced automotive gas turbine engine is described. A design iteration to improve the weight and production cost associated with the original concept is discussed. Major rig tests included 15 hours of compressor testing to 80% design speed and the results are presented. Approximately 150 hours of cold flow testing showed duct loss to be less than the design goal. Combustor test results are presented for initial checkout tests. Turbine design and rig fabrication is discussed. From a materials study of six methods to fabricate rotors, two have been selected for further effort. A discussion of all six methods is given.

  3. Advanced Gas Turbine (AGT) technology development

    NASA Technical Reports Server (NTRS)

    1983-01-01

    A 74.5 kW (100 hp) automotive gas turbine was evaluated. The engine structure, bearings, oil system, and electronics were demonstrated and no shaft dynamics or other vibration problem were encountered. Areas identified during the five tests are the scroll retention features, and transient thermal deflection of turbine backplates. Modifications were designed. Seroll retention is addressed by modifying the seal arrangement in front of the gasifier turbine assembly, which will increase the pressure load on the scroll in the forward direction and thereby increase the retention forces. the backplate thermal deflection is addressed by geometric changes and thermal insulation to reduce heat input. Combustor rig proof testing of two ceramic combustor assemblies was completed. The combustor was modified to incorporate slots and reduce sharp edges, which should reduce thermal stresses. The development work focused on techniques to sinter these barrier materials onto the ceramic rotors with successes for both material systems. Silicon carbide structural parts, including engine configuration gasifier rotors (ECRs), preliminary gasifier scroll parts, and gasifier and power turbine vanes are fabricated.

  4. Association of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals.

    PubMed

    Johnson, Andrew D; Newton-Cheh, Christopher; Chasman, Daniel I; Ehret, Georg B; Johnson, Toby; Rose, Lynda; Rice, Kenneth; Verwoert, Germaine C; Launer, Lenore J; Gudnason, Vilmundur; Larson, Martin G; Chakravarti, Aravinda; Psaty, Bruce M; Caulfield, Mark; van Duijn, Cornelia M; Ridker, Paul M; Munroe, Patricia B; Levy, Daniel

    2011-05-01

    We previously conducted genome-wide association meta-analysis of systolic blood pressure, diastolic blood pressure, and hypertension in 29,136 people from 6 cohort studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Here we examine associations of these traits with 30 gene regions encoding known antihypertensive drug targets. We find nominal evidence of association of ADRB1, ADRB2, AGT, CACNA1A, CACNA1C, and SLC12A3 polymorphisms with 1 or more BP traits in the Cohorts for Heart and Aging Research in Genomic Epidemiology genome-wide association meta-analysis. We attempted replication of the top meta-analysis single nucleotide polymorphisms for these genes in the Global BPgen Consortium (n=34,433) and the Women's Genome Health Study (n=23,019) and found significant results for rs1801253 in ADRB1 (Arg389Gly), with the Gly allele associated with a lower mean systolic blood pressure (β: 0.57 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=4.7×10(-10)), diastolic blood pressure (β: 0.36 mm Hg; SE: 0.06 mm Hg; meta-analysis: P=9.5×10(-10)), and prevalence of hypertension (β: 0.06 mm Hg; SE: 0.02 mm Hg; meta-analysis: P=3.3×10(-4)). Variation in AGT (rs2004776) was associated with systolic blood pressure (β: 0.42 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=3.8×10(-6)), as well as diastolic blood pressure (P=5.0×10(-8)) and hypertension (P=3.7×10(-7)). A polymorphism in ACE (rs4305) showed modest replication of association with increased hypertension (β: 0.06 mm Hg; SE: 0.01 mm Hg; meta-analysis: P=3.0×10(-5)). Two loci, ADRB1 and AGT, contain single nucleotide polymorphisms that reached a genome-wide significance threshold in meta-analysis for the first time. Our findings suggest that these genes warrant further studies of their genetic effects on blood pressure, including pharmacogenetic interactions.

  5. CYP3A variation and the evolution of salt-sensitivity variants.

    PubMed

    Thompson, E E; Kuttab-Boulos, H; Witonsky, D; Yang, L; Roe, B A; Di Rienzo, A

    2004-12-01

    Members of the cytochrome P450 3A subfamily catalyze the metabolism of endogenous substrates, environmental carcinogens, and clinically important exogenous compounds, such as prescription drugs and therapeutic agents. In particular, the CYP3A4 and CYP3A5 genes play an especially important role in pharmacogenetics, since they metabolize >50% of the drugs on the market. However, known genetic variants at these two loci are not sufficient to account for the observed phenotypic variability in drug response. We used a comparative genomics approach to identify conserved coding and noncoding regions at these genes and resequenced them in three ethnically diverse human populations. We show that remarkable interpopulation differences exist with regard to frequency spectrum and haplotype structure. The non-African samples are characterized by a marked excess of rare variants and the presence of a homogeneous group of long-range haplotypes at high frequency. The CYP3A5*1/*3 polymorphism, which is likely to influence salt and water retention and risk for salt-sensitive hypertension, was genotyped in >1,000 individuals from 52 worldwide population samples. The results reveal an unusual geographic pattern whereby the CYP3A5*3 frequency shows extreme variation across human populations and is significantly correlated with distance from the equator. Furthermore, we show that an unlinked variant, AGT M235T, previously implicated in hypertension and pre-eclampsia, exhibits a similar geographic distribution and is significantly correlated in frequency with CYP3A5*1/*3. Taken together, these results suggest that variants that influence salt homeostasis were the targets of a shared selective pressure that resulted from an environmental variable correlated with latitude.

  6. Differences in genotype frequencies of salt-sensitive genes between fishing and nonfishing communities in Japan

    PubMed Central

    Harada, Masanori; Takeshima, Taro; Okayama, Masanobu; Kajii, Eiji

    2016-01-01

    Purpose To identify the differences in genotype frequencies of salt-sensitive genes between residents of fishing communities (FCs) and nonfishing communities (NFCs). Methods The subjects included 18,156 individuals (8,043 males [44%] and 10,113 females [56%]; average age: 57.2±16.1 years) from the general population who were registered with large-scale genome banks and resided in 30 prefectures and 78 different regions in Japan. The measurement items were age, sex, blood pressure, presence or absence of hypertension, body mass index, alcohol consumption, and smoking habit. Furthermore, to analyze the genotype frequencies of salt-sensitive genes, α-adducin 1 (ADD1), angiotensinogen (AGT), angiotensin II receptor type 1 (AT1), and guanine nucleotide-binding protein β peptide 3 (GNB3) were measured. According to the 2004 government classification of municipalities (cities, towns, and villages), communities existing in areas bordering an ocean and with an ocean port were defined as FCs (28 areas). The others were defined as NFCs (50 areas). A logistic regression model was used for comparison of genotype frequencies between subjects residing in FCs and NFCs. Results Of the included subjects, 4,916 (27.0%) and 13,240 (73.0%) resided in FCs and NFCs, respectively. In FCs, the mean age was 59.4±16.7 years and men accounted for 41.0% of the cohort (n=2,015). In NFCs, the mean age was 56.4±15.8 years and men accounted for 45.5% of the cohort (n=6,028). The adjusted odds ratios of the AA and AG genotypes compared with the GG genotype for AGT were 0.80 (95% confidence interval [CI]: 0.68–0.95) and 0.76 (95% CI: 0.64–0.91), respectively. The adjusted odds ratio of the CC genotype compared with AA for AT1 was 0.63 (95% CI: 0.40–0.93). Conclusion The incidence of the salt-sensitive genotypes AGT and AT1 in residents of FCs were significantly lower than in NFCs. PMID:27110136

  7. Gene expression signatures of primary and metastatic uterine leiomyosarcoma

    PubMed Central

    Davidson, Ben; Abeler, Vera Maria; Førsund, Mette; Holth, Arild; Yang, Yanqin; Kobayashi, Yusuke; Chen, Lily; Kristensen, Gunnar B.; Shih, Ie-Ming; Wang, Tian-Li

    2013-01-01

    Leiomyosarcoma (LMS) is the most common uterine sarcoma. Although the disease is relatively rare, it is responsible for considerable mortality due to frequent metastasis and chemoresistance. The molecular events related to LMS metastasis are unknown to date. The present study compared the global gene expression patterns of primary uterine LMS and LMS metastases. Gene expression profiles of 13 primary and 15 metastatic uterine LMS were analyzed using the HumanRef-8 BeadChip from Illumina. Differentially expressed candidate genes were validated using quantitative real-time PCR and immunohistochemistry. To identify differently expressed genes between primary and metastatic tumors, we performed one-way ANOVA with Benjamini-Hochberg correction. This lead to identification of 203 unique probes that were significantly differentially expressed in the two tumor groups by greater than 1.58-fold with p-value <0.01%, of which 94 and 109 were overexpressed in primary and metastatic LMS, respectively. Genes overexpressed in primary uterine LMS included OSTN, NLGN4X, NLGN1, SLITRK4, MASP1, XRN2, ASS1, RORB, HRASLS and TSPAN7. Genes overexpressed in LMS metastases included TNNT1, FOLR3, TDO2, CRYM, GJA1, TSPAN10, THBS1, SGK1, SHMT1, EGR2 and AGT. Quantitative real-time PCR confirmed significant anatomic site-related differences in FOLR3, OSTN and NLGN4X levels, and immunohistochemistry showed significant differences in TDO2 expression. Gene expression profiling differentiates primary uterine LMS from LMS metastases. The molecular signatures unique to primary and metastatic LMS may aid in understanding tumor progression in this cancer and in providing a molecular basis for prognostic studies and therapeutic target discovery. PMID:24485798

  8. Genes and Gene Therapy

    MedlinePlus

    ... correctly, a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... or prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

  9. Identification of key pathways and genes in colorectal cancer using bioinformatics analysis.

    PubMed

    Liang, Bin; Li, Chunning; Zhao, Jianying

    2016-10-01

    Colorectal cancer (CRC) is the most common malignant tumor of digestive system. The aim of this study was to identify gene signatures during CRC and uncover their potential mechanisms. The gene expression profiles of GSE21815 were downloaded from GEO database. The GSE21815 dataset contained 141 samples, including 132 CRC and 9 normal colon epitheliums. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed, and protein-protein interaction (PPI) network of the differentially expressed genes (DEGs) was constructed by Cytoscape software. In total, 3500 DEGs were identified in CRC, including 1370 up-regulated genes and 2130 down-regulated genes. GO analysis results showed that up-regulated DEGs were significantly enriched in biological processes (BP), including cell cycle, cell division, and cell proliferation; the down-regulated DEGs were significantly enriched in biological processes, including immune response, intracellular signaling cascade and defense response. KEGG pathway analysis showed the up-regulated DEGs were enriched in cell cycle and DNA replication, while the down-regulated DEGs were enriched in drug metabolism, metabolism of xenobiotics by cytochrome P450, and retinol metabolism pathways. The top 10 hub genes, GNG2, AGT, SAA1, ADCY5, LPAR1, NMU, IL8, CXCL12, GNAI1, and CCR2 were identified from the PPI network, and sub-networks revealed these genes were involved in significant pathways, including G protein-coupled receptors signaling pathway, gastrin-CREB signaling pathway via PKC and MAPK, and extracellular matrix organization. In conclusion, the present study indicated that the identified DEGs and hub genes promote our understanding of the molecular mechanisms underlying the development of CRC, and might be used as molecular targets and diagnostic biomarkers for the treatment of CRC. PMID:27581154

  10. Gene panels to help identify subgroups at high and low risk of CHD among those randomized to antihypertensive treatment: The GenHAT Study

    PubMed Central

    Lynch, Amy I.; Eckfeldt, John H.; Davis, Barry R.; Ford, Charles E.; Boerwinkle, Eric; Leiendecker-Foster, Catherine; Arnett, Donna K.

    2012-01-01

    Objective To identify panels of genetic variants that predict treatment-related coronary heart disease (CHD) outcomes in hypertensive patients on one of four different classes of initial antihypertensive treatment. The goal was to identify subgroups of people based on their genetic profile who benefit most from a particular treatment. Methods Candidate genetic variants (n=78) were genotyped in 39,114 participants from GenHAT, ancillary to ALLHAT. ALLHAT randomized hypertensive participants (>=55 years) to one of four treatments (amlodipine, chlorthalidone, doxazosin, lisinopril). The primary outcome was fatal CHD or non-fatal MI (mean follow-up=4.9 years). A pharmacogenetic panel was derived within each of the four treatment groups. ROC curves estimated the discrimination rate between those with and without a CHD event, based on the addition of the genetic panel risk score. Results For each treatment group, we identified a panel of genetic variants that collectively improved prediction of CHD to a small but statistically significant extent. Chlorthalidone (A): NOS3, rs3918226; SELE, rs5361; ICAM1, rs1799969; AGT, rs5051; GNAS, rs7121; ROC comparison p=.004; Amlodipine (B): MMP1, rs1799750; F5, rs6025; NPPA, rs5065; PDE4D, rs6450512; MMP9, rs2274756; ROC comparison p=.006; Lisinopril (C): AGT, rs5051; PON1, rs705379; MMP12, rs652438; F12, rs1801020; GP1BA, rs6065; PDE4D, rs27653; ROC comparison p=.01; Doxazosin (D): F2, rs1799963; PAI1, rs1799768; MMP7, rs11568818; AGT, rs5051; ACE, rs4343; MMP2, rs243865; ROC comparison p=.007. Each panel was tested for a pharmacogenetic effect; panels A, B and D showed such evidence (p=.009, .006, and .001 respectively), panel C did not (p=.09). Conclusion Because each panel was associated with CHD in a specific treatment group but not the others, this research provides evidence that it may be possible to use gene panel scores as a tool to better assess antihypertensive treatment choices to reduce CHD risk in hypertensive

  11. A novel mutation in the AGXT gene causing primary hyperoxaluria type I: genotype-phenotype correlation.

    PubMed

    M'Dimegh, Saoussen; Aquaviva-Bourdain, Cécile; Omezzine, Asma; M'Barek, Ibtihel; Souche, Geneviéve; Zellama, Dorsaf; Abidi, Kamel; Achour, Abdelattif; Gargah, Tahar; Abroug, Saoussen; Bouslama, Ali

    2016-09-01

    Primary hyperoxaluria type I (PH1) is an autosomal recessive metabolic disorder caused by inherited mutations in the AGXT gene encoding liver peroxisomal alanine : glyoxylate aminotransferase (AGT) which is deficient or mistargeted to mitochondria. PH1 shows considerable phenotypic and genotypic heterogeneity. The incidence and severity of PH1 varies in different geographic regions. DNA samples of the affected members from two unrelated Tunisian families were tested by amplifying and sequencing each of the AGXT exons and intron-exon junctions. We identified a novel frameshift mutation in the AGXT gene, the c.406_410dupACTGC resulting in a truncated protein (p.Gln137Hisfs*19). It is found in homozygous state in two nonconsanguineous unrelated families from Tunisia. These molecular findings provide genotype/phenotype correlations in the intrafamilial phenotypic and permit accurate carrier detection, and prenatal diagnosis. The novel p.Gln137Hisfs*19 mutation detected in our study extend the spectrum of known AGXT gene mutations in Tunisia. PMID:27659337

  12. Polymorphisms in genes of the renin-angiotensin-aldosterone system and renal cell cancer risk: interplay with hypertension and intakes of sodium, potassium and fluid.

    PubMed

    Deckers, Ivette A; van den Brandt, Piet A; van Engeland, Manon; van Schooten, Frederik-Jan; Godschalk, Roger W; Keszei, András P; Schouten, Leo J

    2015-03-01

    Hypertension is an established risk factor for renal cell cancer (RCC). The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure and is closely linked to hypertension. RAAS additionally influences homeostasis of electrolytes (e.g. sodium and potassium) and fluid. We investigated single nucleotide polymorphisms (SNPs) in RAAS and their interactions with hypertension and intakes of sodium, potassium and fluid regarding RCC risk in the Netherlands Cohort Study (NLCS), which was initiated in 1986 and included 120,852 participants aged 55 to 69 years. Diet and lifestyle were assessed by questionnaires and toenail clippings were collected. Genotyping of toenail DNA was performed using the SEQUENOM® MassARRAY® platform for a literature-based selection of 13 candidate SNPs in seven key RAAS genes. After 20.3 years of follow-up, Cox regression analyses were conducted using a case-cohort approach including 3,583 subcohort members and 503 RCC cases. Two SNPs in AGTR1 were associated with RCC risk. AGTR1_rs1492078 (AA vs. GG) decreased RCC risk [hazard ratio (HR) (95% confidence interval (CI)): 0.70(0.49-1.00)], whereas AGTR1_rs5186 (CC vs. AA) increased RCC risk [HR(95%CI): 1.49(1.08-2.05)]. Associations were stronger in participants with hypertension. The RCC risk for AGT_rs3889728 (AG + AA vs. GG) was modified by hypertension (p interaction = 0.039). SNP-diet interactions were not significant, although HRs suggested interaction between SNPs in ACE and sodium intake. SNPs in AGTR1 and AGT influenced RCC susceptibility, and their effects were modified by hypertension. Sodium intake was differentially associated with RCC risk across genotypes of several SNPs, yet some analyses had probably inadequate power to show significant interaction. Results suggest that RAAS may be a candidate pathway in RCC etiology.

  13. Renin-Angiotensin System Genes Polymorphisms and Essential Hypertension in Burkina Faso, West Africa

    PubMed Central

    Tchelougou, Daméhan; Kologo, Jonas K.; Karou, Simplice D.; Yaméogo, Valentin N.; Bisseye, Cyrille; Djigma, Florencia W.; Ouermi, Djeneba; Compaoré, Tegwindé R.; Assih, Maléki; Pietra, Virginio; Zabsonré, Patrice; Simpore, Jacques

    2015-01-01

    Objective. This study aimed to investigate the association between three polymorphisms of renin-angiotensin system and the essential hypertension in the population of Burkina Faso. Methodology. This was a case-control study including 202 cases and 204 matched controls subjects. The polymorphisms were identified by a classical and a real-time PCR. Results. The AGT 235M/T and AT1R 1166A/C polymorphisms were not associated with the hypertension while the genotype frequencies of the ACE I/D polymorphism between patients and controls (DD: 66.83% and 35.78%, ID: 28.22% and 50.98%, II: 4.95% and 13.24%, resp.) were significantly different (p < 10−4). The genotype DD of ACE gene (OR = 3.40, p < 0.0001), the increasing age (OR = 3.83, p < 0.0001), obesity (OR = 4.84, p < 0.0001), dyslipidemia (OR = 3.43, p = 0.021), and alcohol intake (OR = 2.76, p < 0.0001) were identified as the independent risk factors for hypertension by multinomial logistic regression. Conclusion. The DD genotype of the ACE gene is involved in susceptibility to hypertension. Further investigations are needed to better monitor and provide individualized care for hypertensive patients. PMID:26351579

  14. An extreme-sib-pair genome scan for genes regulating blood pressure.

    PubMed

    Xu, X; Rogus, J J; Terwedow, H A; Yang, J; Wang, Z; Chen, C; Niu, T; Wang, B; Xu, H; Weiss, S; Schork, N J; Fang, Z

    1999-06-01

    Hypertension, a risk factor for many cardiovascular, cerebrovascular, and renal diseases, affects one in four Americans, at an annual cost of>$30 billion. Although genetic mutations have been identified in rare forms of hypertension, including Liddle syndrome and glucocorticoid-remediable aldosteronism, the abundance of plausible candidate genes and potential environmental risk factors has complicated the genetic dissection of more prevalent essential hypertension. To search systematically for chromosomal regions containing genes that regulate blood pressure, we scanned the entire autosomal genome by using 367 polymorphic markers. Our study population, selected from a blood-pressure screen of >200,000 Chinese adults, comprises rare but highly efficient extreme sib pairs (207 discordant, 258 high concordant, and 99 low concordant) and all but a single parent of these sibs. By virtue of the sampling design, the number of sib pairs, and the availability of genotyped parents, this study represents one of the most powerful of its kind. Although no regions achieved a 5% genomewide significance level, maximum LOD-score values were >2.0 (unadjusted P<.001) for regions containing five markers (D3S2387, D11S2019, D15S657, D16S3396, and D17S1303), in our primary analysis. Other promising regions identified through secondary analyses include loci near D4S3248, D7S2195, D10S1423, D20S470, D20S482, D21S2052, PAH, and AGT.

  15. Blood Pressure Loci Identified with a Gene-Centric Array

    PubMed Central

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

    2011-01-01

    Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10−7 study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r2 = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10−7 at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies. PMID:22100073

  16. Genes and gene regulation

    SciTech Connect

    MacLean, N.

    1988-01-01

    Genetics has long been a central topic for biologists, and recent progress has captured the public imagination as well. This book addresses questions that are at the leading edge of this continually advancing discipline. In tune with the increasing emphasis on molecular biology and genetic engineering, this text emphasizes the molecular aspects of gene expression, and the evolution of gene sequence organization and control. It reviews the genetic material of viruses, bacteria, and of higher organisms. Cells and organisms are compared in terms of gene numbers, their arrangements within a cell, and the control mechanisms which regulate the activity of genes.

  17. Advanced Gas Turbine (AGT) powertrain system development for automotive applications

    NASA Technical Reports Server (NTRS)

    1981-01-01

    Compressor development, turbine, combustion, regenerator system, gearbox/transmission, ceramic material and component development, foil gas bearings, bearings and seals, rotor dynamics development, and controls and accessories are discussed.

  18. Advanced Gas Turbine (AGT) powertrain system development for automotive applications

    NASA Technical Reports Server (NTRS)

    1984-01-01

    Rotor dynamic instability investigations were conducted. Forward ball bearing hydraulic mount configurations were tested with little effect. Trial assembly of S/N 002 ceramic engine was initiated. Impeller design activities were completed on the straight line element (SLE) blade definition to address near-net-shape powder metal die forging. Performance characteristics of the Baseline Test 2A impeller were closely preserved. The modified blading design has been released for tooling procurement. Developmental testing of the diffusion flame combustor (DFC) for initial use in the S/N 002 2100 F ceramic structures engine was completed. A natural gas slave preheater was designed and fabricated. Preliminary regenerator static seal rig testing showed a significant reduction in leakage and sensitivity to stack height. Ceramic screening tests were completed and two complete sets of ceramic static structures were qualified for engine testing. Efforts on rotor dynamics development to resolve subsynchronous motion were continued.

  19. Advanced Gas Turbine (AGT) power-train system development

    NASA Technical Reports Server (NTRS)

    Helms, H. E.; Johnson, R. A.; Gibson, R. K.

    1982-01-01

    Technical work on the design and component testing of a 74.5 kW (100 hp) advanced automotive gas turbine is described. Selected component ceramic component design, and procurement were tested. Compressor tests of a modified rotor showed high speed performance improvement over previous rotor designs; efficiency improved by 2.5%, corrected flow by 4.6%, and pressure ratio by 11.6% at 100% speed. The aerodynamic design is completed for both the gasifier and power turbines. Ceramic (silicon carbide) gasifier rotors were spin tested to failure. Improving strengths is indicated by burst speeds and the group of five rotors failed at speeds between 104% and 116% of engine rated speed. The emission results from combustor testing showed NOx levels to be nearly one order of magnitude lower than with previous designs. A one piece ceramic exhaust duct/regenerator seal platform is designed with acceptable low stress levels.

  20. Surface operator, bubbling Calabi-Yau and AGT relation

    NASA Astrophysics Data System (ADS)

    Taki, Masato

    2011-07-01

    Surface operators in mathcal{N} = 2 four-dimensional gauge theories are interesting half-BPS objects. These operators inherit the connection of gauge theory with the Liouville conformal field theory, which was discovered by Alday, Gaiotto and Tachikawa. Moreover it has been proposed that toric branes in the A-model topological strings lead to surface operators via the geometric engineering. We analyze the surface operators by making good use of topological string theory. Starting from this point of view, we propose that the wave-function behavior of the topological open string amplitudes geometrically engineers the surface operator partition functions and the Gaiotto curves of corresponding gauge theories. We then study a peculiar feature that the surface operator corresponds to the insertion of the degenerate fields in the conformal field theory side. We show that this aspect can be realized as the geometric transition in topological string theory, and the insertion of a surface operator leads to the bubbling of the toric Calabi-Yau geometry.

  1. Advanced Gas Turbine (AGT): Power-train system development

    NASA Technical Reports Server (NTRS)

    Helms, H. E.; Johnson, R. A.; Gibson, R. K.; Smith, L. B.

    1983-01-01

    Technical work on the design and effort leading to the testing of a 74.5 kW (100 hp) automotive gas turbine is described. The general effort was concentrated on building an engine for test starting in July. The buildup progressed with only routine problems and the engine was delivered to the test stand 9 July. In addition to the engine build effort, work continued in selected component areas. Ceramic turbine parts were built and tested. Burst tests of ceramic rotors show strengths are approaching that achieved in test bars; proof testing is required for acceptable strength ceramic vanes. Over 25 hours was accumulated on the combustor rig in three test modes: pilot nozzle only, start nozzle, and main nozzle operation. Satisfactory ignition was achieved for a wide range of starting speeds and the lean blowout limit was as low as 0.06 kg/b (0.14 lb/hr). Lean blowout was more a function of nozzle atomization than fuel/air ratio. A variety of cycle points were tested. Transition from start nozzle flow to main nozzle flow was done manually without difficulty. Regenerator parts were qualification tested without incident and the parts were assembled on schedule. Rig based performance matched first build requirements. Repeated failures in the harmonic drive gearbox during rig testing resulted in that concept being abandoned for an alternate scheme.

  2. Advanced Gas Turbine (AGT) powertrain system initial development report

    NASA Technical Reports Server (NTRS)

    1980-01-01

    The powertrain consists of a single shaft regenerated gas turbine engine utilizing ceramic hot section components, coupled to a slit differential gearbox with an available variable stator torque converter and an available Ford intergral overdrive four-speed automatic transmission. Predicted fuel economy using gasoline fuel over the combined federal driving cycle (CFDC) is 15.3 km/1, which represents a 59% improvement over the spark-ignition-powered baseline vehicle. Using DF2 fuel, CFDC mileage estimates are 17.43 km/1. Zero to 96.6 km/hr acceleration time is 11.9 seconds with a four-second accleration distance of 21.0 m. The ceramic radial turbine rotor is discussed along with the control system for the powertrain.

  3. Advanced Gas Turbine (AGT) powertrain system development for automotive applications

    NASA Technical Reports Server (NTRS)

    1981-01-01

    Preliminary layouts were made for the exhaust system, air induction system, and battery installation. Points of interference were identified and resolved by altering either the vehicle or engine designs. An engine general arrangement evolved to meet the vehicle engine compartment constraints while minimizing the duct pressure losses and the heat rejection. A power transfer system (between gasifier and power turbines) was developed to maintain nearly constant temperatures throughout the entire range of engine operation. An advanced four speed automatic transmission was selected to be used with the engine. Performance calculations show improvements in component efficiencies and an increase in fuel economy. A single stage centrifugal compressor design was completed and released for procurement. Gasifier turbine, power turbine, combustor, generator, secondary systems, materials, controls, and transmission development are reported.

  4. Studying Genes

    MedlinePlus

    ... Area What are genes? Genes are sections of DNA that contain instructions for making the molecules—many ... material in an organism. This includes genes and DNA elements that control the activity of genes. Does ...

  5. The effects of angiotensinogen gene polymorphisms on cardiovascular disease outcomes during antihypertensive treatment in the GenHAT study.

    PubMed

    Do, Anh N; Irvin, Marguerite R; Lynch, Amy I; Claas, Steven A; Boerwinkle, Eric; Davis, Barry R; Ford, Charles E; Eckfeldt, John H; Tiwari, Hemant K; Limdi, Nita A; Arnett, Donna K

    2014-01-01

    Previous studies have reported that risk of cardiovascular morbidity and mortality substantially increases in hypertensive patients, especially among those with inadequate blood pressure control. Two common antihypertensive drug classes including thiazide diuretics and angiotensin-converting enzyme (ACE) inhibitors affect different enzymes in the renin-angiotensin-aldosterone system (RAAS). In the RAAS, angiotensinogen is converted into angiotensin II which increases blood pressure through vasoconstriction. Using a case-only design with 3448 high-risk hypertensive individuals from the Genetics of Hypertension Associated Treatment (GenHAT) study, we examined whether seven single nucleotide polymorphisms (SNPs) in the angiotensinogen gene (AGT) interact with three classes of antihypertensive drugs including chlorthalidone (a thiazide diuretic), lisinopril (an ACE inhibitor), and amlodipine (a calcium channel blocker) to modify the risk of incident coronary heart disease (CHD) and heart failure (HF) among Caucasian and African American participants, separately. We found no gene by treatment interactions to be statistically significant after correction for multiple testing. However, some suggestive results were found. African American participants with the minor allele of rs11122576 had over two-fold higher risk of CHD when using chlorthalidone compared to using amlodipine, or lisinopril compared to amlodipine (p = 0.006 and p = 0.01, respectively). Other marginal associations are also reported among both race groups. The findings reported here suggest that rs11122576 could contribute to future personalization of antihypertensive treatment among African Americans though more studies are needed.

  6. The effects of angiotensinogen gene polymorphisms on cardiovascular disease outcomes during antihypertensive treatment in the GenHAT study

    PubMed Central

    Do, Anh N.; Irvin, Marguerite R.; Lynch, Amy I.; Claas, Steven A.; Boerwinkle, Eric; Davis, Barry R.; Ford, Charles E.; Eckfeldt, John H.; Tiwari, Hemant K.; Limdi, Nita A.; Arnett, Donna K.

    2014-01-01

    Previous studies have reported that risk of cardiovascular morbidity and mortality substantially increases in hypertensive patients, especially among those with inadequate blood pressure control. Two common antihypertensive drug classes including thiazide diuretics and angiotensin-converting enzyme (ACE) inhibitors affect different enzymes in the renin-angiotensin-aldosterone system (RAAS). In the RAAS, angiotensinogen is converted into angiotensin II which increases blood pressure through vasoconstriction. Using a case-only design with 3448 high-risk hypertensive individuals from the Genetics of Hypertension Associated Treatment (GenHAT) study, we examined whether seven single nucleotide polymorphisms (SNPs) in the angiotensinogen gene (AGT) interact with three classes of antihypertensive drugs including chlorthalidone (a thiazide diuretic), lisinopril (an ACE inhibitor), and amlodipine (a calcium channel blocker) to modify the risk of incident coronary heart disease (CHD) and heart failure (HF) among Caucasian and African American participants, separately. We found no gene by treatment interactions to be statistically significant after correction for multiple testing. However, some suggestive results were found. African American participants with the minor allele of rs11122576 had over two-fold higher risk of CHD when using chlorthalidone compared to using amlodipine, or lisinopril compared to amlodipine (p = 0.006 and p = 0.01, respectively). Other marginal associations are also reported among both race groups. The findings reported here suggest that rs11122576 could contribute to future personalization of antihypertensive treatment among African Americans though more studies are needed. PMID:25278896

  7. Serum angiotensinogen concentration in relation to gonadal hormones, body size, and genotype in growing young people.

    PubMed

    Pratt, J H; Ambrosius, W T; Tewksbury, D A; Wagner, M A; Zhou, L; Hanna, M P

    1998-11-01

    Multiple factors are thought to influence the level of circulating angiotensinogen (AGT). We showed previously that the serum AGT concentration was significantly related to body mass index (BMI) in a cohort of young people. In the present study, we studied whether levels of the gonadal hormones estradiol and testosterone might also predict the AGT level and might contribute to the BMI effect, since both the production of these hormones and BMI increase with age. In boys (n=127; mean+/-SD age, 14.7+/-1.9 years) and girls (n=104; age, 14.8+/-1.9 years) studied as a single group, we found a significant association of AGT level with level of estradiol (P=0.015) after adjustment for haplotype, age, race, testosterone concentration, and BMI. In girls studied alone, the level of AGT showed a significantly positive relation to level of testosterone (P=0.043), possibly a result of peripheral conversion of testosterone to estradiol, after adjustment for haplotype, age, race, estradiol concentration, and BMI. In boys, on the other hand, the level of testosterone was inversely related to AGT concentration (P=0.019), again after making adjustments for the other variables. Finally, in pairs of subjects matched for BMI, age, race, and gender where 1 member of each pair had either 1 or 2 copies of an AGT gene haplotype (T235 and -1074t) and the other member had no copy, the level of AGT was higher in the carrier of a haplotype in 24 of the 34 pairs (P<0.001). In conclusion, gonadal hormones are an additional influence on the circulating level of AGT in growing young people. In addition, with matching for BMI and other covariates, there is a strong association of AGT genotype with the serum level of AGT, emphasizing the importance of AGT gene expression as a determinant of the circulating level of AGT. PMID:9822447

  8. FCRL3 Gene Polymorphisms Confer Autoimmunity Risk for Allergic Rhinitis in a Chinese Han Population

    PubMed Central

    Gu, Zheng; Hong, Su-Ling; Ke, Xia; Shen, Yang; Wang, Xiao-Qiang; Hu, Di; Hu, Guo-Hua; Kang, Hou-Yong

    2015-01-01

    Background Heredity and environmental exposures may contribute to a predisposition to allergic rhinitis (AR). Autoimmunity may also involve into this pathologic process. FCRL3 (Fc receptor-like 3 gene), a novel immunoregulatory gene, has recently been reported to play a role in autoimmune diseases. Objective This study was performed to evaluate the potential association of FCRL3 polymorphisms with AR in a Chinese Han population. Methods Five single-nucleotide polymorphisms of FCRL3, rs945635, rs3761959, rs7522061, rs10489678 and rs7528684 were genotyped in 540 AR patients and 600 healthy controls using a PCR-restriction fragment length polymorphism assay. Allele, genotype and haplotype frequencies were compared between patients and controls using the χ2 test. The online software platform SHEsis was used to analyze their haplotypes. Results This study identified three strong risk SNPs rs7528684, rs10489678, rs7522061 and one weak risk SNP rs945635 of FCRL3 in Chinese Han AR patients. For rs7528684, a significantly increased prevalence of the AA genotype and A allele in AR patients was recorded. The frequency of the GG genotype and G allele of rs10489678 was markedly higher in AR patients than those in controls. For rs7522061, a higher frequency of the TT genotype, and a lower frequency of the CT genotype were found in AR patients. Concerning rs945635, a lower frequency of the CC genotype, and a higher frequency of G allele were observed in AR patients. According to the analysis of the three strong positive SNPs, the haplotype of AGT increased significantly in AR cases (AR = 38.8%, Controls = 24.3%, P = 8.29×10-14, OR [95% CI] 1.978 [1.652~2.368]). Conclusions This study found a significant association between the SNPs in FCRL3 gene and AR in Chinese Han patients. The results suggest these gene polymorphisms might be the autoimmunity risk for AR. PMID:25594855

  9. Association of a novel polymorphism in the bovine PPARGC1A gene with growth, slaughter and meat quality traits in Brangus steers.

    PubMed

    Soria, L A; Corva, P M; Branda Sica, A; Villarreal, E L; Melucci, L M; Mezzadra, C A; Papaleo Mazzucco, J; Fernández Macedo, G; Silvestro, C; Schor, A; Miquel, M C

    2009-12-01

    The PPARGC1A gene (peroxysome proliferator-activated receptor-gamma coactivator 1alpha gene) controls muscle fiber type and brown adipocyte differentiation; therefore, it is a candidate gene for beef quality traits (tenderness and fat content). Two SNPs (Single Nucleotide Polymorphisms) were identified within exon 8 by multiple alignment of DNA sequences obtained from 24 bulls: a transition G/A (SNP 1181) and a transversion A/T (SNP 1299). The SNP 1181 is a novel SNP, corresponding to a non-conservative substitution (AGT/AAT) that could be the cause of amino acid substitution ((364)Serine/(364)Asparagine). A Mismatch PCR method was designed to determine genotypes of 73 bulls and 268 steers for SNP 1181. Growth, slaughter and meat quality information were available for the group of steers. Allele A of SNP 1181 was not found in Angus. In 243 steers, no significant differences (P > 0.05) were found for either final live body weight, gain in backfat thickness in Spring, kidney fat weight, kidney fat percentage, Warner-Bratzler shear force at 7 days postmortem, intramuscular fat percentage or meat colour between genotype GG and AG. This SNP could be included in breed composition and population admixture analyses because there are marked differences in allelic frequencies between Bos taurus and Bos indicus breeds. PMID:19665052

  10. Hypoxia-Induced Endothelial Progenitor Cell Function Is Blunted in Angiotensinogen Knockout Mice

    PubMed Central

    Choi, Jin-Hwa; Nguyen, Minh-Phuong; Lee, Dongjin; Oh, Goo-Taeg; Lee, You-Mie

    2014-01-01

    Angiotensinogen (AGT), the precursor of angiotensin I, is known to be involved in tumor angiogenesis and associated with the pathogenesis of coronary atherosclerosis. This study was undertaken to determine the role played by AGT in endothelial progenitor cells (EPCs) in tumor progression and metastasis. It was found that the number of EPC colonies formed by AGT heterozygous knockout (AGT+/−) cells was less than that formed by wild-type (WT) cells, and that the migration and tube formation abilities of AGT+/− EPCs were significantly lower than those of WT EPCs. In addition, the gene expressions of vascular endothelial growth factor (VEGF), Flk1, angiopoietin (Ang)-1, Ang-2, Tie-2, stromal derived factor (SDF)-1, C-X-C chemokine receptor type 4 (CXCR4), and of endothelial nitric oxide synthase (eNOS) were suppressed in AGT+/− EPCs. Furthermore, the expressions of hypoxia-inducible factor (HIF)-1α and -2α were downregulated in AGT+/− early EPCs under hypoxic conditions, suggesting a blunting of response to hypoxia. Moreover, the activation of Akt/eNOS signaling pathways induced by VEGF, epithelial growth factor (EGF), or SDF-1α were suppressed in AGT+/− EPCs. In AGT+/− mice, the incorporation of EPCs into the tumor vasculature was significantly reduced, and lung tumor growth and melanoma metastasis were attenuated. In conclusion, AGT is required for hypoxia-induced vasculogenesis. PMID:24938229

  11. Association of renin-angiotensin and endothelial nitric oxide synthase gene polymorphisms with blood pressure progression and incident hypertension: prospective cohort study

    PubMed Central

    Conen, David; Glynn, Robert J.; Buring, Julie E.; Ridker, Paul M; Zee, Robert Y.L.

    2009-01-01

    Objective The renin-angiotensin system and endothelial function have both been associated with hypertension. The aim of the present study was to assess the relationship of six previously characterized gene variants in the renin-angiotensin system and the NOS3 gene with blood pressure progression and incident hypertension. Methods We analyzed data from 18436 Caucasian women who participated in a prospective cohort study and were free of hypertension at baseline. Six previously characterized single nucleotide polymorphisms (NOS3 rs1800779, NOS3 rs3918226, NOS3 rs1799983, ACE rs1799752, AGT rs699, and AGTR1 rs5186) were genotyped. Blood pressure progression at 48 months and incident hypertension during the entire follow-up according to the different genotypes and inferred haplotypes were assessed by logistic regression and Cox proportional-hazards models, respectively. Results At 48 months, 47.4% of the women had blood pressure progression. The odds ratios (95% confidence intervals (CI)) for blood pressure progression associated with NOS3 rs1800779, NOS3 rs3918226, NOS3 rs1799983, ACE rs1799752, AGT rs699, and AGTR1 rs5186 were 1.00 (0.96–1.05), 1.00 (0.92–1.09), 0.99 (0.94–1.04), 0.96 (0.92–1.01), 1.04 (0.99–1.08), and 1.03 (0.98–1.08). During 9.8 years of follow-up, 29.6% of women developed incident hypertension. The hazard ratios (95% CI) for the six polymorphisms were 1.01 (0.97–1.06), 1.06 (0.99–1.14), 1.05 (1.01–1.09), 0.99 (0.95–1.02), 1.01 (0.97–1.05) and 0.99 (0.95–1.04). NOS3-haplotypes were not significantly associated with blood pressure progression (p=0.91) or incident hypertension (p=0.10). Conclusion Blood pressure progression and incident hypertension are not consistently associated with six well-characterized genetic polymorphisms of the renin-angiotensin system and the NOS3 gene in a large cohort of Caucasian women. PMID:18698212

  12. Lead exposure increases blood pressure by increasing angiotensinogen expression.

    PubMed

    Jiao, Jiandong; Wang, Miaomiao; Wang, Yiqing; Sun, Na; Li, Chunping

    2016-01-01

    Lead exposure can induce increased blood pressure. Several mechanisms have been proposed to explain lead-induced hypertension. Changes in angiotensinogen (AGT) expression levels or gene variants may also influence blood pressure. In this study, we hypothesized that AGT expression levels or gene variants contribute to lead-induced hypertension. A preliminary HEK293 cell model experiment was performed to analyze the association between AGT expression and lead exposure. In a population-based study, serum AGT level was measured in both lead-exposed and control populations. To further detect the influence of AGT gene single nucleotide polymorphisms (SNPs) in lead-induced hypertension, two SNPs (rs699 and rs4762) were genotyped in a case-control study including 219 lead-exposed subjects and 393 controls. Lead exposure caused an increase in AGT expression level in HEK 293 cell models (P < 0.001) compared to lead-free cells, and individuals exposed to lead had higher systolic and diastolic blood pressure (P < 0.001). Lead-exposed individuals had higher serum AGT levels compared to controls (P < 0.001). However, no association was found between AGT gene SNPs (rs699 and rs4762) and lead exposure. Nevertheless, the change in AGT expression level may play an important role in the development of lead-induced hypertension.

  13. Alkyltransferase-mediated toxicity of bis-electrophiles in mammalian cells

    PubMed Central

    Kalapila, Aley G.; Pegg, Anthony E.

    2009-01-01

    The primary function of O6-alkylguanine-DNA alkyltransferase (AGT) is to maintain genomic integrity in the face of damage by both endogenous and exogenous alkylating agents. However, paradoxically, bacterial and mammalian AGTs have been shown to increase cytotoxicity and mutagenicity of dihaloalkanes and other bis-electrophiles when expressed in bacterial cells. We have extended these studies to mammalian cells using CHO cells that lack AGT expression and CHO cells stably transfected with a plasmid that expresses human AGT. The cytotoxicity of 1,2-dibromoethane, dibromomethane and epibromohydrin was significantly increased by the presence of AGT but cytotoxicity of butadiene diepoxide was not affected. Mutations caused by these agents were assessed using hypoxanthine-guanine phosphoribosyltransferase (HPRT) as a reporter gene. There was a small (c. 2–3-fold) but statistically significant AGT-mediated increase in mutations caused by 1,2-dibromoethane, dibromomethane and epibromohydrin. Analysis of the mutation spectrum induced by 1,2-dibromoethane showed that the presence of AGT also altered the types of mutations with an increase in total base substitution mutants due to a rise in transversions at both G:C and A:T sites. AGT expression also led to mutations arising from the transcribed strand, which were not seen in cells lacking AGT. Although the frequency of deletion mutations was decreased by AGT expression, the formation of large deletions (≥3 exons) was increased. This work demonstrates that interaction of AGT with some bis-electrophiles can cause mutagenicity and diminished cell survival in mammalian cells. It is consistent with the hypothesis that DNA-AGT cross-links, which have been characterized in experiments with purified AGT protein and such bis-electrophiles, can be formed in mammalian cells. PMID:19941875

  14. Do genetic variants of the Renin-Angiotensin system predict blood pressure response to Renin-Angiotensin system-blocking drugs?: a systematic review of pharmacogenomics in the Renin-Angiotensin system.

    PubMed

    Konoshita, Tadashi

    2011-10-01

    The concept of "pharmacogenomics" or "pharmacogenetics" promises to offer the ultimate in personalized medicine, and the renin-angiotensin system (RAS) is one of the most plausible candidates for the application of this approach in the area of hypertension. For the past two decades, genetic variants of the RAS have been tested for association with blood pressure response, but the results have been inconsistent. The problems have been attributed to many issues, but the most fundamental concern is thought to be the statistical power of the studies. Therefore, we have tried to put together a new systematic review using a database search including only recent reports with adequate numbers of subjects, and 11 reports were identified. From the results, we were able to draw conclusions with nearly consistent findings that the conventional genetic variants of the system (i.e., the ACE I/D, AGT M235T, AT1 A1166C, and AT2 variant) are not associated with antihypertensive effects by RAS blockade, at least by one individual SNP. By contrast, significant associations have been reported (by one report each) for AGT rs7079, AT1 haplotype, REN, and ACE2. For these variants, further evaluations and confirmation are anticipated. PMID:21562941

  15. Gene doping.

    PubMed

    Harridge, Stephen D R; Velloso, Cristiana P

    2008-01-01

    Gene doping is the misuse of gene therapy to enhance athletic performance. It has recently been recognised as a potential threat and subsequently been prohibited by the World Anti-Doping Agency. Despite concerns with safety and efficacy of gene therapy, the technology is progressing steadily. Many of the genes/proteins which are involved in determining key components of athletic performance have been identified. Naturally occurring mutations in humans as well as gene-transfer experiments in adult animals have shown that altered expression of these genes does indeed affect physical performance. For athletes, however, the gains in performance must be weighed against the health risks associated with the gene-transfer process, whereas the detection of such practices will provide new challenges for the anti-doping authorities.

  16. Synonymous single nucleotide polymorphisms in the MC4R gene that are significantly associated with milk production traits in water buffaloes.

    PubMed

    Deng, T X; Pang, C Y; Liu, M Q; Zhang, C; Liang, X W

    2016-07-14

    Melanocortin-4 receptor (MC4R) is associated with feed intake, growth, fatness, and carcass composition in many domestic animals. The aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in MC4R with milk production traits in water buffalo. Eight SNPs were identified by direct polymerase chain reaction sequencing of samples from 18 buffaloes. SNPs were then genotyped using the matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) method in 332 buffaloes. Two of eight SNPs were not in Hardy-Weinberg equilibrium. Based on the SNP data, seven haplotypes were constructed. Three SNPs H1 (AGT), H2 (GAT), and H3 (GAC) accounted for 93.0% of the total individuals. Statistical analysis indicated that the SNP g.1104C>T was significantly associated with milk yield, protein, and fat percentage (P < 0.05). In conclusion, these results provide evidence that polymorphisms in the buffalo MC4R gene are associated with milk production traits and might be potential biomarkers for water buffalo breeding.

  17. Synonymous single nucleotide polymorphisms in the MC4R gene that are significantly associated with milk production traits in water buffaloes.

    PubMed

    Deng, T X; Pang, C Y; Liu, M Q; Zhang, C; Liang, X W

    2016-01-01

    Melanocortin-4 receptor (MC4R) is associated with feed intake, growth, fatness, and carcass composition in many domestic animals. The aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in MC4R with milk production traits in water buffalo. Eight SNPs were identified by direct polymerase chain reaction sequencing of samples from 18 buffaloes. SNPs were then genotyped using the matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) method in 332 buffaloes. Two of eight SNPs were not in Hardy-Weinberg equilibrium. Based on the SNP data, seven haplotypes were constructed. Three SNPs H1 (AGT), H2 (GAT), and H3 (GAC) accounted for 93.0% of the total individuals. Statistical analysis indicated that the SNP g.1104C>T was significantly associated with milk yield, protein, and fat percentage (P < 0.05). In conclusion, these results provide evidence that polymorphisms in the buffalo MC4R gene are associated with milk production traits and might be potential biomarkers for water buffalo breeding. PMID:27420995

  18. Similarities and differences of X and Y chromosome homologous genes, SRY and SOX3, in regulating the renin-angiotensin system promoters

    PubMed Central

    Araujo, Fabiano C.; Milsted, Amy; Watanabe, Ingrid K. M.; Del Puerto, Helen L.; Santos, Robson A. S.; Lazar, Jozef; Reis, Fernando M.

    2015-01-01

    The renin-angiotensin system (RAS) is subject to sex-specific modulation by hormones and gene products. However, sex differences in the balance between the vasoconstrictor/proliferative ACE/ANG II/AT1 axis, and the vasodilator/antiproliferative ACE2/ANG-(1–7)/MAS axis are poorly known. Data in the rat have suggested the male-specific Y-chromosome gene Sry to contribute to balance between these two axes, but why the testis-determining gene has these functions remains unknown. A combination of in silico genetic/protein comparisons, functional luciferase assays for promoters of the human RAS, and RNA-Seq profiling in rat were used to address if regulation of Sry on the RAS is conserved in the homologous X-chromosome gene, Sox3. Both SRY and SOX3 upregulated the promoter of Angiotensinogen (AGT) and downregulated the promoters of ACE2, AT2, and MAS, likely through overlapping mechanisms. The regulation by both SRY and SOX3 on the MAS promoter indicates a cis regulation through multiple SOX binding sites. The Renin (REN) promoter is upregulated by SRY and downregulated by SOX3, likely through trans and cis mechanisms, respectively. Sry transcripts are found in all analyzed male rat tissues including the kidney, while Sox3 transcripts are found only in the brain and testis, suggesting that the primary tissue for renin production (kidney) can only be regulated by SRY and not SOX3. These results suggest that SRY regulation of the RAS is partially shared with its X-chromosome homolog SOX3, but SRY gained a sex-specific control in the kidney for the rate-limiting step of the RAS, potentially resulting in male-specific blood pressure regulation. PMID:25759379

  19. Trichoderma genes

    SciTech Connect

    Foreman, Pamela; Goedegebuur, Frits; Van Solingen, Pieter; Ward, Michael

    2012-06-19

    Described herein are novel gene sequences isolated from Trichoderma reesei. Two genes encoding proteins comprising a cellulose binding domain, one encoding an arabionfuranosidase and one encoding an acetylxylanesterase are described. The sequences, CIP1 and CIP2, contain a cellulose binding domain. These proteins are especially useful in the textile and detergent industry and in pulp and paper industry.

  20. [Gene therapy].

    PubMed

    Rodríguez-Fragoso, L

    1997-01-01

    In the last years there has been much progress in our understanding of molecular mechanisms in the pathogenesis of disease. In this review we provide an overview of gene therapy, its most actualized techniques for gene delivery, and we give specific examples of laboratory and clinical achievements to date. The development of methods for delivering genes to mammalian cells has stimulated great interest in the possibility of treating human disease by gene-based therapies. As a result, concepts and methods that would have been considered purely science fiction 50 years ago are now used in the treatment of diseases. The widespread application of gene therapy technology to many diseases is already breaking down the traditional boundaries of modern medicine. However, despite its progress, several key technical drawbacks need to be overcome before gene therapy can be used safely and effectively in clinical settings. Technological developments, particularly in the areas of gene delivery and cell transplantation, will be critical for the successful practice of gene therapy.

  1. Gene Therapy

    PubMed Central

    Baum, Bruce J

    2014-01-01

    Applications of gene therapy have been evaluated in virtually every oral tissue, and many of these have proved successful at least in animal models. While gene therapy will not be used routinely in the next decade, practitioners of oral medicine should be aware of the potential of this novel type of treatment that doubtless will benefit many patients with oral diseases. PMID:24372817

  2. Upstream Stimulatory Factor is Required for Human Angiotensinogen Expression and Differential Regulation by the A-20C Polymorphism

    PubMed Central

    Dickson, Matthew E.; Tian, Xin; Liu, Xuebo; Davis, Deborah R.; Sigmund, Curt D.

    2008-01-01

    Among naturally-occurring polymorphisms in the 5’ flanking region of the human angiotensinogen (AGT) gene, the −20 and −217 polymorphisms have the strongest effects on AGT regulation in AGT-expressing cells derived from liver, kidney, brain, and fat. These polymorphisms may affect allele-specific transcription factor binding, and the high-expressing alleles are both relatively common. We show herein that the −20C allele has higher transcriptional activity than −20A, and the −20A allele confers no additional transactivation potential beyond that of a mutated vector. Gel shift assays show that USF1 and USF2 preferentially bind the −20C allele whereas the −20A allele retains a low affinity USF binding site. Plasmid immunoprecipitation assays confirmed preferential association of USF1 with the −20C allele in transfected HepG2 cells. Chromatin immunoprecipitation confirmed that USF1 binds to the endogenous AGT −20C allele in CCF cells, the only cell line tested that carries the −20C allele, and to the human AGT promoter in liver and adipose tissue from transgenic mice. Transduction of AGT-expressing cells with shRNAs specifically targeting USF1 or USF2, resulted in cell- and allele-specific attenuation of AGT promoter activity. In vivo, knockdown of USF expression in the liver of transgenic mice expressing the −20C allele of AGT resulted in lower AGT expression, a decrease in circulating human AGT protein, but no change in expression of GAPDH or HNF-4α. We conclude that USF1 functionally and differentially regulates AGT expression via the −20 polymorphism and that the differential expression exhibited by −20 can be accounted for by differential association with USF1. PMID:18802024

  3. The adipose renin-angiotensin system modulates sysemic markers of insulin sensitivity activates the intrarenal renin-angiotensin system

    SciTech Connect

    Kim, Suyeon; Soltani-Bejnood, Morvarid; Quignard-Boulange, Annie; Massiera, Florence; Teboul, Michele; Ailhaud, Gerard; Kim, Jung; Moustaid-Moussa, Naima; Voy, Brynn H

    2006-07-01

    BACKGROUND: A growing body of data provides increasing evidence that the adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass. Beyond its paracrine actions within adipose tissue, adipocyte-derived angiotensin II (Ang II) may also impact systemic functions such as blood pressure and metabolism. METHODS AND RESULTS: We used a genetic approach to manipulate adipose RAS activity in mice and then study the consequences on metabolic parameters and on feedback regulation of the RAS. The models included deletion of the angiotensinogen (Agt) gene (Agt-KO), its expression solely in adipose tissue under the control of an adipocyte-specific promoter (aP2-Agt/ Agt-KO), and overexpression in adipose tissue of wild type mice (aP2-Agt). Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin and resistin were significantly decreased in Agt-KO mice, while plasma adiponectin levels were increased. Overexpression of Agt in adipose tissue resulted in increased adiposity and plasma leptin and insulin levels compared to wild type (WT) controls. Angiotensinogen and type I Ang II receptor protein levels were also markedly elevated in kidney of aP2-Agt mice, suggesting that hypertension in these animals may be in part due to stimulation of the intrarenal RAS. CONCLUSIONS: Taken together, the results from this study demonstrate that alterations in adipose RAS activity significantly alter both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity.

  4. Designer Genes.

    ERIC Educational Resources Information Center

    Miller, Judith; Miller, Mark

    1983-01-01

    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)

  5. Attention Genes

    ERIC Educational Resources Information Center

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

    2007-01-01

    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…

  6. Vulnerability genes or plasticity genes?

    PubMed Central

    Belsky, J; Jonassaint, C; Pluess, M; Stanton, M; Brummett, B; Williams, R

    2009-01-01

    The classic diathesis–stress framework, which views some individuals as particularly vulnerable to adversity, informs virtually all psychiatric research on behavior–gene–environment (G × E) interaction. An alternative framework of ‘differential susceptibility' is proposed, one which regards those most susceptible to adversity because of their genetic make up as simultaneously most likely to benefit from supportive or enriching experiences—or even just the absence of adversity. Recent G × E findings consistent with this perspective and involving monoamine oxidase-A, 5-HTTLPR (5-hydroxytryptamine-linked polymorphic region polymorphism) and dopamine receptor D4 (DRD4) are reviewed for illustrative purposes. Results considered suggest that putative ‘vulnerability genes' or ‘risk alleles' might, at times, be more appropriately conceptualized as ‘plasticity genes', because they seem to make individuals more susceptible to environmental influences—for better and for worse. PMID:19455150

  7. Cytotoxic T lymphocyte antigen 4 (CTLA4) gene polymorphism with bladder cancer risk in North Indian population.

    PubMed

    Jaiswal, Praveen Kumar; Singh, Vibha; Mittal, Rama Devi

    2014-02-01

    Cytotoxic T Lymphocyte antigen 4 (CTLA4) is a potent immunoregulatory molecule that suppresses antitumor response by down-regulating T cell activation. We examined candidate disease-susceptibility single nucleotide polymorphism (SNPs) of CTLA4 at +49A/G, CT60A/G and -318C/T genes in bladder cancer (BC) patients of North Indian population. Histopathologically confirmed 200 patients of BC and 200 unrelated, healthy controls of similar ethnicity were genotyped by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation specific (PCR-ARMS) methods. In present study SNP CTLA4 +49A/G, variant genotype showed 3.74-fold risks for BC. While looking at G allele carrier level, risk for BC was high (OR = 1.54). The risk for BC was also evident in case G allele (OR = 1.58). CTLA4 CT60A/G gene polymorphism variant genotype showed 1.36-fold risks for BC. While at G allele carrier and with variant G allele it showed significantly reduced risk for BC. CTLA4 +49A/G genotype exhibited 1.57-fold risks with smoking in BC patients in homozygous mutant condition. In silico analysis further supports the results of SNP at CTLA4 +49A/G and CTLA4 CT60A/G. None of the above SNPs of CTLA4 demonstrated association with tumor stage/grade for BC severity and progression. BCG immunotherapy had no impact on CTLA4 gene polymorphism revealing no significant association. Haplotype GAC showed high risk for BC while other haplotype AGT showed reduced risk for BC. Our results indicated that genetic variations in CTLA4 gene (+49A/G, CT60A/G) play role in susceptibility to BC. Haplotype GAC showed high risk for BC. An association study utilizing a larger sample size and different ethnicity warrant further investigation through replication and advance techniques.

  8. Genes and Hearing Loss

    MedlinePlus

    ... Meeting Calendar Find an ENT Doctor Near You Genes and Hearing Loss Genes and Hearing Loss Patient ... mutation may only have dystopia canthorum. How Do Genes Work? Genes are a road map for the ...

  9. Neuromarkers of the common angiotensinogen polymorphism in healthy older adults: A comprehensive assessment of white matter integrity and cognition.

    PubMed

    Salminen, Lauren E; Schofield, Peter R; Pierce, Kerrie D; Zhao, Yi; Luo, Xi; Wang, Youdan; Laidlaw, David H; Cabeen, Ryan P; Conturo, Thomas E; Tate, David F; Akbudak, Erbil; Lane, Elizabeth M; Heaps, Jodi M; Bolzenius, Jacob D; Baker, Laurie M; Cagle, Lee M; Paul, Robert H

    2016-01-01

    The common angiotensinogen (AGT) M268T polymorphism (rs699; historically referred to as M235T) has been identified as a significant risk factor for cerebrovascular pathologies, yet it is unclear if healthy older adults carrying the threonine amino acid variant have a greater risk for white matter damage in specific fiber tracts. Further, the impact of the threonine variant on cognitive function remains unknown. The present study utilized multiple indices of diffusion tensor imaging (DTI) and neuropsychological assessment to examine the integrity of specific white matter tracts and cognition between individuals with homozygous genotypes of M268T (MetMet n=27, ThrThr n=27). Differences in subcortical hyperintensity (SH) volume were also examined between groups. Results indicated that the threonine variant was associated with significantly reduced integrity in the superior longitudinal fasciculus (SLF) and the cingulate gyrus segment of the cingulum bundle (cingulum CG) compared to those with the methionine variant, and poorer cognitive performance on tests of attention/processing speed and language. Despite these associations, integrity of these tracts did not significantly mediate relationships between cognition and genetic status, and SH did not differ significantly between groups. Collectively our results suggest that the threonine variant of M268T is a significant risk factor for abnormalities in specific white matter tracts and cognitive domains in healthy older adults, independent of SH burden.

  10. Neuromarkers of the common angiotensinogen polymorphism in healthy older adults: A comprehensive assessment of white matter integrity and cognition.

    PubMed

    Salminen, Lauren E; Schofield, Peter R; Pierce, Kerrie D; Zhao, Yi; Luo, Xi; Wang, Youdan; Laidlaw, David H; Cabeen, Ryan P; Conturo, Thomas E; Tate, David F; Akbudak, Erbil; Lane, Elizabeth M; Heaps, Jodi M; Bolzenius, Jacob D; Baker, Laurie M; Cagle, Lee M; Paul, Robert H

    2016-01-01

    The common angiotensinogen (AGT) M268T polymorphism (rs699; historically referred to as M235T) has been identified as a significant risk factor for cerebrovascular pathologies, yet it is unclear if healthy older adults carrying the threonine amino acid variant have a greater risk for white matter damage in specific fiber tracts. Further, the impact of the threonine variant on cognitive function remains unknown. The present study utilized multiple indices of diffusion tensor imaging (DTI) and neuropsychological assessment to examine the integrity of specific white matter tracts and cognition between individuals with homozygous genotypes of M268T (MetMet n=27, ThrThr n=27). Differences in subcortical hyperintensity (SH) volume were also examined between groups. Results indicated that the threonine variant was associated with significantly reduced integrity in the superior longitudinal fasciculus (SLF) and the cingulate gyrus segment of the cingulum bundle (cingulum CG) compared to those with the methionine variant, and poorer cognitive performance on tests of attention/processing speed and language. Despite these associations, integrity of these tracts did not significantly mediate relationships between cognition and genetic status, and SH did not differ significantly between groups. Collectively our results suggest that the threonine variant of M268T is a significant risk factor for abnormalities in specific white matter tracts and cognitive domains in healthy older adults, independent of SH burden. PMID:26318936

  11. Compare Gene Profiles

    SciTech Connect

    2014-05-31

    Compare Gene Profiles (CGP) performs pairwise gene content comparisons among a relatively large set of related bacterial genomes. CGP performs pairwise BLAST among gene calls from a set of input genome and associated annotation files, and combines the results to generate lists of common genes, unique genes, homologs, and genes from each genome that differ substantially in length from corresponding genes in the other genomes. CGP is implemented in Python and runs in a Linux environment in serial or parallel mode.

  12. Gene gymnastics

    PubMed Central

    Vijayachandran, Lakshmi S; Thimiri Govinda Raj, Deepak B; Edelweiss, Evelina; Gupta, Kapil; Maier, Josef; Gordeliy, Valentin; Fitzgerald, Daniel J; Berger, Imre

    2013-01-01

    Most essential activities in eukaryotic cells are catalyzed by large multiprotein assemblies containing up to ten or more interlocking subunits. The vast majority of these protein complexes are not easily accessible for high resolution studies aimed at unlocking their mechanisms, due to their low cellular abundance and high heterogeneity. Recombinant overproduction can resolve this bottleneck and baculovirus expression vector systems (BEVS) have emerged as particularly powerful tools for the provision of eukaryotic multiprotein complexes in high quality and quantity. Recently, synthetic biology approaches have begun to make their mark in improving existing BEVS reagents by de novo design of streamlined transfer plasmids and by engineering the baculovirus genome. Here we present OmniBac, comprising new custom designed reagents that further facilitate the integration of heterologous genes into the baculovirus genome for multiprotein expression. Based on comparative genome analysis and data mining, we herein present a blueprint to custom design and engineer the entire baculovirus genome for optimized production properties using a bottom-up synthetic biology approach. PMID:23328086

  13. Enzymological and mutational analysis of a complex primary hyperoxaluria type I phenotype involving alanine: Glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation

    SciTech Connect

    Danpure, C.J.; Purdue, P.E.; Allsop, J.; Lumb, M.J.; Jennings, P.R. ); Scheinman, J.I. ); Mauer, S.M. ); Davidson, N.O. )

    1993-08-01

    Primary hyperoxaluri type 1 (PH1) is a rare autosomal recessive disease caused by a deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). Three unrelated PH1 patients, who possess a novel complex phenotype, are described. At the enzymological level, this phenotype is characterized by a complete, or nearly complete, absence of AGT catalytic activity and reduced AGT immunoreactivity. Unlike normal individuals in whom the AGT is confined to the peroxisomal matrix, the immunoreactive AGT in these three patients was distributed approximately equally between the peroxisomes and mitochondria. The peroxisomal AGT appeared to be aggregated into amorphous core-like structures in which no other peroxisomal enzymes could be identified. Mutational analysis of the AGT gene showed that two of the three patients were compound heterozygotes for two previously unrecognized point mutations which caused Gly41[yields]Arg and Phe152[yields]Iso amino acid substitutions. The third patient was shown to be a compound heterozygote for the Gly41[yields]Arg mutation and a previously recognized Gly170[yields]Arg mutation. All three patients were homozygous for the Pro11[yields]Leu polymorphism that had been found previously with a high allelic frequency in normal populations. It is suggested the the Phe152[yields]Iso and Gly170[yields]Arg substitutions, which are only eighteen residues apart and located in the same highly conserved internal region of 58 amino acids, might be involved in the inhibition of peroxisomal targeting and/or import of AGT and, in combination with the Pro11[yields]Leu polymorphism, be responsible for its aberrant mitochondrial compartmentalization. On the other hand, the Gly41[yields]Arg substitution, either in combination with the Pro11[yields]Leu polymorphism or by itself, is predicted to be responsible for the intraperoxisomal aggregation of the AGT protein. 50 refs., 8 figs., 4 tabs.

  14. Organization of immunoglobulin genes.

    PubMed

    Tonegawa, S; Brack, C; Hozumi, N; Pirrotta, V

    1978-01-01

    The nucleotide-sequence determination of a cloned, embryonic Vlambda gene directly demonstrated that V genes are separate from a corresponding C gene in embryonic cells. Analysis by restriction enzymes of total cellular DNA from various sources strongly suggested that the two separate immunoglobulin genes become continuous during differentiation of B lymphocytes. There seems to be a strict correlation between the joining event and activation of the joined genes. Cloning of more immunoglobulin genes from embryo and plasma cells will not only provide direct demonstration of such a gene-joining event but also help in the elucidation of a possible relationship of the event to gene activation mechanisms.

  15. AGT 101: Ceramic component development: Advanced Gas Turbine Program: Topical report, October 1979-July 1987

    SciTech Connect

    Ten Eyck, M.O.; MacBeth, J.W.; Sweeting, T.B.

    1987-11-01

    This topical report summarizes the ceramic component technology development activity conducted by Standard Oil Engineered Materials Company. Standard Oil, acting as a principal subcontractor and supplier of ceramic components, directed its efforts toward the development of ceramic materials in the silicon-carbide family. Various shape forming and fabrication methods, and non-destructive evaluation techniques were explored to produce the static structural components for the ceramic engine. This enabled engine testing to proceed without program slippage, and developed the approaches for producing low-cost, production quantity processes. Standard Oil contributed to the acceptance of ceramics as a viable approach for automotive gas turbine engines and to the advancement of this vital ceramic technology. 174 figs., 33 tabs.

  16. Materials Data on AgTe (SG:62) by Materials Project

    SciTech Connect

    Kristin Persson

    2014-07-09

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  17. Materials Data on AgTe2Au (SG:51) by Materials Project

    DOE Data Explorer

    Kristin Persson

    2016-02-05

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  18. Materials Data on Lu6AgTe2 (SG:62) by Materials Project

    SciTech Connect

    Kristin Persson

    2014-07-09

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  19. Generalized Jack polynomials and the AGT relations for the SU(3) group

    NASA Astrophysics Data System (ADS)

    Mironov, S.; Morozov, A.; Zenkevich, Y.

    2014-03-01

    We find generalized Jack polynomials for the SU(3) group and verify that their Selberg averages for several first levels are given by Nekrasov functions. To compute the averages, we derive recurrence relations for the Selberg integrals.

  20. The properties of conformal blocks, the AGT hypothesis, and knot polynomials

    NASA Astrophysics Data System (ADS)

    Morozov, A. A.

    2016-09-01

    Various properties of correlators of the two-dimensional conformal field theory are discussed. Specifically, their relation to the partition function of the four-dimensional supersymmetric theory is analyzed. In addition to being of interest in its own right, this relation is of practical importance. For example, it is much easier to calculate the known expressions for the partition function of supersymmetric theory than to calculate directly the expressions for correlators in conformal theory. The examined representation of conformal theory correlators as a matrix model serves the same purpose. The integral form of these correlators allows one to generalize the obtained results for the Virasoro algebra to more complicated cases of the W algebra or the quantum Virasoro algebra. This provides an opportunity to examine more complex configurations in conformal field theory. The three-dimensional Chern-Simons theory is discussed in the second part of the present review. The current interest in this theory stems largely from its relation to the mathematical knot theory (a rather well-developed area of mathematics known since the 17th century). The primary objective of this theory is to develop an algorithm that allows one to distinguish different knots (closed loops in three-dimensional space). The basic way to do this is by constructing the so-called knot invariants.

  1. Gene doping: gene delivery for olympic victory.

    PubMed

    Gould, David

    2013-08-01

    With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called 'gene doping'. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted from the engineered cells or is retained locally to, or inside engineered cells will, to some extent, determine the likelihood of detection. It is clear that effective gene delivery technologies now exist and it is important that detection and prevention plans are in place. PMID:23082866

  2. Gene doping: gene delivery for olympic victory

    PubMed Central

    Gould, David

    2013-01-01

    With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called ‘gene doping’. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted from the engineered cells or is retained locally to, or inside engineered cells will, to some extent, determine the likelihood of detection. It is clear that effective gene delivery technologies now exist and it is important that detection and prevention plans are in place. PMID:23082866

  3. Gene doping: gene delivery for olympic victory.

    PubMed

    Gould, David

    2013-08-01

    With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called 'gene doping'. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted from the engineered cells or is retained locally to, or inside engineered cells will, to some extent, determine the likelihood of detection. It is clear that effective gene delivery technologies now exist and it is important that detection and prevention plans are in place.

  4. Autism and Genes

    ERIC Educational Resources Information Center

    National Institutes of Health, 2005

    2005-01-01

    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…

  5. Compare Gene Profiles

    2014-05-31

    Compare Gene Profiles (CGP) performs pairwise gene content comparisons among a relatively large set of related bacterial genomes. CGP performs pairwise BLAST among gene calls from a set of input genome and associated annotation files, and combines the results to generate lists of common genes, unique genes, homologs, and genes from each genome that differ substantially in length from corresponding genes in the other genomes. CGP is implemented in Python and runs in a Linuxmore » environment in serial or parallel mode.« less

  6. Multiple adaptive losses of alanine-glyoxylate aminotransferase mitochondrial targeting in fruit-eating bats.

    PubMed

    Liu, Yang; Xu, Huihui; Yuan, Xinpu; Rossiter, Stephen J; Zhang, Shuyi

    2012-06-01

    The enzyme alanine-glyoxylate aminotransferase 1 (AGT) functions to detoxify glyoxylate before it is converted into harmful oxalate. In mammals, mitochondrial targeting of AGT in carnivorous species versus peroxisomal targeting in herbivores is controlled by two signal peptides that correspond to these respective organelles. Differential expression of the mitochondrial targeting sequence (MTS) is considered an adaptation to diet-specific subcellular localization of glyoxylate precursors. Bats are an excellent group in which to study adaptive changes in dietary enzymes; they show unparalleled mammalian dietary diversification as well as independent origins of carnivory, frugivory, and nectarivory. We studied the AGT gene in bats and other mammals with diverse diets and found that the MTS has been lost in unrelated lineages of frugivorous bats. Conversely, species exhibiting piscivory, carnivory, insectivory, and sanguinivory possessed intact MTSs. Detected positive selection in the AGT of ancestral fruit bats further supports adaptations related to evolutionary changes in diet.

  7. Multiple adaptive losses of alanine-glyoxylate aminotransferase mitochondrial targeting in fruit-eating bats.

    PubMed

    Liu, Yang; Xu, Huihui; Yuan, Xinpu; Rossiter, Stephen J; Zhang, Shuyi

    2012-06-01

    The enzyme alanine-glyoxylate aminotransferase 1 (AGT) functions to detoxify glyoxylate before it is converted into harmful oxalate. In mammals, mitochondrial targeting of AGT in carnivorous species versus peroxisomal targeting in herbivores is controlled by two signal peptides that correspond to these respective organelles. Differential expression of the mitochondrial targeting sequence (MTS) is considered an adaptation to diet-specific subcellular localization of glyoxylate precursors. Bats are an excellent group in which to study adaptive changes in dietary enzymes; they show unparalleled mammalian dietary diversification as well as independent origins of carnivory, frugivory, and nectarivory. We studied the AGT gene in bats and other mammals with diverse diets and found that the MTS has been lost in unrelated lineages of frugivorous bats. Conversely, species exhibiting piscivory, carnivory, insectivory, and sanguinivory possessed intact MTSs. Detected positive selection in the AGT of ancestral fruit bats further supports adaptations related to evolutionary changes in diet. PMID:22319153

  8. The ras responsive transcription factor RREB1 is a novel candidate gene for type 2 diabetes associated end-stage kidney disease.

    PubMed

    Bonomo, Jason A; Guan, Meijian; Ng, Maggie C Y; Palmer, Nicholette D; Hicks, Pamela J; Keaton, Jacob M; Lea, Janice P; Langefeld, Carl D; Freedman, Barry I; Bowden, Donald W

    2014-12-15

    Familial clustering and presumed genetic risk for type 2 diabetic (T2D) and non-diabetic end-stage kidney disease (ESKD) appear strong in African Americans. Examination of exome sequencing data in African American T2D-ESKD cases and non-diabetic non-nephropathy controls identified two low-frequency variants in the RREB1 gene, a repressor of the angiotensinogen (AGT) gene previously associated with kidney function, as being associated with T2D-ESKD: rs9379084 (P = 0.00087, OR = 0.26; D1171N) and rs41302867 (P = 0.00078, OR = 0.21; splice site variant). Rs41302867 replicated association in an independent sample of African Americans with T2D-ESKD [rs41302867 P = 0.033 (OR = 0.50)], and a trend towards rs9379084 association was observed (P = 0.070). In European Americans with T2D-ESKD compared with European American population based controls, both RREB1 variants replicated association [rs9379084 P = 1.67 × 10(-4) (OR = 0.54) and rs41302867 P = 0.013 (OR = 0.69)]. Rs9379084 was not associated with non-T2D-ESKD or T2D in African Americans (P = 0.55 and P = 0.37, respectively), but was associated with T2D in European Americans (P = 0.014, OR = 0.65). In African Americans, rs41302867 was associated with non-T2D-ESKD [P = 0.036 (OR = 0.54)] and hypertension attributed ESKD [H-ESKD, P = 0.029 (OR = 0.50)]. A meta-analysis combining African American and European American T2D-ESKD data revealed P = 3.52 × 10(-7) and 3.70 × 10(-5) for rs9379084 and rs41302867 association, respectfully. A locus-wide analysis evaluating putatively functional SNPs revealed several nominal associations with T2D-ESKD, non-T2D-ESKD and T2D in African and European Americans. RREB1 is a large, complex gene which codes a multidomain zinc finger binding protein and transcription factor. We posit that variants in RREB1 modulate seemingly disparate phenotypes (i.e. T2D, T2D-ESKD and non-T2D-ESKD) through altered activity resulting from splice site and missense variants. PMID:25027322

  9. The ras responsive transcription factor RREB1 is a novel candidate gene for type 2 diabetes associated end-stage kidney disease

    PubMed Central

    Bonomo, Jason A.; Guan, Meijian; Ng, Maggie C.Y.; Palmer, Nicholette D.; Hicks, Pamela J.; Keaton, Jacob M.; Lea, Janice P.; Langefeld, Carl D.; Freedman, Barry I.; Bowden, Donald W.

    2014-01-01

    Familial clustering and presumed genetic risk for type 2 diabetic (T2D) and non-diabetic end-stage kidney disease (ESKD) appear strong in African Americans. Examination of exome sequencing data in African American T2D-ESKD cases and non-diabetic non-nephropathy controls identified two low-frequency variants in the RREB1 gene, a repressor of the angiotensinogen (AGT) gene previously associated with kidney function, as being associated with T2D-ESKD: rs9379084 (P = 0.00087, OR = 0.26; D1171N) and rs41302867 (P = 0.00078, OR = 0.21; splice site variant). Rs41302867 replicated association in an independent sample of African Americans with T2D-ESKD [rs41302867 P = 0.033 (OR = 0.50)], and a trend towards rs9379084 association was observed (P = 0.070). In European Americans with T2D-ESKD compared with European American population based controls, both RREB1 variants replicated association [rs9379084 P = 1.67 × 10−4 (OR = 0.54) and rs41302867 P = 0.013 (OR = 0.69)]. Rs9379084 was not associated with non-T2D-ESKD or T2D in African Americans (P = 0.55 and P = 0.37, respectively), but was associated with T2D in European Americans (P = 0.014, OR = 0.65). In African Americans, rs41302867 was associated with non-T2D-ESKD [P = 0.036 (OR = 0.54)] and hypertension attributed ESKD [H-ESKD, P = 0.029 (OR = 0.50)]. A meta-analysis combining African American and European American T2D-ESKD data revealed P = 3.52 × 10−7 and 3.70 × 10−5 for rs9379084 and rs41302867 association, respectfully. A locus-wide analysis evaluating putatively functional SNPs revealed several nominal associations with T2D-ESKD, non-T2D-ESKD and T2D in African and European Americans. RREB1 is a large, complex gene which codes a multidomain zinc finger binding protein and transcription factor. We posit that variants in RREB1 modulate seemingly disparate phenotypes (i.e. T2D, T2D-ESKD and non-T2D-ESKD) through altered activity resulting from splice site and missense variants. PMID:25027322

  10. The ras responsive transcription factor RREB1 is a novel candidate gene for type 2 diabetes associated end-stage kidney disease.

    PubMed

    Bonomo, Jason A; Guan, Meijian; Ng, Maggie C Y; Palmer, Nicholette D; Hicks, Pamela J; Keaton, Jacob M; Lea, Janice P; Langefeld, Carl D; Freedman, Barry I; Bowden, Donald W

    2014-12-15

    Familial clustering and presumed genetic risk for type 2 diabetic (T2D) and non-diabetic end-stage kidney disease (ESKD) appear strong in African Americans. Examination of exome sequencing data in African American T2D-ESKD cases and non-diabetic non-nephropathy controls identified two low-frequency variants in the RREB1 gene, a repressor of the angiotensinogen (AGT) gene previously associated with kidney function, as being associated with T2D-ESKD: rs9379084 (P = 0.00087, OR = 0.26; D1171N) and rs41302867 (P = 0.00078, OR = 0.21; splice site variant). Rs41302867 replicated association in an independent sample of African Americans with T2D-ESKD [rs41302867 P = 0.033 (OR = 0.50)], and a trend towards rs9379084 association was observed (P = 0.070). In European Americans with T2D-ESKD compared with European American population based controls, both RREB1 variants replicated association [rs9379084 P = 1.67 × 10(-4) (OR = 0.54) and rs41302867 P = 0.013 (OR = 0.69)]. Rs9379084 was not associated with non-T2D-ESKD or T2D in African Americans (P = 0.55 and P = 0.37, respectively), but was associated with T2D in European Americans (P = 0.014, OR = 0.65). In African Americans, rs41302867 was associated with non-T2D-ESKD [P = 0.036 (OR = 0.54)] and hypertension attributed ESKD [H-ESKD, P = 0.029 (OR = 0.50)]. A meta-analysis combining African American and European American T2D-ESKD data revealed P = 3.52 × 10(-7) and 3.70 × 10(-5) for rs9379084 and rs41302867 association, respectfully. A locus-wide analysis evaluating putatively functional SNPs revealed several nominal associations with T2D-ESKD, non-T2D-ESKD and T2D in African and European Americans. RREB1 is a large, complex gene which codes a multidomain zinc finger binding protein and transcription factor. We posit that variants in RREB1 modulate seemingly disparate phenotypes (i.e. T2D, T2D-ESKD and non-T2D-ESKD) through altered activity resulting from splice site and missense variants.

  11. [Genes associated to cancer].

    PubMed

    Peralta-Rodríguez, Raúl; Valdivia, Alejandra; Mendoza, Mónica; Rodríguez, Jade; Marrero, Daniel; Paniagua, Lucero; Romero, Pablo; Taniguchi, Keiko; Salcedo, Mauricio

    2015-01-01

    In 2010, in a cancer genes census, 291 genes were enumerated. These represent near to the 1 % of the total genes, for which there is enough biological evidence that they belong to a new genes classification, known as the cancer genes. These have been defined as the causal genes for sporadic or familiar cancer, when they mutate. The mutation types for these genes includes amplifications, point mutations, deletions, genomic rearranges, amongst others, which lead to a protein over-expression, muting, production of chimeric proteins or a de novo expression. In conjunction these genomic alterations or those of the genetic expression, when they affect specific genes which contribute to the development of cancer, are denominated as cancer genes. It is possible that the list of these alterations will grow longer due to new strategies being developed, for example, the genomic analysis.

  12. Gene doping in sports.

    PubMed

    Unal, Mehmet; Ozer Unal, Durisehvar

    2004-01-01

    Gene or cell doping is defined by the World Anti-Doping Agency (WADA) as "the non-therapeutic use of genes, genetic elements and/or cells that have the capacity to enhance athletic performance". New research in genetics and genomics will be used not only to diagnose and treat disease, but also to attempt to enhance human performance. In recent years, gene therapy has shown progress and positive results that have highlighted the potential misuse of this technology and the debate of 'gene doping'. Gene therapies developed for the treatment of diseases such as anaemia (the gene for erythropoietin), muscular dystrophy (the gene for insulin-like growth factor-1) and peripheral vascular diseases (the gene for vascular endothelial growth factor) are potential doping methods. With progress in gene technology, many other genes with this potential will be discovered. For this reason, it is important to develop timely legal regulations and to research the field of gene doping in order to develop methods of detection. To protect the health of athletes and to ensure equal competitive conditions, the International Olympic Committee, WADA and International Sports Federations have accepted performance-enhancing substances and methods as being doping, and have forbidden them. Nevertheless, the desire to win causes athletes to misuse these drugs and methods. This paper reviews the current status of gene doping and candidate performance enhancement genes, and also the use of gene therapy in sports medicine and ethics of genetic enhancement.

  13. Human Gene Therapy: Genes without Frontiers?

    ERIC Educational Resources Information Center

    Simon, Eric J.

    2002-01-01

    Describes the latest advancements and setbacks in human gene therapy to provide reference material for biology teachers to use in their science classes. Focuses on basic concepts such as recombinant DNA technology, and provides examples of human gene therapy such as severe combined immunodeficiency syndrome, familial hypercholesterolemia, and…

  14. Myocardial gene therapy

    NASA Astrophysics Data System (ADS)

    Isner, Jeffrey M.

    2002-01-01

    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.

  15. Evolution of Gene Expression after Gene Amplification

    PubMed Central

    Garcia, Nelson; Zhang, Wei; Wu, Yongrui; Messing, Joachim

    2015-01-01

    We took a rather unique approach to investigate the conservation of gene expression of prolamin storage protein genes across two different subfamilies of the Poaceae. We took advantage of oat plants carrying single maize chromosomes in different cultivars, called oat–maize addition (OMA) lines, which permitted us to determine whether regulation of gene expression was conserved between the two species. We found that γ-zeins are expressed in OMA7.06, which carries maize chromosome 7 even in the absence of the trans-acting maize prolamin-box-binding factor (PBF), which regulates their expression. This is likely because oat PBF can substitute for the function of maize PBF as shown in our transient expression data, using a γ-zein promoter fused to green fluorescent protein (GFP). Despite this conservation, the younger, recently amplified prolamin genes in maize, absent in oat, are not expressed in the corresponding OMAs. However, maize can express the oldest prolamin gene, the wheat high-molecular weight glutenin Dx5 gene, even when maize Pbf is knocked down (through PbfRNAi), and/or another maize transcription factor, Opaque-2 (O2) is knocked out (in maize o2 mutant). Therefore, older genes are conserved in their regulation, whereas younger ones diverged during evolution and eventually acquired a new repertoire of suitable transcriptional activators. PMID:25912045

  16. Reading and Generalist Genes

    ERIC Educational Resources Information Center

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

    2007-01-01

    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…

  17. CEST MRI reporter genes.

    PubMed

    Liu, Guanshu; Bulte, Jeff W M; Gilad, Assaf A

    2011-01-01

    In recent years, several reporter genes have been developed that can serve as a beacon for non-invasive magnetic resonance imaging (MRI). Here, we provide a brief summary of recent advances in MRI reporter gene technology, as well as detailed "hands-on" protocols for cloning, expression, and imaging of reporter genes based on chemical exchange saturation transfer (CEST).

  18. Gene hunting in autoinflammation

    PubMed Central

    2013-01-01

    Steady progress in our understanding of the genetic basis of autoinflammatory diseases has been made over the past 16 years. Since the discovery of the familial Mediterranean fever gene MEFV (also known as marenostrin) in 1997, 18 other genes responsible for monogenic autoinflammatory diseases have been identified to date. The discovery of these genes was made through the utilisation of many genetic mapping techniques, including next generation sequencing platforms. This review article clearly describes the gene hunting approaches, methods of data analysis and the technological platforms used, which has relevance to all those working within the field of gene discovery for Mendelian disorders. PMID:24070009

  19. Human disease genes.

    PubMed

    Jimenez-Sanchez, G; Childs, B; Valle, D

    2001-02-15

    The complete human genome sequence will facilitate the identification of all genes that contribute to disease. We propose that the functional classification of disease genes and their products will reveal general principles of human disease. We have determined functional categories for nearly 1,000 documented disease genes, and found striking correlations between the function of the gene product and features of disease, such as age of onset and mode of inheritance. As knowledge of disease genes grows, including those contributing to complex traits, more sophisticated analyses will be possible; their results will yield a deeper understanding of disease and an enhanced integration of medicine with biology.

  20. Journey from Jumping Genes to Gene Therapy.

    PubMed

    Whartenby, Katharine A

    2015-01-01

    Gene therapy for cancer is a still evolving approach that resulted from a long history of studies into genetic modification of organisms. The fascination with manipulating gene products has spanned hundreds if not thousands of years, beginning with observations of the hereditary nature of traits in plants and culminating to date in the alteration of genetic makeup in humans via modern technology. From early discoveries noting the potential for natural mobility of genetic material to the culmination of clinical trials in a variety of disease, gene transfer has had an eventful and sometimes tumultuous course. Within the present review is a brief history of the biology of gene transfer, how it came to be applied to genetic diseases, and its early applications to cancer therapies. Some of the different types of methods used to modify cells, the theories behind the approaches, and some of the limitations encountered along the way are reviewed. PMID:27279244

  1. Regulated Gene Therapy.

    PubMed

    Breger, Ludivine; Wettergren, Erika Elgstrand; Quintino, Luis; Lundberg, Cecilia

    2016-01-01

    Gene therapy represents a promising approach for the treatment of monogenic and multifactorial neurological disorders. It can be used to replace a missing gene and mutated gene or downregulate a causal gene. Despite the versatility of gene therapy, one of the main limitations lies in the irreversibility of the process: once delivered to target cells, the gene of interest is constitutively expressed and cannot be removed. Therefore, efficient, safe and long-term gene modification requires a system allowing fine control of transgene expression.Different systems have been developed over the past decades to regulate transgene expression after in vivo delivery, either at transcriptional or post-translational levels. The purpose of this chapter is to give an overview on current regulatory system used in the context of gene therapy for neurological disorders. Systems using external regulation of transgenes using antibiotics are commonly used to control either gene expression using tetracycline-controlled transcription or protein levels using destabilizing domain technology. Alternatively, specific promoters of genes that are regulated by disease mechanisms, increasing expression as the disease progresses or decreasing expression as disease regresses, are also examined. Overall, this chapter discusses advantages and drawbacks of current molecular methods for regulated gene therapy in the central nervous system.

  2. Gene conversion in human rearranged immunoglobulin genes.

    PubMed

    Darlow, John M; Stott, David I

    2006-07-01

    Over the past 20 years, many DNA sequences have been published suggesting that all or part of the V(H) segment of a rearranged immunoglobulin gene may be replaced in vivo. Two different mechanisms appear to be operating. One of these is very similar to primary V(D)J recombination, involving the RAG proteins acting upon recombination signal sequences, and this has recently been proven to occur. Other sequences, many of which show partial V(H) replacements with no addition of untemplated nucleotides at the V(H)-V(H) joint, have been proposed to occur by an unusual RAG-mediated recombination with the formation of hybrid (coding-to-signal) joints. These appear to occur in cells already undergoing somatic hypermutation in which, some authors are convinced, RAG genes are silenced. We recently proposed that the latter type of V(H) replacement might occur by homologous recombination initiated by the activity of AID (activation-induced cytidine deaminase), which is essential for somatic hypermutation and gene conversion. The latter has been observed in other species, but not in human Ig genes, so far. In this paper, we present a new analysis of sequences published as examples of the second type of rearrangement. This not only shows that AID recognition motifs occur in recombination regions but also that some sequences show replacement of central sections by a sequence from another gene, similar to gene conversion in the immunoglobulin genes of other species. These observations support the proposal that this type of rearrangement is likely to be AID-mediated rather than RAG-mediated and is consistent with gene conversion.

  3. Retrieval with gene queries

    PubMed Central

    Sehgal, Aditya K; Srinivasan, Padmini

    2006-01-01

    Background Accuracy of document retrieval from MEDLINE for gene queries is crucially important for many applications in bioinformatics. We explore five information retrieval-based methods to rank documents retrieved by PubMed gene queries for the human genome. The aim is to rank relevant documents higher in the retrieved list. We address the special challenges faced due to ambiguity in gene nomenclature: gene terms that refer to multiple genes, gene terms that are also English words, and gene terms that have other biological meanings. Results Our two baseline ranking strategies are quite similar in performance. Two of our three LocusLink-based strategies offer significant improvements. These methods work very well even when there is ambiguity in the gene terms. Our best ranking strategy offers significant improvements on three different kinds of ambiguities over our two baseline strategies (improvements range from 15.9% to 17.7% and 11.7% to 13.3% depending on the baseline). For most genes the best ranking query is one that is built from the LocusLink (now Entrez Gene) summary and product information along with the gene names and aliases. For others, the gene names and aliases suffice. We also present an approach that successfully predicts, for a given gene, which of these two ranking queries is more appropriate. Conclusion We explore the effect of different post-retrieval strategies on the ranking of documents returned by PubMed for human gene queries. We have successfully applied some of these strategies to improve the ranking of relevant documents in the retrieved sets. This holds true even when various kinds of ambiguity are encountered. We feel that it would be very useful to apply strategies like ours on PubMed search results as these are not ordered by relevance in any way. This is especially so for queries that retrieve a large number of documents. PMID:16630348

  4. Oncogenes, genes, and growth factors

    SciTech Connect

    Guroff, G.

    1989-01-01

    This book contains 12 chapters. Some of the chapter titles are: The Epidermal Growth Factor Receptor Gene; Structure and Expression of the Nerve Growth Factor Gene; The Erythropoietin Gene; The Interleukin-2 Gene; The Transferrin Gene; and The Transferrin Receptor Gene.

  5. Do Housekeeping Genes Exist?

    PubMed Central

    Sun, Bingyun

    2015-01-01

    The searching of human housekeeping (HK) genes has been a long quest since the emergence of transcriptomics, and is instrumental for us to understand the structure of genome and the fundamentals of biological processes. The resolved genes are frequently used in evolution studies and as normalization standards in quantitative gene-expression analysis. Within the past 20 years, more than a dozen HK-gene studies have been conducted, yet none of them sampled human tissues completely. We believe an integration of these results will help remove false positive genes owing to the inadequate sampling. Surprisingly, we only find one common gene across 15 examined HK-gene datasets comprising 187 different tissue and cell types. Our subsequent analyses suggest that it might not be appropriate to rigidly define HK genes as expressed in all tissue types that have diverse developmental, physiological, and pathological states. It might be beneficial to use more robustly identified HK functions for filtering criteria, in which the representing genes can be a subset of genome. These genes are not necessarily the same, and perhaps need not to be the same, everywhere in our body. PMID:25970694

  6. Do housekeeping genes exist?

    PubMed

    Zhang, Yijuan; Li, Ding; Sun, Bingyun

    2015-01-01

    The searching of human housekeeping (HK) genes has been a long quest since the emergence of transcriptomics, and is instrumental for us to understand the structure of genome and the fundamentals of biological processes. The resolved genes are frequently used in evolution studies and as normalization standards in quantitative gene-expression analysis. Within the past 20 years, more than a dozen HK-gene studies have been conducted, yet none of them sampled human tissues completely. We believe an integration of these results will help remove false positive genes owing to the inadequate sampling. Surprisingly, we only find one common gene across 15 examined HK-gene datasets comprising 187 different tissue and cell types. Our subsequent analyses suggest that it might not be appropriate to rigidly define HK genes as expressed in all tissue types that have diverse developmental, physiological, and pathological states. It might be beneficial to use more robustly identified HK functions for filtering criteria, in which the representing genes can be a subset of genome. These genes are not necessarily the same, and perhaps need not to be the same, everywhere in our body. PMID:25970694

  7. Towards Consensus Gene Ages.

    PubMed

    Liebeskind, Benjamin J; McWhite, Claire D; Marcotte, Edward M

    2016-01-01

    Correctly estimating the age of a gene or gene family is important for a variety of fields, including molecular evolution, comparative genomics, and phylogenetics, and increasingly for systems biology and disease genetics. However, most studies use only a point estimate of a gene's age, neglecting the substantial uncertainty involved in this estimation. Here, we characterize this uncertainty by investigating the effect of algorithm choice on gene-age inference and calculate consensus gene ages with attendant error distributions for a variety of model eukaryotes. We use 13 orthology inference algorithms to create gene-age datasets and then characterize the error around each age-call on a per-gene and per-algorithm basis. Systematic error was found to be a large factor in estimating gene age, suggesting that simple consensus algorithms are not enough to give a reliable point estimate. We also found that different sources of error can affect downstream analyses, such as gene ontology enrichment. Our consensus gene-age datasets, with associated error terms, are made fully available at so that researchers can propagate this uncertainty through their analyses (geneages.org). PMID:27259914

  8. Human HOX gene disorders.

    PubMed

    Quinonez, Shane C; Innis, Jeffrey W

    2014-01-01

    The Hox genes are an evolutionarily conserved family of genes, which encode a class of important transcription factors that function in numerous developmental processes. Following their initial discovery, a substantial amount of information has been gained regarding the roles Hox genes play in various physiologic and pathologic processes. These processes range from a central role in anterior-posterior patterning of the developing embryo to roles in oncogenesis that are yet to be fully elucidated. In vertebrates there are a total of 39 Hox genes divided into 4 separate clusters. Of these, mutations in 10 Hox genes have been found to cause human disorders with significant variation in their inheritance patterns, penetrance, expressivity and mechanism of pathogenesis. This review aims to describe the various phenotypes caused by germline mutation in these 10 Hox genes that cause a human phenotype, with specific emphasis paid to the genotypic and phenotypic differences between allelic disorders. As clinical whole exome and genome sequencing is increasingly utilized in the future, we predict that additional Hox gene mutations will likely be identified to cause distinct human phenotypes. As the known human phenotypes closely resemble gene-specific murine models, we also review the homozygous loss-of-function mouse phenotypes for the 29 Hox genes without a known human disease. This review will aid clinicians in identifying and caring for patients affected with a known Hox gene disorder and help recognize the potential for novel mutations in patients with phenotypes informed by mouse knockout studies.

  9. Notch signaling genes

    PubMed Central

    Terragni, Jolyon; Zhang, Guoqiang; Sun, Zhiyi; Pradhan, Sriharsa; Song, Lingyun; Crawford, Gregory E; Lacey, Michelle; Ehrlich, Melanie

    2014-01-01

    Notch intercellular signaling is critical for diverse developmental pathways and for homeostasis in various types of stem cells and progenitor cells. Because Notch gene products need to be precisely regulated spatially and temporally, epigenetics is likely to help control expression of Notch signaling genes. Reduced representation bisulfite sequencing (RRBS) indicated significant hypomethylation in myoblasts, myotubes, and skeletal muscle vs. many nonmuscle samples at intragenic or intergenic regions of the following Notch receptor or ligand genes: NOTCH1, NOTCH2, JAG2, and DLL1. An enzymatic assay of sites in or near these genes revealed unusually high enrichment of 5-hydroxymethylcytosine (up to 81%) in skeletal muscle, heart, and cerebellum. Epigenetics studies and gene expression profiles suggest that hypomethylation and/or hydroxymethylation help control expression of these genes in heart, brain, myoblasts, myotubes, and within skeletal muscle myofibers. Such regulation could promote cell renewal, cell maintenance, homeostasis, and a poised state for repair of tissue damage. PMID:24670287

  10. Gene therapy for radioprotection.

    PubMed

    Everett, W H; Curiel, D T

    2015-03-01

    Radiation therapy is a critical component of cancer treatment with over half of patients receiving radiation during their treatment. Despite advances in image-guided therapy and dose fractionation, patients receiving radiation therapy are still at risk for side effects due to off-target radiation damage of normal tissues. To reduce normal tissue damage, researchers have sought radioprotectors, which are agents capable of protecting tissue against radiation by preventing radiation damage from occurring or by decreasing cell death in the presence of radiation damage. Although much early research focused on small-molecule radioprotectors, there has been a growing interest in gene therapy for radioprotection. The amenability of gene therapy vectors to targeting, as well as the flexibility of gene therapy to accomplish ablation or augmentation of biologically relevant genes, makes gene therapy an excellent strategy for radioprotection. Future improvements to vector targeting and delivery should greatly enhance radioprotection through gene therapy.

  11. Towards Consensus Gene Ages

    PubMed Central

    Liebeskind, Benjamin J.; McWhite, Claire D.; Marcotte, Edward M.

    2016-01-01

    Correctly estimating the age of a gene or gene family is important for a variety of fields, including molecular evolution, comparative genomics, and phylogenetics, and increasingly for systems biology and disease genetics. However, most studies use only a point estimate of a gene’s age, neglecting the substantial uncertainty involved in this estimation. Here, we characterize this uncertainty by investigating the effect of algorithm choice on gene-age inference and calculate consensus gene ages with attendant error distributions for a variety of model eukaryotes. We use 13 orthology inference algorithms to create gene-age datasets and then characterize the error around each age-call on a per-gene and per-algorithm basis. Systematic error was found to be a large factor in estimating gene age, suggesting that simple consensus algorithms are not enough to give a reliable point estimate. We also found that different sources of error can affect downstream analyses, such as gene ontology enrichment. Our consensus gene-age datasets, with associated error terms, are made fully available at so that researchers can propagate this uncertainty through their analyses (geneages.org). PMID:27259914

  12. Supervised clustering of genes

    PubMed Central

    Dettling, Marcel; Bühlmann, Peter

    2002-01-01

    Background We focus on microarray data where experiments monitor gene expression in different tissues and where each experiment is equipped with an additional response variable such as a cancer type. Although the number of measured genes is in the thousands, it is assumed that only a few marker components of gene subsets determine the type of a tissue. Here we present a new method for finding such groups of genes by directly incorporating the response variables into the grouping process, yielding a supervised clustering algorithm for genes. Results An empirical study on eight publicly available microarray datasets shows that our algorithm identifies gene clusters with excellent predictive potential, often superior to classification with state-of-the-art methods based on single genes. Permutation tests and bootstrapping provide evidence that the output is reasonably stable and more than a noise artifact. Conclusions In contrast to other methods such as hierarchical clustering, our algorithm identifies several gene clusters whose expression levels clearly distinguish the different tissue types. The identification of such gene clusters is potentially useful for medical diagnostics and may at the same time reveal insights into functional genomics. PMID:12537558

  13. Integron associated mobile genes

    PubMed Central

    Labbate, Maurizio; Boucher, Yan; Luu, Ivan; Chowdhury, Piklu Roy; Stokes, H.W.

    2012-01-01

    Lateral gene transfer (LGT) impacts on the evolution of prokaryotes in both the short and long-term. The short-term impacts of mobilized genes are a concern to humans since LGT explains the global rise of multi drug resistant pathogens seen in the past 70 years. However, LGT has been a feature of prokaryotes from the earliest days of their existence and the concept of a bifurcating tree of life is not entirely applicable to prokaryotes since most genes in extant prokaryotic genomes have probably been acquired from other lineages. Successful transfer and maintenance of a gene in a new host is understandable if it acts independently of cell networks and confers an advantage. Antibiotic resistance provides an example of this whereby a gene can be advantageous in virtually any cell across broad species backgrounds. In a longer evolutionary context however laterally transferred genes can be assimilated into even essential cell networks. How this happens is not well understood and we discuss recent work that identifies a mobile gene, unique to a cell lineage, which is detrimental to the cell when lost. We also present some additional data and believe our emerging model will be helpful in understanding how mobile genes integrate into cell networks. PMID:22754748

  14. Your Genes, Your Choices

    MedlinePlus

    Table of Contents Your Genes, Your Choices describes the Human Genome Project, the science behind it, and the ethical, legal, and social issues that are ... Nothing could be further from the truth. Your Genes, Your Choices points out how the progress of ...

  15. What Is a Gene?

    MedlinePlus

    ... a new kind of medicine — so new that scientists are still doing experiments to see if it works. It uses the technology of genetic engineering to treat a disease caused by a gene that has changed in some way. One method being tested is replacing sick genes with healthy ...

  16. Engineered gene circuits

    NASA Astrophysics Data System (ADS)

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

    2002-11-01

    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.

  17. A gene expression screen.

    PubMed Central

    Wang, Z; Brown, D D

    1991-01-01

    A gene expression screen identifies mRNAs that differ in abundance between two mRNA mixtures by a subtractive hybridization method. The two mRNA populations are converted to double-stranded cDNAs, fragmented, and ligated to linkers for polymerase chain reaction (PCR) amplification. The multiple cDNA fragments isolated from any given gene can be treated as alleles in a genetic screen. Probability analysis of the frequency with which multiple alleles are found provides an estimation of the total number of up- and down-regulated genes. We have applied this method to genes that are differentially expressed in amphibian tadpole tail tissue in the first 24 hr after thyroid hormone treatment, which ultimately induces tail resorption. We estimate that there are about 30 up-regulated genes; 16 have been isolated. Images PMID:1722336

  18. Autophagy genes in immunity

    PubMed Central

    Virgin, Herbert W; Levine, Beth

    2009-01-01

    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. PMID:19381141

  19. Genes, genome and Gestalt.

    PubMed

    Grisolia, Cesar Koppe

    2005-01-01

    According to Gestalt thinking, biological systems cannot be viewed as the sum of their elements, but as processes of the whole. To understand organisms we must start from the whole, observing how the various parts are related. In genetics, we must observe the genome over and above the sum of its genes. Either loss or addition of one gene in a genome can change the function of the organism. Genomes are organized in networks of genes, which need to be well integrated. In the case of genetically modified organisms (GMOs), for example, soybeans, rats, Anopheles mosquitoes, and pigs, the insertion of an exogenous gene into a receptive organism generally causes disturbance in the networks, resulting in the breakdown of gene interactions. In these cases, genetic modification increased the genetic load of the GMO and consequently decreased its adaptability (fitness). Therefore, it is hard to claim that the production of such organisms with an increased genetic load does not have ethical implications.

  20. 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

  1. Duplicate genes increase gene expression diversity within and between species.

    PubMed

    Gu, Zhenglong; Rifkin, Scott A; White, Kevin P; Li, Wen-Hsiung

    2004-06-01

    Using microarray gene expression data from several Drosophila species and strains, we show that duplicated genes, compared with single-copy genes, significantly increase gene expression diversity during development. We show further that duplicate genes tend to cause expression divergences between Drosophila species (or strains) to evolve faster than do single-copy genes. This conclusion is also supported by data from different yeast strains.

  2. [Is gene technology immoral?].

    PubMed

    Halter, H

    1994-10-01

    Since it came into being in the USA in the early 1970s, gene technology has always been fundamentally controversial, especially in the German-speaking countries. The optimistic--or critical--supporters of gene technology are convinced that, in view of gene technology's not otherwise attainable advantages for human and animal health, for food production and other important aims, it would be ethically unacceptable to restrict to the minimum or even ban it. On the other hand, the radical critics are convinced that gene technology, in view of its anthropologically false starting-point, the questionable interests behind it, and above all its unforeseeable, serious negative implications for mankind and environment, is unacceptable on ethical grounds. Critical reflexion on these polarized arguments must start from the question why precisely gene technology is so controversial, and what are the criteria for ethical assessment. These reflexions presuppose that the prior judgement of gene technology as a technology in the ideological field is rooted in life attitudes, history and nature in general, and this is true not only of gene technology's opponents but also its supporters. It is thus a question of one ideology vs. another. Chief importance here attaches to the mankind-nature relationship and the need to take seriously the fundamental ambivalence of all (!) human action with unforeseeable consequences. The conclusion is that neither to demonize nor to glorify gene technology, as a matter of principle, does justice to its wide and varied positive or negative potential. The ethical assessment of gene technology must be differentiated according to the aims and possible implications.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7939540

  3. Clock genes and cancer.

    PubMed

    Wood, Patricia A; Yang, Xiaoming; Hrushesky, William J M

    2009-12-01

    Period genes ( Per2, Per1) are essential circadian clock genes. They also function as negative growth regulators. Per2 mutant mice show de novo and radiation-induced epithelial hyperplasia, tumors, and an abnormal DNA damage response. Human tumors show Period gene mutations or decreased expression. Other murine clock gene mutations are not associated with a tumor prone phenotype. Shift work and nocturnal light exposure are associated with circadian clock disruption and with increased cancer risk. The mechanisms responsible for the connection between the circadian clock and cancer are not well defined. We propose that circadian disruption per se is not uniformly tumor promoting and the mechanisms for tumor promotion by specific circadian clock disturbances will differ dependent upon the genes and pathways involved. We propose that Period clock gene mutations promote tumorigenesis by unique molecular pathways. Per2 and Per1 modulate beta-catenin and cell proliferation in colon and non-colon cancer cells. Per2 mutation increases intestinal beta-catenin levels and colon polyp formation. Per2 mutation also increases Apc(Min/+)-mediated intestinal and colonic polyp formation. Intestinal tumorigenesis per se may also alter clock function as a result of increased beta-catenin destabilizing PER2 protein. Levels and circadian rhythm of PER2 in Apc(Min/+) mouse intestine are markedly decreased, and selective abnormalities in intestinal clock gene and clock-controlled gene expression are seen. We propose that tumor promotion by loss of PERIOD clock proteins is unique to these clock genes as a result of altered beta-catenin signaling and DNA damage response. PERIOD proteins may offer new targets for cancer prevention and control.

  4. Genes in sweeping competition.

    PubMed

    Nurminsky, D I

    2001-01-01

    Analysis of DNA variation is a powerful tool for detecting adaptation at the genomic level. The contribution of adaptive evolution is evident from examples of rapidly evolving genes, which represent the likely targets for strong selection. More subtle adaptation is also an integral component of routine maintenance of gene performance, continuously applied to every gene. Adaptive changes in the population are accomplished through selective sweeps, i.e. complete or partial fixation of beneficial alleles. The evidence is accumulating that selective sweeps are quite frequent events which, together with associated genetic hitchhiking, represent dominant forces that influence molecular evolution by shaping the variability pattern in the genome.

  5. Modulation of renin angiotensin system predominantly alters sclerotic phenotype of glomeruli in HIVAN.

    PubMed

    Plagov, Andrei; Lan, Xiqian; Rai, Partab; Kumar, Dileep; Lederman, Rivka; Rehman, Shabina; Malhotra, Ashwani; Ding, Guohua; Chander, Praveen N; Singhal, Pravin C

    2014-12-01

    HIV-associated nephropathy (HIVAN) is a common complication of HIV-1 infection in patients with African ancestry in general and with APOL1 gene risk variants in particular. Although collapsing glomerulopathy is considered a hallmark of HIVAN, significant numbers of glomeruli in patients with HIVAN also display other variants of focal segmental glomerulosclerosis (FSGS). We propose that collapsed glomeruli as well as glomeruli with other variants of FSGS are manifestations of HIVAN and their prevalence depends on associated host factors. We explored the role of the renin-angiotensin system (RAS) in the manifestation of any specific glomerular phenotype in HIVAN. To evaluate the role of the RAS we have used a genetically engineered mouse model of HIVAN (Tg26) with two and four copies of angiotensinogen (Agt) gene (Tg26/Agt2 and Tg26/Agt4). In Tg26/Agt2, 1 out of 6 glomeruli exhibited sclerosed phenotype, whereas 1 out of 25 glomeruli displayed collapsed phenotype; on the other hand, in Tg26/Agt4, 1 out of 3 glomeruli exhibited sclerotic phenotype and only 1 out of 7 glomeruli showed collapsed phenotype. To inhibit the effect of RAS, Tg26/Agt2 were administered captopril, aliskiren, aliskiren plus captopril or aliskiren plus telmisartan by miniosmotic pumps for 4 weeks. In all experimental groups there was a significant reduction in percentage of sclerosed glomeruli and only minimal reduction in collapsed glomeruli compared to normal saline receiving Tg26/Agt2. These findings suggest that the manifestation of the sclerosed phenotype in HIVAN is predominantly dependent on activation of the RAS. PMID:24892944

  6. Gene structure and expression

    SciTech Connect

    Hawkins, J. )

    1990-01-01

    This book describes the structure of genes in molecular terms and summarizes present knowledge about how their activity is regulated. It covers a range of topics, including a review of the structure and replication of DNA, transcription and translation, prokaryotic and eukaryotic gene organization and expression, retroviruses and oncogenes. The book also includes a chapter on the methodology of DNA manipulation including sections on site-directed mutagenesis, the polymerase chain reaction, reporter genes and restriction fragment length polymorphisms. The hemoglobin gene system and the genetics of the proteins of the immune system are presented in the latter half of the book to show the structure and expression of the most well-studied systems in higher eukaryotes. The final chapter reviews the differences between prokaryotic and the eukaryotic genomes.

  7. GeneLab

    NASA Technical Reports Server (NTRS)

    Berrios, Daniel C.; Thompson, Terri G.

    2015-01-01

    NASA GeneLab is expected to capture and distribute omics data and experimental and process conditions most relevant to research community in their statistical and theoretical analysis of NASAs omics data.

  8. Epigenetics and gene expression.

    PubMed

    Gibney, E R; Nolan, C M

    2010-07-01

    Transcription, translation and subsequent protein modification represent the transfer of genetic information from the archival copy of DNA to the short-lived messenger RNA, usually with subsequent production of protein. Although all cells in an organism contain essentially the same DNA, cell types and functions differ because of qualitative and quantitative differences in their gene expression. Thus, control of gene expression is at the heart of differentiation and development. Epigenetic processes, including DNA methylation, histone modification and various RNA-mediated processes, are thought to influence gene expression chiefly at the level of transcription; however, other steps in the process (for example, translation) may also be regulated epigenetically. The following paper will outline the role epigenetics is believed to have in influencing gene expression.

  9. "Bad genes" & criminal responsibility.

    PubMed

    González-Tapia, María Isabel; Obsuth, Ingrid

    2015-01-01

    The genetics of the accused is trying to break into the courts. To date several candidate genes have been put forward and their links to antisocial behavior have been examined and documented with some consistency. In this paper, we focus on the so called "warrior gene", or the low-activity allele of the MAOA gene, which has been most consistently related to human behavior and specifically to violence and antisocial behavior. In preparing this paper we had two objectives. First, to summarize and analyze the current scientific evidence, in order to gain an in depth understanding of the state of the issue and determine whether a dominant line of generally accepted scientific knowledge in this field can be asserted. Second, to derive conclusions and put forward recommendations related to the use of genetic information, specifically the presence of the low-activity genotype of the MAOA gene, in modulation of criminal responsibility in European and US courts.

  10. "Bad genes" & criminal responsibility.

    PubMed

    González-Tapia, María Isabel; Obsuth, Ingrid

    2015-01-01

    The genetics of the accused is trying to break into the courts. To date several candidate genes have been put forward and their links to antisocial behavior have been examined and documented with some consistency. In this paper, we focus on the so called "warrior gene", or the low-activity allele of the MAOA gene, which has been most consistently related to human behavior and specifically to violence and antisocial behavior. In preparing this paper we had two objectives. First, to summarize and analyze the current scientific evidence, in order to gain an in depth understanding of the state of the issue and determine whether a dominant line of generally accepted scientific knowledge in this field can be asserted. Second, to derive conclusions and put forward recommendations related to the use of genetic information, specifically the presence of the low-activity genotype of the MAOA gene, in modulation of criminal responsibility in European and US courts. PMID:25708001

  11. Vaginal gene therapy.

    PubMed

    Rodríguez-Gascón, Alicia; Del Pozo-Rodríguez, Ana; Isla, Arantxazu; Solinís, María Angeles

    2015-09-15

    In the last years, vaginal gene therapy has gained increasing attention mainly for the treatment and control of sexually transmitted infections. DNA delivery has been also suggested to improve reproductive outcomes for women with deficiencies in the female reproductive tract. Although no product has reached clinical phase, preclinical investigations reveal the potential of the vaginal tract as an effective administration route for gene delivery. This review focuses on the main advantages and challenges of vaginal gene therapy, and on the most used nucleic acid delivery systems, including viral and non-viral vectors. Additionally, the advances in the application of vaginal gene therapy for the treatment and/or prevention of infectious diseases such as the human immunodeficiency virus (HIV), the human papillomavirus (HPV) or the herpes simplex virus (HSV) are presented.

  12. Evolution of alanine:glyoxylate aminotransferase 1 peroxisomal and mitochondrial targeting. A survey of its subcellular distribution in the livers of various representatives of the classes Mammalia, Aves and Amphibia.

    PubMed

    Danpure, C J; Fryer, P; Jennings, P R; Allsop, J; Griffiths, S; Cunningham, A

    1994-08-01

    to vary markedly between the different members, in other orders (e.g. Primates, Rodentia and Marsupialia) it fluctuated widely between the different species. Phylogenetic analysis indicates that the subcellular distribution of AGT1 has changed radically on numerous occasions during the evolution of mammals. The new observations presented in this paper are compatible with our previous demonstration of a relationship between AGT1 subcellular distribution and either present or putative ancestral dietary habit, and our previous suggestion that the molecular evolution of the AGT gene has been markedly influenced by dietary selection pressure. PMID:7813517

  13. Evidence for homosexuality gene

    SciTech Connect

    Pool, R.

    1993-07-16

    A genetic analysis of 40 pairs of homosexual brothers has uncovered a region on the X chromosome that appears to contain a gene or genes for homosexuality. When analyzing the pedigrees of homosexual males, the researcheres found evidence that the trait has a higher likelihood of being passed through maternal genes. This led them to search the X chromosome for genes predisposing to homosexuality. The researchers examined the X chromosomes of pairs of homosexual brothers for regions of DNA that most or all had in common. Of the 40 sets of brothers, 33 shared a set of five markers in the q28 region of the long arm of the X chromosome. The linkage has a LOD score of 4.0, which translates into a 99.5% certainty that there is a gene or genes in this area that predispose males to homosexuality. The chief researcher warns, however, that this one site cannot explain all instances of homosexuality, since there were some cases where the trait seemed to be passed paternally. And even among those brothers where there was no evidence that the trait was passed paternally, seven sets of brothers did not share the Xq28 markers. It seems likely that homosexuality arises from a variety of causes.

  14. [Integrons: gene collectors].

    PubMed

    Di Conza, J A; Gutkind, G O

    2010-01-01

    Integrons gained great interest due to their participation in resistance gene recruitment and expression. Their basic structure includes a fragment that encodes an integrase (intI) followed by a recognition sequence (attI) into which they may incorporate gene cassettes (encoding resistance mechanisms). A promoter (Pc) embedded within the integrase gene controls the transcription of integrated resistance markers, as these genes do not have their own promoters. When in cassettes, resistance genes are flanked by specific sequences (attC), which are recognized by the integrase that, by site specific recombination, incorporates them after attI in proper orientation for their expression. In the past, integrons were classified according to their sequence homology; currently they are classified according to their location. In general, they are divided into "mobile" integrons (those associated with insertion sequences, transposons and/or plasmids, being most of them associated with resistance mechanisms), and chromosomally-located "super" integrons with large arrangements of cassette genes. "Mobile" class 1 integrons are the most abundant in clinical isolates and are generally associated with Tn21 subgroup transposons, followed by class 2, derived primarily from Tn7. These elements are not mobile themselves, but their association with mobile platforms that facilitate horizontal transfer, explains their wide distribution among bacteria. This review also attempts to describe the mobile integrons described so far in Argentina.

  15. Identification of four soybean reference genes for gene expression normalization

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Gene expression analysis requires the use of reference genes stably expressed independently of specific tissues or environmental conditions. Housekeeping genes (e.g., actin, tubulin, ribosomal, polyubiquitin and elongation factor 1-alpha) are commonly used as reference genes with the assumption tha...

  16. 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

  17. Hox genes and study of Hox genes in crustacean

    NASA Astrophysics Data System (ADS)

    Hou, Lin; Chen, Zhijuan; Xu, Mingyu; Lin, Shengguo; Wang, Lu

    2004-12-01

    Homeobox genes have been discovered in many species. These genes are known to play a major role in specifying regional identity along the anterior-posterior axis of animals from a wide range of phyla. The products of the homeotic genes are a set of evolutionarily conserved transcription factors that control elaborate developmental processes and specify cell fates in metazoans. Crustacean, presenting a variety of body plans not encountered in any other class or phylum of the Metazoa, has been shown to possess a single set of homologous Hox genes like insect. The ancestral crustacean Hox gene complex comprised ten genes: eight homologous to the hometic Hox genes and two related to nonhomeotic genes presented within the insect Hox complexes. The crustacean in particular exhibits an abundant diversity segment specialization and tagmosis. This morphological diversity relates to the Hox genes. In crustacean body plan, different Hox genes control different segments and tagmosis.

  18. GeneCards Version 3: the human gene integrator.

    PubMed

    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

    2010-08-05

    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

  19. GeneCards Version 3: the human gene integrator.

    PubMed

    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

    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

  20. Neighboring Genes Show Correlated Evolution in Gene Expression.

    PubMed

    Ghanbarian, Avazeh T; Hurst, Laurence D

    2015-07-01

    When considering the evolution of a gene's expression profile, we commonly assume that this is unaffected by its genomic neighborhood. This is, however, in contrast to what we know about the lack of autonomy between neighboring genes in gene expression profiles in extant taxa. Indeed, in all eukaryotic genomes genes of similar expression-profile tend to cluster, reflecting chromatin level dynamics. Does it follow that if a gene increases expression in a particular lineage then the genomic neighbors will also increase in their expression or is gene expression evolution autonomous? To address this here we consider evolution of human gene expression since the human-chimp common ancestor, allowing for both variation in estimation of current expression level and error in Bayesian estimation of the ancestral state. We find that in all tissues and both sexes, the change in gene expression of a focal gene on average predicts the change in gene expression of neighbors. The effect is highly pronounced in the immediate vicinity (<100 kb) but extends much further. Sex-specific expression change is also genomically clustered. As genes increasing their expression in humans tend to avoid nuclear lamina domains and be enriched for the gene activator 5-hydroxymethylcytosine, we conclude that, most probably owing to chromatin level control of gene expression, a change in gene expression of one gene likely affects the expression evolution of neighbors, what we term expression piggybacking, an analog of hitchhiking.

  1. Saporin suicide gene therapy.

    PubMed

    Zarovni, Natasa; Vago, Riccardo; Fabbrini, Maria Serena

    2009-01-01

    New genes useful in suicide gene therapy are those encoding toxins such as plant ribosome-inactivating proteins (RIPs), which can irreversibly block protein synthesis, triggering apoptotic cell death. Plasmids expressing a cytosolic saporin (SAP) gene from common soapwort (Saponaria officinalis) are generated by placing the region encoding the mature plant toxin under the control of strong viral promoters and may be placed under tumor-specific promoters. The ability of the resulting constructs to inhibit protein synthesis is tested in cultured tumor cells co-transfected with a luciferase reporter gene. SAP expression driven by the cytomegalovirus (CMV) promoter (pCI-SAP) demonstrates that only 10 ng ofplasmid DNA per 1.6 x 10(4) B16 melanoma cells drastically reduces luciferase reporter activity to 18% of that in control cells (1). Direct intratumoral injections are performed in an aggressive melanoma model. B16 melanoma-bearing mice injected with pCI-SAP complexed with lipofectamine or N-(2,3-dioleoyloxy-1-propyl) trimethylammonium methyl sulfate (DOTAP) show a noteworthy attenuation in tumor growth, and this effect is significantly augmented by repeated administrations of the DNA complexes. Here, we describe in detail this cost-effective and safe suicide gene approach. PMID:19565907

  2. On sports and genes.

    PubMed

    Zilberman-Schapira, Gili; Chen, Jieming; Gerstein, Mark

    2012-12-01

    Our genes influence our athletic ability. However, the causal genetic factors and mechanisms, and the extent of their effects, remain largely elusive. Many studies investigate this association between specific genes and athletic performance. Such studies have increased in number over the past few years, as recent developments and patents in DNA sequencing have made large amounts of sequencing data available for such analysis. In this paper, we consider four of the most intensively studied genes in relation to athletic ability: angiotensin I-converting enzyme, alpha-actinin 3, peroxismose proliferator-activator receptor alpha and nitric oxide synthase 3. We investigate the connection between genotype and athletic phenotype in the context of these four genes in various sport fields and across different ethnicities and genders. We do an extensive literature survey on these genes and the polymorphisms (single nucleotide polymorphisms or indels) found to be associated with athletic performance. We also present, for each of these polymorphisms, the allele frequencies in the different ethnicities reported in the pilot phase of the 1000 Genomes Project - arguably the largest human genome-sequencing endeavor to date. We discuss the considerable success, and significant drawbacks, of past research along these lines, and propose interesting directions for future research.

  3. Hox genes and evolution

    PubMed Central

    Hrycaj, Steven M.; Wellik, Deneen M.

    2016-01-01

    Hox proteins are a deeply conserved group of transcription factors originally defined for their critical roles in governing segmental identity along the antero-posterior (AP) axis in Drosophila. Over the last 30 years, numerous data generated in evolutionarily diverse taxa have clearly shown that changes in the expression patterns of these genes are closely associated with the regionalization of the AP axis, suggesting that Hox genes have played a critical role in the evolution of novel body plans within Bilateria. Despite this deep functional conservation and the importance of these genes in AP patterning, key questions remain regarding many aspects of Hox biology. In this commentary, we highlight recent reports that have provided novel insight into the origins of the mammalian Hox cluster, the role of Hox genes in the generation of a limbless body plan, and a novel putative mechanism in which Hox genes may encode specificity along the AP axis. Although the data discussed here offer a fresh perspective, it is clear that there is still much to learn about Hox biology and the roles it has played in the evolution of the Bilaterian body plan. PMID:27239281

  4. LQTS gene LOVD database.

    PubMed

    Zhang, Tao; Moss, Arthur; Cong, Peikuan; Pan, Min; Chang, Bingxi; Zheng, Liangrong; Fang, Quan; Zareba, Wojciech; Robinson, Jennifer; Lin, Changsong; Li, Zhongxiang; Wei, Junfang; Zeng, Qiang; Qi, Ming

    2010-11-01

    The Long QT Syndrome (LQTS) is a group of genetically heterogeneous disorders that predisposes young individuals to ventricular arrhythmias and sudden death. LQTS is mainly caused by mutations in genes encoding subunits of cardiac ion channels (KCNQ1, KCNH2,SCN5A, KCNE1, and KCNE2). Many other genes involved in LQTS have been described recently(KCNJ2, AKAP9, ANK2, CACNA1C, SCNA4B, SNTA1, and CAV3). We created an online database(http://www.genomed.org/LOVD/introduction.html) that provides information on variants in LQTS-associated genes. As of February 2010, the database contains 1738 unique variants in 12 genes. A total of 950 variants are considered pathogenic, 265 are possible pathogenic, 131 are unknown/unclassified, and 292 have no known pathogenicity. In addition to these mutations collected from published literature, we also submitted information on gene variants, including one possible novel pathogenic mutation in the KCNH2 splice site found in ten Chinese families with documented arrhythmias. The remote user is able to search the data and is encouraged to submit new mutations into the database. The LQTS database will become a powerful tool for both researchers and clinicians. PMID:20809527

  5. LQTS gene LOVD database.

    PubMed

    Zhang, Tao; Moss, Arthur; Cong, Peikuan; Pan, Min; Chang, Bingxi; Zheng, Liangrong; Fang, Quan; Zareba, Wojciech; Robinson, Jennifer; Lin, Changsong; Li, Zhongxiang; Wei, Junfang; Zeng, Qiang; Qi, Ming

    2010-11-01

    The Long QT Syndrome (LQTS) is a group of genetically heterogeneous disorders that predisposes young individuals to ventricular arrhythmias and sudden death. LQTS is mainly caused by mutations in genes encoding subunits of cardiac ion channels (KCNQ1, KCNH2,SCN5A, KCNE1, and KCNE2). Many other genes involved in LQTS have been described recently(KCNJ2, AKAP9, ANK2, CACNA1C, SCNA4B, SNTA1, and CAV3). We created an online database(http://www.genomed.org/LOVD/introduction.html) that provides information on variants in LQTS-associated genes. As of February 2010, the database contains 1738 unique variants in 12 genes. A total of 950 variants are considered pathogenic, 265 are possible pathogenic, 131 are unknown/unclassified, and 292 have no known pathogenicity. In addition to these mutations collected from published literature, we also submitted information on gene variants, including one possible novel pathogenic mutation in the KCNH2 splice site found in ten Chinese families with documented arrhythmias. The remote user is able to search the data and is encouraged to submit new mutations into the database. The LQTS database will become a powerful tool for both researchers and clinicians.

  6. Gene therapy for brain tumors.

    PubMed

    Bansal, K; Engelhard, H H

    2000-09-01

    "Gene therapy" can be defined as the transfer of genetic material into a patient's cells for therapeutic purposes. To date, a diverse and creative assortment of treatment strategies utilizing gene therapy have been devised, including gene transfer for modulating the immune system, enzyme prodrug ("suicide gene") therapy, oncolytic therapy, replacement/therapeutic gene transfer, and antisense therapy. For malignant glioma, gene-directed prodrug therapy using the herpes simplex virus thymidine kinase gene was the first gene therapy attempted clinically. A variety of different strategies have now been pursued experimentally and in clinical trials. Although, to date, gene therapy for brain tumors has been found to be reasonably safe, concerns still exist regarding issues related to viral delivery, transduction efficiency, potential pathologic response of the brain, and treatment efficacy. Improved viral vectors are being sought, and potential use of gene therapy in combination with other treatments is being investigated.

  7. How old is my gene?

    PubMed Central

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

    2013-01-01

    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 reduce this history to a single age estimate. Focusing on eukaryotic gene families, we introduce a framework in which 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

  8. Gene therapy prospects--intranasal delivery of therapeutic genes.

    PubMed

    Podolska, Karolina; Stachurska, Anna; Hajdukiewicz, Karolina; Małecki, Maciej

    2012-01-01

    Gene therapy is recognized to be a novel method for the treatment of various disorders. Gene therapy strategies involve gene manipulation on broad biological processes responsible for the spreading of diseases. Cancer, monogenic diseases, vascular and infectious diseases are the main targets of gene therapy. In order to obtain valuable experimental and clinical results, sufficient gene transfer methods are required. Therapeutic genes can be administered into target tissues via gene carriers commonly defined as vectors. The retroviral, adenoviral and adeno-associated virus based vectors are most frequently used in the clinic. So far, gene preparations may be administered directly into target organs or by intravenous, intramuscular, intratumor or intranasal injections. It is common knowledge that the number of gene therapy clinical trials has rapidly increased. However, some limitations such as transfection efficiency and stable and long-term gene expression are still not resolved. Consequently, great effort is focused on the evaluation of new strategies of gene delivery. There are many expectations associated with intranasal delivery of gene preparations for the treatment of diseases. Intranasal delivery of therapeutic genes is regarded as one of the most promising forms of pulmonary gene therapy research. Gene therapy based on inhalation of gene preparations offers an alternative way for the treatment of patients suffering from such lung diseases as cystic fibrosis, alpha-1-antitrypsin defect, or cancer. Experimental and first clinical trials based on plasmid vectors or recombinant viruses have revealed that gene preparations can effectively deliver therapeutic or marker genes to the cells of the respiratory tract. The noninvasive intranasal delivery of gene preparations or conventional drugs seems to be very encouraging, although basic scientific research still has to continue.

  9. GeneCards Version 3: the human gene integrator

    PubMed Central

    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

    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

  10. FunGene: the functional gene pipeline and repository

    PubMed Central

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

    2013-01-01

    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

  11. Human DNA repair genes.

    PubMed

    Wood, R D; Mitchell, M; Sgouros, J; Lindahl, T

    2001-02-16

    Cellular DNA is subjected to continual attack, both by reactive species inside cells and by environmental agents. Toxic and mutagenic consequences are minimized by distinct pathways of repair, and 130 known human DNA repair genes are described here. Notable features presently include four enzymes that can remove uracil from DNA, seven recombination genes related to RAD51, and many recently discovered DNA polymerases that bypass damage, but only one system to remove the main DNA lesions induced by ultraviolet light. More human DNA repair genes will be found by comparison with model organisms and as common folds in three-dimensional protein structures are determined. Modulation of DNA repair should lead to clinical applications including improvement of radiotherapy and treatment with anticancer drugs and an advanced understanding of the cellular aging process. PMID:11181991

  12. Frequent gene conversion between human red and green opsin genes.

    PubMed

    Zhao, Z; Hewett-Emmett, D; Li, W H

    1998-04-01

    To study the evolution of human X-linked red and green opsin genes, genomic sequences in large regions of the two genes were compared. The divergences in introns 3, 4, and 5 and the 3' flanking sequence of the two genes are significantly lower than those in exons 4 and 5. The homogenization mechanism of introns and the 3' flanking sequence of human red and green opsin genes is probably gene conversion, which also occurred in exons 1 and 6. At least one gene conversion event occurred in each of three regions (1, 3, and 5) in the sequences compared. In conclusion, gene conversion has occurred frequently between human red and green opsin genes, but exons 2, 3, 4, and 5 have been maintained distinct between the two genes by natural selection.

  13. Neighboring Genes Show Correlated Evolution in Gene Expression

    PubMed Central

    Ghanbarian, Avazeh T.; Hurst, Laurence D.

    2015-01-01

    When considering the evolution of a gene’s expression profile, we commonly assume that this is unaffected by its genomic neighborhood. This is, however, in contrast to what we know about the lack of autonomy between neighboring genes in gene expression profiles in extant taxa. Indeed, in all eukaryotic genomes genes of similar expression-profile tend to cluster, reflecting chromatin level dynamics. Does it follow that if a gene increases expression in a particular lineage then the genomic neighbors will also increase in their expression or is gene expression evolution autonomous? To address this here we consider evolution of human gene expression since the human-chimp common ancestor, allowing for both variation in estimation of current expression level and error in Bayesian estimation of the ancestral state. We find that in all tissues and both sexes, the change in gene expression of a focal gene on average predicts the change in gene expression of neighbors. The effect is highly pronounced in the immediate vicinity (<100 kb) but extends much further. Sex-specific expression change is also genomically clustered. As genes increasing their expression in humans tend to avoid nuclear lamina domains and be enriched for the gene activator 5-hydroxymethylcytosine, we conclude that, most probably owing to chromatin level control of gene expression, a change in gene expression of one gene likely affects the expression evolution of neighbors, what we term expression piggybacking, an analog of hitchhiking. PMID:25743543

  14. Genes and Vocal Learning

    PubMed Central

    White, Stephanie A.

    2009-01-01

    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 primates, rodents and birds suggests that FoxP2 and other language-related genes are interactors in the neuromolecular networks that underlie subsystems of language, such symbolic understanding, vocal learning and theory of mind. The whole picture will only come together through comparative and integrative study into how the human language singularity evolved. PMID:19913899

  15. The gene tree delusion.

    PubMed

    Springer, Mark S; Gatesy, John

    2016-01-01

    Higher-level relationships among placental mammals are mostly resolved, but several polytomies remain contentious. Song et al. (2012) claimed to have resolved three of these using shortcut coalescence methods (MP-EST, STAR) and further concluded that these methods, which assume no within-locus recombination, are required to unravel deep-level phylogenetic problems that have stymied concatenation. Here, we reanalyze Song et al.'s (2012) data and leverage these re-analyses to explore key issues in systematics including the recombination ratchet, gene tree stoichiometry, the proportion of gene tree incongruence that results from deep coalescence versus other factors, and simulations that compare the performance of coalescence and concatenation methods in species tree estimation. Song et al. (2012) reported an average locus length of 3.1 kb for the 447 protein-coding genes in their phylogenomic dataset, but the true mean length of these loci (start codon to stop codon) is 139.6 kb. Empirical estimates of recombination breakpoints in primates, coupled with consideration of the recombination ratchet, suggest that individual coalescence genes (c-genes) approach ∼12 bp or less for Song et al.'s (2012) dataset, three to four orders of magnitude shorter than the c-genes reported by these authors. This result has general implications for the application of coalescence methods in species tree estimation. We contend that it is illogical to apply coalescence methods to complete protein-coding sequences. Such analyses amalgamate c-genes with different evolutionary histories (i.e., exons separated by >100,000 bp), distort true gene tree stoichiometry that is required for accurate species tree inference, and contradict the central rationale for applying coalescence methods to difficult phylogenetic problems. In addition, Song et al.'s (2012) dataset of 447 genes includes 21 loci with switched taxonomic names, eight duplicated loci, 26 loci with non-homologous sequences that are

  16. The gene tree delusion.

    PubMed

    Springer, Mark S; Gatesy, John

    2016-01-01

    Higher-level relationships among placental mammals are mostly resolved, but several polytomies remain contentious. Song et al. (2012) claimed to have resolved three of these using shortcut coalescence methods (MP-EST, STAR) and further concluded that these methods, which assume no within-locus recombination, are required to unravel deep-level phylogenetic problems that have stymied concatenation. Here, we reanalyze Song et al.'s (2012) data and leverage these re-analyses to explore key issues in systematics including the recombination ratchet, gene tree stoichiometry, the proportion of gene tree incongruence that results from deep coalescence versus other factors, and simulations that compare the performance of coalescence and concatenation methods in species tree estimation. Song et al. (2012) reported an average locus length of 3.1 kb for the 447 protein-coding genes in their phylogenomic dataset, but the true mean length of these loci (start codon to stop codon) is 139.6 kb. Empirical estimates of recombination breakpoints in primates, coupled with consideration of the recombination ratchet, suggest that individual coalescence genes (c-genes) approach ∼12 bp or less for Song et al.'s (2012) dataset, three to four orders of magnitude shorter than the c-genes reported by these authors. This result has general implications for the application of coalescence methods in species tree estimation. We contend that it is illogical to apply coalescence methods to complete protein-coding sequences. Such analyses amalgamate c-genes with different evolutionary histories (i.e., exons separated by >100,000 bp), distort true gene tree stoichiometry that is required for accurate species tree inference, and contradict the central rationale for applying coalescence methods to difficult phylogenetic problems. In addition, Song et al.'s (2012) dataset of 447 genes includes 21 loci with switched taxonomic names, eight duplicated loci, 26 loci with non-homologous sequences that are

  17. Huntington's disease gene located.

    PubMed

    Kolata, G

    1983-11-25

    Investigators have found a restriction enzyme marker, a piece of DNA that can be located with recombinant DNA techniques, that is so close to the Huntington's disease gene that its presence can be used as an indicator for that gene. If this marker is used as a diagnostic test for Huntington's disease, people at risk for getting the disease will be able to learn whether or not they will in fact develop the disease. The ability to predict the inevitable onset of this progressive, degenerative disease raises ethical questions about counseling, screening, and disclosure of risk status to patients and family members.

  18. Gene therapy: progress and predictions

    PubMed Central

    Collins, Mary; Thrasher, Adrian

    2015-01-01

    The first clinical gene delivery, which involved insertion of a marker gene into lymphocytes from cancer patients, was published 25 years ago. In this review, we describe progress since then in gene therapy. Patients with some inherited single-gene defects can now be treated with their own bone marrow stem cells that have been engineered with a viral vector carrying the missing gene. Patients with inherited retinopathies and haemophilia B can also be treated by local or systemic injection of viral vectors. There are also a number of promising gene therapy approaches for cancer and infectious disease. We predict that the next 25 years will see improvements in safety, efficacy and manufacture of gene delivery vectors and introduction of gene-editing technologies to the clinic. Gene delivery may also prove a cost-effective method for the delivery of biological medicines. PMID:26702034

  19. Gene Characterization Index: Assessing the Depth of Gene Annotation

    PubMed Central

    Yusuf, Dimas; Brumm, Jochen; Cheung, Warren; Wahlestedt, Claes; Lenhard, Boris; Wasserman, Wyeth W.

    2008-01-01

    Background We introduce the Gene Characterization Index, a bioinformatics method for scoring the extent to which a protein-encoding gene is functionally described. Inherently a reflection of human perception, the Gene Characterization Index is applied for assessing the characterization status of individual genes, thus serving the advancement of both genome annotation and applied genomics research by rapid and unbiased identification of groups of uncharacterized genes for diverse applications such as directed functional studies and delineation of novel drug targets. Methodology/Principal Findings The scoring procedure is based on a global survey of researchers, who assigned characterization scores from 1 (poor) to 10 (extensive) for a sample of genes based on major online resources. By evaluating the survey as training data, we developed a bioinformatics procedure to assign gene characterization scores to all genes in the human genome. We analyzed snapshots of functional genome annotation over a period of 6 years to assess temporal changes reflected by the increase of the average Gene Characterization Index. Applying the Gene Characterization Index to genes within pharmaceutically relevant classes, we confirmed known drug targets as high-scoring genes and revealed potentially interesting novel targets with low characterization indexes. Removing known drug targets and genes linked to sequence-related patent filings from the entirety of indexed genes, we identified sets of low-scoring genes particularly suited for further experimental investigation. Conclusions/Significance The Gene Characterization Index is intended to serve as a tool to the scientific community and granting agencies for focusing resources and efforts on unexplored areas of the genome. The Gene Characterization Index is available from http://cisreg.ca/gci/. PMID:18213364

  20. Naming genes beyond Caenorhabditis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The nomenclature of genes in Caenorhabditis elegans is based on long-standing, successful guidelines established in the late 1970s. Over time these guidelines have matured into a comprehensive, systematic nomenclature that is easy to apply, descriptive and therefore highly informative. Recently, a f...

  1. Gene targeting in livestock.

    PubMed

    Thomson, A J; Marques, M M; McWhir, J

    2003-01-01

    The development of nuclear transfer from tissue culture cells in livestock made it possible in principle to produce animals with subtle, directed genetic changes by in vitro modification of nuclear donor cells. In the short period since nuclear transfer was first performed, gene targeting in livestock has become a reality. Although gene targeting has immediate potential in biotechnology, it is unclear whether there are practical agricultural applications, at present. The first livestock targeting experiments have been directed at engineering animals either to render their organs immunologically compatible for human transplantation, or for improving the commercial production of recombinant proteins in the transgenic mammary gland. All successful examples of targeting have involved target loci that are expressed in the nuclear donor cell line. Two important barriers to the further development of this technology are adapting protocols for non-expressed genes and modifying procedures to enhance the lifespan of targeted cells in vitro. This review provides data that illustrate the difficulty in targeting non-expressed genes and discusses some of the practical issues associated with providing targeted nuclear donor cells that are competent for nuclear transfer.

  2. Inferring horizontal gene transfer.

    PubMed

    Ravenhall, Matt; Škunca, Nives; Lassalle, Florent; Dessimoz, Christophe

    2015-05-01

    Horizontal or Lateral Gene Transfer (HGT or LGT) is the transmission of portions of genomic DNA between organisms through a process decoupled from vertical inheritance. In the presence of HGT events, different fragments of the genome are the result of different evolutionary histories. This can therefore complicate the investigations of evolutionary relatedness of lineages and species. Also, as HGT can bring into genomes radically different genotypes from distant lineages, or even new genes bearing new functions, it is a major source of phenotypic innovation and a mechanism of niche adaptation. For example, of particular relevance to human health is the lateral transfer of antibiotic resistance and pathogenicity determinants, leading to the emergence of pathogenic lineages. Computational identification of HGT events relies upon the investigation of sequence composition or evolutionary history of genes. Sequence composition-based ("parametric") methods search for deviations from the genomic average, whereas evolutionary history-based ("phylogenetic") approaches identify genes whose evolutionary history significantly differs from that of the host species. The evaluation and benchmarking of HGT inference methods typically rely upon simulated genomes, for which the true history is known. On real data, different methods tend to infer different HGT events, and as a result it can be difficult to ascertain all but simple and clear-cut HGT events. PMID:26020646

  3. Gene-Environment Interdependence

    ERIC Educational Resources Information Center

    Rutter, Michael

    2007-01-01

    Behavioural genetics was initially concerned with partitioning population variance into that due to genetics and that due to environmental influences. The implication was that the two were separate and it was assumed that gene-environment interactions were usually of so little importance that they could safely be ignored. Theoretical…

  4. Zmspds2 maize gene

    PubMed Central

    Rodríguez-Kessler, Margarita

    2008-01-01

    During the last decade, growing evidence has arisen referring the importance of the proper regulation of plant polyamine metabolism in the response to stress conditions. Being the activation of signaling pathways, the stabilization of anionic molecules and prevention of their degradation, as well as the free radical scavenger properties of polyamines some possible mechanisms exerted by these amines. Accumulation of polyamines (putrescine, spermidine and spermine) has been associated to plant tolerance to a wide array of environmental stresses. The synthesis of spermidine and spermine is mediated by aminopropyltransferases (spermidine and spermine synthases) which constitute a class of widely distributed enzymes that use decarboxylated S-adenosylmethionine as an aminopropyl donor, and putrescine or spermidine as an amino acceptor. We recently reported the effect of salt stress on the expression of aminopropyltransferase genes in maize seedlings. Our data revealed a time and NaCl dependent regulation of the Zmspds2 and Zmspds1 genes, possibly mediated by abscisic acid, since these genes were regulated at the transcriptional level by this plant hormone. In this addendum, we show that the Zmspds2 gene initially classified as spermidine synthase might encode a spermine synthase based on an in silico analysis. This is discussed in terms of protein homologies and specific amino acid substitutions between aminopropyltransferase enzymes. PMID:19704464

  5. Rhabdovirus accessory genes.

    PubMed

    Walker, Peter J; Dietzgen, Ralf G; Joubert, D Albert; Blasdell, Kim R

    2011-12-01

    The Rhabdoviridae is one of the most ecologically diverse families of RNA viruses with members infecting a wide range of organisms including placental mammals, marsupials, birds, reptiles, fish, insects and plants. The availability of complete nucleotide sequences for an increasing number of rhabdoviruses has revealed that their ecological diversity is reflected in the diversity and complexity of their genomes. The five canonical rhabdovirus structural protein genes (N, P, M, G and L) that are shared by all rhabdoviruses are overprinted, overlapped and interspersed with a multitude of novel and diverse accessory genes. Although not essential for replication in cell culture, several of these genes have been shown to have roles associated with pathogenesis and apoptosis in animals, and cell-to-cell movement in plants. Others appear to be secreted or have the characteristics of membrane-anchored glycoproteins or viroporins. However, most encode proteins of unknown function that are unrelated to any other known proteins. Understanding the roles of these accessory genes and the strategies by which rhabdoviruses use them to engage, divert and re-direct cellular processes will not only present opportunities to develop new anti-viral therapies but may also reveal aspects of cellar function that have broader significance in biology, agriculture and medicine.

  6. Genes and Vocal Learning

    ERIC Educational Resources Information Center

    White, Stephanie A.

    2010-01-01

    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…

  7. Inferring Horizontal Gene Transfer

    PubMed Central

    Lassalle, Florent; Dessimoz, Christophe

    2015-01-01

    Horizontal or Lateral Gene Transfer (HGT or LGT) is the transmission of portions of genomic DNA between organisms through a process decoupled from vertical inheritance. In the presence of HGT events, different fragments of the genome are the result of different evolutionary histories. This can therefore complicate the investigations of evolutionary relatedness of lineages and species. Also, as HGT can bring into genomes radically different genotypes from distant lineages, or even new genes bearing new functions, it is a major source of phenotypic innovation and a mechanism of niche adaptation. For example, of particular relevance to human health is the lateral transfer of antibiotic resistance and pathogenicity determinants, leading to the emergence of pathogenic lineages [1]. Computational identification of HGT events relies upon the investigation of sequence composition or evolutionary history of genes. Sequence composition-based ("parametric") methods search for deviations from the genomic average, whereas evolutionary history-based ("phylogenetic") approaches identify genes whose evolutionary history significantly differs from that of the host species. The evaluation and benchmarking of HGT inference methods typically rely upon simulated genomes, for which the true history is known. On real data, different methods tend to infer different HGT events, and as a result it can be difficult to ascertain all but simple and clear-cut HGT events. PMID:26020646

  8. Genes in mammalian reproduction

    SciTech Connect

    Gwatkin, R.B.L.

    1996-11-01

    This is an informative book which deals mainly with genomic imprinting, the role of steroid hormones in development, the expression of a variety of genes during development and the link to hereditary diseases. It is an up-to-date review in a field that is quickly changing and provides valuable basic information and current research trends.

  9. Airway gene therapy.

    PubMed

    Davies, Jane C; Alton, Eric W F W

    2005-01-01

    Given both the accessibility and the genetic basis of several pulmonary diseases, the lungs and airways initially seemed ideal candidates for gene therapy. Several routes of access are available, many of which have been refined and optimized for nongene drug delivery. Two respiratory diseases, cystic fibrosis (CF) and alpha1-antitrypsin (alpha1-AT) deficiency, are relatively common; the single gene responsible has been identified and current treatment strategies are not curative. This type of inherited disease was the obvious initial target for gene therapy, but it has become clear that nongenetic and acquired diseases, including cancer, may also be amenable to this approach. The majority of preclinical and clinical studies in the airway have involved viral vectors, although for diseases such as CF, likely to require repeated application, non-viral delivery systems have clear advantages. However, with both approaches a range of barriers to gene expression have been identified that are limiting success in the airway and alveolar region. This chapter reviews these issues, strategies aimed at overcoming them, and progress into clinical trials with non-viral vectors in a variety of pulmonary diseases.

  10. Gene stacking by recombinases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Efficient methods of stacking genes into plant genomes are needed to expedite transfer of multigenic traits into diverse crops grown in a variety of environments. Over two decades of research has identified several site-specific recombinases that carry out efficient cis and trans recombination betw...

  11. Old genes experience stronger translational selection than young genes.

    PubMed

    Yin, Hongyan; Ma, Lina; Wang, Guangyu; Li, Mengwei; Zhang, Zhang

    2016-09-15

    Selection on synonymous codon usage for translation efficiency and/or accuracy has been identified as a widespread mechanism in many living organisms. However, it remains unknown whether translational selection associates closely with gene age and acts differentially on genes with different evolutionary ages. To address this issue, here we investigate the strength of translational selection acting on different aged genes in human. Our results show that old genes present stronger translational selection than young genes, demonstrating that translational selection correlates positively with gene age. We further explore the difference of translational selection in duplicates vs. singletons and in housekeeping vs. tissue-specific genes. We find that translational selection acts comparably in old singletons and old duplicates and stronger translational selection in old genes is contributed primarily by housekeeping genes. For young genes, contrastingly, singletons experience stronger translational selection than duplicates, presumably due to redundant function of duplicated genes during their early evolutionary stage. Taken together, our results indicate that translational selection acting on a gene would not be constant during all stages of evolution, associating closely with gene age.

  12. Genes2FANs: connecting genes through functional association networks

    PubMed Central

    2012-01-01

    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

  13. Industrial scale gene synthesis.

    PubMed

    Notka, Frank; Liss, Michael; Wagner, Ralf

    2011-01-01

    The most recent developments in the area of deep DNA sequencing and downstream quantitative and functional analysis are rapidly adding a new dimension to understanding biochemical pathways and metabolic interdependencies. These increasing insights pave the way to designing new strategies that address public needs, including environmental applications and therapeutic inventions, or novel cell factories for sustainable and reconcilable energy or chemicals sources. Adding yet another level is building upon nonnaturally occurring networks and pathways. Recent developments in synthetic biology have created economic and reliable options for designing and synthesizing genes, operons, and eventually complete genomes. Meanwhile, high-throughput design and synthesis of extremely comprehensive DNA sequences have evolved into an enabling technology already indispensable in various life science sectors today. Here, we describe the industrial perspective of modern gene synthesis and its relationship with synthetic biology. Gene synthesis contributed significantly to the emergence of synthetic biology by not only providing the genetic material in high quality and quantity but also enabling its assembly, according to engineering design principles, in a standardized format. Synthetic biology on the other hand, added the need for assembling complex circuits and large complexes, thus fostering the development of appropriate methods and expanding the scope of applications. Synthetic biology has also stimulated interdisciplinary collaboration as well as integration of the broader public by addressing socioeconomic, philosophical, ethical, political, and legal opportunities and concerns. The demand-driven technological achievements of gene synthesis and the implemented processes are exemplified by an industrial setting of large-scale gene synthesis, describing production from order to delivery.

  14. Endovascular Gene Delivery from a Stent Platform: Gene- Eluting Stents

    PubMed Central

    Fishbein, Ilia; Chorny, Michael; Adamo, Richard F; Forbes, Scott P; Corrales, Ricardo A; Alferiev, Ivan S; Levy, Robert J

    2015-01-01

    A synergistic impact of research in the fields of post-angioplasty restenosis, drug-eluting stents and vascular gene therapy over the past 15 years has shaped the concept of gene-eluting stents. Gene-eluting stents hold promise of overcoming some biological and technical problems inherent to drug-eluting stent technology. As the field of gene-eluting stents matures it becomes evident that all three main design modules of a gene-eluting stent: a therapeutic transgene, a vector and a delivery system are equally important for accomplishing sustained inhibition of neointimal formation in arteries treated with gene delivery stents. This review summarizes prior work on stent-based gene delivery and discusses the main optimization strategies required to move the field of gene-eluting stents to clinical translation. PMID:26225356

  15. Optimal Reference Genes for Gene Expression Normalization in Trichomonas vaginalis.

    PubMed

    dos Santos, Odelta; de Vargas Rigo, Graziela; Frasson, Amanda Piccoli; Macedo, Alexandre José; Tasca, Tiana

    2015-01-01

    Trichomonas vaginalis is the etiologic agent of trichomonosis, the most common non-viral sexually transmitted disease worldwide. This infection is associated with several health consequences, including cervical and prostate cancers and HIV acquisition. Gene expression analysis has been facilitated because of available genome sequences and large-scale transcriptomes in T. vaginalis, particularly using quantitative real-time polymerase chain reaction (qRT-PCR), one of the most used methods for molecular studies. Reference genes for normalization are crucial to ensure the accuracy of this method. However, to the best of our knowledge, a systematic validation of reference genes has not been performed for T. vaginalis. In this study, the transcripts of nine candidate reference genes were quantified using qRT-PCR under different cultivation conditions, and the stability of these genes was compared using the geNorm and NormFinder algorithms. The most stable reference genes were α-tubulin, actin and DNATopII, and, conversely, the widely used T. vaginalis reference genes GAPDH and β-tubulin were less stable. The PFOR gene was used to validate the reliability of the use of these candidate reference genes. As expected, the PFOR gene was upregulated when the trophozoites were cultivated with ferrous ammonium sulfate when the DNATopII, α-tubulin and actin genes were used as normalizing gene. By contrast, the PFOR gene was downregulated when the GAPDH gene was used as an internal control, leading to misinterpretation of the data. These results provide an important starting point for reference gene selection and gene expression analysis with qRT-PCR studies of T. vaginalis.

  16. Optimal Reference Genes for Gene Expression Normalization in Trichomonas vaginalis.

    PubMed

    dos Santos, Odelta; de Vargas Rigo, Graziela; Frasson, Amanda Piccoli; Macedo, Alexandre José; Tasca, Tiana

    2015-01-01

    Trichomonas vaginalis is the etiologic agent of trichomonosis, the most common non-viral sexually transmitted disease worldwide. This infection is associated with several health consequences, including cervical and prostate cancers and HIV acquisition. Gene expression analysis has been facilitated because of available genome sequences and large-scale transcriptomes in T. vaginalis, particularly using quantitative real-time polymerase chain reaction (qRT-PCR), one of the most used methods for molecular studies. Reference genes for normalization are crucial to ensure the accuracy of this method. However, to the best of our knowledge, a systematic validation of reference genes has not been performed for T. vaginalis. In this study, the transcripts of nine candidate reference genes were quantified using qRT-PCR under different cultivation conditions, and the stability of these genes was compared using the geNorm and NormFinder algorithms. The most stable reference genes were α-tubulin, actin and DNATopII, and, conversely, the widely used T. vaginalis reference genes GAPDH and β-tubulin were less stable. The PFOR gene was used to validate the reliability of the use of these candidate reference genes. As expected, the PFOR gene was upregulated when the trophozoites were cultivated with ferrous ammonium sulfate when the DNATopII, α-tubulin and actin genes were used as normalizing gene. By contrast, the PFOR gene was downregulated when the GAPDH gene was used as an internal control, leading to misinterpretation of the data. These results provide an important starting point for reference gene selection and gene expression analysis with qRT-PCR studies of T. vaginalis. PMID:26393928

  17. Optimal Reference Genes for Gene Expression Normalization in Trichomonas vaginalis

    PubMed Central

    dos Santos, Odelta; de Vargas Rigo, Graziela; Frasson, Amanda Piccoli; Macedo, Alexandre José; Tasca, Tiana

    2015-01-01

    Trichomonas vaginalis is the etiologic agent of trichomonosis, the most common non-viral sexually transmitted disease worldwide. This infection is associated with several health consequences, including cervical and prostate cancers and HIV acquisition. Gene expression analysis has been facilitated because of available genome sequences and large-scale transcriptomes in T. vaginalis, particularly using quantitative real-time polymerase chain reaction (qRT-PCR), one of the most used methods for molecular studies. Reference genes for normalization are crucial to ensure the accuracy of this method. However, to the best of our knowledge, a systematic validation of reference genes has not been performed for T. vaginalis. In this study, the transcripts of nine candidate reference genes were quantified using qRT-PCR under different cultivation conditions, and the stability of these genes was compared using the geNorm and NormFinder algorithms. The most stable reference genes were α-tubulin, actin and DNATopII, and, conversely, the widely used T. vaginalis reference genes GAPDH and β-tubulin were less stable. The PFOR gene was used to validate the reliability of the use of these candidate reference genes. As expected, the PFOR gene was upregulated when the trophozoites were cultivated with ferrous ammonium sulfate when the DNATopII, α-tubulin and actin genes were used as normalizing gene. By contrast, the PFOR gene was downregulated when the GAPDH gene was used as an internal control, leading to misinterpretation of the data. These results provide an important starting point for reference gene selection and gene expression analysis with qRT-PCR studies of T. vaginalis. PMID:26393928

  18. Dominance from the perspective of gene-gene and gene-chemical interactions.

    PubMed

    Gladki, Arkadiusz; Zielenkiewicz, Piotr; Kaczanowski, Szymon

    2016-02-01

    In this study, we used genetic interaction (GI) and gene-chemical interaction (GCI) data to compare mutations with different dominance phenotypes. Our analysis focused primarily on Saccharomyces cerevisiae, where haploinsufficient genes (HI; genes with dominant loss-of-function mutations) were found to be participating in gene expression processes, namely, the translation and regulation of gene transcription. Non-ribosomal HI genes (mainly regulators of gene transcription) were found to have more GIs and GCIs than haplosufficient (HS) genes. Several properties seem to lead to the enrichment of interactions, most notably, the following: importance, pleiotropy, gene expression level and gene expression variation. Importantly, after these properties were appropriately considered in the analysis, the correlation between dominance and GI/GCI degrees was still observed. Strikingly, for the GCIs of heterozygous strains, haploinsufficiency was the only property significantly correlated with the number of GCIs. We found ribosomal HI genes to be depleted in GIs/GCIs. This finding can be explained by their high variation in gene expression under different genetic backgrounds and environmental conditions. We observed the same distributions of GIs among non-ribosomal HI, ribosomal HI and HS genes in three other species: Schizosaccharomyces pombe, Drosophila melanogaster and Homo sapiens. One potentially interesting exception was the lack of significant differences in the degree of GIs between non-ribosomal HI and HS genes in Schizosaccharomyces pombe.

  19. Avirulence Genes in Cereal Powdery Mildews: The Gene-for-Gene Hypothesis 2.0.

    PubMed

    Bourras, Salim; McNally, Kaitlin E; Müller, Marion C; Wicker, Thomas; Keller, Beat

    2016-01-01

    The gene-for-gene hypothesis states that for each gene controlling resistance in the host, there is a corresponding, specific gene controlling avirulence in the pathogen. Allelic series of the cereal mildew resistance genes Pm3 and Mla provide an excellent system for genetic and molecular analysis of resistance specificity. Despite this opportunity for molecular research, avirulence genes in mildews remain underexplored. Earlier work in barley powdery mildew (B.g. hordei) has shown that the reaction to some Mla resistance alleles is controlled by multiple genes. Similarly, several genes are involved in the specific interaction of wheat mildew (B.g. tritici) with the Pm3 allelic series. We found that two mildew genes control avirulence on Pm3f: one gene is involved in recognition by the resistance protein as demonstrated by functional studies in wheat and the heterologous host Nicotiana benthamiana. A second gene is a suppressor, and resistance is only observed in mildew genotypes combining the inactive suppressor and the recognized Avr. We propose that such suppressor/avirulence gene combinations provide the basis of specificity in mildews. Depending on the particular gene combinations in a mildew race, different genes will be genetically identified as the "avirulence" gene. Additionally, the observation of two LINE retrotransposon-encoded avirulence genes in B.g. hordei further suggests that the control of avirulence in mildew is more complex than a canonical gene-for-gene interaction. To fully understand the mildew-cereal interactions, more knowledge on avirulence determinants is needed and we propose ways how this can be achieved based on recent advances in the field.

  20. Avirulence Genes in Cereal Powdery Mildews: The Gene-for-Gene Hypothesis 2.0

    PubMed Central

    Bourras, Salim; McNally, Kaitlin E.; Müller, Marion C.; Wicker, Thomas; Keller, Beat

    2016-01-01

    The gene-for-gene hypothesis states that for each gene controlling resistance in the host, there is a corresponding, specific gene controlling avirulence in the pathogen. Allelic series of the cereal mildew resistance genes Pm3 and Mla provide an excellent system for genetic and molecular analysis of resistance specificity. Despite this opportunity for molecular research, avirulence genes in mildews remain underexplored. Earlier work in barley powdery mildew (B.g. hordei) has shown that the reaction to some Mla resistance alleles is controlled by multiple genes. Similarly, several genes are involved in the specific interaction of wheat mildew (B.g. tritici) with the Pm3 allelic series. We found that two mildew genes control avirulence on Pm3f: one gene is involved in recognition by the resistance protein as demonstrated by functional studies in wheat and the heterologous host Nicotiana benthamiana. A second gene is a suppressor, and resistance is only observed in mildew genotypes combining the inactive suppressor and the recognized Avr. We propose that such suppressor/avirulence gene combinations provide the basis of specificity in mildews. Depending on the particular gene combinations in a mildew race, different genes will be genetically identified as the “avirulence” gene. Additionally, the observation of two LINE retrotransposon-encoded avirulence genes in B.g. hordei further suggests that the control of avirulence in mildew is more complex than a canonical gene-for-gene interaction. To fully understand the mildew–cereal interactions, more knowledge on avirulence determinants is needed and we propose ways how this can be achieved based on recent advances in the field. PMID:26973683

  1. Chapter 15: Disease Gene Prioritization

    PubMed Central

    Bromberg, Yana

    2013-01-01

    Disease-causing aberrations in the normal function of a gene define that gene as a disease gene. Proving a causal link between a gene and a disease experimentally is expensive and time-consuming. Comprehensive prioritization of candidate genes prior to experimental testing drastically reduces the associated costs. Computational gene prioritization is based on various pieces of correlative evidence that associate each gene with the given disease and suggest possible causal links. A fair amount of this evidence comes from high-throughput experimentation. Thus, well-developed methods are necessary to reliably deal with the quantity of information at hand. Existing gene prioritization techniques already significantly improve the outcomes of targeted experimental studies. Faster and more reliable techniques that account for novel data types are necessary for the development of new diagnostics, treatments, and cure for many diseases. PMID:23633938

  2. Evolutionary genomics: transdomain gene transfers.

    PubMed

    Bordenstein, Seth R

    2007-11-01

    Biologists have until now conceded that bacterial gene transfer to multicellular animals is relatively uncommon in Nature. A new study showing promiscuous insertions of bacterial endosymbiont genes into invertebrate genomes ushers in a shift in this paradigm.

  3. Gene Therapy for Lung Cancer.

    PubMed

    Lara-Guerra, Humberto; Roth, Jack A

    2016-01-01

    Gene therapy was originally conceived to treat monogenic diseases. The replacement of a defective gene with a functional gene can theoretically cure the disease. In cancer, multiple genetic defects are present and the molecular profile changes during the course of the disease, making the replacement of all defective genes impossible. To overcome these difficulties, various gene therapy strategies have been adopted, including immune stimulation, transfer of suicide genes, inhibition of driver oncogenes, replacement of tumor-suppressor genes that could mediate apoptosis or anti-angiogenesis, and transfer of genes that enhance conventional treatments such as radiotherapy and chemotherapy. Some of these strategies have been tested successfully in non-small-cell lung cancer patients and the results of laboratory studies and clinical trials are reviewed herein. PMID:27481008

  4. Gene Testing for Hereditary Ataxia

    MedlinePlus

    ... have a family history of ataxia, but diagnostic tests for known ataxia genes cannot explain the ataxia in their family. In recent years, scientists have developed technologies to sequence thousands of genes at the same ...

  5. RNA-mediated gene activation

    PubMed Central

    Jiao, Alan L; Slack, Frank J

    2014-01-01

    The regulation of gene expression by non-coding RNAs (ncRNAs) has become a new paradigm in biology. RNA-mediated gene silencing pathways have been studied extensively, revealing diverse epigenetic and posttranscriptional mechanisms. In contrast, the roles of ncRNAs in activating gene expression remains poorly understood. In this review, we summarize the current knowledge of gene activation by small RNAs, long non-coding RNAs, and enhancer-derived RNAs, with an emphasis on epigenetic mechanisms. PMID:24185374

  6. Gene expression technology

    SciTech Connect

    Goeddel, D.V. )

    1990-01-01

    The articles in this volume were assemble to enable the reader to design effective strategies for the expression of cloned genes and cDNAs. More than a compilation of papers describing the multitude of techniques now available for expressing cloned genes, this volume provides a manual that should prove useful for solving the majority of expression problems one likely to encounter. The four major expression systems commonly available to most investigators are stressed: Escherichia coli, Bacillus subtilis, yeast, and mammalian cells. Each of these system has its advantages and disadvantages, details of which are found in Chapter 1 and the strategic overviews for the four major sections of the volume. The papers in each of these sections provide many suggestions on how to proceed if initial expression levels are not sufficient.

  7. Brains, Genes and Primates

    PubMed Central

    Belmonte, Juan Carlos Izpisua; Callaway, Edward M.; Churchland, Patricia; Caddick, Sarah J.; Feng, Guoping; Homanics, Gregg E.; Lee, Kuo-Fen; Leopold, David A.; Miller, Cory T.; Mitchell, Jude F.; Mitalipov, Shoukhrat; Moutri, Alysson R.; Movshon, J. Anthony; Okano, Hideyuki; Reynolds, John H.; Ringach, Dario; Sejnowski, Terrence J.; Silva, Afonso C.; Strick, Peter L.; Wu, Jun; Zhang, Feng

    2015-01-01

    One of the great strengths of the mouse model is the wide array of genetic tools that have been developed. Striking examples include methods for directed modification of the genome, and for regulated expression or inactivation of genes. Within neuroscience, it is now routine to express reporter genes, neuronal activity indicators and opsins in specific neuronal types in the mouse. However, there are considerable anatomical, physiological, cognitive and behavioral differences between the mouse and the human that, in some areas of inquiry, limit the degree to which insights derived from the mouse can be applied to understanding human neurobiology. Several recent advances have now brought into reach the goal of applying these tools to understanding the primate brain. Here we describe these advances, consider their potential to advance our understanding of the human brain and brain disorders, discuss bioethical considerations, and describe what will be needed to move forward. PMID:25950631

  8. Agrobacterium virulence gene induction.

    PubMed

    Gelvin, Stanton B

    2006-01-01

    The ability of Agrobacterium to transform plants and other organisms is under highly regulated genetic control. Two Virulence (Vir) proteins, VirA and VirG, function as a two-component regulatory system to sense particular phenolic compounds synthesized by wounded plant tissues. Induction by these phenolic compounds, in the presence of certain neutral or acid sugars, results in activation of other vir genes, leading to the processing of T-DNA from the Ti-plasmid and transfer of T-DNA to recipient host cells. Many plant, and most nonplant, species do not provide sufficient quantities of the correct phenolic compounds to permit efficient Agrobacterium-mediated genetic transformation to occur. In order to transform these species, phenolic inducing compounds must be added to agrobacteria before and/or during cocultivation of recipient cells with the bacteria. This chapter discusses conditions for efficient induction of Agrobacterium virulence genes by phenolic compounds. PMID:16988335

  9. Graphene based gene transfection

    NASA Astrophysics Data System (ADS)

    Feng, Liangzhu; Zhang, Shuai; Liu, Zhuang

    2011-03-01

    Graphene as a star in materials research has been attracting tremendous attentions in the past few years in various fields including biomedicine. In this work, for the first time we successfully use graphene as a non-toxic nano-vehicle for efficient gene transfection. Graphene oxide (GO) is bound with cationic polymers, polyethyleneimine (PEI) with two different molecular weights at 1.2 kDa and 10 kDa, forming GO-PEI-1.2k and GO-PEG-10k complexes, respectively, both of which are stable in physiological solutions. Cellular toxicity tests reveal that our GO-PEI-10k complex exhibits significantly reduced toxicity to the treated cells compared to the bare PEI-10k polymer. The positively charged GO-PEI complexes are able to further bind with plasmid DNA (pDNA) for intracellular transfection of the enhanced green fluorescence protein (EGFP) gene in HeLa cells. While EGFP transfection with PEI-1.2k appears to be ineffective, high EGFP expression is observed using the corresponding GO-PEI-1.2k as the transfection agent. On the other hand, GO-PEI-10k shows similar EGFP transfection efficiency but lower toxicity compared with PEI-10k. Our results suggest graphene to be a novel gene delivery nano-vector with low cytotoxicity and high transfection efficiency, promising for future applications in non-viral based gene therapy.Graphene as a star in materials research has been attracting tremendous attentions in the past few years in various fields including biomedicine. In this work, for the first time we successfully use graphene as a non-toxic nano-vehicle for efficient gene transfection. Graphene oxide (GO) is bound with cationic polymers, polyethyleneimine (PEI) with two different molecular weights at 1.2 kDa and 10 kDa, forming GO-PEI-1.2k and GO-PEG-10k complexes, respectively, both of which are stable in physiological solutions. Cellular toxicity tests reveal that our GO-PEI-10k complex exhibits significantly reduced toxicity to the treated cells compared to the bare PEI

  10. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization

    PubMed Central

    Chen, Jing; Bardes, Eric E.; Aronow, Bruce J.; Jegga, Anil G.

    2009-01-01

    ToppGene Suite (http://toppgene.cchmc.org; this web site is free and open to all users and does not require a login to access) is a one-stop portal for (i) gene list functional enrichment, (ii) candidate gene prioritization using either functional annotations or network analysis and (iii) identification and prioritization of novel disease candidate genes in the interactome. Functional annotation-based disease candidate gene prioritization uses a fuzzy-based similarity measure to compute the similarity between any two genes based on semantic annotations. The similarity scores from individual features are combined into an overall score using statistical meta-analysis. A P-value of each annotation of a test gene is derived by random sampling of the whole genome. The protein–protein interaction network (PPIN)-based disease candidate gene prioritization uses social and Web networks analysis algorithms (extended versions of the PageRank and HITS algorithms, and the K-Step Markov method). We demonstrate the utility of ToppGene Suite using 20 recently reported GWAS-based gene–disease associations (including novel disease genes) representing five diseases. ToppGene ranked 19 of 20 (95%) candidate genes within the top 20%, while ToppNet ranked 12 of 16 (75%) candidate genes among the top 20%. PMID:19465376

  11. Independent Gene Discovery and Testing

    ERIC Educational Resources Information Center

    Palsule, Vrushalee; Coric, Dijana; Delancy, Russell; Dunham, Heather; Melancon, Caleb; Thompson, Dennis; Toms, Jamie; White, Ashley; Shultz, Jeffry

    2010-01-01

    A clear understanding of basic gene structure is critical when teaching molecular genetics, the central dogma and the biological sciences. We sought to create a gene-based teaching project to improve students' understanding of gene structure and to integrate this into a research project that can be implemented by instructors at the secondary level…

  12. nanosheets for gene therapy

    NASA Astrophysics Data System (ADS)

    Kou, Zhongyang; Wang, Xin; Yuan, Renshun; Chen, Huabin; Zhi, Qiaoming; Gao, Ling; Wang, Bin; Guo, Zhaoji; Xue, Xiaofeng; Cao, Wei; Guo, Liang

    2014-10-01

    A new class of two-dimensional (2D) nanomaterial, transition metal dichalcogenides (TMDCs) such as MoS2, MoSe2, WS2, and WSe2 which have fantastic physical and chemical properties, has drawn tremendous attention in different fields recently. Herein, we for the first time take advantage of the great potential of MoS2 with well-engineered surface as a novel type of 2D nanocarriers for gene delivery and therapy of cancer. In our system, positively charged MoS2-PEG-PEI is synthesized with lipoic acid-modified polyethylene glycol (LA-PEG) and branched polyethylenimine (PEI). The amino end of positively charged nanomaterials can bind to the negatively charged small interfering RNA (siRNA). After detection of physical and chemical characteristics of the nanomaterial, cell toxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Polo-like kinase 1 (PLK1) was investigated as a well-known oncogene, which was a critical regulator of cell cycle transmission at multiple levels. Through knockdown of PLK1 with siRNA carried by novel nanovector, qPCR and Western blot were used to measure the interfering efficiency; apoptosis assay was used to detect the transfection effect of PLK1. All results showed that the novel nanocarrier revealed good biocompatibility, reduced cytotoxicity, as well as high gene-carrying ability without serum interference, thus would have great potential for gene delivery and therapy.

  13. From SNPs to Genes: Disease Association at the Gene Level

    PubMed Central

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

    2011-01-01

    Interpreting Genome-Wide Association Studies (GWAS) at a gene level is an important step towards understanding the molecular processes that lead to disease. In order to incorporate prior biological knowledge such as pathways and protein interactions in the analysis of GWAS data it is necessary to derive one measure of association for each gene. We compare three different methods to obtain gene-wide test statistics from Single Nucleotide Polymorphism (SNP) based association data: choosing the test statistic from the most significant SNP; the mean test statistics of all SNPs; and the mean of the top quartile of all test statistics. We demonstrate that the gene-wide test statistics can be controlled for the number of SNPs within each gene and show that all three methods perform considerably better than expected by chance at identifying genes with confirmed associations. By applying each method to GWAS data for Crohn's Disease and Type 1 Diabetes we identified new potential disease genes. PMID:21738570

  14. Physical methods for gene transfer.

    PubMed

    Alsaggar, Mohammad; Liu, Dexi

    2015-01-01

    The key impediment to the successful application of gene therapy in clinics is not the paucity of therapeutic genes. It is rather the lack of nontoxic and efficient strategies to transfer therapeutic genes into target cells. Over the past few decades, considerable progress has been made in gene transfer technologies, and thus far, three different delivery systems have been developed with merits and demerits characterizing each system. Viral and chemical methods of gene transfer utilize specialized carrier to overcome membrane barrier and facilitate gene transfer into cells. Physical methods, on the other hand, utilize various forms of mechanical forces to enforce gene entry into cells. Starting in 1980s, physical methods have been introduced as alternatives to viral and chemical methods to overcome various extra- and intracellular barriers that limit the amount of DNA reaching the intended cells. Accumulating evidence suggests that it is quite feasible to directly translocate genes into cytoplasm or even nuclei of target cells by means of mechanical force, bypassing endocytosis, a common pathway for viral and nonviral vectors. Indeed, several methods have been developed, and the majority of them share the same underlying mechanism of gene transfer, i.e., physically created transient pores in cell membrane through which genes get into cells. Here, we provide an overview of the current status and future research directions in the field of physical methods of gene transfer.

  15. Horizontal gene transfer in choanoflagellates.

    PubMed

    Tucker, Richard P

    2013-01-01

    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.

  16. RANGE: Gene Transfer of Reversibly Controlled Polycistronic Genes

    PubMed Central

    Chen, Yiwei; Cao, Liji; Luo, Chonglin; Ditzel, Désirée AW; Peter, Jörg; Sprengel, Rolf

    2013-01-01

    We developed a single vector recombinant adeno-associated viral (rAAV) expression system for spatial and reversible control of polycistronic gene expression. Our approach (i) integrates the advantages of the tetracycline (Tet)-controlled transcriptional silencer tTSKid and the self-cleaving 2A peptide bridge, (ii) combines essential regulatory components as an autoregulatory loop, (iii) simplifies the gene delivery scheme, and (iv) regulates multiple genes in a synchronized manner. Controlled by an upstream Tet-responsive element (TRE), both the ubiquitous chicken β-actin promoter (CAG) and the neuron-specific synapsin-1 promoter (Syn) could regulate expression of tTSKid together with two 2A-linked reporter genes. Transduction in vitro exhibited maximally 50-fold regulation by doxycycline (Dox). Determined by gene delivery method as well as promoter, highly specific tissues were transduced in vivo. Bioluminescence imaging (BLI) visualized reversible “ON/OFF” gene switches over repeated “Doxy-Cycling” in living mice. Thus, the reversible rAAV-mediated N-cistronic gene expression system, termed RANGE, may serve as a versatile tool to achieve reversible polycistronic gene regulation for the study of gene function as well as gene therapy. PMID:23571608

  17. Diseases originate and terminate by genes: unraveling nonviral gene delivery.

    PubMed

    Swami, Rajan; Singh, Indu; Khan, Wahid; Ramakrishna, Sistla

    2013-12-01

    The world is driving in to the era of transformation of chemical therapeutic molecules to biological genetic material therapeutics, and that is where the biological drugs especially "genes" come into existence. These genes worked as "magical bullets" to specifically silence faulty genes responsible for progression of diseases. Viral gene delivery research is far ahead of nonviral gene delivery technique. However, with more advancement in polymer science, new ways are opening for better and efficient nonviral gene delivery. But efficient delivery method is always considered as a bottleneck for gene delivery as success of which will decide the fate of gene in cells. During the past decade, it became evident that extracellular as well as intracellular barriers compromise the transfection efficiency of nonviral vectors. The challenge for gene therapy research is to pinpoint the rate-limiting steps in this complex process and implement strategies to overcome the biological physiochemical and metabolic barriers encountered during targeting. The synergy between studies that investigate the mechanism of breaking in and breaking out of nonviral gene delivery carrier through various extracellular and intracellular barriers with desired characteristics will enable the rational design of vehicles and revolutionize the treatment of various diseases.

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

    PubMed

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

    2010-01-01

    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.

  19. Five New Genes Linked to Colon Cancer

    MedlinePlus

    ... More Health News on: Colorectal Cancer Genes and Gene Therapy Recent Health News Related MedlinePlus Health Topics Colorectal Cancer Genes and Gene Therapy About MedlinePlus Site Map FAQs Contact Us Get ...

  20. Breast cancer susceptibility genes.

    PubMed

    Lubinski, Jan; Korzen, Marcin; Gorski, Bohdan; Cybulski, Cezary; Debniak, Tadeusz; Jakubowska, Anna; Medrek, Krzysztof; Matyjasik, Joanna; Huzarski, Tomasz; Byrski, Tomasz; Gronwald, Jacek; Masojc, Bartlomiej; Lener, Marcin; Szymanska, Anna; Szymanska-Pasternak, Jolanta; Fernandez, Pablo Serrano; Wokolorczyk, Dominika; Piegat, Andrzej; Ucinski, Michal; Domagala, Pawel; Kladny, Jozef; Gorecka, Barbara; Scott, Rodney; Narod, Steven

    2007-09-01

    In 1999 it has been recognized that 3 BRCA1 abnormalities - 5382insC, C61G and 4153delA - constitute almost 90% of all germline mutations of this gene in Poland. Due to the above findings we started performing the cheap and quick large scale testing for BRCA1 mutations and, these days, we have almost 4,000 carriers diagnosed and under direct or indirect supervision what is probably the largest number in the world. Additionally, the above results pushed us to hypothesize that genetic homogeneity will be seen in Poland in studies of other genes. Actually, the next studies allowed us to identify genes / changes associated with moderate / low breast cancer risk and showed, similarly to BRCA1, high level of genetic homogeneity. This series included BRCA2, C5972T, CHEK2 del5395; 1100delC, I157T or IVS2 + 1G > A, CDKN2A (p16) A148T, XPD Asp312Asn and Lys751Gln, CYP1B1 R48G, A119S and L43V. The results of the above studies led us in 2004 already to hypothesize that >90% of all cancers have genetic (constitutional) background. Two years later we were able to show a panel of markers covering 92% of consecutive breast cancers in Poland, and we formulated the hypothesis that all cancers have a genetic background. These days we are demonstrating for the first time that genetic components to malignancy play a role in all cancers. We are presenting it on examples of late-onset breast cancers from Poland, but it seems to be justified to expect that similar results can be achieved from other malignancies. PMID:17935274

  1. Gene transfer: transduction.

    PubMed

    Frangipani, Emanuela

    2014-01-01

    Bacteriophages able to propagate on Pseudomonas strains are very common and can be easily isolated from natural environments or lysogenic strains. The development of transducing systems has allowed bacterial geneticists to perform chromosome analyses and mutation mapping. Moreover, these systems have also been proved to be a successful tool for molecular microbiologists to introduce a foreign gene or a mutation into the chromosome of a bacterial cell. This chapter provides a description of the phage methodology illustrated by Adams in 1959 and applicable to strain PAO1 derivatives. PMID:24818891

  2. MYCN Gene Amplification

    PubMed Central

    Yoshimoto, Maisa; Caminada de Toledo, Silvia Regina; Monteiro Caran, Eliana Maria; de Seixas, Maria Teresa; de Martino Lee, Maria Lucia; de Campos Vieira Abib, Simone; Vianna, Sonia Maria Rossi; Schettini, Sergio Thomaz; Anderson Duffles Andrade, Joyce

    1999-01-01

    Neuroblastoma is the second most common solid tumor occurring in children. Amplification of the MYCN oncogene is associated with poor prognosis. To identify neuroblastoma tumors with MYCN amplification, we studied the number of copies of MYCN in interphase cells by fluorescence in situ hybridization in 20 neuroblastoma patients. MYCN amplification appeared in 7 tumor specimens. Interphase and metaphase studies showed a tumor cell population with both forms of amplification, double minutes and homogeneously staining regions, in two patients. These patients showed a smaller tumor cell subpopulation with the presence of more than one homogeneously staining region, suggesting that gene amplification was undergoing karyotype evolution. PMID:10550298

  3. Computation in gene networks

    NASA Astrophysics Data System (ADS)

    Ben-Hur, Asa; Siegelmann, Hava T.

    2004-03-01

    Genetic regulatory networks have the complex task of controlling all aspects of life. Using a model of gene expression by piecewise linear differential equations we show that this process can be considered as a process of computation. This is demonstrated by showing that this model can simulate memory bounded Turing machines. The simulation is robust with respect to perturbations of the system, an important property for both analog computers and biological systems. Robustness is achieved using a condition that ensures that the model equations, that are generally chaotic, follow a predictable dynamics.

  4. Human AZU-1 gene, variants thereof and expressed gene products

    DOEpatents

    Chen, Huei-Mei; Bissell, Mina

    2004-06-22

    A human AZU-1 gene, mutants, variants and fragments thereof. Protein products encoded by the AZU-1 gene and homologs encoded by the variants of AZU-1 gene acting as tumor suppressors or markers of malignancy progression and tumorigenicity reversion. Identification, isolation and characterization of AZU-1 and AZU-2 genes localized to a tumor suppressive locus at chromosome 10q26, highly expressed in nonmalignant and premalignant cells derived from a human breast tumor progression model. A recombinant full length protein sequences encoded by the AZU-1 gene and nucleotide sequences of AZU-1 and AZU-2 genes and variant and fragments thereof. Monoclonal or polyclonal antibodies specific to AZU-1, AZU-2 encoded protein and to AZU-1, or AZU-2 encoded protein homologs.

  5. Imprinting genes associated with endometriosis

    PubMed Central

    Kobayashi, Hiroshi

    2014-01-01

    Purpose: Much work has been carried out to investigate the genetic and epigenetic basis of endometriosis and proposed that endometriosis has been described as an epigenetic disease. The purpose of this study was to extract the imprinting genes that are associated with endometriosis development. Methods: The information on the imprinting genes can be accessed publicly from a web-based interface at http://www.geneimprint.com/site/genes-by-species. Results: In the current version, the database contains 150 human imprinted genes derived from the literature. We searched gene functions and their roles in particular biological processes or events, such as development and pathogenesis of endometriosis. From the genomic imprinting database, we picked 10 genes that were highly associated with female reproduction; prominent among them were paternally expressed genes (DIRAS3, BMP8B, CYP1B1, ZFAT, IGF2, MIMT1, or MIR296) and maternally expressed genes (DVL1, FGFRL1, or CDKN1C). These imprinted genes may be associated with reproductive biology such as endometriosis, pregnancy loss, decidualization process and preeclampsia. Discussion: This study supports the possibility that aberrant epigenetic dysregulation of specific imprinting genes may contribute to endometriosis predisposition. PMID:26417259

  6. Vectors for cancer gene therapy.

    PubMed

    Zhang, J; Russell, S J

    1996-09-01

    Many viral and non-viral vector systems have now been developed for gene therapy applications. In this article, the pros and cons of these vector systems are discussed in relation to the different cancer gene therapy strategies. The protocols used in cancer gene therapy can be broadly divided into six categories including gene transfer to explanted cells for use as cell-based cancer vaccines; gene transfer to a small number of tumour cells in situ to achieve a vaccine effect; gene transfer to vascular endothelial cells (VECs) lining the blood vessels of the tumour to interfere with tumour angiogenesis; gene transfer to T lymphocytes to enhance their antitumour effector capability; gene transfer to haemopoietic stem cells (HSCs) to enhance their resistance to cytotoxic drugs and gene transfer to a large number of tumour cells in situ to achieve nonimmune tumour reduction with or without bystander effect. Each of the six strategies makes unique demands on the vector system and these are discussed with reference to currently available vectors. Aspects of vector biology that are in need of further development are discussed in some detail. The final section points to the potential use of replicating viruses as delivery vehicles for efficient in vivo gene transfer to disseminated cancers.

  7. The Zebrafish Annexin Gene Family

    PubMed Central

    Farber, Steven A.; De Rose, Robert A.; Olson, Eric S.; Halpern, Marnie E.

    2003-01-01

    The Annexins (ANXs) are a family of calcium- and phospholipid-binding proteins that have been implicated in many cellular processes, including channel formation, membrane fusion, vesicle transport, and regulation of phospholipase A2 activity. As a first step toward understanding in vivo function, we have cloned 11 zebrafish anx genes. Four genes (anx1a, anx2a, anx5,and anx11a) were identified by screening a zebrafish cDNA library with a Xenopus anx2 fragment. For these genes, full-length cDNA sequences were used to cluster 212 EST sequences generated by the Zebrafish Genome Resources Project. The EST analysis revealed seven additional anx genes that were subsequently cloned. The genetic map positions of all 11 genes were determined by using a zebrafish radiation hybrid panel. Sequence and syntenic relationships between zebrafish and human genes indicate that the 11 genes represent orthologs of human anx1,2,4,5,6,11,13,and suggest that several zebrafish anx genes resulted from duplications that arose after divergence of the zebrafish and mammalian genomes. Zebrafish anx genes are expressed in a wide range of tissues during embryonic and larval stages. Analysis of the expression patterns of duplicated genes revealed both redundancy and divergence, with the most similar genes having almost identical tissue-specific patterns of expression and with less similar duplicates showing no overlap. The differences in gene expression of recently duplicated anx genes could explain why highly related paralogs were maintained in the genome and did not rapidly become pseudogenes. PMID:12799347

  8. Learning About Gene Regulatory Networks From Gene Deletion Experiments

    PubMed Central

    Brazma, Alvis

    2002-01-01

    Gene regulatory networks are a major focus of interest in molecular biology. A crucial question is how complex regulatory systems are encoded and controlled by the genome. Three recent publications have raised the question of what can be learned about gene regulatory networks from microarray experiments on gene deletion mutants. Using this indirect approach, topological features such as connectivity and modularity have been studied. PMID:18629255

  9. Ancient origins of axial patterning genes: Hox genes and ParaHox genes in the Cnidaria.

    PubMed

    Finnerty, J R; Martindale, M Q

    1999-01-01

    Among the bilaterally symmetrical, triploblastic animals (the Bilateria), a conserved set of developmental regulatory genes are known to function in patterning the anterior-posterior (AP) axis. This set includes the well-studied Hox cluster genes, and the recently described genes of the ParaHox cluster, which is believed to be the evolutionary sister of the Hox cluster (Brooke et al. 1998). The conserved role of these axial patterning genes in animals as diverse as frogs and flies is believed to reflect an underlying homology (i.e., all bilaterians derive from a common ancestor which possessed an AP axis and the developmental mechanisms responsible for patterning the axis). However, the origin and early evolution of Hox genes and ParaHox genes remain obscure. Repeated attempts have been made to reconstruct the early evolution of Hox genes by analyzing data from the triphoblastic animals, the Bilateria (Schubert et al. 1993; Zhang and Nei 1996). A more precise dating of Hox origins has been elusive due to a lack of sufficient information from outgroup taxa such as the phylum Cnidaria (corals, hydras, jellyfishes, and sea anemones). In combination with outgroup taxa, another potential source of information about Hox origins is outgroup genes (e.g., the genes of the ParaHox cluster). In this article, we present cDNA sequences of two Hox-like genes (anthox2 and anthox6) from the sea anemone, Nematostella vectensis. Phylogenetic analysis indicates that anthox2 (= Cnox2) is homologous to the GSX class of ParaHox genes, and anthox6 is homologous to the anterior class of Hox genes. Therefore, the origin of Hox genes and ParaHox genes occurred prior to the evolutionary split between the Cnidaria and the Bilateria and predated the evolution of the anterior-posterior axis of bilaterian animals. Our analysis also suggests that the central Hox class was invented in the bilaterian lineage, subsequent to their split from the Cnidaria.

  10. Identifying driver genes in cancer by triangulating gene expression, gene location, and survival data.

    PubMed

    Rouam, Sigrid; Miller, Lance D; Karuturi, R Krishna Murthy

    2014-01-01

    Driver genes are directly responsible for oncogenesis and identifying them is essential in order to fully understand the mechanisms of cancer. However, it is difficult to delineate them from the larger pool of genes that are deregulated in cancer (ie, passenger genes). In order to address this problem, we developed an approach called TRIAngulating Gene Expression (TRIAGE through clinico-genomic intersects). Here, we present a refinement of this approach incorporating a new scoring methodology to identify putative driver genes that are deregulated in cancer. TRIAGE triangulates - or integrates - three levels of information: gene expression, gene location, and patient survival. First, TRIAGE identifies regions of deregulated expression (ie, expression footprints) by deriving a newly established measure called the Local Singular Value Decomposition (LSVD) score for each locus. Driver genes are then distinguished from passenger genes using dual survival analyses. Incorporating measurements of gene expression and weighting them according to the LSVD weight of each tumor, these analyses are performed using the genes located in significant expression footprints. Here, we first use simulated data to characterize the newly established LSVD score. We then present the results of our application of this refined version of TRIAGE to gene expression data from five cancer types. This refined version of TRIAGE not only allowed us to identify known prominent driver genes, such as MMP1, IL8, and COL1A2, but it also led us to identify several novel ones. These results illustrate that TRIAGE complements existing tools, allows for the identification of genes that drive cancer and could perhaps elucidate potential future targets of novel anticancer therapeutics.

  11. Ancient origins of axial patterning genes: Hox genes and ParaHox genes in the Cnidaria.

    PubMed

    Finnerty, J R; Martindale, M Q

    1999-01-01

    Among the bilaterally symmetrical, triploblastic animals (the Bilateria), a conserved set of developmental regulatory genes are known to function in patterning the anterior-posterior (AP) axis. This set includes the well-studied Hox cluster genes, and the recently described genes of the ParaHox cluster, which is believed to be the evolutionary sister of the Hox cluster (Brooke et al. 1998). The conserved role of these axial patterning genes in animals as diverse as frogs and flies is believed to reflect an underlying homology (i.e., all bilaterians derive from a common ancestor which possessed an AP axis and the developmental mechanisms responsible for patterning the axis). However, the origin and early evolution of Hox genes and ParaHox genes remain obscure. Repeated attempts have been made to reconstruct the early evolution of Hox genes by analyzing data from the triphoblastic animals, the Bilateria (Schubert et al. 1993; Zhang and Nei 1996). A more precise dating of Hox origins has been elusive due to a lack of sufficient information from outgroup taxa such as the phylum Cnidaria (corals, hydras, jellyfishes, and sea anemones). In combination with outgroup taxa, another potential source of information about Hox origins is outgroup genes (e.g., the genes of the ParaHox cluster). In this article, we present cDNA sequences of two Hox-like genes (anthox2 and anthox6) from the sea anemone, Nematostella vectensis. Phylogenetic analysis indicates that anthox2 (= Cnox2) is homologous to the GSX class of ParaHox genes, and anthox6 is homologous to the anterior class of Hox genes. Therefore, the origin of Hox genes and ParaHox genes occurred prior to the evolutionary split between the Cnidaria and the Bilateria and predated the evolution of the anterior-posterior axis of bilaterian animals. Our analysis also suggests that the central Hox class was invented in the bilaterian lineage, subsequent to their split from the Cnidaria. PMID:11324016

  12. Genes and causation.

    PubMed

    Noble, Denis

    2008-09-13

    Relating genotypes to phenotypes is problematic not only owing to the extreme complexity of the interactions between genes, proteins and high-level physiological functions but also because the paradigms for genetic causality in biological systems are seriously confused. This paper examines some of the misconceptions, starting with the changing definitions of a gene, from the cause of phenotype characters to the stretches of DNA. I then assess whether the 'digital' nature of DNA sequences guarantees primacy in causation compared to non-DNA inheritance, whether it is meaningful or useful to refer to genetic programs, and the role of high-level (downward) causation. The metaphors that served us well during the molecular biological phase of recent decades have limited or even misleading impacts in the multilevel world of systems biology. New paradigms are needed if we are to succeed in unravelling multifactorial genetic causation at higher levels of physiological function and so to explain the phenomena that genetics was originally about. Because it can solve the 'genetic differential effect problem', modelling of biological function has an essential role to play in unravelling genetic causation.

  13. Gene set enrichment analysis.

    PubMed

    Tilford, Charles A; Siemers, Nathan O

    2009-01-01

    Set enrichment analytical methods have become commonplace tools applied to the analysis and interpretation of biological data. The statistical techniques are used to identify categorical biases within lists of genes, proteins, or metabolites. The goal is to discover the shared functions or properties of the biological items represented within the lists. Application of these methods can provide great biological insight, including the discovery of participation in the same biological activity or pathway, shared interacting genes or regulators, common cellular compartmentalization, or association with disease. The methods require ordered or unordered lists of biological items as input, understanding of the reference set from which the lists were selected, categorical classifiers describing the items, and a statistical algorithm to assess bias of each classifier. Due to the complexity of most algorithms and the number of calculations performed, computer software is almost always used for execution of the algorithm, as well as for presentation of the results. This chapter will provide an overview of the statistical methods used to perform an enrichment analysis. Guidelines for assembly of the requisite information will be presented, with a focus on careful definition of the sets used by the statistical algorithms. The need for multiple test correction when working with large libraries of classifiers is emphasized, and we outline several options for performing the corrections. Finally, interpreting the results of such analysis will be discussed along with examples of recent research utilizing the techniques.

  14. Tetraspanin genes in plants.

    PubMed

    Wang, Feng; Vandepoele, Klaas; Van Lijsebettens, Mieke

    2012-07-01

    Tetraspanins represent a four-transmembrane protein superfamily with a conserved structure and amino acid residues that are present in mammals, insects, fungi and plants. Tetraspanins interact with each other or with other membrane proteins to form tetraspanin-enriched microdomains that play important roles in development, pathogenesis and immune responses via facilitating cell-cell adhesion and fusion, ligand binding and intracellular trafficking. Here, we emphasize evolutionary aspects within the plant kingdom based on genomic sequence information. A phylogenetic tree based on 155 tetraspanin genes of 11 plant species revealed ancient and fast evolving clades. Tetraspanins were only present in multicellular plants, were often duplicated in the plant genomes and predicted by the electronic Fluorescent Pictograph for gene expression analysis to be either functionally redundant or divergent. Tetraspanins contain a large extracellular loop with conserved cysteines that provide the binding sites for the interactions. The Arabidopsis thaliana TETRASPANIN1/TORNADO2/EKEKO has a function in leaf and root patterning and TETRASPANIN3 was identified in the plasmodesmatal proteome, suggesting a role in cell-cell communication during plant development.

  15. Genes of aging.

    PubMed

    Hamet, Pavel; Tremblay, Johanne

    2003-10-01

    According to developmental genetics theories, aging is a genetically programmed and controlled continuum of development and maturation. Being dynamic and malleable processes, development and aging are controlled not only by genes but also by environmental and epigenetic influences that predominate in the second half of life. Genetic mutations affect many phenotypes in flies, worms, rodents, and humans which share several diseases or their equivalents, including cancer, neurodegeneration, and infectious disorders as well as their susceptibility to them. Life span and stress resistance are closely linked. Oxidative stress actually constitutes a defined hypothesis of aging in that macromolecule oxidative damage accumulates with age and tends to be associated with life expectancy. DNA methylation, a force in the regulation of gene expression, is also one of the biomarkers of genetic damage. The mitotic clock of aging is marked, if not guided, by telomeres, essential genetic elements stabilizing natural chromosomic ends. The dream of humans to live longer, healthy lives is being tested by attempts to modify longevity in animal models, frequently by dietary manipulation. The quest continues to understand the mechanisms of healthy aging, one of the most compelling areas of research in the 21st century. PMID:14577056

  16. Adenoviral vector-mediated gene transfer for human gene therapy.

    PubMed

    Breyer, B; Jiang, W; Cheng, H; Zhou, L; Paul, R; Feng, T; He, T C

    2001-07-01

    Human gene therapy promises to change the practice of medicine by treating the causes of disease rather than the symptoms. Since the first clinical trial made its debut ten years ago, there are over 400 approved protocols in the United States alone, most of which have failed to show convincing data of clinical efficacy. This setback is largely due to the lack of efficient and adequate gene transfer vehicles. With the recent progress in elucidating the molecular mechanisms of human diseases and the imminent arrival of the post genomic era, there are increasing numbers of therapeutic genes or targets that are available for gene therapy. Therefore, the urgency and need for efficacious gene therapies are greater than ever. Clearly, the current fundamental obstacle is to develop delivery vectors that exhibit high efficacy and specificity of gene transfer. Recombinant adenoviruses have provided a versatile system for gene expression studies and therapeutic applications. Of late, there has been a remarkable increase in adenoviral vector-based clinical trials. Recent endeavors in the development of recombinant adenoviral vectors have focused on modification of virus tropism, accommodation of larger genes, increase in stability and control of transgene expression, and down-modulation of host immune responses. These modifications and continued improvements in adenoviral vectors will provide a great opportunity for human gene therapy to live up to its enormous potential in the second decade.

  17. Bacteriophage phiX174: gene A overlaps gene B.

    PubMed Central

    Weisbeek, P J; Borrias, W E; Langeveld, S A; Baas, P D; Van Arkel, G A

    1977-01-01

    The map position of several phiX174 mutations in the genes A and B was determined by marker rescue with DNA fragments produced by the restriction enzymes Hha I, HindII, Hae III, and Alu I. All the gene B mutants were found to be located within gene A. Genetic complementation and analysis of phage-specific protein synthesis show that, under restrictive conditions, nonsense mutants in gene A do not block the synthesis and activity of the B protein and nonsense mutants in gene B do not affect the gene A function. The map position of the COOH-terminal end of gene A was determined using an amber mutant that synthesizes slightly shortened A and A proteins. It is concluded from these experiments that gene A overlaps gene B completely (or almost completely) and that the overlap region can be translated in two ways with different reading frames: one frame for the synthesis of the A and A proteins and another for the synthesis of the B protein. Images PMID:267943

  18. Gene-targeting pharmaceuticals for single-gene disorders.

    PubMed

    Beaudet, Arthur L; Meng, Linyan

    2016-04-15

    The concept of orphan drugs for treatment of orphan genetic diseases is perceived enthusiastically at present, and this is leading to research investment on the part of governments, disease-specific foundations and industry. This review attempts to survey the potential to use traditional pharmaceuticals as opposed to biopharmaceuticals to treat single-gene disorders. The available strategies include the use of antisense oligonucleotides (ASOs) to alter splicing or knock-down expression of a transcript, siRNAs to knock-down gene expression and drugs for nonsense mutation read-through. There is an approved drug for biallelic knock-down of the APOB gene as treatment for familial hypercholesterolemia. Both ASOs and siRNAs are being explored to knock-down the transthyretin gene to prevent the related form of amyloidosis. The use of ASOs to alter gene-splicing to treat spinal muscular atrophy is in phase 3 clinical trials. Work is progressing on the use of ASOs to activate the normally silent paternal copy of the imprinted UBE3A gene in neurons as a treatment for Angelman syndrome. A gene-activation or gene-specific ramp-up strategy would be generally helpful if such could be developed. There is exciting theoretical potential for converting biopharmaceutical strategies such gene correction and CRISPR-Cas9 editing to a synthetic pharmaceutical approach. PMID:26628634

  19. Sexually antagonistic genes: experimental evidence.

    PubMed

    Rice, W R

    1992-06-01

    When selection differs between the sexes, a mutation beneficial to one sex may be harmful to the other (sexually antagonistic). Because the sexes share a common gene pool, selection in one sex can interfere with the other's adaptive evolution. Theory predicts that sexually antagonistic mutations should accumulate in tight linkage with a new sex-determining gene, even when the harm to benefit ratio is high. Genetic markers and artificial selection were used to make a pair of autosomal genes segregate like a new pair of sex-determining genes in a Drosophila melanogaster model system. A 29-generation study provides experimental evidence that sexually antagonistic genes may be common in nature and will accumulate in response to a new sex-determining gene. PMID:1604317

  20. Gene Therapy for Cartilage Repair

    PubMed Central

    Madry, Henning; Orth, Patrick; Cucchiarini, Magali

    2011-01-01

    The concept of using gene transfer strategies for cartilage repair originates from the idea of transferring genes encoding therapeutic factors into the repair tissue, resulting in a temporarily and spatially defined delivery of therapeutic molecules to sites of cartilage damage. This review focuses on the potential benefits of using gene therapy approaches for the repair of articular cartilage and meniscal fibrocartilage, including articular cartilage defects resulting from acute trauma, osteochondritis dissecans, osteonecrosis, and osteoarthritis. Possible applications for meniscal repair comprise meniscal lesions, meniscal sutures, and meniscal transplantation. Recent studies in both small and large animal models have demonstrated the applicability of gene-based approaches for cartilage repair. Chondrogenic pathways were stimulated in the repair tissue and in osteoarthritic cartilage using genes for polypeptide growth factors and transcription factors. Although encouraging data have been generated, a successful translation of gene therapy for cartilage repair will require an ongoing combined effort of orthopedic surgeons and of basic scientists. PMID:26069580

  1. Gene targeting with retroviral vectors

    SciTech Connect

    Ellis, J.; Bernstein, A. )

    1989-04-01

    The authors have designed and constructed integration-defective retroviral vectors to explore their potential for gene targeting in mammalian cells. Two nonoverlapping deletion mutants of the bacterial neomycin resistance (neo) gene were used to detect homologous recombination events between viral and chromosomal sequences. Stable neo gene correction events were selected at a frequency of approximately 1 G418/sup r/ cell per 3 x 10/sup 6/ infected cells. Analysis of the functional neo gene in independent targeted cell clones indicated that unintegrated retroviral linear DNA recombined with the target by gene conversion for variable distances into regions of nonhomology. In addition, transient neo gene correction events which were associated with the complete loss of the chromosomal target sequences were observed. These results demonstrated that retroviral vectors can recombine with homologous chromosomal sequences in rodent and human cells.

  2. The coalescent with gene conversion.

    PubMed Central

    Wiuf, C; Hein, J

    2000-01-01

    In this article we develop a coalescent model with intralocus gene conversion. The distribution of the tract length is geometric in concordance with results published in the literature. We derive a simulation scheme and deduce a number of analytical results for this coalescent with gene conversion. We compare patterns of variability in samples simulated according to the coalescent with recombination with similar patterns simulated according to the coalescent with gene conversion alone. Further, an expression for the expected number of topology shifts in a sample of present-day sequences caused by gene conversion events is derived. PMID:10790416

  3. Serial analysis of gene expression.

    PubMed

    Velculescu, V E; Zhang, L; Vogelstein, B; Kinzler, K W

    1995-10-20

    The characteristics of an organism are determined by the genes expressed within it. A method was developed, called serial analysis of gene expression (SAGE), that allows the quantitative and simultaneous analysis of a large number of transcripts. To demonstrate this strategy, short diagnostic sequence tags were isolated from pancreas, concatenated, and cloned. Manual sequencing of 1000 tags revealed a gene expression pattern characteristic of pancreatic function. New pancreatic transcripts corresponding to novel tags were identified. SAGE should provide a broadly applicable means for the quantitative cataloging and comparison of expressed genes in a variety of normal, developmental, and disease states. PMID:7570003

  4. Method for cloning genes

    SciTech Connect

    Weissman, S.M.; Pereira, D.; Sood, A.

    1988-04-19

    This patent describes a recombinant cloning vehicle comprising an inserted human gene, the improvement wherein the cloning vehicle is isolated from a recombinant clone which is isolated and identified by a process comprising the steps of: (a) effecting cDNA synthesis on a mixture of mRNAs containing a target mRNA coding for a major hisitocompatibility antigen, and isolating the resultant cDNA mixture; (b) inserting the resultant cDNA into recombinant cloning vehicles, and transforming hosts with the vehicles; and (c) separating the transformants and isolating and identifying a recombinant clone containing a DNA segment which is homologous over at least a portion thereof to at least one oligonucleotide probe specific for the DNA segment.

  5. New genes for boys

    SciTech Connect

    Sinclair, A.H.

    1995-11-01

    Sex is a fascinating topic, particularly at the level of molecular genetics, since it represents a wonderful paradigm for mammalian organ development. Recently, interest in the molecular basis for mammalian sex determination has been heating up as new pieces are added to the jigsaw puzzle of testis development. In mammals, the Y chromosome is male determining and encodes a gene referred to as TDF (testis-determining factor), which induces the indifferent embryonic gonad to develop as a testis. Subsequent male sexual differentiation is largely a consequence of hormonal secretion from the testis. In the absence of the Y chromosome, the testis-determining pathway fails to be initiated, and the embryonic gonad develops as an ovary, resulting in female development. 32 refs.

  6. Copyright and gene technology.

    PubMed

    Coke, Sue

    2002-08-01

    The rapid growth of gene technology and its commercialisation raises concerns for scientific researchers and research institutions wishing to place information in the public domain. This article examines whether copyright laws in the United States, United Kingdom and Australia provide any protection for genetically modified DNA, proteins, and genetically modified organisms, in contrast with any copyright protection extending to a record of the lettering of a sequence representing a series of nucleotides of modified DNA or the amino acids comprising a protein. Whilst it is arguable that protection may be available in the United States and the United Kingdom, it is submitted that it would be difficult to persuade a court in Australia that genetically modified DNA and genetically modified organisms directly constitute "literary" or "artistic" works.

  7. Taste Receptor Genes

    PubMed Central

    Bachmanov, Alexander A.; Beauchamp, Gary K.

    2009-01-01

    In the past several years, tremendous progress has been achieved with the discovery and characterization of vertebrate taste receptors from the T1R and T2R families, which are involved in recognition of bitter, sweet, and umami taste stimuli. Individual differences in taste, at least in some cases, can be attributed to allelic variants of the T1R and T2R genes. Progress with understanding how T1R and T2R receptors interact with taste stimuli and with identifying their patterns of expression in taste cells sheds light on coding of taste information by the nervous system. Candidate mechanisms for detection of salts, acids, fat, complex carbohydrates, and water have also been proposed, but further studies are needed to prove their identity. PMID:17444812

  8. Gene-environment interaction.

    PubMed

    Manuck, Stephen B; McCaffery, Jeanne M

    2014-01-01

    With the advent of increasingly accessible technologies for typing genetic variation, studies of gene-environment (G×E) interactions have proliferated in psychological research. Among the aims of such studies are testing developmental hypotheses and models of the etiology of behavioral disorders, defining boundaries of genetic and environmental influences, and identifying individuals most susceptible to risk exposures or most amenable to preventive and therapeutic interventions. This research also coincides with the emergence of unanticipated difficulties in detecting genetic variants of direct association with behavioral traits and disorders, which may be obscured if genetic effects are expressed only in predisposing environments. In this essay we consider these and other rationales for positing G×E interactions, review conceptual models meant to inform G×E interpretations from a psychological perspective, discuss points of common critique to which G×E research is vulnerable, and address the role of the environment in G×E interactions.

  9. Gene therapy for hemophilia

    PubMed Central

    Rogers, Geoffrey L.; Herzog, Roland W.

    2015-01-01

    Hemophilia is an X-linked inherited bleeding disorder consisting of two classifications, hemophilia A and hemophilia B, depending on the underlying mutation. Although the disease is currently treatable with intravenous delivery of replacement recombinant clotting factor, this approach represents a significant cost both monetarily and in terms of quality of life. Gene therapy is an attractive alternative approach to the treatment of hemophilia that would ideally provide life-long correction of clotting activity with a single injection. In this review, we will discuss the multitude of approaches that have been explored for the treatment of both hemophilia A and B, including both in vivo and ex vivo approaches with viral and nonviral delivery vectors. PMID:25553466

  10. Gene Express Inc.

    PubMed

    Saccomanno, Colette F

    2006-07-01

    Gene Express, Inc. is a technology-licensing company and provider of Standardized Reverse Transcription Polymerase Chain Reaction (StaRT-PCR) services. Designed by and for clinical researchers involved in pharmaceutical, biomarker and molecular diagnostic product development, StaRT-PCR is a unique quantitative and standardized multigene expression measurement platform. StaRT-PCR meets all of the performance characteristics defined by the US FDA as required to support regulatory submissions [101,102] , and by the Clinical Laboratory Improvement Act of 1988 (CLIA) as necessary to support diagnostic testing [1] . A standardized mixture of internal standards (SMIS), manufactured in bulk, provides integrated quality control wherein each native template target gene is measured relative to a competitive template internal standard. Bulk production enables the compilation of a comprehensive standardized database from across multiple experiments, across collaborating laboratories and across the entire clinical development lifecycle of a given compound or diagnostic product. For the first time, all these data are able to be directly compared. Access to such a database can dramatically shorten the time from investigational new drug (IND) to new drug application (NDA), or save time and money by hastening a substantiated 'no-go' decision. High-throughput StaRT-PCR is conducted at the company's automated Standardized Expression Measurement (SEM) Center. Currently optimized for detection on a microcapillary electrophoretic platform, StaRT-PCR products also may be analyzed on microarray, high-performance liquid chromatography (HPLC), or matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) platforms. SEM Center services deliver standardized genomic data--data that will accelerate the application of pharmacogenomic technology to new drug and diagnostic test development and facilitate personalized medicine.

  11. Contributions of Gene Marking to Cell and Gene Therapies

    PubMed Central

    Barese, Cecilia N.

    2011-01-01

    Abstract The first human genetic modification studies used replication-incompetent integrating vector vectors to introduce marker genes into T lymphocytes and subsequently into hematopoietic stem cells. Such studies have provided numerous insights into the biology of hematopoiesis and immune reconstitution and contributed to clinical development of gene and cell therapies. Tracking of hematopoietic reconstitution and analysis of the origin of residual malignant disease after hematopoietic transplantation has been possible via gene marking. Introduction of selectable marker genes has enabled preselection of specific T-cell populations for tumor and viral immunotherapy and reduced the threat of graft-versus-host disease, improving the survival of patients after allogeneic marrow transplantation. Marking studies in humans, murine xenografts, and large animals have helped optimize conditions for gene transfer into CD34+ hematopoietic progenitors, contributing to the achievement of gene transfer efficiencies sufficient for clinical benefit in several serious genetic diseases such as X-linked severe combined immunodeficiency and adrenoleukodystropy. When adverse events linked to insertional mutagenesis arose in clinical gene therapy trials for inherited immunodeficiencies, additional animal studies using gene-marking vectors have greatly increased our understanding of genotoxicity. The knowledge gained from these studies is being translated into new vector designs and clinical protocols, which we hope will continue to improve the efficiency, effectiveness and safety of these promising therapeutic approaches. PMID:21261461

  12. Contributions of gene marking to cell and gene therapies.

    PubMed

    Barese, Cecilia N; Dunbar, Cynthia E

    2011-06-01

    The first human genetic modification studies used replication-incompetent integrating vector vectors to introduce marker genes into T lymphocytes and subsequently into hematopoietic stem cells. Such studies have provided numerous insights into the biology of hematopoiesis and immune reconstitution and contributed to clinical development of gene and cell therapies. Tracking of hematopoietic reconstitution and analysis of the origin of residual malignant disease after hematopoietic transplantation has been possible via gene marking. Introduction of selectable marker genes has enabled preselection of specific T-cell populations for tumor and viral immunotherapy and reduced the threat of graft-versus-host disease, improving the survival of patients after allogeneic marrow transplantation. Marking studies in humans, murine xenografts, and large animals have helped optimize conditions for gene transfer into CD34(+) hematopoietic progenitors, contributing to the achievement of gene transfer efficiencies sufficient for clinical benefit in several serious genetic diseases such as X-linked severe combined immunodeficiency and adrenoleukodystrophy. When adverse events linked to insertional mutagenesis arose in clinical gene therapy trials for inherited immunodeficiencies, additional animal studies using gene-marking vectors have greatly increased our understanding of genotoxicity. The knowledge gained from these studies is being translated into new vector designs and clinical protocols, which we hope will continue to improve the efficiency, effectiveness and safety of these promising therapeutic approaches.

  13. Candidate reference genes for gene expression studies in water lily.

    PubMed

    Luo, Huolin; Chen, Sumei; Wan, Hongjian; Chen, Fadi; Gu, Chunsun; Liu, Zhaolei

    2010-09-01

    The selection of an appropriate reference gene(s) is a prerequisite for the proper interpretation of quantitative Real-Time polymerase chain reaction data. We report the evaluation of eight candidate reference genes across various tissues and treatments in the water lily by the two software packages geNorm and NormFinder. Across all samples, clathrin adaptor complexes medium subunit (AP47) and actin 11 (ACT11) emerged as the most suitable reference genes. Across different tissues, ACT11 and elongation factor 1-alpha (EF1alpha) exhibited a stable expression pattern. ACT11 and AP47 also stably expressed in roots subjected to various treatments, but in the leaves of the same plants the most stably expressed genes were ubiquitin-conjugating enzyme 16 (UBC16) and ACT11. PMID:20452325

  14. Abnormal glucose tolerance and insulin resistance in polycystic ovary syndrome amongst the Taiwanese population- not correlated with insulin receptor substrate-1 Gly972Arg/Ala513Pro polymorphism

    PubMed Central

    Lin, Ta-Chin; Yen, Jui-Mei; Gong, Kum-Bing; Kuo, Tsung-Cheng; Ku, Dong-Chi; Liang, Shu-Fen; Wu, Ming-Jiuan

    2006-01-01

    Background Insulin resistance and glucose dysmetabolism in polycystic ovary syndrome (PCOS) are related with the polymorphisms in the genes encoding the insulin receptor substrate (IRS) proteins, especially Gly972Arg/Ala513Pro polymorphism being reported to be associated with type-2 diabetes and PCOS. We intended to assess the prevalence of abnormal glucose tolerance (AGT) and insulin resistance in Taiwanese PCOS women. We also tried to assess whether the particular identity of Gly972Arg/Ala513Pro polymorphic alleles of the IRS-1 gene mutation can be used as an appropriate diagnostic indicator for PCOS. Methods We designed a prospective clinical study. Forty-seven Taiwanese Hoklo and Hakka women, diagnosed with PCOS were enrolled in this study as were forty-five healthy Hoklo and Hakka women as the control group. Insulin resistance was evaluated with fasting insulin, fasting glucose/insulin ratio, and homeostasis model assessment index for insulin resistance (HOMAIR). The genomic DNA of the subjects was amplified by PCR and digested by restriction fragmented length polymorphism (RFLP) with Bst N1 used for codon 972 and Dra III for codon 513. Results AGT was found in 46.8% of these PCOS patients and was significantly related to high insulin resistance rather than the low insulin resistance. Those patients with either insulin resistance or AGT comprised the majority of PCOS affected patients (AGT + fasting insulin ≥17: 83%, AGT + glucose/insulin ratio ≥6.5: 85.1%, AGT + HOMAIR ≥ 2: 87.2%, and AGT + HOMAIR ≥ 3.8: 72.3%). None of the tested samples revealed any polymorphism due to the absence of any Dra III recognition site or any Bst N1 recognition site in the amplified PCR fragment digested by restriction fragmented length polymorphism. Conclusion There is significantly high prevalence of AGT and insulin resistance in PCOS women, but Gly972Arg and Ala513Pro polymorphic alleles of IRS-1 are rare and are not associated with the elevated risk of PCOS amongst

  15. Using Genes to Guide Prescriptions

    MedlinePlus

    ... Science > Using Genes to Guide Prescriptions Inside Life Science View All Articles | Inside Life Science Home Page Using Genes to Guide Prescriptions By ... to Zoloft: Ways Medicines Work This Inside Life Science article also appears on LiveScience . Learn about related ...

  16. Determining Semantically Related Significant Genes.

    PubMed

    Taha, Kamal

    2014-01-01

    GO relation embodies some aspects of existence dependency. If GO term xis existence-dependent on GO term y, the presence of y implies the presence of x. Therefore, the genes annotated with the function of the GO term y are usually functionally and semantically related to the genes annotated with the function of the GO term x. A large number of gene set enrichment analysis methods have been developed in recent years for analyzing gene sets enrichment. However, most of these methods overlook the structural dependencies between GO terms in GO graph by not considering the concept of existence dependency. We propose in this paper a biological search engine called RSGSearch that identifies enriched sets of genes annotated with different functions using the concept of existence dependency. We observe that GO term xcannot be existence-dependent on GO term y, if x- and y- have the same specificity (biological characteristics). After encoding into a numeric format the contributions of GO terms annotating target genes to the semantics of their lowest common ancestors (LCAs), RSGSearch uses microarray experiment to identify the most significant LCA that annotates the result genes. We evaluated RSGSearch experimentally and compared it with five gene set enrichment systems. Results showed marked improvement.

  17. From genes to genome biology

    SciTech Connect

    Pennisi, E.

    1996-06-21

    This article describes a change in the approach to mapping genomes, from looking at one gene at a time, to other approaches. Strategies include everything from lab techniques to computer programs designed to analyze whole batches of genes at once. Also included is a update on the work on the human genome.

  18. Susceptibility Genes in Thyroid Autoimmunity

    PubMed Central

    Ban, Yoshiyuki; Tomer, Yaron

    2005-01-01

    The autoimmune thyroid diseases (AITD) are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine) is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT) and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4) and thyroid specific genes (e.g. TSHR, Tg). Most likely, these loci interact and their interactions may influence disease phenotype and severity. PMID:15712599

  19. Gene therapy on the move

    PubMed Central

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

    2013-01-01

    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. PMID:24106209

  20. Candidate gene prioritization with Endeavour.

    PubMed

    Tranchevent, Léon-Charles; Ardeshirdavani, Amin; ElShal, Sarah; Alcaide, Daniel; Aerts, Jan; Auboeuf, Didier; Moreau, Yves

    2016-07-01

    Genomic studies and high-throughput experiments often produce large lists of candidate genes among which only a small fraction are truly relevant to the disease, phenotype or biological process of interest. Gene prioritization tackles this problem by ranking candidate genes by profiling candidates across multiple genomic data sources and integrating this heterogeneous information into a global ranking. We describe an extended version of our gene prioritization method, Endeavour, now available for six species and integrating 75 data sources. The performance (Area Under the Curve) of Endeavour on cross-validation benchmarks using 'gold standard' gene sets varies from 88% (for human phenotypes) to 95% (for worm gene function). In addition, we have also validated our approach using a time-stamped benchmark derived from the Human Phenotype Ontology, which provides a setting close to prospective validation. With this benchmark, using 3854 novel gene-phenotype associations, we observe a performance of 82%. Altogether, our results indicate that this extended version of Endeavour efficiently prioritizes candidate genes. The Endeavour web server is freely available at https://endeavour.esat.kuleuven.be/.

  1. Genes, Tolerance and Systemic Autoimmunity

    PubMed Central

    Singh, Ram P.; Waldron, Richard T.; Hahn, Bevra H.

    2011-01-01

    The characterization of functional CD8+ inhibitory or regulatory T cells and their gene regulation remains a critical challenge in the field of tolerance and autoimmunity. Investigating the genes induced in regulatory cells and the regulatory networks and pathways that underlie mechanisms of immune resistance and prevent apoptosis in the CD8+ T cell compartment are crucial to understanding tolerance mechanisms in systemic autoimmunity. Little is currently known about the genetic control that governs the ability of CD8+ Ti or regulatory cells to suppress anti-DNA Ab production in B cells. Silencing genes with siRNA or shRNA and overexpression of genes with lentiviral cDNA transduction are established approaches to identifying and understanding the function of candidate genes in tolerance and immunity. Elucidation of interactions between genes and proteins, and their synergistic effects in establishing cell-cell cross talk, including receptor modulation/antagonism, are essential for delineating the roles of these cells. In this review, we will examine recent reports which describe the modulation of cells from lupus prone mice or lupus patients to confer anti-inflammatory and protective gene expression and novel associated phenotypes. We will highlight recent findings on the role of selected genes induced by peptide tolerance in CD8+ Ti. PMID:22155015

  2. Method of controlling gene expression

    DOEpatents

    Peters, Norman K.; Frost, John W.; Long, Sharon R.

    1991-12-03

    A method of controlling expression of a DNA segment under the control of a nod gene promoter which comprises administering to a host containing a nod gene promoter an amount sufficient to control expression of the DNA segment of a compound of the formula: ##STR1## in which each R is independently H or OH, is described.

  3. Fusion genes in solid tumors.

    PubMed

    Aman, P

    1999-08-01

    Tumor development in different cell types and tissue locations involves many pathways, distinct genes and exogenous factors. Tumor type-specific chromosome rearrangements resulting in fusion genes or promoter swapping are believed to be involved in the early development of many tumor types. They are present in almost all cases of a particular tumor type and cases have been described that carry only tumor type-specific translocations without any signs of other cytogenetic changes. The mechanisms behind chromosome rearrangements in solid tumors are largely unknown. Radiation is an important factor in thyroid carcinomas but no com-$bmon sequence motifs are made out in the break points of solid tumors. The fusion genes found in sarcomas are dominated by the transcription factor type of genes with the TLS/FUS and EWS series of fusion genes as the largest group. More than 50% of papillary thyroid carcinomas carry fusion proteins with tyrosine kinase activity. Rearrangements involving HMGIC, HMGIY, and PLAG1 are common in benign mesenchymal tumors and salivary gland adenomas. Many recurrent tumor translocations show a strict specificity for tumor type. This specificity can most likely be explained by the specific sets of target genes that are deregulated by the fusion gene products. Identification of the downstream target genes is currently the object of intense research and may provide us with information that will help design better diagnostic tools and eventually find a cure for these diseases.

  4. Nonviral Vectors for Gene Delivery

    NASA Astrophysics Data System (ADS)

    Baoum, Abdulgader Ahmed

    2011-12-01

    The development of nonviral vectors for safe and efficient gene delivery has been gaining considerable attention recently. An ideal nonviral vector must protect the gene against degradation by nuclease in the extracellular matrix, internalize the plasma membrane, escape from the endosomal compartment, unpackage the gene at some point and have no detrimental effects. In comparison to viruses, nonviral vectors are relatively easy to synthesize, less immunogenic, low in cost, and have no limitation in the size of a gene that can be delivered. Significant progress has been made in the basic science and applications of various nonviral gene delivery vectors; however, the majority of nonviral approaches are still inefficient and often toxic. To this end, two nonviral gene delivery systems using either biodegradable poly(D,L-lactide- co-glycolide) (PLG) nanoparticles or cell penetrating peptide (CPP) complexes have been designed and studied using A549 human lung epithelial cells. PLG nanoparticles were optimized for gene delivery by varying particle surface chemistry using different coating materials that adsorb to the particle surface during formation. A variety of cationic coating materials were studied and compared to more conventional surfactants used for PLG nanoparticle fabrication. Nanoparticles (˜200 nm) efficiently encapsulated plasmids encoding for luciferase (80-90%) and slowly released the same for two weeks. After a delay, moderate levels of gene expression appeared at day 5 for certain positively charged PLG particles and gene expression was maintained for at least two weeks. In contrast, gene expression mediated by polyethyleneimine (PEI) ended at day 5. PLG particles were also significantly less cytotoxic than PEI suggesting the use of these vehicles for localized, sustained gene delivery to the pulmonary epithelium. On the other hand, a more simple method to synthesize 50-200 nm complexes capable of high transfection efficiency or high gene knockdown was

  5. Regulation of Neuronal Gene Expression

    NASA Astrophysics Data System (ADS)

    Thiel, Gerald; Lietz, Michael; Leichter, Michael

    Humans as multicellular organisms contain a variety of different cell types where each cell population must fulfill a distinct function in the interest of the whole organism. The molecular basis for the variations in morphology, biochemistry, molecular biology, and function of the various cell types is the cell-type specific expression of genes. These genes encode proteins necessary for executing the specialized functions of each cell type within an organism. We describe here a regulatory mechanism for the expression of neuronal genes. The zinc finger protein REST binds to the regulatory region of many neuronal genes and represses neuronal gene expression in nonneuronal tissues. A negative regulatory mechanism, involving a transcriptional repressor, seems to play an important role in establishing the neuronal phenotype.

  6. Gene Therapy for Retinal Diseases

    PubMed Central

    Samiy, Nasrollah

    2014-01-01

    Gene therapy has a growing research potential particularly in the field of ophthalmic and retinal diseases owing to three main characteristics of the eye; accessibility in terms of injections and surgical interventions, its immune-privileged status facilitating the accommodation to the antigenicity of a viral vector, and tight blood-ocular barriers which save other organs from unwanted contamination. Gene therapy has tremendous potential for different ocular diseases. In fact, the perspective of gene therapy in the field of eye research does not confine to exclusive monogenic ophthalmic problems and it has the potential to include gene based pharmacotherapies for non-monogenic problems such as age related macular disease and diabetic retinopathy. The present article has focused on how gene transfer into the eye has been developed and used to treat retinal disorders with no available therapy at present. PMID:25709778

  7. [Transcriptional control of ciliary genes].

    PubMed

    Vieillard, Jennifer; Jerber, Julie; Durand, Bénédicte

    2014-11-01

    Cilia are found in many eukaryotic species and share a common microtubule architecture that can nonetheless show very diverse features within one animal. The genesis of cilia and their diversity require the expression of different specific genes. At least two classes of transcription factors are involved in ciliogenesis: the RFX family, essential for the assembly of most cilia and the FOXJ1 transcription factors that are key regulators of motile cilia assembly. These two different families of transcription factors have both specific and common target genes and they can also cooperate for the formation of cilia. In collaboration with cell type specific factors, they also contribute to the specialisation of cilia. As a consequence, the identification of RFX and FOXJ1 target genes has emerged as an efficient strategy to identify novel ciliary genes, and in particular genes potentially implicated in ciliopathies.

  8. Nanoparticle-Mediated Gene Delivery

    NASA Astrophysics Data System (ADS)

    Jin, Sha; Leach, John C.; Ye, Kaiming

    Nonviral gene delivery has been gaining considerable attention recently. Although the efficacy of DNA transfection, which is a major concern, is low in nonviral vector-mediated gene transfer compared with viral ones, nonviral vectors are relatively easy to prepare, less immunogenic and oncogenic, and have no potential of virus recombination and no limitation on the size of a transferred gene. The ability to incorporate genetic materials such as plasmid DNA, RNA, and siRNA into functionalized nanoparticles with little toxicity demonstrates a new era in pharmacotherapy for delivering genes selectively to tissues and cells. In this chapter, we highlight the basic concepts and applications of nonviral gene delivery using super paramagnetic iron oxide nanoparticles and functionalized silica nanoparticles. The experimental protocols related to these topics are described in the chapter.

  9. Gene therapy for lung disease.

    PubMed

    Ennist, D L

    1999-06-01

    Gene therapy is a new field of medical research that has great potential to influence the course of treatment of human disease. The lung has been a particularly attractive target organ for gene therapy due to its accessibility and the identification of genetic deficits for a number of lung diseases. Several clinical trials have shown evidence of low levels of gene transfer and expression, but without any benefit to the patients involved. Thus, current studies are focusing on further research and technological improvements to the vectors. Gene therapy is now beginning to benefit from a shift in emphasis from clinical trials to the development of better tools and procedures to deliver gene therapy to the bedside.

  10. Genes and gene networks implicated in aggression related behaviour.

    PubMed

    Malki, Karim; Pain, Oliver; Du Rietz, Ebba; Tosto, Maria Grazia; Paya-Cano, Jose; Sandnabba, Kenneth N; de Boer, Sietse; Schalkwyk, Leonard C; Sluyter, Frans

    2014-10-01

    Aggressive behaviour is a major cause of mortality and morbidity. Despite of moderate heritability estimates, progress in identifying the genetic factors underlying aggressive behaviour has been limited. There are currently three genetic mouse models of high and low aggression created using selective breeding. This is the first study to offer a global transcriptomic characterization of the prefrontal cortex across all three genetic mouse models of aggression. A systems biology approach has been applied to transcriptomic data across the three pairs of selected inbred mouse strains (Turku Aggressive (TA) and Turku Non-Aggressive (TNA), Short Attack Latency (SAL) and Long Attack Latency (LAL) mice and North Carolina Aggressive (NC900) and North Carolina Non-Aggressive (NC100)), providing novel insight into the neurobiological mechanisms and genetics underlying aggression. First, weighted gene co-expression network analysis (WGCNA) was performed to identify modules of highly correlated genes associated with aggression. Probe sets belonging to gene modules uncovered by WGCNA were carried forward for network analysis using ingenuity pathway analysis (IPA). The RankProd non-parametric algorithm was then used to statistically evaluate expression differences across the genes belonging to modules significantly associated with aggression. IPA uncovered two pathways, involving NF-kB and MAPKs. The secondary RankProd analysis yielded 14 differentially expressed genes, some of which have previously been implicated in pathways associated with aggressive behaviour, such as Adrbk2. The results highlighted plausible candidate genes and gene networks implicated in aggression-related behaviour.

  11. Immunoglobulin λ Gene Rearrangement Can Precede κ Gene Rearrangement

    DOE PAGES

    Berg, Jörg; Mcdowell, Mindy; Jäck, Hans-Martin; Wabl, Matthias

    1990-01-01

    Imore » mmunoglobulin genes are generated during differentiation of B lymphocytes by joining gene segments. A mouse pre-B cell contains a functional immunoglobulin heavy-chain gene, but no light-chain gene. Although there is only one heavy-chain locus, there are two lightchain loci: κ and λ .It has been reported that κ loci in the germ-line configuration are never (in man) or very rarely (in the mouse) present in cells with functionally rearranged λ -chain genes. Two explanations have been proposed to explain this: (a) the ordered rearrangement theory, which postulates that light-chain gene rearrangement in the pre-B cell is first attempted at the κ locus, and that only upon failure to produce a functional κ chain is there an attempt to rearrange the λ locus; and (b) the stochastic theory, which postulates that rearrangement at the λ locus proceeds at a rate that is intrinsically much slower than that at the κ locus. We show here that λ -chain genes are generated whether or not the κ locus has lost its germ-line arrangement, a result that is compatible only with the stochastic theory.« less

  12. Therapeutic genes for anti-HIV/AIDS gene therapy.

    PubMed

    Bovolenta, Chiara; Porcellini, Simona; Alberici, Luca

    2013-01-01

    The multiple therapeutic approaches developed so far to cope HIV-1 infection, such as anti-retroviral drugs, germicides and several attempts of therapeutic vaccination have provided significant amelioration in terms of life-quality and survival rate of AIDS patients. Nevertheless, no approach has demonstrated efficacy in eradicating this lethal, if untreated, infection. The curative power of gene therapy has been proven for the treatment of monogenic immunodeficiensies, where permanent gene modification of host cells is sufficient to correct the defect for life-time. No doubt, a similar concept is not applicable for gene therapy of infectious immunodeficiensies as AIDS, where there is not a single gene to be corrected; rather engineered cells must gain immunotherapeutic or antiviral features to grant either short- or long-term efficacy mostly by acquisition of antiviral genes or payloads. Anti-HIV/AIDS gene therapy is one of the most promising strategy, although challenging, to eradicate HIV-1 infection. In fact, genetic modification of hematopoietic stem cells with one or multiple therapeutic genes is expected to originate blood cell progenies resistant to viral infection and thereby able to prevail on infected unprotected cells. Ultimately, protected cells will re-establish a functional immune system able to control HIV-1 replication. More than hundred gene therapy clinical trials against AIDS employing different viral vectors and transgenes have been approved or are currently ongoing worldwide. This review will overview anti-HIV-1 infection gene therapy field evaluating strength and weakness of the transgenes and payloads used in the past and of those potentially exploitable in the future.

  13. Genes, Economics, and Happiness.

    PubMed

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

    2012-11-01

    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.

  14. Environment, genes, and cancer

    SciTech Connect

    Manuel, J.

    1996-03-01

    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.

  15. RNA splicing and genes

    SciTech Connect

    Sharp, P.A.

    1988-11-25

    The splicing of long transcripts RNA (copied from DNA in the cell nucleus) into smaller specific mRNA is an important event in the regulation of gene expression in eukaryotic cells. The splicing reaction occurs as a late step in the nuclear pathway for synthesis of mRNAs. This pathway commences with initiation of transcription by RNA polymerase II and probably involves an integrated series of steps each dependent on previous events. Splicing of precursors to mRNAs involves the formation of a spliceosome complex containing 5' and 3' splice sites. This complex contains the evolutionary highly conserved small nuclear RNAs (snRNAs) Us, U4, U5, and U6. The most abundant snRNA, U1, is required to form the spliceosome and may be a part of the spliceosome. Analogues of these snRNAs have been identified in yeast. Assembly of the spliceosome probably involves the binding of a multi-snRNA complex containing U4, U5, and U6 snRNAs. Several observations suggest that the association of snRNAs in such complexes is quite dynamic. It is argued that the snRANs in the spliceosome form a catalytic RNA structure that is responsible for the cleavage and ligation steps during splicing.

  16. Genes, Economics, and Happiness *

    PubMed Central

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

    2012-01-01

    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. PMID:24349601

  17. Candidate gene prioritization with Endeavour

    PubMed Central

    Tranchevent, Léon-Charles; Ardeshirdavani, Amin; ElShal, Sarah; Alcaide, Daniel; Aerts, Jan; Auboeuf, Didier; Moreau, Yves

    2016-01-01

    Genomic studies and high-throughput experiments often produce large lists of candidate genes among which only a small fraction are truly relevant to the disease, phenotype or biological process of interest. Gene prioritization tackles this problem by ranking candidate genes by profiling candidates across multiple genomic data sources and integrating this heterogeneous information into a global ranking. We describe an extended version of our gene prioritization method, Endeavour, now available for six species and integrating 75 data sources. The performance (Area Under the Curve) of Endeavour on cross-validation benchmarks using ‘gold standard’ gene sets varies from 88% (for human phenotypes) to 95% (for worm gene function). In addition, we have also validated our approach using a time-stamped benchmark derived from the Human Phenotype Ontology, which provides a setting close to prospective validation. With this benchmark, using 3854 novel gene–phenotype associations, we observe a performance of 82%. Altogether, our results indicate that this extended version of Endeavour efficiently prioritizes candidate genes. The Endeavour web server is freely available at https://endeavour.esat.kuleuven.be/. PMID:27131783

  18. Nonadditive gene expression in polyploids.

    PubMed

    Yoo, Mi-Jeong; Liu, Xiaoxian; Pires, J Chris; Soltis, Pamela S; Soltis, Douglas E

    2014-01-01

    Allopolyploidy involves hybridization and duplication of divergent parental genomes and provides new avenues for gene expression. The expression levels of duplicated genes in polyploids can show deviation from parental additivity (the arithmetic average of the parental expression levels). Nonadditive expression has been widely observed in diverse polyploids and comprises at least three possible scenarios: (a) The total gene expression level in a polyploid is similar to that of one of its parents (expression-level dominance); (b) total gene expression is lower or higher than in both parents (transgressive expression); and (c) the relative contribution of the parental copies (homeologs) to the total gene expression is unequal (homeolog expression bias). Several factors may result in expression nonadditivity in polyploids, including maternal-paternal influence, gene dosage balance, cis- and/or trans-regulatory networks, and epigenetic regulation. As our understanding of nonadditive gene expression in polyploids remains limited, a new generation of investigators should explore additional phenomena (i.e., alternative splicing) and use other high-throughput "omics" technologies to measure the impact of nonadditive expression on phenotype, proteome, and metabolome. PMID:25421600

  19. Simulating evolution by gene duplication.

    PubMed

    Ohta, T

    1987-01-01

    By considering the recent finding that unequal crossing over and other molecular interactions are contributing to the evolution of multigene families, a model of the origin of repetitive genes was studied by Monte Carlo simulations. Starting from a single gene copy, how genetic systems evolve was examined under unequal crossing over, random drift and natural selection. Both beneficial and deteriorating mutations were incorporated, and the latter were assumed to occur ten times more frequently than the former. Positive natural selection favors those chromosomes with more beneficial mutations in redundant copies than others in the population, but accumulation of deteriorating mutations (pseudogenes) have no effect on fitness so long as there remains a functional gene. The results imply the following: Positive natural selection is needed in order to acquire gene families with new functions. Without it, too many pseudogenes accumulate before attaining a functional gene family. There is a large fluctuation in the outcome even if parameters are the same. When unequal crossing over occurs more frequently, the system evolves more rapidly. It was also shown, under realistic values of parameters, that the genetic load for acquiring a new gene is not as large as J.B.S. Haldane suggested, but not so small as in a model in which a system for selection started from already redundant genes. PMID:3557113

  20. Linking Genes to Cardiovascular Diseases: Gene Action and Gene-Environment Interactions.

    PubMed

    Pasipoularides, Ares

    2015-12-01

    A unique myocardial characteristic is its ability to grow/remodel in order to adapt; this is determined partly by genes and partly by the environment and the milieu intérieur. In the "post-genomic" era, a need is emerging to elucidate the physiologic functions of myocardial genes, as well as potential adaptive and maladaptive modulations induced by environmental/epigenetic factors. Genome sequencing and analysis advances have become exponential lately, with escalation of our knowledge concerning sometimes controversial genetic underpinnings of cardiovascular diseases. Current technologies can identify candidate genes variously involved in diverse normal/abnormal morphomechanical phenotypes, and offer insights into multiple genetic factors implicated in complex cardiovascular syndromes. The expression profiles of thousands of genes are regularly ascertained under diverse conditions. Global analyses of gene expression levels are useful for cataloging genes and correlated phenotypes, and for elucidating the role of genes in maladies. Comparative expression of gene networks coupled to complex disorders can contribute insights as to how "modifier genes" influence the expressed phenotypes. Increasingly, a more comprehensive and detailed systematic understanding of genetic abnormalities underlying, for example, various genetic cardiomyopathies is emerging. Implementing genomic findings in cardiology practice may well lead directly to better diagnosing and therapeutics. There is currently evolving a strong appreciation for the value of studying gene anomalies, and doing so in a non-disjointed, cohesive manner. However, it is challenging for many-practitioners and investigators-to comprehend, interpret, and utilize the clinically increasingly accessible and affordable cardiovascular genomics studies. This survey addresses the need for fundamental understanding in this vital area.

  1. GenePRIMP: A GENE PRediction IMprovement Pipeline for Prokaryotic genomes

    SciTech Connect

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

    2010-04-01

    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.

  2. [Gene doping: gene transfer and possible molecular detection].

    PubMed

    Argüelles, Carlos Francisco; Hernández-Zamora, Edgar

    2007-01-01

    The use of illegal substances in sports to enhance athletic performance during competition has caused international sports organizations such as the COI and WADA to take anti doping measures. A new doping method know as gene doping is defined as "the non-therapeutic use of genes, genetic elements and/or cells that have the capacity to enhance athletic performance". However, gene doping in sports is not easily identified and can cause serious consequences. Molecular biology techniques are needed in order to distinguish the difference between a "normal" and an "altered" genome. Further, we need to develop new analytic methods and biological molecular techniques in anti-doping laboratories, and design programs that avoid the non therapeutic use of genes.

  3. BRCA1 and BRCA2 gene testing

    MedlinePlus

    ... gov/ency/patientinstructions/000690.htm BRCA1 and BRCA2 gene testing To use the sharing features on this ... br east ca ncer. What is the BRCA Gene Mutation? BRCA1 and BRCA2 are genes that suppress ...

  4. [Pathogenicity and pneumococcal capsular genes].

    PubMed

    García, E; García, P; López, R

    1994-01-01

    Pneumococci remain to be one of the most prominent human pathogens. Increasing efforts are being dedicated to the development of improved vaccines with wider specificity. Since a clear understanding of the genetics of capsular types in Streptococcus pneumoniae is missing, our efforts are oriented to characterize, at the molecular level, the genes involved in capsular polysaccharide biosynthesis. We have cloned and sequenced a chromosomal DNA fragment of a clinical isolate of type 3 pneumococcus and showed that it contains a type 3 specific gene as well as genes common to other serotypes.

  5. The design of synthetic genes.

    PubMed Central

    Presnell, S R; Benner, S A

    1988-01-01

    Computer programs are described that aid in the design of synthetic genes coding for proteins that are targets of a research program in site directed mutagenesis. These programs "reverse-translate" protein sequences into general nucleic acid sequences (those where codons have not yet been selected), map restriction sites into general DNA sequences, identify points in the synthetic gene where unique restriction sites can be introduced, and assist in the design of genes coding for hybrids and evolutionary intermediates between homologous proteins. Application of these programs therefore facilitates the use of modular mutagenesis to create variants of proteins, and the implementation of evolutionary guidance as a strategy for selecting mutants. PMID:2451218

  6. The hunt for gene dopers.

    PubMed

    Mansour, Mai M H; Azzazy, Hassan M E

    2009-07-01

    Gene doping, the abuse of gene therapy for illicit athletic enhancement, is perceived as a coming threat and is a prime concern to the anti-doping community. This doping technique represents a significant ethical challenge and there are concerns regarding its safety for athletes. This article presents the basics of gene doping, potential strategies for its detection and the role of promising new technologies in aiding detection efforts. These include the use of lab-on-a-chip techniques as well as nanoparticles to enhance the performance of current analytical methods and to develop new doping detection strategies. PMID:20355209

  7. Gene expression and fractionation resistance

    PubMed Central

    2014-01-01

    Background Previous work on whole genome doubling in plants established the importance of gene functional category in provoking or suppressing duplicate gene loss, or fractionation. Other studies, particularly in Paramecium have correlated levels of gene expression with vulnerability or resistance to duplicate loss. Results Here we analyze the simultaneous effect of function category and expression in two plant data sets, rosids and asterids. Conclusion We demonstrate function category and expression level have independent effects, though expression does not play the dominant role it does in Paramecium. PMID:25573431

  8. The Ensembl gene annotation system.

    PubMed

    Aken, Bronwen L; Ayling, Sarah; Barrell, Daniel; Clarke, Laura; Curwen, Valery; Fairley, Susan; Fernandez Banet, Julio; Billis, Konstantinos; García Girón, Carlos; Hourlier, Thibaut; Howe, Kevin; Kähäri, Andreas; Kokocinski, Felix; Martin, Fergal J; Murphy, Daniel N; Nag, Rishi; Ruffier, Magali; Schuster, Michael; Tang, Y Amy; Vogel, Jan-Hinnerk; White, Simon; Zadissa, Amonida; Flicek, Paul; Searle, Stephen M J

    2016-01-01

    The Ensembl gene annotation system has been used to annotate over 70 different vertebrate species across a wide range of genome projects. Furthermore, it generates the automatic alignment-based annotation for the human and mouse GENCODE gene sets. The system is based on the alignment of biological sequences, including cDNAs, proteins and RNA-seq reads, to the target genome in order to construct candidate transcript models. Careful assessment and filtering of these candidate transcripts ultimately leads to the final gene set, which is made available on the Ensembl website. Here, we describe the annotation process in detail.Database URL: http://www.ensembl.org/index.html. PMID:27337980

  9. Gene therapy: proceed with caution.

    PubMed

    Grobstein, C; Flower, M

    1984-04-01

    On 6 February 1984 the Recombinant DNA Advisory Committee of the National Institutes of Health approved a recommendation that the committee provide prior review of research protocols involving human gene therapy. Grobstein and Flower trace the development of public policy in response to concerns about the dangers of gene therapy, especially as it applies to germ line alteration. They offer guidelines and propose principles for an oversight body to confront the immediate and long term technical, social, and ethical implications of human genetic modification. An accompanying article presents a plea for the development of gene therapy by the mother of three children who have sickle cell anemia.

  10. Panspermia and horizontal gene transfer

    NASA Astrophysics Data System (ADS)

    Klyce, Brig

    2009-08-01

    Evidence that extremophiles are hardy and ubiquitous is helping to make panspermia a respectable theory. But even if life on Earth originally came from space, biologists assume that the subsequent evolution of life is still governed by the darwinian paradigm. In this review we show how panspermia could amend darwinism and point to a cosmic source for, not only extremophiles but, all of life. This version of panspermia can be called "strong panspermia." To support this theory we will discuss recent evidence pertaining to horizontal gene transfer, viruses, genes apparently older than the Earthly evolution of the features they encode, and primate-specific genes without identifiable precursors.

  11. The Ensembl gene annotation system

    PubMed Central

    Aken, Bronwen L.; Ayling, Sarah; Barrell, Daniel; Clarke, Laura; Curwen, Valery; Fairley, Susan; Fernandez Banet, Julio; Billis, Konstantinos; García Girón, Carlos; Hourlier, Thibaut; Howe, Kevin; Kähäri, Andreas; Kokocinski, Felix; Martin, Fergal J.; Murphy, Daniel N.; Nag, Rishi; Ruffier, Magali; Schuster, Michael; Tang, Y. Amy; Vogel, Jan-Hinnerk; White, Simon; Zadissa, Amonida; Flicek, Paul

    2016-01-01

    The Ensembl gene annotation system has been used to annotate over 70 different vertebrate species across a wide range of genome projects. Furthermore, it generates the automatic alignment-based annotation for the human and mouse GENCODE gene sets. The system is based on the alignment of biological sequences, including cDNAs, proteins and RNA-seq reads, to the target genome in order to construct candidate transcript models. Careful assessment and filtering of these candidate transcripts ultimately leads to the final gene set, which is made available on the Ensembl website. Here, we describe the annotation process in detail. Database URL: http://www.ensembl.org/index.html PMID:27337980

  12. Saporin as a novel suicide gene in anticancer gene therapy.

    PubMed

    Zarovni, N; Vago, R; Soldà, T; Monaco, L; Fabbrini, M S

    2007-02-01

    We used a non-viral gene delivery approach to explore the potential of the plant saporin (SAP) gene as an alternative to the currently employed suicide genes in cancer therapy. Plasmids expressing cytosolic SAP were generated by placing the region encoding the mature plant ribosome-inactivating protein under the control of cytomegalovirus (CMV) or simian virus 40 (SV40) promoters. Their ability to inhibit protein synthesis was first tested in cultured tumor cells co-transfected with a luciferase reporter gene. In particular, SAP expression driven by CMV promoter (pCI-SAP) demonstrated that only 10 ng of plasmid per 1.6 x 10(4) B16 cells drastically reduced luciferase activity to 18% of that in control cells. Direct intratumoral injection of pCI-SAP complexed with either lipofectamine or N-(2,3-dioleoyloxy-1-propyl) trimethylammonium methyl sulfate (DOTAP) in B16 melanoma-bearing mice resulted in a noteworthy attenuation of tumor growth. This antitumor effect was increased in mice that received repeated intratumoral injections. A SAP catalytic inactive mutant (SAP-KQ) failed to exert any antitumor effect demonstrating that this was specifically owing to the SAP N-glycosidase activity. Our overall data strongly suggest that the gene encoding SAP, owing to its rapid and effective action and its independence from the proliferative state of target cells might become a suitable candidate suicide gene for oncologic applications. PMID:17008932

  13. Gene amplification and insecticide resistance.

    PubMed

    Bass, Chris; Field, Linda M

    2011-08-01

    Pesticide resistance in arthropods has been shown to evolve by two main mechanisms, the enhanced production of metabolic enzymes, which bind to and/or detoxify the pesticide, and mutation of the target protein, which makes it less sensitive to the pesticide. One route that leads to enhanced metabolism is the duplication or amplification of the structural gene(s) encoding the detoxifying enzyme, and this has now been described for the three main families (esterases, glutathione S-transferases and cytochrome P450 monooxygenases) implicated in resistance. More recently, a direct or indirect role for gene duplication or amplification has been described for target-site resistance in several arthropod species. This mini-review summarises the involvement of gene duplication/amplification in the insecticide/acaricide resistance of insect and mite pests and highlights recent developments in this area in relation to P450-mediated and target-site resistance.

  14. Gene Cernan on Apollo 17

    NASA Video Gallery

    Apollo 17 Commander Gene Cernan recalls fixing a lunar rover problem with duct tape during his December 1972 mission. Cernan's interview was part of the commemoration of NASA's 50th anniversary in ...

  15. Autophagy Genes as Tumor Suppressors

    PubMed Central

    Liang, Chengyu; Jung, Jae U.

    2009-01-01

    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. PMID:19945837

  16. Gene flow and population differentiation.

    PubMed

    Endler, J A

    1973-01-19

    There are many possible spatial patterns of selection and gene flow that can produce a given cline structure; the actual geography of natural selection and gene flow must be worked out before an attempt is made to explain a given natural cline in terms of a model. The results of experimental and theoretical models show that it is possible for local differentiation to evolve parapatrically in spite of considerable gene flow if the selection gradients are relatively uniform. Irregularities in environmental gradients increase the sensitivity of clines to the effects of gene flow in proportion to the increase in the differences in gene frequencies between the emigrants and the demes receiving the immigrants. It is not necessary for a sharp spatial environmental change to be present for distinct differentiation to occur. In some cases even a gentle environmental gradient can give rise to marked spatial differentiation along a genetically continuous series of demes; such environmental differences may be below the practical limits of resolution in field studies. Any asymmetry in gene flow does not lead to dedifferentiation if the environmental gradient is smooth; it merely shifts the position of the transition zone between the differentiated areas from that which would be expected if there were no asymmetry. Abrupt geographic differences in gene, genotype, or morph frequencies should not, therefore, be interpreted as evidence for environmental changes in the immediate vicinity of the steepest part of the cline; neither should they be interpreted as evidence for geographic barriers, sharp environmental differences, or sexual isolation among the differentiated groups of populations when there are no other sources of evidence for these phenomena. Gene flow may be unimportant in the differentiation of populations along environmental gradients.

  17. Gene therapy and nasopharyngeal carcinoma.

    PubMed

    Hughes, J; Alusi, G; Wang, Y

    2012-06-01

    In 2003, a non-replicating adenoviral gene therapy product received the world`s first government licence for the treatment of head and neck cancer. Two years later approval was granted to a replication-selective adenovirus for the treatment of nasopharyngeal carcinoma in combination with chemotherapy. This review introduces the reader to gene therapy as an emerging treatment modality, and outlines its application to the management of nasopharyngeal carcinoma by examining recent pre-clinical and clinical research.

  18. Gene Transfer into Cardiac Myocytes

    PubMed Central

    Lang, Sarah E.; Westfall, Margaret V.

    2016-01-01

    Traditional methods for DNA transfection are often inefficient and toxic for terminally differentiated cells, such as cardiac myocytes. Vector-based gene transfer is an efficient approach for introducing exogenous cDNA into these types of primary cell cultures. In this chapter, separate protocols for adult rat cardiac myocyte isolation and gene transfer with recombinant adenovirus are provided and are routinely utilized for studying the effects of sarcomeric proteins on myofilament function. PMID:25836585

  19. Transgenic Arabidopsis Gene Expression System

    NASA Technical Reports Server (NTRS)

    Ferl, Robert; Paul, Anna-Lisa

    2009-01-01

    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.

  20. Gene-culture coevolution between cattle milk protein genes and human lactase genes.

    PubMed

    Beja-Pereira, Albano; Luikart, Gordon; England, Phillip R; Bradley, Daniel G; Jann, Oliver C; Bertorelle, Giorgio; Chamberlain, Andrew T; Nunes, Telmo P; Metodiev, Stoitcho; Ferrand, Nuno; Erhardt, Georg

    2003-12-01

    Milk from domestic cows has been a valuable food source for over 8,000 years, especially in lactose-tolerant human societies that exploit dairy breeds. We studied geographic patterns of variation in genes encoding the six most important milk proteins in 70 native European cattle breeds. We found substantial geographic coincidence between high diversity in cattle milk genes, locations of the European Neolithic cattle farming sites (>5,000 years ago) and present-day lactose tolerance in Europeans. This suggests a gene-culture coevolution between cattle and humans.

  1. Nutritional regulation of gene expression.

    PubMed

    Cousins, R J

    1999-01-25

    Genes are regulated by complex arrays of response elements that influence the rate of transcription. Nutrients and hormones either act directly to influence these rates or act indirectly through specialized signaling pathways. Metabolites of vitamins A and D, fatty acids, some sterols, and zinc are among the nutrients that influence transcription directly. Components of dietary fiber may influence gene expression indirectly through changes in hormonal signaling, mechanical stimuli, and metabolites produced by the intestinal microflora. In addition, consumption of water-soluble fibers may lead to changes in gene expression mediated through indirect mechanisms that influence transcription rates. In the large intestine, short-chain fatty acids, including butyric acid, are produced by microflora. Butyric acid can indirectly influence gene expression. Some sources of fiber limit nutrient absorption, particularly of trace elements. This could have direct or indirect effects on gene expression. Identification of genes in colonic epithelial cells that are differentially regulated by dietary fiber will be an important step toward understanding the role of dietary factors in colorectal cancer progression.

  2. Homologous gene replacement in Physarum

    SciTech Connect

    Burland, T.G.; Pallotta, D.

    1995-01-01

    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{Delta}1, of the ardD actin gene; ardD{Delta}1 mutates the critical carboxy-terminal region of the gene product. Because ardD is not expressed in the amoeba, replacement of ardD{sup +} with ardD{Delta}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{Delta}1 in addition to ardD{sup +}, but in two (5%), ardD{sup +} was replaced by a single copy of ardD{Delta}1. This is the first example of homologous gene replacement in Physarum. ardD{Delta}1 was stably maintained in the genome through growth, development and meiosis. We found no effect of ardD{Delta}l 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. 38 refs., 6 figs., 1 tab.

  3. Gene Polymorphisms in Chronic Periodontitis

    PubMed Central

    Laine, Marja L.; Loos, Bruno G.; Crielaard, W.

    2010-01-01

    We aimed to conduct a review of the literature for gene polymorphisms associated with chronic periodontitis (CP) susceptibility. A comprehensive search of the literature in English was performed using the keywords: periodontitis, periodontal disease, combined with the words genes, mutation, or polymorphism. Candidate gene polymorphism studies with a case-control design and reported genotype frequencies in CP patients were searched and reviewed. There is growing evidence that polymorphisms in the IL1, IL6, IL10, vitamin D receptor, and CD14 genes may be associated with CP in certain populations. However, carriage rates of the rare (R)-allele of any polymorphism varied considerably among studies and most of the studies appeared under-powered and did not correct for other risk factors. Larger cohorts, well-defined phenotypes, control for other risk factors, and analysis of multiple genes and polymorphisms within the same pathway are needed to get a more comprehensive insight into the contribution of gene polymorphisms in CP. PMID:20339487

  4. Cationic Bolaamphiphiles for Gene Delivery

    NASA Astrophysics Data System (ADS)

    Tan, Amelia Li Min; Lim, Alisa Xue Ling; Zhu, Yiting; Yang, Yi Yan; Khan, Majad

    2014-05-01

    Advances in medical research have shed light on the genetic cause of many human diseases. Gene therapy is a promising approach which can be used to deliver therapeutic genes to treat genetic diseases at its most fundamental level. In general, nonviral vectors are preferred due to reduced risk of immune response, but they are also commonly associated with low transfection efficiency and high cytotoxicity. In contrast to viral vectors, nonviral vectors do not have a natural mechanism to overcome extra- and intracellular barriers when delivering the therapeutic gene into cell. Hence, its design has been increasingly complex to meet challenges faced in targeting of, penetration of and expression in a specific host cell in achieving more satisfactory transfection efficiency. Flexibility in design of the vector is desirable, to enable a careful and controlled manipulation of its properties and functions. This can be met by the use of bolaamphiphile, a special class of lipid. Unlike conventional lipids, bolaamphiphiles can form asymmetric complexes with the therapeutic gene. The advantage of having an asymmetric complex lies in the different purposes served by the interior and exterior of the complex. More effective gene encapsulation within the interior of the complex can be achieved without triggering greater aggregation of serum proteins with the exterior, potentially overcoming one of the great hurdles faced by conventional single-head cationic lipids. In this review, we will look into the physiochemical considerations as well as the biological aspects of a bolaamphiphile-based gene delivery system.

  5. PET genes of Saccharomyces cerevisiae.

    PubMed Central

    Tzagoloff, A; Dieckmann, C L

    1990-01-01

    We describe a collection of nuclear respiratory-defective mutants (pet mutants) of Saccharomyces cerevisiae consisting of 215 complementation groups. This set of mutants probably represents a substantial fraction of the total genetic information of the nucleus required for the maintenance of functional mitochondria in S. cerevisiae. The biochemical lesions of mutants in approximately 50 complementation groups have been related to single enzymes or biosynthetic pathways, and the corresponding wild-type genes have been cloned and their structures have been determined. The genes defined by an additional 20 complementation groups were identified by allelism tests with mutants characterized in other laboratories. Mutants representative of the remaining complementation groups have been assigned to one of the following five phenotypic classes: (i) deficiency in cytochrome oxidase, (ii) deficiency in coenzyme QH2-cytochrome c reductase, (iii) deficiency in mitochondrial ATPase, (iv) absence of mitochondrial protein synthesis, and (v) normal composition of respiratory-chain complexes and of oligomycin-sensitive ATPase. In addition to the genes identified through biochemical and genetic analyses of the pet mutants, we have cataloged PET genes not matched to complementation groups in the mutant collection and other genes whose products function in the mitochondria but are not necessary for respiration. Together, this information provides an up-to-date list of the known genes coding for mitochondrial constituents and for proteins whose expression is vital for the respiratory competence of S. cerevisiae. PMID:2215420

  6. Gene-gene, gene-environment, gene-nutrient interactions and single nucleotide polymorphisms of inflammatory cytokines.

    PubMed

    Nadeem, Amina; Mumtaz, Sadaf; Naveed, Abdul Khaliq; Aslam, Muhammad; Siddiqui, Arif; Lodhi, Ghulam Mustafa; Ahmad, Tausif

    2015-05-15

    Inflammation plays a significant role in the etiology of type 2 diabetes mellitus (T2DM). The rise in the pro-inflammatory cytokines is the essential step in glucotoxicity and lipotoxicity induced mitochondrial injury, oxidative stress and beta cell apoptosis in T2DM. Among the recognized markers are interleukin (IL)-6, IL-1, IL-10, IL-18, tissue necrosis factor-alpha (TNF-α), C-reactive protein, resistin, adiponectin, tissue plasminogen activator, fibrinogen and heptoglobins. Diabetes mellitus has firm genetic and very strong environmental influence; exhibiting a polygenic mode of inheritance. Many single nucleotide polymorphisms (SNPs) in various genes including those of pro and anti-inflammatory cytokines have been reported as a risk for T2DM. Not all the SNPs have been confirmed by unifying results in different studies and wide variations have been reported in various ethnic groups. The inter-ethnic variations can be explained by the fact that gene expression may be regulated by gene-gene, gene-environment and gene-nutrient interactions. This review highlights the impact of these interactions on determining the role of single nucleotide polymorphism of IL-6, TNF-α, resistin and adiponectin in pathogenesis of T2DM. PMID:25987962

  7. Immunoglobulin genes of the turtles.

    PubMed

    Magadán-Mompó, Susana; Sánchez-Espinel, Christian; Gambón-Deza, Francisco

    2013-03-01

    The availability of reptile genomes for the use of the scientific community is an exceptional opportunity to study the evolution of immunoglobulin genes. The genome of Chrysemys picta bellii and Pelodiscus sinensis is the first one that has been reported for turtles. The scanning for immunoglobulin genes resulted in the presence of a complex locus for the immunoglobulin heavy chain (IGH). This IGH locus in both turtles contains genes for 13 isotypes in C. picta bellii and 17 in P. sinensis. These correspond with one immunoglobulin M, one immunoglobulin D, several immunoglobulins Y (six in C. picta bellii and eight in P. sinensis), and several immunoglobulins that are similar to immunoglobulin D2 (five in C. picta belli and seven in P. sinensis) that was previously described in Eublepharis macularius. It is worthy to note that IGHD2 are placed in an inverted transcriptional orientation and present sequences for two immunoglobulin domains that are similar to bird IgA domains. Furthermore, its phylogenetic analysis allows us to consider about the presence of IGHA gene in a primitive reptile, so we would be dealing with the memory of the gene that originated from the bird IGHA. In summary, we provide a clear picture of the immunoglobulins present in a turtle, whose analysis supports the idea that turtles emerged from the evolutionary line from the differentiation of birds and the presence of the IGHA gene present in a common ancestor.

  8. Gene therapy for paediatric leukaemia.

    PubMed

    Rousseau, R F; Bollard, C M; Heslop, H E

    2001-07-01

    Improvements in the chemotherapeutic and transplant regimens have had a significant impact in improving survival rates for paediatric leukaemia. However, there are still important problems to address including what options are available for patients with chemoresistant disease and what strategies are available to avoid the concerns regarding the toxicity associated with highly cytotoxic treatment regimens. Gene therapy and immunotherapy protocols hold great promise. Using gene transfer of a marker gene, a number of biological issues in the therapy of leukaemia have been addressed. For example, by gene marking autologous bone marrow grafts it has been possible to demonstrate that infused marrow contributes to relapse in acute and chronic myeloid leukaemias. In the allogeneic transplant setting, genetically modified T-cells have proven valuable for the prophylaxis and treatment of viral diseases and may have an important role in preventing or treating disease relapse. Gene transfer is also being used to modify tumour function, enhance immunogenicity, and confer drug-resistance to normal haematopoietic stem cells. With the continued scientific advancements in this field, gene therapy will almost certainly have a major impact on the treatment of paediatric leukaemia in the future. PMID:11727502

  9. New gene evolution: little did we know.

    PubMed

    Long, Manyuan; VanKuren, Nicholas W; Chen, Sidi; Vibranovski, Maria D

    2013-01-01

    Genes are perpetually added to and deleted from genomes during evolution. Thus, it is important to understand how new genes are formed and how they evolve to be critical components of the genetic systems that determine the biological diversity of life. Two decades of effort have shed light on the process of new gene origination and have contributed to an emerging comprehensive picture of how new genes are added to genomes, ranging from the mechanisms that generate new gene structures to the presence of new genes in different organisms to the rates and patterns of new gene origination and the roles of new genes in phenotypic evolution. We review each of these aspects of new gene evolution, summarizing the main evidence for the origination and importance of new genes in evolution. We highlight findings showing that new genes rapidly change existing genetic systems that govern various molecular, cellular, and phenotypic functions.

  10. Homology-dependent Gene Silencing in Paramecium

    PubMed Central

    Ruiz, Françoise; Vayssié, Laurence; Klotz, Catherine; Sperling, Linda; Madeddu, Luisa

    1998-01-01

    Microinjection at high copy number of plasmids containing only the coding region of a gene into the Paramecium somatic macronucleus led to a marked reduction in the expression of the corresponding endogenous gene(s). The silencing effect, which is stably maintained throughout vegetative growth, has been observed for all Paramecium genes examined so far: a single-copy gene (ND7), as well as members of multigene families (centrin genes and trichocyst matrix protein genes) in which all closely related paralogous genes appeared to be affected. This phenomenon may be related to posttranscriptional gene silencing in transgenic plants and quelling in Neurospora and allows the efficient creation of specific mutant phenotypes thus providing a potentially powerful tool to study gene function in Paramecium. For the two multigene families that encode proteins that coassemble to build up complex subcellular structures the analysis presented herein provides the first experimental evidence that the members of these gene families are not functionally redundant. PMID:9529389

  11. OGEE: an online gene essentiality database.

    PubMed

    Chen, Wei-Hua; Minguez, Pablo; Lercher, Martin J; Bork, Peer

    2012-01-01

    OGEE is an Online GEne Essentiality database. Its main purpose is to enhance our understanding of the essentiality of genes. This is achieved by collecting not only experimentally tested essential and non-essential genes, but also associated gene features such as expression profiles, duplication status, conservation across species, evolutionary origins and involvement in embryonic development. We focus on large-scale experiments and complement our data with text-mining results. Genes are organized into data sets according to their sources. Genes with variable essentiality status across data sets are tagged as conditionally essential, highlighting the complex interplay between gene functions and environments. Linked tools allow the user to compare gene essentiality among different gene groups, or compare features of essential genes to non-essential genes, and visualize the results. OGEE is freely available at http://ogeedb.embl.de.

  12. PoplarGene: poplar gene network and resource for mining functional information for genes from woody plants.

    PubMed

    Liu, Qi; Ding, Changjun; Chu, Yanguang; Chen, Jiafei; Zhang, Weixi; Zhang, Bingyu; Huang, Qinjun; Su, Xiaohua

    2016-01-01

    Poplar is not only an important resource for the production of paper, timber and other wood-based products, but it has also emerged as an ideal model system for studying woody plants. To better understand the biological processes underlying various traits in poplar, e.g., wood development, a comprehensive functional gene interaction network is highly needed. Here, we constructed a genome-wide functional gene network for poplar (covering ~70% of the 41,335 poplar genes) and created the network web service PoplarGene, offering comprehensive functional interactions and extensive poplar gene functional annotations. PoplarGene incorporates two network-based gene prioritization algorithms, neighborhood-based prioritization and context-based prioritization, which can be used to perform gene prioritization in a complementary manner. Furthermore, the co-functional information in PoplarGene can be applied to other woody plant proteomes with high efficiency via orthology transfer. In addition to poplar gene sequences, the webserver also accepts Arabidopsis reference gene as input to guide the search for novel candidate functional genes in PoplarGene. We believe that PoplarGene (http://bioinformatics.caf.ac.cn/PoplarGene and http://124.127.201.25/PoplarGene) will greatly benefit the research community, facilitating studies of poplar and other woody plants. PMID:27515999

  13. PoplarGene: poplar gene network and resource for mining functional information for genes from woody plants

    PubMed Central

    Liu, Qi; Ding, Changjun; Chu, Yanguang; Chen, Jiafei; Zhang, Weixi; Zhang, Bingyu; Huang, Qinjun; Su, Xiaohua

    2016-01-01

    Poplar is not only an important resource for the production of paper, timber and other wood-based products, but it has also emerged as an ideal model system for studying woody plants. To better understand the biological processes underlying various traits in poplar, e.g., wood development, a comprehensive functional gene interaction network is highly needed. Here, we constructed a genome-wide functional gene network for poplar (covering ~70% of the 41,335 poplar genes) and created the network web service PoplarGene, offering comprehensive functional interactions and extensive poplar gene functional annotations. PoplarGene incorporates two network-based gene prioritization algorithms, neighborhood-based prioritization and context-based prioritization, which can be used to perform gene prioritization in a complementary manner. Furthermore, the co-functional information in PoplarGene can be applied to other woody plant proteomes with high efficiency via orthology transfer. In addition to poplar gene sequences, the webserver also accepts Arabidopsis reference gene as input to guide the search for novel candidate functional genes in PoplarGene. We believe that PoplarGene (http://bioinformatics.caf.ac.cn/PoplarGene and http://124.127.201.25/PoplarGene) will greatly benefit the research community, facilitating studies of poplar and other woody plants. PMID:27515999

  14. Murine erythropoietin gene: cloning, expression, and human gene homology.

    PubMed Central

    Shoemaker, C B; Mitsock, L D

    1986-01-01

    The gene for murine erythropoietin (EPO) was isolated from a mouse genomic library with a human EPO cDNA probe. Nucleotide sequence analysis permitted the identification of the murine EPO coding sequence and the prediction of the encoded amino acid sequence based on sequence conservation between the mouse and human EPO genes. Both the coding DNA and the amino acid sequences were 80% conserved between the two species. Transformation of COS-1 cells with a mammalian cell expression vector containing the murine EPO coding region resulted in secretion of murine EPO with biological activity on both murine and human erythroid progenitor cells. The transcription start site for the murine EPO gene in kidneys was determined. This permitted tentative identification of the transcription control region. The region included 140 base pairs upstream of the cap site which was over 90% conserved between the murine and human genes. Surprisingly, the first intron and much of the 5'- and 3'-untranslated sequences were also substantially conserved between the genes of the two species. Images PMID:3773894

  15. Newer gene editing technologies toward HIV gene therapy.

    PubMed

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

    2013-11-01

    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.

  16. Noninvasive Tracking of Gene Transcript and Neuroprotection after Gene Therapy

    PubMed Central

    Ren, Jiaqian; Chen, Y. Iris; Liu, Christina H.; Chen, Po-Chih; Prentice, Howard; Wu, Jang-Yen; Liu, Philip K.

    2015-01-01

    Gene therapy holds exceptional potential for translational medicine by improving the products of defective genes in diseases and/or providing necessary biologics from endogenous sources during recovery processes. However, validating methods for the delivery, distribution and expression of the exogenous genes from such therapy can generally not be applicable to monitor effects over the long term because they are invasive. We report here that human granulocyte colony-stimulating factor (hG-CSF) cDNA encoded in scAAV-type 2 adeno-associated virus, as delivered through eye drops at multiple time points after cerebral ischemia using bilateral carotid occlusion for 60 min (BCAO-60) led to significant reduction in mortality rates, cerebral atrophy, and neurological deficits in C57black6 mice. Most importantly, we validated hG-CSF cDNA expression using translatable magnetic resonance imaging (MRI) in living brains. This noninvasive approach for monitoring exogenous gene expression in the brains has potential for great impact in the area of experimental gene therapy in animal models of heart attack, stroke, Alzheimer’s dementia, Parkinson’s disorder and amyotrophic lateral sclerosis, and the translation of such techniques to emergency medicine. PMID:26207935

  17. [Developments in gene delivery vectors for ocular gene therapy].

    PubMed

    Khabou, Hanen; Dalkara, Deniz

    2015-05-01

    Gene therapy is quickly becoming a reality applicable in the clinic for inherited retinal diseases. Its remarkable success in safety and efficacy, in clinical trials for Leber's congenital amaurosis (LCA) type II generated significant interest and opened up possibilities for a new era of retinal gene therapies. Success in these clinical trials was mainly due to the favorable characteristics of the retina as a target organ. The eye offers several advantages as it is readily accessible and has some degree of immune privilege making it suitable for application of viral vectors. The viral vectors most frequently used for retinal gene delivery are lentivirus, adenovirus and adeno-associated virus (AAV). Here we will discuss the use of these viral vectors in retinal gene delivery with a strong focus on favorable properties of AAV. Thanks to its small size, AAV diffuses well in the inter-neural matrix making it suitable for applications in neural retina. Building on this initial clinical success with LCA II, we have now many opportunities to extend this proof-of-concept to other retinal diseases using AAV as a vector. This article will discuss what are some of the most imminent cellular targets for such therapies and the AAV toolkit that has been built to target these cells successfully. We will also discuss some of the challenges that we face in translating AAV-based gene therapies to the clinic.

  18. The biology of novel animal genes: Mouse APEX gene knockout

    SciTech Connect

    MacInnes, M.; Altherr, M.R.; Ludwig, D.; Pedersen, R.; Mold, C.

    1997-07-01

    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.

  19. Newer Gene Editing Technologies toward HIV Gene Therapy

    PubMed Central

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

    2013-01-01

    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. PMID:24284874

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

    SciTech Connect

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

    2007-03-01

    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.

  1. Genes and Abdominal Aortic Aneurysm

    PubMed Central

    Hinterseher, Irene; Tromp, Gerard; Kuivaniemi, Helena

    2010-01-01

    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. PMID:21146954

  2. A hybrid approach of gene sets and single genes for the prediction of survival risks with gene expression data.

    PubMed

    Seok, Junhee; Davis, Ronald W; Xiao, Wenzhong

    2015-01-01

    Accumulated biological knowledge is often encoded as gene sets, collections of genes associated with similar biological functions or pathways. The use of gene sets in the analyses of high-throughput gene expression data has been intensively studied and applied in clinical research. However, the main interest remains in finding modules of biological knowledge, or corresponding gene sets, significantly associated with disease conditions. Risk prediction from censored survival times using gene sets hasn't been well studied. In this work, we propose a hybrid method that uses both single gene and gene set information together to predict patient survival risks from gene expression profiles. In the proposed method, gene sets provide context-level information that is poorly reflected by single genes. Complementarily, single genes help to supplement incomplete information of gene sets due to our imperfect biomedical knowledge. Through the tests over multiple data sets of cancer and trauma injury, the proposed method showed robust and improved performance compared with the conventional approaches with only single genes or gene sets solely. Additionally, we examined the prediction result in the trauma injury data, and showed that the modules of biological knowledge used in the prediction by the proposed method were highly interpretable in biology. A wide range of survival prediction problems in clinical genomics is expected to benefit from the use of biological knowledge.

  3. Clock Genes in Glia Cells

    PubMed Central

    Chi-Castañeda, Donají

    2016-01-01

    Circadian rhythms are periodic patterns in biological processes that allow the organisms to anticipate changes in the environment. These rhythms are driven by the suprachiasmatic nucleus (SCN), the master circadian clock in vertebrates. At a molecular level, circadian rhythms are regulated by the so-called clock genes, which oscillate in a periodic manner. The protein products of clock genes are transcription factors that control their own and other genes’ transcription, collectively known as “clock-controlled genes.” Several brain regions other than the SCN express circadian rhythms of clock genes, including the amygdala, the olfactory bulb, the retina, and the cerebellum. Glia cells in these structures are expected to participate in rhythmicity. However, only certain types of glia cells may be called “glial clocks,” since they express PER-based circadian oscillators, which depend of the SCN for their synchronization. This contribution summarizes the current information about clock genes in glia cells, their plausible role as oscillators and their medical implications. PMID:27666286

  4. Gene therapy for metachromatic leukodystrophy.

    PubMed

    Rosenberg, Jonathan B; Kaminsky, Stephen M; Aubourg, Patrick; Crystal, Ronald G; Sondhi, Dolan

    2016-11-01

    Leukodystrophies (LDs) are rare, often devastating genetic disorders with neurologic symptoms. There are currently no disease-specific therapeutic approaches for these diseases. In this review we use metachromatic leukodystrophy as an example to outline in the brief the therapeutic approaches to MLD that have been tested in animal models and in clinical trials, such as enzyme-replacement therapy, bone marrow/umbilical cord blood transplants, ex vivo transplantation of genetically modified hematopoietic stem cells, and gene therapy. These studies suggest that to be successful the ideal therapy for MLD must provide persistent and high level expression of the deficient gene, arylsulfatase A in the CNS. Gene therapy using adeno-associated viruses is therefore the ideal choice for clinical development as it provides the best balance of potential for efficacy with reduced safety risk. Here we have summarized the published preclinical data from our group and from others that support the use of a gene therapy with AAVrh.10 serotype for clinical development as a treatment for MLD, and as an example of the potential of gene therapy for LDs especially for Krabbe disease, which is the focus of this special issue. © 2016 Wiley Periodicals, Inc. PMID:27638601

  5. Gene Therapy for Pituitary Tumors

    PubMed Central

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

    2009-01-01

    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. PMID:16457646

  6. Melatonin Receptor Genes in Vertebrates

    PubMed Central

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

    2013-01-01

    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

  7. 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

  8. Systems Biophysics of Gene Expression

    PubMed Central

    Vilar, Jose M.G.; Saiz, Leonor

    2013-01-01

    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. PMID:23790365

  9. Gene Ontology Consortium: going forward

    PubMed Central

    2015-01-01

    The Gene Ontology (GO; http://www.geneontology.org) is a community-based bioinformatics resource that supplies information about gene product function using ontologies to represent biological knowledge. Here we describe improvements and expansions to several branches of the ontology, as well as updates that have allowed us to more efficiently disseminate the GO and capture feedback from the research community. The Gene Ontology Consortium (GOC) has expanded areas of the ontology such as cilia-related terms, cell-cycle terms and multicellular organism processes. We have also implemented new tools for generating ontology terms based on a set of logical rules making use of templates, and we have made efforts to increase our use of logical definitions. The GOC has a new and improved web site summarizing new developments and documentation, serving as a portal to GO data. Users can perform GO enrichment analysis, and search the GO for terms, annotations to gene products, and associated metadata across multiple species using the all-new AmiGO 2 browser. We encourage and welcome the input of the research community in all biological areas in our continued effort to improve the Gene Ontology. PMID:25428369

  10. Gene Chips and Functional Genomics

    NASA Astrophysics Data System (ADS)

    Hamadeh, Hisham; Afshari, Cynthia

    2000-11-01

    These past few years of scientific discovery will undoubtedly be remembered as the "genomics era," the period in which biologists succeeded in enumerating the sequence of nucleotides making up all, or at least most, of human DNA. And while this achievement has been heralded as a technological feat equal to the moon landing, it is only the first of many advances in DNA technology. Scientists are now faced with the task of understanding the meaning of the DNA sequence. Specifically, they want to learn how the DNA code relates to protein function. An important tool in the study of "functional genomics," is the cDNA microarray—also known as the gene chip. Inspired by computer microchips, gene chips allow scientists to monitor the expression of hundreds, even thousands, of genes in a fraction of the time it used to take to monitor the expression of a single one. By altering the conditions under which a particular tissue expresses genes—say, by exposing it to toxins or growth factors—scientists can determine the suite of genes expressed in different situations and hence start to get a handle on the function of these genes. The authors discuss this important new technology and some of its practical applications.

  11. Hox gene dysregulation in acute myeloid leukemia.

    PubMed

    De Braekeleer, Etienne; Douet-Guilbert, Nathalie; Basinko, Audrey; Le Bris, Marie-Josée; Morel, Frédéric; De Braekeleer, Marc

    2014-02-01

    In humans, class I homeobox genes (HOX genes) are distributed in four clusters. Upstream regulators include transcriptional activators and members of the CDX family of transcription factors. HOX genes encode proteins and need cofactor interactions, to increase their specificity and selectivity. HOX genes contribute to the organization and regulation of hematopoiesis by controlling the balance between proliferation and differentiation. Changes in HOX gene expression can be associated with chromosomal rearrangements generating fusion genes, such as those involving MLL and NUP98, or molecular defects, such as mutations in NPM1 and CEBPA for example. Several miRNAs are involved in the control of HOX gene expression and their expression correlates with HOX gene dysregulation. HOX genes dysregulation is a dominant mechanism of leukemic transformation. A better knowledge of their target genes and the mechanisms by which their dysregulated expression contributes to leukemogenesis could lead to the development of new drugs.

  12. Gene-Gene and Gene-Environment Interactions in Ulcerative Colitis

    PubMed Central

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

    2014-01-01

    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

  13. Activities of Human Gene Nomenclature Committee

    SciTech Connect

    2002-07-16

    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).

  14. The Basic Science of Gene Therapy

    NASA Astrophysics Data System (ADS)

    Mulligan, Richard C.

    1993-05-01

    The development over the past decade of methods for delivering genes to mammalian cells has stimulated great interest in the possibility of treating human disease by gene-based therapies. However, despite substantial progress, a number of key technical issues need to be resolved before gene therapy can be safely and effectively applied in the clinic. Future technological developments, particularly in the areas of gene delivery and cell transplantation, will be critical for the successful practice of gene therapy.

  15. Gene Body Methylation Patterns in Daphnia Are Associated with Gene Family Size

    PubMed Central

    Asselman, Jana; De Coninck, Dieter I. M.; Pfrender, Michael E.; De Schamphelaere, Karel A. C.

    2016-01-01

    The relation between gene body methylation and gene function remains elusive. Yet, our understanding of this relationship can contribute significant knowledge on how and why organisms target specific gene bodies for methylation. Here, we studied gene body methylation patterns in two Daphnia species. We observed both highly methylated genes and genes devoid of methylation in a background of low global methylation levels. A small but highly significant number of genes was highly methylated in both species. Remarkably, functional analyses indicate that variation in methylation within and between Daphnia species is primarily targeted to small gene families whereas large gene families tend to lack variation. The degree of sequence similarity could not explain the observed pattern. Furthermore, a significant negative correlation between gene family size and the degree of methylation suggests that gene body methylation may help regulate gene family expansion and functional diversification of gene families leading to phenotypic variation. PMID:27017526

  16. Characterization of the mammalian DNA polymerase gene(s) and enzyme(s). Annual progress report

    SciTech Connect

    Mishra, N.C.

    1995-01-01

    Two Genes for DNA polymerase delta were identified from the wild type Chinese hamster ovary cells. These genes were cloned via RT-PCR from mRNA prepared the Chinese hamster ovary cells using primers specific to conserved sequences of the DNA polymerase {delta} gene. The first gene encodes a PCNA dependent DNA polymerase {delta} gene whereas the second gene encodes a PCNA independent DNA polymerase {delta} gene. Methods were developed to clone these genes in expression vector and host systems. The role of the two genes in DNA replication and repair was determined.

  17. Search for Basonuclin Target Genes

    PubMed Central

    Wang, Junwen; Zhang, Shengliang; Schultz, Richard M.; Tseng, Hung

    2006-01-01

    Basonuclin (Bnc 1) is a transcription factor that has an unusual ability to interact with promoters of both RNA polymerases I and II. The action of basonuclin is mediated through three pairs of evolutionarily conserved zinc fingers, which produce three DNase I footprints on the promoters of rDNA and the basonuclin gene. Using these DNase footprints, we built a computational model for the basonuclin DNA-binding module, which was used to identify in silico potential RNA polymerase II target genes in the human and mouse promoter databases. The target genes of basonuclin show that it regulates the expression of proteins involved in chromatin structure, transcription/DNA-binding, ion-channels, adhesion/cell-cell junction, signal transduction and intracellular transport. Our results suggest that basonuclin, like MYC, may coordinate transcriptional activities among the three RNA polymerases. But basonuclin regulates a distinctive set of pathways, which differ from that regulated by MYC. PMID:16919236

  18. Composite Nanoparticles for Gene Delivery

    PubMed Central

    Wang, Yuhua; Huang, Leaf

    2016-01-01

    Nanoparticle-mediated gene and siRNA delivery has been an appealing area to gene therapists when they attempt to treat the diseases by manipulating the genetic information in the target cells. However, the advances in materials science could not keep up with the demand for multifunctional nanomaterials to achieve desired delivery efficiency. Researchers have thus taken an alternative approach to incorporate various materials into single composite nanoparticle using different fabrication methods. This approach allows nanoparticles to possess defined nanostructures as well as multiple functionalities to overcome the critical extracellular and intracellular barriers to successful gene delivery. This chapter will highlight the advances of fabrication methods that have the most potential to translate nanoparticles from bench to bedside. Furthermore, a major class of composite nanoparticle–lipid-based composite nanoparticles will be classified based on the components and reviewed in details. PMID:25409605

  19. [Gene therapy for osteoarticular disorders].

    PubMed

    Gouze, Jean-Noël; Evans, Christopher H; Ghivizzani, Steven C; Gouze, Elvire

    2007-03-01

    Osteoarticular disorders are the major cause of disability in Europe and North America. It is estimated that rheumatoid arthritis affects 1 % of the population and that more than two third of people over age 55 develop osteoarthritis. Because there are no satisfactory treatments, gene therapy offers a new therapeutic approach. The delivery of cDNA encoding anti-arthritic proteins to articular cells has shown therapeutic efficacy in numerous animal models in vivo. Through the development and the experimental progresses that have been made for both rheumatoid arthritis and osteoarthritis, this review discusses the different gene therapy strategies available today and the safety issues with which they may be associated. Among the different vectors available today, adeno-associated virus seems the best candidate for a direct in vivo gene delivery approach for the treatment of joint disorders. PMID:17349293

  20. Gene therapy in corneal transplantation.

    PubMed

    Qazi, Yureeda; Hamrah, Pedram

    2013-01-01

    Corneal transplantation is the most commonly performed organ transplantation. Immune privilege of the cornea is widely recognized, partly because of the relatively favorable outcome of corneal grafts. The first-time recipient of corneal allografts in an avascular, low-risk setting can expect a 90% success rate without systemic immunosuppressive agents and histocompatibility matching. However, immunologic rejection remains the major cause of graft failure, particularly in patients with a high risk for rejection. Corticosteroids remain the first-line therapy for the prevention and treatment of immune rejection. However, current pharmacological measures are limited in their side-effect profiles, repeated application, lack of targeted response, and short duration of action. Experimental ocular gene therapy may thus present new horizons in immunomodulation. From efficient viral vectors to sustainable alternative splicing, we discuss the progress of gene therapy in promoting graft survival and postulate further avenues for gene-mediated prevention of allogeneic graft rejection.

  1. Comparative gene map of hypertriglyceridaemia.

    PubMed

    Seda, O

    2004-01-01

    Elevated triglyceride levels in the circulation are currently recognized as an independent risk factor for coronary artery disease. Hypertriglyceridaemia represents one of the attributes of metabolic syndrome and is present in the most common genetic dyslipidaemia, the familial combined hyperlipidaemia. The factual concentration of triglycerides is determined by a complex interaction of environmental and genetic components. Deeper understanding of the causative gene variants and the mode of their participation in the pathogenesis of hypertriglyceridaemia is required for devising efficient therapy of hypertriglyceridaemia. This is the first systematic review of linkage and candidate gene studies dealing with the dissection of genetic determinants of (hyper)triglyceridaemia in human and two major mammalian model species, mouse and rat. Based on the merged sets of data, a synthetic view of the genetic component of triglyceridaemia, the "hypertriglyceridaemia gene map", is presented.

  2. Gene encoding plant asparagine synthetase

    DOEpatents

    Coruzzi, Gloria M.; Tsai, Fong-Ying

    1993-10-26

    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.

  3. Lateral gene transfer in eukaryotes.

    PubMed

    Andersson, J O

    2005-06-01

    Lateral gene transfer -- the transfer of genetic material between species -- has been acknowledged as a major mechanism in prokaryotic genome evolution for some time. Recently accumulating data indicate that the process also occurs in the evolution of eukaryotic genomes. However, there are large rate variations between groups of eukaryotes; animals and fungi seem to be largely unaffected, with a few exceptions, while lateral gene transfer frequently occurs in protists with phagotrophic lifestyles, possibly with rates comparable to prokaryotic organisms. Gene transfers often facilitate the acquisition of functions encoded in prokaryotic genomes by eukaryotic organisms, which may enable them to colonize new environments. Transfers between eukaryotes also occur, mainly into larger phagotrophic eukaryotes that ingest eukaryotic cells, but also between plant lineages. These findings have implications for eukaryotic genomic research in general, and studies of the origin and phylogeny of eukaryotes in particular.

  4. The plant ADH gene family.

    PubMed

    Strommer, Judith

    2011-04-01

    The structures, evolution and functions of alcohol dehydrogenase gene families and their products have been scrutinized for half a century. Our understanding of the enzyme structure and catalytic activity of plant alcohol dehydrogenase (ADH-P) is based on the vast amount of information available for its animal counterpart. The probable origins of the enzyme from a simple β-coil and eventual emergence from a glutathione-dependent formaldehyde dehydrogenase have been well described. There is compelling evidence that the small ADH gene families found in plants today are the survivors of multiple rounds of gene expansion and contraction. To the probable original function of their products in the terminal reaction of anaerobic fermentation have been added roles in yeast-like aerobic fermentation and the production of characteristic scents that act to attract animals that serve as pollinators or agents of seed dispersal and to protect against herbivores.

  5. Gene Expression Studies in Mosquitoes

    PubMed Central

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

    2009-01-01

    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. PMID:19161831

  6. Codon usage in plant genes.

    PubMed Central

    Murray, E E; Lotzer, J; Eberle, M

    1989-01-01

    We have examined codon bias in 207 plant gene sequences collected from Genbank and the literature. When this sample was further divided into 53 monocot and 154 dicot genes, the pattern of relative use of synonymous codons was shown to differ between these taxonomic groups, primarily in the use of G + C in the degenerate third base. Maize and soybean codon bias were examined separately and followed the monocot and dicot codon usage patterns respectively. Codon preference in ribulose 1,5 bisphosphate and chlorophyll a/b binding protein, two of the most abundant proteins in leaves was investigated. These highly expressed are more restricted in their codon usage than plant genes in general. PMID:2644621

  7. Metagenomics and novel gene discovery

    PubMed Central

    Culligan, Eamonn P; Sleator, Roy D; Marchesi, Julian R; Hill, Colin

    2014-01-01

    Metagenomics provides a means of assessing the total genetic pool of all the microbes in a particular environment, in a culture-independent manner. It has revealed unprecedented diversity in microbial community composition, which is further reflected in the encoded functional diversity of the genomes, a large proportion of which consists of novel genes. Herein, we review both sequence-based and functional metagenomic methods to uncover novel genes and outline some of the associated problems of each type of approach, as well as potential solutions. Furthermore, we discuss the potential for metagenomic biotherapeutic discovery, with a particular focus on the human gut microbiome and finally, we outline how the discovery of novel genes may be used to create bioengineered probiotics. PMID:24317337

  8. Electroporation-mediated gene delivery.

    PubMed

    Young, Jennifer L; Dean, David A

    2015-01-01

    Electroporation has been used extensively to transfer DNA to bacteria, yeast, and mammalian cells in culture for the past 30 years. Over this time, numerous advances have been made, from using fields to facilitate cell fusion, delivery of chemotherapeutic drugs to cells and tissues, and most importantly, gene and drug delivery in living tissues from rodents to man. Electroporation uses electrical fields to transiently destabilize the membrane allowing the entry of normally impermeable macromolecules into the cytoplasm. Surprisingly, at the appropriate field strengths, the application of these fields to tissues results in little, if any, damage or trauma. Indeed, electroporation has even been used successfully in human trials for gene delivery for the treatment of tumors and for vaccine development. Electroporation can lead to between 100 and 1000-fold increases in gene delivery and expression and can also increase both the distribution of cells taking up and expressing the DNA as well as the absolute amount of gene product per cell (likely due to increased delivery of plasmids into each cell). Effective electroporation depends on electric field parameters, electrode design, the tissues and cells being targeted, and the plasmids that are being transferred themselves. Most importantly, there is no single combination of these variables that leads to greatest efficacy in every situation; optimization is required in every new setting. Electroporation-mediated in vivo gene delivery has proven highly effective in vaccine production, transgene expression, enzyme replacement, and control of a variety of cancers. Almost any tissue can be targeted with electroporation, including muscle, skin, heart, liver, lung, and vasculature. This chapter will provide an overview of the theory of electroporation for the delivery of DNA both in individual cells and in tissues and its application for in vivo gene delivery in a number of animal models. PMID:25620008

  9. Electroporation-mediated gene delivery.

    PubMed

    Young, Jennifer L; Dean, David A

    2015-01-01

    Electroporation has been used extensively to transfer DNA to bacteria, yeast, and mammalian cells in culture for the past 30 years. Over this time, numerous advances have been made, from using fields to facilitate cell fusion, delivery of chemotherapeutic drugs to cells and tissues, and most importantly, gene and drug delivery in living tissues from rodents to man. Electroporation uses electrical fields to transiently destabilize the membrane allowing the entry of normally impermeable macromolecules into the cytoplasm. Surprisingly, at the appropriate field strengths, the application of these fields to tissues results in little, if any, damage or trauma. Indeed, electroporation has even been used successfully in human trials for gene delivery for the treatment of tumors and for vaccine development. Electroporation can lead to between 100 and 1000-fold increases in gene delivery and expression and can also increase both the distribution of cells taking up and expressing the DNA as well as the absolute amount of gene product per cell (likely due to increased delivery of plasmids into each cell). Effective electroporation depends on electric field parameters, electrode design, the tissues and cells being targeted, and the plasmids that are being transferred themselves. Most importantly, there is no single combination of these variables that leads to greatest efficacy in every situation; optimization is required in every new setting. Electroporation-mediated in vivo gene delivery has proven highly effective in vaccine production, transgene expression, enzyme replacement, and control of a variety of cancers. Almost any tissue can be targeted with electroporation, including muscle, skin, heart, liver, lung, and vasculature. This chapter will provide an overview of the theory of electroporation for the delivery of DNA both in individual cells and in tissues and its application for in vivo gene delivery in a number of animal models.

  10. Genomics of local adaptation with gene flow.

    PubMed

    Tigano, Anna; Friesen, Vicki L

    2016-05-01

    Gene flow is a fundamental evolutionary force in adaptation that is especially important to understand as humans are rapidly changing both the natural environment and natural levels of gene flow. Theory proposes a multifaceted role for gene flow in adaptation, but it focuses mainly on the disruptive effect that gene flow has on adaptation when selection is not strong enough to prevent the loss of locally adapted alleles. The role of gene flow in adaptation is now better understood due to the recent development of both genomic models of adaptive evolution and genomic techniques, which both point to the importance of genetic architecture in the origin and maintenance of adaptation with gene flow. In this review, we discuss three main topics on the genomics of adaptation with gene flow. First, we investigate selection on migration and gene flow. Second, we discuss the three potential sources of adaptive variation in relation to the role of gene flow in the origin of adaptation. Third, we explain how local adaptation is maintained despite gene flow: we provide a synthesis of recent genomic models of adaptation, discuss the genomic mechanisms and review empirical studies on the genomics of adaptation with gene flow. Despite predictions on the disruptive effect of gene flow in adaptation, an increasing number of studies show that gene flow can promote adaptation, that local adaptations can be maintained despite high gene flow, and that genetic architecture plays a fundamental role in the origin and maintenance of local adaptation with gene flow.

  11. Signature Genes as a Phylogenomic Tool

    PubMed Central

    Snel, Berend; Ettema, Thijs J. G.; Huynen, Martijn A.

    2008-01-01

    Gene content has been shown to contain a strong phylogenetic signal, yet its usage for phylogenetic questions is hampered by horizontal gene transfer and parallel gene loss and until now required completely sequenced genomes. Here, we introduce an approach that allows the phylogenetic signal in gene content to be applied to any set of sequences, using signature genes for phylogenetic classification. The hundreds of publicly available genomes allow us to identify signature genes at various taxonomic depths, and we show how the presence of signature genes in an unspecified sample can be used to characterize its taxonomic composition. We identify 8,362 signature genes specific for 112 prokaryotic taxa. We show that these signature genes can be used to address phylogenetic questions on the basis of gene content in cases where classic gene content or sequence analyses provide an ambiguous answer, such as for Nanoarchaeum equitans, and even in cases where complete genomes are not available, such as for metagenomics data. Cross-validation experiments leaving out up to 30% of the species show that ∼92% of the signature genes correctly place the species in a related clade. Analyses of metagenomics data sets with the signature gene approach are in good agreement with the previously reported species distributions based on phylogenetic analysis of marker genes. Summarizing, signature genes can complement traditional sequence-based methods in addressing taxonomic questions. PMID:18492663

  12. GeneMANIA prediction server 2013 update.

    PubMed

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

    2013-07-01

    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.

  13. A gene-based information gain method for detecting gene-gene interactions in case-control studies.

    PubMed

    Li, Jin; Huang, Dongli; Guo, Maozu; Liu, Xiaoyan; Wang, Chunyu; Teng, Zhixia; Zhang, Ruijie; Jiang, Yongshuai; Lv, Hongchao; Wang, Limei

    2015-11-01

    Currently, most methods for detecting gene-gene interactions (GGIs) in genome-wide association studies are divided into SNP-based methods and gene-based methods. Generally, the gene-based methods can be more powerful than SNP-based methods. Some gene-based entropy methods can only capture the linear relationship between genes. We therefore proposed a nonparametric gene-based information gain method (GBIGM) that can capture both linear relationship and nonlinear correlation between genes. Through simulation with different odds ratio, sample size and prevalence rate, GBIGM was shown to be valid and more powerful than classic KCCU method and SNP-based entropy method. In the analysis of data from 17 genes on rheumatoid arthritis, GBIGM was more effective than the other two methods as it obtains fewer significant results, which was important for biological verification. Therefore, GBIGM is a suitable and powerful tool for detecting GGIs in case-control studies.

  14. Identification of genes and gene clusters involved in mycotoxin synthesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Research methods to identify and characterize genes involved in mycotoxin biosynthetic pathways have evolved considerably over the years. Before whole genome sequences were available (e.g. pre-genomics), work focused primarily on chemistry, biosynthetic mutant strains and molecular analysis of sing...

  15. Horizontal gene transfer of stress resistance genes through plasmid transport.

    PubMed

    Shoeb, Erum; Badar, Uzma; Akhter, Jameela; Shams, Hina; Sultana, Maria; Ansari, Maqsood A

    2012-03-01

    The horizontal gene transfer of plasmid-determined stress tolerance was achieved under lab conditions. Bacterial isolates, Enterobacter cloacae (DGE50) and Escherichia coli (DGE57) were used throughout the study. Samples were collected from contaminated marine water and soil to isolate bacterial strains having tolerance against heavy metals and antimicrobial agents. We have demonstrated plasmid transfer, from Amp(+)Cu(+)Zn(-) strain (DGE50) to Amp(-)Cu(-)Zn(+) strain (DGE57), producing Amp(+)Cu(+)Zn(+) transconjugants (DGE(TC50→57)) and Amp(+)Cu(-)Zn(+) transformants (DGE(TF50→57)). DGE57 did not carry any plasmid, therefore, it can be speculated that zinc tolerance gene in DGE57 is located on chromosome. DGE50 was found to carry three plasmids, out of which two were transferred through conjugation into DGE57, and only one was transferred through transformation. Plasmid transferred through transformation was one out of the two transferred through conjugation. Through the results of transformation it was revealed that the genes of copper and ampicillin tolerance in DGE50 were located on separate plasmids, since only ampicillin tolerance genes were transferred through transformation as a result of one plasmid transfer. By showing transfer of plasmids under lab conditions and monitoring retention of respective phenotype via conjugation and transformation, it is very well demonstrated how multiple stress tolerant strains are generated in nature. PMID:22805823

  16. The yeast ubiquitin genes: a family of natural gene fusions.

    PubMed

    Ozkaynak, E; Finley, D; Solomon, M J; Varshavsky, A

    1987-05-01

    Ubiquitin is a 76-residue protein highly conserved among eukaryotes. Conjugation of ubiquitin to intracellular proteins mediates their selective degradation in vivo. We describe a family of four ubiquitin-coding loci in the yeast Saccharomyces cerevisiae. UB11, UB12 and UB13 encode hybrid proteins in which ubiquitin is fused to unrelated ('tail') amino acid sequences. The ubiquitin coding elements of UB11 and UB12 are interrupted at identical positions by non-homologous introns. UB11 and UB12 encode identical 52-residue tails, whereas UB13 encodes a different 76-residue tail. The tail amino acid sequences are highly conserved between yeast and mammals. Each tail contains a putative metal-binding, nucleic acid-binding domain of the form Cys-X2-4-Cys-X2-15-Cys-X2-4-Cys, suggesting that these proteins may function by binding to DNA. The fourth gene, UB14, encodes a polyubiquitin precursor protein containing five ubiquitin repeats in a head-to-tail, spacerless arrangement. All four ubiquitin genes are expressed in exponentially growing cells, while in stationary-phase cells the expression of UB11 and UB12 is repressed. The UB14 gene, which is strongly inducible by starvation, high temperatures and other stresses, contains in its upstream region strong homologies to the consensus 'heat shock box' nucleotide sequence. Elsewhere we show that the essential function of the UB14 gene is to provide ubiquitin to cells under stress. PMID:3038523

  17. JavaGenes Molecular Evolution

    NASA Technical Reports Server (NTRS)

    Lohn, Jason; Smith, David; Frank, Jeremy; Globus, Al; Crawford, James

    2007-01-01

    JavaGenes is a general-purpose, evolutionary software system written in Java. It implements several versions of a genetic algorithm, simulated annealing, stochastic hill climbing, and other search techniques. This software has been used to evolve molecules, atomic force field parameters, digital circuits, Earth Observing Satellite schedules, and antennas. This version differs from version 0.7.28 in that it includes the molecule evolution code and other improvements. Except for the antenna code, JaveGenes is available for NASA Open Source distribution.

  18. Cytoskeletal genes regulating brain size.

    PubMed

    Bond, Jacquelyn; Woods, C Geoffrey

    2006-02-01

    One of the most notable trends in human evolution is the dramatic increase in brain size that has occurred in the great ape clade, culminating in humans. Of particular interest is the vast expanse of the cerebral cortex, which is believed to have resulted in our ability to perform higher cognitive functions. Recent investigations of congenital microcephaly in humans have resulted in the identification of several genes that non-redundantly and specifically influence mammalian brain size. These genes appear to affect neural progenitor cell number through microtubular organisation at the centrosome. PMID:16337370

  19. Gene therapy in clinical medicine

    PubMed Central

    Selkirk, S

    2004-01-01

    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. PMID:15466989

  20. Zipf's Law in Gene Expression

    NASA Astrophysics Data System (ADS)

    Furusawa, Chikara; Kaneko, Kunihiko

    2003-02-01

    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.

  1. Persistence drives gene clustering in bacterial genomes

    PubMed Central

    Fang, Gang; Rocha, Eduardo PC; Danchin, Antoine

    2008-01-01

    Background Gene clustering plays an important role in the organization of the bacterial chromosome and several mechanisms have been proposed to explain its extent. However, the controversies raised about the validity of each of these mechanisms remind us that the cause of this gene organization remains an open question. Models proposed to explain clustering did not take into account the function of the gene products nor the likely presence or absence of a given gene in a genome. However, genomes harbor two very different categories of genes: those genes present in a majority of organisms – persistent genes – and those present in very few organisms – rare genes. Results We show that two classes of genes are significantly clustered in bacterial genomes: the highly persistent and the rare genes. The clustering of rare genes is readily explained by the selfish operon theory. Yet, genes persistently present in bacterial genomes are also clustered and we try to understand why. We propose a model accounting specifically for such clustering, and show that indispensability in a genome with frequent gene deletion and insertion leads to the transient clustering of these genes. The model describes how clusters are created via the gene flux that continuously introduces new genes while deleting others. We then test if known selective processes, such as co-transcription, physical interaction or functional neighborhood, account for the stabilization of these clusters. Conclusion We show that the strong selective pressure acting on the function of persistent genes, in a permanent state of flux of genes in bacterial genomes, maintaining their size fairly constant, that drives persistent genes clustering. A further selective stabilization process might contribute to maintaining the clustering. PMID:18179692

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

    PubMed

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

    2013-08-10

    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, β-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

  3. Concerted evolution of human amylase genes

    SciTech Connect

    Gumucio, D.L.; Wiebauer, K.; Caldwell, R.M.; Samuelson, L.C.; Meisler, M.H.

    1988-03-01

    Cosmid clones containing 250 kilobases of genomic DNA from the human amylase gene cluster have been isolated. These clones contain seven distinct amylase genes which appear to comprise the complete multigene family. By sequence comparison with the cDNAs, the authors have identified two pancreatic amylase gene and three salivary amylase genes. Two truncated pseudogenes were also recovered. Intergenic distances of 17 to 22 kilobases separate the amylase gene copies. Within the past 10 million years, duplications, gene conversion, and unequal crossover events have resulted in a very high level of sequence similarity among human amylase gene copies. To identify sequence elements involved in tissue-specific expression and hormonal regulation, the promoter regions of the human amylase genes were sequenced and compared with those of the corresponding mouse genes. The promoters of the human and mouse pancreatic amylase genes are highly homologous between nucleotide - 160 and the cap site. Two sequence elements througth to influence pancreas-specific expression of the rodent genes are present in the human genes. In contrast, similarity in the 5' lanking sequences of the salivary amylase genes is limited to several short sequence elements whose positions and orientations differ in the two species. Some of these sequence elements are also associated with other parotid-specific genes and may be involved in their tissue-specific expression. A glucocorticoid response element and a general enhancer element are closely associated in several of the amylase promoters.

  4. Plastid ndh genes in plant evolution.

    PubMed

    Martín, Mercedes; Sabater, Bartolomé

    2010-08-01

    The plastid ndh genes encode components of the thylakoid Ndh complex which purportedly acts as an electron feeding valve to adjust the redox level of the cyclic photosynthetic electron transporters. During the process of evolution from endosymbiosis to modern chloroplast, most cyanobacterial genes were lost or transferred to nucleus. Eleven ndh genes are among the 150-200 genes remaining in higher plant chloroplast DNA, out of some 3000 genes in the original prokaryotic Cyanobacteria in which homologues to ndh genes encode components of the respiratory Complex I and probably other complexes. The ndh genes are absent in all sequenced plastid DNAs of algae except for the Charophyceae and some Prasinophyceae. With the possible exclusion of some Conifers and Gnetales, the plastid DNA of all photosynthetic land plants contains the ndh genes, whereas they are absent in epiphytic plants that have also lost genes for the photosynthetic machinery. Therefore, the functional role of the ndh genes seems closely related to the land adaptation of photosynthesis. Transcripts of several plastid genes require C to U editing. The ndh genes concentrate about 50% of the editing sites of angiosperm plastid transcripts. Editing sites may be remnants from an ancestor in which a number of T to C inactivating mutations took place in the ndh genes which, during evolution, are being corrected back to T. The comparison of homologous editing sites in the mRNAs of angiosperm ndh genes provides a tool to investigate selective and permissive environmental conditions of past evolutionary events.

  5. Making Your Own Gene Library.

    ERIC Educational Resources Information Center

    Perez-Ortin, Jose E.; Li Del Olmo, Marcel; Matallana, Emilia; Tordera, Vicente

    1997-01-01

    Presents an experiment aimed at constructing a genomic library that can be carried out over a week. Helps students learn concepts such as donor and vector DNAs, construction of recombinant DNA, host strain, and experiments in gene cloning more clearly. (PVD)

  6. Gene expression profile of pulpitis

    PubMed Central

    Galicia, Johnah C.; Henson, Brett R.; Parker, Joel S.; Khan, Asma A.

    2016-01-01

    The cost, prevalence and pain associated with endodontic disease necessitate an understanding of the fundamental molecular aspects of its pathogenesis. This study was aimed to identify the genetic contributors to pulpal pain and inflammation. Inflamed pulps were collected from patients diagnosed with irreversible pulpitis (n=20). Normal pulps from teeth extracted for various reasons served as controls (n=20). Pain level was assessed using a visual analog scale (VAS). Genome-wide microarray analysis was performed using Affymetrix GeneTitan Multichannel Instrument. The difference in gene expression levels were determined by the Significance Analysis of Microarray program using a false discovery rate (q-value) of 5%. Genes involved in immune response, cytokine-cytokine receptor interaction and signaling, integrin cell surface interactions, and others were expressed at relatively higher levels in the in the pulpitis group. Moreover, several genes known to modulate pain and inflammation showed differential expression in asymptomatic and mild pain patients (≥30mm on VAS) compared to those with moderate to severe pain. This exploratory study provides a molecular basis for the clinical diagnosis of pulpitis. With an enhanced understanding of pulpal inflammation, future studies on treatment and management of pulpitis and on pain associated with it can have a biological reference to bridge treatment strategies with pulpal biology. PMID:27052691

  7. Genes, Environment, and Human Behavior.

    ERIC Educational Resources Information Center

    Bloom, Mark V.; Cutter, Mary Ann; Davidson, Ronald; Dougherty, Michael J.; Drexler, Edward; Gelernter, Joel; McCullough, Laurence B.; McInerney, Joseph D.; Murray, Jeffrey C.; Vogler, George P.; Zola, John

    This curriculum module explores genes, environment, and human behavior. This book provides materials to teach about the nature and methods of studying human behavior, raise some of the ethical and public policy dilemmas emerging from the Human Genome Project, and provide professional development for teachers. An extensive Teacher Background…

  8. Buffering in cyclic gene networks

    NASA Astrophysics Data System (ADS)

    Glyzin, S. D.; Kolesov, A. Yu.; Rozov, N. Kh.

    2016-06-01

    We consider cyclic chains of unidirectionally coupled delay differential-difference equations that are mathematical models of artificial oscillating gene networks. We establish that the buffering phenomenon is realized in these system for an appropriate choice of the parameters: any given finite number of stable periodic motions of a special type, the so-called traveling waves, coexist.

  9. Genes and Surroundings: Teacher's Guide.

    ERIC Educational Resources Information Center

    Biological Sciences Curriculum Study, Colorado Springs, CO. Center for Education in Human and Medical Genetics.

    This teacher's guide is intended to be used with "Genes and Surroundings," an activity unit on human and medical genetics for junior high and middle school students. The unit emphasizes variability and diversity in genetics and is organized around five themes: (1) individuality; (2) continuity; (3) variability in relation to others; (4)…

  10. Ethics of Gene Therapy Debated.

    ERIC Educational Resources Information Center

    Borman, Stu

    1991-01-01

    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)

  11. Genes and Syndromic Hearing Loss.

    ERIC Educational Resources Information Center

    Keats, Bronya J. B.

    2002-01-01

    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…

  12. Gene-Culture Coevolutionary Games

    ERIC Educational Resources Information Center

    Blute, Marion

    2006-01-01

    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…

  13. Codon Adaptation of Plastid Genes

    PubMed Central

    Suzuki, Haruo; Morton, Brian R.

    2016-01-01

    Codon adaptation is codon usage bias that results from selective pressure to increase the translation efficiency of a gene. Codon adaptation has been studied across a wide range of genomes and some early analyses of plastids have shown evidence for codon adaptation in a limited set of highly expressed plastid genes. Here we study codon usage bias across all fully sequenced plastid genomes which includes representatives of the Rhodophyta, Alveolata, Cryptophyta, Euglenozoa, Glaucocystophyceae, Rhizaria, Stramenopiles and numerous lineages within the Viridiplantae, including Chlorophyta and Embryophyta. We show evidence that codon adaptation occurs in all genomes except for two, Theileria parva and Heicosporidium sp., both of which have highly reduced gene contents and no photosynthesis genes. We also show evidence that selection for codon adaptation increases the representation of the same set of codons, which we refer to as the adaptive codons, across this wide range of taxa, which is probably due to common features descended from the initial endosymbiont. We use various measures to estimate the relative strength of selection in the different lineages and show that it appears to be fairly strong in certain Stramenopiles and Chlorophyta lineages but relatively weak in many members of the Rhodophyta, Euglenozoa and Embryophyta. Given these results we propose that codon adaptation in plastids is widespread and displays the same general features as adaptation in eubacterial genomes. PMID:27196606

  14. Circadian gene variants in cancer.

    PubMed

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

    2014-06-01

    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

  15. Gene therapy for bone healing

    PubMed Central

    Evans, Christopher H.

    2015-01-01

    Clinical problems in bone healing include large segmental defects, nonunion and delayed union of fractures, and spinal fusions. Gene-transfer technologies have the potential to aid healing by permitting the local delivery and sustained expression of osteogenic gene products within osseous lesions. Key questions for such an approach include the choice of transgene, vector and gene-transfer strategy. Most experimental data have been obtained using cDNAs encoding osteogenic growth factors such as bone morphogenetic protein-2 (BMP-2), BMP-4 and BMP-7, in conjunction with both nonviral and viral vectors using in vivo and ex vivo delivery strategies. Proof of principle has been convincingly demonstrated in small-animal models. Relatively few studies have used large animals, but the results so far are encouraging. Once a reliable method has been developed, it will be necessary to perform detailed pharmacological and toxicological studies, as well as satisfy other demands of the regulatory bodies, before human clinical trials can be initiated. Such studies are very expensive and often protracted. Thus, progress in developing a clinically useful gene therapy for bone healing is determined not only by scientific considerations, but also by financial constraints and the ambient regulatory environment. PMID:20569532

  16. Codon Adaptation of Plastid Genes.

    PubMed

    Suzuki, Haruo; Morton, Brian R

    2016-01-01

    Codon adaptation is codon usage bias that results from selective pressure to increase the translation efficiency of a gene. Codon adaptation has been studied across a wide range of genomes and some early analyses of plastids have shown evidence for codon adaptation in a limited set of highly expressed plastid genes. Here we study codon usage bias across all fully sequenced plastid genomes which includes representatives of the Rhodophyta, Alveolata, Cryptophyta, Euglenozoa, Glaucocystophyceae, Rhizaria, Stramenopiles and numerous lineages within the Viridiplantae, including Chlorophyta and Embryophyta. We show evidence that codon adaptation occurs in all genomes except for two, Theileria parva and Heicosporidium sp., both of which have highly reduced gene contents and no photosynthesis genes. We also show evidence that selection for codon adaptation increases the representation of the same set of codons, which we refer to as the adaptive codons, across this wide range of taxa, which is probably due to common features descended from the initial endosymbiont. We use various measures to estimate the relative strength of selection in the different lineages and show that it appears to be fairly strong in certain Stramenopiles and Chlorophyta lineages but relatively weak in many members of the Rhodophyta, Euglenozoa and Embryophyta. Given these results we propose that codon adaptation in plastids is widespread and displays the same general features as adaptation in eubacterial genomes. PMID:27196606

  17. Gene Duplication in SACCHAROMYCES CEREVISIAE

    PubMed Central

    Hansche, P. E.; Beres, V.; Lange, P.

    1978-01-01

    Five indepdendent duplications of the acid-phosphatase (aphtase) structural gene (acp1) were recovered from chemostat populations of S. cerevisiae that were subject to selection for in vivo hyper-aphtase activity. Two of the duplications arose spontaneously. Three of them were induced by UV. All five of the duplication events involved the transpositioning of the aphtase structural gene, acp1, and all known genes distal to acp1 on the right arm of chromosome II, to the terminus of an arm of other unknown chromosomes. One of the five duplicated regions of the right arm of chromosome II was found to be transmitted mitotically and meiotically with very high fidelity. The other four duplicated regions of the right arm of chromosome II were found to be unstable, being lost at a rate of about 2% per mitosis. However, selection for increased fidelity of mitotic transmission was effective in one of these strains. No tandem duplications of the aphtase structural gene were found. PMID:348562

  18. Patching genes to fight disease

    SciTech Connect

    Holzman, D.

    1990-09-03

    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.

  19. Gene expression profile of pulpitis.

    PubMed

    Galicia, J C; Henson, B R; Parker, J S; Khan, A A

    2016-06-01

    The cost, prevalence and pain associated with endodontic disease necessitate an understanding of the fundamental molecular aspects of its pathogenesis. This study was aimed to identify the genetic contributors to pulpal pain and inflammation. Inflamed pulps were collected from patients diagnosed with irreversible pulpitis (n=20). Normal pulps from teeth extracted for various reasons served as controls (n=20). Pain level was assessed using a visual analog scale (VAS). Genome-wide microarray analysis was performed using Affymetrix GeneTitan Multichannel Instrument. The difference in gene expression levels were determined by the significance analysis of microarray program using a false discovery rate (q-value) of 5%. Genes involved in immune response, cytokine-cytokine receptor interaction and signaling, integrin cell surface interactions, and others were expressed at relatively higher levels in the pulpitis group. Moreover, several genes known to modulate pain and inflammation showed differential expression in asymptomatic and mild pain patients (⩾30 mm on VAS) compared with those with moderate to severe pain. This exploratory study provides a molecular basis for the clinical diagnosis of pulpitis. With an enhanced understanding of pulpal inflammation, future studies on treatment and management of pulpitis and on pain associated with it can have a biological reference to bridge treatment strategies with pulpal biology. PMID:27052691

  20. Circadian gene variants in cancer

    PubMed Central

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

    2014-01-01

    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

  1. Immunoglobulin gene diversification in cattle.

    PubMed

    Meyer, A; Parng, C L; Hansal, S A; Osborne, B A; Goldsby, R A

    1997-01-01

    Research in several species has revealed that different types of mammals have evolved divergent molecular and cellular strategies for generating immunoglobulin diversity. Other chapters in this text have highlighted the specific characteristics unique to chicken, rabbit, mouse, human and sheep B lymphocyte development; namely indicating differences in the mechanisms of diversity and the site of primary B cell development. Studies of the bovine system have indicated that like the sheep system, the ileal Peyer's patch (IPP) is a likely chicken bursal equivalent, and is a site of primary B lymphocyte development. Substantial investigation in sheep has indicated that Ig diversity is created by untemplated somatic mutation and intense selective pressure (Reynaud et al., 1991). The frequency of alteration in the sheep Ig light chain gene locus also is characteristic of the bovine system, however, recent evidence from sequencing of bovine lambda light chain genes indicates that one mechanism that contributes to diversity is gene conversion, utilizing several pseudogenes located in the Ig locus (Parng et al., 1996). The mechanism by which this hyperalteration of Ig genes occurs in both sheep and cattle is poorly understood and is thus the focus of considerable investigation. The study of events in the IPP may also have informative ramifications for secondary diversification of the Ig repertoire by somatic hyperalteration in germinal centers.

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

    PubMed Central

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

    2008-01-01

    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. PMID:18241342

  3. Identification of gene-gene and gene-environment interactions within the fibrinogen gene cluster for fibrinogen levels in three ethnically diverse populations.

    PubMed

    Jeff, Janina M; Brown-Gentry, Kristin; Crawford, Dana C

    2015-01-01

    Elevated levels of plasma fibrinogen are associated with clot formation in the absence of inflammation or injury and is a biomarker for arterial clotting, the leading cause of cardiovascular disease. Fibrinogen levels are heritable with >50% attributed to genetic factors, however little is known about possible genetic modifiers that might explain the missing heritability. The fibrinogen gene cluster is comprised of three genes (FGA, FGB, and FGG) that make up the fibrinogen polypeptide essential for fibrinogen production in the blood. Given the known interaction with these genes, we tested 25 variants in the fibrinogen gene cluster for gene x gene and gene x environment interactions in 620 non-Hispanic blacks, 1,385 non-Hispanic whites, and 664 Mexican Americans from a cross-sectional dataset enriched with environmental data, the Third National Health and Nutrition Examination Survey (NHANES III). Using a multiplicative approach, we added cross product terms (gene x gene or gene x environment) to a linear regression model and declared significance at p < 0.05. We identified 19 unique gene x gene and 13 unique gene x environment interactions that impact fibrinogen levels in at least one population at p < 0.05. Over 90% of the gene x gene interactions identified include a variant in the rate-limiting gene, FGB that is essential for the formation of the fibrinogen polypeptide. We also detected gene x environment interactions with fibrinogen variants and sex, smoking, and body mass index. These findings highlight the potential for the discovery of genetic modifiers for complex phenotypes in multiple populations and give a better understanding of the interaction between genes and/or the environment for fibrinogen levels. The need for more powerful and robust methods to identify genetic modifiers is still warranted. PMID:25592583

  4. IDENTIFICATION OF GENE-GENE AND GENE-ENVIRONMENT INTERACTIONS WITHIN THE FIBRINOGEN GENE CLUSTER FOR FIBRINOGEN LEVELS IN THREE ETHNICALLY DIVERSE POPULATIONS

    PubMed Central

    Jeff, Janina M.; Brown-Gentry, Kristin; Crawford, Dana C.

    2014-01-01

    Elevated levels of plasma fibrinogen are associated with clot formation in the absence of inflammation or injury and is a biomarker for arterial clotting, the leading cause of cardiovascular disease. Fibrinogen levels are heritable with >50% attributed to genetic factors, however little is known about possible genetic modifiers that might explain the missing heritability. The fibrinogen gene cluster is comprised of three genes (FGA, FGB, and FGG) that make up the fibrinogen polypeptide essential for fibrinogen production in the blood. Given the known interaction with these genes, we tested 25 variants in the fibrinogen gene cluster for gene × gene and gene × environment interactions in 620 non-Hispanic blacks, 1,385 non-Hispanic whites, and 664 Mexican Americans from a cross-sectional dataset enriched with environmental data, the Third National Health and Nutrition Examination Survey (NHANES III). Using a multiplicative approach, we added cross product terms (gene × gene or gene × environment) to a linear regression model and declared significance at p < 0.05. We identified 19 unique gene × gene and 13 unique gene × environment interactions that impact fibrinogen levels in at least one population at p <0.05. Over 90% of the gene × gene interactions identified include a variant in the rate-limiting gene, FGB that is essential for the formation of the fibrinogen polypeptide. We also detected gene × environment interactions with fibrinogen variants and sex, smoking, and body mass index. These findings highlight the potential for the discovery of genetic modifiers for complex phenotypes in multiple populations and give a better understanding of the interaction between genes and/or the environment for fibrinogen levels. The need for more powerful and robust methods to identify genetic modifiers is still warranted. PMID:25592583

  5. Identification of gene-gene and gene-environment interactions within the fibrinogen gene cluster for fibrinogen levels in three ethnically diverse populations.

    PubMed

    Jeff, Janina M; Brown-Gentry, Kristin; Crawford, Dana C

    2015-01-01

    Elevated levels of plasma fibrinogen are associated with clot formation in the absence of inflammation or injury and is a biomarker for arterial clotting, the leading cause of cardiovascular disease. Fibrinogen levels are heritable with >50% attributed to genetic factors, however little is known about possible genetic modifiers that might explain the missing heritability. The fibrinogen gene cluster is comprised of three genes (FGA, FGB, and FGG) that make up the fibrinogen polypeptide essential for fibrinogen production in the blood. Given the known interaction with these genes, we tested 25 variants in the fibrinogen gene cluster for gene x gene and gene x environment interactions in 620 non-Hispanic blacks, 1,385 non-Hispanic whites, and 664 Mexican Americans from a cross-sectional dataset enriched with environmental data, the Third National Health and Nutrition Examination Survey (NHANES III). Using a multiplicative approach, we added cross product terms (gene x gene or gene x environment) to a linear regression model and declared significance at p < 0.05. We identified 19 unique gene x gene and 13 unique gene x environment interactions that impact fibrinogen levels in at least one population at p < 0.05. Over 90% of the gene x gene interactions identified include a variant in the rate-limiting gene, FGB that is essential for the formation of the fibrinogen polypeptide. We also detected gene x environment interactions with fibrinogen variants and sex, smoking, and body mass index. These findings highlight the potential for the discovery of genetic modifiers for complex phenotypes in multiple populations and give a better understanding of the interaction between genes and/or the environment for fibrinogen levels. The need for more powerful and robust methods to identify genetic modifiers is still warranted.

  6. Gene expression profiles in skeletal muscle after gene electrotransfer

    PubMed Central

    Hojman, Pernille; Zibert, John R; Gissel, Hanne; Eriksen, Jens; Gehl, Julie

    2007-01-01

    Background Gene transfer by electroporation (DNA electrotransfer) to muscle results in high level long term transgenic expression, showing great promise for treatment of e.g. protein deficiency syndromes. However little is known about the effects of DNA electrotransfer on muscle fibres. We have therefore investigated transcriptional changes through gene expression profile analyses, morphological changes by histological analysis, and physiological changes by force generation measurements. DNA electrotransfer was obtained using a combination of a short high voltage pulse (HV, 1000 V/cm, 100 μs) followed by a long low voltage pulse (LV, 100 V/cm, 400 ms); a pulse combination optimised for efficient and safe gene transfer. Muscles were transfected with green fluorescent protein (GFP) and excised at 4 hours, 48 hours or 3 weeks after treatment. Results Differentially expressed genes were investigated by microarray analysis, and descriptive statistics were performed to evaluate the effects of 1) electroporation, 2) DNA injection, and 3) time after treatment. The biological significance of the results was assessed by gene annotation and supervised cluster analysis. Generally, electroporation caused down-regulation of structural proteins e.g. sarcospan and catalytic enzymes. Injection of DNA induced down-regulation of intracellular transport proteins e.g. sentrin. The effects on muscle fibres were transient as the expression profiles 3 weeks after treatment were closely related with the control muscles. Most interestingly, no changes in the expression of proteins involved in inflammatory responses or muscle regeneration was detected, indicating limited muscle damage and regeneration. Histological analysis revealed structural changes with loss of cell integrity and striation pattern in some fibres after DNA+HV+LV treatment, while HV+LV pulses alone showed preservation of cell integrity. No difference in the force generation capacity was observed in the muscles 2 weeks

  7. Vascular gene expression: a hypothesis

    PubMed Central

    Martínez-Navarro, Angélica C.; Galván-Gordillo, Santiago V.; Xoconostle-Cázares, Beatriz; Ruiz-Medrano, Roberto

    2013-01-01

    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. PMID:23882276

  8. The MDM2 gene family.

    PubMed

    Mendoza, Michael; Mandani, Garni; Momand, Jamil

    2014-03-01

    MDM2 is an oncoprotein that blocks p53 tumor suppressor-mediated transcriptional transactivation, escorts p53 from the cell nucleus to the cytoplasm, and polyubiquitylates p53. Polyubiquitylated p53 is rapidly degraded in the cytoplasm by the 26S proteasome. MDM2 is abnormally upregulated in several types of cancers, especially those of mesenchymal origin. MDM4 is a homolog of MDM2 that also inhibits p53 by blocking p53-mediated transactivation. MDM4 is required for MDM2-mediated polyubiquitylated of p53 and is abnormally upregulated in several cancer types. MDM2 and MDM4 genes have been detected in all vertebrates to date and only a single gene homolog, named MDM, has been detected in some invertebrates. MDM2, MDM4, and MDM have similar gene structures, suggesting that MDM2 and MDM4 arose through a duplication event more than 440 million years ago. All members of this small MDM2 gene family contain a single really interesting new gene (RING) domain (with the possible exception of lancelet MDM) which places them in the RING-domain superfamily. Similar to MDM2, the vast majority of proteins with RING domains are E3 ubiquitin ligases. Other RING domain E3 ubiquitin ligases that target p53 are COP1, Pirh2, and MSL2. In this report, we present evidence that COP1, Pirh2, and MSL2 evolved independently of MDM2 and MDM4. We also show, through structure homology models of invertebrate MDM RING domains, that MDM2 is more evolutionarily conserved than MDM4. PMID:25372739

  9. Gene doping: the hype and the harm.

    PubMed

    McKanna, Trudy A; Toriello, Helga V

    2010-06-01

    "Gene doping" is the term used to describe the potential abuse of gene therapy as a performance-enhancing agent. Gene doping would apply the techniques used in gene therapy to provide altered expression of genes that would promote physical superiority. For example, insulin-like growth factor 1 (IGF-1) is a primary target for growth hormone; overexpression of IGF-1 can lead to increased muscle mass and power. Although gene doping is still largely theoretical, its implications for sports, health, ethics, and medical genetics are significant. PMID:20538153

  10. Therapeutic Targeting of Tumor Suppressor Genes

    PubMed Central

    Morris, Luc G. T.; Chan, Timothy A.

    2015-01-01

    Carcinogenesis is a multistep process attributable to both gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressor genes. Currently, most molecular targeted therapies are inhibitors of oncogenes, because inactivated tumor suppressor genes have proven harder to “drug.” Nevertheless, in cancers, tumor suppressor genes undergo alteration more frequently than do oncogenes. In recent years, several promising strategies directed at tumor suppressor genes, or the pathways controlled by these genes, have emerged. Here, we describe advances in a number of different methodologies aimed at therapeutically targeting tumors driven by inactivated tumor suppressor genes. PMID:25557041

  11. Gene doping: the hype and the harm.

    PubMed

    McKanna, Trudy A; Toriello, Helga V

    2010-06-01

    "Gene doping" is the term used to describe the potential abuse of gene therapy as a performance-enhancing agent. Gene doping would apply the techniques used in gene therapy to provide altered expression of genes that would promote physical superiority. For example, insulin-like growth factor 1 (IGF-1) is a primary target for growth hormone; overexpression of IGF-1 can lead to increased muscle mass and power. Although gene doping is still largely theoretical, its implications for sports, health, ethics, and medical genetics are significant.

  12. The P450 gene superfamily: recommended nomenclature.

    PubMed

    Nebert, D W; Adesnik, M; Coon, M J; Estabrook, R W; Gonzalez, F J; Guengerich, F P; Gunsalus, I C; Johnson, E F; Kemper, B; Levin, W

    1987-02-01

    A nomenclature for the P450 gene superfamily is proposed based on evolution. Recommendations include Roman numerals for distinct gene families, capital letters for subfamilies, and Arabic numerals for individual genes. An updating of this list, which presently includes 65 entries, will be required every 1-2 years. Assignment of orthologous genes is presently uncertain in some cases--between widely diverged species and especially in the P450II family due to the large number of genes. As more is known, it might become necessary to change some gene assignments that are based on our present knowledge. PMID:3829886

  13. Identification of essential genes and synthetic lethal gene combinations in Escherichia coli K-12.

    PubMed

    Mori, Hirotada; Baba, Tomoya; Yokoyama, Katsushi; Takeuchi, Rikiya; Nomura, Wataru; Makishi, Kazuichi; Otsuka, Yuta; Dose, Hitomi; Wanner, Barry L

    2015-01-01

    Here we describe the systematic identification of single genes and gene pairs, whose knockout causes lethality in Escherichia coli K-12. During construction of precise single-gene knockout library of E. coli K-12, we identified 328 essential gene candidates for growth in complex (LB) medium. Upon establishment of the Keio single-gene deletion library, we undertook the development of the ASKA single-gene deletion library carrying a different antibiotic resistance. In addition, we developed tools for identification of synthetic lethal gene combinations by systematic construction of double-gene knockout mutants. We introduce these methods herein.

  14. Genome-wide analysis of homeobox genes from Mesobuthus martensii reveals Hox gene duplication in scorpions.

    PubMed

    Di, Zhiyong; Yu, Yao; Wu, Yingliang; Hao, Pei; He, Yawen; Zhao, Huabin; Li, Yixue; Zhao, Guoping; Li, Xuan; Li, Wenxin; Cao, Zhijian

    2015-06-01

    Homeobox genes belong to a large gene group, which encodes the famous DNA-binding homeodomain that plays a key role in development and cellular differentiation during embryogenesis in animals. Here, one hundred forty-nine homeobox genes were identified from the Asian scorpion, Mesobuthus martensii (Chelicerata: Arachnida: Scorpiones: Buthidae) based on our newly assembled genome sequence with approximately 248 × coverage. The identified homeobox genes were categorized into eight classes including 82 families: 67 ANTP class genes, 33 PRD genes, 11 LIM genes, five POU genes, six SINE genes, 14 TALE genes, five CUT genes, two ZF genes and six unclassified genes. Transcriptome data confirmed that more than half of the genes were expressed in adults. The homeobox gene diversity of the eight classes is similar to the previously analyzed Mandibulata arthropods. Interestingly, it is hypothesized that the scorpion M. martensii may have two Hox clusters. The first complete genome-wide analysis of homeobox genes in Chelicerata not only reveals the repertoire of scorpion, arachnid and chelicerate homeobox genes, but also shows some insights into the evolution of arthropod homeobox genes.

  15. Genes from scratch--the evolutionary fate of de novo genes.

    PubMed

    Schlötterer, Christian

    2015-04-01

    Although considered an extremely unlikely event, many genes emerge from previously noncoding genomic regions. This review covers the entire life cycle of such de novo genes. Two competing hypotheses about the process of de novo gene birth are discussed as well as the high death rate of de novo genes. Despite the high death rate, some de novo genes are retained and remain functional, even in distantly related species, through their integration into gene networks. Further studies combining gene expression with ribosome profiling in multiple populations across different species will be instrumental for an improved understanding of the evolutionary processes operating on de novo genes.

  16. Identification of essential genes and synthetic lethal gene combinations in Escherichia coli K-12.

    PubMed

    Mori, Hirotada; Baba, Tomoya; Yokoyama, Katsushi; Takeuchi, Rikiya; Nomura, Wataru; Makishi, Kazuichi; Otsuka, Yuta; Dose, Hitomi; Wanner, Barry L

    2015-01-01

    Here we describe the systematic identification of single genes and gene pairs, whose knockout causes lethality in Escherichia coli K-12. During construction of precise single-gene knockout library of E. coli K-12, we identified 328 essential gene candidates for growth in complex (LB) medium. Upon establishment of the Keio single-gene deletion library, we undertook the development of the ASKA single-gene deletion library carrying a different antibiotic resistance. In addition, we developed tools for identification of synthetic lethal gene combinations by systematic construction of double-gene knockout mutants. We introduce these methods herein. PMID:25636612

  17. Mouse histone H2A and H2B genes: four functional genes and a pseudogene undergoing gene conversion with a closely linked functional gene.

    PubMed Central

    Liu, T J; Liu, L; Marzluff, W F

    1987-01-01

    The sequence of five mouse histone genes, two H2a and three H2b genes on chromosome 13 has been determined. The three H2b genes all code for different proteins, each differing in two amino acids from the others. The H2b specific elements present 5' to H2b genes from other species are present in all three mouse H2b genes. All three H2b genes are expressed in the same relative amounts in three different mouse cell lines and fetal mice. The H2b gene with the H2b specific sequence closest to the TATAA sequence is expressed in the highest amount. One of the H2a genes lacks the first 9 amino acids, the promoter region, the last 3 amino acids and contains an altered 3' end sequence. Despite these multiple defects, there is only one nucleotide change between the two H2a genes from codon 9 to 126. This indicates that a recent gene conversion has occurred between these two genes. The similarity of the nucleotide sequences in the coding regions of mouse histone genes is probably due to gene conversion events targeted precisely at the coding region. Images PMID:3562244

  18. Gene family matters: expanding the HGNC resource.

    PubMed

    Daugherty, Louise C; Seal, Ruth L; Wright, Mathew W; Bruford, Elspeth A

    2012-01-01

    The HUGO Gene Nomenclature Committee (HGNC) assigns approved gene symbols to human loci. There are currently over 33,000 approved gene symbols, the majority of which represent protein-coding genes, but we also name other locus types such as non-coding RNAs, pseudogenes and phenotypic loci. Where relevant, the HGNC organise these genes into gene families and groups. The HGNC website http://www.genenames.org/ is an online repository of HGNC-approved gene nomenclature and associated resources for human genes, and includes links to genomic, proteomic and phenotypic information. In addition to this, we also have dedicated gene family web pages and are currently expanding and generating more of these pages using data curated by the HGNC and from information derived from external resources that focus on particular gene families. Here, we review our current online resources with a particular focus on our gene family data, using it to highlight our new Gene Symbol Report and gene family data downloads. PMID:23245209

  19. Genomic evidence for adaptation by gene duplication.

    PubMed

    Qian, Wenfeng; Zhang, Jianzhi

    2014-08-01

    Gene duplication is widely believed to facilitate adaptation, but unambiguous evidence for this hypothesis has been found in only a small number of cases. Although gene duplication may increase the fitness of the involved organisms by doubling gene dosage or neofunctionalization, it may also result in a simple division of ancestral functions into daughter genes, which need not promote adaptation. Hence, the general validity of the adaptation by gene duplication hypothesis remains uncertain. Indeed, a genome-scale experiment found similar fitness effects of deleting pairs of duplicate genes and deleting individual singleton genes from the yeast genome, leading to the conclusion that duplication rarely results in adaptation. Here we contend that the above comparison is unfair because of a known duplication bias among genes with different fitness contributions. To rectify this problem, we compare homologous genes from the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe. We discover that simultaneously deleting a duplicate gene pair in S. cerevisiae reduces fitness significantly more than deleting their singleton counterpart in S. pombe, revealing post-duplication adaptation. The duplicates-singleton difference in fitness effect is not attributable to a potential increase in gene dose after duplication, suggesting that the adaptation is owing to neofunctionalization, which we find to be explicable by acquisitions of binary protein-protein interactions rather than gene expression changes. These results provide genomic evidence for the role of gene duplication in organismal adaptation and are important for understanding the genetic mechanisms of evolutionary innovation. PMID:24904045

  20. Structures of two molluscan hemocyanin genes: significance for gene evolution.

    PubMed

    Lieb, B; Altenhein, B; Markl, J; Vincent, A; van Olden, E; van Holde, K E; Miller, K I

    2001-04-10

    We present here the description of genes coding for molluscan hemocyanins. Two distantly related mollusks, Haliotis tuberculata and Octopus dofleini, were studied. The typical architecture of a molluscan hemocyanin subunit, which is a string of seven or eight globular functional units (FUs, designated a to h, about 50 kDa each), is reflected by the gene organization: a series of eight structurally related coding regions in Haliotis, corresponding to FU-a to FU-h, with seven highly variable linker introns of 174 to 3,198 bp length (all in phase 1). In Octopus seven coding regions (FU-a to FU-g) are found, separated by phase 1 introns varying in length from 100 bp to 910 bp. Both genes exhibit typical signal (export) sequences, and in both cases these are interrupted by an additional intron. Each gene also contains an intron between signal peptide and FU-a and in the 3' untranslated region. Of special relevance for evolutionary considerations are introns interrupting those regions that encode a discrete functional unit. We found that five of the eight FUs in Haliotis each are encoded by a single exon, whereas FU-f, FU-g, and FU-a are encoded by two, three and four exons, respectively. Similarly, in Octopus four of the FUs each correspond to an uninterrupted exon, whereas FU-b, FU-e, and FU-f each contain a single intron. Although the positioning of the introns between FUs is highly conserved in the two mollusks, the introns within FUs show no relationship either in location nor phase. It is proposed that the introns between FUs were generated as the eight-unit polypeptide evolved from a monomeric precursor, and that the internal introns have been added later. A hypothesis for evolution of the ring-like quaternary structure of molluscan hemocyanins is presented. PMID:11287637

  1. Structures of two molluscan hemocyanin genes: Significance for gene evolution

    PubMed Central

    Lieb, Bernhard; Altenhein, Benjamin; Markl, Jürgen; Vincent, Alexandra; van Olden, Erin; van Holde, Kensal E.; Miller, Karen I.

    2001-01-01

    We present here the description of genes coding for molluscan hemocyanins. Two distantly related mollusks, Haliotis tuberculata and Octopus dofleini, were studied. The typical architecture of a molluscan hemocyanin subunit, which is a string of seven or eight globular functional units (FUs, designated a to h, about 50 kDa each), is reflected by the gene organization: a series of eight structurally related coding regions in Haliotis, corresponding to FU-a to FU-h, with seven highly variable linker introns of 174 to 3,198 bp length (all in phase 1). In Octopus seven coding regions (FU-a to FU-g) are found, separated by phase 1 introns varying in length from 100 bp to 910 bp. Both genes exhibit typical signal (export) sequences, and in both cases these are interrupted by an additional intron. Each gene also contains an intron between signal peptide and FU-a and in the 3′ untranslated region. Of special relevance for evolutionary considerations are introns interrupting those regions that encode a discrete functional unit. We found that five of the eight FUs in Haliotis each are encoded by a single exon, whereas FU-f, FU-g, and FU-a are encoded by two, three and four exons, respectively. Similarly, in Octopus four of the FUs each correspond to an uninterrupted exon, whereas FU-b, FU-e, and FU-f each contain a single intron. Although the positioning of the introns between FUs is highly conserved in the two mollusks, the introns within FUs show no relationship either in location nor phase. It is proposed that the introns between FUs were generated as the eight-unit polypeptide evolved from a monomeric precursor, and that the internal introns have been added later. A hypothesis for evolution of the ring-like quaternary structure of molluscan hemocyanins is presented. PMID:11287637

  2. Gene-gene interactions in breast cancer susceptibility.

    PubMed

    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

    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

  3. Sequence and gene expression evolution of paralogous genes in willows.

    PubMed

    Harikrishnan, Srilakshmy L; Pucholt, Pascal; Berlin, Sofia

    2015-12-22

    Whole genome duplications (WGD) have had strong impacts on species diversification by triggering evolutionary novelties, however, relatively little is known about the balance between gene loss and forces involved in the retention of duplicated genes originating from a WGD. We analyzed putative Salicoid duplicates in willows, originating from the Salicoid WGD, which took place more than 45 Mya. Contigs were constructed by de novo assembly of RNA-seq data derived from leaves and roots from two genotypes. Among the 48,508 contigs, 3,778 pairs were, based on fourfold synonymous third-codon transversion rates and syntenic positions, predicted to be Salicoid duplicates. Both copies were in most cases expressed in both tissues and 74% were significantly differentially expressed. Mean Ka/Ks was 0.23, suggesting that the Salicoid duplicates are evolving by purifying selection. Gene Ontology enrichment analyses showed that functions related to DNA- and nucleic acid binding were over-represented among the non-differentially expressed Salicoid duplicates, while functions related to biosynthesis and metabolism were over-represented among the differentially expressed Salicoid duplicates. We propose that the differentially expressed Salicoid duplicates are regulatory neo- and/or subfunctionalized, while the non-differentially expressed are dose sensitive, hence, functionally conserved. Multiple evolutionary processes, thus drive the retention of Salicoid duplicates in willows.

  4. Sequence and gene expression evolution of paralogous genes in willows

    PubMed Central

    Harikrishnan, Srilakshmy L.; Pucholt, Pascal; Berlin, Sofia

    2015-01-01

    Whole genome duplications (WGD) have had strong impacts on species diversification by triggering evolutionary novelties, however, relatively little is known about the balance between gene loss and forces involved in the retention of duplicated genes originating from a WGD. We analyzed putative Salicoid duplicates in willows, originating from the Salicoid WGD, which took place more than 45 Mya. Contigs were constructed by de novo assembly of RNA-seq data derived from leaves and roots from two genotypes. Among the 48,508 contigs, 3,778 pairs were, based on fourfold synonymous third-codon transversion rates and syntenic positions, predicted to be Salicoid duplicates. Both copies were in most cases expressed in both tissues and 74% were significantly differentially expressed. Mean Ka/Ks was 0.23, suggesting that the Salicoid duplicates are evolving by purifying selection. Gene Ontology enrichment analyses showed that functions related to DNA- and nucleic acid binding were over-represented among the non-differentially expressed Salicoid duplicates, while functions related to biosynthesis and metabolism were over-represented among the differentially expressed Salicoid duplicates. We propose that the differentially expressed Salicoid duplicates are regulatory neo- and/or subfunctionalized, while the non-differentially expressed are dose sensitive, hence, functionally conserved. Multiple evolutionary processes, thus drive the retention of Salicoid duplicates in willows. PMID:26689951

  5. A powerful latent variable method for detecting and characterizing gene-based gene-gene interaction on multiple quantitative traits

    PubMed Central

    2013-01-01

    Background On thinking quantitatively of complex diseases, there are at least three statistical strategies for analyzing the gene-gene interaction: SNP by SNP interaction on single trait, gene-gene (each can involve multiple SNPs) interaction on single trait and gene-gene interaction on multiple traits. The third one is the most general in dissecting the genetic mechanism underlying complex diseases underpinning multiple quantitative traits. In this paper, we developed a novel statistic for this strategy through modifying the Partial Least Squares Path Modeling (PLSPM), called mPLSPM statistic. Results Simulation studies indicated that mPLSPM statistic was powerful and outperformed the principal component analysis (PCA) based linear regression method. Application to real data in the EPIC-Norfolk GWAS sub-cohort showed suggestive interaction (γ) between TMEM18 gene and BDNF gene on two composite body shape scores (γ = 0.047 and γ = 0.058, with P = 0.021, P = 0.005), and BMI (γ = 0.043, P = 0.034). This suggested these scores (synthetically latent traits) were more suitable to capture the obesity related genetic interaction effect between genes compared to single trait. Conclusions The proposed novel mPLSPM statistic is a valid and powerful gene-based method for detecting gene-gene interaction on multiple quantitative phenotypes. PMID:24059907

  6. Mechanisms of gene targeting in higher eukaryotes.

    PubMed

    Tokunaga, Akinori; Anai, Hirofumi; Hanada, Katsuhiro

    2016-02-01

    Targeted genome modifications using techniques that alter the genomic information of interest have contributed to multiple studies in both basic and applied biology. Traditionally, in gene targeting, the target-site integration of a targeting vector by homologous recombination is used. However, this strategy has several technical problems. The first problem is the extremely low frequency of gene targeting, which makes obtaining recombinant clones an extremely labor intensive task. The second issue is the limited number of biomaterials to which gene targeting can be applied. Traditional gene targeting hardly occurs in most of the human adherent cell lines. However, a new approach using designer nucleases that can introduce site-specific double-strand breaks in genomic DNAs has increased the efficiency of gene targeting. This new method has also expanded the number of biomaterials to which gene targeting could be applied. Here, we summarize various strategies for target gene modification, including a comparison of traditional gene targeting with designer nucleases.

  7. Genes and Disease: Prader-Willi Syndrome

    MedlinePlus

    ... Medicine, National Institutes of Health. National Center for Biotechnology Information (US). Genes and Disease [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 1998-. Genes and Disease [Internet]. Show ...

  8. Gene Therapy and Children (For Parents)

    MedlinePlus

    ... screenings or other regular exams. previous continue The Future of Gene Therapy To cure genetic diseases, scientists ... Gene therapy's potential to revolutionize medicine in the future is exciting, and hopes are high for its ...

  9. Alzheimer's Gene May Show Effects in Childhood

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_159854.html Alzheimer's Gene May Show Effects in Childhood Brain scans ... 13, 2016 (HealthDay News) -- A gene related to Alzheimer's disease may start to show effects on brain ...

  10. Plant Evolution: Evolving Antagonistic Gene Regulatory Networks.

    PubMed

    Cooper, Endymion D

    2016-06-20

    Developing a structurally complex phenotype requires a complex regulatory network. A new study shows how gene duplication provides a potential source of antagonistic interactions, an important component of gene regulatory networks. PMID:27326708

  11. Gene Conversion in Human Genetic Disease

    PubMed Central

    Chen, Jian-Min; Férec, Claude; Cooper, David N.

    2010-01-01

    Gene conversion is a specific type of homologous recombination that involves the unidirectional transfer of genetic material from a ‘donor’ sequence to a highly homologous ‘acceptor’. We have recently reviewed the molecular mechanisms underlying gene conversion, explored the key part that this process has played in fashioning extant human genes, and performed a meta-analysis of gene-conversion events known to have caused human genetic disease. Here we shall briefly summarize some of the latest developments in the study of pathogenic gene conversion events, including (i) the emerging idea of minimal efficient sequence homology (MESH) for homologous recombination, (ii) the local DNA sequence features that appear to predispose to gene conversion, (iii) a mechanistic comparison of gene conversion and transient hypermutability, and (iv) recently reported examples of pathogenic gene conversion events. PMID:24710102

  12. Immunoglobulins and immunoglobulin genes of the horse.

    PubMed

    Wagner, Bettina

    2006-01-01

    Antibodies of the horse were studied intensively by many notable immunologists throughout the past century until the early 1970's. After a large gap of interest in horse immunology, additional basic studies on horse immunoglobulin genes performed during the past 10 years have resulted in new insights into the equine humoral immune system. These include the characterization of the immunoglobulin lambda and kappa light chain genes, the immunoglobulin heavy chain constant (IGHC) gene regions, and initial studies regarding the heavy chain variable genes. Horses express predominately lambda light chains and seem to have a relatively restricted germline repertoire of both lambda and kappa chain variable genes. The IGHC region contains eleven constant heavy chain genes, seven of which are gamma heavy chain genes. It is suggested that all seven genes encoding IgG isotypes are expressed and have distinct functions in equine immune responses.

  13. Researchers Pinpoint More Genes Linked to Vitiligo

    MedlinePlus

    ... gov/news/fullstory_161452.html Researchers Pinpoint More Genes Linked to Vitiligo Genetic clues to this autoimmune ... HealthDay News) -- Researchers say they've identified more genes linked to the autoimmune disease vitiligo, which causes ...

  14. 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- ...

  15. Plant Evolution: Evolving Antagonistic Gene Regulatory Networks.

    PubMed

    Cooper, Endymion D

    2016-06-20

    Developing a structurally complex phenotype requires a complex regulatory network. A new study shows how gene duplication provides a potential source of antagonistic interactions, an important component of gene regulatory networks.

  16. Ethics of Cancer Gene Transfer Clinical Research.

    PubMed

    Kimmelman, Jonathan

    2015-01-01

    Translation of cancer gene transfer confronts many familiar-and some distinctive-ethical challenges. In what follows, I survey three major ethical dimensions of cancer gene transfer development. Subheading 1 centers on the ethics of planning, designing, and reporting animal studies. Subheading 2 describes basic elements of human subjects protection as pertaining to cancer gene transfer. In Subheading 3, I describe how cancer gene transfer researchers have obligations to downstream consumers of the evidence they produce.

  17. Plant nitrogen regulatory P-PII genes

    DOEpatents

    Coruzzi, Gloria M.; Lam, Hon-Ming; Hsieh, Ming-Hsiun

    2001-01-01

    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

  18. [Detection of transgenic crop with gene chip].

    PubMed

    Huang, Ying-Chun; Sun, Chun-Yun; Feng, Hong; Hu, Xiao-Dong; Yin, Hai-Bin

    2003-05-01

    Some selected available sequences of reporter genes,resistant genes, promoters and terminators are amplified by PCR for the probes of transgenic crop detection gene chip. These probes are arrayed at definite density and printed on the surface of amino-slides by bioRobot MicroGrid II. Results showed that gene chip worked quickly and correctly, when transgenic rice, pawpaw,maize and soybean were applied. PMID:15639876

  19. Leader genes in osteogenesis: a theoretical study.

    PubMed

    Orlando, Bruno; Giacomelli, Luca; Ricci, Massimiliano; Barone, Antonio; Covani, Ugo

    2013-01-01

    Little is still known about the molecular mechanisms involved in the process of osteogenesis. In this paper, the leader genes approach, a new bioinformatics method which has already been experimentally validated, is adopted in order to identify the genes involved in human osteogenesis. Interactions among genes are then calculated and genes are ranked according to their relative importance in this process. In total, 167 genes were identified as being involved in osteogenesis. Genes were divided into 4 groups, according to their main function in the osteogenic processes: skeletal development; cell adhesion and proliferation; ossification; and calcium ion binding. Seven genes were consistently identified as leader genes (i.e. the genes with the greatest importance in osteogenesis), while 14 were found to have slightly less importance (class B genes). It was interesting to notice that the larger part of leader and class B genes belonged to the cell adhesion and proliferation or to the ossification sub-groups. This finding suggested that these two particular sub-processes could play a more important role in osteogenesis. Moreover, among the 7 leader genes, it is interesting to notice that RUNX2, BMP2, SPARC, PTH play a direct role in bone formation, while the 3 other leader genes (VEGF, IL6, FGF2) seem to be more connected with an angiogenetic process. Twenty-nine genes have no known interactions (orphan genes). From these results, it may be possible to plan an ad hoc experimentation, for instance by microarray analyses, focused on leader, class B and orphan genes, with the aim to shed new light on the molecular mechanisms underlying osteogenesis.

  20. Nickel and epigenetic gene silencing.

    PubMed

    Sun, Hong; Shamy, Magdy; Costa, Max

    2013-01-01

    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

  1. Gene therapy for retinal degeneration.

    PubMed

    Reichel, M B; Ali, R R; Hunt, D M; Bhattacharya, S S

    1997-01-01

    Inherited retinal degenerations are a group of diseases leading to blindness through progressive loss of vision in many patients. Although with the cloning of more and more disease genes the knowledge on the molecular genetics of these conditions and on the apoptotic pathway as the common disease mechanism is steadily increasing, there is still no cure for those affected. In recent years, new experimental treatments have evolved through the efforts of many investigators and have been explored in animal models. The rationale of the different strategies for developing a treatment based on gene replacement or rescue of the diseased neuronal tissue with growth factors will be outlined and discussed in this paper. PMID:9323717

  2. Gene mutations in Cushing's disease

    PubMed Central

    Xiong, Qi; Ge, Wei

    2016-01-01

    Cushing's disease (CD) is a severe (and potentially fatal) disease caused by adrenocorticotropic hormone (ACTH)-secreting adenomas of the pituitary gland (often termed pituitary adenomas). The majority of ACTH-secreting corticotroph tumors are sporadic and CD rarely appears as a familial disorder, thus, the genetic mechanisms underlying CD are poorly understood. Studies have reported that various mutated genes are associated with CD, such as those in menin 1, aryl hydrocarbon receptor-interacting protein and the nuclear receptor subfamily 3 group C member 1. Recently it was identified that ubiquitin-specific protease 8 mutations contribute to CD, which was significant towards elucidating the genetic mechanisms of CD. The present study reviews the associated gene mutations in CD patients. PMID:27588171

  3. Pumilio genes from the Platyhelminthes.

    PubMed

    Koziol, Uriel; Marín, Monica; Castillo, Estela

    2008-01-01

    Pumilio proteins are proposed to have a conserved primordial function in the maintenance of proliferation in stem cells through post-transcriptional regulation. In this work, a search for pumilio homology domain (PUM-HD) sequences of pumilio genes from several Platyhelminthes species was performed, including representatives form Cestoda, Trematoda and Tricladida. Only one PUM-HD sequence was found in each triclad species; however, two PUM-HD homologues were found in all the parasitic species. These sequences formed two clearly separated clades: PlatyPum1, with sequences from all species, and PlatyPum2, composed exclusively of neodermatan sequences. Therefore, at least one duplication of the pumilio gene must have occurred before the divergence of cestodes and trematodes. Further duplications of PUM-HD were found in Fasciola hepatica, but these consist of retropseudogenes. This is the first comparative analysis of PUM-HD sequences in the Platyhelminthes and, more generally, in any lophotrochozoan phylum.

  4. Method for determining gene knockouts

    DOEpatents

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

    2013-06-04

    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.

  5. Method for determining gene knockouts

    DOEpatents

    Maranas, Costas D.; Burgard, Anthony R.; Pharkya, Priti

    2011-09-27

    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.

  6. Jumping Genes: The Transposable DNAs of Bacteria.

    ERIC Educational Resources Information Center

    Berg, Claire M.; Berg, Douglas E.

    1984-01-01

    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)

  7. Problem-Solving Test: Targeted Gene Disruption

    ERIC Educational Resources Information Center

    Szeberenyi, Jozsef

    2008-01-01

    Mutational inactivation of a specific gene is the most powerful technique to analyze the biological function of the gene. This approach has been used for a long time in viruses, bacteria, yeast, and fruit fly, but looked quite hopeless in more complex organisms. Targeted inactivation of specific genes (also known as knock-out mutation) in mice is…

  8. Evolutionary genomics: new genes for new jobs.

    PubMed

    Presgraves, Daven C

    2005-01-26

    Whole genome sequence analyses have confirmed that gene duplication and divergence play major roles in genome evolution. But the details of how young, functionally redundant gene duplicates escape mutational degradation have remained elusive. Several recent studies show that new genes survive because they evolve new, and sometimes essential, functions.

  9. ALCOdb: Gene Coexpression Database for Microalgae

    PubMed Central

    Aoki, Yuichi; Okamura, Yasunobu; Ohta, Hiroyuki; Kinoshita, Kengo; Obayashi, Takeshi

    2016-01-01

    In the era of energy and food shortage, microalgae have gained much attention as promising sources of biofuels and food ingredients. However, only a small fraction of microalgal genes have been functionally characterized. Here, we have developed the Algae Gene Coexpression database (ALCOdb; http://alcodb.jp), which provides gene coexpression information to survey gene modules for a function of interest. ALCOdb currently supports two model algae: the green alga Chlamydomonas reinhardtii and the red alga Cyanidioschyzon merolae. Users can retrieve coexpression information for genes of interest through three unique data pages: (i) Coexpressed Gene List; (ii) Gene Information; and (iii) Coexpressed Gene Network. In addition to the basal coexpression information, ALCOdb also provides several advanced functionalities such as an expression profile viewer and a differentially expressed gene search tool. Using these user interfaces, we demonstrated that our gene coexpression data have the potential to detect functionally related genes and are useful in extrapolating the biological roles of uncharacterized genes. ALCOdb will facilitate molecular and biochemical studies of microalgal biological phenomena, such as lipid metabolism and organelle development, and promote the evolutionary understanding of plant cellular systems. PMID:26644461

  10. Aeromonas hydrophila Lateral Flagellar Gene Transcriptional Hierarchy

    PubMed Central

    Wilhelms, Markus; Gonzalez, Victor; Merino, Susana

    2013-01-01

    Aeromonas hydrophila AH-3 lateral flagella are not assembled when bacteria grow in liquid media; however, lateral flagellar genes are transcribed. Our results indicate that A. hydrophila lateral flagellar genes are transcribed at three levels (class I to III genes) and share some similarities with, but have many important differences from, genes of Vibrio parahaemolyticus. A. hydrophila lateral flagellum class I gene transcription is σ70 dependent, which is consistent with the fact that lateral flagellum is constitutively transcribed, in contrast to the characteristics of V. parahaemolyticus. The fact that multiple genes are included in class I highlights that lateral flagellar genes are less hierarchically transcribed than polar flagellum genes. The A. hydrophila lafK-fliEJL gene cluster (where the subscript L distinguishes genes for lateral flagella from those for polar flagella) is exclusively from class I and is in V. parahaemolyticus class I and II. Furthermore, the A. hydrophila flgAMNL cluster is not transcribed from the σ54/LafK-dependent promoter and does not contain class II genes. Here, we propose a gene transcriptional hierarchy for the A. hydrophila lateral flagella. PMID:23335410

  11. Uses of antimicrobial genes from microbial genome

    DOEpatents

    Sorek, Rotem; Rubin, Edward M.

    2013-08-20

    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.

  12. Mitochondrial RNA granules: Compartmentalizing mitochondrial gene expression

    PubMed Central

    Jourdain, Alexis A.; Boehm, Erik; Maundrell, Kinsey

    2016-01-01

    In mitochondria, DNA replication, gene expression, and RNA degradation machineries coexist within a common nondelimited space, raising the question of how functional compartmentalization of gene expression is achieved. Here, we discuss the recently characterized “mitochondrial RNA granules,” mitochondrial subdomains with an emerging role in the regulation of gene expression. PMID:26953349

  13. Chromatin, gene silencing and HIV latency

    PubMed Central

    Mok, Hoi-Ping; Lever, Andrew ML

    2007-01-01

    One of the cellular defenses against virus infection is the silencing of viral gene expression. There is evidence that at least two gene-silencing mechanisms are used against the human immuno-deficiency virus (HIV). Paradoxically, this cellular defense mechanism contributes to viral latency and persistence, and we review here the relationship of viral latency to gene-silencing mechanisms. PMID:18036274

  14. Error margin analysis for feature gene extraction

    PubMed Central

    2010-01-01

    Background Feature gene extraction is a fundamental issue in microarray-based biomarker discovery. It is normally treated as an optimization problem of finding the best predictive feature genes that can effectively and stably discriminate distinct types of disease conditions, e.g. tumors and normals. Since gene microarray data normally involves thousands of genes at, tens or hundreds of samples, the gene extraction process may fall into local optimums if the gene set is optimized according to the maximization of classification accuracy of the classifier built from it. Results In this paper, we propose a novel gene extraction method of error margin analysis to optimize the feature genes. The proposed algorithm has been tested upon one synthetic dataset and two real microarray datasets. Meanwhile, it has been compared with five existing gene extraction algorithms on each dataset. On the synthetic dataset, the results show that the feature set extracted by our algorithm is the closest to the actual gene set. For the two real datasets, our algorithm is superior in terms of balancing the size and the validation accuracy of the resultant gene set when comparing to other algorithms. Conclusion Because of its distinct features, error margin analysis method can stably extract the relevant feature genes from microarray data for high-performance classification. PMID:20459827

  15. Discovery of Tumor Suppressor Gene Function.

    ERIC Educational Resources Information Center

    Oppenheimer, Steven B.

    1995-01-01

    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)

  16. Network Topology Reveals Key Cardiovascular Disease Genes

    PubMed Central

    Stojković, Neda; Radak, Djordje; Pržulj, Nataša

    2013-01-01

    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

  17. Chromosomal destabilization during gene amplification.

    PubMed Central

    Ruiz, J C; Wahl, G M

    1990-01-01

    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 PMID:2188107

  18. Mutations in cardiovascular connexin genes.

    PubMed

    Molica, Filippo; Meens, Merlijn J P; Morel, Sandrine; Kwak, Brenda R

    2014-09-01

    Connexins (Cxs) form a family of transmembrane proteins comprising 21 members in humans. Cxs differ in their expression patterns, biophysical properties and ability to combine into homomeric or heteromeric gap junction channels between neighbouring cells. The permeation of ions and small metabolites through gap junction channels or hemichannels confers a crucial role to these proteins in intercellular communication and in maintaining tissue homeostasis. Among others, Cx37, Cx40, Cx43, Cx45 and Cx47 are found in heart, blood and lymphatic vessels. Mutations or polymorphisms in the genes coding for these Cxs have not only been implicated in cardiovascular pathologies but also in a variety of other disorders. While mutations in Cx43 are mostly linked to oculodentodigital dysplasia, Cx47 mutations are associated with Pelizaeus-Merzbacher-like disease and lymphoedema. Cx40 mutations are principally linked to atrial fibrillation. Mutations in Cx37 have not yet been described, but polymorphisms in the Cx37 gene have been implicated in the development of arterial disease. This review addresses current knowledge on gene mutations in cardiovascular Cxs systematically and links them to alterations in channel properties and disease.

  19. The Gene Expression Omnibus database

    PubMed Central

    Clough, Emily; Barrett, Tanya

    2016-01-01

    The Gene Expression Omnibus (GEO) database is an international public repository that archives and freely distributes high-throughput gene expression and other functional genomics data sets. Created in 2000 as a worldwide resource for gene expression studies, GEO has evolved with rapidly changing technologies and now accepts high-throughput data for many other data applications, including those that examine genome methylation, chromatin structure, and genome–protein interactions. GEO supports community-derived reporting standards that specify provision of several critical study elements including raw data, processed data, and descriptive metadata. The database not only provides access to data for tens of thousands of studies, but also offers various Web-based tools and strategies that enable users to locate data relevant to their specific interests, as well as to visualize and analyze the data. This chapter includes detailed descriptions of methods to query and download GEO data and use the analysis and visualization tools. The GEO homepage is at http://www.ncbi.nlm.nih.gov/geo/. PMID:27008011

  20. The Gene Expression Omnibus Database.

    PubMed

    Clough, Emily; Barrett, Tanya

    2016-01-01

    The Gene Expression Omnibus (GEO) database is an international public repository that archives and freely distributes high-throughput gene expression and other functional genomics data sets. Created in 2000 as a worldwide resource for gene expression studies, GEO has evolved with rapidly changing technologies and now accepts high-throughput data for many other data applications, including those that examine genome methylation, chromatin structure, and genome-protein interactions. GEO supports community-derived reporting standards that specify provision of several critical study elements including raw data, processed data, and descriptive metadata. The database not only provides access to data for tens of thousands of studies, but also offers various Web-based tools and strategies that enable users to locate data relevant to their specific interests, as well as to visualize and analyze the data. This chapter includes detailed descriptions of methods to query and download GEO data and use the analysis and visualization tools. The GEO homepage is at http://www.ncbi.nlm.nih.gov/geo/. PMID:27008011

  1. Targeted gene flow for conservation.

    PubMed

    Kelly, Ella; Phillips, Ben L

    2016-04-01

    Anthropogenic threats often impose strong selection on affected populations, causing rapid evolutionary responses. Unfortunately, these adaptive responses are rarely harnessed for conservation. We suggest that conservation managers pay close attention to adaptive processes and geographic variation, with an eye to using them for conservation goals. Translocating pre-adapted individuals into recipient populations is currently considered a potentially important management tool in the face of climate change. Targeted gene flow, which involves moving individuals with favorable traits to areas where these traits would have a conservation benefit, could have a much broader application in conservation. Across a species' range there may be long-standing geographic variation in traits or variation may have rapidly developed in response to a threatening process. Targeted gene flow could be used to promote natural resistance to threats to increase species resilience. We suggest that targeted gene flow is a currently underappreciated strategy in conservation that has applications ranging from the management of invasive species and their impacts to controlling the impact and virulence of pathogens.

  2. A gene mapping expert system.

    PubMed

    Galland, J; Skolnick, M H

    1990-08-01

    Expert systems are now commonly developed to solve practical problems. Nevertheless, genetics has just begun to benefit from this new technology, since genetic expert systems are extremely rare and often purely experimental. A prototype for risk calculation in pedigrees was developed at the University of Utah, using a commercial frames/rules developmental shell (Intelligence Compiler), which runs on an IBM PC. When small data sets were used, the implementation functioned well, but it could not handle larger data sets. Performance became a major issue, with two possible solutions. The first possibility would have been to port the system to a more powerful machine, and the second would have been to use several different shells or languages, each efficiently representing a specific type of knowledge. Neither of these solutions was applicable in this case. From this experience, we learned that performance, portability, and modifiability were three major requirements for genetic expert systems. To achieve these goals, we implemented the gene mapping expert system GMES: (GMES is unrelated to the gene mapping system, GMS in Lisp combined with a frame/object shell (FROBS). We were able to efficiently represent, control, and optimize a gene mapping experiment, achieving portability by building GMES on top of a C-based version of Common Lisp. Lisp combined with the FROBS expert system shell permitted a declarative representation of each of the components of the experiment, resulting in a transplant specification of the problem within a maintainable system. PMID:2394090

  3. Gene therapy for heart failure.

    PubMed

    Greenberg, Barry

    2015-09-01

    Heart failure is a major public health problem throughout the world and it is likely that its prevalence will continue to grow over the next several decades. Despite advances in the treatment of heart failure, morbidity and mortality remain unacceptably high. Gene transfer therapy provides a novel strategy for targeting abnormalities in cardiac cells that adversely affect cardiac function. New vectors for gene delivery, mainly adeno-associated viruses (AAVs) that are preferentially taken up by cardiomyocytes, can result in sustained transgene expression. The cardiac isoform of sarco(endo)plasmic reticulum Ca(2+)ATPase (SERCA2a) plays a major role in regulating calcium levels in cardiomyocytes. Abnormal calcium handling by the failing heart caused by a reduction in SERCA2a activity adversely affects both systolic and diastolic function. The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) study was a Phase 2a double-blind, randomized, placebo-controlled, dose-finding study that was performed in patients with advanced heart failure due to systolic dysfunction. Eligible patients received AAV/SERCA2a or placebo by direct antegrade infusion into the coronary circulation. At the end of 12 months, patients receiving high-dose therapy (i.e. 1×10(13) DNase Resistant Particles) had evidence of favorable changes in several clinically relevant domains compared to patients treated with placebo. There were no safety concerns at any dose of AAV/SERCA2a. Patients treated with AAV/SERCA2a exhibited a striking reduction in cardiovascular events that persisted through 36 months of follow-up compared to patients who received placebo. Transgene expression was detected in the myocardium of patients receiving AAV/SERCA2a gene therapy as long as 31 months after delivery. A second Phase 2b study, CUPID 2, designed to confirm this favorable effect on heart failure events, is currently underway with the results expected to be presented later in

  4. Evolutionary and Topological Properties of Genes and Community Structures in Human Gene Regulatory Networks.

    PubMed

    Szedlak, Anthony; Smith, Nicholas; Liu, Li; Paternostro, Giovanni; Piermarocchi, Carlo

    2016-06-01

    The diverse, specialized genes present in today's lifeforms evolved from a common core of ancient, elementary genes. However, these genes did not evolve individually: gene expression is controlled by a complex network of interactions, and alterations in one gene may drive reciprocal changes in its proteins' binding partners. Like many complex networks, these gene regulatory networks (GRNs) are composed of communities, or clusters of genes with relatively high connectivity. A deep understanding of the relationship between the evolutionary history of single genes and the topological properties of the underlying GRN is integral to evolutionary genetics. Here, we show that the topological properties of an acute myeloid leukemia GRN and a general human GRN are strongly coupled with its genes' evolutionary properties. Slowly evolving ("cold"), old genes tend to interact with each other, as do rapidly evolving ("hot"), young genes. This naturally causes genes to segregate into community structures with relatively homogeneous evolutionary histories. We argue that gene duplication placed old, cold genes and communities at the center of the networks, and young, hot genes and communities at the periphery. We demonstrate this with single-node centrality measures and two new measures of efficiency, the set efficiency and the interset efficiency. We conclude that these methods for studying the relationships between a GRN's community structures and its genes' evolutionary properties provide new perspectives for understanding evolutionary genetics.

  5. Evaluation of Quantitative PCR Reference Genes for Gene Expression Studies in Tribolium castaneum After Fungal Challenge

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To investigate gene expression in Tribolium castaneum exposed to Beauveria bassiana, reference genes for qPCR were evaluated. Of these, the widely used genes for ß-actin, a-tubulin, and RPS6 were not stable. The most stable were ribosomal protein genes, RPS3, RPS18, and RPL13a. Syntaxin1, syntaxin6...

  6. Integrating Ontological Knowledge and Textual Evidence in Estimating Gene and Gene Product Similarity

    SciTech Connect

    Sanfilippo, Antonio P.; Posse, Christian; Gopalan, Banu; Tratz, Stephen C.; Gregory, Michelle L.

    2006-06-08

    With the rising influence of the Gene On-tology, new approaches have emerged where the similarity between genes or gene products is obtained by comparing Gene Ontology code annotations associ-ated with them. So far, these approaches have solely relied on the knowledge en-coded in the Gene Ontology and the gene annotations associated with the Gene On-tology database. The goal of this paper is to demonstrate that improvements to these approaches can be obtained by integrating textual evidence extracted from relevant biomedical literature.

  7. Gene therapy for dyslipidemia: a review of gene replacement and gene inhibition strategies

    PubMed Central

    Kassim, Sadik H; Wilson, James M; Rader, Daniel J

    2012-01-01

    Despite numerous technological and pharmacological advances and more detailed knowledge of molecular etiologies, cardiovascular diseases remain the leading cause of morbidity and mortality worldwide claiming over 17 million lives a year. Abnormalities in the synthesis, processing and catabolism of lipoprotein particles can result in severe hypercholesterolemia, hypertriglyceridemia or low HDL-C. Although a plethora of antidyslipidemic pharmacological agents are available, these drugs are relatively ineffective in many patients with Mendelian lipid disorders, indicating the need for new and more effective interventions. In vivo somatic gene therapy is one such intervention. This article summarizes current strategies being pursued for the development of clinical gene therapy for dyslipidemias that cannot effectively be treated with existing drugs. PMID:22505953

  8. Review: the dominant flocculation genes of Saccharomyces cerevisiae constitute a new subtelomeric gene family.

    PubMed

    Teunissen, A W; Steensma, H Y

    1995-09-15

    The quality of brewing strains is, in large part, determined by their flocculation properties. By classical genetics, several dominant, semidominant and recessive flocculation genes have been recognized. Recent results of experiments to localize the flocculation genes FLO5 and FLO8, combined with the in silicio analysis of the available sequence data of the yeast genome, have revealed that the flocculation genes belong to a family which comprises at least four genes and three pseudogenes. All members of this gene family are located near the end of chromosomes, just like the SUC, MEL and MAL genes, which are also important for good quality baking or brewing strains. Transcription of the flocculation genes is repressed by several regulatory genes. In addition, a number of genes have been found which cause cell aggregation upon disruption or overexpression in an as yet unknown manner. In total, 33 genes have been reported that are involved in flocculation or cell aggregation.

  9. A Mixture Model Approach in Gene-Gene and Gene-Environmental Interactions for Binary Phenotypes

    PubMed Central

    Li, Lang; Yu, Menggang; Jason, Robarge D.; Shen, Changyu; Azzouz, Faouzi; McLeod, Howard L.; Borges-Gonzales, Silvana; Nguyen, Anne; Skaar, Todd; Desta, Zeruesenay; Sweeney, Christopher J.; Flockhart, David A

    2009-01-01

    Summary In translational research, a genetic association study of a binary outcome has a two-fold aim: test whether genetic/environmental variables or their combinations are associated with a clinical phenotype; and determine how those combinations are grouped to predict the phenotype (i.e. which combinations have a similarly distributed phenotype, and which ones have differently distributed phenotypes). The second part of this aim has high clinical appeal, because it can directly facilitate clinical decisions. Although traditional logistic regression can detect gene-gene or gene-environmental interaction effects on binary phenotypes, they cannot decisively determine how genotype combinations are grouped to predict the phenotype. Our proposed mixture model approach is valuable in this context. It concurrently detects main and interaction effects of genetic and environmental variables through a likelihood ratio test (LRT), and conducts phenotype cluster analysis based on genetic and environmental variable combinations. The theoretical distribution of the proposed mixture model’s likelihood ratio test is robust not only to small sample size, but also to unequal sample size in various genotype and environmental subgroups. Hypothesis testing through a likelihood ratio test results in a fast algorithm for p-value calculations. Extensive simulation studies demonstrate that mixture model, overall test in logistic regression, and Monte Carlo based logic regression constantly possess the best power to detect multi-way gene/environmental combinations. The mixture model approach has the highest recovery probability to recover the true partition in the simulation studies. Its applications are exemplified in interim data analyses for two cancer studies. PMID:18991114

  10. Gene doping: of mice and men.

    PubMed

    Azzazy, Hassan M E; Mansour, Mai M H; Christenson, Robert H

    2009-04-01

    Gene doping is the newest threat to the spirit of fair play in sports. Its concept stemmed out from legitimate gene therapy trials, but anti-doping authorities fear that they now may be facing a form of doping that is virtually undetectable and extremely appealing to athletes. This paper presents studies that generated mouse models with outstanding physical performance, by manipulating genes such as insulin-like growth factor 1 (IGF-1) or phosphoenolpyruvate carboxykinase (PEPCK), which are likely to be targeted for gene doping. The potential transition from super mice to super athletes will also be discussed, in addition to possible strategies for detection of gene doping. PMID:19272337

  11. Gene drive systems for insect disease vectors.

    PubMed

    Sinkins, Steven P; Gould, Fred

    2006-06-01

    The elegant mechanisms by which naturally occurring selfish genetic elements, such as transposable elements, meiotic drive genes, homing endonuclease genes and Wolbachia, spread at the expense of their hosts provide some of the most fascinating and remarkable subjects in evolutionary genetics. These elements also have enormous untapped potential to be used in the control of some of the world's most devastating diseases. Effective gene drive systems for spreading genes that can block the transmission of insect-borne pathogens are much needed. Here we explore the potential of natural gene drive systems and discuss the artificial constructs that could be envisaged for this purpose.

  12. Gene doping: of mice and men.

    PubMed

    Azzazy, Hassan M E; Mansour, Mai M H; Christenson, Robert H

    2009-04-01

    Gene doping is the newest threat to the spirit of fair play in sports. Its concept stemmed out from legitimate gene therapy trials, but anti-doping authorities fear that they now may be facing a form of doping that is virtually undetectable and extremely appealing to athletes. This paper presents studies that generated mouse models with outstanding physical performance, by manipulating genes such as insulin-like growth factor 1 (IGF-1) or phosphoenolpyruvate carboxykinase (PEPCK), which are likely to be targeted for gene doping. The potential transition from super mice to super athletes will also be discussed, in addition to possible strategies for detection of gene doping.

  13. Thermostable cellulase from a thermomonospora gene

    DOEpatents

    Wilson, D.B.; Walker, L.P.; Zhang, S.

    1997-10-14

    The invention relates to a gene isolated from Thermomonospora fusca, wherein the gene encodes a thermostable cellulase. Disclosed is the nucleotide sequence of the T. fusca gene; and nucleic acid molecules comprising the gene, or a fragment of the gene, that can be used to recombinantly express the cellulase or a catalytically active polypeptide thereof, respectively. The isolated and purified recombinant cellulase or catalytically active polypeptide may be used to hydrolyze substrate either by itself; or in combination with other cellulases, with the resultant combination having unexpected hydrolytic activity. 3 figs.

  14. Thermostable cellulase from a thermomonospora gene

    DOEpatents

    Wilson, David B.; Walker, Larry P.; Zhang, Sheng

    1997-10-14

    The invention relates to a gene isolated from Thermomonospora fusca, wherein the gene encodes a thermostable cellulase. Disclosed is the nucleotide sequence of the T. fusca gene; and nucleic acid molecules comprising the gene, or a fragment of the gene, that can be used to recombinantly express the cellulase or a catalytically active polypeptide thereof, respectively. The isolated and purified recombinant cellulase or catalytically active polypeptide may be used to hydrolyze substrate either by itself; or in combination with other cellulases, with the resultant combination having unexpected hydrolytic activity.

  15. Approaches for gene targeting and targeted gene expression in plants.

    PubMed

    Husaini, Amjad Masood; Rashid, Zerka; Mir, Reyaz-ul Rouf; Aquil, Bushra

    2011-01-01

    Transgenic science and technology are fundamental to state-of-the-art plant molecular genetics and crop improvement. The new generation of technology endeavors to introduce genes 'stably' into 'site-specific' locations and in 'single copy' without the integration of extraneous vector 'backbone' sequences or selectable markers and with a 'predictable and consistent' expression. Several similar strategies and technologies, which can push the development of 'smart' genetically modified plants with desirable attributes, as well as enhance their consumer acceptability, are discussed in this review.

  16. Gene therapy: Biological pacemaker created by gene transfer

    NASA Astrophysics Data System (ADS)

    Miake, Junichiro; Marbán, Eduardo; Nuss, H. Bradley

    2002-09-01

    The pacemaker cells of the heart initiate the heartbeat, sustain the circulation, and dictate the rate and rhythm of cardiac contraction. Circulatory collapse ensues when these specialized cells are damaged by disease, a situation that currently necessitates the implantation of an electronic pacemaker. Here we report the use of viral gene transfer to convert quiescent heart-muscle cells into pacemaker cells, and the successful generation of spontaneous, rhythmic electrical activity in the ventricle in vivo. Our results indicate that genetically engineered pacemakers could be developed as a possible alternative to implantable electronic devices.

  17. Structures and Assumptions: Strategies to Harness Gene × Gene and Gene × Environment Interactions in GWAS

    PubMed Central

    Kooperberg, Charles; LeBlanc, Michael; Dai, James Y.; Rajapakse, Indika

    2009-01-01

    Genome-wide association studies, in which as many as a million single nucleotide polymorphisms (SNP) are measured on several thousand samples, are quickly becoming a common type of study for identifying genetic factors associated with many phenotypes. There is a strong assumption that interactions between SNPs or genes and interactions between genes and environmental factors substantially contribute to the genetic risk of a disease. Identification of such interactions could potentially lead to increased understanding about disease mechanisms; drug × gene interactions could have profound applications for personalized medicine; strong interaction effects could be beneficial for risk prediction models. In this paper we provide an overview of different approaches to model interactions, emphasizing approaches that make specific use of the structure of genetic data, and those that make specific modeling assumptions that may (or may not) be reasonable to make. We conclude that to identify interactions it is often necessary to do some selection of SNPs, for example, based on prior hypothesis or marginal significance, but that to identify SNPs that are marginally associated with a disease it may also be useful to consider larger numbers of interactions. PMID:20640184

  18. The Chaperoning Activity of Amino-oxyacetic Acid on Folding-Defective Variants of Human Alanine:Glyoxylate Aminotransferase Causing Primary Hyperoxaluria Type I.

    PubMed

    Oppici, Elisa; Montioli, Riccardo; Dindo, Mirco; Maccari, Laura; Porcari, Valentina; Lorenzetto, Antonio; Chellini, Sara; Voltattorni, Carla Borri; Cellini, Barbara

    2015-10-16

    The rare disease Primary Hyperoxaluria Type I (PH1) results from the deficit of liver peroxisomal alanine:glyoxylate aminotransferase (AGT), as a consequence of inherited mutations on the AGXT gene frequently leading to protein misfolding. Pharmacological chaperone (PC) therapy is a newly developed approach for misfolding diseases based on the use of small molecule ligands able to promote the correct folding of a mutant enzyme. In this report, we describe the interaction of amino-oxyacetic acid (AOA) with the recombinant purified form of two polymorphic species of AGT, AGT-Ma and AGT-Mi, and with three pathogenic variants bearing previously identified folding defects: G41R-Ma, G170R-Mi, and I244T-Mi. We found that for all these enzyme AOA (i) forms an oxime at the active site, (ii) behaves as a slow, tight-binding inhibitor with KI values in the nanomolar range, and (iii) increases the thermal stability. Furthermore, experiments performed in mammalian cells revealed that AOA acts as a PC by partly preventing the intracellular aggregation of G41R-Ma and by promoting the correct peroxisomal import of G170R-Mi and I244T-Mi. Based on these data, we carried out a small-scale screening campaign. We identified four AOA analogues acting as AGT inhibitors, even if only one was found to act as a PC. The possible relationship between the structure and the PC activity of these compounds is discussed. Altogether, these results provide the proof-of-principle for the feasibility of a therapy with PCs for PH1-causing variants bearing folding defects and provide the scaffold for the identification of more specific ligands. PMID:26161999

  19. Gene Duplicability of Core Genes Is Highly Consistent across All Angiosperms.

    PubMed

    Li, Zhen; Defoort, Jonas; Tasdighian, Setareh; Maere, Steven; Van de Peer, Yves; De Smet, Riet

    2016-02-01

    Gene duplication is an important mechanism for adding to genomic novelty. Hence, which genes undergo duplication and are preserved following duplication is an important question. It has been observed that gene duplicability, or the ability of genes to be retained following duplication, is a nonrandom process, with certain genes being more amenable to survive duplication events than others. Primarily, gene essentiality and the type of duplication (small-scale versus large-scale) have been shown in different species to influence the (long-term) survival of novel genes. However, an overarching view of "gene duplicability" is lacking, mainly due to the fact that previous studies usually focused on individual species and did not account for the influence of genomic context and the time of duplication. Here, we present a large-scale study in which we investigated duplicate retention for 9178 gene families shared between 37 flowering plant species, referred to as angiosperm core gene families. For most gene families, we observe a strikingly consistent pattern of gene duplicability across species, with gene families being either primarily single-copy or multicopy in all species. An intermediate class contains gene families that are often retained in duplicate for periods extending to tens of millions of years after whole-genome duplication, but ultimately appear to be largely restored to singleton status, suggesting that these genes may be dosage balance sensitive. The distinction between single-copy and multicopy gene families is reflected in their functional annotation, with single-copy genes being mainly involved in the maintenance of genome stability and organelle function and multicopy genes in signaling, transport, and metabolism. The intermediate class was overrepresented in regulatory genes, further suggesting that these represent putative dosage-balance-sensitive genes.

  20. Gene Duplicability of Core Genes Is Highly Consistent across All Angiosperms[OPEN

    PubMed Central

    Li, Zhen; Van de Peer, Yves; De Smet, Riet

    2016-01-01

    Gene duplication is an important mechanism for adding to genomic novelty. Hence, which genes undergo duplication and are preserved following duplication is an important question. It has been observed that gene duplicability, or the ability of genes to be retained following duplication, is a nonrandom process, with certain genes being more amenable to survive duplication events than others. Primarily, gene essentiality and the type of duplication (small-scale versus large-scale) have been shown in different species to influence the (long-term) survival of novel genes. However, an overarching view of “gene duplicability” is lacking, mainly due to the fact that previous studies usually focused on individual species and did not account for the influence of genomic context and the time of duplication. Here, we present a large-scale study in which we investigated duplicate retention for 9178 gene families shared between 37 flowering plant species, referred to as angiosperm core gene families. For most gene families, we observe a strikingly consistent pattern of gene duplicability across species, with gene families being either primarily single-copy or multicopy in all species. An intermediate class contains gene families that are often retained in duplicate for periods extending to tens of millions of years after whole-genome duplication, but ultimately appear to be largely restored to singleton status, suggesting that these genes may be dosage balance sensitive. The distinction between single-copy and multicopy gene families is reflected in their functional annotation, with single-copy genes being mainly involved in the maintenance of genome stability and organelle function and multicopy genes in signaling, transport, and metabolism. The intermediate class was overrepresented in regulatory genes, further suggesting that these represent putative dosage-balance-sensitive genes. PMID:26744215

  1. Reconstruction of a Functional Human Gene Network, with an Application for Prioritizing Positional Candidate Genes

    PubMed Central

    Franke, Lude; Bakel, Harm van; Fokkens, Like; de Jong, Edwin D.; Egmont-Petersen, Michael; Wijmenga, Cisca

    2006-01-01

    Most common genetic disorders have a complex inheritance and may result from variants in many genes, each contributing only weak effects to the disease. Pinpointing these disease genes within the myriad of susceptibility loci identified in linkage studies is difficult because these loci may contain hundreds of genes. However, in any disorder, most of the disease genes will be involved in only a few different molecular pathways. If we know something about the relationships between the genes, we can assess whether some genes (which may reside in different loci) functionally interact with each other, indicating a joint basis for the disease etiology. There are various repositories of information on pathway relationships. To consolidate this information, we developed a functional human gene network that integrates information on genes and the functional relationships between genes, based on data from the Kyoto Encyclopedia of Genes and Genomes, the Biomolecular Interaction Network Database, Reactome, the Human Protein Reference Database, the Gene Ontology database, predicted protein-protein interactions, human yeast two-hybrid interactions, and microarray coexpressions. We applied this network to interrelate positional candidate genes from different disease loci and then tested 96 heritable disorders for which the Online Mendelian Inheritance in Man database reported at least three disease genes. Artificial susceptibility loci, each containing 100 genes, were constructed around each disease gene, and we used the network to rank these genes on the basis of their functional interactions. By following up the top five genes per artificial locus, we were able to detect at least one known disease gene in 54% of the loci studied, representing a 2.8-fold increase over random selection. This suggests that our method can significantly reduce the cost and effort of pinpointing true disease genes in analyses of disorders for which numerous loci have been reported but for which

  2. Biological cluster evaluation for gene function prediction.

    PubMed

    Klie, Sebastian; Nikoloski, Zoran; Selbig, Joachim

    2014-06-01

    Recent advances in high-throughput omics techniques render it possible to decode the function of genes by using the "guilt-by-association" principle on biologically meaningful clusters of gene expression data. However, the existing frameworks for biological evaluation of gene clusters are hindered by two bottleneck issues: (1) the choice for the number of clusters, and (2) the external measures which do not take in consideration the structure of the analyzed data and the ontology of the existing biological knowledge. Here, we address the identified bottlenecks by developing a novel framework that allows not only for biological evaluation of gene expression clusters based on existing structured knowledge, but also for prediction of putative gene functions. The proposed framework facilitates propagation of statistical significance at each of the following steps: (1) estimating the number of clusters, (2) evaluating the clusters in terms of novel external structural measures, (3) selecting an optimal clustering algorithm, and (4) predicting gene functions. The framework also includes a method for evaluation of gene clusters based on the structure of the employed ontology. Moreover, our method for obtaining a probabilistic range for the number of clusters is demonstrated valid on synthetic data and available gene expression profiles from Saccharomyces cerevisiae. Finally, we propose a network-based approach for gene function prediction which relies on the clustering of optimal score and the employed ontology. Our approach effectively predicts gene function on the Saccharomyces cerevisiae data set and is also employed to obtain putative gene functions for an Arabidopsis thaliana data set.

  3. Gene Targeting in Mice: a Review

    PubMed Central

    Bouabe, Hicham; Okkenhaug, Klaus

    2015-01-01

    Summary The ability to introduce DNA sequences (e.g. genes) of interest into the germline genome has rendered the mouse a powerful and indispensable experimental model in fundamental and medical research. The DNA sequences can be integrated into the genome randomly or into a specific locus by homologous recombination, in order to: (i) delete or insert mutations into genes of interest to determine their function, (ii) introduce human genes into the genome of mice to generate animal models enabling study of human-specific genes and diseases, e.g. mice susceptible to infections by human-specific pathogens of interest, (iii) introduce individual genes or genomes of pathogens (such as viruses) in order to examine the contributions of such genes to the pathogenesis of the parent pathogens, (iv) and last but not least introduce reporter genes that allow monitoring in vivo or ex vivo the expression of genes of interest. Furthermore, the use of recombination systems, such as Cre/loxP or FRT/FLP, enables conditional induction or suppression of gene expression of interest in a restricted period of mouse’s lifetime, in a particular cell type, or in a specific tissue. In this review, we will give an updated summary of the gene targeting technology and discuss some important considerations in the design of gene-targeted mice. PMID:23996268

  4. HOX genes: seductive science, mysterious mechanisms.

    PubMed

    Lappin, Terence R J; Grier, David G; Thompson, Alexander; Halliday, Henry L

    2006-01-01

    HOX genes are evolutionarily highly conserved. The HOX proteins which they encode are master regulators of embryonic development and continue to be expressed throughout postnatal life. The 39 human HOX genes are located in four clusters (A-D) on different chromosomes at 7p15, 17q21 [corrected] 12q13, and 2q31 respectively and are assumed to have arisen by duplication and divergence from a primordial homeobox gene. Disorders of limb formation, such as hand-foot-genital syndrome, have been traced to mutations in HOXA13 and HOXD13. Evolutionary conservation provides unlimited scope for experimental investigation of the functional control of the Hox gene network which is providing important insights into human disease. Chromosomal translocations involving the MLL gene, the human homologue of the Drosophila gene trithorax, create fusion genes which exhibit gain of function and are associated with aggressive leukaemias in both adults and children. To date 39 partner genes for MLL have been cloned from patients with leukaemia. Models based on specific translocations of MLL and individual HOX genes are now the subject of intense research aimed at understanding the molecular programs involved, and ultimately the design of chemotherapeutic agents for leukaemia. Investigation of the role of HOX genes in cancer has led to the concept that oncology may recapitulate ontology, a challenging postulate for experimentalists in view of the functional redundancy implicit in the HOX gene network.

  5. Evolutionary preservation of redundant duplicated genes.

    PubMed

    Krakauer, D C; Nowak, M A

    1999-10-01

    Gene duplication events produce both perfect and imperfect copies of genes. Perfect copies are said to be functionally redundant when knockout of one gene produces no 'scoreable', phenotypic effects. Preserving identical, duplicate copies of genes is problematic as all copies are prone to accumulate neutral mutations as pseudogenes, or more rarely, evolve into new genes with novel functions. We summarise theoretical treatments for the invasion and subsequent evolutionary modification of functionally redundant genes. We then consider the preservation of functionally identical copies of a gene over evolutionary time. We present several models for conserving redundancy: asymmetric mutation, asymmetric efficacy, pleiotropy, developmental buffering, allelic competition and regulatory asymmetries. In all cases, some form of symmetry breaking is required to maintain functional redundancy indefinitely.

  6. Apolipoprotein gene involved in lipid metabolism

    DOEpatents

    Rubin, Edward; Pennacchio, Len A.

    2007-07-03

    Methods and materials for studying the effects of a newly identified human gene, APOAV, and the corresponding mouse gene apoAV. The sequences of the genes are given, and transgenic animals which either contain the gene or have the endogenous gene knocked out are described. In addition, single nucleotide polymorphisms (SNPs) in the gene are described and characterized. It is demonstrated that certain SNPs are associated with diseases involving lipids and triglycerides and other metabolic diseases. These SNPs may be used alone or with SNPs from other genes to study individual risk factors. Methods for intervention in lipid diseases, including the screening of drugs to treat lipid-related or diabetic diseases are also disclosed.

  7. Cardiac gene therapy: are we there yet?

    PubMed

    Matkar, P N; Leong-Poi, H; Singh, K K

    2016-08-01

    The incidence of cardiovascular disease (CVD) is increasing throughout the world and is associated with elevated morbidity and mortality. Gene therapy to treat cardiac dysfunction is gaining importance because of the limited therapeutic benefit offered by pharmacotherapies. The growing knowledge of the complex signaling pathways and the development of sophisticated vectors and delivery systems, are facilitating identification and targeting of specific molecular candidates involved in initiation and progression of CVDs. Several preclinical and clinical studies have shown the therapeutic efficiency of gene therapy in different disease models and patients. Hence, gene therapy might plausibly become an unconventional treatment modality for CVD patients. In this review, we summarize the gene delivery carriers, modes of delivery, recent preclinical/clinical studies and potential therapeutic targets. We also briefly discuss the existing limitations of gene therapy, technical challenges surrounding gene carriers and delivery systems, and some approaches to overcome these limitations for bringing CVD gene therapy one step closer to reality. PMID:27128687

  8. Gene therapy for sensorineural hearing loss.

    PubMed

    Chien, Wade W; Monzack, Elyssa L; McDougald, Devin S; Cunningham, Lisa L

    2015-01-01

    Gene therapy is a promising treatment modality that is being explored for several inherited disorders. Multiple human gene therapy clinical trials are currently ongoing, but few are directed at hearing loss. Hearing loss is one of the most prevalent sensory disabilities in the world, and genetics play an important role in the pathophysiology of hearing loss. Gene therapy offers the possibility of restoring hearing by overcoming the functional deficits created by the underlying genetic mutations. In addition, gene therapy could potentially be used to induce hair cell regeneration by delivering genes that are critical to hair cell differentiation into the cochlea. In this review, we examine the promises and challenges of applying gene therapy to the cochlea. We also summarize recent studies that have applied gene therapy to animal models of hearing loss.

  9. Gene therapy oversight: lessons for nanobiotechnology.

    PubMed

    Wolf, Susan M; Gupta, Rishi; Kohlhepp, Peter

    2009-01-01

    Oversight of human gene transfer research ("gene therapy") presents an important model with potential application to oversight of nanobiology research on human participants. Gene therapy oversight adds centralized federal review at the National Institutes of Health's Office of Biotechnology Activities and its Recombinant DNA Advisory Committee to standard oversight of human subjects research at the researcher's institution (by the Institutional Review Board and, for some research, the Institutional Biosafety Committee) and at the federal level by the Office for Human Research Protections. The Food and Drug Administration's Center for Biologics Evaluation and Research oversees human gene transfer research in parallel, including approval of protocols and regulation of products. This article traces the evolution of this dual oversight system; describes how the system is already addressing nanobiotechnology in gene transfer: evaluates gene therapy oversight based on public opinion, the literature, and preliminary expert elicitation; and offers lessons of the gene therapy oversight experience for oversight of nanobiotechnology. PMID:20122108

  10. GeneTack database: genes with frameshifts in prokaryotic genomes and eukaryotic mRNA sequences.

    PubMed

    Antonov, Ivan; Baranov, Pavel; Borodovsky, Mark

    2013-01-01

    Database annotations of prokaryotic genomes and eukaryotic mRNA sequences pay relatively low attention to frame transitions that disrupt protein-coding genes. Frame transitions (frameshifts) could be caused by sequencing errors or indel mutations inside protein-coding regions. Other observed frameshifts are related to recoding events (that evolved to control expression of some genes). Earlier, we have developed an algorithm and software program GeneTack for ab initio frameshift finding in intronless genes. Here, we describe a database (freely available at http://topaz.gatech.edu/GeneTack/db.html) containing genes with frameshifts (fs-genes) predicted by GeneTack. The database includes 206 991 fs-genes from 1106 complete prokaryotic genomes and 45 295 frameshifts predicted in mRNA sequences from 100 eukaryotic genomes. The whole set of fs-genes was grouped into clusters based on sequence similarity between fs-proteins (conceptually translated fs-genes), conservation of the frameshift position and frameshift direction (-1, +1). The fs-genes can be retrieved by similarity search to a given query sequence via a web interface, by fs-gene cluster browsing, etc. Clusters of fs-genes are characterized with respect to their likely origin, such as pseudogenization, phase variation, etc. The largest clusters contain fs-genes with programed frameshifts (related to recoding events).

  11. With Reference to Reference Genes: A Systematic Review of Endogenous Controls in Gene Expression Studies

    PubMed Central

    Chapman, Joanne R.; Waldenström, Jonas

    2015-01-01

    The choice of reference genes that are stably expressed amongst treatment groups is a crucial step in real-time quantitative PCR gene expression studies. Recent guidelines have specified that a minimum of two validated reference genes should be used for normalisation. However, a quantitative review of the literature showed that the average number of reference genes used across all studies was 1.2. Thus, the vast majority of studies continue to use a single gene, with β-actin (ACTB) and/or glyceraldehyde 3-phosphate dehydrogenase (GAPDH) being commonly selected in studies of vertebrate gene expression. Few studies (15%) tested a panel of potential reference genes for stability of expression before using them to normalise data. Amongst studies specifically testing reference gene stability, few found ACTB or GAPDH to be optimal, whereby these genes were significantly less likely to be chosen when larger panels of potential reference genes were screened. Fewer reference genes were tested for stability in non-model organisms, presumably owing to a dearth of available primers in less well characterised species. Furthermore, the experimental conditions under which real-time quantitative PCR analyses were conducted had a large influence on the choice of reference genes, whereby different studies of rat brain tissue showed different reference genes to be the most stable. These results highlight the importance of validating the choice of normalising reference genes before conducting gene expression studies. PMID:26555275

  12. Lineage-specific expansion of IFIT gene family: an insight into coevolution with IFN gene family.

    PubMed

    Liu, Ying; Zhang, Yi-Bing; Liu, Ting-Kai; Gui, Jian-Fang

    2013-01-01

    In mammals, IFIT (Interferon [IFN]-induced proteins with Tetratricopeptide Repeat [TPR] motifs) family genes are involved in many cellular and viral processes, which are tightly related to mammalian IFN response. However, little is known about non-mammalian IFIT genes. In the present study, IFIT genes are identified in the genome databases from the jawed vertebrates including the cartilaginous elephant shark but not from non-vertebrates such as lancelet, sea squirt and acorn worm, suggesting that IFIT gene family originates from a vertebrate ancestor about 450 million years ago. IFIT family genes show conserved gene structure and gene arrangements. Phylogenetic analyses reveal that this gene family has expanded through lineage-specific and species-specific gene duplication. Interestingly, IFN gene family seem to share a common ancestor and a similar evolutionary mechanism; the function link of IFIT genes to IFN response is present early since the origin of both gene families, as evidenced by the finding that zebrafish IFIT genes are upregulated by fish IFNs, poly(I:C) and two transcription factors IRF3/IRF7, likely via the IFN-stimulated response elements (ISRE) within the promoters of vertebrate IFIT family genes. These coevolution features creates functional association of both family genes to fulfill a common biological process, which is likely selected by viral infection during evolution of vertebrates. Our results are helpful for understanding of evolution of vertebrate IFN system. PMID:23818968

  13. With Reference to Reference Genes: A Systematic Review of Endogenous Controls in Gene Expression Studies.

    PubMed

    Chapman, Joanne R; Waldenström, Jonas

    2015-01-01

    The choice of reference genes that are stably expressed amongst treatment groups is a crucial step in real-time quantitative PCR gene expression studies. Recent guidelines have specified that a minimum of two validated reference genes should be used for normalisation. However, a quantitative review of the literature showed that the average number of reference genes used across all studies was 1.2. Thus, the vast majority of studies continue to use a single gene, with β-actin (ACTB) and/or glyceraldehyde 3-phosphate dehydrogenase (GAPDH) being commonly selected in studies of vertebrate gene expression. Few studies (15%) tested a panel of potential reference genes for stability of expression before using them to normalise data. Amongst studies specifically testing reference gene stability, few found ACTB or GAPDH to be optimal, whereby these genes were significantly less likely to be chosen when larger panels of potential reference genes were screened. Fewer reference genes were tested for stability in non-model organisms, presumably owing to a dearth of available primers in less well characterised species. Furthermore, the experimental conditions under which real-time quantitative PCR analyses were conducted had a large influence on the choice of reference genes, whereby different studies of rat brain tissue showed different reference genes to be the most stable. These results highlight the importance of validating the choice of normalising reference genes before conducting gene expression studies.

  14. Gene family evolution across 12 Drosophila genomes.

    PubMed

    Hahn, Matthew W; Han, Mira V; Han, Sang-Gook

    2007-11-01

    Comparison of whole genomes has revealed large and frequent changes in the size of gene families. These changes occur because of high rates of both gene gain (via duplication) and loss (via deletion or pseudogenization), as well as the evolution of entirely new genes. Here we use the genomes of 12 fully sequenced Drosophila species to study the gain and loss of genes at unprecedented resolution. We find large numbers of both gains and losses, with over 40% of all gene families differing in size among the Drosophila. Approximately 17 genes are estimated to be duplicated and fixed in a genome every million years, a rate on par with that previously found in both yeast and mammals. We find many instances of extreme expansions or contractions in the size of gene families, including the expansion of several sex- and spermatogenesis-related families in D. melanogaster that also evolve under positive selection at the nucleotide level. Newly evolved gene families in our dataset are associated with a class of testes-expressed genes known to have evolved de novo in a number of cases. Gene family comparisons also allow us to identify a number of annotated D. melanogaster genes that are unlikely to encode functional proteins, as well as to identify dozens of previously unannotated D. melanogaster genes with conserved homologs in the other Drosophila. Taken together, our results demonstrate that the apparent stasis in total gene number among species has masked rapid turnover in individual gene gain and loss. It is likely that this genomic revolving door has played a large role in shaping the morphological, physiological, and metabolic differences among species.

  15. Evolutionary Signatures amongst Disease Genes Permit Novel Methods for Gene Prioritization and Construction of Informative Gene-Based Networks

    PubMed Central

    Priedigkeit, Nolan; Wolfe, Nicholas; Clark, Nathan L.

    2015-01-01

    Genes involved in the same function tend to have similar evolutionary histories, in that their rates of evolution covary over time. This coevolutionary signature, termed Evolutionary Rate Covariation (ERC), is calculated using only gene sequences from a set of closely related species and has demonstrated potential as a computational tool for inferring functional relationships between genes. To further define applications of ERC, we first established that roughly 55% of genetic diseases posses an ERC signature between their contributing genes. At a false discovery rate of 5% we report 40 such diseases including cancers, developmental disorders and mitochondrial diseases. Given these coevolutionary signatures between disease genes, we then assessed ERC's ability to prioritize known disease genes out of a list of unrelated candidates. We found that in the presence of an ERC signature, the true disease gene is effectively prioritized to the top 6% of candidates on average. We then apply this strategy to a melanoma-associated region on chromosome 1 and identify MCL1 as a potential causative gene. Furthermore, to gain global insight into disease mechanisms, we used ERC to predict molecular connections between 310 nominally distinct diseases. The resulting “disease map” network associates several diseases with related pathogenic mechanisms and unveils many novel relationships between clinically distinct diseases, such as between Hirschsprung's disease and melanoma. Taken together, these results demonstrate the utility of molecular evolution as a gene discovery platform and show that evolutionary signatures can be used to build informative gene-based networks. PMID:25679399

  16. Family Lifestyles May Be as Important to Health as Genes

    MedlinePlus

    ... More Health News on: Family History Genes and Gene Therapy Recent Health News Related MedlinePlus Health Topics Family History Genes and Gene Therapy About MedlinePlus Site Map FAQs Contact Us Get ...

  17. Autism-Linked Genes Often Differ Between Siblings

    MedlinePlus

    ... on: Autism Spectrum Disorder Family History Genes and Gene Therapy Recent Health News Related MedlinePlus Health Topics Autism Spectrum Disorder Family History Genes and Gene Therapy About MedlinePlus Site Map FAQs Contact Us Get ...

  18. Gene flow from transgenic common beans expressing the bar gene.

    PubMed

    Faria, Josias C; Carneiro, Geraldo E S; Aragão, Francisco J L

    2010-01-01

    Gene flow is a common phenomenon even in self-pollinated plant species. With the advent of genetically modified plants this subject has become of the utmost importance due to the need for controlling the spread of transgenes. This study was conducted to determine the occurrence and intensity of outcrossing in transgenic common beans. In order to evaluate the outcross rates, four experiments were conducted in Santo Antonio de Goiás (GO, Brazil) and one in Londrina (PR, Brazil), using transgenic cultivars resistant to the herbicide glufosinate ammonium and their conventional counterparts as recipients of the transgene. Experiments with cv. Olathe Pinto and the transgenic line Olathe M1/4 were conducted in a completely randomized design with ten replications for three years in one location, whereas the experiments with cv. Pérola and the transgenic line Pérola M1/4 were conducted at two locations for one year, with the transgenic cultivar surrounded on all sides by the conventional counterpart. The outcross occurred at a negligible rate of 0.00741% in cv. Pérola, while none was observed (0.0%) in cv. Olathe Pinto. The frequency of gene flow was cultivar dependent and most of the observed outcross was within 2.5 m from the edge of the pollen source. Index terms: Phaseolus vulgaris, outcross, glufosinate ammonium. PMID:21865877

  19. Wnt gene loss in flatworms.

    PubMed

    Riddiford, Nick; Olson, Peter D

    2011-10-01

    Wnt genes encode secreted glycoproteins that act in cell-cell signalling to regulate a wide array of developmental processes, ranging from cellular differentiation to axial patterning. Discovery that canonical Wnt/β-catenin signalling is responsible for regulating head/tail specification in planarian regeneration has recently highlighted their importance in flatworm (phylum Platyhelminthes) development, but examination of their roles in the complex development of the diverse parasitic groups has yet to be conducted. Here, we characterise Wnt genes in the model tapeworm Hymenolepis microstoma and mine genomic resources of free-living and parasitic species for the presence of Wnts and downstream signalling components. We identify orthologs through a combination of BLAST and phylogenetic analyses, showing that flatworms have a highly reduced and dispersed complement that includes orthologs of only five subfamilies (Wnt1, Wnt2, Wnt4, Wnt5 and Wnt11) and fewer paralogs in parasitic flatworms (5-6) than in planarians (9). All major signalling components are identified, including antagonists and receptors, and key binding domains are intact, indicating that the canonical (Wnt/β-catenin) and non-canonical (planar cell polarity and Wnt/Ca(2+)) pathways are functional. RNA-Seq data show expression of all Hymenolepis Wnts and most downstream components in adults and larvae with the notable exceptions of wnt1, expressed only in adults, and wnt2 expressed only in larvae. The distribution of Wnt subfamilies in animals corroborates the idea that the last common ancestor of the Cnidaria and Bilateria possessed all contemporary Wnts and highlights the extent of gene loss in flatworms.

  20. NME genes in epithelial morphogenesis

    PubMed Central

    2012-01-01

    The NME family of genes encodes highly conserved multifunctional proteins that have been shown to participate in nucleic acid metabolism, energy homeostasis, cell signaling, and cancer progression. Some family members, particularly isoforms 1 and 2, have attracted extensive interests because of their potential anti-metastasis activity. Unfortunately, there have been few consensus mechanistic explanations for this critical function because of the numerous molecular functions ascribed to these proteins, including nucleoside diphosphate kinase, protein kinase, nuclease, transcription factor, growth factor, among others. In addition, different studies showed contradictory prognostic correlations between NME expression levels and tumor progression in clinical samples. Thus, analyses using pliable in vivo systems have become critical for unraveling at least some aspects of the complex functions of this family of genes. Recent works using the Drosophila genetic system have suggested a role for NME in regulating epithelial cell motility and morphogenesis, which has also been demonstrated in mammalian epithelial cell culture. This function is mediated by promoting internalization of growth factor receptors in motile epithelial cells, and the adherens junction components such as E-cadherin and β-catenin in epithelia that form the tissue linings. Interestingly, NME genes in epithelial cells appear to function in a defined range of expression levels. Either down-regulation or over-expression can perturb epithelial integrity, resulting in different aspects of epithelial abnormality. Such biphasic functions provide a plausible explanation for the documented anti-metastatic activity and the suspected oncogenic function. This review summarizes these recent findings and discusses their implications. PMID:21336542