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Sample records for pathway gene variation

  1. Genomic Copy Number Variation Affecting Genes Involved in the Cell Cycle Pathway: Implications for Somatic Mosaicism

    PubMed Central

    Iourov, Ivan Y.; Vorsanova, Svetlana G.; Zelenova, Maria A.; Korostelev, Sergei A.; Yurov, Yuri B.

    2015-01-01

    Somatic genome variations (mosaicism) seem to represent a common mechanism for human intercellular/interindividual diversity in health and disease. However, origins and mechanisms of somatic mosaicism remain a matter of conjecture. Recently, it has been hypothesized that zygotic genomic variation naturally occurring in humans is likely to predispose to nonheritable genetic changes (aneuploidy) acquired during the lifetime through affecting cell cycle regulation, genome stability maintenance, and related pathways. Here, we have evaluated genomic copy number variation (CNV) in genes implicated in the cell cycle pathway (according to Kyoto Encyclopedia of Genes and Genomes/KEGG) within a cohort of patients with intellectual disability, autism, and/or epilepsy, in which the phenotype was not associated with genomic rearrangements altering this pathway. Benign CNVs affecting 20 genes of the cell cycle pathway were detected in 161 out of 255 patients (71.6%). Among them, 62 individuals exhibited >2 CNVs affecting the cell cycle pathway. Taking into account the number of individuals demonstrating CNV of these genes, a support for this hypothesis appears to be presented. Accordingly, we speculate that further studies of CNV burden across the genes implicated in related pathways might clarify whether zygotic genomic variation generates somatic mosaicism in health and disease. PMID:26421275

  2. The association of environmental, individual factors, and dopamine pathway gene variation with smoking cessation.

    PubMed

    Li, Suyun; Wang, Qiang; Pan, Lulu; Yang, Xiaorong; Li, Huijie; Jiang, Fan; Zhang, Nan; Han, Mingkui; Jia, Chongqi

    2017-09-01

    This study aimed to examine whether dopamine (DA) pathway gene variation were associated with smoking cessation, and compare the relative importance of infulence factors on smoking cessation. Participants were recruited from 17 villages of Shandong Province, China. Twenty-five single nucleotide polymorphisms in 8 DA pathway genes were genotyped. Weighted gene score of each gene was used to analyze the whole gene effect. Logistic regression was used to calculate odds ratios (OR) of the total gene score for smoking cessation. Dominance analysis was employed to compare the relative importance of individual, heaviness of smoking, psychological and genetic factors on smoking cessation. 415 successful spontaneous smoking quitters served as the cases, and 404 unsuccessful quitters served as the controls. A significant negative association of total DA pathway gene score and smoking cessation was observed (p < 0.001, OR: 0.25, 95% CI 0.16-0.38). Dominance analysis showed that the most important predictor for smoking cessation was heaviness of smoking score (42%), following by individual (40%), genetic (10%) and psychological score (8%). In conclusion, although the DA pathway gene variation was significantly associated with successful smoking cessation, heaviness of smoking and individual factors had bigger effect than genetic factors on smoking cessation.

  3. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

    PubMed Central

    Purrington, Kristen S.; Slettedahl, Seth; Bolla, Manjeet K.; Michailidou, Kyriaki; Czene, Kamila; Nevanlinna, Heli; Bojesen, Stig E.; Andrulis, Irene L.; Cox, Angela; Hall, Per; Carpenter, Jane; Yannoukakos, Drakoulis; Haiman, Christopher A.; Fasching, Peter A.; Mannermaa, Arto; Winqvist, Robert; Brenner, Hermann; Lindblom, Annika; Chenevix-Trench, Georgia; Benitez, Javier; Swerdlow, Anthony; Kristensen, Vessela; Guénel, Pascal; Meindl, Alfons; Darabi, Hatef; Eriksson, Mikael; Fagerholm, Rainer; Aittomäki, Kristiina; Blomqvist, Carl; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Wang, Xianshu; Olswold, Curtis; Olson, Janet E.; Mulligan, Anna Marie; Knight, Julia A.; Tchatchou, Sandrine; Reed, Malcolm W.R.; Cross, Simon S.; Liu, Jianjun; Li, Jingmei; Humphreys, Keith; Clarke, Christine; Scott, Rodney; Fostira, Florentia; Fountzilas, George; Konstantopoulou, Irene; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Ekici, Arif B.; Hartmann, Arndt; Beckmann, Matthias W.; Hartikainen, Jaana M.; Kosma, Veli-Matti; Kataja, Vesa; Jukkola-Vuorinen, Arja; Pylkäs, Katri; Kauppila, Saila; Dieffenbach, Aida Karina; Stegmaier, Christa; Arndt, Volker; Margolin, Sara; Balleine, Rosemary; Arias Perez, Jose Ignacio; Pilar Zamora, M.; Menéndez, Primitiva; Ashworth, Alan; Jones, Michael; Orr, Nick; Arveux, Patrick; Kerbrat, Pierre; Truong, Thérèse; Bugert, Peter; Toland, Amanda E.; Ambrosone, Christine B.; Labrèche, France; Goldberg, Mark S.; Dumont, Martine; Ziogas, Argyrios; Lee, Eunjung; Dite, Gillian S.; Apicella, Carmel; Southey, Melissa C.; Long, Jirong; Shrubsole, Martha; Deming-Halverson, Sandra; Ficarazzi, Filomena; Barile, Monica; Peterlongo, Paolo; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Tollenaar, Robert A.E.M.; Seynaeve, Caroline; Brüning, Thomas; Ko, Yon-Dschun; Van Deurzen, Carolien H.M.; Martens, John W.M.; Kriege, Mieke; Figueroa, Jonine D.; Chanock, Stephen J.; Lissowska, Jolanta; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Schneeweiss, Andreas; Tapper, William J.; Gerty, Susan M.; Durcan, Lorraine; Mclean, Catriona; Milne, Roger L.; Baglietto, Laura; dos Santos Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Van'T Veer, Laura J.; Cornelissen, Sten; Försti, Asta; Torres, Diana; Rüdiger, Thomas; Rudolph, Anja; Flesch-Janys, Dieter; Nickels, Stefan; Weltens, Caroline; Floris, Giuseppe; Moisse, Matthieu; Dennis, Joe; Wang, Qin; Dunning, Alison M.; Shah, Mitul; Brown, Judith; Simard, Jacques; Anton-Culver, Hoda; Neuhausen, Susan L.; Hopper, John L.; Bogdanova, Natalia; Dörk, Thilo; Zheng, Wei; Radice, Paolo; Jakubowska, Anna; Lubinski, Jan; Devillee, Peter; Brauch, Hiltrud; Hooning, Maartje; García-Closas, Montserrat; Sawyer, Elinor; Burwinkel, Barbara; Marmee, Frederick; Eccles, Diana M.; Giles, Graham G.; Peto, Julian; Schmidt, Marjanka; Broeks, Annegien; Hamann, Ute; Chang-Claude, Jenny; Lambrechts, Diether; Pharoah, Paul D.P.; Easton, Douglas; Pankratz, V. Shane; Slager, Susan; Vachon, Celine M.; Couch, Fergus J.

    2014-01-01

    Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16–1.33, P = 4.2 × 10−10) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04–1.11, P = 8.7 × 10−6) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07–1.23, P = 7.9 × 10−5) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10−3). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer. PMID:24927736

  4. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.

    PubMed

    Purrington, Kristen S; Slettedahl, Seth; Bolla, Manjeet K; Michailidou, Kyriaki; Czene, Kamila; Nevanlinna, Heli; Bojesen, Stig E; Andrulis, Irene L; Cox, Angela; Hall, Per; Carpenter, Jane; Yannoukakos, Drakoulis; Haiman, Christopher A; Fasching, Peter A; Mannermaa, Arto; Winqvist, Robert; Brenner, Hermann; Lindblom, Annika; Chenevix-Trench, Georgia; Benitez, Javier; Swerdlow, Anthony; Kristensen, Vessela; Guénel, Pascal; Meindl, Alfons; Darabi, Hatef; Eriksson, Mikael; Fagerholm, Rainer; Aittomäki, Kristiina; Blomqvist, Carl; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Wang, Xianshu; Olswold, Curtis; Olson, Janet E; Mulligan, Anna Marie; Knight, Julia A; Tchatchou, Sandrine; Reed, Malcolm W R; Cross, Simon S; Liu, Jianjun; Li, Jingmei; Humphreys, Keith; Clarke, Christine; Scott, Rodney; Fostira, Florentia; Fountzilas, George; Konstantopoulou, Irene; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Ekici, Arif B; Hartmann, Arndt; Beckmann, Matthias W; Hartikainen, Jaana M; Kosma, Veli-Matti; Kataja, Vesa; Jukkola-Vuorinen, Arja; Pylkäs, Katri; Kauppila, Saila; Dieffenbach, Aida Karina; Stegmaier, Christa; Arndt, Volker; Margolin, Sara; Balleine, Rosemary; Arias Perez, Jose Ignacio; Pilar Zamora, M; Menéndez, Primitiva; Ashworth, Alan; Jones, Michael; Orr, Nick; Arveux, Patrick; Kerbrat, Pierre; Truong, Thérèse; Bugert, Peter; Toland, Amanda E; Ambrosone, Christine B; Labrèche, France; Goldberg, Mark S; Dumont, Martine; Ziogas, Argyrios; Lee, Eunjung; Dite, Gillian S; Apicella, Carmel; Southey, Melissa C; Long, Jirong; Shrubsole, Martha; Deming-Halverson, Sandra; Ficarazzi, Filomena; Barile, Monica; Peterlongo, Paolo; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Tollenaar, Robert A E M; Seynaeve, Caroline; Brüning, Thomas; Ko, Yon-Dschun; Van Deurzen, Carolien H M; Martens, John W M; Kriege, Mieke; Figueroa, Jonine D; Chanock, Stephen J; Lissowska, Jolanta; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Schneeweiss, Andreas; Tapper, William J; Gerty, Susan M; Durcan, Lorraine; Mclean, Catriona; Milne, Roger L; Baglietto, Laura; dos Santos Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Van'T Veer, Laura J; Cornelissen, Sten; Försti, Asta; Torres, Diana; Rüdiger, Thomas; Rudolph, Anja; Flesch-Janys, Dieter; Nickels, Stefan; Weltens, Caroline; Floris, Giuseppe; Moisse, Matthieu; Dennis, Joe; Wang, Qin; Dunning, Alison M; Shah, Mitul; Brown, Judith; Simard, Jacques; Anton-Culver, Hoda; Neuhausen, Susan L; Hopper, John L; Bogdanova, Natalia; Dörk, Thilo; Zheng, Wei; Radice, Paolo; Jakubowska, Anna; Lubinski, Jan; Devillee, Peter; Brauch, Hiltrud; Hooning, Maartje; García-Closas, Montserrat; Sawyer, Elinor; Burwinkel, Barbara; Marmee, Frederick; Eccles, Diana M; Giles, Graham G; Peto, Julian; Schmidt, Marjanka; Broeks, Annegien; Hamann, Ute; Chang-Claude, Jenny; Lambrechts, Diether; Pharoah, Paul D P; Easton, Douglas; Pankratz, V Shane; Slager, Susan; Vachon, Celine M; Couch, Fergus J

    2014-11-15

    Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.

  5. Candidate Gene Approach for Parasite Resistance in Sheep – Variation in Immune Pathway Genes and Association with Fecal Egg Count

    PubMed Central

    Periasamy, Kathiravan; Pichler, Rudolf; Poli, Mario; Cristel, Silvina; Cetrá, Bibiana; Medus, Daniel; Basar, Muladno; A. K., Thiruvenkadan; Ramasamy, Saravanan; Ellahi, Masroor Babbar; Mohammed, Faruque; Teneva, Atanaska; Shamsuddin, Mohammed; Podesta, Mario Garcia; Diallo, Adama

    2014-01-01

    Sheep chromosome 3 (Oar3) has the largest number of QTLs reported to be significantly associated with resistance to gastro-intestinal nematodes. This study aimed to identify single nucleotide polymorphisms (SNPs) within candidate genes located in sheep chromosome 3 as well as genes involved in major immune pathways. A total of 41 SNPs were identified across 38 candidate genes in a panel of unrelated sheep and genotyped in 713 animals belonging to 22 breeds across Asia, Europe and South America. The variations and evolution of immune pathway genes were assessed in sheep populations across these macro-environmental regions that significantly differ in the diversity and load of pathogens. The mean minor allele frequency (MAF) did not vary between Asian and European sheep reflecting the absence of ascertainment bias. Phylogenetic analysis revealed two major clusters with most of South Asian, South East Asian and South West Asian breeds clustering together while European and South American sheep breeds clustered together distinctly. Analysis of molecular variance revealed strong phylogeographic structure at loci located in immune pathway genes, unlike microsatellite and genome wide SNP markers. To understand the influence of natural selection processes, SNP loci located in chromosome 3 were utilized to reconstruct haplotypes, the diversity of which showed significant deviations from selective neutrality. Reduced Median network of reconstructed haplotypes showed balancing selection in force at these loci. Preliminary association of SNP genotypes with phenotypes recorded 42 days post challenge revealed significant differences (P<0.05) in fecal egg count, body weight change and packed cell volume at two, four and six SNP loci respectively. In conclusion, the present study reports strong phylogeographic structure and balancing selection operating at SNP loci located within immune pathway genes. Further, SNP loci identified in the study were found to have potential for

  6. Rare Copy Number Variations in Adults with Tetralogy of Fallot Implicate Novel Risk Gene Pathways

    PubMed Central

    Costain, Gregory; Merico, Daniele; Migita, Ohsuke; Liu, Ben; Yuen, Tracy; Rickaby, Jessica; Thiruvahindrapuram, Bhooma; Marshall, Christian R.; Scherer, Stephen W.; Bassett, Anne S.

    2012-01-01

    Structural genetic changes, especially copy number variants (CNVs), represent a major source of genetic variation contributing to human disease. Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease, but to date little is known about the role of CNVs in the etiology of TOF. Using high-resolution genome-wide microarrays and stringent calling methods, we investigated rare CNVs in a prospectively recruited cohort of 433 unrelated adults with TOF and/or pulmonary atresia at a single centre. We excluded those with recognized syndromes, including 22q11.2 deletion syndrome. We identified candidate genes for TOF based on converging evidence between rare CNVs that overlapped the same gene in unrelated individuals and from pathway analyses comparing rare CNVs in TOF cases to those in epidemiologic controls. Even after excluding the 53 (10.7%) subjects with 22q11.2 deletions, we found that adults with TOF had a greater burden of large rare genic CNVs compared to controls (8.82% vs. 4.33%, p = 0.0117). Six loci showed evidence for recurrence in TOF or related congenital heart disease, including typical 1q21.1 duplications in four (1.18%) of 340 Caucasian probands. The rare CNVs implicated novel candidate genes of interest for TOF, including PLXNA2, a gene involved in semaphorin signaling. Independent pathway analyses highlighted developmental processes as potential contributors to the pathogenesis of TOF. These results indicate that individually rare CNVs are collectively significant contributors to the genetic burden of TOF. Further, the data provide new evidence for dosage sensitive genes in PLXNA2-semaphorin signaling and related developmental processes in human cardiovascular development, consistent with previous animal models. PMID:22912587

  7. Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways

    PubMed Central

    Griswold, Anthony J.; Ma, Deqiong; Cukier, Holly N.; Nations, Laura D.; Schmidt, Mike A.; Chung, Ren-Hua; Jaworski, James M.; Salyakina, Daria; Konidari, Ioanna; Whitehead, Patrice L.; Wright, Harry H.; Abramson, Ruth K.; Williams, Scott M.; Menon, Ramkumar; Martin, Eden R.; Haines, Jonathan L.; Gilbert, John R.; Cuccaro, Michael L.; Pericak-Vance, Margaret A.

    2012-01-01

    Autism spectrum disorders (ASDs) are highly heritable, yet relatively few associated genetic loci have been replicated. Copy number variations (CNVs) have been implicated in autism; however, the majority of loci contribute to <1% of the disease population. Therefore, independent studies are important to refine associated CNV regions and discover novel susceptibility genes. In this study, a genome-wide SNP array was utilized for CNV detection by two distinct algorithms in a European ancestry case–control data set. We identify a significantly higher burden in the number and size of deletions, and disrupting more genes in ASD cases. Moreover, 18 deletions larger than 1 Mb were detected exclusively in cases, implicating novel regions at 2q22.1, 3p26.3, 4q12 and 14q23. Case-specific CNVs provided further evidence for pathways previously implicated in ASDs, revealing new candidate genes within the GABAergic signaling and neural development pathways. These include DBI, an allosteric binder of GABA receptors, GABARAPL1, the GABA receptor-associated protein, and SLC6A11, a postsynaptic GABA transporter. We also identified CNVs in COBL, deletions of which cause defects in neuronal cytoskeleton morphogenesis in model vertebrates, and DNER, a neuron-specific Notch ligand required for cerebellar development. Moreover, we found evidence of genetic overlap between ASDs and other neurodevelopmental and neuropsychiatric diseases. These genes include glutamate receptors (GRID1, GRIK2 and GRIK4), synaptic regulators (NRXN3, SLC6A8 and SYN3), transcription factor (ZNF804A) and RNA-binding protein FMR1. Taken together, these CNVs may be a few of the missing pieces of ASD heritability and lead to discovering novel etiological mechanisms. PMID:22543975

  8. Association study of genetic variation in DNA repair pathway genes and risk of basal cell carcinoma.

    PubMed

    Lin, Yuan; Chahal, Harvind S; Wu, Wenting; Cho, Hyunje G; Ransohoff, Katherine J; Song, Fengju; Tang, Jean Y; Sarin, Kavita Y; Han, Jiali

    2017-09-01

    DNA repair plays a critical role in protecting the genome from ultraviolet radiation and maintaining the genomic integrity of cells. Genetic variants in DNA repair-related genes can influence an individual's DNA repair capacity, which may be related to the risk of developing basal cell carcinoma (BCC). We comprehensively assessed the associations of 2,965 independent single-nucleotide polymorphisms (SNPs) across 165 DNA repair pathway genes with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified three SNPs (rs2805831 upstream of XPA: OR = 0.93, P = 1.35 × 10(-6) ; rs659857 in exon of MUS81: OR = 1.06, P = 3.09 × 10(-6) and rs57343616 in 3' UTR of NABP2: OR = 1.11, P = 6.47 × 10(-6) ) as significantly associated with BCC risk in meta-analysis, and all of them were nominally significant in both data sets. Furthermore, rs659857 [T] was significantly associated with decreased expression of MUS81 mRNA in the expression quantitative trait locus (eQTL) analysis. Our findings suggest that the inherited common variation in three DNA repair genes-XPA, MUS81 and NABP2-may be involved in the development of BCC. To our knowledge, our study is the first report thoroughly examining the effects of SNPs across DNA repair pathway genes on BCC risk based on a genome-wide association meta-analysis. © 2017 UICC.

  9. Gene Expression in Transformed Lymphocytes Reveals Variation in Endomembrane and HLA Pathways Modifying Cystic Fibrosis Pulmonary Phenotypes

    PubMed Central

    O’Neal, Wanda K.; Gallins, Paul; Pace, Rhonda G.; Dang, Hong; Wolf, Whitney E.; Jones, Lisa C.; Guo, XueLiang; Zhou, Yi-Hui; Madar, Vered; Huang, Jinyan; Liang, Liming; Moffatt, Miriam F.; Cutting, Garry R.; Drumm, Mitchell L.; Rommens, Johanna M.; Strug, Lisa J.; Sun, Wei; Stonebraker, Jaclyn R.; Wright, Fred A.; Knowles, Michael R.

    2015-01-01

    Variation in cystic fibrosis (CF) phenotypes, including lung disease severity, age of onset of persistent Pseudomonas aeruginosa (P. aeruginosa) lung infection, and presence of meconium ileus (MI), has been partially explained by genome-wide association studies (GWASs). It is not expected that GWASs alone are sufficiently powered to uncover all heritable traits associated with CF phenotypic diversity. Therefore, we utilized gene expression association from lymphoblastoid cells lines from 754 p.Phe508del CF-affected homozygous individuals to identify genes and pathways. LPAR6, a G protein coupled receptor, associated with lung disease severity (false discovery rate q value = 0.0006). Additional pathway analyses, utilizing a stringent permutation-based approach, identified unique signals for all three phenotypes. Pathways associated with lung disease severity were annotated in three broad categories: (1) endomembrane function, containing p.Phe508del processing genes, providing evidence of the importance of p.Phe508del processing to explain lung phenotype variation; (2) HLA class I genes, extending previous GWAS findings in the HLA region; and (3) endoplasmic reticulum stress response genes. Expression pathways associated with lung disease were concordant for some endosome and HLA pathways, with pathways identified using GWAS associations from 1,978 CF-affected individuals. Pathways associated with age of onset of persistent P. aeruginosa infection were enriched for HLA class II genes, and those associated with MI were related to oxidative phosphorylation. Formal testing demonstrated that genes showing differential expression associated with lung disease severity were enriched for heritable genetic variation and expression quantitative traits. Gene expression provided a powerful tool to identify unrecognized heritable variation, complementing ongoing GWASs in this rare disease. PMID:25640674

  10. Catecholamine pathway gene variation is associated with norepinephrine and epinephrine concentrations at rest and after exercise.

    PubMed

    Ghimire, Laxmi V; Kohli, Utkarsh; Li, Chun; Sofowora, Gbenga G; Muszkat, Mordechai; Friedman, Eitan A; Solus, Joseph F; Wood, Alastair J J; Stein, C Michael; Kurnik, Daniel

    2012-04-01

    To examine the hypothesis that genetic variation in enzymes and transporters associated with synthesis, storage, release, and metabolism of catecholamines contributes to the interindividual variability in plasma catecholamine concentrations at rest and after exercise. We measured plasma norepinephrine (NE) and epinephrine concentrations at rest and after a standardized exercise protocol in 165 healthy individuals (60% White, 40% African-American) and examined 29 functional or common variants in 14 genes involved in synthesis, transport, or metabolism of catecholamines. We examined the relationship between genotypes and NE concentrations at rest and the increase after exercise (ΔNE) by multiple linear regression with adjustment for covariates [age, race, sex, BMI, fitness, and resting NE (for ΔNE)]. As a secondary outcome, we carried out similar analyses for epinephrine concentrations. There was large interindividual variability in resting NE (mean, 204±102 pg/ml; range, 39-616 pg/ml) and ΔNE (mean, 256±206 pg/ml; range, -97 to 953 pg/ml). Resting NE was significantly associated with variants of four genes: CYB561 (P<0.001), VMAT2 (P=0.016), CHGA (P=0.039), and PNMT (P=0.038). ΔNE after exercise was associated with three variants of PNMT (P=0.041) and COMT (P=0.033 and 0.035), and resting and exercise epinephrine concentrations were associated with two variants each. The findings of this exploratory study suggest that variation in catecholamine pathway genes contributes to the interindividual variability in plasma NE and epinephrine concentrations at rest and after exercise.

  11. Genetic variation in nucleotide excision repair pathway genes, pesticide exposure and prostate cancer risk

    PubMed Central

    Barry, Kathryn Hughes; Koutros, Stella; Andreotti, Gabriella; Sandler, Dale P.; Burdette, Laurie A.; Yeager, Meredith; Beane Freeman, Laura E.; Lubin, Jay H.; Zheng, Tongzhang; Alavanja, Michael C.R.; Berndt, Sonja I.

    2012-01-01

    Previous research demonstrates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, human biomonitoring studies indicate increased genetic damage (e.g. chromosomal aberrations) with pesticide exposure. Given that the nucleotide excision repair (NER) pathway repairs a broad range of DNA damage, we evaluated interactions between pesticide exposure and 324 single-nucleotide polymorphisms (SNPs) tagging 27 NER genes among 776 prostate cancer cases and 1444 male controls in a nested case–control study of white Agricultural Health Study pesticide applicators. We determined interaction P values using likelihood ratio tests from logistic regression models and three-level pesticide variables (none/low/high) based on lifetime days of use weighted to an intensity score. We adjusted for multiple comparisons using the false discovery rate (FDR) method. Of the 17 interactions that met FDR <0.2, 3 displayed a monotonic increase in prostate cancer risk with increasing exposure in one genotype group and no significant association in the other group. Men carrying the variant A allele at ERCC1 rs2298881 exhibited increased prostate cancer risk with high versus no fonofos use [odds ratio (OR) 2.98; 95% confidence interval (CI) 1.65–5.39; Pinteract = 3.6 × 10−4; FDR-adjusted P = 0.11]. Men carrying the homozygous wild-type TT genotype at two correlated CDK7 SNPs, rs11744596 and rs2932778 (r2 = 1.0), exhibited increased risk with high versus no carbofuran use (OR 2.01; 95% CI 1.31–3.10 for rs11744596; Pinteract = 7.2 × 10−4; FDR-adjusted P = 0.09). In contrast, we did not observe associations among men with other genotypes at these loci. While requiring replication, our findings suggest a role for NER genetic variation in pesticide-associated prostate cancer risk. PMID:22102698

  12. Genetic Variation in Base Excision Repair Pathway Genes, Pesticide Exposure, and Prostate Cancer Risk

    PubMed Central

    Koutros, Stella; Berndt, Sonja I.; Andreotti, Gabriella; Hoppin, Jane A.; Sandler, Dale P.; Burdette, Laurie A.; Yeager, Meredith; Freeman, Laura E. Beane; Lubin, Jay H.; Ma, Xiaomei; Zheng, Tongzhang; Alavanja, Michael C.R.

    2011-01-01

    Background: Previous research indicates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, evidence suggests a role of oxidative DNA damage. Objectives: Because base excision repair (BER) is the predominant pathway involved in repairing oxidative damage, we evaluated interactions between 39 pesticides and 394 tag single-nucleotide polymorphisms (SNPs) for 31 BER genes among 776 prostate cancer cases and 1,444 male controls in a nested case–control study of white Agricultural Health Study (AHS) pesticide applicators. Methods: We used likelihood ratio tests from logistic regression models to determine p-values for interactions between three-level pesticide exposure variables (none/low/high) and SNPs (assuming a dominant model), and the false discovery rate (FDR) multiple comparison adjustment approach. Results: The interaction between fonofos and rs1983132 in NEIL3 [nei endonuclease VIII-like 3 (Escherichia coli)], which encodes a glycosylase that can initiate BER, was the most significant overall [interaction p-value (pinteract) = 9.3 × 10–6; FDR-adjusted p-value = 0.01]. Fonofos exposure was associated with a monotonic increase in prostate cancer risk among men with CT/TT genotypes for rs1983132 [odds ratios (95% confidence intervals) for low and high use compared with no use were 1.65 (0.91, 3.01) and 3.25 (1.78, 5.92), respectively], whereas fonofos was not associated with prostate cancer risk among men with the CC genotype. Carbofuran and S-ethyl dipropylthiocarbamate (EPTC) interacted similarly with rs1983132; however, these interactions did not meet an FDR < 0.2. Conclusions: Our significant finding regarding fonofos is consistent with previous AHS findings of increased prostate cancer risk with fonofos exposure among those with a family history of prostate cancer. Although requiring replication, our findings suggest a role of BER genetic variation in pesticide

  13. Genetic variations in the homologous recombination repair pathway genes modify risk of glioma.

    PubMed

    Zhang, Haishi; Liu, Yanhong; Zhou, Keke; Zhou, Chengcheng; Zhou, Renke; Cheng, Chunxia; Wei, Qingyi; Lu, Daru; Zhou, Liangfu

    2016-01-01

    Accumulative epidemiological evidence suggests that single nucleotide polymorphisms (SNPs) in genes involved in homologous recombination (HR) DNA repair pathway play an important role in glioma susceptibility. However, the effects of such SNPs on glioma risk remain unclear. We used a used a candidate pathway-based approach to elucidate the relationship between glioma risk and 12 putative functional SNPs in genes involved in the HR pathway. Genotyping was conducted on 771 histologically-confirmed glioma patients and 752 cancer-free controls from the Chinese Han population. Odds ratios (OR) were calculated both for each SNP individually and for grouped analyses, examining the effects of the numbers of adverse alleles on glioma risk, and evaluated their potential gene-gene interactions using the multifactor dimensionality reduction (MDR). In the single-locus analysis, two variants, the NBS1 rs1805794 (OR 1.42, 95% CI 1.15-1.76, P = 0.001), and RAD54L rs1048771 (OR 1.61, 95% CI 1.17-2.22, P = 0.002) were significantly associated with glioma risk. When we examined the joint effects of the risk-conferring alleles of these three SNPs, we found a significant trend indicating that the risk increases as the number of adverse alleles increase (P = 0.005). Moreover, the MDR analysis suggested a significant three-locus interaction model involving NBS1 rs1805794, MRE11 rs10831234, and ATM rs227062. These results suggested that these variants of the genes involved in the HR pathway may contribute to glioma susceptibility.

  14. Identification of additive, dominant, and epistatic variation conferred by key genes in cellulose biosynthesis pathway in Populus tomentosa†.

    PubMed

    Du, Qingzhang; Tian, Jiaxing; Yang, Xiaohui; Pan, Wei; Xu, Baohua; Li, Bailian; Ingvarsson, Pär K; Zhang, Deqiang

    2015-02-01

    Economically important traits in many species generally show polygenic, quantitative inheritance. The components of genetic variation (additive, dominant and epistatic effects) of these traits conferred by multiple genes in shared biological pathways remain to be defined. Here, we investigated 11 full-length genes in cellulose biosynthesis, on 10 growth and wood-property traits, within a population of 460 unrelated Populus tomentosa individuals, via multi-gene association. To validate positive associations, we conducted single-marker analysis in a linkage population of 1,200 individuals. We identified 118, 121, and 43 associations (P< 0.01) corresponding to additive, dominant, and epistatic effects, respectively, with low to moderate proportions of phenotypic variance (R(2)). Epistatic interaction models uncovered a combination of three non-synonymous sites from three unique genes, representing a significant epistasis for diameter at breast height and stem volume. Single-marker analysis validated 61 associations (false discovery rate, Q ≤ 0.10), representing 38 SNPs from nine genes, and its average effect (R(2) = 3.8%) nearly 2-fold higher than that identified with multi-gene association, suggesting that multi-gene association can capture smaller individual variants. Moreover, a structural gene-gene network based on tissue-specific transcript abundances provides a better understanding of the multi-gene pathway affecting tree growth and lignocellulose biosynthesis. Our study highlights the importance of pathway-based multiple gene associations to uncover the nature of genetic variance for quantitative traits and may drive novel progress in molecular breeding. © The Author 2014. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

  15. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

    PubMed Central

    Hampras, Shalaka S.; Sucheston-Campbell, Lara E.; Cannioto, Rikki; Chang-Claude, Jenny; Modugno, Francesmary; Dörk, Thilo; Hillemanns, Peter; Preus, Leah; Knutson, Keith L.; Wallace, Paul K.; Hong, Chi-Chen; Friel, Grace; Davis, Warren; Nesline, Mary; Pearce, Celeste L.; Kelemen, Linda E.; Goodman, Marc T.; Bandera, Elisa V.; Terry, Kathryn L.; Schoof, Nils; Eng, Kevin H.; Clay, Alyssa; Singh, Prashant K.; Joseph, Janine M.; Aben, Katja K.H.; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bean, Yukie; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Cook, Linda S.; Cramer, Daniel W.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Despierre, Evelyn; Dicks, Ed; Doherty, Jennifer A.; du Bois, Andreas; Dürst, Matthias; Easton, Doug; Eccles, Diana; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Gronwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hogdall, Claus; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Klapdor, Rüdiger; Kolomeyevskaya, Nonna; Krakstad, Camilla; Kjaer, Susanne K.; Kruszka, Bridget; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashikant; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Liu, Song; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valeria; McLaughlin, John R.; McNeish, Ian; Menon, Usha; Moes-Sosnowska, Joanna; Narod, Steven A.; Nedergaard, Lotte; Nevanlinna, Heli; Nickels, Stefan; Olson, Sara H.; Orlow, Irene; Weber, Rachel Palmieri; Paul, James; Pejovic, Tanja; Pelttari, Liisa M.; Perkins, Barbara; Permuth-Wey, Jenny; Pike, Malcolm C.; Plisiecka-Halasa, Joanna; Poole, Elizabeth M.; Risch, Harvey A.; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schernhammer, Eva; Schmitt, Kristina; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Tangen, Ingvild L.; Teo, Soo-Hwang; Thompson, Pamela J.; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S.; Tyrer, Jonathan; van Altena, Anna M.; Vergote, Ignace; Vierkant, Robert A.; Walsh, Christine; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wu, Anna H.; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Gayther, Simon A.; Ramus, Susan J.; Sellers, Thomas A.; Schildkraut, Joellen M.; Phelan, Catherine M.; Berchuck, Andrew; Chenevix-Trench, Georgia; Cunningham, Julie M.; Pharoah, Paul P.; Ness, Roberta B.; Odunsi, Kunle; Goode, Ellen L.; Moysich, Kirsten B.

    2016-01-01

    Background Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with (p = 0.001) and clear cell EOC. Gene associations with histotypes at< 0.05 included:(p = 0.005 and = 0.008, serous and high-grade serous, respectively), (p = 0.035, endometrioid and mucinous), (p = 0.03, mucinous), (p = 0.022, clear cell), (p = 0.021 endometrioid) and (p = 0.017 and = 0.025, endometrioid and mucinous, respectively). Conclusions Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients. PMID:27533245

  16. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer.

    PubMed

    Hampras, Shalaka S; Sucheston-Campbell, Lara E; Cannioto, Rikki; Chang-Claude, Jenny; Modugno, Francesmary; Dörk, Thilo; Hillemanns, Peter; Preus, Leah; Knutson, Keith L; Wallace, Paul K; Hong, Chi-Chen; Friel, Grace; Davis, Warren; Nesline, Mary; Pearce, Celeste L; Kelemen, Linda E; Goodman, Marc T; Bandera, Elisa V; Terry, Kathryn L; Schoof, Nils; Eng, Kevin H; Clay, Alyssa; Singh, Prashant K; Joseph, Janine M; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bean, Yukie; Beckmann, Matthias W; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Cook, Linda S; Cramer, Daniel W; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Despierre, Evelyn; Dicks, Ed; Doherty, Jennifer A; du Bois, Andreas; Dürst, Matthias; Easton, Doug; Eccles, Diana; Edwards, Robert P; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Gronwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hogdall, Claus; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kellar, Melissa; Kelley, Joseph L; Kiemeney, Lambertus A; Klapdor, Rüdiger; Kolomeyevskaya, Nonna; Krakstad, Camilla; Kjaer, Susanne K; Kruszka, Bridget; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashikant; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lissowska, Jolanta; Liu, Song; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valeria; McLaughlin, John R; McNeish, Ian; Menon, Usha; Moes-Sosnowska, Joanna; Narod, Steven A; Nedergaard, Lotte; Nevanlinna, Heli; Nickels, Stefan; Olson, Sara H; Orlow, Irene; Weber, Rachel Palmieri; Paul, James; Pejovic, Tanja; Pelttari, Liisa M; Perkins, Barbara; Permuth-Wey, Jenny; Pike, Malcolm C; Plisiecka-Halasa, Joanna; Poole, Elizabeth M; Risch, Harvey A; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schernhammer, Eva; Schmitt, Kristina; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Tangen, Ingvild L; Teo, Soo-Hwang; Thompson, Pamela J; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S; Tyrer, Jonathan; van Altena, Anna M; Vergote, Ignace; Vierkant, Robert A; Walsh, Christine; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Wu, Anna H; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Gayther, Simon A; Ramus, Susan J; Sellers, Thomas A; Schildkraut, Joellen M; Phelan, Catherine M; Berchuck, Andrew; Chenevix-Trench, Georgia; Cunningham, Julie M; Pharoah, Paul P; Ness, Roberta B; Odunsi, Kunle; Goode, Ellen L; Moysich, Kirsten B

    2016-10-25

    Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

  17. Association between Genetic Variation in the Oxytocin Receptor Gene and Emotional Withdrawal, but not between Oxytocin Pathway Genes and Diagnosis in Psychotic Disorders

    PubMed Central

    Haram, Marit; Tesli, Martin; Bettella, Francesco; Djurovic, Srdjan; Andreassen, Ole Andreas; Melle, Ingrid

    2015-01-01

    Social dysfunction is common in patients with psychotic disorders. Oxytocin is a neuropeptide with a central role in social behavior. This study aims to explore the relationship between oxytocin pathway genes and symptoms related to social dysfunction in patients with psychotic disorders. We performed association analyses between four oxytocin pathway genes (OXT, OXTR, AVP, and CD38) and four areas of social behavior-related psychopathology as measured by Positive and Negative Syndrome Scale. For this purpose, we used both a polygenic risk score (PGRS) and single OXTR candidate single nucleotide polymorphism previously reported in the literature (rs53576, rs237902, and rs2254298). A total of 734 subjects with DSM-IV psychotic spectrum disorders and 420 healthy controls were included. Oxytocin pathway PGRSs were calculated based on the independent Psychiatric Genomics Consortium study sample. There was a significant association between symptom of Emotional Withdrawal and the previously reported OXTR risk allele A in rs53576. No significant associations between oxytocin pathway gene variants and a diagnosis of psychotic disorder were found. Our findings indicate that while oxytocin pathway genes do not appear to contribute to the susceptibility to psychotic disorders, variations in the OXTR gene might play a role in the development of impaired social behavior. PMID:25667571

  18. Association of genetic variations in the Wnt signaling pathway genes with myocardial infarction susceptibility in Chinese Han population

    PubMed Central

    Abudoukelimu, Mayila; Yang, Yi-ning; Li, Xiao-mei; Xie, Xiang; Chen, Bang-dang; Liu, Fen; He, Chun-hui; Li, Hua-yin; Ma, Yi-tong

    2016-01-01

    Numerous studies have implicated the Wnt pathway in the development and progression of myocardial infarction (MI); however, there are very few investigations addressing the effects of polymorphisms in the Wnt pathway genes on MI susceptibility. We investigated the possible correlation between genetic variations in Wnt pathway genes and MI risk. Three polymorphisms (rs7832767 C > T in SFRP1 gene, rs2293303 C > T in CTNNB1 gene, rs16893344 C > T in WISP1 gene) were finally selected and genotyped in 465 MI patients and 485 healthy controls, using the PCR-RFLP method. We found that the SFRP1 rs7832767 variant allele (T) was associated with a significantly increased risk of MI [TT vs. CC: adjusted odds ratio (AOR) = 3.13, 95% CI = 1.78-5.51; CT/TT vs. CC: AOR = 1.53, 95% CI = 1.12-2.08; TT vs. CC/CT: AOR = 2.87, 95% CI = 1.66-4.97)]. The significant association with MI risk was also found for the CTNNB1 rs2293303 (CT vs. CC: AOR = 3.48, 95% CI = 2.28-5.33; TT vs. CC: AOR = 7.37, 95% CI = 2.08-26.16; CT/TT vs. CC: AOR = 3.72, 95% CI = 2.46-5.62; TT vs. CC/CT: AOR = 5.52, 95% CI = 1.58-19.28), and WISP1 rs16893344 polymorphisms (CT vs. CC: AOR = 2.43, 95% CI = 1.70-3.47; TT vs. CC: AOR = 5.17, 95% CI = 1.85-14.41; CT/TT vs. CC: AOR = 2.58, 95% CI = 1.83-3.66; TT vs. CC/CT: AOR = 3.88, 95% CI = 1.41-10.64). The associations remain significant in stratified analysis by demographic and clinical characteristics of participants, with few exceptions. Our study provided the first evidence of the association between polymorphisms in the Wnt pathway genes and MI susceptibility in Chinese Han population. Epidemiological studies with larger samples and functional analyses are warranted to further verify our results. PMID:27391264

  19. Variation in genes in the endothelin pathway and endothelium-dependent and endothelium-independent vasodilation in an elderly population.

    PubMed

    Lind, L; Syvänen, A-C; Axelsson, T; Lundmark, P; Hägg, S; Larsson, A

    2013-05-01

    Indirect evidences by blockade of the endothelin receptors have suggested a role of endothelin in endothelium-dependent vasodilation. This study aimed to investigate whether circulating levels of endotehlin-1 or genetic variations in genes in the endothelin pathway were related to endothelium-dependent vasodilation. In 1016 seventy-year-old participants of the population-based Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (52% women), we measured endothelium-dependent vasodilation using the invasive forearm technique with acetylcholine given in the brachial artery (EDV) and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD). Plasma endothelin-1 levels were measured and 60 SNPs in genes in the endothelin pathway (ECE1, EDN1, EDNRA, EDNRB) were genotyped. No significant associations were found between circulating endothelin levels and EDV or FMD. No single genotype was related to EDV or FMD following adjustment for multiple testing, but a genotype score for 3 SNPs (rs11618266 in EDNRB, rs17675063 in EDNRA, rs3026868 in ECE1) was significantly related to EDV (beta coefficient 0.070, 95% CI 0.025-0.12, P = 0.002) when adjusting for gender, systolic blood pressure, HDL and LDL cholesterol, serum triglycerides, BMI, diabetes, smoking, antihypertensive medication or statins and CRP. This score was also related to nitroprusside-induced vasodilation in the forearm. A combination of genotypes in the endothelin pathway was related to both endothelium-dependent and endothelium-independent vasodilation in forearm resistance vessels, but not in the brachial artery in an elderly population, giving evidence for a role of the endothelin system in resistance vessel reactivity independent of major cardiovascular risk factors. Acta Physiologica © 2013 Scandinavian Physiological Society.

  20. Genetic Variations in Xenobiotic Metabolic Pathway Genes, Personal Hair Dye Use, and Risk of Non-Hodgkin Lymphoma

    PubMed Central

    Zhang, Yawei; Hughes, Kathryn J.; Zahm, Shelia Hoar; Holford, Theodore R.; Dai, Li; Bai, Yana; Han, Xuesong; Qin, Qin; Lan, Qing; Rothman, Nathaniel; Zhu, Yong; Leaderer, Brian; Zheng, Tongzhang

    2009-01-01

    From 1996 to 2000, the authors conducted a population-based case-control study among Connecticut women to test the hypothesis that genetic variation in xenobiotic metabolic pathway genes modifies the relation between hair dye use and risk of non-Hodgkin lymphoma. No effect modifications were found for women who started using hair dyes in 1980 or afterward. For women who started using hair dye before 1980 as compared with never users, a statistically significantly increased risk of non-Hodgkin lymphoma was found for carriers of CYP2C9 Ex3-52C>T TT/CT genotypes (odds ratio (OR) = 2.9, 95% confidence interval (CI): 1.4, 6.1), CYP2E1 -332T>A AT/AA genotypes (OR = 2.0, 95% CI: 1.2, 3.4), a homozygous or heterozygous 3-base-pair deletion in intron 6 of GSTM3 (OR = 2.3, 95% CI: 1.3, 4.1), GSTP1 Ex5-24A>G AA genotypes (OR = 1.8, 95% CI: 1.1, 2.9), or NAT2 genotypes conferring intermediate/rapid acetylator status (OR = 1.6, 95% CI: 1.0, 2.7). The observed associations were mainly seen for follicular lymphoma. In contrast, no significantly increased risk was observed for starting hair dye use before 1980 (relative to never use) among women who were homozygous wild-type for the CYP2C9, CYP2E1, or GSTM3 polymorphisms, women carrying 1 or 2 copies of the variant GSTP1 allele, or women who were slow NAT2 acetylators. A possible role of genetic variation in xenobiotic metabolism in the carcinogenicity of hair dye use needs to be confirmed in larger studies. PMID:19822571

  1. Genetic variations in xenobiotic metabolic pathway genes, personal hair dye use, and risk of non-Hodgkin lymphoma.

    PubMed

    Zhang, Yawei; Hughes, Kathryn J; Zahm, Shelia Hoar; Zhang, Yaqun; Holford, Theodore R; Dai, Li; Bai, Yana; Han, Xuesong; Qin, Qin; Lan, Qing; Rothman, Nathaniel; Zhu, Yong; Leaderer, Brian; Zheng, Tongzhang

    2009-11-15

    From 1996 to 2000, the authors conducted a population-based case-control study among Connecticut women to test the hypothesis that genetic variation in xenobiotic metabolic pathway genes modifies the relation between hair dye use and risk of non-Hodgkin lymphoma. No effect modifications were found for women who started using hair dyes in 1980 or afterward. For women who started using hair dye before 1980 as compared with never users, a statistically significantly increased risk of non-Hodgkin lymphoma was found for carriers of CYP2C9 Ex3-52C>T TT/CT genotypes (odds ratio (OR) = 2.9, 95% confidence interval (CI): 1.4, 6.1), CYP2E1 -332T>A AT/AA genotypes (OR = 2.0, 95% CI: 1.2, 3.4), a homozygous or heterozygous 3-base-pair deletion in intron 6 of GSTM3 (OR = 2.3, 95% CI: 1.3, 4.1), GSTP1 Ex5-24A>G AA genotypes (OR = 1.8, 95% CI: 1.1, 2.9), or NAT2 genotypes conferring intermediate/rapid acetylator status (OR = 1.6, 95% CI: 1.0, 2.7). The observed associations were mainly seen for follicular lymphoma. In contrast, no significantly increased risk was observed for starting hair dye use before 1980 (relative to never use) among women who were homozygous wild-type for the CYP2C9, CYP2E1, or GSTM3 polymorphisms, women carrying 1 or 2 copies of the variant GSTP1 allele, or women who were slow NAT2 acetylators. A possible role of genetic variation in xenobiotic metabolism in the carcinogenicity of hair dye use needs to be confirmed in larger studies.

  2. Human Lipoxygenase Pathway Gene Variation and Association with Markers of Subclinical Atherosclerosis in the Diabetes Heart Study

    PubMed Central

    Burdon, Kathryn P.; Rudock, Megan E.; Lehtinen, Allison B.; Langefeld, Carl D.; Bowden, Donald W.; Register, Thomas C.; Liu, Yongmei; Freedman, Barry I.; Carr, J. Jeffrey; Hedrick, Catherine C.; Rich, Stephen S.

    2010-01-01

    Aims. Genes of the 5-lipoxygenase pathway are compelling candidates for atherosclerosis. We hypothesize that polymorphisms in ALOX12, ALOX15, ALOX5, and ALOX5AP genes are associated with subclinical atherosclerosis in multiple vascular beds. Methods. Families with two or more siblings with type 2 diabetes and their nondiabetic siblings were studied as part of the Diabetes Heart Study (DHS). European American diabetic (n = 828) and nondiabetic (n = 170) siblings were genotyped for SNPs in the ALOX12, ALOX15, ALOX5, and ALOX5AP genes. Subclinical measures of atherosclerosis (IMT, coronary (CorCP), carotid (CarCP) and aortic (AorCP) calcified plaque) were obtained. Results. Associations were observed between ALOX12 with CorCP, ALOX5 with CorCP, AorCP, and IMT, and ALOX5AP with CorCP and CarCP, independent of known epidemiologic risk factors. Further, lipoxygenase pathway SNPs that were associated with measures of atherosclerosis were associated with markers of inflammation (CRP, ICAM-1) and calcification (MGP). Conclusions. Polymorphisms within ALOX12, ALOX5, and ALOX5AP are genetically associated with subclinical atherosclerosis and with biomarkers of disease in families with type 2 diabetes. These results suggest that variants in lipoxygenase pathway genes may have pleiotropic effects on multiple components that determine risk of cardiovascular disease. PMID:20592751

  3. Impact of diurnal temperature variation on grape berry development, proanthocyanidin accumulation, and the expression of flavonoid pathway genes

    PubMed Central

    Cohen, Seth D.; Tarara, Julie M.; Gambetta, Greg A.; Matthews, Mark A.; Kennedy, James A.

    2012-01-01

    Little is known about the impact of temperature on proanthocyanidin (PA) accumulation in grape skins, despite its significance in berry composition and wine quality. Field-grown grapes (cv. Merlot) were cooled during the day or heated at night by +/–8 °C, from fruit set to véraison in three seasons, to determine the effect of temperature on PA accumulation. Total PA content per berry varied only in one year, when PA content was highest in heated berries (1.46 mg berry−1) and lowest in cooled berries (0.97 mg berry−1). In two years, cooling berries resulted in a significant increase in the proportion of (–)-epigallocatechin as an extension subunit. In the third year, rates of berry development, PA accumulation, and the expression levels of several genes involved in flavonoid biosynthesis were assessed. Heating and cooling berries altered the initial rates of PA accumulation, which was correlated strongly with the expression of core genes in the flavonoid pathway. Both heating and cooling altered the rate of berry growth and coloration, and the expression of several structural genes within the flavonoid pathway. PMID:22268158

  4. Sex-specific variation in signaling pathways and gene expression patterns in human leukocytes in response to endotoxin and exercise.

    PubMed

    Abbasi, Asghar; de Paula Vieira, Rodolfo; Bischof, Felix; Walter, Michael; Movassaghi, Masoud; Berchtold, Nicole C; Niess, Andreas M; Cotman, Carl W; Northoff, Hinnak

    2016-11-10

    While exercise effects on the immune system have received increasing attention in recent years, it remains unclear to what extent gender and fluctuations in sex hormones during menstrual cycle influence immunological responses to exercise. We investigated mRNA changes induced through exhaustive exercise (half-marathon; pre-exercise and post-exercise [30 min, 3 h, 24 h] on whole blood cultures ± lipopolysaccharide [LPS] [1 h]) with a specific focus on sex differences (men vs women in luteal phase) as an extension of our previous study. Inflammation related signaling pathways, TLRs, cytosolic DNA sensing and RIG-I like receptors were differentially activated between sexes in LPS-stimulated cultures. Genes differentially regulated between sexes included TNIP-1, TNIP-3, IL-6, HIVEP1, CXCL3, CCR3, IL-8, and CD69, revealing a bias towards less anti-inflammatory gene regulation in women compared to men. In addition, several genes relevant to brain function (KMO, DDIT4, VEGFA, IGF1R, IGF2R, and FGD4) showed differential activation between sexes. Some of these genes (e.g., KMO in women, DDIT4 in both sexes) potentially constitute neuroprotective mechanisms. These data reveal that the exercise-induced change in gene expression might be gender and menstrual cycle phase dependent.

  5. Genetic variation of fifteen folate metabolic pathway associated gene loci and the risk of incident head and neck carcinoma: The Women’s Genome Health Study

    PubMed Central

    Zee, Robert Y.L.; Rose, Lynda; Chasman, Daniel I.; Ridker, Paul M

    2013-01-01

    Objective Recent studies have demonstrated the importance of folate metabolic pathway (FMP) in the pathogenesis of head and neck cancinoma (HNC). Whether the genetic variation within the FMP associated genes modulates HNC remains elusive. To date, prospective, epidemiological data on the relationship of FMP gene variation with the risk of HNC are sparse. Methods The association between 203 tag-SNPs (tSNPs) of 15 FMP associated genes (CBS, BHMT, DHFR, FOLR1, FOLR2, FOLR3, MTHFR, MTR, MTRR, MTHFD1, RFC1, SHMT1, SLC19A1, TCN2, and TYMS) and incident HNC was investigated in 23,294 Caucasian female participants of the prospective Women’s Genome Health Study. All were free of known cancer at baseline. During a 15-year follow-up period, 55 participants developed a first ever HNC. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and HNC risk assuming an additive genetic model. Haplotype-block analysis was also performed. Results A total of 11 tSNPs within DHFR, MTHFR, RFC1, and TYMS were associated with HNC risk (all p-uncorrected <0.050). Further investigation using the haplotype-block analysis revealed an association of several prespecified haplotypes of RFC1 with HNC risk (all p-uncorrected <0.050). Conclusion If corroborated in other large prospective studies, the present findings suggest that genetic variation within the folate metabolic pathway gene loci examined, in particular, the replication factor C-1 (RFC1) gene variation may influence HNC risk. PMID:23276522

  6. Wild rodents as a model to discover genes and pathways underlying natural variation in infectious disease susceptibility.

    PubMed

    Turner, A K; Paterson, S

    2013-11-01

    Individuals vary in their susceptibility to infectious disease, and it is now well established that host genetic factors form a major component of this variation. The discovery of genes underlying susceptibility has the potential to lead to improved disease control, through the identification and management of vulnerable individuals and the discovery of novel therapeutic targets. Laboratory rodents have proved invaluable for ascertaining the function of genes involved in immunity to infection. However, these captive animals experience conditions very different to the natural environment, lacking the genetic diversity and environmental pressures characteristic of natural populations, including those of humans. It has therefore often proved difficult to translate basic laboratory research to the real world. In order to further our understanding of the genetic basis of infectious disease resistance, and the evolutionary forces that drive variation in susceptibility, we propose that genetic research traditionally conducted on laboratory animals is expanded to the more ecologically valid arena of natural populations. In this article, we highlight the potential of using wild rodents as a new resource for biomedical research, to link the functional genetic knowledge gained from laboratory rodents with the variation in infectious disease susceptibility observed in humans and other natural populations. © 2013 John Wiley & Sons Ltd.

  7. Copy number variations and genome-wide associations reveal putative genes and metabolic pathways involved with the feed conversion ratio in beef cattle.

    PubMed

    de Almeida Santana, Miguel Henrique; Junior, Gerson Antônio Oliveira; Cesar, Aline Silva Mello; Freua, Mateus Castelani; da Costa Gomes, Rodrigo; da Luz E Silva, Saulo; Leme, Paulo Roberto; Fukumasu, Heidge; Carvalho, Minos Esperândio; Ventura, Ricardo Vieira; Coutinho, Luiz Lehmann; Kadarmideen, Haja N; Ferraz, José Bento Sterman

    2016-11-01

    The use of genome-wide association results combined with other genomic approaches may uncover genes and metabolic pathways related to complex traits. In this study, the phenotypic and genotypic data of 1475 Nellore (Bos indicus) cattle and 941,033 single nucleotide polymorphisms (SNPs) were used for genome-wide association study (GWAS) and copy number variations (CNVs) analysis in order to identify candidate genes and putative pathways involved with the feed conversion ratio (FCR). The GWAS was based on the Bayes B approach analyzing genomic windows with multiple regression models to estimate the proportion of genetic variance explained by each window. The CNVs were detected with PennCNV software using the log R ratio and B allele frequency data. CNV regions (CNVRs) were identified with CNVRuler and a linear regression was used to associate CNVRs and the FCR. Functional annotation of associated genomic regions was performed with the Database for Annotation, Visualization and Integrated Discovery (DAVID) and the metabolic pathways were obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG). We showed five genomic windows distributed over chromosomes 4, 6, 7, 8, and 24 that explain 12 % of the total genetic variance for FCR, and detected 12 CNVRs (chromosomes 1, 5, 7, 10, and 12) significantly associated [false discovery rate (FDR) < 0.05] with the FCR. Significant genomic regions (GWAS and CNV) harbor candidate genes involved in pathways related to energetic, lipid, and protein metabolism. The metabolic pathways found in this study are related to processes directly connected to feed efficiency in beef cattle. It was observed that, even though different genomic regions and genes were found between the two approaches (GWAS and CNV), the metabolic processes covered were related to each other. Therefore, a combination of the approaches complement each other and lead to a better understanding of the FCR.

  8. Variation in genes of β-glucan recognition pathway and susceptibility to opportunistic infections in HIV-positive patients.

    PubMed

    Rosentul, Diana C; Plantinga, Theo S; Papadopoulos, Antonios; Joosten, Leo A B; Antoniadou, Anastasia; Venselaar, Hanka; Kullberg, Bart-Jan; van der Meer, Jos W M; Giamarellos-Bourboulis, Evangelos J; Netea, Mihai G

    2011-01-01

    Opportunistic infections are the main cause of morbidity and death among HIV-positive patients. Most of these infections are linked to the immunodeficiency due to low CD4+ counts. However, not all patients with low CD4+ counts are equally susceptible to infections, and we hypothesize that variability in genes of innate immunity may also play an important role. The dectin-1/CARD9 pathway is crucial for recognition of both fungal and bacterial pathogens. The aim of this study was to assess the possible association between the occurrence of opportunistic infections and single nucleotide polymorphisms in DECTIN-1 and CARD9 in a cohort of 187 HIV-infected patients. The incidence of oropharyngeal candidiasis and other opportunistic infections was not influenced by either the Y238X DECTIN-1 or the S12N CARD9 polymorphism. Surprisingly however, the prevalence of pneumonia was significantly higher in patients bearing the defective variant DECTIN-1 allele. These results suggest a role of dectin-1 in the host defense against respiratory bacterial infections, and future studies are warranted to confirm this association.

  9. Sequence and expression variations in 23 genes involved in mitochondrial and non-mitochondrial apoptotic pathways and risk of oral leukoplakia and cancer.

    PubMed

    Datta, Sayantan; Ray, Anindita; Singh, Richa; Mondal, Pinaki; Basu, Analabha; De Sarkar, Navonil; Majumder, Mousumi; Maiti, Guruparasad; Baral, Aradhita; Jha, Ganga Nath; Mukhopadhyay, Indranil; Panda, Chinmay; Chowdhury, Shantanu; Ghosh, Saurabh; Roychoudhury, Susanta; Roy, Bidyut

    2015-11-01

    Oral cancer is usually preceded by pre-cancerous lesion and related to tobacco abuse. Tobacco carcinogens damage DNA and cells harboring such damaged DNA normally undergo apoptotic death, but cancer cells are exceptionally resistant to apoptosis. Here we studied association between sequence and expression variations in apoptotic pathway genes and risk of oral cancer and precancer. Ninety nine tag SNPs in 23 genes, involved in mitochondrial and non-mitochondrial apoptotic pathways, were genotyped in 525 cancer and 253 leukoplakia patients and 538 healthy controls using Illumina Golden Gate assay. Six SNPs (rs1473418 at BCL2; rs1950252 at BCL2L2; rs8190315 at BID; rs511044 at CASP1; rs2227310 at CASP7 and rs13010627 at CASP10) significantly modified risk of oral cancer but SNPs only at BCL2, CASP1and CASP10 modulated risk of leukoplakia. Combination of SNPs showed a steep increase in risk of cancer with increase in "effective" number of risk alleles. In silico analysis of published data set and our unpublished RNAseq data suggest that change in expression of BID and CASP7 may have affected risk of cancer. In conclusion, three SNPs, rs1473418 in BCL2, rs1950252 in BCL2L2 and rs511044 in CASP1, are being implicated for the first time in oral cancer. Since SNPs at BCL2, CASP1 and CASP10 modulated risk of both leukoplakia and cancer, so, they should be studied in more details for possible biomarkers in transition of leukoplakia to cancer. This study also implies importance of mitochondrial apoptotic pathway gene (such as BCL2) in progression of leukoplakia to oral cancer. Copyright © 2015 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  10. Genetic variation in estrogen and progesterone pathway genes and breast cancer risk: an exploration of tumor subtype-specific effects

    PubMed Central

    Nyante, Sarah J.; Gammon, Marilie D.; Kaufman, Jay S.; Bensen, Jeannette T.; Lin, Dan Yu; Barnholtz-Sloan, Jill S.; Hu, Yijuan; He, Qianchuan; Luo, Jingchun; Millikan, Robert C.

    2014-01-01

    Purpose To determine whether associations between estrogen pathway-related single nucleotide polymorphisms (SNPs) and breast cancer risk differ by molecular subtype, we evaluated associations between SNPs in cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1), estrogen receptor (ESR1), 3-beta hydroxysteroid dehydrogenase type I (HSD3B1), 17-beta hydroxysteroid dehydrogenase type II (HSD17B2), progesterone receptor (PGR), and sex hormone-binding globulin (SHBG) and breast cancer risk in a case-control study in North Carolina. Methods Cases (N=1,972) were women 20–74 years old and diagnosed with breast cancer between 1993 and 2001. Population-based controls (N=1,776) were frequency-matched to cases by age and race. 195 SNPs were genotyped and linkage disequilibrium was evaluated using the r2 statistic. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations with breast cancer overall and by molecular subtype were estimated using logistic regression. Monte Carlo methods were used to control for multiple comparisons; two-sided P values <3.3 × 10−4 were statistically significant. Heterogeneity tests comparing the two most common subtypes, luminal A (N=679) and basal-like (N=200), were based on the Wald statistic. Results ESR1 rs6914211 (AA vs. AT+TT, OR=2.24, CI: 1.51, 3.33), ESR1 rs985191 (CC vs. AA, OR=2.11, CI: 1.43, 3.13), and PGR rs1824128 (TT+GT vs. GG, OR=1.33, CI: 1.14, 1.55) were associated with risk after accounting for multiple comparisons. Rs6914211 and rs985191 were in strong linkage disequilibrium among controls (African Americans r2=0.70; whites r2=0.95). There was no evidence of heterogeneity between luminal A and basal-like subtypes, and the three SNPs were also associated with elevated risk of the less common luminal B, HER2+/ER− and unclassified subtypes. Conclusions ESR1 and PGR SNPs were associated with risk, but lack of heterogeneity between subtypes suggests variants in hormone-related genes may play similar roles in

  11. Human Longevity and Variation in GH/IGF-1/Insulin Signaling, DNA Damage Signaling and Repair and Pro/antioxidant Pathway Genes: Cross Sectional and Longitudinal Studies

    PubMed Central

    Soerensen, Mette; Dato, Serena; Tan, Qihua; Thinggaard, Mikael; Kleindorp, Rabea; Beekman, Marian; Jacobsen, Rune; Suchiman, H. Eka D.; de Craen, Anton J.M.; Westendorp, Rudi G.J.; Schreiber, Stefan; Stevnsner, Tinna; Bohr, Vilhelm A.; Slagboom, P. Eline; Nebel, Almut; Vaupel, James W.; Christensen, Kaare; McGue, Matt; Christiansen, Lene

    2012-01-01

    Here we explore association with human longevity of common genetic variation in three major candidate pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by investigating 1273 tagging SNPs in 148 genes composing these pathways. In a case-control study of 1089 oldest-old (age 92–93) and 736 middle-aged Danes we found 1 pro/antioxidant SNP (rs1002149 (GSR)), 5 GH/IGF-1/INS SNPs (rs1207362 (KL), rs2267723 (GHRHR), rs3842755 (INS), rs572169 (GHSR), rs9456497 (IGF2R)) and 5 DNA repair SNPs (rs11571461 (RAD52), rs13251813 (WRN), rs1805329 (RAD23B), rs2953983 (POLB), rs3211994 (NTLH1)) to be associated with longevity after correction for multiple testing. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes we found 2 pro/antioxidant SNPs (rs10047589 (TNXRD1), rs207444 (XDH)), 1 GH/IGF-1/INS SNP (rs26802 (GHRL)) and 3 DNA repair SNPs (rs13320360 (MLH1), rs2509049 (H2AFX) and rs705649 (XRCC5)) to be associated with mortality in late life after correction for multiple testing. When examining the 11 SNPs from the case-control study in the longitudinal data, rs3842755 (INS), rs13251813 (WRN) and rs3211994 (NTHL1) demonstrated the same directions of effect (p<0.05), while rs9456497 (IGF2R) and rs1157146 (RAD52) showed non-significant tendencies, indicative of effects also in late life survival. In addition, rs207444 (XDH) presented the same direction of effect when inspecting the 6 SNPs from the longitudinal study in the case-control data, hence, suggesting an effect also in survival from middle age to old age. No formal replications were observed when investigating the 11 SNPs from the case-control study in 1613 oldest-old (age 95–110) and 1104 middle-aged Germans, although rs11571461 (RAD52) did show a supportive non-significant tendency (OR = 1.162, 95% CI = 0.927–1.457). The same was true for rs10047589 (TNXRD1) (HR = 0.758, 95%CI = 0.543–1.058) when examining the 6 SNPs from the longitudinal

  12. Variations in target gene expression and pathway profiles in the mouse hippocampus following treatment with different effective compounds for ischemia-reperfusion injury.

    PubMed

    Chen, Yinying; Zhou, Caixiu; Yu, Yanan; Liu, Jun; Jing, Zhiwei; Lv, Aiping; Meng, Fanyun; Wang, Zhong; Wang, Yongyan

    2012-08-01

    In order to elucidate the overlapping and diverse pharmacological protective mechanisms of different Chinese medicinal compounds, we investigated the alteration of gene expression and activation of signaling pathways in the mouse hippocampus after treatment of cerebral ischemia-reperfusion injury with various compounds. A microarray including 16,463 genes was used to identify differentially expressed genes among six treatment groups: baicalin (BA), jasminoidin (JA), cholic acid (CA), concha margaritiferausta (CM), sham, and vehicle. The US Food and Drug Administration (FDA) ArrayTrack system and Kyoto Encyclopedia of Genes and Genomes (KEGG) database were used to screen significantly altered genes and pathways (P < 0.05, fold change >1.5). Vehicle treatment alone resulted in alteration of 726 genes (283 upregulated, 443 downregulated) compared to the sham treatment group. BA, JA, and CA treatments, but not CM treatment, were effective in reducing infarct volume compared with vehicle treatment (P < 0.05). Compared with the CM group, a total of 167 (73 upregulated, 94 downregulated), 379 (211 upregulated, 168 downregulated), and 181 (76 upregulated, 105 downregulated) altered genes were found in the BA, JA, and CA groups, respectively. The numbers of overlapping genes between the BA and JA, BA and CA, and JA and CA groups were 28 (16 upregulated, 12 downregulated), 14 (4 upregulated, 10 downregulated), and 31 (8 upregulated, 23 downregulated), respectively. Three overlapping genes were identified among the BA, JA, and CA treatment groups: Il1rap, Gnb5, and Wdr38. Based on KEGG pathway analysis, two, seven, and four pathways were significantly activated in the BA, JA, and CA groups, respectively, when compared to the CM group. The ATP-binding cassette (ABC) transporters general pathway was activated by BA and JA treatment, and the mitogen-activated protein kinase (MAPK) signaling pathway was activated by JA and CA treatment. Alteration of IL-1 and Hspa1a expression

  13. SNP Variation in MicroRNA Biogenesis Pathway Genes as a New Innovation Strategy for Alzheimer Disease Diagnostics: A Study of 10 Candidate Genes in an Understudied Population From the Eastern Mediterranean.

    PubMed

    Görücü Yilmaz, Şenay; Erdal, Mehmet E; Avci Özge, Aynur; Sungur, Mehmet A

    2016-01-01

    Alzheimer disease (AD) is a common complex neurodegenerative disorder accounting for nearly 50% to 70% of dementias worldwide. Yet the current diagnostic options for AD are limited. New diagnostic innovation strategies focusing on novel molecules and pathways are sorely needed. In this connection, microRNAs (miRNAs) are conserved small noncoding RNAs that regulate posttranscriptional gene expression and are vital for neuronal development and its functional sustainability. Conceivably, biological pathways responsible for the biogenesis of miRNAs represent a veritable set of upstream candidate genes that can be potentially associated with the AD pathophysiology. Notably, whereas functional single-nucleotide polymorphisms (SNPs) in miRNA biogenesis pathway genes have been studied in other complex diseases, surprisingly, virtually no such study has been conducted on their relevance in AD. Moreover, novel diagnostics identified in easily accessible peripheral tissues such as the whole blood samples represent the initial entry or gateway points on the biomarker discovery critical path for AD. To the best of our knowledge, we report here the first association study of functional SNPs, as measured by real-time PCR in 10 "upstream" candidate genes critically situated on the miRNA biogenesis pathway, in a large sample of AD patients (N=172) and healthy controls (N=109) in a hitherto understudied world population from the Mersin region of the Eastern Mediterranean. We observed a significant association between 2 candidate genes and AD, TARBP2 rs784567 genotype and AD (χ=6.292, P=0.043), and a trend for RNASEN rs10719 genotype (χ=4.528, P=0.104) and allele (P=0.035). Functional SNP variations in the other 8 candidate genes (DGCR8, XPO5, RAN, DICER1, AGO1, AGO2, GEMIN3, and GEMIN4) did not associate with AD in our sample. Given the putative biological importance of miRNA biogenesis pathways, these emerging data can provide a new foundation to stimulate future debate and

  14. Whole Genome Pathway Analysis Identifies an Association of Cadmium Response Gene Loss with Copy Number Variation in Mutant p53 Bearing Uterine Endometrial Carcinomas

    PubMed Central

    Stupack, Dwayne G

    2016-01-01

    Background Massive chromosomal aberrations are a signature of advanced cancer, although the factors promoting the pervasive incidence of these copy number alterations (CNAs) are poorly understood. Gatekeeper mutations, such as p53, contribute to aneuploidy, yet p53 mutant tumors do not always display CNAs. Uterine Corpus Endometrial Carcinoma (UCEC) offers a unique system to begin to evaluate why some cancers acquire high CNAs while others evolve another route to oncogenesis, since about half of p53 mutant UCEC tumors have a relatively flat CNA landscape and half have 20–90% of their genome altered in copy number. Methods We extracted copy number information from 68 UCEC genomes mutant in p53 by the GISTIC2 algorithm. GO term pathway analysis, via GOrilla, was used to identify suppressed pathways. Genes within these pathways were mapped for focal or wide distribution. Deletion hotspots were evaluated for temporal incidence. Results Multiple pathways contributed to the development of pervasive CNAs, including developmental, metabolic, immunological, cell adhesion and cadmium response pathways. Surprisingly, cadmium response pathway genes are predicted as the earliest loss events within these tumors: in particular, the metallothionein genes involved in heavy metal sequestration. Loss of cadmium response genes were associated with copy number changes and poorer prognosis, contrasting with 'copy number flat' tumors which instead exhibited substantive mutation. Conclusion Metallothioneins are lost early in the development of high CNA endometrial cancer, providing a potential mechanism and biological rationale for increased incidence of endometrial cancer with cadmium exposure. Developmental and metabolic pathways are altered later in tumor progression. PMID:27391266

  15. WNT3A gene polymorphisms are associated with bone mineral density variation in postmenopausal mestizo women of an urban Mexican population: findings of a pathway-based high-density single nucleotide screening.

    PubMed

    Velázquez-Cruz, Rafael; García-Ortiz, Humberto; Castillejos-López, Manuel; Quiterio, Manuel; Valdés-Flores, Margarita; Orozco, Lorena; Villarreal-Molina, Teresa; Salmerón, Jorge

    2014-06-01

    Osteoporosis (OP) is a common skeletal disorder characterized by low bone mineral density (BMD) and is a common health problem in Mexico. To date, few genes affecting BMD variation in the Mexican population have been identified. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) located in genes of the Wnt pathway with BMD variation at various skeletal sites in a cohort of postmenopausal Mexican women. A total of 121 SNPs in or near 15 Wnt signaling pathway genes and 96 ancestry informative markers were genotyped in 425 postmenopausal women using the Illumina GoldenGate microarray SNP genotyping method. BMD was measured by dual-energy X-ray absorptiometry in total hip, femoral neck, Ward's triangle, and lumbar spine. Associations were tested by linear regression for quantitative traits adjusting for possible confounding factors. SNP rs752107 in WNT3A was strongly associated with decreased total hip BMD showing the highest significance under the recessive model (P = 0.00012). This SNP is predicted to disrupt a binding site for microRNA-149. In addition, a polymorphism of the Wnt antagonist DKK2 was associated with BMD in femoral neck under a recessive model (P = 0.009). Several LRP4, LRP5, and LRP6 gene variants showed site-specific associations with BMD. In conclusion, this is the first report associating Wnt pathway gene variants with BMD in the Mexican population.

  16. Genetic Variation in Dopamine Pathways Differentially Associated with Smoking Progression in Adolescence

    ERIC Educational Resources Information Center

    Laucht, Manfred; Becker, Katja; Frank, Josef; Schmidt, Martin H.; Esser, Gunter; Treutlein, Jens; Skowronek, Markus H.; Schumann, Gunter

    2008-01-01

    A study examines whether genetic variation in dopamine pathways differentially associate with smoking progression in adolescence. Results indicate the influence of specific dopamine genes in different stages of smoking progression in adolescents.

  17. Genetic Variation in Dopamine Pathways Differentially Associated with Smoking Progression in Adolescence

    ERIC Educational Resources Information Center

    Laucht, Manfred; Becker, Katja; Frank, Josef; Schmidt, Martin H.; Esser, Gunter; Treutlein, Jens; Skowronek, Markus H.; Schumann, Gunter

    2008-01-01

    A study examines whether genetic variation in dopamine pathways differentially associate with smoking progression in adolescence. Results indicate the influence of specific dopamine genes in different stages of smoking progression in adolescents.

  18. Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium.

    PubMed

    Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B; Behrens, Sabine; Goode, Ellen L; Bolla, Manjeet K; Dennis, Joe; Dunning, Alison M; Easton, Douglas F; Wang, Qin; Benitez, Javier; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Fasching, Peter A; Haeberle, Lothar; Peto, Julian; Dos-Santos-Silva, Isabel; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marmé, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Nielsen, Sune F; Nordestgaard, Børge G; González-Neira, Anna; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Fagerholm, Rainer; Dörk, Thilo; Bogdanova, Natalia V; Mannermaa, Arto; Hartikainen, Jaana M; Van Dijck, Laurien; Smeets, Ann; Flesch-Janys, Dieter; Eilber, Ursula; Radice, Paolo; Peterlongo, Paolo; Couch, Fergus J; Hallberg, Emily; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Schumacher, Fredrick; Simard, Jacques; Goldberg, Mark S; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Beeghly-Fadiel, Alicia; Winqvist, Robert; Grip, Mervi; Andrulis, Irene L; Glendon, Gord; García-Closas, Montserrat; Figueroa, Jonine; Czene, Kamila; Brand, Judith S; Darabi, Hatef; Eriksson, Mikael; Hall, Per; Li, Jingmei; Cox, Angela; Cross, Simon S; Pharoah, Paul D P; Shah, Mitul; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Ademuyiwa, Foluso; Ambrosone, Christine B; Swerdlow, Anthony; Jones, Michael; Chang-Claude, Jenny

    2016-01-01

    Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 × 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10(-3) and 7.0 × 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10(-3), 4.5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.

  19. Pathway level analysis of gene expression using singular value decomposition

    PubMed Central

    Tomfohr, John; Lu, Jun; Kepler, Thomas B

    2005-01-01

    Background A promising direction in the analysis of gene expression focuses on the changes in expression of specific predefined sets of genes that are known in advance to be related (e.g., genes coding for proteins involved in cellular pathways or complexes). Such an analysis can reveal features that are not easily visible from the variations in the individual genes and can lead to a picture of expression that is more biologically transparent and accessible to interpretation. In this article, we present a new method of this kind that operates by quantifying the level of 'activity' of each pathway in different samples. The activity levels, which are derived from singular value decompositions, form the basis for statistical comparisons and other applications. Results We demonstrate our approach using expression data from a study of type 2 diabetes and another of the influence of cigarette smoke on gene expression in airway epithelia. A number of interesting pathways are identified in comparisons between smokers and non-smokers including ones related to nicotine metabolism, mucus production, and glutathione metabolism. A comparison with results from the related approach, 'gene-set enrichment analysis', is also provided. Conclusion Our method offers a flexible basis for identifying differentially expressed pathways from gene expression data. The results of a pathway-based analysis can be complementary to those obtained from one more focused on individual genes. A web program PLAGE (Pathway Level Analysis of Gene Expression) for performing the kinds of analyses described here is accessible at . PMID:16156896

  20. Inter-individual variation in nucleotide excision repair pathway is modulated by non-synonymous polymorphisms in ERCC4 and MBD4 genes.

    PubMed

    Allione, Alessandra; Guarrera, Simonetta; Russo, Alessia; Ricceri, Fulvio; Purohit, Rituraj; Pagnani, Andrea; Rosa, Fabio; Polidoro, Silvia; Voglino, Floriana; Matullo, Giuseppe

    2013-01-01

    Inter-individual differences in DNA repair capacity (DRC) may lead to genome instability and, consequently, modulate individual cancer risk. Among the different DNA repair pathways, nucleotide excision repair (NER) is one of the most versatile, as it can eliminate a wide range of helix-distorting DNA lesions caused by ultraviolet light irradiation and chemical mutagens. We performed a genotype-phenotype correlation study in 122 healthy subjects in order to assess if any associations exist between phenotypic profiles of NER and DNA repair gene single nucleotide polymorphisms (SNPs). Individuals were genotyped for 768 SNPs with a custom Illumina Golden Gate Assay, and peripheral blood mononuclear cells (PBMCs) of the same subjects were tested for a NER comet assay to measure DRC after challenging cells by benzo(a)pyrene diolepoxide (BPDE). We observed a large inter-individual variability of NER capacity, with women showing a statistically significant lower DRC (mean ± SD: 6.68 ± 4.76; p = 0.004) than men (mean ± SD: 8.89 ± 5.20). Moreover, DRC was significantly lower in individuals carrying a variant allele for the ERCC4 rs1800124 non-synonymous SNP (nsSNP) (p = 0.006) and significantly higher in subjects with the variant allele of MBD4 rs2005618 SNP (p = 0.008), in linkage disequilibrium (r(2) = 0.908) with rs10342 nsSNP. Traditional in silico docking approaches on protein-DNA and protein-protein interaction showed that Gly875 variant in ERCC4 (rs1800124) decreases the DNA-protein interaction and that Ser273 and Thr273 variants in MBD4 (rs10342) indicate complete loss of protein-DNA interactions. Our results showed that NER inter-individual capacity can be modulated by cross-talk activity involving nsSNPs in ERCC4 and MBD4 genes, and they suggested to better investigate SNP effect on cancer risk and response to chemo- and radiotherapies.

  1. Identifying Causal Genes and Dysregulated Pathways in Complex Diseases

    PubMed Central

    Kim, Yoo-Ah; Wuchty, Stefan; Przytycka, Teresa M.

    2011-01-01

    In complex diseases, various combinations of genomic perturbations often lead to the same phenotype. On a molecular level, combinations of genomic perturbations are assumed to dys-regulate the same cellular pathways. Such a pathway-centric perspective is fundamental to understanding the mechanisms of complex diseases and the identification of potential drug targets. In order to provide an integrated perspective on complex disease mechanisms, we developed a novel computational method to simultaneously identify causal genes and dys-regulated pathways. First, we identified a representative set of genes that are differentially expressed in cancer compared to non-tumor control cases. Assuming that disease-associated gene expression changes are caused by genomic alterations, we determined potential paths from such genomic causes to target genes through a network of molecular interactions. Applying our method to sets of genomic alterations and gene expression profiles of 158 Glioblastoma multiforme (GBM) patients we uncovered candidate causal genes and causal paths that are potentially responsible for the altered expression of disease genes. We discovered a set of putative causal genes that potentially play a role in the disease. Combining an expression Quantitative Trait Loci (eQTL) analysis with pathway information, our approach allowed us not only to identify potential causal genes but also to find intermediate nodes and pathways mediating the information flow between causal and target genes. Our results indicate that different genomic perturbations indeed dys-regulate the same functional pathways, supporting a pathway-centric perspective of cancer. While copy number alterations and gene expression data of glioblastoma patients provided opportunities to test our approach, our method can be applied to any disease system where genetic variations play a fundamental causal role. PMID:21390271

  2. Autism: many genes, common pathways?

    PubMed

    Geschwind, Daniel H

    2008-10-31

    Autism is a heterogeneous neurodevelopmental syndrome with a complex genetic etiology. It is still not clear whether autism comprises a vast collection of different disorders akin to intellectual disability or a few disorders sharing common aberrant pathways. Unifying principles among cases of autism are likely to be at the level of brain circuitry in addition to molecular pathways.

  3. A chain reaction approach to modelling gene pathways

    PubMed Central

    Cheng, Gary C.; Chen, Dung-Tsa; Chen, James J.; Soong, Seng-jaw; Lamartiniere, Coral; Barnes, Stephen

    2012-01-01

    the nutrient-containing diets regulate gene expression in the estrogen synthesis pathway during puberty; (II) global tests to assess an overall association of this particular pathway with time factor by utilizing generalized linear models to analyze microarray data; and (III) a chain reaction model to simulate the pathway. This is a novel application because we are able to translate the gene pathway into the chemical reactions in which each reaction channel describes gene-gene relationship in the pathway. In the chain reaction model, the implicit scheme is employed to efficiently solve the differential equations. Data analysis results show the proposed model is capable of predicting gene expression changes and demonstrating the effect of nutrient-containing diets on gene expression changes in the pathway. One of the objectives of this study is to explore and develop a numerical approach for simulating the gene expression change so that it can be applied and calibrated when the data of more time slices are available, and thus can be used to interpolate the expression change at a desired time point without conducting expensive experiments for a large amount of time points. Hence, we are not claiming this is either essential or the most efficient way for simulating this problem, rather a mathematical/numerical approach that can model the expression change of a large set of genes of a complex pathway. In addition, we understand the limitation of this experiment and realize that it is still far from being a complete model of predicting nutrient-gene interactions. The reason is that in the present model, the reaction rates were estimated based on available data at two time points; hence, the gene expression change is dependent upon the reaction rates and a linear function of the gene expressions. More data sets containing gene expression at various time slices are needed in order to improve the present model so that a non-linear variation of gene expression changes at

  4. A chain reaction approach to modelling gene pathways.

    PubMed

    Cheng, Gary C; Chen, Dung-Tsa; Chen, James J; Soong, Seng-Jaw; Lamartiniere, Coral; Barnes, Stephen

    2012-08-01

    nutrient-containing diets regulate gene expression in the estrogen synthesis pathway during puberty; (II) global tests to assess an overall association of this particular pathway with time factor by utilizing generalized linear models to analyze microarray data; and (III) a chain reaction model to simulate the pathway. This is a novel application because we are able to translate the gene pathway into the chemical reactions in which each reaction channel describes gene-gene relationship in the pathway. In the chain reaction model, the implicit scheme is employed to efficiently solve the differential equations. Data analysis results show the proposed model is capable of predicting gene expression changes and demonstrating the effect of nutrient-containing diets on gene expression changes in the pathway. One of the objectives of this study is to explore and develop a numerical approach for simulating the gene expression change so that it can be applied and calibrated when the data of more time slices are available, and thus can be used to interpolate the expression change at a desired time point without conducting expensive experiments for a large amount of time points. Hence, we are not claiming this is either essential or the most efficient way for simulating this problem, rather a mathematical/numerical approach that can model the expression change of a large set of genes of a complex pathway. In addition, we understand the limitation of this experiment and realize that it is still far from being a complete model of predicting nutrient-gene interactions. The reason is that in the present model, the reaction rates were estimated based on available data at two time points; hence, the gene expression change is dependent upon the reaction rates and a linear function of the gene expressions. More data sets containing gene expression at various time slices are needed in order to improve the present model so that a non-linear variation of gene expression changes at different time

  5. Genetic variation in the dopamine pathway and smoking cessation.

    PubMed

    David, Sean P; Munafò, Marcus R

    2008-09-01

    Twin and family studies have established that genetic factors account for much of the variation in tobacco dependence. Therefore, identification of genetic variants predictive of successful smoking cessation has implications for the future prospect of personalized smoking cessation therapies. Converging data implicate the dopamine pathway as an important neural substrate for tobacco dependence. Several candidate genes within the dopamine pathway (e.g., DRD2 and COMT) have been reported to be associated with the efficacy of bupropion and nicotine replacement therapy, and others (e.g., SLC6A3 and DRD4) have been reported to be associated with smoking cessation independent of pharmacotherapy. However, few of these candidate genes are present within regions of suggestive or significant linkage or overlap with genome-wide linkage or association studies of tobacco dependence or smoking cessation. Future studies should seek to replicate genome-wide association analyses with individual-level genotyping, and use better-defined smoking cessation phenotypes. Once robust evidence for association is established, which may take several more years, further research into the likely cost-effectiveness, feasibility and acceptability of personalized medicine for smoking cessation will be necessary before it can be translated into practice.

  6. Modeling biochemical pathways in the gene ontology

    SciTech Connect

    Hill, David P.; D’Eustachio, Peter; Berardini, Tanya Z.; Mungall, Christopher J.; Renedo, Nikolai; Blake, Judith A.

    2016-09-01

    The concept of a biological pathway, an ordered sequence of molecular transformations, is used to collect and represent molecular knowledge for a broad span of organismal biology. Representations of biomedical pathways typically are rich but idiosyncratic presentations of organized knowledge about individual pathways. Meanwhile, biomedical ontologies and associated annotation files are powerful tools that organize molecular information in a logically rigorous form to support computational analysis. The Gene Ontology (GO), representing Molecular Functions, Biological Processes and Cellular Components, incorporates many aspects of biological pathways within its ontological representations. Here we present a methodology for extending and refining the classes in the GO for more comprehensive, consistent and integrated representation of pathways, leveraging knowledge embedded in current pathway representations such as those in the Reactome Knowledgebase and MetaCyc. With carbohydrate metabolic pathways as a use case, we discuss how our representation supports the integration of variant pathway classes into a unified ontological structure that can be used for data comparison and analysis.

  7. Polymorphism of starch pathway genes in cassava.

    PubMed

    Vasconcelos, L M; Brito, A C; Carmo, C D; Oliveira, E J

    2016-12-02

    The distribution and frequency of single nucleotide polymorphisms (SNPs) can help to understand changes associated with characteristics of interest. We aimed to evaluate nucleotide diversity in six genes involved in starch biosynthesis in cassava using a panel of 96 unrelated accessions. The genes were sequenced, aligned, and used to obtain values for nucleotide diversity (π), segregating sites (θ), Tajima's D test, and neighbor-joining (NJ) clustering. On average, one SNP per 147 and 171 bp was identified in exon and intron regions, respectively. Thirteen heterozygous loci were found. Three of seven SNPs in the exon region resulted in non-synonymous replacement or four synonymous substitutions. However, no associations were noted between SNPs and root dry-matter content. The parameter π ranged from 0.0001 (granule bound starch synthase I) to 0.0033 (α-amylase), averaging 0.0011, while θ ranged from 0.00014 (starch branching enzyme) to 0.00584 (starch synthase I), averaging 0.002353. The θ diversity value was typically double that of the π. Results of the D test did not suggest any evidence of deviance of neutrality in these genes. Among the evaluated accession, 82/96 were clustered using the NJ method but without a clear separation of the root dry-matter content, root pulp coloration, and classification of the cyanogenic compound content. High variation in genes of the starch biosynthetic pathway can be used to identify associations with the functional properties of starch for the use of polymorphisms for selection purposes.

  8. Genes and (common) pathways underlying drug addiction.

    PubMed

    Li, Chuan-Yun; Mao, Xizeng; Wei, Liping

    2008-01-01

    Drug addiction is a serious worldwide problem with strong genetic and environmental influences. Different technologies have revealed a variety of genes and pathways underlying addiction; however, each individual technology can be biased and incomplete. We integrated 2,343 items of evidence from peer-reviewed publications between 1976 and 2006 linking genes and chromosome regions to addiction by single-gene strategies, microrray, proteomics, or genetic studies. We identified 1,500 human addiction-related genes and developed KARG (http://karg.cbi.pku.edu.cn), the first molecular database for addiction-related genes with extensive annotations and a friendly Web interface. We then performed a meta-analysis of 396 genes that were supported by two or more independent items of evidence to identify 18 molecular pathways that were statistically significantly enriched, covering both upstream signaling events and downstream effects. Five molecular pathways significantly enriched for all four different types of addictive drugs were identified as common pathways which may underlie shared rewarding and addictive actions, including two new ones, GnRH signaling pathway and gap junction. We connected the common pathways into a hypothetical common molecular network for addiction. We observed that fast and slow positive feedback loops were interlinked through CAMKII, which may provide clues to explain some of the irreversible features of addiction.

  9. Genes and (Common) Pathways Underlying Drug Addiction

    PubMed Central

    Li, Chuan-Yun; Mao, Xizeng; Wei, Liping

    2008-01-01

    Drug addiction is a serious worldwide problem with strong genetic and environmental influences. Different technologies have revealed a variety of genes and pathways underlying addiction; however, each individual technology can be biased and incomplete. We integrated 2,343 items of evidence from peer-reviewed publications between 1976 and 2006 linking genes and chromosome regions to addiction by single-gene strategies, microrray, proteomics, or genetic studies. We identified 1,500 human addiction-related genes and developed KARG (http://karg.cbi.pku.edu.cn), the first molecular database for addiction-related genes with extensive annotations and a friendly Web interface. We then performed a meta-analysis of 396 genes that were supported by two or more independent items of evidence to identify 18 molecular pathways that were statistically significantly enriched, covering both upstream signaling events and downstream effects. Five molecular pathways significantly enriched for all four different types of addictive drugs were identified as common pathways which may underlie shared rewarding and addictive actions, including two new ones, GnRH signaling pathway and gap junction. We connected the common pathways into a hypothetical common molecular network for addiction. We observed that fast and slow positive feedback loops were interlinked through CAMKII, which may provide clues to explain some of the irreversible features of addiction. PMID:18179280

  10. Evolutionary Rate Heterogeneity of Primary and Secondary Metabolic Pathway Genes in Arabidopsis thaliana.

    PubMed

    Mukherjee, Dola; Mukherjee, Ashutosh; Ghosh, Tapash Chandra

    2015-11-10

    Primary metabolism is essential to plants for growth and development, and secondary metabolism helps plants to interact with the environment. Many plant metabolites are industrially important. These metabolites are produced by plants through complex metabolic pathways. Lack of knowledge about these pathways is hindering the successful breeding practices for these metabolites. For a better knowledge of the metabolism in plants as a whole, evolutionary rate variation of primary and secondary metabolic pathway genes is a prerequisite. In this study, evolutionary rate variation of primary and secondary metabolic pathway genes has been analyzed in the model plant Arabidopsis thaliana. Primary metabolic pathway genes were found to be more conserved than secondary metabolic pathway genes. Several factors such as gene structure, expression level, tissue specificity, multifunctionality, and domain number are the key factors behind this evolutionary rate variation. This study will help to better understand the evolutionary dynamics of plant metabolism.

  11. Evolutionary Rate Heterogeneity of Primary and Secondary Metabolic Pathway Genes in Arabidopsis thaliana

    PubMed Central

    Mukherjee, Dola; Mukherjee, Ashutosh; Ghosh, Tapash Chandra

    2016-01-01

    Primary metabolism is essential to plants for growth and development, and secondary metabolism helps plants to interact with the environment. Many plant metabolites are industrially important. These metabolites are produced by plants through complex metabolic pathways. Lack of knowledge about these pathways is hindering the successful breeding practices for these metabolites. For a better knowledge of the metabolism in plants as a whole, evolutionary rate variation of primary and secondary metabolic pathway genes is a prerequisite. In this study, evolutionary rate variation of primary and secondary metabolic pathway genes has been analyzed in the model plant Arabidopsis thaliana. Primary metabolic pathway genes were found to be more conserved than secondary metabolic pathway genes. Several factors such as gene structure, expression level, tissue specificity, multifunctionality, and domain number are the key factors behind this evolutionary rate variation. This study will help to better understand the evolutionary dynamics of plant metabolism. PMID:26556590

  12. Natural Genetic Variation Influences Protein Abundances in C. elegans Developmental Signalling Pathways

    PubMed Central

    Singh, Kapil Dev; Roschitzki, Bernd; Snoek, L. Basten; Grossmann, Jonas; Zheng, Xue; Elvin, Mark; Kamkina, Polina; Schrimpf, Sabine P.; Poulin, Gino B.; Kammenga, Jan E.; Hengartner, Michael O.

    2016-01-01

    Complex traits, including common disease-related traits, are affected by many different genes that function in multiple pathways and networks. The apoptosis, MAPK, Notch, and Wnt signalling pathways play important roles in development and disease progression. At the moment we have a poor understanding of how allelic variation affects gene expression in these pathways at the level of translation. Here we report the effect of natural genetic variation on transcript and protein abundance involved in developmental signalling pathways in Caenorhabditis elegans. We used selected reaction monitoring to analyse proteins from the abovementioned four pathways in a set of recombinant inbred lines (RILs) generated from the wild-type strains N2 (Bristol) and CB4856 (Hawaii) to enable quantitative trait locus (QTL) mapping. About half of the cases from the 44 genes tested showed a statistically significant change in protein abundance between various strains, most of these were however very weak (below 1.3-fold change). We detected a distant QTL on the left arm of chromosome II that affected protein abundance of the phosphatidylserine receptor protein PSR-1, and two separate QTLs that influenced embryonic and ionizing radiation-induced apoptosis on chromosome IV. Our results demonstrate that natural variation in C. elegans is sufficient to cause significant changes in signalling pathways both at the gene expression (transcript and protein abundance) and phenotypic levels. PMID:26985669

  13. Pathways-Driven Sparse Regression Identifies Pathways and Genes Associated with High-Density Lipoprotein Cholesterol in Two Asian Cohorts

    PubMed Central

    Silver, Matt; Chen, Peng; Li, Ruoying; Cheng, Ching-Yu; Wong, Tien-Yin; Tai, E-Shyong; Teo, Yik-Ying; Montana, Giovanni

    2013-01-01

    Standard approaches to data analysis in genome-wide association studies (GWAS) ignore any potential functional relationships between gene variants. In contrast gene pathways analysis uses prior information on functional structure within the genome to identify pathways associated with a trait of interest. In a second step, important single nucleotide polymorphisms (SNPs) or genes may be identified within associated pathways. The pathways approach is motivated by the fact that genes do not act alone, but instead have effects that are likely to be mediated through their interaction in gene pathways. Where this is the case, pathways approaches may reveal aspects of a trait's genetic architecture that would otherwise be missed when considering SNPs in isolation. Most pathways methods begin by testing SNPs one at a time, and so fail to capitalise on the potential advantages inherent in a multi-SNP, joint modelling approach. Here, we describe a dual-level, sparse regression model for the simultaneous identification of pathways and genes associated with a quantitative trait. Our method takes account of various factors specific to the joint modelling of pathways with genome-wide data, including widespread correlation between genetic predictors, and the fact that variants may overlap multiple pathways. We use a resampling strategy that exploits finite sample variability to provide robust rankings for pathways and genes. We test our method through simulation, and use it to perform pathways-driven gene selection in a search for pathways and genes associated with variation in serum high-density lipoprotein cholesterol levels in two separate GWAS cohorts of Asian adults. By comparing results from both cohorts we identify a number of candidate pathways including those associated with cardiomyopathy, and T cell receptor and PPAR signalling. Highlighted genes include those associated with the L-type calcium channel, adenylate cyclase, integrin, laminin, MAPK signalling and immune

  14. PathwaysWeb: a gene pathways API with directional interactions, expanded gene ontology, and versioning.

    PubMed

    Melott, James M; Weinstein, John N; Broom, Bradley M

    2016-01-15

    PathwaysWeb is a resource-based, well-documented web system that provides publicly available information on genes, biological pathways, Gene Ontology (GO) terms, gene-gene interaction networks (importantly, with the directionality of interactions) and links to key-related PubMed documents. The PathwaysWeb API simplifies the construction of applications that need to retrieve and interrelate information across multiple, pathway-related data types from a variety of original data sources. PathwaysBrowser is a companion website that enables users to explore the same integrated pathway data. The PathwaysWeb system facilitates reproducible analyses by providing access to all versions of the integrated datasets. Although its GO subsystem includes data for mouse, PathwaysWeb currently focuses on human data. However, pathways for mouse and many other species can be inferred with a high success rate from human pathways. PathwaysWeb can be accessed via the Internet at http://bioinformatics.mdanderson.org/main/PathwaysWeb:Overview. jmmelott@mdanderson.org Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  15. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

    PubMed

    Biankin, Andrew V; Waddell, Nicola; Kassahn, Karin S; Gingras, Marie-Claude; Muthuswamy, Lakshmi B; Johns, Amber L; Miller, David K; Wilson, Peter J; Patch, Ann-Marie; Wu, Jianmin; Chang, David K; Cowley, Mark J; Gardiner, Brooke B; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J; Gill, Anthony J; Pinho, Andreia V; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R Scott; Humphris, Jeremy L; Kaplan, Warren; Jones, Marc D; Colvin, Emily K; Nagrial, Adnan M; Humphrey, Emily S; Chou, Angela; Chin, Venessa T; Chantrill, Lorraine A; Mawson, Amanda; Samra, Jaswinder S; Kench, James G; Lovell, Jessica A; Daly, Roger J; Merrett, Neil D; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M; Fisher, William E; Brunicardi, F Charles; Hodges, Sally E; Reid, Jeffrey G; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R; Dinh, Huyen; Buhay, Christian J; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E; Yung, Christina K; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming-Sound; Shaw, Patricia A; Petersen, Gloria M; Gallinger, Steven; Hruban, Ralph H; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Schulick, Richard D; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A; Mann, Karen M; Jenkins, Nancy A; Perez-Mancera, Pedro A; Adams, David J; Largaespada, David A; Wessels, Lodewyk F A; Rust, Alistair G; Stein, Lincoln D; Tuveson, David A; Copeland, Neal G; Musgrove, Elizabeth A; Scarpa, Aldo; Eshleman, James R; Hudson, Thomas J; Sutherland, Robert L; Wheeler, David A; Pearson, John V; McPherson, John D; Gibbs, Richard A; Grimmond, Sean M

    2012-11-15

    Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

  16. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

    PubMed Central

    Biankin, Andrew V.; Waddell, Nicola; Kassahn, Karin S.; Gingras, Marie-Claude; Muthuswamy, Lakshmi B.; Johns, Amber L.; Miller, David K.; Wilson, Peter J.; Patch, Ann-Marie; Wu, Jianmin; Chang, David K.; Cowley, Mark J.; Gardiner, Brooke B.; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J.; Gill, Anthony J.; Pinho, Andreia V.; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J. Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R. Scott; Humphris, Jeremy L.; Kaplan, Warren; Jones, Marc D.; Colvin, Emily K.; Nagrial, Adnan M.; Humphrey, Emily S.; Chou, Angela; Chin, Venessa T.; Chantrill, Lorraine A.; Mawson, Amanda; Samra, Jaswinder S.; Kench, James G.; Lovell, Jessica A.; Daly, Roger J.; Merrett, Neil D.; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q.; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M.; Fisher, William E.; Brunicardi, F. Charles; Hodges, Sally E.; Reid, Jeffrey G.; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R.; Dinh, Huyen; Buhay, Christian J.; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E.; Yung, Christina K.; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming-Sound; Shaw, Patricia A.; Petersen, Gloria M.; Gallinger, Steven; Hruban, Ralph H.; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Schulick, Richard D.; Wolfgang, Christopher L.; Morgan, Richard A.; Lawlor, Rita T.; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A.; Mann, Karen M.; Jenkins, Nancy A.; Perez-Mancera, Pedro A.; Adams, David J.; Largaespada, David A.; Wessels, Lodewyk F. A.; Rust, Alistair G.; Stein, Lincoln D.; Tuveson, David A.; Copeland, Neal G.; Musgrove, Elizabeth A.; Scarpa, Aldo; Eshleman, James R.; Hudson, Thomas J.; Sutherland, Robert L.; Wheeler, David A.; Pearson, John V.; McPherson, John D.; Gibbs, Richard A.; Grimmond, Sean M.

    2012-01-01

    Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis. PMID:23103869

  17. Modeling biochemical pathways in the gene ontology

    DOE PAGES

    Hill, David P.; D’Eustachio, Peter; Berardini, Tanya Z.; ...

    2016-09-01

    The concept of a biological pathway, an ordered sequence of molecular transformations, is used to collect and represent molecular knowledge for a broad span of organismal biology. Representations of biomedical pathways typically are rich but idiosyncratic presentations of organized knowledge about individual pathways. Meanwhile, biomedical ontologies and associated annotation files are powerful tools that organize molecular information in a logically rigorous form to support computational analysis. The Gene Ontology (GO), representing Molecular Functions, Biological Processes and Cellular Components, incorporates many aspects of biological pathways within its ontological representations. Here we present a methodology for extending and refining the classes inmore » the GO for more comprehensive, consistent and integrated representation of pathways, leveraging knowledge embedded in current pathway representations such as those in the Reactome Knowledgebase and MetaCyc. With carbohydrate metabolic pathways as a use case, we discuss how our representation supports the integration of variant pathway classes into a unified ontological structure that can be used for data comparison and analysis.« less

  18. Modeling biochemical pathways in the gene ontology

    PubMed Central

    Hill, David P.; D’Eustachio, Peter; Berardini, Tanya Z.; Mungall, Christopher J.; Renedo, Nikolai; Blake, Judith A.

    2016-01-01

    The concept of a biological pathway, an ordered sequence of molecular transformations, is used to collect and represent molecular knowledge for a broad span of organismal biology. Representations of biomedical pathways typically are rich but idiosyncratic presentations of organized knowledge about individual pathways. Meanwhile, biomedical ontologies and associated annotation files are powerful tools that organize molecular information in a logically rigorous form to support computational analysis. The Gene Ontology (GO), representing Molecular Functions, Biological Processes and Cellular Components, incorporates many aspects of biological pathways within its ontological representations. Here we present a methodology for extending and refining the classes in the GO for more comprehensive, consistent and integrated representation of pathways, leveraging knowledge embedded in current pathway representations such as those in the Reactome Knowledgebase and MetaCyc. With carbohydrate metabolic pathways as a use case, we discuss how our representation supports the integration of variant pathway classes into a unified ontological structure that can be used for data comparison and analysis. PMID:27589964

  19. Lysoplex: An efficient toolkit to detect DNA sequence variations in the autophagy-lysosomal pathway

    PubMed Central

    Di Fruscio, Giuseppina; Schulz, Angela; De Cegli, Rossella; Savarese, Marco; Mutarelli, Margherita; Parenti, Giancarlo; Banfi, Sandro; Braulke, Thomas; Nigro, Vincenzo; Ballabio, Andrea

    2015-01-01

    The autophagy-lysosomal pathway (ALP) regulates cell homeostasis and plays a crucial role in human diseases, such as lysosomal storage disorders (LSDs) and common neurodegenerative diseases. Therefore, the identification of DNA sequence variations in genes involved in this pathway and their association with human diseases would have a significant impact on health. To this aim, we developed Lysoplex, a targeted next-generation sequencing (NGS) approach, which allowed us to obtain a uniform and accurate coding sequence coverage of a comprehensive set of 891 genes involved in lysosomal, endocytic, and autophagic pathways. Lysoplex was successfully validated on 14 different types of LSDs and then used to analyze 48 mutation-unknown patients with a clinical phenotype of neuronal ceroid lipofuscinosis (NCL), a genetically heterogeneous subtype of LSD. Lysoplex allowed us to identify pathogenic mutations in 67% of patients, most of whom had been unsuccessfully analyzed by several sequencing approaches. In addition, in 3 patients, we found potential disease-causing variants in novel NCL candidate genes. We then compared the variant detection power of Lysoplex with data derived from public whole exome sequencing (WES) efforts. On average, a 50% higher number of validated amino acid changes and truncating variations per gene were identified. Overall, we identified 61 truncating sequence variations and 488 missense variations with a high probability to cause loss of function in a total of 316 genes. Interestingly, some loss-of-function variations of genes involved in the ALP pathway were found in homozygosity in the normal population, suggesting that their role is not essential. Thus, Lysoplex provided a comprehensive catalog of sequence variants in ALP genes and allows the assessment of their relevance in cell biology as well as their contribution to human disease. PMID:26075876

  20. New Genes Originated via Multiple Recombinational Pathways in the β-Globin Gene Family of Rodents

    PubMed Central

    Hoffmann, Federico G.; Opazo, Juan C.; Storz, Jay F.

    2008-01-01

    Species differences in the size or membership composition of multigene families can be attributed to lineage-specific additions of new genes via duplication, losses of genes via deletion or inactivation, and the creation of chimeric genes via domain shuffling or gene fusion. In principle, it should be possible to infer the recombinational pathways responsible for each of these different types of genomic change by conducting detailed comparative analyses of genomic sequence data. Here, we report an attempt to unravel the complex evolutionary history of the β-globin gene family in a taxonomically diverse set of rodent species. The main objectives were: 1) to characterize the genomic structure of the β-globin gene cluster of rodents; 2) to assign orthologous and paralogous relationships among duplicate copies of β-like globin genes; and 3) to infer the specific recombinational pathways responsible for gene duplications, gene deletions, and the creation of chimeric fusion genes. Results of our comparative genomic analyses revealed that variation in gene family size among rodent species is mainly attributable to the differential gain and loss of later expressed β-globin genes via unequal crossing-over. However, two distinct recombinational mechanisms were implicated in the creation of chimeric fusion genes. In muroid rodents, a chimeric γ/ε fusion gene was created by unequal crossing-over between the embryonic ε- and γ-globin genes. Interestingly, this γ/ε fusion gene was generated in the same fashion as the “anti-Lepore” 5′-δ-(β/δ)-β-3′ duplication mutant in humans (the reciprocal exchange product of the pathological hemoglobin Lepore deletion mutant). By contrast, in the house mouse, Mus musculus, a chimeric β/δ fusion pseudogene was created by a β-globin → δ-globin gene conversion event. Although the γ/ε and β/δ fusion genes share a similar chimeric gene structure, they originated via completely different recombinational pathways. PMID

  1. Gene Transposition Causing Natural Variation for Growth in Arabidopsis thaliana

    PubMed Central

    Vlad, Daniela; Rappaport, Fabrice; Simon, Matthieu; Loudet, Olivier

    2010-01-01

    A major challenge in biology is to identify molecular polymorphisms responsible for variation in complex traits of evolutionary and agricultural interest. Using the advantages of Arabidopsis thaliana as a model species, we sought to identify new genes and genetic mechanisms underlying natural variation for shoot growth using quantitative genetic strategies. More quantitative trait loci (QTL) still need be resolved to draw a general picture as to how and where in the pathways adaptation is shaping natural variation and the type of molecular variation involved. Phenotypic variation for shoot growth in the Bur-0 × Col-0 recombinant inbred line set was decomposed into several QTLs. Nearly-isogenic lines generated from the residual heterozygosity segregating among lines revealed an even more complex picture, with major variation controlled by opposite linked loci and masked by the segregation bias due to the defective phenotype of SG3 (Shoot Growth-3), as well as epistasis with SG3i (SG3-interactor). Using principally a fine-mapping strategy, we have identified the underlying gene causing phenotypic variation at SG3: At4g30720 codes for a new chloroplast-located protein essential to ensure a correct electron flow through the photosynthetic chain and, hence, photosynthesis efficiency and normal growth. The SG3/SG3i interaction is the result of a structural polymorphism originating from the duplication of the gene followed by divergent paralogue's loss between parental accessions. Species-wide, our results illustrate the very dynamic rate of duplication/transposition, even over short periods of time, resulting in several divergent—but still functional—combinations of alleles fixed in different backgrounds. In predominantly selfing species like Arabidopsis, this variation remains hidden in wild populations but is potentially revealed when divergent individuals outcross. This work highlights the need for improved tools and algorithms to resolve structural variation

  2. Large Variations in Bacterial Ribosomal RNA Genes

    PubMed Central

    Lim, Kyungtaek; Furuta, Yoshikazu; Kobayashi, Ichizo

    2012-01-01

    Ribosomal RNA (rRNA) genes, essential to all forms of life, have been viewed as highly conserved and evolutionarily stable, partly because very little is known about their natural variations. Here, we explored large-scale variations of rRNA genes through bioinformatic analyses of available complete bacterial genomic sequences with an emphasis on formation mechanisms and biological significance. Interestingly, we found bacterial genomes in which no 16S rRNA genes harbor the conserved core of the anti–Shine-Dalgarno sequence (5′-CCTCC-3′). This loss was accompanied by elimination of Shine-Dalgarno–like sequences upstream of their protein-coding genes. Those genomes belong to 1 or 2 of the following categories: primary symbionts, hemotropic Mycoplasma, and Flavobacteria. We also found many rearranged rRNA genes and reconstructed their history. Conjecturing the underlying mechanisms, such as inversion, partial duplication, transposon insertion, deletion, and substitution, we were able to infer their biological significance, such as co-orientation of rRNA transcription and chromosomal replication, lateral transfer of rRNA gene segments, and spread of rRNA genes with an apparent structural defect through gene conversion. These results open the way to understanding dynamic evolutionary changes of rRNA genes and the translational machinery. PMID:22446745

  3. Genomic variations of the mevalonate pathway in porokeratosis

    PubMed Central

    Zhang, Zhenghua; Li, Caihua; Wu, Fei; Ma, Ruixiao; Luan, Jing; Yang, Feng; Liu, Weida; Wang, Li; Zhang, Shoumin; Liu, Yan; Gu, Jun; Hua, Wenlian; Fan, Min; Peng, Hua; Meng, Xuemei; Song, Ningjing; Bi, Xinling; Gu, Chaoying; Zhang, Zhen; Huang, Qiong; Chen, Lianjun; Xiang, Leihong; Xu, Jinhua; Zheng, Zhizhong; Jiang, Zhengwen

    2015-01-01

    Porokeratosis (PK) is a heterogeneous group of keratinization disorders. No causal genes except MVK have been identified, even though the disease was linked to several genomic loci. Here, we performed massively parallel sequencing and exonic CNV screening of 12 isoprenoid genes in 134 index PK patients (61 familial and 73 sporadic) and identified causal mutations in three novel genes (PMVK, MVD, and FDPS) in addition to MVK in the mevalonate pathway. Allelic expression imbalance (AEI) assays were performed in 13 lesional tissues. At least one mutation in one of the four genes in the mevalonate pathway was found in 60 (98%) familial and 53 (73%) sporadic patients, which suggests that isoprenoid biosynthesis via the mevalonate pathway may play a role in the pathogenesis of PK. Significantly reduced expression of the wild allele was common in lesional tissues due to gene conversion or some other unknown mechanism. A G-to-A RNA editing was observed in one lesional tissue without AEI. In addition, we observed correlations between the mutations in the four mevalonate pathway genes and clinical manifestations in the PK patients, which might support a new and simplified classification of PK under the guidance of genetic testing. DOI: http://dx.doi.org/10.7554/eLife.06322.001 PMID:26202976

  4. Genomic variations of the mevalonate pathway in porokeratosis.

    PubMed

    Zhang, Zhenghua; Li, Caihua; Wu, Fei; Ma, Ruixiao; Luan, Jing; Yang, Feng; Liu, Weida; Wang, Li; Zhang, Shoumin; Liu, Yan; Gu, Jun; Hua, Wenlian; Fan, Min; Peng, Hua; Meng, Xuemei; Song, Ningjing; Bi, Xinling; Gu, Chaoying; Zhang, Zhen; Huang, Qiong; Chen, Lianjun; Xiang, Leihong; Xu, Jinhua; Zheng, Zhizhong; Jiang, Zhengwen

    2015-07-23

    Porokeratosis (PK) is a heterogeneous group of keratinization disorders. No causal genes except MVK have been identified, even though the disease was linked to several genomic loci. Here, we performed massively parallel sequencing and exonic CNV screening of 12 isoprenoid genes in 134 index PK patients (61 familial and 73 sporadic) and identified causal mutations in three novel genes (PMVK, MVD, and FDPS) in addition to MVK in the mevalonate pathway. Allelic expression imbalance (AEI) assays were performed in 13 lesional tissues. At least one mutation in one of the four genes in the mevalonate pathway was found in 60 (98%) familial and 53 (73%) sporadic patients, which suggests that isoprenoid biosynthesis via the mevalonate pathway may play a role in the pathogenesis of PK. Significantly reduced expression of the wild allele was common in lesional tissues due to gene conversion or some other unknown mechanism. A G-to-A RNA editing was observed in one lesional tissue without AEI. In addition, we observed correlations between the mutations in the four mevalonate pathway genes and clinical manifestations in the PK patients, which might support a new and simplified classification of PK under the guidance of genetic testing.

  5. Population Genetics of Anopheles coluzzii Immune Pathways and Genes

    PubMed Central

    Rottschaefer, Susan M.; Crawford, Jacob E.; Riehle, Michelle M.; Guelbeogo, Wamdaogo M.; Gneme, Awa; Sagnon, N’Fale; Vernick, Kenneth D.; Lazzaro, Brian P.

    2014-01-01

    Natural selection is expected to drive adaptive evolution in genes involved in host–pathogen interactions. In this study, we use molecular population genetic analyses to understand how natural selection operates on the immune system of Anopheles coluzzii (formerly A. gambiae “M form”). We analyzed patterns of intraspecific and interspecific genetic variation in 20 immune-related genes and 17 nonimmune genes from a wild population of A. coluzzii and asked if patterns of genetic variation in the immune genes are consistent with pathogen-driven selection shaping the evolution of defense. We found evidence of a balanced polymorphism in CTLMA2, which encodes a C-type lectin involved in regulation of the melanization response. The two CTLMA2 haplotypes, which are distinguished by fixed amino acid differences near the predicted peptide cleavage site, are also segregating in the sister species A. gambiae (“S form”) and A. arabiensis. Comparison of the two haplotypes between species indicates that they were not shared among the species through introgression, but rather that they arose before the species divergence and have been adaptively maintained as a balanced polymorphism in all three species. We additionally found that STAT-B, a retroduplicate of STAT-A, shows strong evidence of adaptive evolution that is consistent with neofunctionalization after duplication. In contrast to the striking patterns of adaptive evolution observed in these Anopheles-specific immune genes, we found no evidence of adaptive evolution in the Toll and Imd innate immune pathways that are orthologously conserved throughout insects. Genes encoding the Imd pathway exhibit high rates of amino acid divergence between Anopheles species but also display elevated amino acid diversity that is consistent with relaxed purifying selection. These results indicate that adaptive coevolution between A. coluzzii and its pathogens is more likely to involve novel or lineage-specific molecular mechanisms

  6. Variation in the ovine PRKAG3 gene.

    PubMed

    Yang, Guo; Zhou, Huitong; Wang, Ruoyu; Hickford, Jon

    2015-08-10

    The 5'AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that controls cellular energy homeostasis in response to environmental or nutritional stress. The PRKAG3 gene (PRKAG3) encodes the γ3 subunit of the AMPK. Variation in this gene has been found to be associated with meat quality traits in pigs. In this study, we used polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) to investigate variation in exon 3 and exons 4-6 of ovine PRKAG3. In 160 New Zealand Suffolk sheep, two variant sequences (named a and b) were identified in the exon 3 region of the gene and three variant sequences (named A, B and C) were identified in the exon 4-6 region of the gene, respectively. A total of three nucleotide substitutions were revealed and these were located in intron 4, exon 4 and intron 5, respectively. The nucleotide substitution identified in the exon 4 (g.2656 C>T) could nominally lead to an amino acid substitution of tryptophan to arginine at position 230 (R230W) in ovine PRKAG3. In comparison with the PRKAG3 amino acid sequences in other species, this R230W substitution appeared to occur only in sheep. This is the first report of genetic variation in ovine PRKAG3, and the variation found in this study could be functionally important for AMPK activity, which in turn may affect meat quality traits in sheep. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Strain-specific variation in a soilborne phytopathogenic fungus for the expression of genes involved in pH signal transduction pathway, pathogenesis and saprophytic survival in response to environmental pH changes.

    PubMed

    Daval, Stéphanie; Lebreton, Lionel; Gracianne, Cécile; Guillerm-Erckelboudt, Anne-Yvonne; Boutin, Morgane; Marchi, Muriel; Gazengel, Kévin; Sarniguet, Alain

    2013-12-01

    The soilborne fungus Gaeumannomyces graminis var. tritici (Ggt) causes take-all, a wheat root disease. In an original strain-specific way, a previous study indicates that inside the Ggt species, some strains grow preferentially at acidic pH and other strains at neutral/alkaline pH. The most important mechanism for a fungal response to the environmental pH is the Pal pathway which integrates the products of the six pal genes and the transcription factor PacC. To evaluate whether the Ggt strain-specific growth in function of the ambient pH is mediated via the Pal pathway, a transcriptional study of the genes encoding this pathway was carried out. This study provided the first evidence that the pH signalling pathway similar to those described in other fungi operated in Ggt. The pacC gene was induced at neutral pH whatever the strain. In an original way, the expression of Ggt genes coding for the different Pal proteins depended on the strain and on the ambient pH. In the strain growing better at acidic pH, few pal genes were pH-regulated, and some were overexpressed at neutral pH when regulated. In the strain growing better at neutral pH, underexpression of most of the pal genes at neutral pH occurred. The strains displayed higher gene expression in the ambient pH that unfavoured their growth as if it was a compensation system. All pH taken together, a globally weaker Pal transcript level occurred in the strains that were less sensitive to acidic pH, and on the contrary, the strain growing better on neutral pH showed higher Pal mRNA levels. The expression of genes involved in pathogenesis and saprophytic growth was also regulated by the ambient pH and the strain: each gene displayed a specific pH-regulation that was similar between strains. But all pH taken together, the global transcript levels of four out of six genes were higher in the strain growing better on neutral pH. Altogether, for the first time, the results show that inside a species, conditions affecting

  8. Genetic variation in the vitamin D pathway CYP2R1 gene predicts sustained HBeAg seroconversion in chronic hepatitis B patients treated with pegylated interferon: A multicenter study

    PubMed Central

    Thanapirom, Kessarin; Suksawatamnuay, Sirinporn; Sukeepaisarnjareon, Wattana; Tanwandee, Tawesak; Charatcharoenwitthaya, Phunchai; Thongsawat, Satawat; Leerapun, Apinya; Piratvisuth, Teerha; Boonsirichan, Rattana; Bunchorntavakul, Chalermrat; Pattanasirigool, Chaowalit; Pornthisarn, Bubpha; Tantipanichtheerakul, Supot; Sripariwuth, Ekawee; Jeamsripong, Woramon; Sanpajit, Teeranan; Poovorawan, Yong; Komolmit, Piyawat

    2017-01-01

    Evidence of a role of vitamin D in the immune system is increasing. Low serum vitamin D is associated with increased hepatitis B virus replication. Genome-wide association study (GWAS) data has revealed a number of the single nucleotide polymorphisms (SNPs) within the vitamin D synthetic pathway that affect vitamin D functions. We aimed to determine the association between SNPs in the vitamin D gene cascade and response to pegylated interferon (PegIFN) therapy in hepatitis B e-antigen (HBeAg)-positive patients. One hundred and eleven patients treated for 48 weeks with PegIFN-alfa 2a at 13 hospitals were retrospectively evaluated. Thirteen SNPs derived from vitamin D cascade-related genes, including DHCR7 (rs12785878), CYP27B1 (rs10877012), CYP2R1 (rs2060793, rs12794714), GC (rs4588, rs7041, rs222020, rs2282679), and VDR (FokI, BsmI, Tru9I, ApaI, TaqI), were genotyped. Thirty-one patients (27.9%) seroconverted to HBeAg after 24 weeks of treatment. Multivariate analysis found pretreatment qHBsAg <10,000 IU/mL (OR = 7.73, 95% CI: 2.36–25.31, P = 0.001), CYP2R1 rs12794714 TT genotype (OR = 4.16, 95% CI: 1.07–16.25, P = 0.04), and baseline ALT >2 times the upper limit of normal (OR = 3.83, 95% CI: 1.31–11.22, P = 0.014) predicted sustained HBeAg seroconversion after completion of PegIFN treatment. HBV DNA during study period tended to be lower with the rs12794714 CYP2R1 TT than the non-TT genotype. The rs12794714 CYP2R1 polymorphism may be a useful pretreatment factor predictive of sustained HBeAg seroconversion after PegIFN therapy. This study provides evidence that not only vitamin D level but also genetic variation of CYP2R1 in the vitamin D cascade influences host immune response in chronic HBV infection. PMID:28296915

  9. Pathway network inference from gene expression data

    PubMed Central

    2014-01-01

    Background The development of high-throughput omics technologies enabled genome-wide measurements of the activity of cellular elements and provides the analytical resources for the progress of the Systems Biology discipline. Analysis and interpretation of gene expression data has evolved from the gene to the pathway and interaction level, i.e. from the detection of differentially expressed genes, to the establishment of gene interaction networks and the identification of enriched functional categories. Still, the understanding of biological systems requires a further level of analysis that addresses the characterization of the interaction between functional modules. Results We present a novel computational methodology to study the functional interconnections among the molecular elements of a biological system. The PANA approach uses high-throughput genomics measurements and a functional annotation scheme to extract an activity profile from each functional block -or pathway- followed by machine-learning methods to infer the relationships between these functional profiles. The result is a global, interconnected network of pathways that represents the functional cross-talk within the molecular system. We have applied this approach to describe the functional transcriptional connections during the yeast cell cycle and to identify pathways that change their connectivity in a disease condition using an Alzheimer example. Conclusions PANA is a useful tool to deepen in our understanding of the functional interdependences that operate within complex biological systems. We show the approach is algorithmically consistent and the inferred network is well supported by the available functional data. The method allows the dissection of the molecular basis of the functional connections and we describe the different regulatory mechanisms that explain the network's topology obtained for the yeast cell cycle data. PMID:25032889

  10. Pathway network inference from gene expression data.

    PubMed

    Ponzoni, Ignacio; Nueda, María; Tarazona, Sonia; Götz, Stefan; Montaner, David; Dussaut, Julieta; Dopazo, Joaquín; Conesa, Ana

    2014-01-01

    The development of high-throughput omics technologies enabled genome-wide measurements of the activity of cellular elements and provides the analytical resources for the progress of the Systems Biology discipline. Analysis and interpretation of gene expression data has evolved from the gene to the pathway and interaction level, i.e. from the detection of differentially expressed genes, to the establishment of gene interaction networks and the identification of enriched functional categories. Still, the understanding of biological systems requires a further level of analysis that addresses the characterization of the interaction between functional modules. We present a novel computational methodology to study the functional interconnections among the molecular elements of a biological system. The PANA approach uses high-throughput genomics measurements and a functional annotation scheme to extract an activity profile from each functional block -or pathway- followed by machine-learning methods to infer the relationships between these functional profiles. The result is a global, interconnected network of pathways that represents the functional cross-talk within the molecular system. We have applied this approach to describe the functional transcriptional connections during the yeast cell cycle and to identify pathways that change their connectivity in a disease condition using an Alzheimer example. PANA is a useful tool to deepen in our understanding of the functional interdependences that operate within complex biological systems. We show the approach is algorithmically consistent and the inferred network is well supported by the available functional data. The method allows the dissection of the molecular basis of the functional connections and we describe the different regulatory mechanisms that explain the network's topology obtained for the yeast cell cycle data.

  11. Amelogenesis Imperfecta; Genes, Proteins, and Pathways

    PubMed Central

    Smith, Claire E. L.; Poulter, James A.; Antanaviciute, Agne; Kirkham, Jennifer; Brookes, Steven J.; Inglehearn, Chris F.; Mighell, Alan J.

    2017-01-01

    Amelogenesis imperfecta (AI) is the name given to a heterogeneous group of conditions characterized by inherited developmental enamel defects. AI enamel is abnormally thin, soft, fragile, pitted and/or badly discolored, with poor function and aesthetics, causing patients problems such as early tooth loss, severe embarrassment, eating difficulties, and pain. It was first described separately from diseases of dentine nearly 80 years ago, but the underlying genetic and mechanistic basis of the condition is only now coming to light. Mutations in the gene AMELX, encoding an extracellular matrix protein secreted by ameloblasts during enamel formation, were first identified as a cause of AI in 1991. Since then, mutations in at least eighteen genes have been shown to cause AI presenting in isolation of other health problems, with many more implicated in syndromic AI. Some of the encoded proteins have well documented roles in amelogenesis, acting as enamel matrix proteins or the proteases that degrade them, cell adhesion molecules or regulators of calcium homeostasis. However, for others, function is less clear and further research is needed to understand the pathways and processes essential for the development of healthy enamel. Here, we review the genes and mutations underlying AI presenting in isolation of other health problems, the proteins they encode and knowledge of their roles in amelogenesis, combining evidence from human phenotypes, inheritance patterns, mouse models, and in vitro studies. An LOVD resource (http://dna2.leeds.ac.uk/LOVD/) containing all published gene mutations for AI presenting in isolation of other health problems is described. We use this resource to identify trends in the genes and mutations reported to cause AI in the 270 families for which molecular diagnoses have been reported by 23rd May 2017. Finally we discuss the potential value of the translation of AI genetics to clinical care with improved patient pathways and speculate on the

  12. Variation and constraint in Hox gene evolution

    PubMed Central

    Heffer, Alison; Xiang, Jie; Pick, Leslie

    2013-01-01

    Despite enormous body plan variation, genes regulating embryonic development are highly conserved. Here, we probe the mechanisms that predispose ancient regulatory genes to reutilization and diversification rather than evolutionary loss. The Hox gene fushi tarazu (ftz) arose as a homeotic gene but functions as a pair-rule segmentation gene in Drosophila. ftz shows extensive variation in expression and protein coding regions but has managed to elude loss from arthropod genomes. We asked what properties prevent this loss by testing the importance of different protein motifs and partners in the developing CNS, where ftz expression is conserved. Drosophila Ftz proteins with mutated protein motifs were expressed under the control of a neurogenic-specific ftz cis-regulatory element (CRE) in a ftz mutant background rescued for segmentation defects. Ftz CNS function did not require the variable motifs that mediate differential cofactor interactions involved in homeosis or segmentation, which vary in arthropods. Rather, CNS function did require the shared DNA-binding homeodomain, which plays less of a role in Ftz segmentation activity. The Antennapedia homeodomain substituted for Ftz homeodomain function in the Drosophila CNS, but full-length Antennapedia did not rescue CNS defects. These results suggest that a core CNS function retains ftz in arthropod genomes. Acquisition of a neurogenic CRE led to ftz expression in unique CNS cells, differentiating its role from neighboring Hox genes, rendering it nonredundant. The inherent flexibility of modular CREs and protein domains allows for stepwise acquisition of new functions, explaining broad retention of regulatory genes during animal evolution. PMID:23341600

  13. Vitamin D Metabolic Pathway Genes and Pancreatic Cancer Risk

    PubMed Central

    Arem, Hannah; Yu, Kai; Xiong, Xiaoqin; Moy, Kristin; Freedman, Neal D.; Mayne, Susan T.; Albanes, Demetrius; Arslan, Alan A.; Austin, Melissa; Bamlet, William R.; Beane-Freeman, Laura; Bracci, Paige; Canzian, Federico; Cotterchio, Michelle; Duell, Eric J.; Gallinger, Steve; Giles, Graham G.; Goggins, Michael; Goodman, Phyllis J.; Hartge, Patricia; Hassan, Manal; Helzlsouer, Kathy; Henderson, Brian; Holly, Elizabeth A.; Hoover, Robert; Jacobs, Eric J.; Kamineni, Aruna; Klein, Alison; Klein, Eric; Kolonel, Laurence N.; Li, Donghui; Malats, Núria; Männistö, Satu; McCullough, Marjorie L.; Olson, Sara H.; Orlow, Irene; Peters, Ulrike; Petersen, Gloria M.; Porta, Miquel; Severi, Gianluca; Shu, Xiao-Ou; Visvanathan, Kala; White, Emily; Yu, Herbert; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Tobias, Geoffrey S.; Maeder, Dennis; Brotzman, Michelle; Risch, Harvey; Sampson, Joshua N.; Stolzenberg-Solomon, Rachael Z.

    2015-01-01

    Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I-III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (≤50, >50 nmol/L) for the most significant SNPs using a subset of cohort cases (n = 713) and controls (n = 878). The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830). Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p<0.05. SNPs near the VDR (rs2239186), LRP2 (rs4668123), CYP24A1 (rs2762932), GC (rs2282679), and CUBN (rs1810205) genes were the top SNPs associated with pancreatic cancer (p-values 0.008–0.037), but none were statistically significant after adjusting for multiple comparisons. Associations between these SNPs and pancreatic cancer were not modified by circulating concentrations of vitamin D. These findings do not support an association between vitamin D-related genes and pancreatic cancer risk. Future research should explore other pathways through which vitamin D status might be associated with pancreatic cancer risk. PMID:25799011

  14. Pathway-driven discovery of epilepsy genes

    PubMed Central

    Noebels, Jeffrey

    2016-01-01

    Epilepsy genes deliver critical insights into the molecular control of brain synchronization and are revolutionizing our understanding and treatment of the disease. The epilepsy-associated genome is rapidly expanding, and two powerful complementary approaches, isolation of de novo exome variants in patients and targeted mutagenesis in model systems, account for the steep increase. In sheer number, the tally of genes linked to seizures will likely match that of cancer and exceed it in biological diversity. The proteins act within most intracellular compartments and span the molecular determinants of firing and wiring in the developing brain. Every facet of neurotransmission, from dendritic spine to exocytotic machinery, is in play, and defects of synaptic inhibition are over-represented. The contributions of somatic mutations and noncoding microRNAs are also being explored. The functional spectrum of established epilepsy genes and the arrival of rapid, precise technologies for genome editing now provide a robust scaffold to prioritize hypothesis-driven discovery and further populate this genetic proto-map. Although each gene identified offers translational potential to stratify patient care, the complexity of individual variation and covert actions of genetic modifiers may confound single-gene solutions for the clinical disorder. In vivo genetic deconstruction of epileptic networks, ex vivo validation of variant profiles in patient-derived induced pluripotent stem cells, in silico variant modeling and modifier gene discovery, now in their earliest stages, will help clarify individual patterns. Because seizures stand at the crossroads of all neuronal synchronization disorders in the developing and aging brain, the neurobiological analysis of epilepsy-associated genes provides an extraordinary gateway to new insights into higher cortical function. PMID:25710836

  15. No evidence that genetic variation in the myeloid-derived suppressor cell pathway influences ovarian cancer survival

    PubMed Central

    Sucheston-Campbell, Lara E.; Cannioto, Rikki; Clay, Alyssa I.; Etter, John Lewis; Eng, Kevin H.; Liu, Song; Battaglia, Sebastiano; Hu, Qiang; Szender, J. Brian; Minlikeeva, Albina; Joseph, Janine M.; Mayor, Paul; Abrams, Scott I.; Segal, Brahm H.; Wallace, Paul K.; Soh, Kah Teong; Zsiros, Emese; Anton-Culver, Hoda; Bandera, Elisa V.; Beckmann, Matthias W.; Berchuck, Andrew; Bjorge, Line; Bruegl, Amanda; Campbell, Ian; Campbell, Shawn Patrice; Chenevix-Trench, Georgia; Cramer, Daniel W.; Dansonka-Mieszkowska, Agnieszka; Dao, Fanny; Diergaarde, Brenda; Doerk, Thilo; Doherty, Jennifer A.; du Bois, Andreas; Eccles, Diana; Engelholm, Svend Aage; Fasching, Peter A.; Gayther, Simon; Gentry-Maharaj, Aleksandra; Glasspool, Rosalind M.; Goodman, Marc T.; Gronwald, Jacek; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hillemmanns, Peter; Høgdall, Claus; Høgdall, Estrid; Huzarski, Tomasz; Jensen, Allan; Johnatty, Sharon E.; Jung, Audrey; Karlan, Beth Y.; Klapdor, Reudiger; Kluz, Tomasz; Konopka, Bożena; Kjær, Susanne Krüger; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lester, Jenny; Lubiński, Jan; Levine, Douglas A.; Lundvall, Lene; McGuire, Valerie; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Ness, Roberta; Orsulic, Sandra; Paul, Jim; Pearce, Celeste Leigh; Pejovic, Tanja; Pharoah, Paul; Ramus, Susan J.; Rothstein, Joseph; Rossing, Mary Anne; Rübner, Matthias; Schildkraut, Joellen M.; Schmalfeldt, Barbara; Schwaab, Ira; Siddiqui, Nadeem; Sieh, Weiva; Sobiczewski, Piotr; Song, Honglin; Terry, Kathryn L.; Van Nieuwenhuysen, Els; Vanderstichele, Adriaan; Vergote, Ignace; Walsh, Christine; Webb, Penny; Wentzensen, Nicolas; Whittemore, Alice; Wu, Anna H.; Ziogas, Argyrios; Odunsi, Kunle; Chang-Claude, Jenny; Goode, Ellen L.; Moysich, Kirsten B.

    2017-01-01

    Background The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immune suppressive/pro-tumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be one prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses. Methods We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association study (VEGAS) and the Admixture Likelihood method (AML), were used to test gene and pathway associations with survival. Results We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (p<3.5 × 10−5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival. Conclusions In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes. Impact Common inherited variation in genes relevant to MDSCs were not associated with survival in women diagnosed with invasive EOC. PMID:27677730

  16. No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival.

    PubMed

    Sucheston-Campbell, Lara E; Cannioto, Rikki; Clay, Alyssa I; Etter, John Lewis; Eng, Kevin H; Liu, Song; Battaglia, Sebastiano; Hu, Qiang; Szender, J Brian; Minlikeeva, Albina; Joseph, Janine M; Mayor, Paul; Abrams, Scott I; Segal, Brahm H; Wallace, Paul K; Soh, Kah Teong; Zsiros, Emese; Anton-Culver, Hoda; Bandera, Elisa V; Beckmann, Matthias W; Berchuck, Andrew; Bjorge, Line; Bruegl, Amanda; Campbell, Ian G; Campbell, Shawn Patrice; Chenevix-Trench, Georgia; Cramer, Daniel W; Dansonka-Mieszkowska, Agnieszka; Dao, Fanny; Diergaarde, Brenda; Doerk, Thilo; Doherty, Jennifer A; du Bois, Andreas; Eccles, Diana; Engelholm, Svend Aage; Fasching, Peter A; Gayther, Simon A; Gentry-Maharaj, Aleksandra; Glasspool, Rosalind M; Goodman, Marc T; Gronwald, Jacek; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hillemmanns, Peter; Høgdall, Claus; Høgdall, Estrid V S; Huzarski, Tomasz; Jensen, Allan; Johnatty, Sharon E; Jung, Audrey; Karlan, Beth Y; Klapdor, Reudiger; Kluz, Tomasz; Konopka, Bożena; Kjær, Susanne Krüger; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lester, Jenny; Lubiński, Jan; Levine, Douglas A; Lundvall, Lene; McGuire, Valerie; McNeish, Iain A; Menon, Usha; Modugno, Francesmary; Ness, Roberta B; Orsulic, Sandra; Paul, James; Pearce, Celeste Leigh; Pejovic, Tanja; Pharoah, Paul; Ramus, Susan J; Rothstein, Joseph; Rossing, Mary Anne; Rübner, Matthias; Schildkraut, Joellen M; Schmalfeldt, Barbara; Schwaab, Ira; Siddiqui, Nadeem; Sieh, Weiva; Sobiczewski, Piotr; Song, Honglin; Terry, Kathryn L; Van Nieuwenhuysen, Els; Vanderstichele, Adriaan; Vergote, Ignace; Walsh, Christine S; Webb, Penelope M; Wentzensen, Nicolas; Whittemore, Alice S; Wu, Anna H; Ziogas, Argyrios; Odunsi, Kunle; Chang-Claude, Jenny; Goode, Ellen L; Moysich, Kirsten B

    2017-03-01

    Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses.Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival.Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10(-5)), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival.Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes.Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420-4. ©2016 AACR. ©2016 American Association for Cancer Research.

  17. 1-CMDb: A Curated Database of Genomic Variations of the One-Carbon Metabolism Pathway.

    PubMed

    Bhat, Manoj K; Gadekar, Veerendra P; Jain, Aditya; Paul, Bobby; Rai, Padmalatha S; Satyamoorthy, Kapaettu

    2017-01-01

    The one-carbon metabolism pathway is vital in maintaining tissue homeostasis by driving the critical reactions of folate and methionine cycles. A myriad of genetic and epigenetic events mark the rate of reactions in a tissue-specific manner. Integration of these to predict and provide personalized health management requires robust computational tools that can process multiomics data. The DNA sequences that may determine the chain of biological events and the endpoint reactions within one-carbon metabolism genes remain to be comprehensively recorded. Hence, we designed the one-carbon metabolism database (1-CMDb) as a platform to interrogate its association with a host of human disorders. DNA sequence and network information of a total of 48 genes were extracted from a literature survey and KEGG pathway that are involved in the one-carbon folate-mediated pathway. The information generated, collected, and compiled for all these genes from the UCSC genome browser included the single nucleotide polymorphisms (SNPs), CpGs, copy number variations (CNVs), and miRNAs, and a comprehensive database was created. Furthermore, a significant correlation analysis was performed for SNPs in the pathway genes. Detailed data of SNPs, CNVs, CpG islands, and miRNAs for 48 folate pathway genes were compiled. The SNPs in CNVs (9670), CpGs (984), and miRNAs (14) were also compiled for all pathway genes. The SIFT score, the prediction and PolyPhen score, as well as the prediction for each of the SNPs were tabulated and represented for folate pathway genes. Also included in the database for folate pathway genes were the links to 124 various phenotypes and disease associations as reported in the literature and from publicly available information. A comprehensive database was generated consisting of genomic elements within and among SNPs, CNVs, CpGs, and miRNAs of one-carbon metabolism pathways to facilitate (a) single source of information and (b) integration into large-genome scale network

  18. Variations in Antioxidant Genes and Male Infertility

    PubMed Central

    Yu, Bolan; Huang, Zhaofeng

    2015-01-01

    Oxidative stress and reactive oxygen species (ROS) are generated from both endogenous and environmental resources, which in turn may cause defective spermatogenesis and male infertility. Antioxidant genes, which include catalase (CAT), glutathione peroxidase (GPX), glutathione S-transferase (GST), nitric oxide synthase (NOS), nuclear factor erythroid 2-related factor 2 (NRF2), and superoxide dismutase (SOD), play important roles in spermatogenesis and normal sperm function. In this review, we discuss the association between variations in major antioxidant genes and male infertility. Numerous studies have suggested that genetic disruption or functional polymorphisms in these antioxidant genes are associated with a higher risk for male infertility, which include low sperm quality, oligoasthenoteratozoospermia, oligozoospermia, and subfertility. The synergistic effects of environmental ROS and functional polymorphisms on antioxidant genes that result in male infertility have also been reported. Therefore, variants in antioxidant genes, which independently or synergistically occur with environmental ROS, affect spermatogenesis and contribute to the occurrence of male infertility. Large cohort and multiple center-based population studies to identify new antioxidant genetic variants that increase susceptibility to male infertility as well as validate its potential as genetic markers for diagnosis and risk assessment for male infertility for precise clinical approaches are warranted. PMID:26618172

  19. Separate enrichment analysis of pathways for up- and downregulated genes.

    PubMed

    Hong, Guini; Zhang, Wenjing; Li, Hongdong; Shen, Xiaopei; Guo, Zheng

    2014-03-06

    Two strategies are often adopted for enrichment analysis of pathways: the analysis of all differentially expressed (DE) genes together or the analysis of up- and downregulated genes separately. However, few studies have examined the rationales of these enrichment analysis strategies. Using both microarray and RNA-seq data, we show that gene pairs with functional links in pathways tended to have positively correlated expression levels, which could result in an imbalance between the up- and downregulated genes in particular pathways. We then show that the imbalance could greatly reduce the statistical power for finding disease-associated pathways through the analysis of all-DE genes. Further, using gene expression profiles from five types of tumours, we illustrate that the separate analysis of up- and downregulated genes could identify more pathways that are really pertinent to phenotypic difference. In conclusion, analysing up- and downregulated genes separately is more powerful than analysing all of the DE genes together.

  20. Differentially Expressed Genes and Signature Pathways of Human Prostate Cancer

    PubMed Central

    Myers, Jennifer S.; von Lersner, Ariana K.; Robbins, Charles J.; Sang, Qing-Xiang Amy

    2015-01-01

    Genomic technologies including microarrays and next-generation sequencing have enabled the generation of molecular signatures of prostate cancer. Lists of differentially expressed genes between malignant and non-malignant states are thought to be fertile sources of putative prostate cancer biomarkers. However such lists of differentially expressed genes can be highly variable for multiple reasons. As such, looking at differential expression in the context of gene sets and pathways has been more robust. Using next-generation genome sequencing data from The Cancer Genome Atlas, differential gene expression between age- and stage- matched human prostate tumors and non-malignant samples was assessed and used to craft a pathway signature of prostate cancer. Up- and down-regulated genes were assigned to pathways composed of curated groups of related genes from multiple databases. The significance of these pathways was then evaluated according to the number of differentially expressed genes found in the pathway and their position within the pathway using Gene Set Enrichment Analysis and Signaling Pathway Impact Analysis. The “transforming growth factor-beta signaling” and “Ran regulation of mitotic spindle formation” pathways were strongly associated with prostate cancer. Several other significant pathways confirm reported findings from microarray data that suggest actin cytoskeleton regulation, cell cycle, mitogen-activated protein kinase signaling, and calcium signaling are also altered in prostate cancer. Thus we have demonstrated feasibility of pathway analysis and identified an underexplored area (Ran) for investigation in prostate cancer pathogenesis. PMID:26683658

  1. Variations in ORAI1 Gene Associated with Kawasaki Disease.

    PubMed

    Onouchi, Yoshihiro; Fukazawa, Ryuji; Yamamura, Kenichiro; Suzuki, Hiroyuki; Kakimoto, Nobuyuki; Suenaga, Tomohiro; Takeuchi, Takashi; Hamada, Hiromichi; Honda, Takafumi; Yasukawa, Kumi; Terai, Masaru; Ebata, Ryota; Higashi, Kouji; Saji, Tsutomu; Kemmotsu, Yasushi; Takatsuki, Shinichi; Ouchi, Kazunobu; Kishi, Fumio; Yoshikawa, Tetsushi; Nagai, Toshiro; Hamamoto, Kunihiro; Sato, Yoshitake; Honda, Akihito; Kobayashi, Hironobu; Sato, Junichi; Shibuta, Shoichi; Miyawaki, Masakazu; Oishi, Ko; Yamaga, Hironobu; Aoyagi, Noriyuki; Yoshiyama, Megumi; Miyashita, Ritsuko; Murata, Yuji; Fujino, Akihiro; Ozaki, Kouichi; Kawasaki, Tomisaku; Abe, Jun; Seki, Mitsuru; Kobayashi, Tohru; Arakawa, Hirokazu; Ogawa, Shunichi; Hara, Toshiro; Hata, Akira; Tanaka, Toshihiro

    2016-01-01

    Kawasaki disease (KD; MIM#61175) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD suggest possible involvement of the Ca(2+)/NFAT pathway in the pathogenesis of KD. ORAI1 is a Ca(2+) release activated Ca(2+) (CRAC) channel mediating store-operated Ca(2+) entry (SOCE) on the plasma membrane. The gene for ORAI1 is located in chromosome 12q24 where a positive linkage signal was observed in our previous affected sib-pair study of KD. A common non-synonymous single nucleotide polymorphism located within exon 2 of ORAI1 (rs3741596) was significantly associated with KD (P = 0.028 in the discovery sample set (729 KD cases and 1,315 controls), P = 0.0056 in the replication sample set (1,813 KD cases vs. 1,097 controls) and P = 0.00041 in a meta-analysis by the Mantel-Haenszel method). Interestingly, frequency of the risk allele of rs3741596 is more than 20 times higher in Japanese compared to Europeans. We also found a rare 6 base-pair in-frame insertion variant associated with KD (rs141919534; 2,544 KD cases vs. 2,414 controls, P = 0.012). These data indicate that ORAI1 gene variations are associated with KD and may suggest the potential importance of the Ca(2+)/NFAT pathway in the pathogenesis of this disorder.

  2. Variations in ORAI1 Gene Associated with Kawasaki Disease

    PubMed Central

    Suzuki, Hiroyuki; Kakimoto, Nobuyuki; Suenaga, Tomohiro; Takeuchi, Takashi; Hamada, Hiromichi; Honda, Takafumi; Yasukawa, Kumi; Terai, Masaru; Ebata, Ryota; Higashi, Kouji; Saji, Tsutomu; Kemmotsu, Yasushi; Takatsuki, Shinichi; Ouchi, Kazunobu; Kishi, Fumio; Yoshikawa, Tetsushi; Nagai, Toshiro; Hamamoto, Kunihiro; Sato, Yoshitake; Honda, Akihito; Kobayashi, Hironobu; Sato, Junichi; Shibuta, Shoichi; Miyawaki, Masakazu; Oishi, Ko; Yamaga, Hironobu; Aoyagi, Noriyuki; Yoshiyama, Megumi; Miyashita, Ritsuko; Murata, Yuji; Fujino, Akihiro; Ozaki, Kouichi; Kawasaki, Tomisaku; Abe, Jun; Seki, Mitsuru; Kobayashi, Tohru; Arakawa, Hirokazu; Ogawa, Shunichi; Hara, Toshiro; Hata, Akira; Tanaka, Toshihiro

    2016-01-01

    Kawasaki disease (KD; MIM#61175) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD suggest possible involvement of the Ca2+/NFAT pathway in the pathogenesis of KD. ORAI1 is a Ca2+ release activated Ca2+ (CRAC) channel mediating store-operated Ca2+ entry (SOCE) on the plasma membrane. The gene for ORAI1 is located in chromosome 12q24 where a positive linkage signal was observed in our previous affected sib-pair study of KD. A common non-synonymous single nucleotide polymorphism located within exon 2 of ORAI1 (rs3741596) was significantly associated with KD (P = 0.028 in the discovery sample set (729 KD cases and 1,315 controls), P = 0.0056 in the replication sample set (1,813 KD cases vs. 1,097 controls) and P = 0.00041 in a meta-analysis by the Mantel-Haenszel method). Interestingly, frequency of the risk allele of rs3741596 is more than 20 times higher in Japanese compared to Europeans. We also found a rare 6 base-pair in-frame insertion variant associated with KD (rs141919534; 2,544 KD cases vs. 2,414 controls, P = 0.012). These data indicate that ORAI1 gene variations are associated with KD and may suggest the potential importance of the Ca2+/NFAT pathway in the pathogenesis of this disorder. PMID:26789410

  3. Integrative analyses reveal biological pathways and key genes in psoriasis.

    PubMed

    Dou, J; Zhang, L; Xie, X; Ye, L; Yang, C; Wen, L; Shen, C; Zhu, C; Zhao, S; Zhu, Z; Liang, B; Wang, Z; Li, H; Fan, X; Liu, S; Yin, X; Zheng, X; Sun, L; Yang, S; Cui, Y; Zhou, F; Zhang, X

    2017-05-25

    Psoriasis is a complex disease that is influenced by both genetic and environmental factors with abnormal gene expression in lesional skin. However, no studies are available on genome-scale gene expression of psoriatic lesions in the Chinese population. In addition, systematic studies on the biological pathways, pathogenicity and interaction networks of psoriasis-related genes with abnormal expression profiles require further investigation. To further explore the associated pathways in psoriasis by functional analysis and to identify the key genes by gene pathogenicity analysis. We performed RNA sequencing on 60 skin biopsy samples from psoriasis patients and healthy controls to identify the primary differentially expressed genes in psoriatic lesional skin. We retrieved all reported psoriasis-associated genes and performed integrative analyses covering gene expression profiling, pathway analysis, gene pathogenicities and protein-protein interaction networks. We found that internal and external stimuli may activate immuno-inflammatory responses to promote the development of psoriasis. Pathways associated with infectious diseases and cancers were identified by functional and pathway analyses. The gene pathogenicity analysis revealed five key genes in psoriasis, including PPARD, GATA3, TIMP3, WNT5A and PTTG1. Our analyses showed that genes contributed to the pathogenesis of psoriasis by activating risk pathways with components abnormality in expression. We identified five potentially pathogenic genes for psoriasis that may serve as important biomarkers for the diagnosis and treatment. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  4. Overlapping 16p13.11 Deletion and Gain of Copies Variations Associated with Childhood Onset Psychosis Include Genes with Mechanistic Implications for Autism Associated Pathways: Two Case Reports

    PubMed Central

    Brownstein, Catherine A.; Kleiman, Robin J.; Engle, Elizabeth C.; Towne, Meghan C.; D’Angelo, Eugene J.; Yu, Timothy W.; Beggs, Alan H.; Picker, Jonathan; Fogler, Jason M.; Carroll, Devon; Schmitt, Rachel C. O.; Wolff, Robert R.; Shen, Yiping; Lip, Va; Bilguvar, Kaya; Kim, April; Tembulkar, Sahil; O’Donnell, Kyle; Gonzalez-Heydrich, Joseph

    2016-01-01

    Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis. PMID:26887912

  5. Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports.

    PubMed

    Brownstein, Catherine A; Kleiman, Robin J; Engle, Elizabeth C; Towne, Meghan C; D'Angelo, Eugene J; Yu, Timothy W; Beggs, Alan H; Picker, Jonathan; Fogler, Jason M; Carroll, Devon; Schmitt, Rachel C O; Wolff, Robert R; Shen, Yiping; Lip, Va; Bilguvar, Kaya; Kim, April; Tembulkar, Sahil; O'Donnell, Kyle; Gonzalez-Heydrich, Joseph

    2016-05-01

    Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis.

  6. Genetic Variation in ACE-related pathways associated with Sudden Cardiac Arrest Risk

    PubMed Central

    Sotoodehnia, Nona; Li, Guo; Johnson, Catherine O.; Lemaitre, Rozenn N.; Rice, Kenneth M.; Rea, Thomas D.; Siscovick, David S.

    2009-01-01

    Background Angiotensin converting enzyme (ACE)-related pathways influence arrhythmias and sudden cardiac arrest (SCA) risk. Objective We investigated whether genetic variation in ACE-related pathways are associated with SCA risk. Because these pathways are sex-dependent and influenced by estrogen, we examined these genotype-SCA associations in the full study population, and tested for interaction with gender. Methods In a population-based case-control study set in King County WA, we genotyped 211 SCA cases (mean age 59, 80% male) and 730 age- and gender-matched controls of European descent for 47 single nucleotide polymorphisms (SNPs) in eight genes (ACE, AGT, REN, AGTR1, AGTR2, ACE2, KNG1, BDKRB2). We examined association of SNPs and haplotypes with SCA risk using logistic regression. Results AGTR1 SNP rs1492099 (allele frequency=15%) was associated with decreased SCA risk (OR=0.62, 95%CI=0.4–0.9). Haplotype variation in AGTR2 was associated with SCA risk (global haplotype test p=0.001), with haplotype 2 (allele frequency=27%) associated with increased risk (OR=1.26, 95%CI=1.1–1.5). There was interaction with gender on SCA risk for variation in KNG1 (interaction p-value range=0.0004–0.017 for 6/8 SNPs). KNG1 SNP rs710448 (allele frequency=42%) was associated with decreased risk (OR=0.44, 95%CI=0.3–0.8) among women but not men. Other SNPs and haplotypes in the eight genes examined were not associated with SCA risk after multiple testing correction. Conclusions Variation in AGTR1 and AGTR2 are associated with SCA risk in a population-based case-control study. There was evidence of interaction with gender on SCA risk for variation in KNG1. Our findings, if replicated, suggest that variation in genes in ACE-related pathways influence SCA risk. PMID:19716087

  7. Genetic variation within the histamine pathway among patients with asthma

    PubMed Central

    Raje, Nikita; Vyhlidal, Carrie A.; Dai, Hongying; Jones, Bridgette L.

    2015-01-01

    Objective Histamine is an important mediator in the pathophysiology of asthma. We have previously reported that HRH1 is differentially expressed among those with asthma compared to those without asthma. Single histamine related genes have also been associated with asthma. We aimed to evaluate known single nucleotide polymorphisms (SNPs) in genes along the histamine biotransformation and response pathway and determine their association with asthma and HRH1 mRNA expression. Methods We enrolled children and adults (n=93) with/without asthma who met inclusion/exclusion criteria. Genotyping was performed for 9 known SNPs in the HDC, HRH1, HRH4, HNMT, and ABP1 genes. HRH1 mRNA expression was determined on RNA from buccal tissue. General linear model, Fisher's exact test, and Chi-square test were used to determine differences in allele, genotype, and haplotype frequency between subjects with and without asthma and differential HRH1 mRNA expression relative to genotype. Statistical significance was determined by p<0.05. Results No difference was observed in genotype/allele frequency for the 9 SNPs between subjects with and without asthma. The HNMT-1639C/ −464C/ 314C/ 3’UTRA haplotype was more frequently observed in those without asthma than those with asthma (p=0.03). We also observed genetic differences relative to race and gender. HNMT 314 genotype CT was more frequent in males with asthma compared to those without asthma (p=0.04). Conclusions Histamine pathway haplotype was associated with a diagnosis of asthma in our cohort but allele and genotype were not. Subgroup evaluations may also be important. Further studies are needed to determine the potential biological/clinical significance of our findings. PMID:25295384

  8. Variations in metabolic pathways create challenges for automated metabolic reconstructions: Examples from the tetrahydrofolate synthesis pathway

    PubMed Central

    de Crécy-Lagard, Valérie

    2014-01-01

    The availability of thousands of sequenced genomes has revealed the diversity of biochemical solutions to similar chemical problems. Even for molecules at the heart of metabolism, such as cofactors, the pathway enzymes first discovered in model organisms like Escherichia coli or Saccharomyces cerevisiae are often not universally conserved. Tetrahydrofolate (THF) (or its close relative tetrahydromethanopterin) is a universal and essential C1-carrier that most microbes and plants synthesize de novo. The THF biosynthesis pathway and enzymes are, however, not universal and alternate solutions are found for most steps, making this pathway a challenge to annotate automatically in many genomes. Comparing THF pathway reconstructions and functional annotations of a chosen set of folate synthesis genes in specific prokaryotes revealed the strengths and weaknesses of different microbial annotation platforms. This analysis revealed that most current platforms fail in metabolic reconstruction of variant pathways. However, all the pieces are in place to quickly correct these deficiencies if the different databases were built on each other's strengths. PMID:25210598

  9. Variations in active outflow along the trabecular outflow pathway.

    PubMed

    Cha, Elliott D K; Xu, Jia; Gong, Lihua; Gong, Haiyan

    2016-05-01

    Previous tracer studies have shown segmental outflow in the trabecular meshwork (TM) and along the inner wall (IW) of Schlemm's canal (SC). Whether segmental outflow is conserved distal to SC has not yet been investigated. This study aims to investigate whether the segmented pattern of outflow is conserved in distal outflow pathways by using a newly developed global imaging method and to evaluate variations of active outflow in three distinct regions along trabecular outflow pathway. Six normal whole globe human eyes were first perfused at 15 mmHg to establish a stable baseline outflow facility. The anterior chamber was then exchanged (5 mL) and perfused with fluorescent microspheres (0.002% v/v, 200 μL) to label areas of active outflow. All eyes were perfusion fixed and dissected into anterior segments. The TM and scleral surface were en face imaged globally. Effective filtration area (EFA) and fluorescent tracer distribution and intensity were analyzed in global images for both the TM and episcleral veins (EPVs). Anterior segments were further dissected into a minimum of 16 radial wedges, from which frontal sections were cut, stained, and imaged, using confocal microscopy. EFA from all three locations along the trabecular outflow pathway were measured and compared. Additionally, TM thickness, SC height, and total number of collector channels (CC) were analyzed and compared between active and inactive areas of outflow. Statistical analysis was performed using Student's t-tests and Wilcoxon signed-rank test with a required significance of p ≤ 0.05. All three locations showed a segmental outflow pattern. The TM had a significantly higher mean EFA (86.3 ± 3.5%) compared to both the IW (34.7 ± 2.9%; p ≤ 0.01) and EPVs (41.1 ± 3.8%; p ≤ 0.01). No significant difference in mean EFA was found between IW and EPVs. Preferential active outflow was observed in the nasal and inferior quadrants. TM thickness was significantly larger in areas of active

  10. Gene-Gene Interactions in the Folate Metabolic Pathway and the Risk of Conotruncal Heart Defects

    PubMed Central

    Lupo, Philip J.; Goldmuntz, Elizabeth; Mitchell, Laura E.

    2010-01-01

    Conotruncal and related heart defects (CTRD) are common, complex malformations. Although there are few established risk factors, there is evidence that genetic variation in the folate metabolic pathway influences CTRD risk. This study was undertaken to assess the association between inherited (i.e., case) and maternal gene-gene interactions in this pathway and the risk of CTRD. Case-parent triads (n = 727), ascertained from the Children's Hospital of Philadelphia, were genotyped for ten functional variants of nine folate metabolic genes. Analyses of inherited genotypes were consistent with the previously reported association between MTHFR A1298C and CTRD (adjusted P = .02), but provided no evidence that CTRD was associated with inherited gene-gene interactions. Analyses of the maternal genotypes provided evidence of a MTHFR C677T/CBS 844ins68 interaction and CTRD risk (unadjusted P = .02). This association is consistent with the effects of this genotype combination on folate-homocysteine biochemistry but remains to be confirmed in independent study populations. PMID:20111745

  11. Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma

    PubMed Central

    Anvari, Sara; Vyhlidal, Carrie A.; Dai, Hongying

    2015-01-01

    Histamine is an important mediator in the pathogenesis of asthma. Variation in genes along the histamine production, response, and degradation pathway may be important in predicting response to antihistamines. We hypothesize that differences exist among single-nucleotide polymorphisms (SNPs) in genes of the histamine pathway between children with allergic versus nonallergic asthma. Children (7–18 yr of age; n = 202) with asthma were classified as allergic or nonallergic based on allergy skin testing. Genotyping was performed to detect known SNPs (n = 10) among genes (HDC, HNMT, ABP1, HRH1, and HRH4) within the histamine pathway. Chi square tests and Cochran-Armitage Trend were used to identify associations between genetic variants and allergic or nonallergic asthma. Significance was determined by P < 0.05 and false-positive report probability. After correction for race differences in genotype were observed, HRH1-17 TT (6% allergic versus 0% nonallergic; P = 0.04), HNMT-464 TT (41% allergic versus 29% nonallergic; P = 0.04), and HNMT-1639 TT (30% allergic versus 20% nonallergic; P = 0.04) were overrepresented among children with allergic asthma. Genotype differences specifically among the African-American children were also observed: HRH1-17 TT (13% allergic versus 0% nonallergic; P = 0.04) and HNMT-1639 TT (23% allergic versus 3% nonallergic; P = 0.03) genotypes were overrepresented among African-American children with allergic asthma. Our study suggests that genetic variation within the histamine pathway may be associated with an allergic versus nonallergic asthma phenotype. Further studies are needed to determine the functional significance of identified SNPs and their impact on antihistamine response in patients with asthma and allergic disease. PMID:25909280

  12. Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma.

    PubMed

    Anvari, Sara; Vyhlidal, Carrie A; Dai, Hongying; Jones, Bridgette L

    2015-12-01

    Histamine is an important mediator in the pathogenesis of asthma. Variation in genes along the histamine production, response, and degradation pathway may be important in predicting response to antihistamines. We hypothesize that differences exist among single-nucleotide polymorphisms (SNPs) in genes of the histamine pathway between children with allergic versus nonallergic asthma. Children (7-18 yr of age; n = 202) with asthma were classified as allergic or nonallergic based on allergy skin testing. Genotyping was performed to detect known SNPs (n = 10) among genes (HDC, HNMT, ABP1, HRH1, and HRH4) within the histamine pathway. Chi square tests and Cochran-Armitage Trend were used to identify associations between genetic variants and allergic or nonallergic asthma. Significance was determined by P < 0.05 and false-positive report probability. After correction for race differences in genotype were observed, HRH1-17 TT (6% allergic versus 0% nonallergic; P = 0.04), HNMT-464 TT (41% allergic versus 29% nonallergic; P = 0.04), and HNMT-1639 TT (30% allergic versus 20% nonallergic; P = 0.04) were overrepresented among children with allergic asthma. Genotype differences specifically among the African-American children were also observed: HRH1-17 TT (13% allergic versus 0% nonallergic; P = 0.04) and HNMT-1639 TT (23% allergic versus 3% nonallergic; P = 0.03) genotypes were overrepresented among African-American children with allergic asthma. Our study suggests that genetic variation within the histamine pathway may be associated with an allergic versus nonallergic asthma phenotype. Further studies are needed to determine the functional significance of identified SNPs and their impact on antihistamine response in patients with asthma and allergic disease.

  13. Key genes and pathways in thyroid cancer based on gene set enrichment analysis.

    PubMed

    He, Wenwu; Qi, Bin; Zhou, Qiuxi; Lu, Chuansen; Huang, Qi; Xian, Lei; Chen, Mingwu

    2013-09-01

    The incidence of thyroid cancer and its associated morbidity has shown the most rapid increase among all cancers since 1982, but the mechanisms involved in thyroid cancer, particularly significant key genes induced in thyroid cancer, remain undefined. In many studies, gene probes have been used to search for key genes involved in causing and facilitating thyroid cancer. As a result, many possible virulence genes and pathways have been identified. However, these studies lack a case contrast for selecting the most possible virulence genes and pathways, as well as conclusive results with which to clarify the mechanisms of cancer development. In the present study, we used gene set enrichment and meta-analysis to select key genes and pathways. Based on gene set enrichment, we identified 5 downregulated and 4 upregulated mixed pathways in 6 tissue datasets. Based on the meta-analysis, there were 17 common pathways in the tissue datasets. One pathway, the p53 signaling pathway, which includes 13 genes, was identified by both the gene set enrichment analysis and meta-analysis. Genes are important elements that form key pathways. These pathways can induce the development of thyroid cancer later in life. The key pathways and genes identified in the present study can be used in the next stage of research, which will involve gene elimination and other methods of experimentation.

  14. Detection of driver pathways using mutated gene network in cancer.

    PubMed

    Li, Feng; Gao, Lin; Ma, Xiaoke; Yang, Xiaofei

    2016-06-21

    Distinguishing driver pathways has been extensively studied because they are critical for understanding the development and molecular mechanisms of cancers. Most existing methods for driver pathways are based on high coverage as well as high mutual exclusivity, with the underlying assumption that mutations are exclusive. However, in many cases, mutated driver genes in the same pathways are not strictly mutually exclusive. Based on this observation, we propose an index for quantifying mutual exclusivity between gene pairs. Then, we construct a mutated gene network for detecting driver pathways by integrating the proposed index and coverage. The detection of driver pathways on the mutated gene network consists of two steps: raw pathways are obtained using a CPM method, and the final driver pathways are selected using a strict testing strategy. We apply this method to glioblastoma and breast cancers and find that our method is more accurate than state-of-the-art methods in terms of enrichment of KEGG pathways. Furthermore, the detected driver pathways intersect with well-known pathways with moderate exclusivity, which cannot be discovered using the existing algorithms. In conclusion, the proposed method provides an effective way to investigate driver pathways in cancers.

  15. Comparative Transcriptomics to Identify Novel Genes and Pathways in Dinoflagellates

    NASA Astrophysics Data System (ADS)

    Ryan, D.

    2016-02-01

    The unarmored dinoflagellate Karenia brevis is among the most prominent harmful, bloom-forming phytoplankton species in the Gulf of Mexico. During blooms, the polyketides PbTx-1 and PbTx-2 (brevetoxins) are produced by K. brevis. Brevetoxins negatively impact human health and the Gulf shellfish harvest. However, the genes underlying brevetoxin synthesis are currently unknown. Because the K. brevis genome is extremely large ( 1 × 1011 base pairs long), and with a high proportion of repetitive, non-coding DNA, it has not been sequenced. In fact, large, repetitive genomes are common among the dinoflagellate group. High-throughput RNA sequencing technology enabled us to assemble Karenia transcriptomes de novo and investigate potential genes in the brevetoxin pathway through comparative transcriptomics. The brevetoxin profile varies among K. brevis clonal cultures. For example, well-documented Wilson-CCFWC268 typically produces 8-10 pg PbTx per cell, whereas SP1 produces < 2 pg PbTx/cell, and the mutant low-toxin Wilson clone produces undetectable to low (<0.05 pg/cell) amounts. Further, PbTx-2 has been measured in Karenia papilionacea but not Karenia mikimotoi. We compared the transcriptomes of four K. brevis clones (Wilson-CCFWC268, SP3, SP1, and mutant low-toxin Wilson) with K. papilionacea and K. mikimotoi to investigate nucleotide-level genetic variations and differences in gene expression. Of the 85,000 transcripts in the K. brevis transcriptome, 4,600 transcripts, including novel unannotated orthologs and putative polyketide synthases (PKSs), were only expressed by brevetoxin-producing K. brevis and K. papilionacea, not K. mikimotoi. Examination of gene expression between the typical- and low-toxin Wilson clones identified about 3,500 genes with significantly different expression levels, including 2 putative PKSs. One of the 2 PKSs was only found in the brevetoxin-producing Karenia species. These transcriptomes could not have been characterized without high

  16. Variation in gene expression within and among natural populations.

    PubMed

    Oleksiak, Marjorie F; Churchill, Gary A; Crawford, Douglas L

    2002-10-01

    Evolution may depend more strongly on variation in gene expression than on differences between variant forms of proteins. Regions of DNA that affect gene expression are highly variable, containing 0.6% polymorphic sites. These naturally occurring polymorphic nucleotides can alter in vivo transcription rates. Thus, one might expect substantial variation in gene expression between individuals. But the natural variation in mRNA expression for a large number of genes has not been measured. Here we report microarray studies addressing the variation in gene expression within and between natural populations of teleost fish of the genus Fundulus. We observed statistically significant differences in expression between individuals within the same population for approximately 18% of 907 genes. Expression typically differed by a factor of 1.5, and often more than 2.0. Differences between populations increased the variation. Much of the variation between populations was a positive function of the variation within populations and thus is most parsimoniously described as random. Some genes showed unexpected patterns of expression--changes unrelated to evolutionary distance. These data suggest that substantial natural variation exists in gene expression and that this quantitative variation is important in evolution.

  17. Carotenoid biosynthetic pathway: molecular phylogenies and evolutionary behavior of crt genes in eubacteria.

    PubMed

    Phadwal, Kanchan

    2005-01-17

    Phylogenetic analysis of carotenoid biosynthetic pathway genes and their evolutionary rate variations were studied among eubacterial taxa. The gene sequences for the enzymes involved in this pathway were obtained for major phylogenetic groups of eubacteria (green sulfur bacteria, green nonsulphur bacteria, Gram-positive bacteria, proteobacteria, flavobacteria, cyanobacteria) and archeabacteria. These gene datasets were distributed under five major steps of carotenoid biosynthesis in eubacteria; isoprenoid precursor biosynthesis, phytoene synthesis, dehydrogenation of phytoene, lycopene cyclization, formation of acyclic xanthophylls, formation of cyclic xanthophylls and carotenoid biosynthesis regulation. The NJ algorithm was used on protein coding DNA sequences to deduce the evolutionary relationship for the respective crt genes among different eubacterial lineages. The rate of nonsynonymous nucleotide substitutions per nonsynonymous site (d(N)) and synonymous nucleotide substitutions per synonymous site (d(S)) were calculated for different clades of the respective phylogenetic tree for specific crt genes. The phylogenetic analysis suggests that evolutionary pattern of crt genes in eubacteria is characterized by lateral gene transfer and gene duplication events. The d(N) values indicate that carotenoid biosynthetic genes are more conserved in proteobacteria than in any other eubacterial phyla. Furthermore, of the genes involved in carotenoid biosynthesis pathway, structural genes evolve slowly than the regulatory genes in eubacteria.

  18. Identification of key target genes and pathways in laryngeal carcinoma

    PubMed Central

    Liu, Feng; Du, Jintao; Liu, Jun; Wen, Bei

    2016-01-01

    The purpose of the present study was to screen the key genes associated with laryngeal carcinoma and to investigate the molecular mechanism of laryngeal carcinoma progression. The gene expression profile of GSE10935 [Gene Expression Omnibus (GEO) accession number], including 12 specimens from laryngeal papillomas and 12 specimens from normal laryngeal epithelia controls, was downloaded from the GEO database. Differentially expressed genes (DEGs) were screened in laryngeal papillomas compared with normal controls using Limma package in R language, followed by Gene Ontology (GO) enrichment analysis and pathway enrichment analysis. Furthermore, the protein-protein interaction (PPI) network of DEGs was constructed using Cytoscape software and modules were analyzed using MCODE plugin from the PPI network. Furthermore, significant biological pathway regions (sub-pathway) were identified by using iSubpathwayMiner analysis. A total of 67 DEGs were identified, including 27 up-regulated genes and 40 down-regulated genes and they were involved in different GO terms and pathways. PPI network analysis revealed that Ras association (RalGDS/AF-6) domain family member 1 (RASSF1) was a hub protein. The sub-pathway analysis identified 9 significantly enriched sub-pathways, including glycolysis/gluconeogenesis and nitrogen metabolism. Genes such as phosphoglycerate kinase 1 (PGK1), carbonic anhydrase II (CA2), and carbonic anhydrase XII (CA12) whose node degrees were >10 were identified in the disease risk sub-pathway. Genes in the sub-pathway, such as RASSF1, PGK1, CA2 and CA12 were presumed to serve critical roles in laryngeal carcinoma. The present study identified DEGs and their sub-pathways in the disease, which may serve as potential targets for treatment of laryngeal carcinoma. PMID:27446427

  19. Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma.

    PubMed

    Buas, Matthew F; He, Qianchuan; Johnson, Lisa G; Onstad, Lynn; Levine, David M; Thrift, Aaron P; Gharahkhani, Puya; Palles, Claire; Lagergren, Jesper; Fitzgerald, Rebecca C; Ye, Weimin; Caldas, Carlos; Bird, Nigel C; Shaheen, Nicholas J; Bernstein, Leslie; Gammon, Marilie D; Wu, Anna H; Hardie, Laura J; Pharoah, Paul D; Liu, Geoffrey; Iyer, Prassad; Corley, Douglas A; Risch, Harvey A; Chow, Wong-Ho; Prenen, Hans; Chegwidden, Laura; Love, Sharon; Attwood, Stephen; Moayyedi, Paul; MacDonald, David; Harrison, Rebecca; Watson, Peter; Barr, Hugh; deCaestecker, John; Tomlinson, Ian; Jankowski, Janusz; Whiteman, David C; MacGregor, Stuart; Vaughan, Thomas L; Madeleine, Margaret M

    2017-10-01

    Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett's oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA. We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-κB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10(-5)) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk. This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1 influence disease susceptibility. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  20. Single nucleotide polymorphism in sugar pathway and disease resistance genes in sugarcane.

    PubMed

    Parida, Swarup K; Kalia, Sanjay; Pandit, Awadhesh; Nayak, Preetam; Singh, Ram Kushal; Gaikwad, Kishor; Srivastava, Prem Shankar; Singh, Nagendra K; Mohapatra, Trilochan

    2016-08-01

    Single nucleotide polymorphism in sugar pathway and disease resistance genes showing genetic association with sugar content and red rot resistance would be useful in marker-assisted genetic improvement of sugarcane. Validation and genotyping of potential sequence variants in candidate genes are necessary to understand their functional significance and trait association potential. We discovered, characterized, validated and genotyped SNPs and InDels in sugar pathway and disease resistance genes of Saccharum complex and sugarcane varieties using amplicon sequencing and CAPS assays. The SNPs were abundant in the non-coding 3'UTRs than 5'UTRs and coding sequences depicting a strong bias toward C to T transition substitutions than transversions. Sequencing of cloned amplicons validated 61.6 and 45.2 % SNPs detected in silico in 21 sugar pathway and 16 disease resistance genes, respectively. Sixteen SNPs in four sugar pathway genes and 10 SNPs in nine disease resistance genes were validated through cost-effective CAPS assay. Functional and adaptive significance of SNP and protein haplotypes identified in sugar pathway and disease resistance genes was assessed by correlating their allelic variation with missense amino acid substitutions in the functional domains, alteration in protein structure models and possible modulation of catalytic enzyme activity in contrasting high and low sugar and moderately red rot resistant and highly susceptible sugarcane genotypes. A strong genetic association of five SNPs in the sugar pathway and disease resistance genes, and an InDel marker in the promoter sequence of sucrose synthase-2 gene, with sugar content and red rot resistance, was evident. The functionally relevant SNPs and InDels, detected and validated in sugar pathway and disease resistance genes, and genic CAPS markers designed, would be of immense use in marker-assisted genetic improvement of sugarcane for sugar content and disease resistance.

  1. Combinations of gene ontology and pathway characterize and predict prognosis genes for recurrence of gastric cancer after surgery.

    PubMed

    Fan, Haiyan; Guo, Zhanjun; Wang, Cuijv

    2015-09-01

    Gastric cancer (GC) is the second leading cause of death from cancer globally. The most common cause of GC is the infection of Helicobacter pylori, but ∼11% of cases are caused by genetic factors. However, recurrences occur in approximately one-third of stage II GC patients, even if they are treated with adjuvant chemotherapy or chemoradiotherapy. This is potentially due to expression variation of genes; some candidate prognostic genes were identified in patients with high-risk recurrences. The objective of this study was to develop an effective computational method for meaningfully interpreting these GC-related genes and accurately predicting novel prognostic genes for high-risk recurrence patients. We employed properties of genes (gene ontology [GO] and KEGG pathway information) as features to characterize GC-related genes. We obtained an optimal set of features for interpreting these genes. By applying the minimum redundancy maximum relevance algorithm, we predicted the GC-related genes. With the same approach, we further predicted the genes for the prognostic of high-risk recurrence. We obtained 1104 GO terms and KEGG pathways and 530 GO terms and KEGG pathways, respectively, that characterized GC-related genes and recurrence-related genes well. Finally, three novel prognostic genes were predicted to help supplement genetic markers of high-risk GC patients for recurrence after surgery. An in-depth text mining indicated that the results are quite consistent with previous knowledge. Survival analysis of patients confirmed the novel prognostic genes as markers. By analyzing the related genes, we developed a systematic method to interpret the possible underlying mechanism of GC. The novel prognostic genes facilitate the understanding and therapy of GC recurrences after surgery.

  2. Genetic variations in interleukin-12 related genes in immune-mediated diseases.

    PubMed

    van Wanrooij, R L J; Zwiers, A; Kraal, G; Bouma, G

    2012-12-01

    The interleukin-12 (IL-12) family comprises a group of heterodimeric cytokines and their respective receptors that play key roles in immune responses. A growing number of autoimmune diseases has been found to be associated with genetic variation in these genes. Based on their respective associations with the IL-12 genes, autoimmune diseases appear to cluster in two groups that either show strong associations with the Th1/Th17 pathway (as indicated by genetic association with IL12B and IL23R) or the Th1/IL-35 pathway as the consequence of their association with polymorphisms in the IL12A gene region. The genetic associations are described in relation to what is known of the functionality of these genes in the various diseases. Comparing association data for gene families in different diseases may lead to better insight in the function of the genes in the onset and course of the disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. Text Mining in Cancer Gene and Pathway Prioritization

    PubMed Central

    Luo, Yuan; Riedlinger, Gregory; Szolovits, Peter

    2014-01-01

    Prioritization of cancer implicated genes has received growing attention as an effective way to reduce wet lab cost by computational analysis that ranks candidate genes according to the likelihood that experimental verifications will succeed. A multitude of gene prioritization tools have been developed, each integrating different data sources covering gene sequences, differential expressions, function annotations, gene regulations, protein domains, protein interactions, and pathways. This review places existing gene prioritization tools against the backdrop of an integrative Omic hierarchy view toward cancer and focuses on the analysis of their text mining components. We explain the relatively slow progress of text mining in gene prioritization, identify several challenges to current text mining methods, and highlight a few directions where more effective text mining algorithms may improve the overall prioritization task and where prioritizing the pathways may be more desirable than prioritizing only genes. PMID:25392685

  4. Text mining in cancer gene and pathway prioritization.

    PubMed

    Luo, Yuan; Riedlinger, Gregory; Szolovits, Peter

    2014-01-01

    Prioritization of cancer implicated genes has received growing attention as an effective way to reduce wet lab cost by computational analysis that ranks candidate genes according to the likelihood that experimental verifications will succeed. A multitude of gene prioritization tools have been developed, each integrating different data sources covering gene sequences, differential expressions, function annotations, gene regulations, protein domains, protein interactions, and pathways. This review places existing gene prioritization tools against the backdrop of an integrative Omic hierarchy view toward cancer and focuses on the analysis of their text mining components. We explain the relatively slow progress of text mining in gene prioritization, identify several challenges to current text mining methods, and highlight a few directions where more effective text mining algorithms may improve the overall prioritization task and where prioritizing the pathways may be more desirable than prioritizing only genes.

  5. Using the Gene Ontology to Enrich Biological Pathways

    SciTech Connect

    Sanfilippo, Antonio P.; Baddeley, Robert L.; Beagley, Nathaniel; McDermott, Jason E.; Riensche, Roderick M.; Taylor, Ronald C.; Gopalan, Banu

    2009-12-10

    Most current approaches to automatic pathway generation are based on a reverse engineering approach in which pathway plausibility is solely derived from microarray gene expression data. These approaches tend to lack in generality and offer no independent validation as they are too reliant on the pathway observables that guide pathway generation. By contrast, alternative approaches that use prior biological knowledge to validate pathways inferred from gene expression data may err in the opposite direction as the prior knowledge is usually not sufficiently tuned to the pathology of focus. In this paper, we present a novel pathway generation approach that combines insights from the reverse engineering and knowledge-based approaches to increase the biological plausibility of automatically generated regulatory networks and describe an application of this approach to transcriptional data from a mouse model of neuroprotection during stroke.

  6. Gene network and pathway generation and analysis: Editorial

    SciTech Connect

    Zhao, Zhongming; Sanfilippo, Antonio P.; Huang, Kun

    2011-02-18

    The past decade has witnessed an exponential growth of biological data including genomic sequences, gene annotations, expression and regulation, and protein-protein interactions. A key aim in the post-genome era is to systematically catalogue gene networks and pathways in a dynamic living cell and apply them to study diseases and phenotypes. To promote the research in systems biology and its application to disease studies, we organized a workshop focusing on the reconstruction and analysis of gene networks and pathways in any organisms from high-throughput data collected through techniques such as microarray analysis and RNA-Seq.

  7. Genetic variations in the VEGF pathway as prognostic factors in metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy.

    PubMed

    Paré-Brunet, L; Sebio, A; Salazar, J; Berenguer-Llergo, A; Río, E; Barnadas, A; Baiget, M; Páez, D

    2015-10-01

    Angiogenesis is a significant biological mechanism in the progression and metastasis of solid tumors. Vascular endothelial growth factor (VEGF), its receptors and signaling effectors have a central role in tumor-induced angiogenesis. Genetic variation in the VEGF pathway may impact on tumor angiogenesis and, hence, on clinical cancer outcomes. This study evaluates the influence of common genetic variations within the VEGF pathway in the clinical outcomes of 172 metastatic colorectal cancer (mCRC) patients treated with first-line oxaliplatin/5-fluorouracil chemotherapy. A total of 27 single-nucleotide polymorphisms (SNPs) in 16 genes in the VEGF-dependent angionenesis process were genotyped using a dynamic array on the BioMark™ system. After assessing the KRAS mutational status, we found that four SNPs located in three genes (KISS1, KRAS and VEGFR2) were associated with progression-free survival. Five SNPs in three genes (ITGAV, KRAS and VEGFR2) correlated with overall survival. The gene-gene interactions identified in the survival tree analysis support the importance of VEGFR2 rs2071559 and KISS1 rs71745629 in modulating these outcomes. This study provides evidence that functional germline polymorphisms in the VEGF pathway may help to predict outcome in mCRC patients who undergo oxaliplatin/5-fluorouracil chemotherapy.

  8. Finding pathway-modulating genes from a novel Ontology Fingerprint-derived gene network.

    PubMed

    Qin, Tingting; Matmati, Nabil; Tsoi, Lam C; Mohanty, Bidyut K; Gao, Nan; Tang, Jijun; Lawson, Andrew B; Hannun, Yusuf A; Zheng, W Jim

    2014-10-01

    To enhance our knowledge regarding biological pathway regulation, we took an integrated approach, using the biomedical literature, ontologies, network analyses and experimental investigation to infer novel genes that could modulate biological pathways. We first constructed a novel gene network via a pairwise comparison of all yeast genes' Ontology Fingerprints--a set of Gene Ontology terms overrepresented in the PubMed abstracts linked to a gene along with those terms' corresponding enrichment P-values. The network was further refined using a Bayesian hierarchical model to identify novel genes that could potentially influence the pathway activities. We applied this method to the sphingolipid pathway in yeast and found that many top-ranked genes indeed displayed altered sphingolipid pathway functions, initially measured by their sensitivity to myriocin, an inhibitor of de novo sphingolipid biosynthesis. Further experiments confirmed the modulation of the sphingolipid pathway by one of these genes, PFA4, encoding a palmitoyl transferase. Comparative analysis showed that few of these novel genes could be discovered by other existing methods. Our novel gene network provides a unique and comprehensive resource to study pathway modulations and systems biology in general.

  9. Phylogenetic Origin and Diversification of RNAi Pathway Genes in Insects

    PubMed Central

    Pauli, Thomas; Donath, Alexander; Meusemann, Karen; Podsiadlowski, Lars; Petersen, Malte; Peters, Ralph S.; Mayer, Christoph; Liu, Shanlin; Zhou, Xin; Misof, Bernhard

    2016-01-01

    Abstract RNA interference (RNAi) refers to the set of molecular processes found in eukaryotic organisms in which small RNA molecules mediate the silencing or down-regulation of target genes. In insects, RNAi serves a number of functions, including regulation of endogenous genes, anti-viral defense, and defense against transposable elements. Despite being well studied in model organisms, such as Drosophila, the distribution of core RNAi pathway genes and their evolution in insects is not well understood. Here we present the most comprehensive overview of the distribution and diversity of core RNAi pathway genes across 100 insect species, encompassing all currently recognized insect orders. We inferred the phylogenetic origin of insect-specific RNAi pathway genes and also identified several hitherto unrecorded gene expansions using whole-body transcriptome data from the international 1KITE (1000 Insect Transcriptome Evolution) project as well as other resources such as i5K (5000 Insect Genome Project). Specifically, we traced the origin of the double stranded RNA binding protein R2D2 to the last common ancestor of winged insects (Pterygota), the loss of Sid-1/Tag-130 orthologs in Antliophora (fleas, flies and relatives, and scorpionflies in a broad sense), and confirm previous evidence for the splitting of the Argonaute proteins Aubergine and Piwi in Brachyceran flies (Diptera, Brachycera). Our study offers new reference points for future experimental research on RNAi-related pathway genes in insects. PMID:28062756

  10. Regional Variation in the Density of Essential Genes in Mice

    PubMed Central

    Hentges, Kathryn E; Pollock, David D; Liu, Bin; Justice, Monica J

    2007-01-01

    In most species, and particularly in vertebrates, the percentage of genes absolutely required for survival, the essential genes, has not been estimated. To obtain this estimation, we used the mouse as an experimental model to carry out high-efficiency N-ethyl-N-nitrosourea (ENU) mutagenesis screens in two balancer chromosome regions, and compared our results to a third previously published screen. The number of essential genes in each region was predicted based on allele frequencies. We determined that the density of essential genes differs by up to an order of magnitude among genomic regions. This indicates that extrapolating from regional estimates to genome-wide estimates of essential genes has a huge variance. A particularly high density of essential genes on mouse Chromosome 11 coincides with a high degree of regional linkage conservation, providing a possible causal explanation for the density variation. This is the first demonstration of regional variation in essential gene density in the mouse genome. PMID:17480122

  11. Population genetic variation in gene expression is associated withphenotypic variation in Saccharomyces cerevisiae

    SciTech Connect

    Fay, Justin C.; McCullough, Heather L.; Sniegowski, Paul D.; Eisen, Michael B.

    2004-02-25

    The relationship between genetic variation in gene expression and phenotypic variation observable in nature is not well understood. Identifying how many phenotypes are associated with differences in gene expression and how many gene-expression differences are associated with a phenotype is important to understanding the molecular basis and evolution of complex traits. Results: We compared levels of gene expression among nine natural isolates of Saccharomyces cerevisiae grown either in the presence or absence of copper sulfate. Of the nine strains, two show a reduced growth rate and two others are rust colored in the presence of copper sulfate. We identified 633 genes that show significant differences in expression among strains. Of these genes,20 were correlated with resistance to copper sulfate and 24 were correlated with rust coloration. The function of these genes in combination with their expression pattern suggests the presence of both correlative and causative expression differences. But the majority of differentially expressed genes were not correlated with either phenotype and showed the same expression pattern both in the presence and absence of copper sulfate. To determine whether these expression differences may contribute to phenotypic variation under other environmental conditions, we examined one phenotype, freeze tolerance, predicted by the differential expression of the aquaporin gene AQY2. We found freeze tolerance is associated with the expression of AQY2. Conclusions: Gene expression differences provide substantial insight into the molecular basis of naturally occurring traits and can be used to predict environment dependent phenotypic variation.

  12. Genes, environment and gene expression in colon tissue: a pathway approach to determining functionality.

    PubMed

    Slattery, Martha L; Pellatt, Daniel F; Wolff, Roger K; Lundgreen, Abbie

    2016-01-01

    Genetic and environmental factors have been shown to work together to alter cancer risk. In this study we evaluate previously identified gene and lifestyle interactions in a candidate pathway that were associated with colon cancer risk to see if these interactions altered gene expression. We analyzed non-tumor RNA-seq data from 144 colon cancer patients who had genotype, recent cigarette smoking, diet, body mass index (BMI), and recent aspirin/non-steroidal anti-inflammatory use data. Using a false discovery rate of 0.1, we evaluated differential gene expression between high and low levels of lifestyle exposure and genotypes using DESeq2. Thirteen pathway genes and 17 SNPs within those genes were associated with altered expression of other genes in the pathway. BMI, NSAIDs use and dietary components of the oxidative balance score (OBS) also were associated with altered gene expression. SNPs previously identified as interacting with these lifestyle factors, altered expression of pathway genes. NSAIDs interacted with 10 genes (15 SNPs) within those genes to alter expression of 28 pathway genes; recent cigarette smoking interacted with seven genes (nine SNPs) to alter expression of 27 genes. BMI interacted with FLT1, KDR, SEPN1, TERT, TXNRD2, and VEGFA to alter expression of eight genes. Three genes (five SNPs) interacted with OBS to alter expression of 12 genes. These data provide support for previously identified lifestyle and gene interactions associated with colon cancer in that they altered expression of key pathway genes. The need to consider lifestyle factors in conjunction with genetic factors is illustrated.

  13. MEFV gene variations in patients with systemic lupus erythematosus.

    PubMed

    Erer, Burak; Cosan, Fulya; Oku, Basar; Ustek, Duran; Inanc, Murat; Aral, Orhan; Gul, Ahmet

    2014-01-01

    The aim of this study was to investigate the frequency of familial Mediterranean fever (FMF)-associated MEFV gene variations in patients with systemic lupus erythematosus (SLE). The study group comprised 190 SLE patients and 101 healthy controls of Turkish origin with no clinical features of FMF. All individuals were genotyped for the four most common MEFV gene variations (M694V, M680I, V726A and E148Q) by PCR-restriction fragment length polymorphism analysis. The frequency of carrying any of the four MEFV gene variations under study was 15 % in patients with SLE and 10 % in the healthy controls (p = 0.23). After the exclusion of the less penetrant E148Q variation, re-analysis for the three penetrant mutations revealed a significant association between exon 10 variations and pericarditis [p = 0.038, odds ratio (OR) 3.5, 95 % confidence interval (CI) 1.0-12.1], and pleural effusion (p = 0.043, OR 5.2, 95 % CI 0.8-30.9). No significant association was detected between the MEFV gene variations and a higher acute phase response. The MEFV gene variations analyzed in our study do not seem to increase the overall susceptibility to SLE and do not have any strong association with its clinical manifestations. The possibility of a modest effect of penetrant exon 10 MEFV variants on the development of serosal effusions needs to be explored in a larger series of patients.

  14. Finding pathway-modulating genes from a novel Ontology Fingerprint-derived gene network

    PubMed Central

    Qin, Tingting; Matmati, Nabil; Tsoi, Lam C.; Mohanty, Bidyut K.; Gao, Nan; Tang, Jijun; Lawson, Andrew B.; Hannun, Yusuf A.; Zheng, W. Jim

    2014-01-01

    To enhance our knowledge regarding biological pathway regulation, we took an integrated approach, using the biomedical literature, ontologies, network analyses and experimental investigation to infer novel genes that could modulate biological pathways. We first constructed a novel gene network via a pairwise comparison of all yeast genes’ Ontology Fingerprints—a set of Gene Ontology terms overrepresented in the PubMed abstracts linked to a gene along with those terms’ corresponding enrichment P-values. The network was further refined using a Bayesian hierarchical model to identify novel genes that could potentially influence the pathway activities. We applied this method to the sphingolipid pathway in yeast and found that many top-ranked genes indeed displayed altered sphingolipid pathway functions, initially measured by their sensitivity to myriocin, an inhibitor of de novo sphingolipid biosynthesis. Further experiments confirmed the modulation of the sphingolipid pathway by one of these genes, PFA4, encoding a palmitoyl transferase. Comparative analysis showed that few of these novel genes could be discovered by other existing methods. Our novel gene network provides a unique and comprehensive resource to study pathway modulations and systems biology in general. PMID:25063300

  15. Insulin signal transduction pathways and insulin-induced gene expression.

    PubMed

    Keeton, Adam B; Amsler, Maggie O; Venable, Derwei Y; Messina, Joseph L

    2002-12-13

    Insulin regulates metabolic activity, gene transcription, and cell growth by modulating the activity of several intracellular signaling pathways. Insulin activation of one mitogen-activated protein kinase cascade, the MEK/ERK kinase cascade, is well described. However, the effect of insulin on the parallel p38 pathway is less well understood. The present work examines the effect of inhibiting the p38 signaling pathway by use of specific inhibitors, either alone or in combination with insulin, on the activation of ERK1/2 and on the regulation of gene transcription in rat hepatoma cells. Activation of ERK1/2 was induced by insulin and was dependent on the activation of MEK1, the kinase upstream of ERK in this pathway. Treatment of cells with p38 inhibitors also induced ERK1/2 activation/phosphorylation. The addition of p38 inhibitors followed by insulin addition resulted in a greater than additive activation of ERK1/2. The two genes studied, c-Fos and Pip92, are immediate-early genes that are dependent on the ERK1/2 pathway for insulin-regulated induction because the insulin effect was inhibited by pretreatment with a MEK1 inhibitor. The addition of p38 inhibitors induced transcription of both genes in a dose-dependent manner, and insulin stimulation of both genes was enhanced by prior treatment with p38 inhibitors. The ability of the p38 inhibitors to induce ERK1/2 and gene transcription, both alone and in combination with insulin, was abolished by prior inhibition of MEK1. These data suggest possible cross-talk between the p38 and ERK1/2 signaling pathways and a potential role of p38 in insulin signaling.

  16. Genetic variations in vitamin D-related pathways and breast cancer risk in African American women in the AMBER consortium.

    PubMed

    Yao, Song; Haddad, Stephen A; Hu, Qiang; Liu, Song; Lunetta, Kathryn L; Ruiz-Narvaez, Edward A; Hong, Chi-Chen; Zhu, Qianqian; Sucheston-Campbell, Lara; Cheng, Ting-Yuan David; Bensen, Jeannette T; Johnson, Candace S; Trump, Donald L; Haiman, Christopher A; Olshan, Andrew F; Palmer, Julie R; Ambrosone, Christine B

    2016-05-01

    Studies of genetic variations in vitamin D-related pathways and breast cancer risk have been conducted mostly in populations of European ancestry, and only sparsely in African Americans (AA), who are known for a high prevalence of vitamin D deficiency. We analyzed 24,445 germline variants in 63 genes from vitamin D-related pathways in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium, including 3,663 breast cancer cases and 4,687 controls. Odds ratios (OR) were derived from logistic regression models for overall breast cancer, by estrogen receptor (ER) status (1,983 ER positive and 1,098 ER negative), and for case-only analyses of ER status. None of the three vitamin D-related pathways were associated with breast cancer risk overall or by ER status. Gene-level analyses identified associations with risk for several genes at a nominal p ≤ 0.05, particularly for ER- breast cancer, including rs4647707 in DDB2. In case-only analyses, vitamin D metabolism and signaling pathways were associated with ER- cancer (pathway-level p = 0.02), driven by a single gene CASR (gene-level p = 0.001). The top SNP in CASR was rs112594756 (p = 7 × 10(-5), gene-wide corrected p = 0.01), followed by a second signal from a nearby SNP rs6799828 (p = 1 × 10(-4), corrected p = 0.03). In summary, several variants in vitamin D pathways were associated with breast cancer risk in AA women. In addition, CASR may be related to tumor ER status, supporting a role of vitamin D or calcium in modifying breast cancer phenotypes.

  17. Genetic variations in vitamin D-related pathways and breast cancer risk in African American women in the AMBER consortium

    PubMed Central

    Yao, Song; Haddad, Stephen A.; Hu, Qiang; Liu, Song; Lunetta, Kathryn L.; Ruiz-Narvaez, Edward A.; Hong, Chi-Chen; Zhu, Qianqian; Sucheston-Campbell, Lara; Cheng, Ting-Yuan David; Bensen, Jeannette T.; Johnson, Candace S.; Trump, Donald L.; Haiman, Christopher A.; Olshan, Andrew F.; Palmer, Julie R.; Ambrosone, Christine B.

    2016-01-01

    Studies of genetic variations in vitamin D-related pathways and breast cancer risk have been conducted mostly in populations of European ancestry, and only sparsely in African Americans (AA), who are known for a high prevalence of vitamin D deficiency. We analyzed 24,445 germline variants in 63 genes from vitamin D-related pathways in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium, including 3,663 breast cancer cases and 4,687 controls. Odds ratios (OR) were derived from logistic regression models for overall breast cancer, by estrogen receptor (ER) status (1,983 ER positive and 1,098 ER negative), and for case-only analyses of ER status. None of the three vitamin D-related pathways were associated with breast cancer risk overall or by ER status. Gene-level analyses identified associations with risk for several genes at a nominal p ≤ 0.05, particularly for ER− breast cancer, including rs4647707 in DDB2. In case-only analyses, vitamin D metabolism and signaling pathways were associated with ER− cancer (pathway-level p = 0.02), driven by a single gene CASR (gene-level p = 0.001). The top SNP in CASR was rs112594756 (p = 7 × 10−5, gene-wide corrected p = 0.01), followed by a second signal from a nearby SNP rs6799828 (p = 1 × 10−4, corrected p = 0.03). In summary, several variants in vitamin D pathways were associated with breast cancer risk in AA women. In addition, CASR may be related to tumor ER status, supporting a role of vitamin D or calcium in modifying breast cancer phenotypes. PMID:26650177

  18. Pathway-Dependent Effectiveness of Network Algorithms for Gene Prioritization

    PubMed Central

    Shim, Jung Eun; Hwang, Sohyun; Lee, Insuk

    2015-01-01

    A network-based approach has proven useful for the identification of novel genes associated with complex phenotypes, including human diseases. Because network-based gene prioritization algorithms are based on propagating information of known phenotype-associated genes through networks, the pathway structure of each phenotype might significantly affect the effectiveness of algorithms. We systematically compared two popular network algorithms with distinct mechanisms – direct neighborhood which propagates information to only direct network neighbors, and network diffusion which diffuses information throughout the entire network – in prioritization of genes for worm and human phenotypes. Previous studies reported that network diffusion generally outperforms direct neighborhood for human diseases. Although prioritization power is generally measured for all ranked genes, only the top candidates are significant for subsequent functional analysis. We found that high prioritizing power of a network algorithm for all genes cannot guarantee successful prioritization of top ranked candidates for a given phenotype. Indeed, the majority of the phenotypes that were more efficiently prioritized by network diffusion showed higher prioritizing power for top candidates by direct neighborhood. We also found that connectivity among pathway genes for each phenotype largely determines which network algorithm is more effective, suggesting that the network algorithm used for each phenotype should be chosen with consideration of pathway gene connectivity. PMID:26091506

  19. Pathway-based factor analysis of gene expression data produces highly heritable phenotypes that associate with age.

    PubMed

    Anand Brown, Andrew; Ding, Zhihao; Viñuela, Ana; Glass, Dan; Parts, Leopold; Spector, Tim; Winn, John; Durbin, Richard

    2015-03-09

    Statistical factor analysis methods have previously been used to remove noise components from high-dimensional data prior to genetic association mapping and, in a guided fashion, to summarize biologically relevant sources of variation. Here, we show how the derived factors summarizing pathway expression can be used to analyze the relationships between expression, heritability, and aging. We used skin gene expression data from 647 twins from the MuTHER Consortium and applied factor analysis to concisely summarize patterns of gene expression to remove broad confounding influences and to produce concise pathway-level phenotypes. We derived 930 "pathway phenotypes" that summarized patterns of variation across 186 KEGG pathways (five phenotypes per pathway). We identified 69 significant associations of age with phenotype from 57 distinct KEGG pathways at a stringent Bonferroni threshold ([Formula: see text]). These phenotypes are more heritable ([Formula: see text]) than gene expression levels. On average, expression levels of 16% of genes within these pathways are associated with age. Several significant pathways relate to metabolizing sugars and fatty acids; others relate to insulin signaling. We have demonstrated that factor analysis methods combined with biological knowledge can produce more reliable phenotypes with less stochastic noise than the individual gene expression levels, which increases our power to discover biologically relevant associations. These phenotypes could also be applied to discover associations with other environmental factors.

  20. Pathway-Based Factor Analysis of Gene Expression Data Produces Highly Heritable Phenotypes That Associate with Age

    PubMed Central

    Anand Brown, Andrew; Ding, Zhihao; Viñuela, Ana; Glass, Dan; Parts, Leopold; Spector, Tim; Winn, John; Durbin, Richard

    2015-01-01

    Statistical factor analysis methods have previously been used to remove noise components from high-dimensional data prior to genetic association mapping and, in a guided fashion, to summarize biologically relevant sources of variation. Here, we show how the derived factors summarizing pathway expression can be used to analyze the relationships between expression, heritability, and aging. We used skin gene expression data from 647 twins from the MuTHER Consortium and applied factor analysis to concisely summarize patterns of gene expression to remove broad confounding influences and to produce concise pathway-level phenotypes. We derived 930 “pathway phenotypes” that summarized patterns of variation across 186 KEGG pathways (five phenotypes per pathway). We identified 69 significant associations of age with phenotype from 57 distinct KEGG pathways at a stringent Bonferroni threshold (P<5.38×10−5). These phenotypes are more heritable (h2=0.32) than gene expression levels. On average, expression levels of 16% of genes within these pathways are associated with age. Several significant pathways relate to metabolizing sugars and fatty acids; others relate to insulin signaling. We have demonstrated that factor analysis methods combined with biological knowledge can produce more reliable phenotypes with less stochastic noise than the individual gene expression levels, which increases our power to discover biologically relevant associations. These phenotypes could also be applied to discover associations with other environmental factors. PMID:25758824

  1. Prediction and analysis of essential genes using the enrichments of gene ontology and KEGG pathways.

    PubMed

    Chen, Lei; Zhang, Yu-Hang; Wang, ShaoPeng; Zhang, YunHua; Huang, Tao; Cai, Yu-Dong

    2017-01-01

    Identifying essential genes in a given organism is important for research on their fundamental roles in organism survival. Furthermore, if possible, uncovering the links between core functions or pathways with these essential genes will further help us obtain deep insight into the key roles of these genes. In this study, we investigated the essential and non-essential genes reported in a previous study and extracted gene ontology (GO) terms and biological pathways that are important for the determination of essential genes. Through the enrichment theory of GO and KEGG pathways, we encoded each essential/non-essential gene into a vector in which each component represented the relationship between the gene and one GO term or KEGG pathway. To analyze these relationships, the maximum relevance minimum redundancy (mRMR) was adopted. Then, the incremental feature selection (IFS) and support vector machine (SVM) were employed to extract important GO terms and KEGG pathways. A prediction model was built simultaneously using the extracted GO terms and KEGG pathways, which yielded nearly perfect performance, with a Matthews correlation coefficient of 0.951, for distinguishing essential and non-essential genes. To fully investigate the key factors influencing the fundamental roles of essential genes, the 21 most important GO terms and three KEGG pathways were analyzed in detail. In addition, several genes was provided in this study, which were predicted to be essential genes by our prediction model. We suggest that this study provides more functional and pathway information on the essential genes and provides a new way to investigate related problems.

  2. Prediction and analysis of essential genes using the enrichments of gene ontology and KEGG pathways

    PubMed Central

    Wang, ShaoPeng; Zhang, YunHua; Huang, Tao

    2017-01-01

    Identifying essential genes in a given organism is important for research on their fundamental roles in organism survival. Furthermore, if possible, uncovering the links between core functions or pathways with these essential genes will further help us obtain deep insight into the key roles of these genes. In this study, we investigated the essential and non-essential genes reported in a previous study and extracted gene ontology (GO) terms and biological pathways that are important for the determination of essential genes. Through the enrichment theory of GO and KEGG pathways, we encoded each essential/non-essential gene into a vector in which each component represented the relationship between the gene and one GO term or KEGG pathway. To analyze these relationships, the maximum relevance minimum redundancy (mRMR) was adopted. Then, the incremental feature selection (IFS) and support vector machine (SVM) were employed to extract important GO terms and KEGG pathways. A prediction model was built simultaneously using the extracted GO terms and KEGG pathways, which yielded nearly perfect performance, with a Matthews correlation coefficient of 0.951, for distinguishing essential and non-essential genes. To fully investigate the key factors influencing the fundamental roles of essential genes, the 21 most important GO terms and three KEGG pathways were analyzed in detail. In addition, several genes was provided in this study, which were predicted to be essential genes by our prediction model. We suggest that this study provides more functional and pathway information on the essential genes and provides a new way to investigate related problems. PMID:28873455

  3. Genetic Variation in Melatonin Pathway Enzymes in Children with Autism Spectrum Disorder and Comorbid Sleep Onset Delay

    PubMed Central

    Pendergast, Julie S.; Allen, Melissa J.; Leu, Roberta M.; Johnson, Carl Hirschie; Elsea, Sarah H.; Malow, Beth A.

    2014-01-01

    Sleep disruption is common in individuals with autism spectrum disorder (ASD). Genes whose products regulate endogenous melatonin modify sleep patterns and have been implicated in ASD. Genetic factors likely contribute to comorbid expression of sleep disorders in ASD. We studied a clinically unique ASD subgroup, consisting solely of children with comorbid expression of sleep onset delay. We evaluated variation in two melatonin pathway genes, acetylserotonin O-methyltransferase (ASMT) and cytochrome P450 1A2 (CYP1A2). We observed higher frequencies than currently reported (p < 0.04) for variants evidenced to decrease ASMT expression and related to decreased CYP1A2 enzyme activity (p ≤ 0.0007). We detected a relationship between genotypes in ASMT and CYP1A2 (r2 = 0.63). Our results indicate that expression of sleep onset delay relates to melatonin pathway genes. PMID:25059483

  4. Top-down approaches to the study of natural variation in complex physiological pathways using the white-footed mouse (Peromyscus leucopus) as a model.

    PubMed

    Heideman, Paul D

    2004-01-01

    Variation in complex physiological pathways has important effects on human function and medical treatment. Complex pathways involve cells at multiple locations, which serve different functions regulated by many genes and include complex neuroendocrine pathways that regulate physiological function. One of two competing hypotheses regarding the effects of selection on complex pathways predicts that variability should be common within complex pathways. If this hypothesis is correct, then we should expect wide variation in neuroendocrine function to be typical within natural populations. To test this hypothesis, a complex neuroendocrine pathway that regulates photoperiod-dependent changes in fertility in a natural population of white-footed mice (Peromyscus leucopus) was used to test for natural genetic variability in multiple components of the pathway. After testing only six elements in the photoperiod pathway in P. leucopus, genetic variation in the following four of these elements was evident: the circadian clock, melatonin receptor abundance or affinity, sensitivity of the reproductive axis to steroid negative feedback, and gonadotropin-releasing hormone neuronal activity. If this result can be extended to humans, the prediction would be that significant variation at multiple loci in complex neuroendocrine pathways is common among humans, and that variation would exist even in human populations from a common genetic background. This finding could only be drawn from an "exotic" animal model derived from a natural source population, confirming the continuing importance of nontraditional models alongside the standard laboratory species.

  5. Streptococcus mutans serotype c tagatose 6-phosphate pathway gene cluster.

    PubMed Central

    Jagusztyn-Krynicka, E K; Hansen, J B; Crow, V L; Thomas, T D; Honeyman, A L; Curtiss, R

    1992-01-01

    DNA cloned into Escherichia coli K-12 from a serotype c strain of Streptococcus mutans encodes three enzyme activities for galactose utilization via the tagatose 6-phosphate pathway: galactose 6-phosphate isomerase, tagatose 6-phosphate kinase, and tagatose-1,6-bisphosphate aldolase. The genes coding for the tagatose 6-phosphate pathway were located on a 3.28-kb HindIII DNA fragment. Analysis of the tagatose proteins expressed by recombinant plasmids in minicells was used to determine the sizes of the various gene products. Mutagenesis of these plasmids with transposon Tn5 was used to determine the order of the tagatose genes. Tagatose 6-phosphate isomerase appears to be composed of 14- and 19-kDa subunits. The sizes of the kinase and aldolase were found to be 34 and 36 kDa, respectively. These values correspond to those reported previously for the tagatose pathway enzymes in Staphylococcus aureus and Lactococcus lactis. Images PMID:1328153

  6. Regulation of methanol utilisation pathway genes in yeasts

    PubMed Central

    Hartner, Franz S; Glieder, Anton

    2006-01-01

    Methylotrophic yeasts such as Candida boidinii, Hansenula polymorpha, Pichia methanolica and Pichia pastoris are an emerging group of eukaryotic hosts for recombinant protein production with an ever increasing number of applications during the last 30 years. Their applications are linked to the use of strong methanol-inducible promoters derived from genes of the methanol utilisation pathway. These promoters are tightly regulated, highly repressed in presence of non-limiting concentrations of glucose in the medium and strongly induced if methanol is used as carbon source. Several factors involved in this tight control and their regulatory effects have been described so far. This review summarises available data about the regulation of promoters from methanol utilisation pathway genes. Furthermore, the role of cis and trans acting factors (e.g. transcription factors, glucose processing enzymes) in the expression of methanol utilisation pathway genes is reviewed both in the context of the native cell environment as well as in heterologous hosts. PMID:17169150

  7. Gene and pathway identification with Lp penalized Bayesian logistic regression

    PubMed Central

    Liu, Zhenqiu; Gartenhaus, Ronald B; Tan, Ming; Jiang, Feng; Jiao, Xiaoli

    2008-01-01

    Background Identifying genes and pathways associated with diseases such as cancer has been a subject of considerable research in recent years in the area of bioinformatics and computational biology. It has been demonstrated that the magnitude of differential expression does not necessarily indicate biological significance. Even a very small change in the expression of particular gene may have dramatic physiological consequences if the protein encoded by this gene plays a catalytic role in a specific cell function. Moreover, highly correlated genes may function together on the same pathway biologically. Finally, in sparse logistic regression with Lp (p < 1) penalty, the degree of the sparsity obtained is determined by the value of the regularization parameter. Usually this parameter must be carefully tuned through cross-validation, which is time consuming. Results In this paper, we proposed a simple Bayesian approach to integrate the regularization parameter out analytically using a new prior. Therefore, there is no longer a need for parameter selection, as it is eliminated entirely from the model. The proposed algorithm (BLpLog) is typically two or three orders of magnitude faster than the original algorithm and free from bias in performance estimation. We also define a novel similarity measure and develop an integrated algorithm to hunt the regulatory genes with low expression changes but having high correlation with the selected genes. Pathways of those correlated genes were identified with DAVID . Conclusion Experimental results with gene expression data demonstrate that the proposed methods can be utilized to identify important genes and pathways that are related to cancer and build a parsimonious model for future patient predictions. PMID:18834526

  8. Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma.

    PubMed

    Zurawel, R H; Allen, C; Chiappa, S; Cato, W; Biegel, J; Cogen, P; de Sauvage, F; Raffel, C

    2000-01-01

    Inactivation of the PTCH tumor suppressor gene occurs in a subset of sporadic medulloblastomas, suggesting that alterations in the PTCH pathway may be important in the development of this tumor. In order to address the frequency of genetic alterations affecting genes in this pathway, we used a combination of loss of heterozygosity (LOH) analysis, single-stranded conformational polymorphism (SSCP) analysis, and direct sequencing of DNA samples from sporadic primitive neuroectodermal tumors (PNETs). To identify alterations in the PTCH gene, we performed LOH analysis on 37 tumor DNA samples. Of those with matched constitutional DNA samples, one demonstrated LOH. Of those without matched constitutional DNA, six were homozygous with all markers. All exons of the PTCH gene were sequenced in these seven tumors, and three mutations were found. To identify alterations in the SHH and SMO genes, we analyzed all exons of both genes in 24 tumors with SSCP and sequenced any exons that showed aberrant band patterns. No mutations were found in either SHH or SMO in any tumor. We also identified the following genes as candidate tumor suppressors based on their roles in controlling hh/ptc signaling in Drosophila: EN-1 and EN-2, deletion of which results in a lack of cerebellar development in mice; SMAD family members 1-7, and protein kinase A subunits RIalpha, RIbeta, RIIbeta, Calpha, and Cbeta. Each of these genes was investigated in a panel of 24 matched constitutional and tumor DNA samples. Our search revealed no mutations in any of these genes. Thus, PTCH is the only gene in this complex pathway that is mutated with notable frequency in PNET. Genes Chromosomes Cancer 27:44-51, 2000.

  9. Characterization of the cis elements in the proximal promoter regions of the anthocyanin pathway genes reveals a common regulatory logic that governs pathway regulation

    PubMed Central

    Zhu, Zhixin; Wang, Hailong; Wang, Yiting; Guan, Shan; Wang, Fang; Tang, Jingyu; Zhang, Ruijuan; Xie, Lulu; Lu, Yingqing

    2015-01-01

    Cellular activities such as compound synthesis often require the transcriptional activation of an entire pathway; however, the molecular mechanisms underlying pathway activation have rarely been explained. Here, the cis regulatory architecture of the anthocyanin pathway genes targeted by the transcription factor (TF) complex including MYB, bHLH, and WDR was systematically analysed in one species and the findings extended to others. In Ipomoea purpurea, the IpMYB1-IpbHLH2-IpWDR1 (IpMBW) complex was found to be orthologous to the PAP1-GL3-TTG1 (AtPGT) complex of Arabidopsis thaliana, and interacted with a 7-bp MYB-recognizing element (MRE) and a 6-bp bHLH-recognizing element (BRE) at the proximal promoter region of the pathway genes. There was little transcription of the gene in the absence of the MRE or BRE. The cis elements identified experimentally converged on two syntaxes, ANCNNCC for MREs and CACN(A/C/T)(G/T) for BREs, and our bioinformatic analysis showed that these were present within anthocyanin gene promoters in at least 35 species, including both gymnosperms and angiosperms. For the anthocyanin pathway, IpMBW and AtPGT recognized the interspecific promoters of both early and later genes. In A. thaliana, the seed-specific TF complex (TT2, TT8, and TTG1) may regulate all the anthocyanin pathway genes, in addition to the proanthocyanidin-specific BAN. When multiple TF complexes in the anthocyanin pathway were compared, the cis architecture played a role larger than the TF complex in determining the variation in promoter activity. Collectively, a cis logic common to the pathway gene promoters was found, and this logic is essential for the trans factors to regulate the pathway. PMID:25911741

  10. Hodgkin disease risk: role of genetic polymorphisms and gene-gene interactions in inflammation pathway genes.

    PubMed

    Monroy, Claudia M; Cortes, Andrea C; Lopez, Mirtha S; D'Amelio, Anthony M; Etzel, Carol J; Younes, Anas; Strom, Sara S; El-Zein, Randa A

    2011-01-01

    Inflammation is a critical component of cancer development. The clinical and pathological features of Hodgkin disease (HD) reflect an abnormal immunity that results from cytokines secreted by Reed-Sternberg cells and the surrounding tumor. Numerous studies have reported the association between genetic polymorphisms in cytokine genes and the susceptibility to different hematologic cancers. However, the effects of such SNPs on modulating HD risk have not yet been investigated. We hypothesized that gene-gene interactions between candidate genes in the anti- and pro-inflammatory pathways carrying suspicious polymorphisms may contribute to susceptibility to HD. To test this hypothesis, we conducted a study on 200 HD cases and 220 controls to assess associations between HD risk and 38 functional SNPs in inflammatory genes. We evaluated potential gene-gene interactions using a multi-analytic strategy combining logistic regression, multi-factor dimensionality reduction, and classification and regression tree (CART) approaches. We observed that, in combination, allelic variants in the COX2, IL18, ILR4, and IL10 genes modify the risk for developing HD. Moreover, the cumulative genetic risk score (CGRS) revealed a significant trend where the risk for developing HD increases as the number of adverse alleles in the cytokine genes increase. These findings support the notion that epigenetic-interactions between these cytokines may influence pathogenesis of HD modulating the proliferation of regulatory T cells. In this way, the innate and adaptative immune responses may be altered and defy their usual functions in the host anti-tumor response. Our study is the first to report the association between polymorphisms in inflammation genes and HD susceptibility risk. © 2010 Wiley-Liss, Inc.

  11. Clock gene variation in Tachycineta swallows

    PubMed Central

    Dor, Roi; Cooper, Caren B; Lovette, Irby J; Massoni, Viviana; Bulit, Flor; Liljesthrom, Marcela; Winkler, David W

    2012-01-01

    Many animals use photoperiod cues to synchronize reproduction with environmental conditions and thereby improve their reproductive success. The circadian clock, which creates endogenous behavioral and physiological rhythms typically entrained to photoperiod, is well characterized at the molecular level. Recent work provided evidence for an association between Clock poly-Q length polymorphism and latitude and, within a population, an association with the date of laying and the length of the incubation period. Despite relatively high overall breeding synchrony, the timing of clutch initiation has a large impact on the fitness of swallows in the genus Tachycineta. We compared length polymorphism in the Clock poly-Q region among five populations from five different Tachycineta species that breed across a hemisphere-wide latitudinal gradient (Fig. 1). Clock poly-Q variation was not associated with latitude; however, there was an association between Clock poly-Q allele diversity and the degree of clutch size decline within breeding seasons. We did not find evidence for an association between Clock poly-Q variation and date of clutch initiation in for any of the five Tachycineta species, nor did we found a relationship between incubation duration and Clock genotype. Thus, there is no general association between latitude, breeding phenology, and Clock polymorphism in this clade of closely related birds. Figure 1 Photos of Tachycineta swallows that were used in this study: A) T. bicolor from Ithaca, New York, B) T. leucorrhoa from Chascomús, Argentina, C) T. albilinea from Hill Bank, Belize, D) T. meyeni from Puerto Varas, Chile, and E) T. thalassina from Mono Lake, California, Photographers: B: Valentina Ferretti; A, C-E: David Winkler. PMID:22408729

  12. Second order optimization for the inference of gene regulatory pathways.

    PubMed

    Das, Mouli; Murthy, Chivukula A; De, Rajat K

    2014-02-01

    With the increasing availability of experimental data on gene interactions, modeling of gene regulatory pathways has gained special attention. Gradient descent algorithms have been widely used for regression and classification applications. Unfortunately, results obtained after training a model by gradient descent are often highly variable. In this paper, we present a new second order learning rule based on the Newton's method for inferring optimal gene regulatory pathways. Unlike the gradient descent method, the proposed optimization rule is independent of the learning parameter. The flow vectors are estimated based on biomass conservation. A set of constraints is formulated incorporating weighting coefficients. The method calculates the maximal expression of the target gene starting from a given initial gene through these weighting coefficients. Our algorithm has been benchmarked and validated on certain types of functions and on some gene regulatory networks, gathered from literature. The proposed method has been found to perform better than the gradient descent learning. Extensive performance comparison with the extreme pathway analysis method has underlined the effectiveness of our proposed methodology.

  13. Gene copy number variation throughout the Plasmodium falciparum genome.

    PubMed

    Cheeseman, Ian H; Gomez-Escobar, Natalia; Carret, Celine K; Ivens, Alasdair; Stewart, Lindsay B; Tetteh, Kevin K A; Conway, David J

    2009-08-04

    Gene copy number variation (CNV) is responsible for several important phenotypes of the malaria parasite Plasmodium falciparum, including drug resistance, loss of infected erythrocyte cytoadherence and alteration of receptor usage for erythrocyte invasion. Despite the known effects of CNV, little is known about its extent throughout the genome. We performed a whole-genome survey of CNV genes in P. falciparum using comparative genome hybridisation of a diverse set of 16 laboratory culture-adapted isolates to a custom designed high density Affymetrix GeneChip array. Overall, 186 genes showed hybridisation signals consistent with deletion or amplification in one or more isolate. There is a strong association of CNV with gene length, genomic location, and low orthology to genes in other Plasmodium species. Sub-telomeric regions of all chromosomes are strongly associated with CNV genes independent from members of previously described multigene families. However, approximately 40% of CNV genes were located in more central regions of the chromosomes. Among the previously undescribed CNV genes, several that are of potential phenotypic relevance are identified. CNV represents a major form of genetic variation within the P. falciparum genome; the distribution of gene features indicates the involvement of highly non-random mutational and selective processes. Additional studies should be directed at examining CNV in natural parasite populations to extend conclusions to clinical settings.

  14. Common genetic variations in cell cycle and DNA repair pathways associated with pediatric brain tumor susceptibility

    PubMed Central

    Fahmideh, Maral Adel; Lavebratt, Catharina; Schüz, Joachim; Röösli, Martin; Tynes, Tore; Grotzer, Michael A.; Johansen, Christoffer; Kuehni, Claudia E; Lannering, Birgitta; Prochazka, Michaela; Schmidt, Lisbeth S; Feychting, Maria

    2016-01-01

    Knowledge on the role of genetic polymorphisms in the etiology of pediatric brain tumors (PBTs) is limited. Therefore, we investigated the association between single nucleotide polymorphisms (SNPs), identified by candidate gene-association studies on adult brain tumors, and PBT risk. The study is based on the largest series of PBT cases to date. Saliva DNA from 245 cases and 489 controls, aged 7–19 years at diagnosis/reference date, was genotyped for 68 SNPs. Data were analyzed using unconditional logistic regression. The results showed EGFRrs730437 and EGFRrs11506105 may decrease susceptibility to PBTs, whereas ERCC1rs3212986 may increase risk of these tumors. Moreover, stratified analyses indicated CHAF1Ars243341, CHAF1Ars2992, and XRCC1rs25487 were associated with a decreased risk of astrocytoma subtype. Furthermore, an increased risk of non-astrocytoma subtype associated with EGFRrs9642393, EME1rs12450550, ATMrs170548, and GLTSCRrs1035938 as well as a decreased risk of this subtype associated with XRCC4rs7721416 and XRCC4rs2662242 were detected. This study indicates SNPs in EGFR, ERCC1, CHAF1A, XRCC1, EME1, ATM, GLTSCR1, and XRCC4 may be associated with the risk of PBTs. Therefore, cell cycle and DNA repair pathways variations associated with susceptibility to adult brain tumors also seem to be associated with PBT risk, suggesting pediatric and adult brain tumors might share similar etiological pathways. PMID:27613841

  15. Signal Transduction Pathways that Regulate CAB Gene Expression

    SciTech Connect

    Chory, Joanne

    2006-01-16

    The process of chloroplast differentiation, involves the coordinate regulation of many nuclear and chloroplast genes. The cues for the initiation of this developmental program are both extrinsic (e.g., light) and intrinsic (cell-type and plastid signals). During this project period, we utilized a molecular genetic approach to select for Arabidopsis mutants that did not respond properly to environmental light conditions, as well as mutants that were unable to perceive plastid damage. These latter mutants, called gun mutants, define two retrograde signaling pathways that regulate nuclear gene expression in response to chloroplasts. A major finding was to identify a signal from chloroplasts that regulates nuclear gene transcription. This signal is the build-up of Mg-Protoporphyrin IX, a key intermediate of the chlorophyll biosynthetic pathway. The signaling pathways downstream of this signal are currently being studied. Completion of this project has provided an increased understanding of the input signals and retrograde signaling pathways that control nuclear gene expression in response to the functional state of chloroplasts. These studies should ultimately influence our abilities to manipulate plant growth and development, and will aid in the understanding of the developmental control of photosynthesis.

  16. Signal Transduction Pathways that Regulate CAB Gene Expression

    SciTech Connect

    Chory, Joanne

    2004-12-31

    The process of chloroplast differentiation, involves the coordinate regulation of many nuclear and chloroplast genes. The cues for the initiation of this developmental program are both extrinsic (e.g., light) and intrinsic (cell-type and plastid signals). During this project period, we utilized a molecular genetic approach to select for Arabidopsis mutants that did not respond properly to environmental light conditions, as well as mutants that were unable to perceive plastid damage. These latter mutants, called gun mutants, define two retrograde signaling pathways that regulate nuclear gene expression in response to chloroplasts. A major finding was to identify a signal from chloroplasts that regulates nuclear gene transcription. This signal is the build-up of Mg-Protoporphyrin IX, a key intermediate of the chlorophyll biosynthetic pathway. The signaling pathways downstream of this signal are currently being studied. Completion of this project has provided an increased understanding of the input signals and retrograde signaling pathways that control nuclear gene expression in response to the functional state of chloroplasts. These studies should ultimately influence our abilities to manipulate plant growth and development, and will aid in the understanding of the developmental control of photosynthesis.

  17. Common variation of the CYP17 gene in Iraqi women with endometriosis disease.

    PubMed

    Al-Rubae'i, Salwa H N; Naji, Tamara Sami; Turki, Kisma M

    2017-03-01

    Common variants among genes coding for enzymes in sex steroid biosynthetic pathways may influence the risk of endometriosis in Iraqi women patients in the last years. Cytochrome P450c17a1 (CYP17), a gene that codes for a key enzyme (cytochrome P450c17a1) in a rate-limiting step of estrogen biosynthesis has attracted considerable attention as an important gene for endometriosis. To evaluate the relationship between common genetic variations in CYP17 and endometriosis risk and determine the main effects of those variations on the gene expression. A women-based case control study of Iraqi women aged range (23-46), the associations between selected single-nucleotide polymorphisms (SNPs) in the CYP17 gene and endometriosis diagnosis in fifty women and thirty disease-free controls were evaluated. The study found a significant association (P ≤ 0.01)between endometriosis and selected SNPs of CYP17 gene, with the homozygous genotype conferring decreased risk. A highly significant difference (P ≤ 0.01) in CYP17 gene expression from women with versus without endometriosis and increased by 1.56-fold in women with endometriosis. These findings suggest that variation in or around CYP17 may be associated with endometriosis development in the Iraqi women.

  18. Evidence of dynamically dysregulated gene expression pathways in hyperresponsive B cells from African American lupus patients.

    PubMed

    Dozmorov, Igor; Dominguez, Nicolas; Sestak, Andrea L; Robertson, Julie M; Harley, John B; James, Judith A; Guthridge, Joel M

    2013-01-01

    Recent application of gene expression profiling to the immune system has shown a great potential for characterization of complex regulatory processes. It is becoming increasingly important to characterize functional systems through multigene interactions to provide valuable insights into differences between healthy controls and autoimmune patients. Here we apply an original systematic approach to the analysis of changes in regulatory gene interconnections between in Epstein-Barr virus transformed hyperresponsive B cells from SLE patients and normal control B cells. Both traditional analysis of differential gene expression and analysis of the dynamics of gene expression variations were performed in combination to establish model networks of functional gene expression. This Pathway Dysregulation Analysis identified known transcription factors and transcriptional regulators activated uniquely in stimulated B cells from SLE patients.

  19. Evidence of Dynamically Dysregulated Gene Expression Pathways in Hyperresponsive B Cells from African American Lupus Patients

    PubMed Central

    Dozmorov, Igor; Dominguez, Nicolas; Sestak, Andrea L.; Robertson, Julie M.; Harley, John B.; James, Judith A.; Guthridge, Joel M.

    2013-01-01

    Recent application of gene expression profiling to the immune system has shown a great potential for characterization of complex regulatory processes. It is becoming increasingly important to characterize functional systems through multigene interactions to provide valuable insights into differences between healthy controls and autoimmune patients. Here we apply an original systematic approach to the analysis of changes in regulatory gene interconnections between in Epstein-Barr virus transformed hyperresponsive B cells from SLE patients and normal control B cells. Both traditional analysis of differential gene expression and analysis of the dynamics of gene expression variations were performed in combination to establish model networks of functional gene expression. This Pathway Dysregulation Analysis identified known transcription factors and transcriptional regulators activated uniquely in stimulated B cells from SLE patients. PMID:23977035

  20. Phylogenetic Origin and Diversification of RNAi Pathway Genes in Insects.

    PubMed

    Dowling, Daniel; Pauli, Thomas; Donath, Alexander; Meusemann, Karen; Podsiadlowski, Lars; Petersen, Malte; Peters, Ralph S; Mayer, Christoph; Liu, Shanlin; Zhou, Xin; Misof, Bernhard; Niehuis, Oliver

    2016-12-01

    RNA interference (RNAi) refers to the set of molecular processes found in eukaryotic organisms in which small RNA molecules mediate the silencing or down-regulation of target genes. In insects, RNAi serves a number of functions, including regulation of endogenous genes, anti-viral defense, and defense against transposable elements. Despite being well studied in model organisms, such as Drosophila, the distribution of core RNAi pathway genes and their evolution in insects is not well understood. Here we present the most comprehensive overview of the distribution and diversity of core RNAi pathway genes across 100 insect species, encompassing all currently recognized insect orders. We inferred the phylogenetic origin of insect-specific RNAi pathway genes and also identified several hitherto unrecorded gene expansions using whole-body transcriptome data from the international 1KITE (1000 Insect Transcriptome Evolution) project as well as other resources such as i5K (5000 Insect Genome Project). Specifically, we traced the origin of the double stranded RNA binding protein R2D2 to the last common ancestor of winged insects (Pterygota), the loss of Sid-1/Tag-130 orthologs in Antliophora (fleas, flies and relatives, and scorpionflies in a broad sense), and confirm previous evidence for the splitting of the Argonaute proteins Aubergine and Piwi in Brachyceran flies (Diptera, Brachycera). Our study offers new reference points for future experimental research on RNAi-related pathway genes in insects. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  1. Integrative analysis of RUNX1 downstream pathways and target genes

    PubMed Central

    Michaud, Joëlle; Simpson, Ken M; Escher, Robert; Buchet-Poyau, Karine; Beissbarth, Tim; Carmichael, Catherine; Ritchie, Matthew E; Schütz, Frédéric; Cannon, Ping; Liu, Marjorie; Shen, Xiaofeng; Ito, Yoshiaki; Raskind, Wendy H; Horwitz, Marshall S; Osato, Motomi; Turner, David R; Speed, Terence P; Kavallaris, Maria; Smyth, Gordon K; Scott, Hamish S

    2008-01-01

    Background The RUNX1 transcription factor gene is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or amplification. It is also responsible for a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML). The disruption of the largely unknown biological pathways controlled by RUNX1 is likely to be responsible for the development of leukemia. We have used multiple microarray platforms and bioinformatic techniques to help identify these biological pathways to aid in the understanding of why RUNX1 mutations lead to leukemia. Results Here we report genes regulated either directly or indirectly by RUNX1 based on the study of gene expression profiles generated from 3 different human and mouse platforms. The platforms used were global gene expression profiling of: 1) cell lines with RUNX1 mutations from FPD-AML patients, 2) over-expression of RUNX1 and CBFβ, and 3) Runx1 knockout mouse embryos using either cDNA or Affymetrix microarrays. We observe that our datasets (lists of differentially expressed genes) significantly correlate with published microarray data from sporadic AML patients with mutations in either RUNX1 or its cofactor, CBFβ. A number of biological processes were identified among the differentially expressed genes and functional assays suggest that heterozygous RUNX1 point mutations in patients with FPD-AML impair cell proliferation, microtubule dynamics and possibly genetic stability. In addition, analysis of the regulatory regions of the differentially expressed genes has for the first time systematically identified numerous potential novel RUNX1 target genes. Conclusion This work is the first large-scale study attempting to identify the genetic networks regulated by RUNX1, a master regulator in the development of the hematopoietic system and leukemia. The biological pathways and target genes controlled by RUNX1 will have considerable importance in disease progression in both

  2. Human brain harbors single nucleotide somatic variations in functionally relevant genes possibly mediated by oxidative stress

    PubMed Central

    Sharma, Anchal; Pandey, Rajesh; Rehman, Rakhshinda; Mehani, Bharati; Varma, Binuja; Desiraju, Bapu K.; Mabalirajan, Ulaganathan; Agrawal, Anurag; Mukhopadhyay, Arijit

    2017-01-01

    Somatic variation in DNA can cause cells to deviate from the preordained genomic path in both disease and healthy conditions. Here, using exome sequencing of paired tissue samples, we show that the normal human brain harbors somatic single base variations measuring up to 0.48% of the total variations. Interestingly, about 64% of these somatic variations in the brain are expected to lead to non-synonymous changes, and as much as 87% of these represent G:C>T:A transversion events. Further, the transversion events in the brain were mostly found in the frontal cortex, whereas the corpus callosum from the same individuals harbors the reference genotype. We found a significantly higher amount of 8-OHdG (oxidative stress marker) in the frontal cortex compared to the corpus callosum of the same subjects (p<0.01), correlating with the higher G:C>T:A transversions in the cortex. We found significant enrichment for axon guidance and related pathways for genes harbouring somatic variations. This could represent either a directed selection of genetic variations in these pathways or increased susceptibility of some loci towards oxidative stress. This study highlights that oxidative stress possibly influence single nucleotide somatic variations in normal human brain. PMID:28149503

  3. Human brain harbors single nucleotide somatic variations in functionally relevant genes possibly mediated by oxidative stress.

    PubMed

    Sharma, Anchal; Ansari, Asgar Hussain; Kumari, Renu; Pandey, Rajesh; Rehman, Rakhshinda; Mehani, Bharati; Varma, Binuja; Desiraju, Bapu K; Mabalirajan, Ulaganathan; Agrawal, Anurag; Mukhopadhyay, Arijit

    2016-01-01

    Somatic variation in DNA can cause cells to deviate from the preordained genomic path in both disease and healthy conditions. Here, using exome sequencing of paired tissue samples, we show that the normal human brain harbors somatic single base variations measuring up to 0.48% of the total variations. Interestingly, about 64% of these somatic variations in the brain are expected to lead to non-synonymous changes, and as much as 87% of these represent G:C>T:A transversion events. Further, the transversion events in the brain were mostly found in the frontal cortex, whereas the corpus callosum from the same individuals harbors the reference genotype. We found a significantly higher amount of 8-OHdG (oxidative stress marker) in the frontal cortex compared to the corpus callosum of the same subjects (p<0.01), correlating with the higher G:C>T:A transversions in the cortex. We found significant enrichment for axon guidance and related pathways for genes harbouring somatic variations. This could represent either a directed selection of genetic variations in these pathways or increased susceptibility of some loci towards oxidative stress. This study highlights that oxidative stress possibly influence single nucleotide somatic variations in normal human brain.

  4. MEFV gene variations in patients with systemic lupus erythematosus.

    PubMed

    Erer, Burak; Cosan, Fulya; Oku, Basar; Ustek, Duran; Inanc, Murat; Aral, Orhan; Gul, Ahmet

    2013-02-24

    OBJECTIVE: The aim of this study was to investigate the frequency of familial Mediterranean fever (FMF)-associated MEFV gene variations in patients with systemic lupus erythematosus (SLE). METHODS: The study group comprised 190 SLE patients and 101 healthy controls of Turkish origin with no clinical features of FMF. All individuals were genotyped for the four most common MEFV gene variations (M694V, M680I, V726A and E148Q) by PCR-restriction fragment length polymorphism analysis. RESULTS: The frequency of carrying any of the four MEFV gene variations under study was 15 % in patients with SLE and 10 % in the healthy controls (p = 0.23). After the exclusion of the less penetrant E148Q variation, re-analysis for the three penetrant mutations revealed a significant association between exon 10 variations and pericarditis [p = 0.038, odds ratio (OR) 3.5, 95 % confidence interval (CI) 1.0-12.1], and pleural effusion (p = 0.043, OR 5.2, 95 % CI 0.8-30.9). No significant association was detected between the MEFV gene variations and a higher acute phase response. CONCLUSIONS: The MEFV gene variations analyzed in our study do not seem to increase the overall susceptibility to SLE and do not have any strong association with its clinical manifestations. The possibility of a modest effect of penetrant exon 10 MEFV variants on the development of serosal effusions needs to be explored in a larger series of patients.

  5. Targeting Co-Stimulatory Pathways in Gene Therapy

    PubMed Central

    Huang, Xiaopei; Yang, Yiping

    2011-01-01

    Gene therapy with recombinant viral vectors such as adenovirus and adenovirus-associated virus holds great promise in treating a wide range of diseases because of the high efficiency with which the viruses transfer their genomes into host cells in vivo. However, the activation of the host immune responses remains a major hurdle to successful gene therapy. Studies in the past two decades have elucidated the important role co-stimulation plays in the activation of both T and B cells. This review summarizes our current understanding of T cell co-stimulatory pathways, and strategies targeting these co-stimulatory pathways in gene therapy applications as well as potential future directions. PMID:22046171

  6. Host genetic variation in mucosal immunity pathways influences the upper airway microbiome.

    PubMed

    Igartua, Catherine; Davenport, Emily R; Gilad, Yoav; Nicolae, Dan L; Pinto, Jayant; Ober, Carole

    2017-02-01

    The degree to which host genetic variation can modulate microbial communities in humans remains an open question. Here, we performed a genetic mapping study of the microbiome in two accessible upper airway sites, the nasopharynx and the nasal vestibule, during two seasons in 144 adult members of a founder population of European decent. We estimated the relative abundances (RAs) of genus level bacteria from 16S rRNA gene sequences and examined associations with 148,653 genetic variants (linkage disequilibrium [LD] r (2) < 0.5) selected from among all common variants discovered in genome sequences in this population. We identified 37 microbiome quantitative trait loci (mbQTLs) that showed evidence of association with the RAs of 22 genera (q < 0.05) and were enriched for genes in mucosal immunity pathways. The most significant association was between the RA of Dermacoccus (phylum Actinobacteria) and a variant 8 kb upstream of TINCR (rs117042385; p = 1.61 × 10(-8); q = 0.002), a long non-coding RNA that binds to peptidoglycan recognition protein 3 (PGLYRP3) mRNA, a gene encoding a known antimicrobial protein. A second association was between a missense variant in PGLYRP4 (rs3006458) and the RA of an unclassified genus of family Micrococcaceae (phylum Actinobacteria) (p = 5.10 × 10(-7); q = 0.032). Our findings provide evidence of host genetic influences on upper airway microbial composition in humans and implicate mucosal immunity genes in this relationship.

  7. Metabolomic profiling and genomic analysis of wheat aneuploid lines to identify genes controlling biochemical pathways in mature grain.

    PubMed

    Francki, Michael G; Hayton, Sarah; Gummer, Joel P A; Rawlinson, Catherine; Trengove, Robert D

    2016-02-01

    Metabolomics is becoming an increasingly important tool in plant genomics to decipher the function of genes controlling biochemical pathways responsible for trait variation. Although theoretical models can integrate genes and metabolites for trait variation, biological networks require validation using appropriate experimental genetic systems. In this study, we applied an untargeted metabolite analysis to mature grain of wheat homoeologous group 3 ditelosomic lines, selected compounds that showed significant variation between wheat lines Chinese Spring and at least one ditelosomic line, tracked the genes encoding enzymes of their biochemical pathway using the wheat genome survey sequence and determined the genetic components underlying metabolite variation. A total of 412 analytes were resolved in the wheat grain metabolome, and principal component analysis indicated significant differences in metabolite profiles between Chinese Spring and each ditelosomic lines. The grain metabolome identified 55 compounds positively matched against a mass spectral library where the majority showed significant differences between Chinese Spring and at least one ditelosomic line. Trehalose and branched-chain amino acids were selected for detailed investigation, and it was expected that if genes encoding enzymes directly related to their biochemical pathways were located on homoeologous group 3 chromosomes, then corresponding ditelosomic lines would have a significant reduction in metabolites compared with Chinese Spring. Although a proportion showed a reduction, some lines showed significant increases in metabolites, indicating that genes directly and indirectly involved in biosynthetic pathways likely regulate the metabolome. Therefore, this study demonstrated that wheat aneuploid lines are suitable experimental genetic system to validate metabolomics-genomics networks.

  8. Extensive Natural Epigenetic Variation at a De Novo Originated Gene

    PubMed Central

    Silveira, Amanda Bortolini; Trontin, Charlotte; Cortijo, Sandra; Barau, Joan; Del Bem, Luiz Eduardo Vieira; Loudet, Olivier; Colot, Vincent; Vincentz, Michel

    2013-01-01

    Epigenetic variation, such as heritable changes of DNA methylation, can affect gene expression and thus phenotypes, but examples of natural epimutations are few and little is known about their stability and frequency in nature. Here, we report that the gene Qua-Quine Starch (QQS) of Arabidopsis thaliana, which is involved in starch metabolism and that originated de novo recently, is subject to frequent epigenetic variation in nature. Specifically, we show that expression of this gene varies considerably among natural accessions as well as within populations directly sampled from the wild, and we demonstrate that this variation correlates negatively with the DNA methylation level of repeated sequences located within the 5′end of the gene. Furthermore, we provide extensive evidence that DNA methylation and expression variants can be inherited for several generations and are not linked to DNA sequence changes. Taken together, these observations provide a first indication that de novo originated genes might be particularly prone to epigenetic variation in their initial stages of formation. PMID:23593031

  9. Variation in the Major Surface Glycoprotein Genes in Pneumocystis jirovecii

    PubMed Central

    Kutty, Geetha; Maldarelli, Frank; Achaz, Guillaume; Kovacs, Joseph A.

    2008-01-01

    The genome of Pneumocystis, which causes life-threatening pneumonia in immunosuppressed patients, contains a multi-copy gene family that encodes the major surface glycoprotein (Msg). Pneumocystis can vary the expressed Msg, presumably as a mechanism to avoid host immune responses. Analysis of 24 msg gene sequences obtained from a single human Pneumocystis isolate demonstrated that the sequences segregate into two branches. Based on a number of analyses, recombination among msg genes appears to be an important mechanism for generating msg diversity. Intra-branch recombination occurred more frequently than inter-branch recombination. Restriction fragment length polymorphism analysis demonstrated substantial variation in the repertoire of the msg gene family among isolates of human Pneumocystis, which was not observed in laboratory isolates of rat or mouse Pneumocystis; this may be the result of examining outbred vs. captive populations. Increased diversity in the Msg repertoire, generated in part by recombination, increases the potential for antigenic variation in this abundant surface protein. PMID:18627244

  10. Genetic Architectures of Quantitative Variation in RNA Editing Pathways.

    PubMed

    Gu, Tongjun; Gatti, Daniel M; Srivastava, Anuj; Snyder, Elizabeth M; Raghupathy, Narayanan; Simecek, Petr; Svenson, Karen L; Dotu, Ivan; Chuang, Jeffrey H; Keller, Mark P; Attie, Alan D; Braun, Robert E; Churchill, Gary A

    2016-02-01

    RNA editing refers to post-transcriptional processes that alter the base sequence of RNA. Recently, hundreds of new RNA editing targets have been reported. However, the mechanisms that determine the specificity and degree of editing are not well understood. We examined quantitative variation of site-specific editing in a genetically diverse multiparent population, Diversity Outbred mice, and mapped polymorphic loci that alter editing ratios globally for C-to-U editing and at specific sites for A-to-I editing. An allelic series in the C-to-U editing enzyme Apobec1 influences the editing efficiency of Apob and 58 additional C-to-U editing targets. We identified 49 A-to-I editing sites with polymorphisms in the edited transcript that alter editing efficiency. In contrast to the shared genetic control of C-to-U editing, most of the variable A-to-I editing sites were determined by local nucleotide polymorphisms in proximity to the editing site in the RNA secondary structure. Our results indicate that RNA editing is a quantitative trait subject to genetic variation and that evolutionary constraints have given rise to distinct genetic architectures in the two canonical types of RNA editing. Copyright © 2016 by the Genetics Society of America.

  11. Genetic Architectures of Quantitative Variation in RNA Editing Pathways

    PubMed Central

    Gu, Tongjun; Gatti, Daniel M.; Srivastava, Anuj; Snyder, Elizabeth M.; Raghupathy, Narayanan; Simecek, Petr; Svenson, Karen L.; Dotu, Ivan; Chuang, Jeffrey H.; Keller, Mark P.; Attie, Alan D.; Braun, Robert E.; Churchill, Gary A.

    2016-01-01

    RNA editing refers to post-transcriptional processes that alter the base sequence of RNA. Recently, hundreds of new RNA editing targets have been reported. However, the mechanisms that determine the specificity and degree of editing are not well understood. We examined quantitative variation of site-specific editing in a genetically diverse multiparent population, Diversity Outbred mice, and mapped polymorphic loci that alter editing ratios globally for C-to-U editing and at specific sites for A-to-I editing. An allelic series in the C-to-U editing enzyme Apobec1 influences the editing efficiency of Apob and 58 additional C-to-U editing targets. We identified 49 A-to-I editing sites with polymorphisms in the edited transcript that alter editing efficiency. In contrast to the shared genetic control of C-to-U editing, most of the variable A-to-I editing sites were determined by local nucleotide polymorphisms in proximity to the editing site in the RNA secondary structure. Our results indicate that RNA editing is a quantitative trait subject to genetic variation and that evolutionary constraints have given rise to distinct genetic architectures in the two canonical types of RNA editing. PMID:26614740

  12. Exploiting natural variation in Saccharomyces cerevisiae to identify genes for increased ethanol resistance.

    PubMed

    Lewis, Jeffrey A; Elkon, Isaac M; McGee, Mick A; Higbee, Alan J; Gasch, Audrey P

    2010-12-01

    Ethanol production from lignocellulosic biomass holds promise as an alternative fuel. However, industrial stresses, including ethanol stress, limit microbial fermentation and thus prevent cost competitiveness with fossil fuels. To identify novel engineering targets for increased ethanol tolerance, we took advantage of natural diversity in wild Saccharomyces cerevisiae strains. We previously showed that an S288c-derived lab strain cannot acquire higher ethanol tolerance after a mild ethanol pretreatment, which is distinct from other stresses. Here, we measured acquired ethanol tolerance in a large panel of wild strains and show that most strains can acquire higher tolerance after pretreatment. We exploited this major phenotypic difference to address the mechanism of acquired ethanol tolerance, by comparing the global gene expression response to 5% ethanol in S288c and two wild strains. Hundreds of genes showed variation in ethanol-dependent gene expression across strains. Computational analysis identified several transcription factor modules and known coregulated genes as differentially expressed, implicating genetic variation in the ethanol signaling pathway. We used this information to identify genes required for acquisition of ethanol tolerance in wild strains, including new genes and processes not previously linked to ethanol tolerance, and four genes that increase ethanol tolerance when overexpressed. Our approach shows that comparative genomics across natural isolates can quickly identify genes for industrial engineering while expanding our understanding of natural diversity.

  13. Exploiting Natural Variation in Saccharomyces cerevisiae to Identify Genes for Increased Ethanol Resistance

    PubMed Central

    Lewis, Jeffrey A.; Elkon, Isaac M.; McGee, Mick A.; Higbee, Alan J.; Gasch, Audrey P.

    2010-01-01

    Ethanol production from lignocellulosic biomass holds promise as an alternative fuel. However, industrial stresses, including ethanol stress, limit microbial fermentation and thus prevent cost competitiveness with fossil fuels. To identify novel engineering targets for increased ethanol tolerance, we took advantage of natural diversity in wild Saccharomyces cerevisiae strains. We previously showed that an S288c-derived lab strain cannot acquire higher ethanol tolerance after a mild ethanol pretreatment, which is distinct from other stresses. Here, we measured acquired ethanol tolerance in a large panel of wild strains and show that most strains can acquire higher tolerance after pretreatment. We exploited this major phenotypic difference to address the mechanism of acquired ethanol tolerance, by comparing the global gene expression response to 5% ethanol in S288c and two wild strains. Hundreds of genes showed variation in ethanol-dependent gene expression across strains. Computational analysis identified several transcription factor modules and known coregulated genes as differentially expressed, implicating genetic variation in the ethanol signaling pathway. We used this information to identify genes required for acquisition of ethanol tolerance in wild strains, including new genes and processes not previously linked to ethanol tolerance, and four genes that increase ethanol tolerance when overexpressed. Our approach shows that comparative genomics across natural isolates can quickly identify genes for industrial engineering while expanding our understanding of natural diversity. PMID:20855568

  14. Standardized Markerless Gene Integration for Pathway Engineering in Yarrowia lipolytica.

    PubMed

    Schwartz, Cory; Shabbir-Hussain, Murtaza; Frogue, Keith; Blenner, Mark; Wheeldon, Ian

    2017-03-17

    The yeast Yarrowia lipolytica is a promising microbial host due to its native capacity to produce lipid-based chemicals. Engineering stable production strains requires genomic integration of modified genes, avoiding episomal expression that requires specialized media to maintain selective pressures. Here, we develop a CRISPR-Cas9-based tool for targeted, markerless gene integration into the Y. lipolytica genome. A set of genomic loci was screened to identify sites that were accepting of gene integrations without impacting cell growth. Five sites were found to meet these criteria. Expression levels from a GFP expression cassette were consistent when inserted into AXP, XPR2, A08, and D17, with reduced expression from MFE1. The standardized tool is comprised of five pairs of plasmids (one homologous donor plasmid and a CRISPR-Cas9 expression plasmid), with each pair targeting gene integration into one of the characterized sites. To demonstrate the utility of the tool we rapidly engineered a semisynthetic lycopene biosynthesis pathway by integrating four different genes at different loci. The capability to integrate multiple genes without the need for marker recovery and into sites with known expression levels will enable more rapid and reliable pathway engineering in Y. lipolytica.

  15. Signalling pathways mediating type I interferon gene expression.

    PubMed

    Edwards, Michael R; Slater, Louise; Johnston, Sebastian L

    2007-09-01

    Type I interferon-alpha/beta play an essential role in immunity to viruses. While interferon-beta has been used as a model of a complex promoter, many of the signalling pathways leading to interferon-beta gene expression remain controversial. Recent milestones include the discovery of Toll-like receptors and RNA helicases that signal via a novel kinase complex composed of I kappa B kinase-iota/epsilon or TANK binding kinase-1. This review provides a timely summary of this rapidly expanding field, focusing specifically on the various viral RNA binding molecules and their associated signalling pathways.

  16. Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation.

    PubMed

    Canli, T; Congdon, E; Gutknecht, L; Constable, R T; Lesch, K P

    2005-11-01

    The tryptophan hydroxylase-2 gene (TPH2) codes for the enzyme of serotonin (5-HT) synthesis in the brain and variation of TPH2 has been implicated in disorders of emotion regulation. Here, we used functional magnetic resonance imaging (fMRI) to demonstrate that a potentially functional variant of TPH2 modulates amygdala responsiveness to emotional stimuli of both negative and positive valence.

  17. Allelic Variation of Gene Expression in Maize HybridsW⃞

    PubMed Central

    Guo, Mei; Rupe, Mary A.; Zinselmeier, Christopher; Habben, Jeffrey; Bowen, Benjamin A.; Smith, Oscar S.

    2004-01-01

    Allelic expression variation of nonimprinted autosomal genes has recently been uncovered in mouse hybrids and humans. The allelic expression variation is attributed to differences in noncoding DNA sequences and does not involve epigenetic regulation or gene imprinting. This expression variation is suggested to play important roles in determining phenotypic diversity. Virtually nothing is known about such allele-specific expression variation in a hybrid plant where two alleles are compared in the same genetic context. We examined parental transcript accumulation in maize (Zea mays) hybrids using allele-specific RT-PCR analysis. Among 15 genes analyzed, 11 showed differences at the RNA level, ranging from unequal expression of the two alleles (biallelic) to expression of a single allele (monoallelic). Maternal or paternal transmission had little effect on the allele-specific transcript ratio of nearly all genes analyzed, suggesting that parent-of-origin effect was minimal. We analyzed the allelic difference in genetically contrasting hybrids and hybrids under high planting density and drought stress. Whereas a genetically improved modern hybrid expressed both alleles, a less improved old hybrid frequently showed mono-allelic expression. Furthermore, the two alleles in the hybrid responded differentially to abiotic stresses. The results of allele-specific regulation in different tissues in responding to environment and stress suggest an unequivalent function of the parental alleles in the hybrid, which may have an impact on heterosis. PMID:15194819

  18. Exploiting natural variation to identify insect-resistance genes.

    PubMed

    Broekgaarden, Colette; Snoeren, Tjeerd A L; Dicke, Marcel; Vosman, Ben

    2011-10-01

    Herbivorous insects are widespread and often serious constraints to crop production. The use of insect-resistant crops is a very effective way to control insect pests in agriculture, and the development of such crops can be greatly enhanced by knowledge on plant resistance mechanisms and the genes involved. Plants have evolved diverse ways to cope with insect attack that has resulted in natural variation for resistance towards herbivorous insects. Studying the molecular genetics and transcriptional background of this variation has facilitated the identification of resistance genes and processes that lead to resistance against insects. With the development of new technologies, molecular studies are not restricted to model plants anymore. This review addresses the need to exploit natural variation in resistance towards insects to increase our knowledge on resistance mechanisms and the genes involved. We will discuss how this knowledge can be exploited in breeding programmes to provide sustainable crop protection against insect pests. Additionally, we discuss the current status of genetic research on insect-resistance genes. We conclude that insect-resistance mechanisms are still unclear at the molecular level and that exploiting natural variation with novel technologies will contribute greatly to the development of insect-resistant crop varieties.

  19. Genetic variations in PI3K-AKT-mTOR pathway and bladder cancer risk.

    PubMed

    Chen, Meng; Cassidy, Adrian; Gu, Jian; Delclos, George L; Zhen, Fan; Yang, Hushan; Hildebrandt, Michelle A T; Lin, Jie; Ye, Yuanqing; Chamberlain, Robert M; Dinney, Colin P; Wu, Xifeng

    2009-12-01

    Genetic variations in phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway may affect critical cellular functions and increase an individual's cancer risk. We systematically evaluate 231 single-nucleotide polymorphisms (SNPs) in 19 genes in the PI3K-AKT-mTOR signaling pathway as predictors of bladder cancer risk. In individual SNP analysis, four SNPs in regulatory associated protein of mTOR (RAPTOR) remained significant after correcting for multiple testing: rs11653499 [odds ratio (OR): 1.79, 95% confidence interval (CI): 1.24-2.60, P = 0.002], rs7211818 (OR: 2.13, 95% CI: 1.35-3.36, P = 0.001), rs7212142 (OR: 1.57, 95% CI: 1.19-2.07, P = 0.002) and rs9674559 (OR: 2.05, 95% CI: 1.31-3.21, P = 0.002), among which rs7211818 and rs9674559 are within the same haplotype block. In haplotype analysis, compared with the most common haplotypes, haplotype containing the rs7212142 wild-type allele showed a protective effect of bladder cancer (OR: 0.83, 95% CI: 0.70-0.97). In contrast, the haplotype containing the rs7211818 variant allele showed a 1.32-fold elevated bladder cancer risk (95% CI: 1.09-1.60). In combined analysis of three independent significant RAPTOR SNPs (rs11653499, rs7211818 and rs7212142), a significant trend was observed for increased risk with an increase in the number of unfavorable genotypes (P for trend <0.001). Compared with the subjects without any of the unfavorable genotypes, those carrying all three unfavorable genotypes showed a 2.22-fold (95% CI: 1.33-3.71) increased bladder cancer risk. This is the first study to evaluate the role of germ line genetic variations in PI3K-AKT-mTOR pathway as cancer susceptibility factors that will help us identify high-risk individuals for bladder cancer.

  20. Comparative SNP diversity among four Eucalyptus species for genes from secondary metabolite biosynthetic pathways

    PubMed Central

    Külheim, Carsten; Hui Yeoh, Suat; Maintz, Jens; Foley, William J; Moran, Gavin F

    2009-01-01

    Background There is little information about the DNA sequence variation within and between closely related plant species. The combination of re-sequencing technologies, large-scale DNA pools and availability of reference gene sequences allowed the extensive characterisation of single nucleotide polymorphisms (SNPs) in genes of four biosynthetic pathways leading to the formation of ecologically relevant secondary metabolites in Eucalyptus. With this approach the occurrence and patterns of SNP variation for a set of genes can be compared across different species from the same genus. Results In a single GS-FLX run, we sequenced over 103 Mbp and assembled them to approximately 50 kbp of reference sequences. An average sequencing depth of 315 reads per nucleotide site was achieved for all four eucalypt species, Eucalyptus globulus, E. nitens, E. camaldulensis and E. loxophleba. We sequenced 23 genes from 1,764 individuals and discovered 8,631 SNPs across the species, with about 1.5 times as many SNPs per kbp in the introns compared to exons. The exons of the two closely related species (E. globulus and E. nitens) had similar numbers of SNPs at synonymous and non-synonymous sites. These species also had similar levels of SNP diversity, whereas E. camaldulensis and E. loxophleba had much higher SNP diversity. Neither the pathway nor the position in the pathway influenced gene diversity. The four species share between 20 and 43% of the SNPs in these genes. Conclusion By using conservative statistical detection methods, we were confident about the validity of each SNP. With numerous individuals sampled over the geographical range of each species, we discovered one SNP in every 33 bp for E. nitens and one in every 31 bp in E. globulus. In contrast, the more distantly related species contained more SNPs: one in every 16 bp for E. camaldulensis and one in 17 bp for E. loxophleba, which is, to the best of our knowledge, the highest frequency of SNPs described in woody plant

  1. Gene expression profiling of epithelial ovarian cancer reveals key genes and pathways associated with chemotherapy resistance.

    PubMed

    Zhang, M; Luo, S C

    2016-01-22

    The aim of this study is to analyze gene expression data to identify key genes and pathways associated with resistance to platinum-based chemotherapy in epithelial ovarian cancer (EOC) and to improve clinical treatment strategies. The gene expression data set was downloaded from Gene Expression Omnibus and included 12 chemotherapy-resistant EOC samples and 16 chemotherapy-sensitive EOC samples. A differential analysis was performed to screen out differentially expressed genes (DEGs). A functional enrichment analysis was conducted for the DEGs using the database for annotation, visualization, and integration discovery. A protein-protein interaction (PPI) network was constructed with information from the human protein reference database. Pathway-pathway interactions were determined with a test based on the hypergeometric distribution. A total of 1564 DEGs were identified in chemotherapy-sensitive EOC, including 654 upregulated genes and 910 downregulated genes. The top three upregulated genes were HIST1H3G, AKT3, and RTN3, while the top three downregulated genes were NBLA00301, TRIM62, and EPHA5. A Gene Ontology enrichment analysis showed that cell adhesion, biological adhesion, and intracellular signaling cascades were significantly enriched in the DEGs. A KEGG pathway enrichment analysis revealed that the calcium, mitogen-activated protein kinase, and B cell receptor signaling pathways were significantly over-represented in the DEGs. A PPI network containing 101 interactions was acquired. The top three hub genes were RAC1, CAV1, and BCL2. Five modules were identified from the PPI network. Taken together, these findings could advance the understanding of the molecular mechanisms underlying intrinsic chemotherapy resistance in EOC.

  2. The regions of sequence variation in caulimovirus gene VI.

    PubMed

    Sanger, M; Daubert, S; Goodman, R M

    1991-06-01

    The sequence of gene VI from figwort mosaic virus (FMV) clone x4 was determined and compared with that previously published for FMV clone DxS. Both clones originated from the same virus isolation, but the virus used to clone DxS was propagated extensively in a host of a different family prior to cloning whereas that used to clone x4 was not. Differences in the amino acid sequence inferred from the DNA sequences occurred in two clusters. An N-terminal conserved region preceded two regions of variation separated by a central conserved region. Variation in cauliflower mosaic virus (CaMV) gene VI sequences, all of which were derived from virus isolates from hosts from one host family, was similar to that seen in the FMV comparison, though the extent of variation was less. Alignment of gene VI domains from FMV and CaMV revealed regions of amino acid sequence identical in both viruses within the conserved regions. The similarity in the pattern of conserved and variable domains of these two viruses suggests common host-interactive functions in caulimovirus gene VI homologues, and possibly an analogy between caulimoviruses and certain animal viruses in the influence of the host on sequence variability of viral genes.

  3. Promoter RNA links transcriptional regulation of inflammatory pathway genes

    PubMed Central

    Matsui, Masayuki; Chu, Yongjun; Zhang, Huiying; Gagnon, Keith T.; Shaikh, Sarfraz; Kuchimanchi, Satya; Manoharan, Muthiah; Corey, David R.; Janowski, Bethany A.

    2013-01-01

    Although many long non-coding RNAs (lncRNAs) have been discovered, their function and their association with RNAi factors in the nucleus have remained obscure. Here, we identify RNA transcripts that overlap the cyclooxygenase-2 (COX-2) promoter and contain two adjacent binding sites for an endogenous miRNA, miR-589. We find that miR-589 binds the promoter RNA and activates COX-2 transcription. In addition to miR-589, fully complementary duplex RNAs that target the COX-2 promoter transcript activate COX-2 transcription. Activation by small RNA requires RNAi factors argonaute-2 (AGO2) and GW182, but does not require AGO2-mediated cleavage of the promoter RNA. Instead, the promoter RNA functions as a scaffold. Binding of AGO2 protein/small RNA complexes to the promoter RNA triggers gene activation. Gene looping allows interactions between the promoters of COX-2 and phospholipase A2 (PLA2G4A), an adjacent pro-inflammatory pathway gene that produces arachidonic acid, the substrate for COX-2 protein. miR-589 and fully complementary small RNAs regulate both COX-2 and PLA2G4A gene expression, revealing an unexpected connection between key steps of the eicosanoid signaling pathway. The work demonstrates the potential for RNA to coordinate locus-dependent assembly of related genes to form functional operons through cis-looping. PMID:23999091

  4. Horizontal gene transfer and the evolution of methanogenic pathways.

    PubMed

    Fournier, Greg

    2009-01-01

    Horizontal gene transfer (HGT) is a driving force in the evolution of metabolic pathways, allowing novel enzymatic functions that provide a selective advantage to be rapidly incorporated into an organism's physiology. Here, the role of two HGT events in the evolution of methanogenesis is described. First, the acetoclastic sub-pathway of methanogenesis is shown to have evolved via a transfer of the ackA and pta genes from a cellulolytic clostridia to a family of methanogenic archaea. Second, the system for encoding the amino acid pyrrolysine, used for the synthesis of enzymes for methanogenesis from methylamines, is shown to likely have evolved via transfer from an ancient, unknown, deeply branching organismal lineage.

  5. Copy number variations exploration of multiple genes in Graves’ disease

    PubMed Central

    Song, Rong-hua; Shao, Xiao-qing; Li, Ling; Wang, Wen; Zhang, Jin-an

    2017-01-01

    Abstract Background: Few previous published papers reported copy number variations of genes could affect the predisposition of Graves’ disease (GD). Herein, the aim of this study was to explore the association between copy number variations (CNV) profile and GD. Methods: The preliminary copy number microarray used to screen copy number variant genes was performed in 6 GD patients. Five CNV candidate genes (CFH, CFHR1, KIAA0125, UGT2B15, and UGT2B17) were then validated in an independent set of samples (50 GD patients and 50 matched healthy ones) by the Accucopy assay method. The CNV of the other 2 genes TRY6 and CCL3L1 was investigated in 144 GD patients and 144 healthy volunteers by the definitive genotyping technique using the Taqman quantitative polymerase-chain-reaction (Taqman qPCR). TRY6 gene-associated single nucleotide polymorphism (SNP), rs13230029, was genotyped by the PCR-ligase detection reaction (LDR) in 675 GD patients and 898 healthy controls. Results: There were no correlation of the gene copy number (GCN) of CFH, CFHR1, KIAA0125, UGT2B15, and UGT2B17 with GD. In comparison with that of controls, the GCN distribution of TRY6 and CCL3L1 in GD patients did not show significantly differ (P > 0.05). Furthermore, TRY6-related polymorphism (rs13230029) showed no difference between GD patients and controls. No correlation was found between CNV or SNP genotype and clinical phenotypes. Generally, there were no link of the copy numbers of several genes, including CFH, CFHR1, KIAA0125, UGT2B15, UGT2B17, TRY6, and CCL3L1 to GD. Conclusion: Our results clearly indicated that the copy number variations of multiple genes, namely CFH, CFHR1, KIAA0125, UGT2B15, UGT2B17, TRY6, and CCL3L1, were not associated with the development of GD. PMID:28121931

  6. Copy number variations exploration of multiple genes in Graves' disease.

    PubMed

    Song, Rong-Hua; Shao, Xiao-Qing; Li, Ling; Wang, Wen; Zhang, Jin-An

    2017-01-01

    Few previous published papers reported copy number variations of genes could affect the predisposition of Graves' disease (GD). Herein, the aim of this study was to explore the association between copy number variations (CNV) profile and GD. The preliminary copy number microarray used to screen copy number variant genes was performed in 6 GD patients. Five CNV candidate genes (CFH, CFHR1, KIAA0125, UGT2B15, and UGT2B17) were then validated in an independent set of samples (50 GD patients and 50 matched healthy ones) by the Accucopy assay method. The CNV of the other 2 genes TRY6 and CCL3L1 was investigated in 144 GD patients and 144 healthy volunteers by the definitive genotyping technique using the Taqman quantitative polymerase-chain-reaction (Taqman qPCR). TRY6 gene-associated single nucleotide polymorphism (SNP), rs13230029, was genotyped by the PCR-ligase detection reaction (LDR) in 675 GD patients and 898 healthy controls. There were no correlation of the gene copy number (GCN) of CFH, CFHR1, KIAA0125, UGT2B15, and UGT2B17 with GD. In comparison with that of controls, the GCN distribution of TRY6 and CCL3L1 in GD patients did not show significantly differ (P > 0.05). Furthermore, TRY6-related polymorphism (rs13230029) showed no difference between GD patients and controls. No correlation was found between CNV or SNP genotype and clinical phenotypes. Generally, there were no link of the copy numbers of several genes, including CFH, CFHR1, KIAA0125, UGT2B15, UGT2B17, TRY6, and CCL3L1 to GD. Our results clearly indicated that the copy number variations of multiple genes, namely CFH, CFHR1, KIAA0125, UGT2B15, UGT2B17, TRY6, and CCL3L1, were not associated with the development of GD.

  7. Gene Expression Profiling of Biological Pathway Alterations by Radiation Exposure

    PubMed Central

    Lee, Kuei-Fang; Weng, Julia Tzu-Ya; Hsu, Paul Wei-Che; Chi, Yu-Hsiang; Chen, Ching-Kai; Liu, Ingrid Y.; Chen, Yi-Cheng; Wu, Lawrence Shih-Hsin

    2014-01-01

    Though damage caused by radiation has been the focus of rigorous research, the mechanisms through which radiation exerts harmful effects on cells are complex and not well-understood. In particular, the influence of low dose radiation exposure on the regulation of genes and pathways remains unclear. In an attempt to investigate the molecular alterations induced by varying doses of radiation, a genome-wide expression analysis was conducted. Peripheral blood mononuclear cells were collected from five participants and each sample was subjected to 0.5 Gy, 1 Gy, 2.5 Gy, and 5 Gy of cobalt 60 radiation, followed by array-based expression profiling. Gene set enrichment analysis indicated that the immune system and cancer development pathways appeared to be the major affected targets by radiation exposure. Therefore, 1 Gy radioactive exposure seemed to be a critical threshold dosage. In fact, after 1 Gy radiation exposure, expression levels of several genes including FADD, TNFRSF10B, TNFRSF8, TNFRSF10A, TNFSF10, TNFSF8, CASP1, and CASP4 that are associated with carcinogenesis and metabolic disorders showed significant alterations. Our results suggest that exposure to low-dose radiation may elicit changes in metabolic and immune pathways, potentially increasing the risk of immune dysfunctions and metabolic disorders. PMID:25276823

  8. Genetic variation in the rhythmonome: ethnic variation and haplotype structure in candidate genes for arrhythmias

    PubMed Central

    Bush, William S; Crawford, Dana C; Alexander, Charles; George, Alfred L; Roden, Dan M; Ritchie, Marylyn D

    2009-01-01

    Aims The ‘rhythmonome’ is the term we have adopted to describe the set of genes that determine the normal coordinated electrical activity in the heart. Elements of this set include pore-forming ion channels, function-modifying proteins and intracellular calcium control elements. Rare mutations in many of these genes are known to cause unusual congenital monogenic arrhythmia syndromes, and single common variants have been reported to modify arrhythmia phenotypes. Here, we report an evaluation of the variation and haplotype structure in six key components of the rhythmonome. Materials & methods SNPs were typed using DNA extracted from Coriell cell lines to survey allele frequencies and haplotype structure in six genes (ANK2, SCN5A, KCNE1 and 2 gene cluster, KCNQ1, KCNH2 and RYR2) across four human populations (African—American, European American, Han Chinese and Mexican American). Results A total of 307 SNPs were analyzed across the six genes, revealing significant allele-frequency differences between populations and clear differences in haplotype structure. Conclusions The pattern of variation we report is an important step towards incorporating common variation across the rhythmonome in studies of arrhythmia susceptibility. PMID:19530973

  9. Detecting gene subnetworks under selection in biological pathways.

    PubMed

    Gouy, Alexandre; Daub, Joséphine T; Excoffier, Laurent

    2017-09-19

    Advances in high throughput sequencing technologies have created a gap between data production and functional data analysis. Indeed, phenotypes result from interactions between numerous genes, but traditional methods treat loci independently, missing important knowledge brought by network-level emerging properties. Therefore, detecting selection acting on multiple genes affecting the evolution of complex traits remains challenging. In this context, gene network analysis provides a powerful framework to study the evolution of adaptive traits and facilitates the interpretation of genome-wide data. We developed a method to analyse gene networks that is suitable to evidence polygenic selection. The general idea is to search biological pathways for subnetworks of genes that directly interact with each other and that present unusual evolutionary features. Subnetwork search is a typical combinatorial optimization problem that we solve using a simulated annealing approach. We have applied our methodology to find signals of adaptation to high-altitude in human populations. We show that this adaptation has a clear polygenic basis and is influenced by many genetic components. Our approach, implemented in the R package signet, improves on gene-level classical tests for selection by identifying both new candidate genes and new biological processes involved in adaptation to altitude. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  10. Gene variants in the angiogenesis pathway and prostate cancer

    PubMed Central

    Amankwah, Ernest K.; Sellers, Thomas A.; Park, Jong Y.

    2012-01-01

    Although the causes of prostate cancer are still unknown, numerous studies support the role of genetic factors in the development and progression of this disease. Single nucleotide polymorphisms (SNPs) in key angiogenesis genes have been studied in prostate cancer. In this review, we provide an overview of the current knowledge of the role of genetic variants in the angiogenesis pathway in prostate cancer risk and progression. Of the 17 prostate cancer genome-wide association studies (GWAS) conducted to date, only one identified disease-associated SNPs in a region of an angiogenesis pathway gene. An association was observed between aggressive disease and three intergenic SNPs (rs11199874, rs10749408 and rs10788165) in a region on chromosome 10q26 that encompasses FGFR2. The majority (27/32, 84.4%) of primary candidate gene studies reviewed had a small (n < 800, 20/32, 62.5%) to medium sample size (n = 800–2000, 7/32, 21.9%), whereas only five (15.6%) had a large sample size (n ≥ 2000). Results from the large studies revealed associations with risk and aggressive disease for SNPs in NOS2A, NOS3 and MMP-2 and risk for HIF1-α. Meta-analyses have so far been conducted on FGFR2, TGF-β, TNF-α, HIF1-α and IL10 and the results reveal an association with risk for SNPs in FGFR2 and TGF-β and aggressive disease for SNPs in IL-10. Thus, existing evidence from GWAS and large candidate gene studies indicates that SNPs from a limited number of angiogenesis pathway genes are associated with prostate cancer risk and progression. PMID:22523086

  11. Gene profiling of the red light signalling pathways in roots.

    PubMed

    Molas, Maria Lia; Kiss, John Z; Correll, Melanie J

    2006-01-01

    Red light, acting through the phytochromes, controls numerous aspects of plant development. Many of the signal transduction elements downstream of the phytochromes have been identified in the aerial portions of the plant; however, very few elements in red-light signalling have been identified specifically for roots. Gene profiling studies using microarrays and quantitative Real-Time PCR were performed to characterize gene expression changes in roots of Arabidopsis seedlings exposed to 1 h of red light. Several factors acting downstream of phytochromes in red-light signalling in roots were identified. Some of the genes found to be differentially expressed in this study have already been characterized in the red-light-signalling pathway for whole plants. For example, PHYTOCHROME KINASE 1 (PKS1), LONG HYPOCOTYL 5 (HY5), EARLY FLOWERING 4 (ELF4), and GIGANTEA (GI) were all significantly up-regulated in roots of seedlings exposed to 1 h of red light. The up-regulation of SUPPRESSOR OF PHYTOCHROME A RESPONSES 1 (SPA1) and CONSTITUTIVE PHOTOMORPHOGENIC 1-like (COP1-like) genes suggests that the PHYA-mediated pathway was attenuated by red light. In addition, genes involved in lateral root and root hair formation, root plastid development, phenylpropanoid metabolism, and hormone signalling were also regulated by exposure to red light. Interestingly, members of the RPT2/NPH3 (ROOT PHOTOTROPIC 2/NON PHOTOTROPIC HYPOCOTYL 3) family, which have been shown to mediate blue-light-induced phototropism, were also differentially regulated in roots in red light. Therefore, these results suggest that red and blue light pathways interact in roots of seedlings and that many elements involved in red-light-signalling found in the aerial portions of the plant are differentially expressed in roots within 1 h of red light exposure.

  12. Steroidogenesis of the testis -- new genes and pathways.

    PubMed

    Flück, Christa E; Pandey, Amit V

    2014-05-01

    Defects of androgen biosynthesis cause 46,XY disorder of sexual development (DSD). All steroids are produced from cholesterol and the early steps of steroidogenesis are common to mineralocorticoid, glucocorticoid and sex steroid production. Genetic mutations in enzymes and proteins supporting the early biosynthesis pathways cause adrenal insufficiency (AI), DSD and gonadal insufficiency. The classic androgen biosynthesis defects with AI are lipoid CAH, CYP11A1 and HSD3B2 deficiencies. Deficiency of CYP17A1 rarely causes AI, and HSD17B3 or SRD5A2 deficiencies only cause 46,XY DSD and gonadal insufficiency. All androgen biosynthesis depends on 17,20 lyase activity of CYP17A1 which is supported by P450 oxidoreductase (POR) and cytochrome b5 (CYB5). Therefore 46,XY DSD with apparent 17,20 lyase deficiency may be due to mutations in CYP17A1, POR or CYB5. Illustrated by patients harboring mutations in SRD5A2, normal development of the male external genitalia depends largely on dihydrotestosterone (DHT) which is converted from circulating testicular testosterone (T) through SRD5A2 in the genital skin. In the classic androgen biosynthetic pathway, T is produced from DHEA and androstenedione/-diol in the testis. However, recently found mutations in AKR1C2/4 genes in undervirilized 46,XY individuals have established a role for a novel, alternative, backdoor pathway for fetal testicular DHT synthesis. In this pathway, which has been first elucidated for the tammar wallaby pouch young, 17-hydroxyprogesterone is converted directly to DHT by 5α-3α reductive steps without going through the androgens of the classic pathway. Enzymes AKR1C2/4 catalyse the critical 3αHSD reductive reaction which feeds 17OH-DHP into the backdoor pathway. In conclusion, androgen production in the fetal testis seems to utilize two pathways but their exact interplay remains to be elucidated.

  13. Variation of Dominance of Newly Arisen Adaptive Genes

    PubMed Central

    Bourguet, D.; Lenormand, T.; Guillemaud, T.; Marcel, V.; Fournier, D.; Raymond, M.

    1997-01-01

    Newly arisen adaptive alleles such as insecticide resistance genes represent a good opportunity to investigate the theories put forth to explain the molecular basis of dominance and its possible evolution. Dominance levels of insecticide resistance conferred by insensitive alleles of the acetylcholinesterase gene were analyzed in five resistant strains of the mosquito Culex pipiens. Dominance levels were found to differ between strains, varying from partial recessivity to complete dominance. This variation was not explained by differences in catalytic properties of the enzyme, since four of the five resistant strains had identical inhibition properties for the insensitive acetylcholinesterase. Among these four laboratory strains and in individuals collected from natural populations, we found a correlation between increased acetylcholinesterase activities and higher dominance levels. We propose a molecular explanation for how variation in acetylcholinesterase activity may result in variation of dominance level. We also conjecture that the four resistant strains did not differ in their amino acid sequence in the catalytically active regions of acetylcholinesterase, but that the expression of the gene was regulated by either neighboring or distant sites, thereby modifying the dominance level. Under this interpretation, dominance levels may evolve in this system, since heritable variation in acetylcholinesterase activity was found. PMID:9383065

  14. Variation of dominance of newly arisen adaptive genes.

    PubMed

    Bourguet, D; Lenormand, T; Guillemaud, T; Marcel, V; Fournier, D; Raymond, M

    1997-11-01

    Newly arisen adaptive alleles such as insecticide resistance genes represent a good opportunity to investigate the theories put forth to explain the molecular basis of dominance and its possible evolution. Dominance levels of insecticide resistance conferred by insensitive alleles of the acetylcholinesterase gene were analyzed in five resistant strains of the mosquito Culex pipiens. Dominance levels were found to differ between strains, varying from partial recessivity to complete dominance. This variation was not explained by differences in catalytic properties of the enzyme, since four of the five resistant strains had identical inhibition properties for the insensitive acetylcholinesterase. Among these four laboratory strains and in individuals collected from natural populations, we found a correlation between increased acetylcholinesterase activities and higher dominance levels. We propose a molecular explanation for how variation in acetylcholinesterase activity may result in variation of dominance level. We also conjecture that the four resistant strains did not differ in their amino acid sequence in the catalytically active regions of acetylcholinesterase, but that the expression of the gene was regulated by either neighboring or distant sites, thereby modifying the dominance level. Under this interpretation, dominance levels may evolve in this system, since heritable variation in acetylcholinesterase activity was found.

  15. Genetic variation in the parasympathetic signaling pathway in patients with reflex syncope.

    PubMed

    Holmegard, H N; Benn, M; Mehlsen, J; Haunsø, S

    2013-01-30

    Reflex syncope is defined by a self-terminating transient loss of consciousness associated with an exaggerated response of the vagal reflexes upon orthostatic challenges. A hereditary component has previously been suggested. We hypothesized that variations in genes encoding proteins mediating the vagal signaling in the heart may be involved in reflex syncope pathogenesis. We systematically resequenced the entire coding regions and flanking intron sequences in 5 genes in the cardiac post-synaptic parasympathetic signaling pathway [muscarinic acetylcholine receptor M2 (CHRM2); G-protein beta-1 subunit (GNB1); G-protein gamma-2 subunit (GNG2); potassium inwardly rectifying channel, subfamily J, member 3 (KCNJ3); and potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5)] in 74 patients with well-characterized reflex syncope of either cardioinhibitory [Vasovagal Syncope International Study (VASIS-IIB), N = 38] or vasodepressor (VASIS-III, N = 36) type. We identified 2 novel genetic variants (CHRM2 c.1114C>G and GNG2 c.87+34G>A) and several known variants (GNB1: c.267+14G>A, c.267+19C>T, and c.738C>T; KCNJ3: c.119A>G, c.591C>T, c.1038T>C, and c.1494T>C; KCNJ5: c. 171T>C, c.810T>G, c.834T>C, c.844C>G, c.938+7C>T, and c.938-10G>A). The minor allele frequency of the KCNJ5 c.938+7C>T variant was significantly lower in patients than in the control group (0.014 versus 0.089, P = 0.001), and the frequency of heterozygosity and homozygosity was lower in cardioinhibitory patients compared to controls. Genetic variations in genes responsible for the vagal signaling in the heart, including CHRM2, GNB1, GNG2, KCNJ3, and KCNJ5, are not major contributors to the pathogenesis of reflex syncope of vasodepressor or cardioinhibitory types.

  16. Exploring the key genes and pathways of osteosarcoma with pulmonary metastasis using a gene expression microarray.

    PubMed

    Shi, Zhongju; Zhou, Hengxing; Pan, Bin; Lu, Lu; Wei, Zhijian; Shi, Linlin; Yao, Xue; Kang, Yi; Feng, Shiqing

    2017-09-21

    Osteosarcoma is a common and highly malignant tumour in children and teenagers that is characterized by drug resistance and high metastatic potential. Patients often develop pulmonary metastasis and have a low survival rate. However, the mechanistic basis for pulmonary metastasis remains unclear. To identify key gene and pathways associated with pulmonary metastasis of osteosarcoma, the authors downloaded the gene expression dataset GSE85537 and obtained the differentially expressed genes (DEGs) by analyzing high‑throughput gene expression in primary tumours and lung metastases. Subsequently, the authors performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses and a protein‑protein interaction (PPI) network was constructed and analyzed by Cytoscape software. In total, 2,493 genes were identified as DEGs. Of these, 485 genes (19.45%) were upregulated, and the remaining 2,008 genes (80.55%) were downregulated. The authors identified the predominant GO categories and KEGG pathways that were significantly over‑represented in the metastatic OS samples compared with the non‑metastatic OS samples. A PPI network was constructed, and the results indicated that ALB, EGFR, INS, IL6, CDH1, FYN, ERBB2, IL8, CXCL12 and RAC2 were the top 10 core genes. The enrichment analyses of the genes involved in the top three significant modules demonstrated that the DEGs were principally related to neuroactive ligand‑receptor interaction, the Rap1 signaling pathway, and protein digestion and absorption. Together, these data elucidated the molecular mechanisms of OS patients with pulmonary metastasis and provide potential therapeutic targets. However, further experimental studies are needed to confirm these results.

  17. Haplotype association analysis of genes within the WNT signalling pathways in diabetic nephropathy

    PubMed Central

    2013-01-01

    Background Renal interstitial fibrosis and glomerular sclerosis are hallmarks of diabetic nephropathy (DN) and several studies have implicated members of the WNT pathways in these pathological processes. This study comprehensively examined common genetic variation within the WNT pathway for association with DN. Methods Genes within the WNT pathways were selected on the basis of nominal significance and consistent direction of effect in the GENIE meta-analysis dataset. Common SNPs and common haplotypes were examined within the selected WNT pathway genes in a white population with type 1 diabetes, discordant for DN (cases: n = 718; controls: n = 749). SNPs were genotyped using Sequenom or Taqman assays. Association analyses were performed using PLINK, to compare allele and haplotype frequencies in cases and controls. Correction for multiple testing was performed by either permutation testing or using false discovery rate. Results A logistic regression model including collection centre, duration of diabetes, and average HbA1c as covariates highlighted three SNPs in GSK3B (rs17810235, rs17471, rs334543), two in DAAM1 (rs1253192, rs1252906) and one in NFAT5 (rs17297207) as being significantly (P < 0.05) associated with DN, however these SNPs did not remain significant after correction for multiple testing. Logistic regression of haplotypes, with ESRD as the outcome, and pairwise interaction analyses did not yield any significant results after correction for multiple testing. Conclusions These results indicate that both common SNPs and common haplotypes of WNT pathway genes are not strongly associated with DN. However, this does not completely exclude these or the WNT pathways from association with DN, as unidentified rare genetic or copy number variants could still contribute towards the genetic architecture of DN. PMID:23777469

  18. Integrated signaling pathway and gene expression regulatory model to dissect dynamics of Escherichia coli challenged mammary epithelial cells.

    PubMed

    den Breems, Nicoline Y; Nguyen, Lan K; Kulasiri, Don

    2014-12-01

    Cells transform external stimuli, through the activation of signaling pathways, which in turn activate gene regulatory networks, in gene expression. As more omics data are generated from experiments, eliciting the integrated relationship between the external stimuli, the signaling process in the cell and the subsequent gene expression is a major challenge in systems biology. The complex system of non-linear dynamic protein interactions in signaling pathways and gene networks regulates gene expression. The complexity and non-linear aspects have resulted in the study of the signaling pathway or the gene network regulation in isolation. However, this limits the analysis of the interaction between the two components and the identification of the source of the mechanism differentiating the gene expression profiles. Here, we present a study of a model of the combined signaling pathway and gene network to highlight the importance of integrated modeling. Based on the experimental findings we developed a compartmental model and conducted several simulation experiments. The model simulates the mRNA expression of three different cytokines (RANTES, IL8 and TNFα) regulated by the transcription factor NFκB in mammary epithelial cells challenged with E. coli. The analysis of the gene network regulation identifies a lack of robustness and therefore sensitivity for the transcription factor regulation. However, analysis of the integrated signaling and gene network regulation model reveals distinctly different underlying mechanisms in the signaling pathway responsible for the variation between the three cytokine's mRNA expression levels. Our key findings reveal the importance of integrating the signaling pathway and gene expression dynamics in modeling. Modeling infers valid research questions which need to be verified experimentally and can assist in the design of future biological experiments.

  19. GAGE: generally applicable gene set enrichment for pathway analysis

    PubMed Central

    Luo, Weijun; Friedman, Michael S; Shedden, Kerby; Hankenson, Kurt D; Woolf, Peter J

    2009-01-01

    Background Gene set analysis (GSA) is a widely used strategy for gene expression data analysis based on pathway knowledge. GSA focuses on sets of related genes and has established major advantages over individual gene analyses, including greater robustness, sensitivity and biological relevance. However, previous GSA methods have limited usage as they cannot handle datasets of different sample sizes or experimental designs. Results To address these limitations, we present a new GSA method called Generally Applicable Gene-set Enrichment (GAGE). We successfully apply GAGE to multiple microarray datasets with different sample sizes, experimental designs and profiling techniques. GAGE shows significantly better results when compared to two other commonly used GSA methods of GSEA and PAGE. We demonstrate this improvement in the following three aspects: (1) consistency across repeated studies/experiments; (2) sensitivity and specificity; (3) biological relevance of the regulatory mechanisms inferred. GAGE reveals novel and relevant regulatory mechanisms from both published and previously unpublished microarray studies. From two published lung cancer data sets, GAGE derived a more cohesive and predictive mechanistic scheme underlying lung cancer progress and metastasis. For a previously unpublished BMP6 study, GAGE predicted novel regulatory mechanisms for BMP6 induced osteoblast differentiation, including the canonical BMP-TGF beta signaling, JAK-STAT signaling, Wnt signaling, and estrogen signaling pathways–all of which are supported by the experimental literature. Conclusion GAGE is generally applicable to gene expression datasets with different sample sizes and experimental designs. GAGE consistently outperformed two most frequently used GSA methods and inferred statistically and biologically more relevant regulatory pathways. The GAGE method is implemented in R in the "gage" package, available under the GNU GPL from . PMID:19473525

  20. Human factors and pathways essential for mediating epigenetic gene silencing.

    PubMed

    Poleshko, Andrey; Kossenkov, Andrew V; Shalginskikh, Natalia; Pecherskaya, Anna; Einarson, Margret B; Marie Skalka, Anna; Katz, Richard A

    2014-09-01

    Cellular identity in both normal and disease processes is determined by programmed epigenetic activation or silencing of specific gene subsets. Here, we have used human cells harboring epigenetically silent GFP-reporter genes to perform a genome-wide siRNA knockdown screen for the identification of cellular factors that are required to maintain epigenetic gene silencing. This unbiased screen interrogated 21,121 genes, and we identified and validated a set of 128 protein factors. This set showed enrichment for functional categories, and protein-protein interactions. Among this set were known epigenetic silencing factors, factors with no previously identified role in epigenetic gene silencing, as well as unstudied factors. The set included non-nuclear factors, for example, components of the integrin-adhesome. A key finding was that the E1 and E2 enzymes of the small ubiquitin-like modifier (SUMO) pathway (SAE1, SAE2/UBA2, UBC9/UBE2I) are essential for maintenance of epigenetic silencing. This work provides the first genome-wide functional view of human factors that mediate epigenetic gene silencing. The screen output identifies novel epigenetic factors, networks, and mechanisms, and provides a set of candidate targets for epigenetic therapy and cellular reprogramming.

  1. Detecting Pathway-Based Gene-Gene and Gene-Environment Interactions in Pancreatic Cancer

    PubMed Central

    Duell, Eric J.; Bracci, Paige M.; Moore, Jason H.; Burk, Robert D.; Kelsey, Karl T.; Holly, Elizabeth A.

    2015-01-01

    Data mining and data reduction methods to detect interactions in epidemiologic data are being developed and tested. In these analyses, multifactor dimensionality reduction, focused interaction testing framework, and traditional logistic regression models were used to identify potential interactions with up to three factors. These techniques were used in a population-based case-control study of pancreatic cancer from the San Francisco Bay Area (308 cases, 964 controls). From 7 biochemical pathways, along with tobacco smoking, 26 polymorphisms in 20 genes were included in these analyses. Combinations of genetic markers and cigarette smoking were identified as potential risk factors for pancreatic cancer, including genes in base excision repair (OGG1), nucleotide excision repair (XPD, XPA, XPC), and double-strand break repair (XRCC3). XPD.751, XPD.312, and cigarette smoking were the best single-factor predictors of pancreatic cancer risk, whereas XRCC3.241*smoking and OGG1.326*XPC.PAT were the best two-factor predictors. There was some evidence for a three-factor combination of OGG1.326*XPD.751*smoking, but the covariate-adjusted relative-risk estimates lacked precision. Multifactor dimensionality reduction and focused interaction testing framework showed little concordance, whereas logistic regression allowed for covariate adjustment and model confirmation. Our data suggest that multiple common alleles from DNA repair pathways in combination with cigarette smoking may increase the risk for pancreatic cancer, and that multiple approaches to data screening and analysis are necessary to identify potentially new risk factor combinations. PMID:18559563

  2. Identifying the risk of producing aneuploids using meiotic recombination genes as biomarkers: A copy number variation approach

    PubMed Central

    Suresh, Raviraj V.; Lingaiah, Kusuma; Veerappa, Avinash M.; Ramachandra, Nallur B.

    2017-01-01

    Background & objectives: Aneuploids are the most common chromosomal abnormality in liveborns and are usually the result of non-disjunction (NDJ) in meiosis. Copy number variations (CNVs) are large structural variations affecting the human genome. CNVs influence critical genes involved in causing NDJ by altering their copy number which affects the clinical outcome. In this study influence of CNVs on critical meiotic recombination was examined using new computational technologies to assess their role in causing aneuploidy. Methods: This investigation was based on the analysis of 12 random normal populations consisting of 1714 individuals for aneuploid causing genes under CNV effect. To examine the effect of CNVs on genes causing aneuploidy, meiotic recombination genes were analyzed using EnrichR, WebGestalt and Ingenuity Pathway Analysis (IPA). Results: Forty three NDJ genes were found under CNV burden; IPA (Ingenuity Pathway Analysis) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis of CNV in meiotic recombination genes revealed a significant role of breast cancer gene 1, amyloid protein precursor, mitogen-activated protein kinase and nerve growth factor as key molecular players involved in causing aneuploidy. Interaction between these genes with other CNV-overlapping genes involved in cell cycle, recombination and meiosis might lead to increased incidences of aneuploidy. Interpretation & conclusions: The findings of this study implied that the effect of CNVs on normal genome contributed in amplifying the occurrences of chromosomal aneuploidies. The normal individuals consisting of variations in the susceptible genes causing aneuploids in the population remain undetected until the disorder genes express in the succeeding generations. PMID:28574013

  3. Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

    PubMed Central

    Kelemen, Linda E.; Terry, Kathryn L.; Goodman, Marc T.; Webb, Penelope M.; Bandera, Elisa V.; McGuire, Valerie; Rossing, Mary Anne; Wang, Qinggang; Dicks, Ed; Tyrer, Jonathan P.; Song, Honglin; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Timorek, Agnieszka; Menon, Usha; Gentry-Maharaj, Aleksandra; Gayther, Simon A.; Ramus, Susan J.; Narod, Steven A.; Risch, Harvey A.; McLaughlin, John R.; Siddiqui, Nadeem; Glasspool, Rosalind; Paul, James; Carty, Karen; Gronwald, Jacek; Lubiński, Jan; Jakubowska, Anna; Cybulski, Cezary; Kiemeney, Lambertus A.; Massuger, Leon F. A. G.; van Altena, Anne M.; Aben, Katja K. H.; Olson, Sara H.; Orlow, Irene; Cramer, Daniel W.; Levine, Douglas A.; Bisogna, Maria; Giles, Graham G.; Southey, Melissa C.; Bruinsma, Fiona; Kjær, Susanne Krüger; Høgdall, Estrid; Jensen, Allan; Høgdall, Claus K.; Lundvall, Lene; Engelholm, Svend-Aage; Heitz, Florian; du Bois, Andreas; Harter, Philipp; Schwaab, Ira; Butzow, Ralf; Nevanlinna, Heli; Pelttari, Liisa M.; Leminen, Arto; Thompson, Pamela J.; Lurie, Galina; Wilkens, Lynne R.; Lambrechts, Diether; Van Nieuwenhuysen, Els; Lambrechts, Sandrina; Vergote, Ignace; Beesley, Jonathan; Fasching, Peter A.; Beckmann, Matthias W.; Hein, Alexander; Ekici, Arif B.; Doherty, Jennifer A.; Wu, Anna H.; Pearce, Celeste L.; Pike, Malcolm C.; Stram, Daniel; Chang-Claude, Jenny; Rudolph, Anja; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo B.; Bogdanova, Natalia; Antonenkova, Natalia; Odunsi, Kunle; Edwards, Robert P.; Kelley, Joseph L.; Modugno, Francesmary; Ness, Roberta B.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Fridley, Brooke L.; Vierkant, Robert A.; Cunningham, Julie M.; Wu, Xifeng; Lu, Karen; Liang, Dong; Hildebrandt, Michelle A.T.; Weber, Rachel Palmieri; Iversen, Edwin S.; Tworoger, Shelley S.; Poole, Elizabeth M.; Salvesen, Helga B.; Krakstad, Camilla; Bjorge, Line; Tangen, Ingvild L.; Pejovic, Tanja; Bean, Yukie; Kellar, Melissa; Wentzensen, Nicolas; Brinton, Louise A.; Lissowska, Jolanta; Garcia-Closas, Montserrat; Campbell, Ian G.; Eccles, Diana; Whittemore, Alice S.; Sieh, Weiva; Rothstein, Joseph H.; Anton-Culver, Hoda; Ziogas, Argyrios; Phelan, Catherine M.; Moysich, Kirsten B.; Goode, Ellen L.; Schildkraut, Joellen M.; Berchuck, Andrew; Pharoah, Paul D.P.; Sellers, Thomas A.; Brooks-Wilson, Angela; Cook, Linda S.; Le, Nhu D.

    2014-01-01

    Scope We re-evaluated previously reported associations between variants in pathways of one-carbon (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. Methods and Results Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls and among 2,281 cases and 3,444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for DPYD variants rs11587873 (OR=0.92, P=6x10−5) and rs828054 (OR=1.06, P=1x10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT and TYMS, also interacted significantly with folate in a multi-variant analysis (corrected P=9.9x10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in one-carbon transfer, previously reported with OC, suggested lower risk at higher folate (Pinteraction=0.03-0.006). Conclusions Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-byfolate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC. PMID:25066213

  4. Gene microarray assessment of multiple genes and signal pathways involved in androgen-dependent prostate cancer becoming androgen independent.

    PubMed

    Liu, Jun-Bao; Dai, Chun-Mei; Su, Xiao-Yun; Cao, Lu; Qin, Rui; Kong, Qing-Bo

    2014-01-01

    To study the gene expression change and possible signal pathway during androgen-dependent prostate cancer (ADPC) becoming androgen-independent prostate cancer (AIPC), an LNCaP cell model of AIPC was established using flutamide in combination with androgen-free environment inducement, and differential expression genes were screened by microarray. Then the biological process, molecular function and KEGG pathway of differential expression genes are analyzed by Molecule Annotation System (MAS). By comparison of 12,207 expression genes, 347 expression genes were acquired, of which 156 were up-ragulated and 191 down-regulated. After analyzing the biological process and molecule function of differential expression genes, these genes are found to play crucial roles in cell proliferation, differntiation, cell cycle control, protein metabolism and modification and other biological process, serve as signal molecules, enzymes, peptide hormones, cytokines, cytoskeletal proteins and adhesion molecules. The analysis of KEGG show that the relevant genes of AIPC transformation participate in glutathione metabolism, cell cycle, P53 signal pathway, cytochrome P450 metabolism, Hedgehog signal pathway, MAPK signal pathway, adipocytokines signal pathway, PPAR signal pathway, TGF-β signal pathway and JAK-STAT signal pathway. In conclusion, during the process of ADPC becoming AIPC, it is not only one specific gene or pathway, but multiple genes and pathways that change. The findings above lay the foundation for study of AIPC mechanism and development of AIPC targeting drugs.

  5. Partitioning of genetic variation between regulatory and coding gene segments: the predominance of software variation in genes encoding introvert proteins.

    PubMed

    Mitchison, A

    1997-01-01

    In considering genetic variation in eukaryotes, a fundamental distinction can be made between variation in regulatory (software) and coding (hardware) gene segments. For quantitative traits the bulk of variation, particularly that near the population mean, appears to reside in regulatory segments. The main exceptions to this rule concern proteins which handle extrinsic substances, here termed extrovert proteins. The immune system includes an unusually large proportion of this exceptional category, but even so its chief source of variation may well be polymorphism in regulatory gene segments. The main evidence for this view emerges from genome scanning for quantitative trait loci (QTL), which in the case of the immune system points to a major contribution of pro-inflammatory cytokine genes. Further support comes from sequencing of major histocompatibility complex (Mhc) class II promoters, where a high level of polymorphism has been detected. These Mhc promoters appear to act, in part at least, by gating the back-signal from T cells into antigen-presenting cells. Both these forms of polymorphism are likely to be sustained by the need for flexibility in the immune response. Future work on promoter polymorphism is likely to benefit from the input from genome informatics.

  6. Genetic variants in sex hormone metabolic pathway genes and risk of esophageal squamous cell carcinoma.

    PubMed

    Hyland, Paula L; Freedman, Neal D; Hu, Nan; Tang, Ze-Zhong; Wang, Lemin; Wang, Chaoyu; Ding, Ti; Fan, Jin-Hu; Qiao, You-Lin; Golozar, Asieh; Wheeler, William; Yu, Kai; Yuenger, Jeff; Burdett, Laurie; Chanock, Stephen J; Dawsey, Sanford M; Tucker, Margaret A; Goldstein, Alisa M; Abnet, Christian C; Taylor, Philip R

    2013-05-01

    In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high-incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single-nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway- and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P = 0.14) or subpathways (androgen synthesis: P = 0.30, estrogen synthesis: P = 0.15 and estrogen removal: P = 0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P < 0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations.

  7. Genetic variants in sex hormone metabolic pathway genes and risk of esophageal squamous cell carcinoma

    PubMed Central

    Hyland, Paula L.

    2013-01-01

    In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high-incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single-nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway- and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P = 0.14) or subpathways (androgen synthesis: P = 0.30, estrogen synthesis: P = 0.15 and estrogen removal: P = 0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P < 0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations. PMID:23358850

  8. The IGF1 pathway genes and their association with age of puberty in cattle.

    PubMed

    Fortes, Marina R S; Li, Yutao; Collis, Eliza; Zhang, Yuandan; Hawken, Rachel J

    2013-02-01

    Insulin-like growth factor I (somatomedin C) (IGF1) influences gonadotrophin-releasing hormone (GnRH) neurons during puberty, and GnRH release guides pubertal development. Therefore, genes of the IGF1 pathway are biological candidates for the identification of single-nucleotide polymorphisms (SNPs) affecting age of puberty. In a genome-wide association study, genotyped heifers were Tropical Composite (TCOMP, n = 866) or Brahman (BRAH, n = 843), with observation of age at first corpus luteum defining puberty. We examined SNPs in or near genes of the IGF1 pathway and report seven genes associated with age at puberty in cattle: IGF1R, IGFBP2, IGFBP4, PERK (HUGO symbol EIF2AK3), PIK3R1, GSK3B and IRS1. SNPs in the IGF1 receptor (IGF1R) showed the most promising associations: two SNPs were associated with puberty in TCOMP (P < 0.05) and one in BRAH (P = 0.00009). This last SNP explained 2% of the genetic variation (R(2) = 2.04%) for age of puberty in BRAH. Hence, IGF1R was examined further. Additional SNPs were genotyped, and haplotypes were analysed. To test more SNPs in this gene, four new SNPs from dbSNP were selected and genotyped. Single SNP and haploytpe analysis revealed associations with age of puberty in both breeds. There were two haplotypes of 12 IGF1R SNPs associated with puberty in BRAH (P < 0.05) and one in TCOMP (P < 0.05). One haplotype of two SNPs was associated (P < 0.01) with puberty in BRAH, but not in TCOMP. In conclusion, the IGF1 pathway appeared more relevant for age of puberty in Brahman cattle, and IGF1R showed higher significance when compared with other genes from the pathway.

  9. Dissecting Dynamic Genetic Variation That Controls Temporal Gene Response in Yeast

    PubMed Central

    Brodt, Avital; Botzman, Maya; David, Eyal; Gat-Viks, Irit

    2014-01-01

    Inter-individual variation in regulatory circuits controlling gene expression is a powerful source of functional information. The study of associations among genetic variants and gene expression provides important insights about cell circuitry but cannot specify whether and when potential variants dynamically alter their genetic effect during the course of response. Here we develop a computational procedure that captures temporal changes in genetic effects, and apply it to analyze transcription during inhibition of the TOR signaling pathway in segregating yeast cells. We found a high-order coordination of gene modules: sets of genes co-associated with the same genetic variant and sharing a common temporal genetic effect pattern. The temporal genetic effects of some modules represented a single state-transitioning pattern; for example, at 10–30 minutes following stimulation, genetic effects in the phosphate utilization module attained a characteristic transition to a new steady state. In contrast, another module showed an impulse pattern of genetic effects; for example, in the poor nitrogen sources utilization module, a spike up of a genetic effect at 10–20 minutes following stimulation reflected inter-individual variation in the timing (rather than magnitude) of response. Our analysis suggests that the same mechanism typically leads to both inter-individual variation and the temporal genetic effect pattern in a module. Our methodology provides a quantitative genetic approach to studying the molecular mechanisms that shape dynamic changes in transcriptional responses. PMID:25474467

  10. Association Study of Wnt Signaling Pathway Genes in Bipolar Disorder

    PubMed Central

    Zandi, Peter P.; Belmonte, Pamela L.; Willour, Virginia L.; Goes, Fernando S.; Badner, Judith A.; Simpson, Sylvia G.; Gershon, Elliot S.; McMahon, Francis J.; DePaulo, J. Raymond; Potash, James B.

    2011-01-01

    Context The Wnt signaling pathways promote cell growth and are best known for their role in embryogenesis and cancer. Several lines of evidence suggest these pathways might also be involved in bipolar disorder (BP). Objective We tested for the association of candidate genes in the Wnt signaling pathways with disease susceptibility in a family-based BP study Design 227 tagSNPs from 34 genes were successfully genotyped. Initial results led us to focus on the gene PPARD, in which we genotyped an additional 13 SNPs for follow-up. Setting Nine academic medical centers in the United States. Participants 554 BP offspring and their parents from 317 families. Main Outcome Measures We tested for family-based association using FBAT and HBAT. Exploratory analyses testing for interactions of PPARD SNPs with clinical covariates and with other Wnt genes were conducted with GENASSOC. Results In the initial analysis, the most significantly associated SNP was rs2267665 in PPARD (nominal p=0.0003). This remained significant at p=0.05 by permutation after accounting for all SNPs tested. Additional genotyping in PPARD yielded four SNPs in one haplotype block that were significantly associated with BP at p<0.01, the most significant being rs9462082 (p=0.0001). Exploratory analyses revealed significant evidence (p<0.01) for interactions of rs9462082 with poor functioning on the Global Assessment Scale (OR = 3.36, 95% CI = 1.85–6.08), and with SNPs in WNT2B (rs3790606, OR = 2.56, 95% CI = 1.67–4.00) and WNT7A (rs4685048, OR = 1.79, 95% CI 1.23–2.63). Conclusions We found evidence for association of BP with PPARD, a gene in the Wnt signaling pathway. The consistency of this result with one from the Wellcome Trust Case-Control Consortium encourages further study. If the finding can be confirmed in additional samples, it may illuminate a new avenue for understanding the pathogenesis of severe BP and developing more effective treatments. PMID:18606951

  11. Variation in the RAD51 gene and familial breast cancer

    PubMed Central

    Lose, Felicity; Lovelock, Paul; Chenevix-Trench, Georgia; Mann, Graham J; Pupo, Gulietta M; Spurdle, Amanda B

    2006-01-01

    Introduction Human RAD51 is a homologue of the Escherichia coli RecA protein and is known to function in recombinational repair of double-stranded DNA breaks. Mutations in the lower eukaryotic homologues of RAD51 result in a deficiency in the repair of double-stranded DNA breaks. Loss of RAD51 function would therefore be expected to result in an elevated mutation rate, leading to accumulation of DNA damage and, hence, to increased cancer risk. RAD51 interacts directly or indirectly with a number of proteins implicated in breast cancer, such as BRCA1 and BRCA2. Similar to BRCA1 mice, RAD51-/- mice are embryonic lethal. The RAD51 gene region has been shown to exhibit loss of heterozygosity in breast tumours, and deregulated RAD51 expression in breast cancer patients has also been reported. Few studies have investigated the role of coding region variation in the RAD51 gene in familial breast cancer, with only one coding region variant – exon 6 c.449G>A (p.R150Q) – reported to date. Methods All nine coding exons of the RAD51 gene were analysed for variation in 46 well-characterised, BRCA1/2-negative breast cancer families using denaturing high-performance liquid chromatography. Genotyping of the exon 6 p.R150Q variant was performed in an additional 66 families. Additionally, lymphoblastoid cell lines from breast cancer patients were subjected to single nucleotide primer extension analysis to assess RAD51 expression. Results No coding region variation was found, and all intronic variation detected was either found in unaffected controls or was unlikely to have functional consequences. Single nucleotide primer extension analysis did not reveal any allele-specific changes in RAD51 expression in all lymphoblastoid cell lines tested. Conclusion Our study indicates that RAD51 is not a major familial breast cancer predisposition gene. PMID:16762046

  12. An integrative systems genetics approach reveals potential causal genes and pathways related to obesity.

    PubMed

    Kogelman, Lisette J A; Zhernakova, Daria V; Westra, Harm-Jan; Cirera, Susanna; Fredholm, Merete; Franke, Lude; Kadarmideen, Haja N

    2015-10-20

    Obesity is a multi-factorial health problem in which genetic factors play an important role. Limited results have been obtained in single-gene studies using either genomic or transcriptomic data. RNA sequencing technology has shown its potential in gaining accurate knowledge about the transcriptome, and may reveal novel genes affecting complex diseases. Integration of genomic and transcriptomic variation (expression quantitative trait loci [eQTL] mapping) has identified causal variants that affect complex diseases. We integrated transcriptomic data from adipose tissue and genomic data from a porcine model to investigate the mechanisms involved in obesity using a systems genetics approach. Using a selective gene expression profiling approach, we selected 36 animals based on a previously created genomic Obesity Index for RNA sequencing of subcutaneous adipose tissue. Differential expression analysis was performed using the Obesity Index as a continuous variable in a linear model. eQTL mapping was then performed to integrate 60 K porcine SNP chip data with the RNA sequencing data. Results were restricted based on genome-wide significant single nucleotide polymorphisms, detected differentially expressed genes, and previously detected co-expressed gene modules. Further data integration was performed by detecting co-expression patterns among eQTLs and integration with protein data. Differential expression analysis of RNA sequencing data revealed 458 differentially expressed genes. The eQTL mapping resulted in 987 cis-eQTLs and 73 trans-eQTLs (false discovery rate < 0.05), of which the cis-eQTLs were associated with metabolic pathways. We reduced the eQTL search space by focusing on differentially expressed and co-expressed genes and disease-associated single nucleotide polymorphisms to detect obesity-related genes and pathways. Building a co-expression network using eQTLs resulted in the detection of a module strongly associated with lipid pathways. Furthermore, we

  13. Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study

    PubMed Central

    2013-01-01

    Background Preterm birth (PTB) is a complex disorder associated with significant neonatal mortality and morbidity and long-term adverse health consequences. Multiple lines of evidence suggest that genetic factors play an important role in its etiology. This study was designed to identify genetic variation associated with PTB in oxytocin pathway genes whose role in parturition is well known. Methods To identify common genetic variants predisposing to PTB, we genotyped 16 single nucleotide polymorphisms (SNPs) in the oxytocin (OXT), oxytocin receptor (OXTR), and leucyl/cystinyl aminopeptidase (LNPEP) genes in 651 case infants from the U.S. and one or both of their parents. In addition, we examined the role of rare genetic variation in susceptibility to PTB by conducting direct sequence analysis of OXTR in 1394 cases and 1112 controls from the U.S., Argentina, Denmark, and Finland. This study was further extended to maternal triads (maternal grandparents-mother of a case infant, N=309). We also performed in vitro analysis of selected rare OXTR missense variants to evaluate their functional importance. Results Maternal genetic effect analysis of the SNP genotype data revealed four SNPs in LNPEP that show significant association with prematurity. In our case–control sequence analysis, we detected fourteen coding variants in exon 3 of OXTR, all but four of which were found in cases only. Of the fourteen variants, three were previously unreported novel rare variants. When the sequence data from the maternal triads were analyzed using the transmission disequilibrium test, two common missense SNPs (rs4686302 and rs237902) in OXTR showed suggestive association for three gestational age subgroups. In vitro functional assays showed a significant difference in ligand binding between wild-type and two mutant receptors. Conclusions Our study suggests an association between maternal common polymorphisms in LNPEP and susceptibility to PTB. Maternal OXTR missense SNPs rs4686302

  14. Estrogen Signaling Multiple Pathways to Impact Gene Transcription

    PubMed Central

    Marino, Maria; Galluzzo, Paola; Ascenzi, Paolo

    2006-01-01

    Steroid hormones exert profound effects on cell growth, development, differentiation, and homeostasis. Their effects are mediated through specific intracellular steroid receptors that act via multiple mechanisms. Among others, the action mechanism starting upon 17β-estradiol (E2) binds to its receptors (ER) is considered a paradigmatic example of how steroid hormones function. Ligand-activated ER dimerizes and translocates in the nucleus where it recognizes specific hormone response elements located in or near promoter DNA regions of target genes. Behind the classical genomic mechanism shared with other steroid hormones, E2 also modulates gene expression by a second indirect mechanism that involves the interaction of ER with other transcription factors which, in turn, bind their cognate DNA elements. In this case, ER modulates the activities of transcription factors such as the activator protein (AP)-1, nuclear factor-κB (NF-κB) and stimulating protein-1 (Sp-1), by stabilizing DNA-protein complexes and/or recruiting co-activators. In addition, E2 binding to ER may also exert rapid actions that start with the activation of a variety of signal transduction pathways (e.g. ERK/MAPK, p38/MAPK, PI3K/AKT, PLC/PKC). The debate about the contribution of different ER-mediated signaling pathways to coordinate the expression of specific sets of genes is still open. This review will focus on the recent knowledge about the mechanism by which ERs regulate the expression of target genes and the emerging field of integration of membrane and nuclear receptor signaling, giving examples of the ways by which the genomic and non-genomic actions of ERs on target genes converge. PMID:18369406

  15. Molecular pathways: targeting ETS gene fusions in cancer.

    PubMed

    Feng, Felix Y; Brenner, J Chad; Hussain, Maha; Chinnaiyan, Arul M

    2014-09-01

    Rearrangements, or gene fusions, involving the ETS family of transcription factors are common driving events in both prostate cancer and Ewing sarcoma. These rearrangements result in pathogenic expression of the ETS genes and trigger activation of transcriptional programs enriched for invasion and other oncogenic features. Although ETS gene fusions represent intriguing therapeutic targets, transcription factors, such as those comprising the ETS family, have been notoriously difficult to target. Recently, preclinical studies have demonstrated an association between ETS gene fusions and components of the DNA damage response pathway, such as PARP1, the catalytic subunit of DNA protein kinase (DNAPK), and histone deactylase 1 (HDAC1), and have suggested that ETS fusions may confer sensitivity to inhibitors of these DNA repair proteins. In this review, we discuss the role of ETS fusions in cancer, the preclinical rationale for targeting ETS fusions with inhibitors of PARP1, DNAPK, and HDAC1, as well as ongoing clinical trials targeting ETS gene fusions. ©2014 American Association for Cancer Research.

  16. Comparative study on gene set and pathway topology-based enrichment methods.

    PubMed

    Bayerlová, Michaela; Jung, Klaus; Kramer, Frank; Klemm, Florian; Bleckmann, Annalen; Beißbarth, Tim

    2015-10-22

    Enrichment analysis is a popular approach to identify pathways or sets of genes which are significantly enriched in the context of differentially expressed genes. The traditional gene set enrichment approach considers a pathway as a simple gene list disregarding any knowledge of gene or protein interactions. In contrast, the new group of so called pathway topology-based methods integrates the topological structure of a pathway into the analysis. We comparatively investigated gene set and pathway topology-based enrichment approaches, considering three gene set and four topological methods. These methods were compared in two extensive simulation studies and on a benchmark of 36 real datasets, providing the same pathway input data for all methods. In the benchmark data analysis both types of methods showed a comparable ability to detect enriched pathways. The first simulation study was conducted with KEGG pathways, which showed considerable gene overlaps between each other. In this study with original KEGG pathways, none of the topology-based methods outperformed the gene set approach. Therefore, a second simulation study was performed on non-overlapping pathways created by unique gene IDs. Here, methods accounting for pathway topology reached higher accuracy than the gene set methods, however their sensitivity was lower. We conducted one of the first comprehensive comparative works on evaluating gene set against pathway topology-based enrichment methods. The topological methods showed better performance in the simulation scenarios with non-overlapping pathways, however, they were not conclusively better in the other scenarios. This suggests that simple gene set approach might be sufficient to detect an enriched pathway under realistic circumstances. Nevertheless, more extensive studies and further benchmark data are needed to systematically evaluate these methods and to assess what gain and cost pathway topology information introduces into enrichment analysis. Both

  17. A PSO-Based Approach for Pathway Marker Identification From Gene Expression Data.

    PubMed

    Mandal, Monalisa; Mondal, Jyotirmay; Mukhopadhyay, Anirban

    2015-09-01

    In this article, a new and robust pathway activity inference scheme is proposed from gene expression data using Particle Swarm Optimization (PSO). From microarray gene expression data, the corresponding pathway information of the genes are collected from a public database. For identifying the pathway markers, the expression values of each pathway consisting of genes, termed as pathway activity, are summarized. To measure the goodness of a pathway activity vector, t-score is widely used in the existing literature. The weakness of existing techniques for inferring pathway activity is that they intend to consider all the member genes of a pathway. But in reality, all the member genes may not be significant to the corresponding pathway. Therefore, those genes, which are responsible in the corresponding pathway, should be included only. Motivated by this, in the proposed method, using PSO, important genes with respect to each pathway are identified. The objective is to maximize the average t-score. For the pathway activities inferred from different percentage of significant pathways, the average absolute t -scores are plotted. In addition, the top 50% pathway markers are evaluated using 10-fold cross validation and its performance is compared with that of other existing techniques. Biological relevance of the results is also studied.

  18. Natural variation and gene regulatory basis for the responses of asparagus beans to soil drought

    PubMed Central

    Xu, Pei; Moshelion, Menachem; Wu, XiaoHua; Halperin, Ofer; Wang, BaoGen; Luo, Jie; Wallach, Rony; Wu, Xinyi; Lu, Zhongfu; Li, Guojing

    2015-01-01

    Asparagus bean (Vigna unguiculata ssp. sesquipedalis) is the Asian subspecies of cowpea, a drought-resistant legume crop native to Africa. In order to explore the genetic variation of drought responses in asparagus bean, we conducted multi-year phenotyping of drought resistance traits across the Chinese asparagus bean mini-core. The phenotypic distribution indicated that the ssp. sesquipedalis subgene pool has maintained high natural variation in drought responses despite known domestic bottleneck. Thirty-nine SNP loci were found to show an association with drought resistance via a genome-wide association study (GWAS). Whole-plant water relations were compared among four genotypes by lysimetric assay. Apparent genotypic differences in transpiration patterns and the critical soil water threshold in relation to dehydration avoidance were observed, indicating a delicate adaptive mechanism for each genotype to its own climate. Microarray gene expression analyses revealed that known drought resistance pathways such as the ABA and phosphate lipid signaling pathways are conserved between different genotypes, while differential regulation of certain aquaporin genes and hormonal genes may be important for the genotypic differences. Our results suggest that divergent sensitivity to soil water content is an important mechanism configuring the genotypic specific responses to water deficit. The SNP markers identified provide useful resources for marker-assisted breeding. PMID:26579145

  19. Assessing the Association of Mitochondrial Genetic Variation With Primary Open-Angle Glaucoma Using Gene-Set Analyses

    PubMed Central

    Khawaja, Anthony P.; Cooke Bailey, Jessica N.; Kang, Jae Hee; Allingham, R. Rand; Hauser, Michael A.; Brilliant, Murray; Budenz, Donald L.; Christen, William G.; Fingert, John; Gaasterland, Douglas; Gaasterland, Terry; Kraft, Peter; Lee, Richard K.; Lichter, Paul R.; Liu, Yutao; Medeiros, Felipe; Moroi, Syoko E.; Richards, Julia E.; Realini, Tony; Ritch, Robert; Schuman, Joel S.; Scott, William K.; Singh, Kuldev; Sit, Arthur J.; Vollrath, Douglas; Wollstein, Gadi; Zack, Donald J.; Zhang, Kang; Pericak-Vance, Margaret; Weinreb, Robert N.; Haines, Jonathan L.; Pasquale, Louis R.; Wiggs, Janey L.

    2016-01-01

    Purpose Recent studies indicate that mitochondrial proteins may contribute to the pathogenesis of primary open-angle glaucoma (POAG). In this study, we examined the association between POAG and common variations in gene-encoding mitochondrial proteins. Methods We examined genetic data from 3430 POAG cases and 3108 controls derived from the combination of the GLAUGEN and NEIGHBOR studies. We constructed biological-system coherent mitochondrial nuclear-encoded protein gene-sets by intersecting the MitoCarta database with the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We examined the mitochondrial gene-sets for association with POAG and with normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) subsets using Pathway Analysis by Randomization Incorporating Structure. Results We identified 22 KEGG pathways with significant mitochondrial protein-encoding gene enrichment, belonging to six general biological classes. Among the pathway classes, mitochondrial lipid metabolism was associated with POAG overall (P = 0.013) and with NTG (P = 0.0006), and mitochondrial carbohydrate metabolism was associated with NTG (P = 0.030). Examining the individual KEGG pathway mitochondrial gene-sets, fatty acid elongation and synthesis and degradation of ketone bodies, both lipid metabolism pathways, were significantly associated with POAG (P = 0.005 and P = 0.002, respectively) and NTG (P = 0.0004 and P < 0.0001, respectively). Butanoate metabolism, a carbohydrate metabolism pathway, was significantly associated with POAG (P = 0.004), NTG (P = 0.001), and HTG (P = 0.010). Conclusions We present an effective approach for assessing the contributions of mitochondrial genetic variation to open-angle glaucoma. Our findings support a role for mitochondria in POAG pathogenesis and specifically point to lipid and carbohydrate metabolism pathways as being important. PMID:27661856

  20. Assessing the Association of Mitochondrial Genetic Variation With Primary Open-Angle Glaucoma Using Gene-Set Analyses.

    PubMed

    Khawaja, Anthony P; Cooke Bailey, Jessica N; Kang, Jae Hee; Allingham, R Rand; Hauser, Michael A; Brilliant, Murray; Budenz, Donald L; Christen, William G; Fingert, John; Gaasterland, Douglas; Gaasterland, Terry; Kraft, Peter; Lee, Richard K; Lichter, Paul R; Liu, Yutao; Medeiros, Felipe; Moroi, Syoko E; Richards, Julia E; Realini, Tony; Ritch, Robert; Schuman, Joel S; Scott, William K; Singh, Kuldev; Sit, Arthur J; Vollrath, Douglas; Wollstein, Gadi; Zack, Donald J; Zhang, Kang; Pericak-Vance, Margaret; Weinreb, Robert N; Haines, Jonathan L; Pasquale, Louis R; Wiggs, Janey L

    2016-09-01

    Recent studies indicate that mitochondrial proteins may contribute to the pathogenesis of primary open-angle glaucoma (POAG). In this study, we examined the association between POAG and common variations in gene-encoding mitochondrial proteins. We examined genetic data from 3430 POAG cases and 3108 controls derived from the combination of the GLAUGEN and NEIGHBOR studies. We constructed biological-system coherent mitochondrial nuclear-encoded protein gene-sets by intersecting the MitoCarta database with the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We examined the mitochondrial gene-sets for association with POAG and with normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) subsets using Pathway Analysis by Randomization Incorporating Structure. We identified 22 KEGG pathways with significant mitochondrial protein-encoding gene enrichment, belonging to six general biological classes. Among the pathway classes, mitochondrial lipid metabolism was associated with POAG overall (P = 0.013) and with NTG (P = 0.0006), and mitochondrial carbohydrate metabolism was associated with NTG (P = 0.030). Examining the individual KEGG pathway mitochondrial gene-sets, fatty acid elongation and synthesis and degradation of ketone bodies, both lipid metabolism pathways, were significantly associated with POAG (P = 0.005 and P = 0.002, respectively) and NTG (P = 0.0004 and P < 0.0001, respectively). Butanoate metabolism, a carbohydrate metabolism pathway, was significantly associated with POAG (P = 0.004), NTG (P = 0.001), and HTG (P = 0.010). We present an effective approach for assessing the contributions of mitochondrial genetic variation to open-angle glaucoma. Our findings support a role for mitochondria in POAG pathogenesis and specifically point to lipid and carbohydrate metabolism pathways as being important.

  1. Interspecies variations in Bordetella catecholamine receptor gene regulation and function.

    PubMed

    Brickman, Timothy J; Suhadolc, Ryan J; Armstrong, Sandra K

    2015-12-01

    Bordetella bronchiseptica can use catecholamines to obtain iron from transferrin and lactoferrin via uptake pathways involving the BfrA, BfrD, and BfrE outer membrane receptor proteins, and although Bordetella pertussis has the bfrD and bfrE genes, the role of these genes in iron uptake has not been demonstrated. In this study, the bfrD and bfrE genes of B. pertussis were shown to be functional in B. bronchiseptica, but neither B. bronchiseptica bfrD nor bfrE imparted catecholamine utilization to B. pertussis. Gene fusion analyses found that expression of B. bronchiseptica bfrA was increased during iron starvation, as is common for iron receptor genes, but that expression of the bfrD and bfrE genes of both species was decreased during iron limitation. As shown previously for B. pertussis, bfrD expression in B. bronchiseptica was also dependent on the BvgAS virulence regulatory system; however, in contrast to the case in B. pertussis, the known modulators nicotinic acid and sulfate, which silence Bvg-activated genes, did not silence expression of bfrD in B. bronchiseptica. Further studies using a B. bronchiseptica bvgAS mutant expressing the B. pertussis bvgAS genes revealed that the interspecies differences in bfrD modulation are partly due to BvgAS differences. Mouse respiratory infection experiments determined that catecholamine utilization contributes to the in vivo fitness of B. bronchiseptica and B. pertussis. Additional evidence of the in vivo importance of the B. pertussis receptors was obtained from serologic studies demonstrating pertussis patient serum reactivity with the B. pertussis BfrD and BfrE proteins.

  2. Interspecies Variations in Bordetella Catecholamine Receptor Gene Regulation and Function

    PubMed Central

    Brickman, Timothy J.; Suhadolc, Ryan J.

    2015-01-01

    Bordetella bronchiseptica can use catecholamines to obtain iron from transferrin and lactoferrin via uptake pathways involving the BfrA, BfrD, and BfrE outer membrane receptor proteins, and although Bordetella pertussis has the bfrD and bfrE genes, the role of these genes in iron uptake has not been demonstrated. In this study, the bfrD and bfrE genes of B. pertussis were shown to be functional in B. bronchiseptica, but neither B. bronchiseptica bfrD nor bfrE imparted catecholamine utilization to B. pertussis. Gene fusion analyses found that expression of B. bronchiseptica bfrA was increased during iron starvation, as is common for iron receptor genes, but that expression of the bfrD and bfrE genes of both species was decreased during iron limitation. As shown previously for B. pertussis, bfrD expression in B. bronchiseptica was also dependent on the BvgAS virulence regulatory system; however, in contrast to the case in B. pertussis, the known modulators nicotinic acid and sulfate, which silence Bvg-activated genes, did not silence expression of bfrD in B. bronchiseptica. Further studies using a B. bronchiseptica bvgAS mutant expressing the B. pertussis bvgAS genes revealed that the interspecies differences in bfrD modulation are partly due to BvgAS differences. Mouse respiratory infection experiments determined that catecholamine utilization contributes to the in vivo fitness of B. bronchiseptica and B. pertussis. Additional evidence of the in vivo importance of the B. pertussis receptors was obtained from serologic studies demonstrating pertussis patient serum reactivity with the B. pertussis BfrD and BfrE proteins. PMID:26371128

  3. Gene pathway development in human epicardial adipose tissue during early life

    PubMed Central

    Ojha, Shalini; Fainberg, Hernan P.; Wilson, Victoria; Pelella, Giuseppe; Castellanos, Marcos; May, Sean T.; Lotto, Attilio A.; Sacks, Harold; Symonds, Michael E.; Budge, Helen

    2016-01-01

    Studies in rodents and newborn humans demonstrate the influence of brown adipose tissue (BAT) in temperature control and energy balance and a critical role in the regulation of body weight. Here, we obtained samples of epicardial adipose tissue (EAT) from neonates, infants, and children in order to evaluate changes in their transcriptional landscape by applying a systems biology approach. Surprisingly, these analyses revealed that the transition to infancy is a critical stage for changes in the morphology of EAT and is reflected in unique gene expression patterns of a substantial proportion of thermogenic gene transcripts (~10%). Our results also indicated that the pattern of gene expression represents a distinct developmental stage, even after the rebound in abundance of thermogenic genes in later childhood. Using weighted gene coexpression network analyses, we found precise anthropometric-specific correlations with changes in gene expression and the decline of thermogenic capacity within EAT. In addition, these results indicate a sequential order of transcriptional events affecting cellular pathways, which could potentially explain the variation in the amount, or activity, of BAT in adulthood. Together, these results provide a resource to elucidate gene regulatory mechanisms underlying the progressive development of BAT during early life. PMID:27699231

  4. Gene pathway development in human epicardial adipose tissue during early life.

    PubMed

    Ojha, Shalini; Fainberg, Hernan P; Wilson, Victoria; Pelella, Giuseppe; Castellanos, Marcos; May, Sean T; Lotto, Attilio A; Sacks, Harold; Symonds, Michael E; Budge, Helen

    2016-08-18

    Studies in rodents and newborn humans demonstrate the influence of brown adipose tissue (BAT) in temperature control and energy balance and a critical role in the regulation of body weight. Here, we obtained samples of epicardial adipose tissue (EAT) from neonates, infants, and children in order to evaluate changes in their transcriptional landscape by applying a systems biology approach. Surprisingly, these analyses revealed that the transition to infancy is a critical stage for changes in the morphology of EAT and is reflected in unique gene expression patterns of a substantial proportion of thermogenic gene transcripts (~10%). Our results also indicated that the pattern of gene expression represents a distinct developmental stage, even after the rebound in abundance of thermogenic genes in later childhood. Using weighted gene coexpression network analyses, we found precise anthropometric-specific correlations with changes in gene expression and the decline of thermogenic capacity within EAT. In addition, these results indicate a sequential order of transcriptional events affecting cellular pathways, which could potentially explain the variation in the amount, or activity, of BAT in adulthood. Together, these results provide a resource to elucidate gene regulatory mechanisms underlying the progressive development of BAT during early life.

  5. Expression data on liver metabolic pathway genes and proteins

    PubMed Central

    Raja Gopal Reddy, Mooli; Pavan Kumar, Chodisetti; Mahesh, Malleswarapu; Sravan Kumar, Manchiryala; Jeyakumar, Shanmugam M.

    2016-01-01

    Here, we present the expression data on various metabolic pathways of liver with special emphasize on lipid and carbohydrate metabolism and long chain polyunsaturated fatty acid (PUFA) synthesis, both at gene and protein levels. The data were obtained to understand the effect of vitamin A deficiency on the expression status (both gene and protein levels) of some of the key factors involved in lipogenesis, fatty acid oxidation, triglyceride secretion, long chain PUFA, resolvin D1 synthesis, glucose transport and glycogen synthesis of liver, using modern biology tools, such as quantitative real-time PCR (RT-PCR) and immunoblotting techniques. This data article provides the supporting evidence to the article “Vitamin A deficiency suppresses high fructose-induced triglyceride synthesis and elevates resolvin D1 levels” [1] and therefore, these data may be referred back, for comprehensive understanding and interpretations and for future studies. PMID:26909377

  6. Polymorphisms of the NER pathway genes, ERCC1 and XPD are associated with esophageal adenocarcinoma risk.

    PubMed

    Tse, Darren; Zhai, Rihong; Zhou, Wei; Heist, Rebecca S; Asomaning, Kofi; Su, Li; Lynch, Thomas J; Wain, John C; Christiani, David C; Liu, Geoffrey

    2008-12-01

    Functional variation in DNA repair capacity through single nucleotide polymorphisms (SNPs) of key repair genes is associated with a higher risk of developing various types of cancer. Studies have focused on the nucleotide excision repair (NER) and base excision repair (BER) pathways. We investigated whether variant alleles in seven SNPs within these pathways increased the risk of esophageal adenocarcinoma. DNA was extracted from prospectively collected blood specimens. The samples were genotyped for SNPs in NER genes (XPD Lys751Gln, XPD Asp312Asn, ERCC1 8092C/A, and ERCC1 118C/T), and BER genes (XRCC1 Arg399Gln, APE1 Asp148Glu, and hOGG1 Ser326Cys). The presence of variant alleles was correlated with risk of esophageal adenocarcinoma both individually and jointly. Variant alleles in NER SNPs XPD Lys751Gln (AOR = 1.50, 95% CI 1.1-2.0), ERCC1 8092 C/A (AOR = 1.44, 95% CI 1.1-1.9), and ERCC1 118C/T (AOR = 1.42, 95% CI 1.0-1.9) were individually associated with esophageal adenocarcinoma risk. An increasing number of variant alleles in NER SNPs showed a significant trend with esophageal adenocarcinoma risk (p = 0.007). The presence of variant alleles in NER genes increases risk of esophageal adenocarcinoma. There is evidence of an additive role for SNPs along a common DNA repair pathway. Future larger studies of esophageal adenocarcinoma etiology should evaluate entire biological pathways.

  7. Polymorphisms of the NER pathway genes, ERCC1 and XPD are associated with esophageal adenocarcinoma risk

    PubMed Central

    Tse, Darren; Zhai, Rihong; Zhou, Wei; Heist, Rebecca S.; Asomaning, Kofi; Su, Li; Lynch, Thomas J.; Wain, John C.; Christiani, David C.

    2011-01-01

    Purpose Functional variation in DNA repair capacity through single nucleotide polymorphisms (SNPs) of key repair genes is associated with a higher risk of developing various types of cancer. Studies have focused on the nucleotide excision repair (NER) and base excision repair (BER) pathways. We investigated whether variant alleles in seven SNPs within these pathways increased the risk of esophageal adenocarcinoma. Methods DNA was extracted from prospectively collected blood specimens. The samples were genotyped for SNPs in NER genes (XPD Lys751Gln, XPD Asp312Asn, ERCC1 8092C/A, and ERCC1 118C/T), and BER genes (XRCC1 Arg399Gln, APE1 Asp148Glu, and hOGG1 Ser326Cys). The presence of variant alleles was correlated with risk of esophageal adenocarcinoma both individually and jointly. Results Variant alleles in NER SNPs XPD Lys751Gln (AOR = 1.50, 95% CI 1.1–2.0), ERCC1 8092 C/A (AOR = 1.44, 95% CI 1.1–1.9), and ERCC1 118C/T (AOR = 1.42, 95% CI 1.0–1.9) were individually associated with esophageal adenocarcinoma risk. An increasing number of variant alleles in NER SNPs showed a significant trend with esophageal adenocarcinoma risk (p = 0.007). Conclusions The presence of variant alleles in NER genes increases risk of esophageal adenocarcinoma. There is evidence of an additive role for SNPs along a common DNA repair pathway. Future larger studies of esophageal adenocarcinoma etiology should evaluate entire biological pathways. PMID:18478337

  8. NODAL PATHWAY GENES ARE DOWNREGULATED IN FACIAL ASYMMETRY

    PubMed Central

    Nicot, Romain; Hottenstein, Molly; Raoul, Gwenael; Ferri, Joel; Horton, Michael; Tobias, John W.; Barton, Elisabeth; Gelé, Patrick; Sciote, James J.

    2014-01-01

    Purpose Facial asymmetry is a common comorbid condition in patients with jaw deformation malocclusion. Heritability of malocclusion is advancing rapidly, but very little is known regarding genetic contributions to asymmetry. This study identifies differences in expression of key asymmetry-producing genes which are down regulated in facial asymmetry patients. Material and Methods Masseter muscle samples were collected during BSSO orthognathic surgery to correct skeletal-based malocclusion. Patients were classified as Class II or III and open or deep bite malocclusion with or without facial asymmetry. Muscle samples were analyzed for gene expression differences on Affymetrix HT2.0 microarray global expression chips. Results Overall gene expression was different for asymmetric patients compared to other malocclusion classifications by principal component analysis (P<0.05). We identified differences in the nodal signaling pathway (NSP) which promotes development of mesoderm and endoderm and left-right patterning during embryogenesis. Nodal and Lefty expression was 1.39–1.84 fold greater (P<3.41×10−5) whereas integral membrane Nodal-modulators Nomo1,2,3 were −5.63 to −5.81 (P<3.05×10−4) less in asymmetry subjects. Fold differences among intracellular pathway members were negative in the range of −7.02 to −2.47 (P<0.003). Finally Pitx2, a upstream effector of Nodal known to influence the size of type II skeletal muscle fibers was also significantly decreased in facial asymmetry (P<0.05). Conclusions When facial asymmetry is part of skeletal malocclusion there are decreases of NSP genes in masseter muscle. This data suggests that the NSP is down regulated to help promote development of asymmetry. Pitx2 expression differences also contributed to both skeletal and muscle development in this condition. PMID:25364968

  9. Characterizing genetic variation of adrenergic signalling pathways in Takotsubo (stress) cardiomyopathy exomes.

    PubMed

    Goodloe, Adele H; Evans, Jared M; Middha, Sumit; Prasad, Abhiram; Olson, Timothy M

    2014-09-01

    Exome sequencing was used to genotype comprehensively a Takotsubo (stress) cardiomyopathy (TC) cohort, enabling investigation of a vast 486 gene network for adrenergic signalling. Twenty-eight TC subjects, including a mother-daughter pair and five recurrent cases, underwent whole-exome sequencing. Frequencies of 17 common, functional adrenergic polymorphisms were statistically similar to those of population controls. Filtering for rare, predicted-deleterious, catecholamine/adrenergic signalling variants revealed heterozygosity in 55 genes in TC cases and 59 genes in healthy controls. Overall allele burden was similar and did not discriminate clinical variables among TC subjects, but gene identities were largely cohort specific, and TC cases were enriched for variants within functional domains (68% vs. 48%, P = 0.031). Two-thirds of TC cases carried more than one filtered adrenergic pathway variant, and 11 genes harboured a variant in ≥ 2 cases. The mother-daughter pair shared missense variants in highly conserved functional domains of ADH5, CACNG1, EPHA4, and PRKCA. An adrenergic pathway-independent analysis of the cohort exposed no common gene for TC. Overall, these data support genetic heterogeneity in TC susceptibility and a likely polygenic basis, conferring a cumulative effect on adrenergic pathway dysregulation in a subset of individual subjects. Study of larger cohorts and non-coding regulatory regions is warranted to define genetic risk factors for TC further. © 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.

  10. Gene conversion and purifying selection shape nucleotide variation in gibbon L/M opsin genes

    PubMed Central

    2011-01-01

    Background Routine trichromatic color vision is a characteristic feature of catarrhines (humans, apes and Old World monkeys). This is enabled by L and M opsin genes arrayed on the X chromosome and an autosomal S opsin gene. In non-human catarrhines, genetic variation affecting the color vision phenotype is reported to be absent or rare in both L and M opsin genes, despite the suggestion that gene conversion has homogenized the two genes. However, nucleotide variation of both introns and exons among catarrhines has only been examined in detail for the L opsin gene of humans and chimpanzees. In the present study, we examined the nucleotide variation of gibbon (Catarrhini, Hylobatidae) L and M opsin genes. Specifically, we focused on the 3.6~3.9-kb region that encompasses the centrally located exon 3 through exon 5, which encode the amino acid sites functional for the spectral tuning of the genes. Results Among 152 individuals representing three genera (Hylobates, Nomascus and Symphalangus), all had both L and M opsin genes and no L/M hybrid genes. Among 94 individuals subjected to the detailed DNA sequencing, the nucleotide divergence between L and M opsin genes in the exons was significantly higher than the divergence in introns in each species. The ratio of the inter-LM divergence to the intra-L/M polymorphism was significantly lower in the introns than that in synonymous sites. When we reconstructed the phylogenetic tree using the exon sequences, the L/M gene duplication was placed in the common ancestor of catarrhines, whereas when intron sequences were used, the gene duplications appeared multiple times in different species. Using the GENECONV program, we also detected that tracts of gene conversions between L and M opsin genes occurred mostly within the intron regions. Conclusions These results indicate the historical accumulation of gene conversions between L and M opsin genes in the introns in gibbons. Our study provides further support for the homogenizing

  11. Gene conversion and purifying selection shape nucleotide variation in gibbon L/M opsin genes.

    PubMed

    Hiwatashi, Tomohide; Mikami, Akichika; Katsumura, Takafumi; Suryobroto, Bambang; Perwitasari-Farajallah, Dyah; Malaivijitnond, Suchinda; Siriaroonrat, Boripat; Oota, Hiroki; Goto, Shunji; Kawamura, Shoji

    2011-10-22

    Routine trichromatic color vision is a characteristic feature of catarrhines (humans, apes and Old World monkeys). This is enabled by L and M opsin genes arrayed on the X chromosome and an autosomal S opsin gene. In non-human catarrhines, genetic variation affecting the color vision phenotype is reported to be absent or rare in both L and M opsin genes, despite the suggestion that gene conversion has homogenized the two genes. However, nucleotide variation of both introns and exons among catarrhines has only been examined in detail for the L opsin gene of humans and chimpanzees. In the present study, we examined the nucleotide variation of gibbon (Catarrhini, Hylobatidae) L and M opsin genes. Specifically, we focused on the 3.6~3.9-kb region that encompasses the centrally located exon 3 through exon 5, which encode the amino acid sites functional for the spectral tuning of the genes. Among 152 individuals representing three genera (Hylobates, Nomascus and Symphalangus), all had both L and M opsin genes and no L/M hybrid genes. Among 94 individuals subjected to the detailed DNA sequencing, the nucleotide divergence between L and M opsin genes in the exons was significantly higher than the divergence in introns in each species. The ratio of the inter-LM divergence to the intra-L/M polymorphism was significantly lower in the introns than that in synonymous sites. When we reconstructed the phylogenetic tree using the exon sequences, the L/M gene duplication was placed in the common ancestor of catarrhines, whereas when intron sequences were used, the gene duplications appeared multiple times in different species. Using the GENECONV program, we also detected that tracts of gene conversions between L and M opsin genes occurred mostly within the intron regions. These results indicate the historical accumulation of gene conversions between L and M opsin genes in the introns in gibbons. Our study provides further support for the homogenizing role of gene conversion between

  12. Sequence and expression variations suggest an adaptive role for the DA1-like gene family in the evolution of soybeans.

    PubMed

    Zhao, Man; Gu, Yongzhe; He, Lingli; Chen, Qingshan; He, Chaoying

    2015-05-15

    The DA1 gene family is plant-specific and Arabidopsis DA1 regulates seed and organ size, but the functions in soybeans are unknown. The cultivated soybean (Glycine max) is believed to be domesticated from the annual wild soybeans (Glycine soja). To evaluate whether DA1-like genes were involved in the evolution of soybeans, we compared variation at both sequence and expression levels of DA1-like genes from G. max (GmaDA1) and G. soja (GsoDA1). Sequence identities were extremely high between the orthologous pairs between soybeans, while the paralogous copies in a soybean species showed a relatively high divergence. Moreover, the expression variation of DA1-like paralogous genes in soybean was much greater than the orthologous gene pairs between the wild and cultivated soybeans during development and challenging abiotic stresses such as salinity. We further found that overexpressing GsoDA1 genes did not affect seed size. Nevertheless, overexpressing them reduced transgenic Arabidopsis seed germination sensitivity to salt stress. Moreover, most of these genes could improve salt tolerance of the transgenic Arabidopsis plants, corroborated by a detection of expression variation of several key genes in the salt-tolerance pathways. Our work suggested that expression diversification of DA1-like genes is functionally associated with adaptive radiation of soybeans, reinforcing that the plant-specific DA1 gene family might have contributed to the successful adaption to complex environments and radiation of the plants.

  13. In vivo continuous evolution of genes and pathways in yeast

    PubMed Central

    Crook, Nathan; Abatemarco, Joseph; Sun, Jie; Wagner, James M.; Schmitz, Alexander; Alper, Hal S.

    2016-01-01

    Directed evolution remains a powerful, highly generalizable approach for improving the performance of biological systems. However, implementations in eukaryotes rely either on in vitro diversity generation or limited mutational capacities. Here we synthetically optimize the retrotransposon Ty1 to enable in vivo generation of mutant libraries up to 1.6 × 107 l−1 per round, which is the highest of any in vivo mutational generation approach in yeast. We demonstrate this approach by using in vivo-generated libraries to evolve single enzymes, global transcriptional regulators and multi-gene pathways. When coupled to growth selection, this approach enables in vivo continuous evolution (ICE) of genes and pathways. Through a head-to-head comparison, we find that ICE libraries yield higher-performing variants faster than error-prone PCR-derived libraries. Finally, we demonstrate transferability of ICE to divergent yeasts, including Kluyveromyces lactis and alternative S. cerevisiae strains. Collectively, this work establishes a generic platform for rapid eukaryotic-directed evolution across an array of target cargo. PMID:27748457

  14. Characterization of purine catabolic pathway genes in coelacanths.

    PubMed

    Forconi, Mariko; Biscotti, Maria Assunta; Barucca, Marco; Buonocore, Francesco; De Moro, Gianluca; Fausto, Anna Maria; Gerdol, Marco; Pallavicini, Alberto; Scapigliati, Giuseppe; Schartl, Manfred; Olmo, Ettore; Canapa, Adriana

    2014-09-01

    Coelacanths are a critically valuable species to explore the gene changes that took place in the transition from aquatic to terrestrial life. One interesting and biologically relevant feature of the genus Latimeria is ureotelism. However not all urea is excreted from the body; in fact high concentrations are retained in plasma and seem to be involved in osmoregulation. The purine catabolic pathway, which leads to urea production in Latimeria, has progressively lost some steps, reflecting an enzyme loss during diversification of terrestrial species. We report the results of analyses of the liver and testis transcriptomes of the Indonesian coelacanth Latimeria menadoensis and of the genome of Latimeria chalumnae, which has recently been fully sequenced in the framework of the coelacanth genome project. We describe five genes, uricase, 5-hydroxyisourate hydrolase, parahox neighbor B, allantoinase, and allantoicase, each coding for one of the five enzymes involved in urate degradation to urea, and report the identification of a putative second form of 5-hydroxyisourate hydrolase that is characteristic of the genus Latimeria. The present data also highlight the activity of the complete purine pathway in the coelacanth liver and suggest its involvement in the maintenance of high plasma urea concentrations.

  15. Database for exchangeable gene trap clones: pathway and gene ontology analysis of exchangeable gene trap clone mouse lines.

    PubMed

    Araki, Masatake; Nakahara, Mai; Muta, Mayumi; Itou, Miharu; Yanai, Chika; Yamazoe, Fumika; Miyake, Mikiko; Morita, Ayaka; Araki, Miyuki; Okamoto, Yoshiyuki; Nakagata, Naomi; Yoshinobu, Kumiko; Yamamura, Ken-ichi; Araki, Kimi

    2014-02-01

    Gene trapping in embryonic stem (ES) cells is a proven method for large-scale random insertional mutagenesis in the mouse genome. We have established an exchangeable gene trap system, in which a reporter gene can be exchanged for any other DNA of interest through Cre/mutant lox-mediated recombination. We isolated trap clones, analyzed trapped genes, and constructed the database for Exchangeable Gene Trap Clones (EGTC) [http://egtc.jp]. The number of registered ES cell lines was 1162 on 31 August 2013. We also established 454 mouse lines from trap ES clones and deposited them in the mouse embryo bank at the Center for Animal Resources and Development, Kumamoto University, Japan. The EGTC database is the most extensive academic resource for gene-trap mouse lines. Because we used a promoter-trap strategy, all trapped genes were expressed in ES cells. To understand the general characteristics of the trapped genes in the EGTC library, we used Kyoto Encyclopedia of Genes and Genomes (KEGG) for pathway analysis and found that the EGTC ES clones covered a broad range of pathways. We also used Gene Ontology (GO) classification data provided by Mouse Genome Informatics (MGI) to compare the functional distribution of genes in each GO term between trapped genes in the EGTC mouse lines and total genes annotated in MGI. We found the functional distributions for the trapped genes in the EGTC mouse lines and for the RefSeq genes for the whole mouse genome were similar, indicating that the EGTC mouse lines had trapped a wide range of mouse genes. © 2014 The Authors Development, Growth & Differentiation © 2014 Japanese Society of Developmental Biologists.

  16. Examining the Polymorphisms in the Hypoxia Pathway Genes in Relation to Outcome in Colorectal Cancer

    PubMed Central

    Haja Mohideen, Asan M. S.; Hyde, Angela; Squires, Jessica; Wang, Jing; Dicks, Elizabeth; Younghusband, Ban; Parfrey, Patrick; Green, Roger; Savas, Sevtap

    2014-01-01

    Introduction Colorectal cancer is a common malignancy. Identification of genetic prognostic markers may help prognostic estimations in colorectal cancer. Genes that regulate response to hypoxia and other genes that are regulated under the hypoxic conditions have been shown to play roles in cancer progression. In this study, we hypothesized that genetic variations in the hypoxia pathway genes were associated with the risk of outcome in colorectal cancer patients. Methods This study was performed in two phases. In the first phase, 49 SNPs from six hypoxia pathway genes (HIF1A, HIF1B, HIF2A, LOX, MIF and CXCL12) in 272 colorectal cancer patients were analyzed. In the second phase, 77 SNPs from seven hypoxia pathway genes (HIF1A, HIF1B, HIF2A, HIF2B, HIF3A, LOX and CXCL12) were analyzed in an additional cohort of 535 patients. Kaplan Meier, Cox univariate and multivariable regression analyses were performed to analyze the relationship between the SNPs and overall survival (OS), disease free survival (DFS) or disease specific survival (DSS). Since this was a hypothesis-generating study, no correction for multiple testing was applied. Results In phase I, one SNP (HIF2A rs11125070) was found to be associated with DFS in multivariable analysis; yet association of a proxy polymorphism (HIF2A rs4953342) was not detected in the phase II patient cohort. In phase II, associations of two SNPs (HIF2A rs4953352 and HIF2B rs12593988) were significant in both OS and DFS multivariable analyses. However, association of HIF2A rs4953352 was not replicated in the phase I cohort using a proxy SNP (HIF2A rs6706003). Conclusion Overall, our study did not find a convincing evidence of association of the investigated polymorphisms with the disease outcomes in colorectal cancer. PMID:25405996

  17. Normal Variation in Size of the FMR2 Gene Is Not Associated with Variation in Intellectual Performance.

    ERIC Educational Resources Information Center

    Mazzocco, Michele M. M.; Reiss, Allan L.

    1999-01-01

    Studied the association between the number of cytosine-guanine-guanine (CCG) repeats in the FMR2 gene (a fragile X mental retardation gene) and IQ score among 902 school age children. Results indicate that variation in CGG size, among normal-size FMR2 alleles, is not a contributor to normal variation in intelligence. (SLD)

  18. The Expression of Petunia Strigolactone Pathway Genes is Altered as Part of the Endogenous Developmental Program

    PubMed Central

    Drummond, Revel S. M.; Sheehan, Hester; Simons, Joanne L.; Martínez-Sánchez, N. Marcela; Turner, Rebecca M.; Putterill, Joanna; Snowden, Kimberley C.

    2012-01-01

    Analysis of mutants with increased branching has revealed the strigolactone synthesis/perception pathway which regulates branching in plants. However, whether variation in this well conserved developmental signaling system contributes to the unique plant architectures of different species is yet to be determined. We examined petunia orthologs of the Arabidopsis MAX1 and MAX2 genes to characterize their role in petunia architecture. A single ortholog of MAX1, PhMAX1 which encodes a cytochrome P450, was identified and was able to complement the max1 mutant of Arabidopsis. Petunia has two copies of the MAX2 gene, PhMAX2A and PhMAX2B which encode F-Box proteins. Differences in the transcript levels of these two MAX2-like genes suggest diverging functions. Unlike PhMAX2B, PhMAX2A mRNA levels change in leaves of differing age/position on the plant. Nonetheless, this gene functionally complements the Arabidopsis max2 mutant indicating that the biochemical activity of the PhMAX2A protein is not significantly different from MAX2. The expression of the petunia strigolactone pathway genes (PhCCD7, PhCCD8, PhMAX1, PhMAX2A, and PhMAX2B) was then further investigated throughout the development of wild-type petunia plants. Three of these genes showed changes in mRNA levels over a development series. Alterations to the expression patterns of these genes may influence the branching growth habit of plants by changing strigolactone production and/or sensitivity. These changes could allow both subtle and dramatic changes to branching within and between species. PMID:22645562

  19. Altered Pathway Analyzer: A gene expression dataset analysis tool for identification and prioritization of differentially regulated and network rewired pathways

    PubMed Central

    Kaushik, Abhinav; Ali, Shakir; Gupta, Dinesh

    2017-01-01

    Gene connection rewiring is an essential feature of gene network dynamics. Apart from its normal functional role, it may also lead to dysregulated functional states by disturbing pathway homeostasis. Very few computational tools measure rewiring within gene co-expression and its corresponding regulatory networks in order to identify and prioritize altered pathways which may or may not be differentially regulated. We have developed Altered Pathway Analyzer (APA), a microarray dataset analysis tool for identification and prioritization of altered pathways, including those which are differentially regulated by TFs, by quantifying rewired sub-network topology. Moreover, APA also helps in re-prioritization of APA shortlisted altered pathways enriched with context-specific genes. We performed APA analysis of simulated datasets and p53 status NCI-60 cell line microarray data to demonstrate potential of APA for identification of several case-specific altered pathways. APA analysis reveals several altered pathways not detected by other tools evaluated by us. APA analysis of unrelated prostate cancer datasets identifies sample-specific as well as conserved altered biological processes, mainly associated with lipid metabolism, cellular differentiation and proliferation. APA is designed as a cross platform tool which may be transparently customized to perform pathway analysis in different gene expression datasets. APA is freely available at http://bioinfo.icgeb.res.in/APA. PMID:28084397

  20. Stage-Specific Effects of Candidate Heterochronic Genes on Variation in Developmental Time along an Altitudinal Cline of Drosophila melanogaster

    PubMed Central

    Mensch, Julián; Carreira, Valeria; Lavagnino, Nicolás; Goenaga, Julieta; Folguera, Guillermo; Hasson, Esteban; Fanara, Juan José

    2010-01-01

    Background Previously, we have shown there is clinal variation for egg-to-adult developmental time along geographic gradients in Drosophila melanogaster. Further, we also have identified mutations in genes involved in metabolic and neurogenic pathways that affect development time (heterochronic genes). However, we do not know whether these loci affect variation in developmental time in natural populations. Methodology/Principal Findings Here, we constructed second chromosome substitution lines from natural populations of Drosophila melanogaster from an altitudinal cline, and measured egg-adult development time for each line. We found not only a large amount of genetic variation for developmental time, but also positive associations of the development time with thermal amplitude and altitude. We performed genetic complementation tests using substitution lines with the longest and shortest developmental times and heterochronic mutations. We identified segregating variation for neurogenic and metabolic genes that largely affected the duration of the larval stages but had no impact on the timing of metamorphosis. Conclusions/Significance Altitudinal clinal variation in developmental time for natural chromosome substitution lines provides a unique opportunity to dissect the response of heterochronic genes to environmental gradients. Ontogenetic stage-specific variation in invected, mastermind, cricklet and CG14591 may affect natural variation in development time and thermal evolution. PMID:20585460

  1. pathDIP: an annotated resource for known and predicted human gene-pathway associations and pathway enrichment analysis

    PubMed Central

    Rahmati, Sara; Abovsky, Mark; Pastrello, Chiara; Jurisica, Igor

    2017-01-01

    Molecular pathway data are essential in current computational and systems biology research. While there are many primary and integrated pathway databases, several challenges remain, including low proteome coverage (57%), low overlap across different databases, unavailability of direct information about underlying physical connectivity of pathway members, and high fraction of protein-coding genes without any pathway annotations, i.e. ‘pathway orphans’. In order to address all these challenges, we developed pathDIP, which integrates data from 20 source pathway databases, ‘core pathways’, with physical protein–protein interactions to predict biologically relevant protein–pathway associations, referred to as ‘extended pathways’. Cross-validation determined 71% recovery rate of our predictions. Data integration and predictions increase coverage of pathway annotations for protein-coding genes to 86%, and provide novel annotations for 5732 pathway orphans. PathDIP (http://ophid.utoronto.ca/pathdip) annotates 17 070 protein-coding genes with 4678 pathways, and provides multiple query, analysis and output options. PMID:27899558

  2. Analysis of tumor suppressor genes based on gene ontology and the KEGG pathway.

    PubMed

    Yang, Jing; Chen, Lei; Kong, Xiangyin; Huang, Tao; Cai, Yu-Dong

    2014-01-01

    Cancer is a serious disease that causes many deaths every year. We urgently need to design effective treatments to cure this disease. Tumor suppressor genes (TSGs) are a type of gene that can protect cells from becoming cancerous. In view of this, correct identification of TSGs is an alternative method for identifying effective cancer therapies. In this study, we performed gene ontology (GO) and pathway enrichment analysis of the TSGs and non-TSGs. Some popular feature selection methods, including minimum redundancy maximum relevance (mRMR) and incremental feature selection (IFS), were employed to analyze the enrichment features. Accordingly, some GO terms and KEGG pathways, such as biological adhesion, cell cycle control, genomic stability maintenance and cell death regulation, were extracted, which are important factors for identifying TSGs. We hope these findings can help in building effective prediction methods for identifying TSGs and thereby, promoting the discovery of effective cancer treatments.

  3. Co-expressed Pathways DataBase for Tomato: a database to predict pathways relevant to a query gene.

    PubMed

    Narise, Takafumi; Sakurai, Nozomu; Obayashi, Takeshi; Ohta, Hiroyuki; Shibata, Daisuke

    2017-06-05

    Gene co-expression, the similarity of gene expression profiles under various experimental conditions, has been used as an indicator of functional relationships between genes, and many co-expression databases have been developed for predicting gene functions. These databases usually provide users with a co-expression network and a list of strongly co-expressed genes for a query gene. Several of these databases also provide functional information on a set of strongly co-expressed genes (i.e., provide biological processes and pathways that are enriched in these strongly co-expressed genes), which is generally analyzed via over-representation analysis (ORA). A limitation of this approach may be that users can predict gene functions only based on the strongly co-expressed genes. In this study, we developed a new co-expression database that enables users to predict the function of tomato genes from the results of functional enrichment analyses of co-expressed genes while considering the genes that are not strongly co-expressed. To achieve this, we used the ORA approach with several thresholds to select co-expressed genes, and performed gene set enrichment analysis (GSEA) applied to a ranked list of genes ordered by the co-expression degree. We found that internal correlation in pathways affected the significance levels of the enrichment analyses. Therefore, we introduced a new measure for evaluating the relationship between the gene and pathway, termed the percentile (p)-score, which enables users to predict functionally relevant pathways without being affected by the internal correlation in pathways. In addition, we evaluated our approaches using receiver operating characteristic curves, which concluded that the p-score could improve the performance of the ORA. We developed a new database, named Co-expressed Pathways DataBase for Tomato, which is available at http://cox-path-db.kazusa.or.jp/tomato . The database allows users to predict pathways that are relevant to a

  4. Screening key genes and pathways in glioma based on gene set enrichment analysis and meta-analysis.

    PubMed

    Tang, Yanyan; He, Wenwu; Wei, Yunfei; Qu, Zhanli; Zeng, Jinming; Qin, Chao

    2013-06-01

    Glioma is a highly invasive, rapidly spreading form of brain cancer, while its etiology is largely unknown. A few recently reported studies have been developed using gene expression microarrays of glioma to identify differentially expressed genes from several to hundreds. This study was designed to analyze vast amounts of glioma-related microarray data and screen the key genes and pathways related to the development and progression of glioma. We used gene set enrichment analysis (GSEA) and meta-analysis of seven included studies after standardized microarray preprocessing, which increased concordance between these gene datasets. After GSEA, there were 14 mixing pathways including 13 up- and 1 down-regulated pathways. Based on the meta-analysis, 268 significant genes were screened out (P < 0.05); there were 249 genes identified by Kyoto Encyclopedia of Genes and Genomes (KEGG), and 27 KEGG pathways closely related to the set of the imported genes were identified. At last, six consistent pathways and key genes in these pathways related to glioma were obtained with combined GSEA and meta-analysis. The gene pathways that we identified could provide insight concerning the development of glioma. Further studies are needed to determine the biological function for the positive genes.

  5. Dissecting the contributions of time and microbe density to variation in immune gene expression.

    PubMed

    Tate, Ann T; Graham, Andrea L

    2017-07-26

    Widespread differential expression of immunological genes is a hallmark of the response to infection in almost all surveyed taxa. However, several challenges remain in the attempt to connect differences in gene expression with functional outcomes like parasite killing and host survival. For example, temporal gene expression patterns are not always monotonic (unidirectional slope), yielding results that qualitatively depend on the time point selected for analysis. They may also be correlated to microbe density, confounding the strength of an immune response and resistance to parasites. In this study, we analyse these relationships in an mRNA-seq time series of Tribolium castaneum infected with Bacillus thuringiensis Our results suggest that many extracellular immunological components with known roles in immunity, like antimicrobial peptides and recognition proteins, are highly correlated to microbe load. On the other hand, intracellular components of immunological signalling pathways overwhelmingly show non-monotonic temporal patterns of gene expression, despite the underlying assumption of monotonicity in most ecological and comparative transcriptomics studies that rely on cross-sectional analyses. Our results raise a host of new questions, including to what extent variation in host resistance, infection tolerance and immunopathology can be explained by variation in the slope or sensitivity of these newly characterized patterns. © 2017 The Author(s).

  6. Diet and colorectal cancer: analysis of a candidate pathway using SNPS, haplotypes, and multi-gene assessment.

    PubMed

    Slattery, Martha L; Lundgreen, Abbie; Herrick, Jennifer S; Caan, Bette J; Potter, John D; Wolff, Roger K

    2011-11-01

    There is considerable biologic plausibility to the hypothesis that genetic variability in pathways involved in insulin signaling and energy homeostasis may modulate dietary risk associated with colorectal cancer. We utilized data from 2 population-based case-control studies of colon (n = 1,574 cases, 1,970 controls) and rectal (n = 791 cases, 999 controls) cancer to evaluate genetic variation in candidate SNPs identified from 9 genes in a candidate pathway: PDK1, RP6KA1, RPS6KA2, RPS6KB1, RPS6KB2, PTEN, FRAP1 (mTOR), TSC1, TSC2, Akt1, PIK3CA, and PRKAG2 with dietary intake of total energy, carbohydrates, fat, and fiber. We employed SNP, haplotype, and multiple-gene analysis to evaluate associations. PDK1 interacted with dietary fat for both colon and rectal cancer and with dietary carbohydrates for colon cancer. Statistically significant interaction with dietary carbohydrates and rectal cancer was detected by haplotype analysis of PDK1. Evaluation of dietary interactions with multiple genes in this candidate pathway showed several interactions with pairs of genes: Akt1 and PDK1, PDK1 and PTEN, PDK1 and TSC1, and PRKAG2 and PTEN. Analyses show that genetic variation influences risk of colorectal cancer associated with diet and illustrate the importance of evaluating dietary interactions beyond the level of single SNPs or haplotypes when a biologically relevant candidate pathway is examined.

  7. Characterization of phenylpropanoid pathway genes within European maize (Zea mays L.) inbreds.

    PubMed

    Andersen, Jeppe Reitan; Zein, Imad; Wenzel, Gerhard; Darnhofer, Birte; Eder, Joachim; Ouzunova, Milena; Lübberstedt, Thomas

    2008-01-03

    Forage quality of maize is influenced by both the content and structure of lignins in the cell wall. Biosynthesis of monolignols, constituting the complex structure of lignins, is catalyzed by enzymes in the phenylpropanoid pathway. In the present study we have amplified partial genomic fragments of six putative phenylpropanoid pathway genes in a panel of elite European inbred lines of maize (Zea mays L.) contrasting in forage quality traits. Six loci, encoding C4H, 4CL1, 4CL2, C3H, F5H, and CAD, displayed different levels of nucleotide diversity and linkage disequilibrium (LD) possibly reflecting different levels of selection. Associations with forage quality traits were identified for several individual polymorphisms within the 4CL1, C3H, and F5H genomic fragments when controlling for both overall population structure and relative kinship. A 1-bp indel in 4CL1 was associated with in vitro digestibility of organic matter (IVDOM), a non-synonymous SNP in C3H was associated with IVDOM, and an intron SNP in F5H was associated with neutral detergent fiber. However, the C3H and F5H associations did not remain significant when controlling for multiple testing. While the number of lines included in this study limit the power of the association analysis, our results imply that genetic variation for forage quality traits can be mined in phenylpropanoid pathway genes of elite breeding lines of maize.

  8. Characterization of phenylpropanoid pathway genes within European maize (Zea mays L.) inbreds

    PubMed Central

    Andersen, Jeppe Reitan; Zein, Imad; Wenzel, Gerhard; Darnhofer, Birte; Eder, Joachim; Ouzunova, Milena; Lübberstedt, Thomas

    2008-01-01

    Background Forage quality of maize is influenced by both the content and structure of lignins in the cell wall. Biosynthesis of monolignols, constituting the complex structure of lignins, is catalyzed by enzymes in the phenylpropanoid pathway. Results In the present study we have amplified partial genomic fragments of six putative phenylpropanoid pathway genes in a panel of elite European inbred lines of maize (Zea mays L.) contrasting in forage quality traits. Six loci, encoding C4H, 4CL1, 4CL2, C3H, F5H, and CAD, displayed different levels of nucleotide diversity and linkage disequilibrium (LD) possibly reflecting different levels of selection. Associations with forage quality traits were identified for several individual polymorphisms within the 4CL1, C3H, and F5H genomic fragments when controlling for both overall population structure and relative kinship. A 1-bp indel in 4CL1 was associated with in vitro digestibility of organic matter (IVDOM), a non-synonymous SNP in C3H was associated with IVDOM, and an intron SNP in F5H was associated with neutral detergent fiber. However, the C3H and F5H associations did not remain significant when controlling for multiple testing. Conclusion While the number of lines included in this study limit the power of the association analysis, our results imply that genetic variation for forage quality traits can be mined in phenylpropanoid pathway genes of elite breeding lines of maize. PMID:18173847

  9. Candidate Gene Analyses of Skeletal Variation in Malocclusion.

    PubMed

    da Fontoura, C S G; Miller, S F; Wehby, G L; Amendt, B A; Holton, N E; Southard, T E; Allareddy, V; Moreno Uribe, L M

    2015-07-01

    This study evaluated associations between craniofacial candidate genes and skeletal variation in patients with malocclusion. Lateral cephalometric radiographs of 269 untreated adults with skeletal classes I, II, and III malocclusion were digitized with 14 landmarks. Two-dimensional coordinates were analyzed using Procrustes fit and principal component (PC) analysis to generate continuous malocclusion phenotypes. Skeletal class classifications (I, II, or III) were used as a categorical phenotype. Individuals were genotyped for 198 single-nucleotide polymorphisms (SNPs) in 71 craniofacial genes and loci. Phenotype-genotype associations were tested via multivariate linear regression for continuous phenotypes and multinomial logistic regression for skeletal malocclusion class. PC analysis resulted in 4 principal components (PCs) explaining 69% of the total skeletal facial variation. PC1 explained 32.7% of the variation and depicted vertical discrepancies ranging from skeletal deep to open bites. PC1 was associated with a SNP near PAX5 (P = 0.01). PC2 explained 21.7% and captured horizontal maxillomandibular discrepancies. PC2 was associated with SNPs upstream of SNAI3 (P = 0.0002) and MYO1H (P = 0.006). PC3 explained 8.2% and captured variation in ramus height, body length, and anterior cranial base orientation. PC3 was associated with TWIST1 (P = 0.000076). Finally, PC4 explained 6.6% and detected variation in condylar inclination as well as symphysis projection. PC4 was associated with PAX7 (P = 0.007). Furthermore, skeletal class II risk increased relative to class I with the minor alleles of SNPs in FGFR2 (odds ratio [OR] = 2.1, P = 0.004) and declined with SNPs in EDN1 (OR = 0.5, P = 0.007). Conversely, skeletal class III risk increased versus class I with SNPs in FGFR2 (OR 2.2, P = 0.005) and COL1A1 (OR = 2.1, P = 0.008) and declined with SNPs in TBX5 (OR = 0.5, P = 0.014). PAX5, SNAI3, MYO1H, TWIST1, and PAX7 are associated with craniofacial skeletal variation

  10. Candidate Gene Analyses of Skeletal Variation in Malocclusion

    PubMed Central

    da Fontoura, C.S.G.; Miller, S.F.; Wehby, G.L.; Amendt, B.A.; Holton, N.E.; Southard, T.E.; Allareddy, V.

    2015-01-01

    This study evaluated associations between craniofacial candidate genes and skeletal variation in patients with malocclusion. Lateral cephalometric radiographs of 269 untreated adults with skeletal classes I, II, and III malocclusion were digitized with 14 landmarks. Two-dimensional coordinates were analyzed using Procrustes fit and principal component (PC) analysis to generate continuous malocclusion phenotypes. Skeletal class classifications (I, II, or III) were used as a categorical phenotype. Individuals were genotyped for 198 single-nucleotide polymorphisms (SNPs) in 71 craniofacial genes and loci. Phenotype-genotype associations were tested via multivariate linear regression for continuous phenotypes and multinomial logistic regression for skeletal malocclusion class. PC analysis resulted in 4 principal components (PCs) explaining 69% of the total skeletal facial variation. PC1 explained 32.7% of the variation and depicted vertical discrepancies ranging from skeletal deep to open bites. PC1 was associated with a SNP near PAX5 (P = 0.01). PC2 explained 21.7% and captured horizontal maxillomandibular discrepancies. PC2 was associated with SNPs upstream of SNAI3 (P = 0.0002) and MYO1H (P = 0.006). PC3 explained 8.2% and captured variation in ramus height, body length, and anterior cranial base orientation. PC3 was associated with TWIST1 (P = 0.000076). Finally, PC4 explained 6.6% and detected variation in condylar inclination as well as symphysis projection. PC4 was associated with PAX7 (P = 0.007). Furthermore, skeletal class II risk increased relative to class I with the minor alleles of SNPs in FGFR2 (odds ratio [OR] = 2.1, P = 0.004) and declined with SNPs in EDN1 (OR = 0.5, P = 0.007). Conversely, skeletal class III risk increased versus class I with SNPs in FGFR2 (OR 2.2, P = 0.005) and COL1A1 (OR = 2.1, P = 0.008) and declined with SNPs in TBX5 (OR = 0.5, P = 0.014). PAX5, SNAI3, MYO1H, TWIST1, and PAX7 are associated with craniofacial skeletal variation

  11. Genes of the Mitochondrial Apoptotic Pathway in Mytilus galloprovincialis

    PubMed Central

    Figueras, Antonio; Novoa, Beatriz

    2013-01-01

    Bivalves play vital roles in marine, brackish, freshwater and terrestrial habitats. In recent years, these ecosystems have become affected through anthropogenic activities. The ecological success of marine bivalves is based on the ability to modify their physiological functions in response to environmental changes. One of the most important mechanisms involved in adaptive responses to environmental and biological stresses is apoptosis, which has been scarcely studied in mollusks, although the final consequence of this process, DNA fragmentation, has been frequently used for pollution monitoring. Environmental stressors induce apoptosis in molluscan cells via an intrinsic pathway. Many of the proteins involved in vertebrate apoptosis have been recognized in model invertebrates; however, this process might not be universally conserved. Mytilus galloprovincialis is presented here as a new model to study the linkage between molecular mechanisms that mediate apoptosis and marine bivalve ecological adaptations. Therefore, it is strictly necessary to identify the key elements involved in bivalve apoptosis. In the present study, six mitochondrial apoptotic-related genes were characterized, and their gene expression profiles following UV irradiation were evaluated. This is the first step for the development of potential biomarkers to assess the biological responses of marine organisms to stress. The results confirmed that apoptosis and, more specifically, the expression of the genes involved in this process can be used to assess the biological responses of marine organisms to stress. PMID:23626691

  12. Landscape-scale variation in an anthropogenic factor shapes immune gene variation within a wild population.

    PubMed

    Gonzalez-Quevedo, Catalina; Davies, Richard G; Phillips, Karl P; Spurgin, Lewis G; Richardson, David S

    2016-09-01

    Understanding the spatial scale at which selection acts upon adaptive genetic variation in natural populations is fundamental to our understanding of evolutionary ecology, and has important ramifications for conservation. The environmental factors to which individuals of a population are exposed can vary at fine spatial scales, potentially generating localized patterns of adaptation. Here, we compared patterns of neutral and major histocompatibility complex (MHC) variation within an island population of Berthelot's pipit (Anthus berthelotii) to assess whether landscape-level differences in pathogen-mediated selection generate fine-scale spatial structuring in these immune genes. Specifically, we tested for spatial associations between the distribution of avian malaria, and the factors previously shown to influence that distribution, and MHC variation within resident individuals. Although we found no overall genetic structure across the population for either neutral or MHC loci, we did find localized associations between environmental factors and MHC variation. One MHC class I allele (ANBE48) was directly associated with malaria infection risk, while the presence of the ANBE48 and ANBE38 alleles within individuals correlated (positively and negatively, respectively) with distance to the nearest poultry farm, an anthropogenic factor previously shown to be an important determinant of disease distribution in the study population. Our findings highlight the importance of considering small spatial scales when studying the patterns and processes involved in evolution at adaptive loci.

  13. Inferring pathway crosstalk networks using gene set co-expression signatures.

    PubMed

    Wang, Ting; Gu, Jin; Yuan, Jun; Tao, Ran; Li, Yanda; Li, Shao

    2013-07-01

    Constructing molecular interaction networks in cells is important for understanding the underlying mechanisms of biological processes. Except for single gene analysis, several gene set-based methods have been proposed to infer pathway crosstalk by analyzing large-scale gene expression data. But most of them take all pathway genes as a whole to infer the crosstalk. Biological evidence suggests that the pathway crosstalk usually occurs between some subsets rather than the whole sets of pathway genes. In this study, we propose a novel method, sGSCA (signature-based gene set co-expression analysis) which can use the co-expression correlations between subsets of pathway genes to infer the pathway crosstalk networks. The method applies sparse canonical correlation analysis (sCCA) to measure the pathway level co-expression and simultaneously obtain the subsets or signature genes that contribute to the co-expression of pathways. On simulated datasets, sGSCA can efficiently detect pathway crosstalk and the corresponding highly correlated signature genes. We applied sGSCA to two cancer gene expression datasets (one for hepatocellular cancer and the other for lung cancer). In the inferred networks, we found several important pathway crosstalks related to the cancers. The identified signature genes also show high enrichment for the cancer related genes. sGSCA can infer pathway crosstalk networks using large-scale gene expression data, and should be a useful tool for systematically studying the molecular mechanisms of complex diseases on both pathway and gene levels at the same time.

  14. Genetic Variation within the Anticoagulant, Procoagulant, Fibrinolytic and Innate Immunity Pathways as Risk Factors for Venous Thromboembolism

    PubMed Central

    Heit, John A.; Cunningham, Julie M.; Petterson, Tanya M.; Armasu, Sebastian M.; Rider, David N.; de Andrade, Mariza

    2011-01-01

    Summary Background Venous thromboembolism (VTE) is highly heritable (estimated heritability [h2]=0.62) and likely a result of multigenic action. Objective To systematically test variation within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways for an independent association with VTE. Methods Non-Hispanic adults of European ancestry with objectively-diagnosed VTE, and age-, sex-group frequency matched controls were genotyped for 13,031 single nucleotide polymorphisms (SNPs) within 764 genes. Analyses (n=12,296 SNPs) were performed with PLINK using an additive genetic model and adjusted for age, sex, state of residence, and myocardial infarction or stroke. Results Among 2927 individuals, one or more SNPs within ABO, F2, F5, F11, KLKB1, SELP and SCUBE1 were significantly associated with VTE, including Factor V Leiden, Prothrombin G20210A, ABO non-O blood type, and a novel association with ABO rs2519093 (OR=1.68, p-value=8.08×10−16) that was independent of blood type. In stratified analyses, SNPs in the following genes were significantly associated with VTE: F5 and ABO among both genders and LY86 among women; F2, ABO and KLKB1 among Factor V Leiden non-carriers; F5, F11, KLKB1 and GFRA1 in ABO non-O blood type; and ABO, F5, F11, KLKB1, SCUBE1 and SELP among Prothrombin G20210A non-carriers. The ABO rs2519093 population-attributable risk (PAR) exceeded that of Factor V Leiden and Prothrombin G20210A, and the joint PAR of Factor V Leiden, Prothrombin G20210A, ABO non-O and ABO rs2519093 was 0.40. Conclusions Anticoagulant, procoagulant, fibrinolytic and innate immunity pathway genetic variation accounts for a large proportion of VTE among non-Hispanic adults of European-ancestry. PMID:21463476

  15. Common Variation in Fatty Acid Metabolic Genes and Risk of Incident Sudden Cardiac Arrest

    PubMed Central

    Lemaitre, Rozenn N.; Johnson, Catherine O.; Hesselson, Stephanie; Sotoodhenia, Nona; McKnight, Barbara; Sitlani, Colleen M.; Rea, Thomas D.; King, Irena B.; Kwok, Pui-Yan; Mak, Angel; Li, Guo; Brody, Jennifer; Larson, Eric; Mozaffarian, Dariush; Psaty, Bruce M.; Huertas-Vazquez, Adriana; Tardif, Jean-Claude; Albert, Christine M.; Lyytikäinen, Leo-Pekka; Arking, Dan E.; Kääb, Stefan; Huikuri, Heikki V.; Krijthe, Bouwe P.; Eijgelsheim, Mark; Wang, Ying A.; Reinier, Kyndaron; Lehtimäki, Terho; Pulit, Sara L.; Brugada, Ramon; Müller-Nurasyid, Martina; Newton-Cheh, Chris H.; Karhunen, Pekka J.; Stricker, Bruno H.; Goyette, Philippe; Rotter, Jerome I.; Chugh, Sumeet S.; Chakravarti, Aravinda; Jouven, Xavier; Siscovick, David S

    2014-01-01

    Background There is limited information on genetic factors associated with sudden cardiac arrest (SCA). Objective To assess the association of common variation in genes in fatty acid pathways with SCA risk. Methods We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n=2160) were from a repository of SCA in the greater Seattle area. Controls (n=2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed p-min permutation tests to account for multiple comparisons within each gene. The SNP associations with corrected p-value < 0.05 were then examined in a meta-analysis of these SNP associations in nine replication studies totaling 2129 SCA cases and 23833 non-cases. Results Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13% lower SCA risk (−21% to −5%) in the discovery phase and 9% lower risk (95% CI −16% to - 1%) in the replication phase. Conclusions While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation. PMID:24418166

  16. Nucleotide variation in the Toxoplasma gondii micronemal protein 8 gene.

    PubMed

    Li, Z Y; Song, H Q; Wang, C R; Zhu, X Q

    2016-05-09

    Toxoplasma gondii is a successful opportunistic protozoan distributed worldwide, which can infect all vertebrates, leading to serious infection, blindness, and abortion. Micronemal (MIC) proteins are critically important for T. gondii infection, as they participate in various stages of the Toxoplasma life cycle, including invasion and attachment to host cells. MIC8 secretion relies on the concentration of intracellular calcium, and can mediate the invasion of T. gondii by interacting with soluble MIC3. To investigate genetic diversity of the MIC8 gene, 16 T. gondii strains from different hosts and geographical locations, and two reference isolates (ToxoDB: TGME49_245490 and TGVEG_245490) were examined in this study. The results showed that all the examined MIC8 genes are 2055 bp, with an A+T content ranging from 50.2 to 50.6%. Conversely, lower levels of variation were detected within their nucleotide and amino acid sequences. Phylogenetic analyses indicated that three classical genotypes of T. gondii and the ToxoDB#9 genotype did not group exclusively via Bayesian inference, maximum parsimony, neighbor joining, and/or maximum likelihood assays based on the nucleotide and amino acid sequences of the MIC8 gene. In summary, the T. gondii MIC8 gene is not a suitable marker for population genetic studies of this parasite.

  17. Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer

    PubMed Central

    Duell, Eric J.; Yu, Kai; Risch, Harvey A.; Olson, Sara H.; Kooperberg, Charles; Wolpin, Brian M.; Jiao, Li; Dong, Xiaoqun; Wheeler, Bill; Arslan, Alan A.; Bueno-de-Mesquita, H. Bas; Fuchs, Charles S.; Gallinger, Steven; Gross, Myron; Hartge, Patricia; Hoover, Robert N.; Holly, Elizabeth A.; Jacobs, Eric J.; Klein, Alison P.; LaCroix, Andrea; Mandelson, Margaret T.; Petersen, Gloria; Zheng, Wei; Agalliu, Ilir; Albanes, Demetrius; Boutron-Ruault, Marie-Christine; Bracci, Paige M.; Buring, Julie E.; Canzian, Federico; Chang, Kenneth; Chanock, Stephen J.; Cotterchio, Michelle; Gaziano, J.Michael; Giovannucci, Edward L.; Goggins, Michael; Hallmans, Göran; Hankinson, Susan E.; Hoffman Bolton, Judith A.; Hunter, David J.; Hutchinson, Amy; Jacobs, Kevin B.; Jenab, Mazda; Khaw, Kay-Tee; Kraft, Peter; Krogh, Vittorio; Kurtz, Robert C.; McWilliams, Robert R.; Mendelsohn, Julie B.; Patel, Alpa V.; Rabe, Kari G.; Riboli, Elio; Shu, Xiao-Ou; Tjønneland, Anne; Tobias, Geoffrey S.; Trichopoulos, Dimitrios; Virtamo, Jarmo; Visvanathan, Kala; Watters, Joanne; Yu, Herbert; Zeleniuch-Jacquotte, Anne; Stolzenberg-Solomon, Rachael Z.

    2012-01-01

    Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case–control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10−6, 1.6 × 10−5, 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10−5), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H. pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer. PMID:22523087

  18. A network-based gene-weighting approach for pathway analysis.

    PubMed

    Fang, Zhaoyuan; Tian, Weidong; Ji, Hongbin

    2012-03-01

    Classical algorithms aiming at identifying biological pathways significantly related to studying conditions frequently reduced pathways to gene sets, with an obvious ignorance of the constitutive non-equivalence of various genes within a defined pathway. We here designed a network-based method to determine such non-equivalence in terms of gene weights. The gene weights determined are biologically consistent and robust to network perturbations. By integrating the gene weights into the classical gene set analysis, with a subsequent correction for the "over-counting" bias associated with multi-subunit proteins, we have developed a novel gene-weighed pathway analysis approach, as implemented in an R package called "Gene Associaqtion Network-based Pathway Analysis" (GANPA). Through analysis of several microarray datasets, including the p53 dataset, asthma dataset and three breast cancer datasets, we demonstrated that our approach is biologically reliable and reproducible, and therefore helpful for microarray data interpretation and hypothesis generation.

  19. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

    PubMed Central

    Jim, Heather S.L.; Lin, Hui-Yi; Tyrer, Jonathan P.; Lawrenson, Kate; Dennis, Joe; Chornokur, Ganna; Chen, Zhihua; Chen, Ann Y.; Permuth-Wey, Jennifer; Aben, Katja KH.; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bunker, Clareann H.; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Sieh, Weiva; Doherty, Jennifer A.; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F.; Eccles, Diana M.; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goodman, Marc T.; Gronwald, Jacek; Harter, Philipp; Hasmad, Hanis N.; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Claus K.; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kellar, Melissa; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Vierkant, Robert A.; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Ian; Menon, Usha; Milne, Roger L.; Modugno, Francesmary; Thomsen, Lotte; Moysich, Kirsten B.; Ness, Roberta B.; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Palmieri Weber, Rachel; Paul, James; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Pike, Malcolm C.; Poole, Elizabeth M.; Schernhammer, Eva; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Song, Honglin; Southey, Melissa C.; Spiewankiewicz, Beata; Sucheston-Campbell, Lara; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Tangen, Ingvild L.; Tworoger, Shelley S.; van Altena, Anne M.; Vergote, Ignace; Walsh, Christine S.; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wu, Anna H.; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Amankwah, Ernest; Berchuck, Andrew; Schildkraut, Joellen M.; Kelemen, Linda E.; Ramus, Susan J.; Monteiro, Alvaro N.A.; Goode, Ellen L.; Narod, Steven A.; Gayther, Simon A.; Pharoah, Paul D. P.; Sellers, Thomas A.; Phelan, Catherine M.

    2016-01-01

    Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68–0.90, p = 5.59 × 10−4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways. PMID:26807442

  20. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).

    PubMed

    Jim, Heather S L; Lin, Hui-Yi; Tyrer, Jonathan P; Lawrenson, Kate; Dennis, Joe; Chornokur, Ganna; Chen, Zhihua; Chen, Ann Y; Permuth-Wey, Jennifer; Aben, Katja Kh; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V; Bean, Yukie T; Beckmann, Matthias W; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bunker, Clareann H; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Sieh, Weiva; Doherty, Jennifer A; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F; Eccles, Diana M; Edwards, Robert P; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goodman, Marc T; Gronwald, Jacek; Harter, Philipp; Hasmad, Hanis N; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Claus K; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kellar, Melissa; Kiemeney, Lambertus A; Krakstad, Camilla; Kjaer, Susanne K; Kupryjanczyk, Jolanta; Vierkant, Robert A; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; McNeish, Ian; Menon, Usha; Milne, Roger L; Modugno, Francesmary; Thomsen, Lotte; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Palmieri Weber, Rachel; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Pike, Malcolm C; Poole, Elizabeth M; Schernhammer, Eva; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Song, Honglin; Southey, Melissa C; Spiewankiewicz, Beata; Sucheston-Campbell, Lara; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Tangen, Ingvild L; Tworoger, Shelley S; van Altena, Anne M; Vergote, Ignace; Walsh, Christine S; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Wu, Anna H; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Amankwah, Ernest; Berchuck, Andrew; Schildkraut, Joellen M; Kelemen, Linda E; Ramus, Susan J; Monteiro, Alvaro N A; Goode, Ellen L; Narod, Steven A; Gayther, Simon A; Pharoah, Paul D P; Sellers, Thomas A; Phelan, Catherine M

    Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10(-4)]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.

  1. Comparative gene expression study and pathway analysis of the human iris- and the retinal pigment epithelium

    PubMed Central

    ten Brink, Jacoline B.; Moerland, Perry D.; Heine, Vivi M.; Bergen, Arthur A.

    2017-01-01

    Background The retinal pigment epithelium (RPE) is a neural monolayer lining the back of the eye. Degeneration of the RPE leads to severe vision loss in, so far incurable, diseases such as age-related macular degeneration and some forms of retinitis pigmentosa. A promising future replacement therapy may be autologous iris epithelial cell transdifferentiation into RPE in vitro and, subsequently, transplantation. In this study we compared the gene expression profiles of the iris epithelium (IE) and the RPE. Methods We collected both primary RPE- and IE cells from 5 freshly frozen human donor eyes, using respectively laser dissection microscopy and excision. We performed whole-genome expression profiling using 44k Agilent human microarrays. We investigated the gene expression profiles on both gene and functional network level, using R and the knowledge database Ingenuity. Results The major molecular pathways related to the RPE and IE were quite similar and yielded basic neuro-epithelial cell functions. Nonetheless, we also found major specific differences: For example, genes and molecular pathways, related to the visual cycle and retinol biosynthesis are significantly higher expressed in the RPE than in the IE. Interestingly, Wnt and aryl hydrocarbon receptor (AhR-) signaling pathways are much higher expressed in the IE than in the RPE, suggesting, respectively, a possible pluripotent and high detoxification state of the IE. Conclusions This study provides a valuation of the similarities and differences between the expression profiles of the RPE and IE. Our data combined with that of the literature, represent a most comprehensive perspective on transcriptional variation, which may support future research in the development of therapeutic transplantation of IE. PMID:28827822

  2. Comparative gene expression study and pathway analysis of the human iris- and the retinal pigment epithelium.

    PubMed

    Bennis, Anna; Ten Brink, Jacoline B; Moerland, Perry D; Heine, Vivi M; Bergen, Arthur A

    2017-01-01

    The retinal pigment epithelium (RPE) is a neural monolayer lining the back of the eye. Degeneration of the RPE leads to severe vision loss in, so far incurable, diseases such as age-related macular degeneration and some forms of retinitis pigmentosa. A promising future replacement therapy may be autologous iris epithelial cell transdifferentiation into RPE in vitro and, subsequently, transplantation. In this study we compared the gene expression profiles of the iris epithelium (IE) and the RPE. We collected both primary RPE- and IE cells from 5 freshly frozen human donor eyes, using respectively laser dissection microscopy and excision. We performed whole-genome expression profiling using 44k Agilent human microarrays. We investigated the gene expression profiles on both gene and functional network level, using R and the knowledge database Ingenuity. The major molecular pathways related to the RPE and IE were quite similar and yielded basic neuro-epithelial cell functions. Nonetheless, we also found major specific differences: For example, genes and molecular pathways, related to the visual cycle and retinol biosynthesis are significantly higher expressed in the RPE than in the IE. Interestingly, Wnt and aryl hydrocarbon receptor (AhR-) signaling pathways are much higher expressed in the IE than in the RPE, suggesting, respectively, a possible pluripotent and high detoxification state of the IE. This study provides a valuation of the similarities and differences between the expression profiles of the RPE and IE. Our data combined with that of the literature, represent a most comprehensive perspective on transcriptional variation, which may support future research in the development of therapeutic transplantation of IE.

  3. Variants in folate pathway genes as modulators of genetic instability and lung cancer risk.

    PubMed

    Piskac-Collier, Amanda L; Monroy, Claudia; Lopez, Mirtha S; Cortes, Andrea; Etzel, Carol J; Greisinger, Anthony J; Spitz, Margaret R; El-Zein, Randa A

    2011-01-01

    Genetic instability plays a crucial role in cancer development. The genetic stability of the cell as well as DNA methylation status could be modulated by folate levels. Several studies suggested associations between polymorphisms in folate genes and alterations in protein expression and variations in serum levels of the folate. The objective of this study was to investigate the effect of folate pathway polymorphisms on modulating genetic instability and lung cancer risk. Genotyping of 5 SNPs in folate pathway genes and cytokinesis-blocked micronucleus cytome assay analysis (to determine the genetic instability at baseline and following NNK treatment) was conducted on 180 lung cancer cases and 180 age-, gender-, and smoking-matched controls. Our results showed that individually, folate pathway SNPs were not associated with cytogenetic damage or lung cancer risk. However, in a polygenic disease such as lung cancer, gene-gene interactions are expected to play an important role in determining the phenotypic variability of the diseases. We observed that interactions between MTHFR677, MTHFR1298, and SHMT polymorphisms may have a significant impact on genetic instability in lung cancer patients. With regard to cytogenetic alterations, our results showed that lymphocytes from lung cancer patients exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK] had considerably increased frequency of cytogenetic damage in presence of MTHFR 677, MTHFR 1298, and SHMT allelic variants. These findings support the notion that significant interactions may potentially modulate the lung cancer susceptibility and alter the overall the repair abilities of lung cancer patients when exposed to tobacco carcinogens such as NNK. © 2010 Wiley-Liss, Inc.

  4. Relation between sonic hedgehog pathway gene polymorphisms and basal cell carcinoma development in the Polish population.

    PubMed

    Lesiak, Aleksandra; Sobolewska-Sztychny, Dorota; Majak, Paweł; Sobjanek, Michał; Wodz, Karolina; Sygut, Karolina Przybyłowska-; Majsterek, Ireneusz; Wozniacka, Anna; Narbutt, Joanna

    2016-01-01

    In recent decades, increases have been observed in the incidence of nonmelanoma skin cancers, including basal cell carcinoma (BCC) and squamous cell carcinoma. BCC is the most common neoplasm in Caucasian populations. Sonic hedgehog (Shh) pathway impairment plays a key role in BCC pathogenesis, and there is evidence that Shh pathway genetic variations may predispose to BCC development. We genotyped 22 single-nucleotide polymorphisms (SNPs) in 4 Shh pathway genes: SHH, GLI, SMO, and PTCH. The study group consisted of 142 BCC patients and 142 age-matched, sex-matched healthy subjects (controls). SNPs were assessed using the PCR-RFLP method. The genotype distribution for the polymorphisms in the rs104894049 331 A/T SHH, rs104894040 349 T/C SHH, and rs41303402 385 G/A SMO genes differed significantly between the BCC patients and the controls. The presence of CC genotype in the SHH rs104894040 349 T/C polymorphism was linked to the highest risk of BCC development (OR 87.9, p < 0.001). Other genotypes, such as the TT in SHH rs104894049 331 A/T and the GG in SMO rs41303402 385 G/A also statistically raised the risk of BCC, but these associations were weaker. Other investigated polymorphisms showed no statistical differences between patients and controls. The results obtained testify to the importance of the SHH and SMO gene polymorphisms in skin cancerogenesis. These results mainly underline the potential role of SHH3 rs104894040 349 T/C gene polymorphism in the development of skin basal cell carcinomas in patients of Polish origin.

  5. Oxytocin receptor gene variation predicts subjective responses to MDMA.

    PubMed

    Bershad, Anya K; Weafer, Jessica J; Kirkpatrick, Matthew G; Wardle, Margaret C; Miller, Melissa A; de Wit, Harriet

    2016-12-01

    3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") enhances desire to socialize and feelings of empathy, which are thought to be related to increased oxytocin levels. Thus, variation in the oxytocin receptor gene (OXTR) may influence responses to the drug. Here, we examined the influence of a single OXTR nucleotide polymorphism (SNP) on responses to MDMA in humans. Based on findings that carriers of the A allele at rs53576 exhibit reduced sensitivity to oxytocin-induced social behavior, we hypothesized that these individuals would show reduced subjective responses to MDMA, including sociability. In this three-session, double blind, within-subjects study, healthy volunteers with past MDMA experience (N = 68) received a MDMA (0, 0.75 mg/kg, and 1.5 mg/kg) and provided self-report ratings of sociability, anxiety, and drug effects. These responses were examined in relation to rs53576. MDMA (1.5 mg/kg) did not increase sociability in individuals with the A/A genotype as it did in G allele carriers. The genotypic groups did not differ in responses at the lower MDMA dose, or in cardiovascular or other subjective responses. These findings are consistent with the idea that MDMA-induced sociability is mediated by oxytocin, and that variation in the oxytocin receptor gene may influence responses to the drug.

  6. Patterns of Individual Variation in Visual Pathway Structure and Function in the Sighted and Blind

    PubMed Central

    Datta, Ritobrato; Benson, Noah C.; Prasad, Sashank; Jacobson, Samuel G.; Cideciyan, Artur V.; Bridge, Holly; Watkins, Kate E.; Butt, Omar H.; Dain, Aleksandra S.; Brandes, Lauren; Gennatas, Efstathios D.

    2016-01-01

    Many structural and functional brain alterations accompany blindness, with substantial individual variation in these effects. In normally sighted people, there is correlated individual variation in some visual pathway structures. Here we examined if the changes in brain anatomy produced by blindness alter the patterns of anatomical variation found in the sighted. We derived eight measures of central visual pathway anatomy from a structural image of the brain from 59 sighted and 53 blind people. These measures showed highly significant differences in mean size between the sighted and blind cohorts. When we examined the measurements across individuals within each group we found three clusters of correlated variation, with V1 surface area and pericalcarine volume linked, and independent of the thickness of V1 cortex. These two clusters were in turn relatively independent of the volumes of the optic chiasm and lateral geniculate nucleus. This same pattern of variation in visual pathway anatomy was found in the sighted and the blind. Anatomical changes within these clusters were graded by the timing of onset of blindness, with those subjects with a post-natal onset of blindness having alterations in brain anatomy that were intermediate to those seen in the sighted and congenitally blind. Many of the blind and sighted subjects also contributed functional MRI measures of cross-modal responses within visual cortex, and a diffusion tensor imaging measure of fractional anisotropy within the optic radiations and the splenium of the corpus callosum. We again found group differences between the blind and sighted in these measures. The previously identified clusters of anatomical variation were also found to be differentially related to these additional measures: across subjects, V1 cortical thickness was related to cross-modal activation, and the volume of the optic chiasm and lateral geniculate was related to fractional anisotropy in the visual pathway. Our findings show that

  7. Patterns of Individual Variation in Visual Pathway Structure and Function in the Sighted and Blind.

    PubMed

    Aguirre, Geoffrey K; Datta, Ritobrato; Benson, Noah C; Prasad, Sashank; Jacobson, Samuel G; Cideciyan, Artur V; Bridge, Holly; Watkins, Kate E; Butt, Omar H; Dain, Aleksandra S; Brandes, Lauren; Gennatas, Efstathios D

    2016-01-01

    Many structural and functional brain alterations accompany blindness, with substantial individual variation in these effects. In normally sighted people, there is correlated individual variation in some visual pathway structures. Here we examined if the changes in brain anatomy produced by blindness alter the patterns of anatomical variation found in the sighted. We derived eight measures of central visual pathway anatomy from a structural image of the brain from 59 sighted and 53 blind people. These measures showed highly significant differences in mean size between the sighted and blind cohorts. When we examined the measurements across individuals within each group we found three clusters of correlated variation, with V1 surface area and pericalcarine volume linked, and independent of the thickness of V1 cortex. These two clusters were in turn relatively independent of the volumes of the optic chiasm and lateral geniculate nucleus. This same pattern of variation in visual pathway anatomy was found in the sighted and the blind. Anatomical changes within these clusters were graded by the timing of onset of blindness, with those subjects with a post-natal onset of blindness having alterations in brain anatomy that were intermediate to those seen in the sighted and congenitally blind. Many of the blind and sighted subjects also contributed functional MRI measures of cross-modal responses within visual cortex, and a diffusion tensor imaging measure of fractional anisotropy within the optic radiations and the splenium of the corpus callosum. We again found group differences between the blind and sighted in these measures. The previously identified clusters of anatomical variation were also found to be differentially related to these additional measures: across subjects, V1 cortical thickness was related to cross-modal activation, and the volume of the optic chiasm and lateral geniculate was related to fractional anisotropy in the visual pathway. Our findings show that

  8. AGTR1 gene variation: association with depression and frontotemporal morphology

    PubMed Central

    Taylor, Warren D; Benjamin, Sophiya; McQuoid, Douglas R; Payne, Martha E; Krishnan, Ranga R; MacFall, James R; Ashley-Koch, Allison

    2012-01-01

    The renin-angiotensin system (RAS) is implicated in the response to physiological and psychosocial stressors however its role in stress-related psychiatric disorders is poorly understood. We examined if variation in AGTR1, the gene coding for the type 1 angiotensin II receptor (AT1R), is associated with a diagnosis of depression and differences in white matter hyperintensities and frontotemporal brain volumes. 257 depressed and 116 nondepressed elderly Caucasian subjects completed clinical assessments and provided blood samples for genotyping. We utilized a haplotype-tagging single nucleotide polymorphism (htSNP) analysis to test for variation in AGTR1. 1.5T MRI data for measurement of hyperintense lesions were available on 281 subjects, while 70 subjects completed 3T MRI allowing for measurements of the hippocampus and dorsolateral prefrontal cortex (dlPFC). Two htSNPs exhibited statistically significant frequency differences between diagnostic cohorts: rs10935724 and rs12721331. Although hyperintense lesion volume did not significantly differ by any htSNP, dlPFC and hippocampus volume differed significantly for several htSNPs. Intriguingly, for those htSNPs differing significantly for both dlPFC and hippocampus volume, the variant associated with smaller dlPFC volume was associated with larger hippocampal volume. This supports that genetic variation in AGTR1 is associated with depression and differences in frontotemporal morphology. PMID:22703619

  9. AGTR1 gene variation: association with depression and frontotemporal morphology.

    PubMed

    Taylor, Warren D; Benjamin, Sophiya; McQuoid, Douglas R; Payne, Martha E; Krishnan, Ranga R; MacFall, James R; Ashley-Koch, Allison

    2012-05-31

    The renin-angiotensin system (RAS) is implicated in the response to physiological and psychosocial stressors, but its role in stress-related psychiatric disorders is poorly understood. We examined if variation in AGTR1, the gene coding for the type 1 angiotensin II receptor (AT(1)R), is associated with a diagnosis of depression and differences in white matter hyperintensities and frontotemporal brain volumes. Participants comprised 257 depressed and 116 nondepressed elderly Caucasian subjects who completed clinical assessments and provided blood samples for genotyping. We used a haplotype-tagging single nucleotide polymorphism (htSNP) analysis to test for variation in AGTR1. For measurement of hyperintense lesions, 1.5 Tesla magnetic resonance imaging (MRI) data were available on 33 subjects. For measurements of the hippocampus and dorsolateral prefrontal cortex (dlPFC), 3 Tesla MRI data were available on 70 subjects. Two htSNPs exhibited statistically significant frequency differences between diagnostic cohorts: rs10935724 and rs12721331. Although hyperintense lesion volume did not significantly differ by any htSNP, dlPFC and hippocampus volume differed significantly for several htSNPs. Intriguingly, for those htSNPs differing significantly for both dlPFC and hippocampus volume, the variant associated with smaller dlPFC volume was associated with larger hippocampal volume. This supports the idea that genetic variation in AGTR1 is associated with depression and differences in frontotemporal morphology. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  10. PTSD and gene variants: new pathways and new thinking.

    PubMed

    Skelton, Kelly; Ressler, Kerry J; Norrholm, Seth D; Jovanovic, Tanja; Bradley-Davino, Bekh

    2012-02-01

    Posttraumatic Stress Disorder (PTSD) is an anxiety disorder which can develop as a result of exposure to a traumatic event and is associated with significant functional impairment. Family and twin studies have found that risk for PTSD is associated with an underlying genetic vulnerability and that more than 30% of the variance associated with PTSD is related to a heritable component. Using a fear conditioning model to conceptualize the neurobiology of PTSD, three primary neuronal systems have been investigated - the hypothalamic-pituitary-adrenal axis, the locus coeruleus-noradrenergic system, and neurocircuitry interconnecting the limbic system and frontal cortex. The majority of the initial investigations into main effects of candidate genes hypothesized to be associated with PTSD risk have been negative, but studies examining the interaction of genetic polymorphisms with specific environments in predicting PTSD have produced several positive results which have increased our understanding of the determinants of risk and resilience in the aftermath of trauma. Promising avenues of inquiry into the role of epigenetic modification have also been proposed to explain the enduring impact of environmental exposures which occur during key, often early, developmental periods on gene expression. Studies of PTSD endophenotypes, which are heritable biomarkers associated with a circumscribed trait within the more complex psychiatric disorder, may be more directly amenable to analysis of the underlying genetics and neural pathways and have provided promising targets for elucidating the neurobiology of PTSD. Knowledge of the genetic underpinnings and neuronal pathways involved in the etiology and maintenance of PTSD will allow for improved targeting of primary prevention amongst vulnerable individuals or populations, as well as timely, targeted treatment interventions. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. Copyright © 2011 Elsevier

  11. Systematic analysis of microarray datasets to identify Parkinson's disease-associated pathways and genes

    PubMed Central

    Feng, Yinling; Wang, Xuefeng

    2017-01-01

    In order to investigate commonly disturbed genes and pathways in various brain regions of patients with Parkinson's disease (PD), microarray datasets from previous studies were collected and systematically analyzed. Different normalization methods were applied to microarray datasets from different platforms. A strategy combining gene co-expression networks and clinical information was adopted, using weighted gene co-expression network analysis (WGCNA) to screen for commonly disturbed genes in different brain regions of patients with PD. Functional enrichment analysis of commonly disturbed genes was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Co-pathway relationships were identified with Pearson's correlation coefficient tests and a hypergeometric distribution-based test. Common genes in pathway pairs were selected out and regarded as risk genes. A total of 17 microarray datasets from 7 platforms were retained for further analysis. Five gene coexpression modules were identified, containing 9,745, 736, 233, 101 and 93 genes, respectively. One module was significantly correlated with PD samples and thus the 736 genes it contained were considered to be candidate PD-associated genes. Functional enrichment analysis demonstrated that these genes were implicated in oxidative phosphorylation and PD. A total of 44 pathway pairs and 52 risk genes were revealed, and a risk gene pathway relationship network was constructed. Eight modules were identified and were revealed to be associated with PD, cancers and metabolism. A number of disturbed pathways and risk genes were unveiled in PD, and these findings may help advance understanding of PD pathogenesis. PMID:28098893

  12. Systematic analysis of microarray datasets to identify Parkinson's disease‑associated pathways and genes.

    PubMed

    Feng, Yinling; Wang, Xuefeng

    2017-03-01

    In order to investigate commonly disturbed genes and pathways in various brain regions of patients with Parkinson's disease (PD), microarray datasets from previous studies were collected and systematically analyzed. Different normalization methods were applied to microarray datasets from different platforms. A strategy combining gene co‑expression networks and clinical information was adopted, using weighted gene co‑expression network analysis (WGCNA) to screen for commonly disturbed genes in different brain regions of patients with PD. Functional enrichment analysis of commonly disturbed genes was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Co‑pathway relationships were identified with Pearson's correlation coefficient tests and a hypergeometric distribution‑based test. Common genes in pathway pairs were selected out and regarded as risk genes. A total of 17 microarray datasets from 7 platforms were retained for further analysis. Five gene coexpression modules were identified, containing 9,745, 736, 233, 101 and 93 genes, respectively. One module was significantly correlated with PD samples and thus the 736 genes it contained were considered to be candidate PD‑associated genes. Functional enrichment analysis demonstrated that these genes were implicated in oxidative phosphorylation and PD. A total of 44 pathway pairs and 52 risk genes were revealed, and a risk gene pathway relationship network was constructed. Eight modules were identified and were revealed to be associated with PD, cancers and metabolism. A number of disturbed pathways and risk genes were unveiled in PD, and these findings may help advance understanding of PD pathogenesis.

  13. Genomic variants, genes, and pathways of Alzheimer's disease: An overview.

    PubMed

    Naj, Adam C; Schellenberg, Gerard D

    2017-01-01

    Alzheimer's disease (AD) (MIM: 104300) is a highly heritable disease with great complexity in its genetic contributors, and represents the most common form of dementia. With the gradual aging of the world's population, leading to increased prevalence of AD, and the substantial cost of care for those afflicted, identifying the genetic causes of disease represents a critical effort in identifying therapeutic targets. Here we provide a comprehensive review of genomic studies of AD, from the earliest linkage studies identifying monogenic contributors to early-onset forms of AD to the genome-wide and rare variant association studies of recent years that are being used to characterize the mosaic of genetic contributors to late-onset AD (LOAD), and which have identified approximately ∼20 genes with common variants contributing to LOAD risk. In addition, we explore studies employing alternative approaches to identify genetic contributors to AD, including studies of AD-related phenotypes and multi-variant association studies such as pathway analyses. Finally, we introduce studies of next-generation sequencing, which have recently helped identify multiple low-frequency and rare variant contributors to AD, and discuss on-going efforts with next-generation sequencing studies to develop statistically well- powered and comprehensive genomic studies of AD. Through this review, we help uncover the many insights the genetics of AD have provided into the pathways and pathophysiology of AD. © 2016 Wiley Periodicals, Inc.

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

    PubMed Central

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

    2007-01-01

    Background The completion of several genome projects showed that most genes have not yet been characterized, especially in multicellular organisms. Although most genes have unknown functions, a large collection of data is available describing their transcriptional activities under many different experimental conditions. In many cases, the coregulatation of a set of genes across a set of conditions can be used to infer roles for genes of unknown function. Results We developed a search engine, the Multiple-Species Gene Recommender (MSGR), which scans gene expression datasets from multiple organisms to identify genes that participate in a genetic pathway. The MSGR takes a query consisting of a list of genes that function together in a genetic pathway from one of six organisms: Homo sapiens, Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, Arabidopsis thaliana, and Helicobacter pylori. Using a probabilistic method to merge searches, the MSGR identifies genes that are significantly coregulated with the query genes in one or more of those organisms. The MSGR achieves its highest accuracy for many human pathways when searches are combined across species. We describe specific examples in which new genes were identified to be involved in a neuromuscular signaling pathway and a cell-adhesion pathway. Conclusion The search engine can scan large collections of gene expression data for new genes that are significantly coregulated with a pathway of interest. By integrating searches across organisms, the MSGR can identify pathway members whose coregulation is either ancient or newly evolved. PMID:17477880

  15. Gene-gene interactions contribute to eye colour variation in humans.

    PubMed

    Pośpiech, Ewelina; Draus-Barini, Jolanta; Kupiec, Tomasz; Wojas-Pelc, Anna; Branicki, Wojciech

    2011-06-01

    Prediction of phenotypes from genetic data is considered to be the first practical application of data gained from association studies, with potential importance for medicine and the forensic sciences. Multiple genes and polymorphisms have been found to be associated with variation in human pigmentation. Their analysis enables prediction of blue and brown eye colour with a reasonably high accuracy. More accurate prediction, especially in the case of intermediate eye colours, may require better understanding of gene-gene interactions affecting this polygenic trait. Using multifactor dimensionality reduction and logistic regression methods, a study of gene-gene interactions was conducted based on variation in 11 known pigmentation genes examined in a cohort of 718 individuals of European descent. The study revealed significant interactions of a redundant character between the HERC2 and OCA2 genes affecting determination of hazel eye colour and between HERC2 and SLC24A4 affecting determination of blue eye colour. Our research indicates interactive effects of a synergistic character between HERC2 and OCA2, and also provides evidence for a novel strong synergistic interaction between HERC2 and TYRP1, both affecting determination of green eye colour.

  16. Tissue Non-Specific Genes and Pathways Associated with Diabetes: An Expression Meta-Analysis.

    PubMed

    Mei, Hao; Li, Lianna; Liu, Shijian; Jiang, Fan; Griswold, Michael; Mosley, Thomas

    2017-01-21

    We performed expression studies to identify tissue non-specific genes and pathways of diabetes by meta-analysis. We searched curated datasets of the Gene Expression Omnibus (GEO) database and identified 13 and five expression studies of diabetes and insulin responses at various tissues, respectively. We tested differential gene expression by empirical Bayes-based linear method and investigated gene set expression association by knowledge-based enrichment analysis. Meta-analysis by different methods was applied to identify tissue non-specific genes and gene sets. We also proposed pathway mapping analysis to infer functions of the identified gene sets, and correlation and independent analysis to evaluate expression association profile of genes and gene sets between studies and tissues. Our analysis showed that PGRMC1 and HADH genes were significant over diabetes studies, while IRS1 and MPST genes were significant over insulin response studies, and joint analysis showed that HADH and MPST genes were significant over all combined data sets. The pathway analysis identified six significant gene sets over all studies. The KEGG pathway mapping indicated that the significant gene sets are related to diabetes pathogenesis. The results also presented that 12.8% and 59.0% pairwise studies had significantly correlated expression association for genes and gene sets, respectively; moreover, 12.8% pairwise studies had independent expression association for genes, but no studies were observed significantly different for expression association of gene sets. Our analysis indicated that there are both tissue specific and non-specific genes and pathways associated with diabetes pathogenesis. Compared to the gene expression, pathway association tends to be tissue non-specific, and a common pathway influencing diabetes development is activated through different genes at different tissues.

  17. Tissue Non-Specific Genes and Pathways Associated with Diabetes: An Expression Meta-Analysis

    PubMed Central

    Mei, Hao; Li, Lianna; Liu, Shijian; Jiang, Fan; Griswold, Michael; Mosley, Thomas

    2017-01-01

    We performed expression studies to identify tissue non-specific genes and pathways of diabetes by meta-analysis. We searched curated datasets of the Gene Expression Omnibus (GEO) database and identified 13 and five expression studies of diabetes and insulin responses at various tissues, respectively. We tested differential gene expression by empirical Bayes-based linear method and investigated gene set expression association by knowledge-based enrichment analysis. Meta-analysis by different methods was applied to identify tissue non-specific genes and gene sets. We also proposed pathway mapping analysis to infer functions of the identified gene sets, and correlation and independent analysis to evaluate expression association profile of genes and gene sets between studies and tissues. Our analysis showed that PGRMC1 and HADH genes were significant over diabetes studies, while IRS1 and MPST genes were significant over insulin response studies, and joint analysis showed that HADH and MPST genes were significant over all combined data sets. The pathway analysis identified six significant gene sets over all studies. The KEGG pathway mapping indicated that the significant gene sets are related to diabetes pathogenesis. The results also presented that 12.8% and 59.0% pairwise studies had significantly correlated expression association for genes and gene sets, respectively; moreover, 12.8% pairwise studies had independent expression association for genes, but no studies were observed significantly different for expression association of gene sets. Our analysis indicated that there are both tissue specific and non-specific genes and pathways associated with diabetes pathogenesis. Compared to the gene expression, pathway association tends to be tissue non-specific, and a common pathway influencing diabetes development is activated through different genes at different tissues. PMID:28117714

  18. High-Throughput Sequencing of mGluR Signaling Pathway Genes Reveals Enrichment of Rare Variants in Autism

    PubMed Central

    Hovhannisyan, Hayk; Trautman, Edwin; Pinard, Robert; Rathmell, Barbara; Carpenter, Randall; Margulies, David

    2012-01-01

    Identification of common molecular pathways affected by genetic variation in autism is important for understanding disease pathogenesis and devising effective therapies. Here, we test the hypothesis that rare genetic variation in the metabotropic glutamate-receptor (mGluR) signaling pathway contributes to autism susceptibility. Single-nucleotide variants in genes encoding components of the mGluR signaling pathway were identified by high-throughput multiplex sequencing of pooled samples from 290 non-syndromic autism cases and 300 ethnically matched controls on two independent next-generation platforms. This analysis revealed significant enrichment of rare functional variants in the mGluR pathway in autism cases. Higher burdens of rare, potentially deleterious variants were identified in autism cases for three pathway genes previously implicated in syndromic autism spectrum disorder, TSC1, TSC2, and SHANK3, suggesting that genetic variation in these genes also contributes to risk for non-syndromic autism. In addition, our analysis identified HOMER1, which encodes a postsynaptic density-localized scaffolding protein that interacts with Shank3 to regulate mGluR activity, as a novel autism-risk gene. Rare, potentially deleterious HOMER1 variants identified uniquely in the autism population affected functionally important protein regions or regulatory sequences and co-segregated closely with autism among children of affected families. We also identified rare ASD-associated coding variants predicted to have damaging effects on components of the Ras/MAPK cascade. Collectively, these findings suggest that altered signaling downstream of mGluRs contributes to the pathogenesis of non-syndromic autism. PMID:22558107

  19. Polymorphisms in genes of the de novo lipogenesis pathway and overall survival of hepatocellular carcinoma patients undergoing transarterial chemoembolization.

    PubMed

    Wu, You-Sheng; Bao, Deng-Ke; Dai, Jing-Yao; Chen, Cheng; Zhang, Hong-Xin; Yang, YeFa; Xing, Jin-Liang; Huang, Xiao-Jun; Wan, Shao-Gui

    2015-01-01

    Aberrant expression of genes in de novo lipogenesis (DNL) pathway were associated with various cancers, including hepatocellular carcinoma (HCC). Single nucleotide polymorphisms (SNPs) of DNL genes have been reported to be associated with prognosis of some malignancies. However, the effects of SNPs in DNL genes on overall survival of HCC patients receiving transarterial chemoembolization (TACE) treatment are still unknown. In present study, nine SNPs in three genes (ACLY, ACACA and FASN) in DNL pathway were genotyped using the Sequenom iPLEX genotyping system in a hospital-based cohort with 419 HCC patients treated with TACE, and their associations with HCC overall survival were evaluated by Cox proportional hazard regression analysis under three genetic models (additive, dominant and recessive). Although we did not find any significant results in total analysis (all p>0.05), our stratified data showed that SNP rs9912300 in ACLY gene was significantly associated with overall survival of HCC patients with lower AFP level and SNP rs11871275 in ACACA gene was significantly associated with overall survival of HCC patients with higher AFP level. We further identified the significant interactions between AFP level and SNP rs9912300 or rs11871275 in the joint analysis. Conclusively, our data suggest that genetic variations in genes of DNL pathway may be a potential biomarker for predicting clinical outcome of HCC patients treated with TACE.

  20. Long genes and genes with multiple splice variants are enriched in pathways linked to cancer and other multigenic diseases.

    PubMed

    Sahakyan, Aleksandr B; Balasubramanian, Shankar

    2016-03-12

    The role of random mutations and genetic errors in defining the etiology of cancer and other multigenic diseases has recently received much attention. With the view that complex genes should be particularly vulnerable to such events, here we explore the link between the simple properties of the human genes, such as transcript length, number of splice variants, exon/intron composition, and their involvement in the pathways linked to cancer and other multigenic diseases. We reveal a substantial enrichment of cancer pathways with long genes and genes that have multiple splice variants. Although the latter two factors are interdependent, we show that the overall gene length and splicing complexity increase in cancer pathways in a partially decoupled manner. Our systematic survey for the pathways enriched with top lengthy genes and with genes that have multiple splice variants reveal, along with cancer pathways, the pathways involved in various neuronal processes, cardiomyopathies and type II diabetes. We outline a correlation between the gene length and the number of somatic mutations. Our work is a step forward in the assessment of the role of simple gene characteristics in cancer and a wider range of multigenic diseases. We demonstrate a significant accumulation of long genes and genes with multiple splice variants in pathways of multigenic diseases that have already been associated with de novo mutations. Unlike the cancer pathways, we note that the pathways of neuronal processes, cardiomyopathies and type II diabetes contain genes long enough for topoisomerase-dependent gene expression to also be a potential contributing factor in the emergence of pathologies, should topoisomerases become impaired.

  1. Defense mechanisms against herbivory in Picea: sequence evolution and expression regulation of gene family members in the phenylpropanoid pathway

    PubMed Central

    2011-01-01

    Background In trees, a substantial amount of carbon is directed towards production of phenolics for development and defense. This metabolic pathway is also a major factor in resistance to insect pathogens in spruce. In such gene families, environmental stimuli may have an important effect on the evolutionary fate of duplicated genes, and different expression patterns may indicate functional diversification. Results Gene families in spruce (Picea) have expanded to superfamilies, including O-methyltransferases, cytochrome-P450, and dirigents/classIII-peroxidases. Neo-functionalization of superfamily members from different clades is reflected in expression diversification. Genetical genomics can provide new insights into the genetic basis and evolution of insect resistance in plants. Adopting this approach, we merged genotype data (252 SNPs in a segregating pedigree), gene expression levels (for 428 phenylpropanoid-related genes) and measures of susceptibility to Pissodes stobi, using a partial-diallel crossing-design with white spruce (Picea glauca). Thirty-eight expressed phenylpropanoid-related genes co-segregated with weevil susceptibility, indicating either causative or reactive effects of these genes to weevil resistance. We identified eight regulatory genomic regions with extensive overlap of quantitative trait loci from susceptibility and growth phenotypes (pQTLs) and expression QTL (eQTL) hotspots. In particular, SNPs within two different CCoAOMT loci regulate phenotypic variation from a common set of 24 genes and three resistance traits. Conclusions Pest resistance was associated with individual candidate genes as well as with trans-regulatory hotspots along the spruce genome. Our results showed that specific genes within the phenylpropanoid pathway have been duplicated and diversified in the conifer in a process fundamentally different from short-lived angiosperm species. These findings add to the information about the role of the phenylpropanoid pathway in

  2. Mutations in human monoamine-related neurotransmitter pathway genes.

    PubMed

    Haavik, Jan; Blau, Nenad; Thöny, Beat

    2008-07-01

    Biosynthesis and metabolism of serotonin and catecholamines involve at least eight individual enzymes that are mainly expressed in tissues derived from the neuroectoderm, e.g., the central nervous system (CNS), pineal gland, adrenal medulla, enterochromaffin tissue, sympathetic nerves, and ganglia. Some of the enzymes appear to have additional biological functions and are also expressed in the heart and various other internal organs. The biosynthetic enzymes are tyrosine hydroxylase (TH), tryptophan hydroxylases type 1 and 2 (TPH1, TPH2), aromatic amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DbetaH), and phenylethanolamine N-methyltransferase (PNMT), and the specific catabolic enzymes are monoamine oxidase A (MAO-A) and catechol O-methyltransferase (COMT). For the TH, DDC, DBH, and MAOA genes, many single nucleotide polymorphisms (SNPs) with unknown function, and small but increasing numbers of cases with autosomal recessive mutations have been recognized. For the remaining genes (TPH1, TPH2, PNMT, and COMT) several different genetic markers have been suggested to be associated with regulation of mood, pain perception, and aggression, as well as psychiatric disturbances such as schizophrenia, depression, suicidality, and attention deficit/hyperactivity disorder. The genetic markers may either have a functional role of their own, or be closely linked to other unknown functional variants. In the future, molecular testing may become important for the diagnosis of such conditions. Here we present an overview on mutations and polymorphisms in the group of genes encoding monoamine neurotransmitter metabolizing enzymes. At the same time we propose a unified nomenclature for the nucleic acid aberrations in these genes. New variations or details on mutations will be updated in the Pediatric Neurotransmitter Disorder Data Base (PNDDB) database (www.bioPKU.org).

  3. Harnessing the complexity of gene expression data from cancer: from single gene to structural pathway methods

    PubMed Central

    2012-01-01

    High-dimensional gene expression data provide a rich source of information because they capture the expression level of genes in dynamic states that reflect the biological functioning of a cell. For this reason, such data are suitable to reveal systems related properties inside a cell, e.g., in order to elucidate molecular mechanisms of complex diseases like breast or prostate cancer. However, this is not only strongly dependent on the sample size and the correlation structure of a data set, but also on the statistical hypotheses tested. Many different approaches have been developed over the years to analyze gene expression data to (I) identify changes in single genes, (II) identify changes in gene sets or pathways, and (III) identify changes in the correlation structure in pathways. In this paper, we review statistical methods for all three types of approaches, including subtypes, in the context of cancer data and provide links to software implementations and tools and address also the general problem of multiple hypotheses testing. Further, we provide recommendations for the selection of such analysis methods. Reviewers This article was reviewed by Arcady Mushegian, Byung-Soo Kim and Joel Bader. PMID:23227854

  4. Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease.

    PubMed

    Ko, Yi-An; Yi, Huiguang; Qiu, Chengxiang; Huang, Shizheng; Park, Jihwan; Ledo, Nora; Köttgen, Anna; Li, Hongzhe; Rader, Daniel J; Pack, Michael A; Brown, Christopher D; Susztak, Katalin

    2017-06-01

    Chronic kidney disease (CKD) is a complex gene-environmental disease affecting close to 10% of the US population. Genome-wide association studies (GWASs) have identified sequence variants, localized to non-coding genomic regions, associated with kidney function. Despite these robust observations, the mechanism by which variants lead to CKD remains a critical unanswered question. Expression quantitative trait loci (eQTL) analysis is a method to identify genetic variation associated with gene expression changes in specific tissue types. We hypothesized that an integrative analysis combining CKD GWAS and kidney eQTL results can identify candidate genes for CKD. We performed eQTL analysis by correlating genotype with RNA-seq-based gene expression levels in 96 human kidney samples. Applying stringent statistical criteria, we detected 1,886 genes whose expression differs with the sequence variants. Using direct overlap and Bayesian methods, we identified new potential target genes for CKD. With respect to one of the target genes, lysosomal beta A mannosidase (MANBA), we observed that genetic variants associated with MANBA expression in the kidney showed statistically significant colocalization with variants identified in CKD GWASs, indicating that MANBA is a potential target gene for CKD. The expression of MANBA was significantly lower in kidneys of subjects with risk alleles. Suppressing manba expression in zebrafish resulted in renal tubule defects and pericardial edema, phenotypes typically induced by kidney dysfunction. Our analysis shows that gene-expression changes driven by genetic variation in the kidney can highlight potential new target genes for CKD development. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  5. Transcriptomic analysis in the developing zebrafish embryo after compound exposure: Individual gene expression and pathway regulation

    SciTech Connect

    Hermsen, Sanne A.B.; Pronk, Tessa E.; Brandhof, Evert-Jan van den; Ven, Leo T.M. van der; Piersma, Aldert H.

    2013-10-01

    The zebrafish embryotoxicity test is a promising alternative assay for developmental toxicity. Classically, morphological assessment of the embryos is applied to evaluate the effects of compound exposure. However, by applying differential gene expression analysis the sensitivity and predictability of the test may be increased. For defining gene expression signatures of developmental toxicity, we explored the possibility of using gene expression signatures of compound exposures based on commonly expressed individual genes as well as based on regulated gene pathways. Four developmental toxic compounds were tested in concentration-response design, caffeine, carbamazepine, retinoic acid and valproic acid, and two non-embryotoxic compounds, D-mannitol and saccharin, were included. With transcriptomic analyses we were able to identify commonly expressed genes, which were mostly development related, after exposure to the embryotoxicants. We also identified gene pathways regulated by the embryotoxicants, suggestive of their modes of action. Furthermore, whereas pathways may be regulated by all compounds, individual gene expression within these pathways can differ for each compound. Overall, the present study suggests that the use of individual gene expression signatures as well as pathway regulation may be useful starting points for defining gene biomarkers for predicting embryotoxicity. - Highlights: • The zebrafish embryotoxicity test in combination with transcriptomics was used. • We explored two approaches of defining gene biomarkers for developmental toxicity. • Four compounds in concentration-response design were tested. • We identified commonly expressed individual genes as well as regulated gene pathways. • Both approaches seem suitable starting points for defining gene biomarkers.

  6. Comprehensive genomic characterization defines human glioblastoma genes and core pathways

    PubMed Central

    2008-01-01

    Human cancer cells typically harbor multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multidimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here, we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas (GBM), the most common type of adult brain cancer, and nucleotide sequence aberrations in 91 of the 206 GBMs. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the PI3 kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of GBM. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer. PMID:18772890

  7. Neurogenic gene regulatory pathways in the sea urchin embryo

    PubMed Central

    Wei, Zheng; Angerer, Lynne M.; Angerer, Robert C.

    2016-01-01

    During embryogenesis the sea urchin early pluteus larva differentiates 40-50 neurons marked by expression of the pan-neural marker synaptotagmin B (SynB) that are distributed along the ciliary band, in the apical plate and pharyngeal endoderm, and 4-6 serotonergic neurons that are confined to the apical plate. Development of all neurons has been shown to depend on the function of Six3. Using a combination of molecular screens and tests of gene function by morpholino-mediated knockdown, we identified SoxC and Brn1/2/4, which function sequentially in the neurogenic regulatory pathway and are also required for the differentiation of all neurons. Misexpression of Brn1/2/4 at low dose caused an increase in the number of serotonin-expressing cells and at higher dose converted most of the embryo to a neurogenic epithelial sphere expressing the Hnf6 ciliary band marker. A third factor, Z167, was shown to work downstream of the Six3 and SoxC core factors and to define a branch specific for the differentiation of serotonergic neurons. These results provide a framework for building a gene regulatory network for neurogenesis in the sea urchin embryo. PMID:26657764

  8. Comprehensive genomic characterization defines human glioblastoma genes and core pathways.

    PubMed

    2008-10-23

    Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas--the most common type of adult brain cancer--and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3-OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

  9. Neurogenic gene regulatory pathways in the sea urchin embryo.

    PubMed

    Wei, Zheng; Angerer, Lynne M; Angerer, Robert C

    2016-01-15

    During embryogenesis the sea urchin early pluteus larva differentiates 40-50 neurons marked by expression of the pan-neural marker synaptotagmin B (SynB) that are distributed along the ciliary band, in the apical plate and pharyngeal endoderm, and 4-6 serotonergic neurons that are confined to the apical plate. Development of all neurons has been shown to depend on the function of Six3. Using a combination of molecular screens and tests of gene function by morpholino-mediated knockdown, we identified SoxC and Brn1/2/4, which function sequentially in the neurogenic regulatory pathway and are also required for the differentiation of all neurons. Misexpression of Brn1/2/4 at low dose caused an increase in the number of serotonin-expressing cells and at higher dose converted most of the embryo to a neurogenic epithelial sphere expressing the Hnf6 ciliary band marker. A third factor, Z167, was shown to work downstream of the Six3 and SoxC core factors and to define a branch specific for the differentiation of serotonergic neurons. These results provide a framework for building a gene regulatory network for neurogenesis in the sea urchin embryo. © 2016. Published by The Company of Biologists Ltd.

  10. Gene-based and pathway-based genome-wide association study of alcohol dependence

    PubMed Central

    ZUO, Lingjun; ZHANG, Clarence K.; SAYWARD, Frederick G.; CHEUNG, Kei-Hoi; WANG, Kesheng; KRYSTAL, John H.; ZHAO, Hongyu; LUO, Xingguang

    2015-01-01

    Background The organization of risk genes within signaling pathways may provide clues about the converging neurobiological effects of risk genes for alcohol dependence. Aim Identify risk genes and risk gene pathways for alcohol dependence. Methods We conducted a pathway-based genome-wide association study (GWAS) of alcohol dependence using a gene-set-rich analytic approach. Approximately one million genetic markers were tested in the discovery sample which included 1409 European-American (EA) alcohol dependent individuals and 1518 EA healthy comparison subjects. An additional 681 African-American (AA) cases and 508 AA healthy subjects served as the replication sample. Results We identified several genome-wide replicable risk genes and risk pathways that were significantly associated with alcohol dependence. After applying the Bonferroni correction for multiple testing, the ‘cellextracellular matrix interactions’ pathway (p<2.0E-4 in EAs) and the PXN gene (which encodes paxillin) (p=3.9E-7 in EAs) within this pathway were the most promising risk factors for alcohol dependence. There were also two nominally replicable pathways enriched in alcohol dependence-related genes in both EAs (0.015≤p≤0.035) and AAs (0.025≤p≤0.050): the ‘Na+/Cl- dependent neurotransmitter transporters’ pathway and the ‘other glycan degradation’ pathway. Conclusion These findings provide new evidence highlighting several genes and biological signaling processes that may be related to the risk for alcohol dependence. PMID:26120261

  11. Sequence variation in the Mc1r gene for a group of polymorphic snakes.

    PubMed

    Cox, Christian L; Rabosky, Alison R Davis; Chippindale, Paul T

    2013-01-25

    Studying the genetic factors underlying phenotypic traits can provide insight into dynamics of selection and molecular basis of adaptation, but this goal can be difficult for non-model organisms without extensive genomic resources. However, sequencing candidate genes for the trait of interest can facilitate the study of evolutionary genetics in natural populations. We sequenced the melanocortin-1 receptor (Mc1r) to study the genetic basis of color polymorphism in a group of snake species with variable black banding, the genera Sonora, Chilomeniscus, and Chionactis. Mc1r is an important gene in the melanin synthesis pathway and is associated with ecologically important variation in color pattern in birds, mammals, and other squamate reptiles. We found that Mc1r nucleotide sequence was variable and that within our focal Sonora species, there are both fixed and heterozygous nucleotide substitutions that result in an amino acid change and selection analyses indicated that Mc1r sequence was likely under purifying selection. However, we did not detect any statistical association with the presence or absence of black bands. Our results agree with other studies that have found no role for sequence variation in Mc1r and highlight the importance of comparative data for studying the phenotypic associations of candidate genes. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. Genes in the Ureteric Budding Pathway: Association Study on Vesico-Ureteral Reflux Patients

    PubMed Central

    van Eerde, Albertien M.; de Kovel, Carolien G. F.; Koeleman, Bobby P. C.; Knoers, Nine V. A. M.; Renkema, Kirsten Y.; van der Horst, Henricus J. R.; Bökenkamp, Arend; van Hagen, Johanna M.; van den Berg, Leonard H.; Wolffenbuttel, Katja P.; van den Hoek, Joop; Feitz, Wouter F.; de Jong, Tom P. V. M.; Giltay, Jacques C.; Wijmenga, Cisca

    2012-01-01

    Vesico-ureteral reflux (VUR) is the retrograde passage of urine from the bladder to the urinary tract and causes 8.5% of end-stage renal disease in children. It is a complex genetic developmental disorder, in which ectopic embryonal ureteric budding is implicated in the pathogenesis. VUR is part of the spectrum of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). We performed an extensive association study for primary VUR using a two-stage, case-control design, investigating 44 candidate genes in the ureteric budding pathway in 409 Dutch VUR patients. The 44 genes were selected from the literature and a set of 567 single nucleotide polymorphisms (SNPs) capturing their genetic variation was genotyped in 207 cases and 554 controls. The 14 SNPs with p<0.005 were included in a follow-up study in 202 cases and 892 controls. Of the total cohort, ∼50% showed a clear-cut primary VUR phenotype and ∼25% had both a duplex collecting system and VUR. We also looked for association in these two extreme phenotype groups. None of the SNPs reached a significant p-value. Common genetic variants in four genes (GREM1, EYA1, ROBO2 and UPK3A) show a trend towards association with the development of primary VUR (GREM1, EYA1, ROBO2) or duplex collecting system (EYA1 and UPK3A). SNPs in three genes (TGFB1, GNB3 and VEGFA) have been shown to be associated with VUR in other populations. Only the result of rs1800469 in TGFB1 hinted at association in our study. This is the first extensive study of common variants in the genes of the ureteric budding pathway and the genetic susceptibility to primary VUR. PMID:22558067

  13. Transcriptome Profiling and Molecular Pathway Analysis of Genes in Association with Salinity Adaptation in Nile Tilapia Oreochromis niloticus

    PubMed Central

    Xu, Zhixin; Gan, Lei; Li, Tongyu; Xu, Chang; Chen, Ke; Wang, Xiaodan; Qin, Jian G.; Chen, Liqiao; Li, Erchao

    2015-01-01

    Nile tilapia Oreochromis niloticus is a freshwater fish but can tolerate a wide range of salinities. The mechanism of salinity adaptation at the molecular level was studied using RNA-Seq to explore the molecular pathways in fish exposed to 0, 8, or 16 (practical salinity unit, psu). Based on the change of gene expressions, the differential genes unions from freshwater to saline water were classified into three categories. In the constant change category (1), steroid biosynthesis, steroid hormone biosynthesis, fat digestion and absorption, complement and coagulation cascades were significantly affected by salinity indicating the pivotal roles of sterol-related pathways in response to salinity stress. In the change-then-stable category (2), ribosomes, oxidative phosphorylation, signaling pathways for peroxisome proliferator activated receptors, and fat digestion and absorption changed significantly with increasing salinity, showing sensitivity to salinity variation in the environment and a responding threshold to salinity change. In the stable-then-change category (3), protein export, protein processing in endoplasmic reticulum, tight junction, thyroid hormone synthesis, antigen processing and presentation, glycolysis/gluconeogenesis and glycosaminoglycan biosynthesis—keratan sulfate were the significantly changed pathways, suggesting that these pathways were less sensitive to salinity variation. This study reveals fundamental mechanism of the molecular response to salinity adaptation in O. niloticus, and provides a general guidance to understand saline acclimation in O. niloticus. PMID:26305564

  14. Transcriptome Profiling and Molecular Pathway Analysis of Genes in Association with Salinity Adaptation in Nile Tilapia Oreochromis niloticus.

    PubMed

    Xu, Zhixin; Gan, Lei; Li, Tongyu; Xu, Chang; Chen, Ke; Wang, Xiaodan; Qin, Jian G; Chen, Liqiao; Li, Erchao

    2015-01-01

    Nile tilapia Oreochromis niloticus is a freshwater fish but can tolerate a wide range of salinities. The mechanism of salinity adaptation at the molecular level was studied using RNA-Seq to explore the molecular pathways in fish exposed to 0, 8, or 16 (practical salinity unit, psu). Based on the change of gene expressions, the differential genes unions from freshwater to saline water were classified into three categories. In the constant change category (1), steroid biosynthesis, steroid hormone biosynthesis, fat digestion and absorption, complement and coagulation cascades were significantly affected by salinity indicating the pivotal roles of sterol-related pathways in response to salinity stress. In the change-then-stable category (2), ribosomes, oxidative phosphorylation, signaling pathways for peroxisome proliferator activated receptors, and fat digestion and absorption changed significantly with increasing salinity, showing sensitivity to salinity variation in the environment and a responding threshold to salinity change. In the stable-then-change category (3), protein export, protein processing in endoplasmic reticulum, tight junction, thyroid hormone synthesis, antigen processing and presentation, glycolysis/gluconeogenesis and glycosaminoglycan biosynthesis-keratan sulfate were the significantly changed pathways, suggesting that these pathways were less sensitive to salinity variation. This study reveals fundamental mechanism of the molecular response to salinity adaptation in O. niloticus, and provides a general guidance to understand saline acclimation in O. niloticus.

  15. RNAseq analysis reveals pathways and candidate genes associated with salinity tolerance in a spaceflight-induced wheat mutant.

    PubMed

    Xiong, Hongchun; Guo, Huijun; Xie, Yongdun; Zhao, Linshu; Gu, Jiayu; Zhao, Shirong; Li, Junhui; Liu, Luxiang

    2017-06-02

    Salinity stress has become an increasing threat to food security worldwide and elucidation of the mechanism for salinity tolerance is of great significance. Induced mutation, especially spaceflight mutagenesis, is one important method for crop breeding. In this study, we show that a spaceflight-induced wheat mutant, named salinity tolerance 1 (st1), is a salinity-tolerant line. We report the characteristics of transcriptomic sequence variation induced by spaceflight, and show that mutations in genes associated with sodium ion transport may directly contribute to salinity tolerance in st1. Furthermore, GO and KEGG enrichment analysis of differentially expressed genes (DEGs) between salinity-treated st1 and wild type suggested that the homeostasis of oxidation-reduction process is important for salt tolerance in st1. Through KEGG pathway analysis, "Butanoate metabolism" was identified as a new pathway for salinity responses. Additionally, key genes for salinity tolerance, such as genes encoding arginine decarboxylase, polyamine oxidase, hormones-related, were not only salt-induced in st1 but also showed higher expression in salt-treated st1 compared with salt-treated WT, indicating that these genes may play important roles in salinity tolerance in st1. This study presents valuable genetic resources for studies on transcriptome variation caused by induced mutation and the identification of salt tolerance genes in crops.

  16. Comprehensive evaluation of one-carbon metabolism pathway gene variants and renal cell cancer risk.

    PubMed

    Gibson, Todd M; Brennan, Paul; Han, Summer; Karami, Sara; Zaridze, David; Janout, Vladimir; Kollarova, Helen; Bencko, Vladimir; Navratilova, Marie; Szeszenia-Dabrowska, Neonila; Mates, Dana; Slamova, Alena; Pfeiffer, Ruth M; Stolzenberg-Solomon, Rachael Z; Mayne, Susan T; Yeager, Meredith; Chanock, Stephen; Rothman, Nat; Chow, Wong-Ho; Rosenberg, Philip S; Boffetta, Paolo; Moore, Lee E

    2011-01-01

    Folate and one-carbon metabolism are linked to cancer risk through their integral role in DNA synthesis and methylation. Variation in one-carbon metabolism genes, particularly MTHFR, has been associated with risk of a number of cancers in epidemiologic studies, but little is known regarding renal cancer. Tag single nucleotide polymorphisms (SNPs) selected to produce high genomic coverage of 13 gene regions of one-carbon metabolism (ALDH1L1, BHMT, CBS, FOLR1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, TYMS) and the closely associated glutathione synthesis pathway (CTH, GGH, GSS) were genotyped for 777 renal cell carcinoma (RCC) cases and 1,035 controls in the Central and Eastern European Renal Cancer case-control study. Associations of individual SNPs (n = 163) with RCC risk were calculated using unconditional logistic regression adjusted for age, sex and study center. Minimum p-value permutation (Min-P) tests were used to identify gene regions associated with risk, and haplotypes were evaluated within these genes. The strongest associations with RCC risk were observed for SLC19A1 (P(min-P) = 0.03) and MTHFR (P(min-P) = 0.13). A haplotype consisting of four SNPs in SLC19A1 (rs12483553, rs2838950, rs2838951, and rs17004785) was associated with a 37% increased risk (p = 0.02), and exploratory stratified analysis suggested the association was only significant among those in the lowest tertile of vegetable intake. To our knowledge, this is the first study to comprehensively examine variation in one-carbon metabolism genes in relation to RCC risk. We identified a novel association with SLC19A1, which is important for transport of folate into cells. Replication in other populations is required to confirm these findings.

  17. Comprehensive Evaluation of One-Carbon Metabolism Pathway Gene Variants and Renal Cell Cancer Risk

    PubMed Central

    Gibson, Todd M.; Brennan, Paul; Han, Summer; Karami, Sara; Zaridze, David; Janout, Vladimir; Kollarova, Helen; Bencko, Vladimir; Navratilova, Marie; Szeszenia-Dabrowska, Neonila; Mates, Dana; Slamova, Alena; Pfeiffer, Ruth M.; Stolzenberg-Solomon, Rachael Z.; Mayne, Susan T.; Yeager, Meredith; Chanock, Stephen; Rothman, Nat; Chow, Wong-Ho; Rosenberg, Philip S.; Boffetta, Paolo; Moore, Lee E.

    2011-01-01

    Introduction Folate and one-carbon metabolism are linked to cancer risk through their integral role in DNA synthesis and methylation. Variation in one-carbon metabolism genes, particularly MTHFR, has been associated with risk of a number of cancers in epidemiologic studies, but little is known regarding renal cancer. Methods Tag single nucleotide polymorphisms (SNPs) selected to produce high genomic coverage of 13 gene regions of one-carbon metabolism (ALDH1L1, BHMT, CBS, FOLR1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, TYMS) and the closely associated glutathione synthesis pathway (CTH, GGH, GSS) were genotyped for 777 renal cell carcinoma (RCC) cases and 1,035 controls in the Central and Eastern European Renal Cancer case-control study. Associations of individual SNPs (n = 163) with RCC risk were calculated using unconditional logistic regression adjusted for age, sex and study center. Minimum p-value permutation (Min-P) tests were used to identify gene regions associated with risk, and haplotypes were evaluated within these genes. Results The strongest associations with RCC risk were observed for SLC19A1 (Pmin-P = 0.03) and MTHFR (Pmin-P = 0.13). A haplotype consisting of four SNPs in SLC19A1 (rs12483553, rs2838950, rs2838951, and rs17004785) was associated with a 37% increased risk (p = 0.02), and exploratory stratified analysis suggested the association was only significant among those in the lowest tertile of vegetable intake. Conclusions To our knowledge, this is the first study to comprehensively examine variation in one-carbon metabolism genes in relation to RCC risk. We identified a novel association with SLC19A1, which is important for transport of folate into cells. Replication in other populations is required to confirm these findings. PMID:22039442

  18. Gene expression analysis reveals the dysregulation of immune and metabolic pathways in Alzheimer's disease

    PubMed Central

    Li, Zhiyan; Xu, Panpan; Yao, Lifen

    2016-01-01

    In recent years, several pathway analyses of genome-wide association studies reported the involvement of metabolic and immune pathways in Alzheimer's disease (AD). Until now, the exact mechanisms of these pathways in AD are still unclear. Here, we conducted a pathway analysis of a whole genome AD case-control expression dataset (n=41, 25 AD cases and 16 controls) from the human temporal cortex tissue. Using the differently expressed AD genes, we identified significant KEGG pathways related to metabolism and immune processes. Using the up- and down- regulated AD gene list, we further found up-regulated AD gene were significantly enriched in immune and metabolic pathways. We further compare the immune and metabolic KEGG pathways from the expression dataset with those from previous GWAS datasets, and found that most of these pathways are shared in both GWAS and expression datasets. PMID:27732949

  19. Protein-Protein Interaction and Pathway Analyses of Top Schizophrenia Genes Reveal Schizophrenia Susceptibility Genes Converge on Common Molecular Networks and Enrichment of Nucleosome (Chromatin) Assembly Genes in Schizophrenia Susceptibility Loci

    PubMed Central

    Luo, Xiongjian; Huang, Liang; Jia, Peilin

    2014-01-01

    Recent genome-wide association studies have identified many promising schizophrenia candidate genes and demonstrated that common polygenic variation contributes to schizophrenia risk. However, whether these genes represent perturbations to a common but limited set of underlying molecular processes (pathways) that modulate risk to schizophrenia remains elusive, and it is not known whether these genes converge on common biological pathways (networks) or represent different pathways. In addition, the theoretical and genetic mechanisms underlying the strong genetic heterogeneity of schizophrenia remain largely unknown. Using 4 well-defined data sets that contain top schizophrenia susceptibility genes and applying protein-protein interaction (PPI) network analysis, we investigated the interactions among proteins encoded by top schizophrenia susceptibility genes. We found proteins encoded by top schizophrenia susceptibility genes formed a highly significant interconnected network, and, compared with random networks, these PPI networks are statistically highly significant for both direct connectivity and indirect connectivity. We further validated these results using empirical functional data (transcriptome data from a clinical sample). These highly significant findings indicate that top schizophrenia susceptibility genes encode proteins that significantly directly interacted and formed a densely interconnected network, suggesting perturbations of common underlying molecular processes or pathways that modulate risk to schizophrenia. Our findings that schizophrenia susceptibility genes encode a highly interconnected protein network may also provide a novel explanation for the observed genetic heterogeneity of schizophrenia, ie, mutation in any member of this molecular network will lead to same functional consequences that eventually contribute to risk of schizophrenia. PMID:23671194

  20. Protein-protein interaction and pathway analyses of top schizophrenia genes reveal schizophrenia susceptibility genes converge on common molecular networks and enrichment of nucleosome (chromatin) assembly genes in schizophrenia susceptibility loci.

    PubMed

    Luo, Xiongjian; Huang, Liang; Jia, Peilin; Li, Ming; Su, Bing; Zhao, Zhongming; Gan, Lin

    2014-01-01

    Recent genome-wide association studies have identified many promising schizophrenia candidate genes and demonstrated that common polygenic variation contributes to schizophrenia risk. However, whether these genes represent perturbations to a common but limited set of underlying molecular processes (pathways) that modulate risk to schizophrenia remains elusive, and it is not known whether these genes converge on common biological pathways (networks) or represent different pathways. In addition, the theoretical and genetic mechanisms underlying the strong genetic heterogeneity of schizophrenia remain largely unknown. Using 4 well-defined data sets that contain top schizophrenia susceptibility genes and applying protein-protein interaction (PPI) network analysis, we investigated the interactions among proteins encoded by top schizophrenia susceptibility genes. We found proteins encoded by top schizophrenia susceptibility genes formed a highly significant interconnected network, and, compared with random networks, these PPI networks are statistically highly significant for both direct connectivity and indirect connectivity. We further validated these results using empirical functional data (transcriptome data from a clinical sample). These highly significant findings indicate that top schizophrenia susceptibility genes encode proteins that significantly directly interacted and formed a densely interconnected network, suggesting perturbations of common underlying molecular processes or pathways that modulate risk to schizophrenia. Our findings that schizophrenia susceptibility genes encode a highly interconnected protein network may also provide a novel explanation for the observed genetic heterogeneity of schizophrenia, ie, mutation in any member of this molecular network will lead to same functional consequences that eventually contribute to risk of schizophrenia.

  1. Genes controlling mimetic colour pattern variation in butterflies.

    PubMed

    Nadeau, Nicola J

    2016-10-01

    Butterfly wing patterns are made up of arrays of coloured scales. There are two genera in which within-species variation in wing patterning is common and has been investigated at the molecular level, Heliconius and Papilio. Both of these species have mimetic relationships with other butterfly species that increase their protection from predators. Heliconius have a 'tool-kit' of five genetic loci that control colour pattern, three of which have been identified at the gene level, and which have been repeatedly used to modify colour pattern by different species in the genus. By contrast, the three Papilio species that have been investigated each have different genetic mechanisms controlling their polymorphic wing patterns.

  2. GeneAnalytics Pathway Analysis and Genetic Overlap among Autism Spectrum Disorder, Bipolar Disorder and Schizophrenia

    PubMed Central

    Khanzada, Naveen S.; Butler, Merlin G.; Manzardo, Ann M.

    2017-01-01

    Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway analysis and genetic profiling to characterize common susceptibility genes obtained from published lists for ASD (792 genes), BPD (290 genes) and SCH (560 genes). Rank scores were derived from the number and nature of overlapping genes, gene-disease association, tissue specificity and gene functions subdivided into categories (e.g., diseases, tissues or functional pathways). Twenty-three genes were common to all three disorders and mapped to nine biological Superpathways including Circadian entrainment (10 genes, score = 37.0), Amphetamine addiction (five genes, score = 24.2), and Sudden infant death syndrome (six genes, score = 24.1). Brain tissues included the medulla oblongata (11 genes, score = 2.1), thalamus (10 genes, score = 2.0) and hypothalamus (nine genes, score = 2.0) with six common genes (BDNF, DRD2, CHRNA7, HTR2A, SLC6A3, and TPH2). Overlapping genes impacted dopamine and serotonin homeostasis and signal transduction pathways, impacting mood, behavior and physical activity level. Converging effects on pathways governing circadian rhythms support a core etiological relationship between neuropsychiatric illnesses and sleep disruption with hypoxia and central brain stem dysfunction. PMID:28264500

  3. GeneAnalytics Pathway Analysis and Genetic Overlap among Autism Spectrum Disorder, Bipolar Disorder and Schizophrenia.

    PubMed

    Khanzada, Naveen S; Butler, Merlin G; Manzardo, Ann M

    2017-02-28

    Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway analysis and genetic profiling to characterize common susceptibility genes obtained from published lists for ASD (792 genes), BPD (290 genes) and SCH (560 genes). Rank scores were derived from the number and nature of overlapping genes, gene-disease association, tissue specificity and gene functions subdivided into categories (e.g., diseases, tissues or functional pathways). Twenty-three genes were common to all three disorders and mapped to nine biological Superpathways including Circadian entrainment (10 genes, score = 37.0), Amphetamine addiction (five genes, score = 24.2), and Sudden infant death syndrome (six genes, score = 24.1). Brain tissues included the medulla oblongata (11 genes, score = 2.1), thalamus (10 genes, score = 2.0) and hypothalamus (nine genes, score = 2.0) with six common genes (BDNF, DRD2, CHRNA7, HTR2A, SLC6A3, and TPH2). Overlapping genes impacted dopamine and serotonin homeostasis and signal transduction pathways, impacting mood, behavior and physical activity level. Converging effects on pathways governing circadian rhythms support a core etiological relationship between neuropsychiatric illnesses and sleep disruption with hypoxia and central brain stem dysfunction.

  4. Identification of genes and pathways associated with cytotoxic T lymphocyte infiltration of serous ovarian cancer

    PubMed Central

    Leffers, N; Fehrmann, R S N; Gooden, M J M; Schulze, U R J; ten Hoor, K A; Hollema, H; Boezen, H M; Daemen, T; de Jong, S; Nijman, H W; van der Zee, A G J

    2010-01-01

    Background: Tumour-infiltrating lymphocytes (TILs) are predictors of disease-specific survival (DSS) in ovarian cancer. It is largely unknown what factors contribute to lymphocyte recruitment. Our aim was to evaluate genes and pathways contributing to infiltration of cytotoxic T lymphocytes (CTLs) in advanced-stage serous ovarian cancer. Methods: For this study global gene expression was compared between low TIL (n=25) and high TIL tumours (n=24). The differences in gene expression were evaluated using parametric T-testing. Selectively enriched biological pathways were identified with gene set enrichment analysis. Prognostic influence was validated in 157 late-stage serous ovarian cancer patients. Using immunohistochemistry, association of selected genes from identified pathways with CTL was validated. Results: The presence of CTL was associated with 320 genes and 23 pathways (P<0.05). In addition, 54 genes and 8 pathways were also associated with DSS in our validation cohort. Immunohistochemical evaluation showed strong correlations between MHC class I and II membrane expression, parts of the antigen processing and presentation pathway, and CTL recruitment. Conclusion: Gene expression profiling and pathway analyses are valuable tools to obtain more understanding of tumour characteristics influencing lymphocyte recruitment in advanced-stage serous ovarian cancer. Identified genes and pathways need to be further investigated for suitability as therapeutic targets. PMID:20664601

  5. Development of EMS-induced mutation population for amylose and resistant starch variation in bread wheat (Triticum aestivum) and identification of candidate genes responsible for amylose variation.

    PubMed

    Mishra, Ankita; Singh, Anuradha; Sharma, Monica; Kumar, Pankaj; Roy, Joy

    2016-10-06

    Starch is a major part of cereal grain. It comprises two glucose polymer fractions, amylose (AM) and amylopectin (AP), that make up about 25 and 75 % of total starch, respectively. The ratio of the two affects processing quality and digestibility of starch-based food products. Digestibility determines nutritional quality, as high amylose starch is considered a resistant or healthy starch (RS type 2) and is highly preferred for preventive measures against obesity and related health conditions. The topic of nutrition security is currently receiving much attention and consumer demand for food products with improved nutritional qualities has increased. In bread wheat (Triticum aestivum L.), variation in amylose content is narrow, hence its limited improvement. Therefore, it is necessary to produce wheat lines or populations showing wide variation in amylose/resistant starch content. In this study, a set of EMS-induced M4 mutant lines showing dynamic variation in amylose/resistant starch content were produced. Furthermore, two diverse mutant lines for amylose content were used to study quantitative expression patterns of 20 starch metabolic pathway genes and to identify candidate genes for amylose biosynthesis. A population comprising 101 EMS-induced mutation lines (M4 generation) was produced in a bread wheat (Triticum aestivum) variety. Two methods of amylose measurement in grain starch showed variation in amylose content ranging from ~3 to 76 % in the population. The method of in vitro digestion showed variation in resistant starch content from 1 to 41 %. One-way ANOVA analysis showed significant variation (p < 0.05) in amylose and resistant starch content within the population. A multiple comparison test (Dunnett's test) showed that significant variation in amylose and resistant starch content, with respect to the parent, was observed in about 89 and 38 % of the mutant lines, respectively. Expression pattern analysis of 20 starch metabolic pathway genes in

  6. Autotetraploid rice methylome analysis reveals methylation variation of transposable elements and their effects on gene expression.

    PubMed

    Zhang, Jie; Liu, Yuan; Xia, En-Hua; Yao, Qiu-Yang; Liu, Xiang-Dong; Gao, Li-Zhi

    2015-12-15

    Polyploidy, or whole-genome duplication (WGD), serves as a key innovation in plant evolution and is an important genomic feature for all eukaryotes. Neopolyploids have to overcome difficulties in meiosis, genomic alterations, changes of gene expression, and epigenomic reorganization. However, the underlying mechanisms for these processes are poorly understood. One of the most interesting aspects is that genome doubling events increase the dosage of all genes. Unlike allopolyploids entangled by both hybridization and polyploidization, autopolyploids, especially artificial lines, in relatively uniform genetic background offer a model system to understand mechanisms of genome-dosage effects. To investigate DNA methylation effects in response to WGD rather than hybridization, we produced autotetraploid rice with its diploid donor, Oryza sativa ssp. indica cv. Aijiaonante, both of which were independently self-pollinated over 48 generations, and generated and compared their comprehensive transcriptomes, base pair-resolution methylomes, and siRNAomes. DNA methylation variation of transposable elements (TEs) was observed as widespread in autotetraploid rice, in which hypermethylation of class II DNA transposons was predominantly noted in CHG and CHH contexts. This was accompanied by changes of 24-nt siRNA abundance, indicating the role of the RNA-directed DNA methylation pathway. Our results showed that the increased methylation state of class II TEs may suppress the expression of neighboring genes in autotetraploid rice that has obtained double alleles, leading to no significant differences in transcriptome alterations for most genes from its diploid donor. Collectively, our findings suggest that chromosome doubling induces methylation variation in TEs that affect gene expression and may become a "genome shock" response factor to help neoautopolyploids adapt to genome-dosage effects.

  7. The impact of gene expression variation on the robustness and evolvability of a developmental gene regulatory network.

    PubMed

    Garfield, David A; Runcie, Daniel E; Babbitt, Courtney C; Haygood, Ralph; Nielsen, William J; Wray, Gregory A

    2013-10-01

    Regulatory interactions buffer development against genetic and environmental perturbations, but adaptation requires phenotypes to change. We investigated the relationship between robustness and evolvability within the gene regulatory network underlying development of the larval skeleton in the sea urchin Strongylocentrotus purpuratus. We find extensive variation in gene expression in this network throughout development in a natural population, some of which has a heritable genetic basis. Switch-like regulatory interactions predominate during early development, buffer expression variation, and may promote the accumulation of cryptic genetic variation affecting early stages. Regulatory interactions during later development are typically more sensitive (linear), allowing variation in expression to affect downstream target genes. Variation in skeletal morphology is associated primarily with expression variation of a few, primarily structural, genes at terminal positions within the network. These results indicate that the position and properties of gene interactions within a network can have important evolutionary consequences independent of their immediate regulatory role.

  8. The Impact of Gene Expression Variation on the Robustness and Evolvability of a Developmental Gene Regulatory Network

    PubMed Central

    Garfield, David A.; Runcie, Daniel E.; Babbitt, Courtney C.; Haygood, Ralph; Nielsen, William J.; Wray, Gregory A.

    2013-01-01

    Regulatory interactions buffer development against genetic and environmental perturbations, but adaptation requires phenotypes to change. We investigated the relationship between robustness and evolvability within the gene regulatory network underlying development of the larval skeleton in the sea urchin Strongylocentrotus purpuratus. We find extensive variation in gene expression in this network throughout development in a natural population, some of which has a heritable genetic basis. Switch-like regulatory interactions predominate during early development, buffer expression variation, and may promote the accumulation of cryptic genetic variation affecting early stages. Regulatory interactions during later development are typically more sensitive (linear), allowing variation in expression to affect downstream target genes. Variation in skeletal morphology is associated primarily with expression variation of a few, primarily structural, genes at terminal positions within the network. These results indicate that the position and properties of gene interactions within a network can have important evolutionary consequences independent of their immediate regulatory role. PMID:24204211

  9. An Epidemiologic Study of Genetic Variation in Hormonal Pathways in Relation to the Effect of Hormone Replacement Therapy on Breast Cancer Risk

    DTIC Science & Technology

    2008-10-01

    1.02-1.9] for carriers of A allele); CYP1B1 (rs1056827: OR = 1.7 ]95% CI:1.2-2.5] for T homozygotes); SRD5A1 (rs248793: OR=1.2 [95% CI: 1.02-1.5... CYP1B1 *2 and GSTP1), breast cancer risk was 1.6 (95% CI: 1.03-2.4) times higher for carriers of 1 high risk genotype and 2.8 (95% CI: 1.5-5.3) times...is modified by variation in genes within hormonal pathways. 15. SUBJECT TERMS Genetic polymorphisms , epidemiology, exogenous risk factors, gene

  10. Analysis of gene evolution and metabolic pathways using the Candida Gene Order Browser

    PubMed Central

    2010-01-01

    Background Candida species are the most common cause of opportunistic fungal infection worldwide. Recent sequencing efforts have provided a wealth of Candida genomic data. We have developed the Candida Gene Order Browser (CGOB), an online tool that aids comparative syntenic analyses of Candida species. CGOB incorporates all available Candida clade genome sequences including two Candida albicans isolates (SC5314 and WO-1) and 8 closely related species (Candida dubliniensis, Candida tropicalis, Candida parapsilosis, Lodderomyces elongisporus, Debaryomyces hansenii, Pichia stipitis, Candida guilliermondii and Candida lusitaniae). Saccharomyces cerevisiae is also included as a reference genome. Results CGOB assignments of homology were manually curated based on sequence similarity and synteny. In total CGOB includes 65617 genes arranged into 13625 homology columns. We have also generated improved Candida gene sets by merging/removing partial genes in each genome. Interrogation of CGOB revealed that the majority of tandemly duplicated genes are under strong purifying selection in all Candida species. We identified clusters of adjacent genes involved in the same metabolic pathways (such as catabolism of biotin, galactose and N-acetyl glucosamine) and we showed that some clusters are species or lineage-specific. We also identified one example of intron gain in C. albicans. Conclusions Our analysis provides an important resource that is now available for the Candida community. CGOB is available at http://cgob.ucd.ie. PMID:20459735

  11. Variation in use of erythrocyte invasion pathways by Plasmodium falciparum mediates evasion of human inhibitory antibodies

    PubMed Central

    Persson, Kristina E.M.; McCallum, Fiona J.; Reiling, Linda; Lister, Nicole A.; Stubbs, Janine; Cowman, Alan F.; Marsh, Kevin; Beeson, James G.

    2007-01-01

    Antibodies that inhibit Plasmodium falciparum invasion of erythrocytes are believed to be an important component of immunity against malaria. During blood-stage infection, P. falciparum can use different pathways for erythrocyte invasion by varying the expression and/or utilization of members of 2 invasion ligand families: the erythrocyte-binding antigens (EBAs) and reticulocyte-binding homologs (PfRhs). Invasion pathways can be broadly classified into 2 groups based on the use of sialic acid (SA) on the erythrocyte surface by parasite ligands. We found that inhibitory antibodies are acquired by malaria-exposed Kenyan children and adults against ligands of SA-dependent and SA-independent invasion pathways, and the ability of antibodies to inhibit erythrocyte invasion depended on the pathway used by P. falciparum isolates. Differential inhibition of P. falciparum lines that varied in their use of specific EBA and PfRh proteins pointed to these ligand families as major targets of inhibitory antibodies. Antibodies against recombinant EBA and PfRh proteins were acquired in an age-associated manner, and inhibitory antibodies against EBA175 appeared prominent among some individuals. These findings suggest that variation in invasion phenotype might have evolved as a mechanism that facilitates immune evasion by P. falciparum and that a broad inhibitory response against multiple ligands may be required for effective immunity. PMID:18064303

  12. VDR Gene variation and insulin resistance related diseases.

    PubMed

    Han, Fei-Fei; Lv, Ya-Li; Gong, Li-Li; Liu, He; Wan, Zi-Rui; Liu, Li-Hong

    2017-08-19

    Vitamin D status may influence the risk of Insulin resistance related diseases such as Type 2 diabetes (T2DM), metabolic syndrome (MetS), and polycystic ovarian syndrome (PCOS). Several studies have assessed vitamin D receptor (VDR) gene polymorphism in relationship with these diseases; however, results remain inconsistent. Our study was conducted to elucidate whether VDR Gene polymorphisms could predict insulin resistance on a large scale. A meta-analysis using MEDLINE and EMBASE, was performed up to December 16th, 2016. Studies reporting association of vitamin D gene polymorphism with incident T2DM, MetS and PCOS outcomes were included and sub-group analysis by pigment of skin and latitude were performed. A total of 28 articles based on four gene variation, and comprising 9232 participants with 5193 Insulin resistance related diseases patients were included. No significant associations of the VDR ApaI, BsmI, FokI and TaqI variant with Insulin resistance related diseases were found. However, sub-group analysis analysis showed that PCOS in TaqI (OR = 1.47, 95% CI = 1.03-2.09, P = 0.03) for T allele and MetS for G allele (OR = 1.41, 95% CI = 1.07-1.85, P = 0.01) in BsmI was significant association with VDR gene polymorphism. Simultaneously, sub-group analysis showed VDR ApaI rs7975232(G > T)variant was associated with insulin resistance related diseases in Asians (GG/GT + TT) (OR, 1.62; 95% CI, 1.03-2.53; P = 0.04) and population who lived in middle latitude district (30-60°) (GG/GT + TT) (OR, 1.22; 95% CI, 1.04-1.43; P = 0.02), VDR BsmI rs1544410 (A > G)and VDR Taq1rs731236 (T/C) variant were associated with insulin resistance related diseases in Caucasian (dark-pigmented). The results suggested that the association between insulin resistance related diseases and VDR ApaI, BsmI, FokI variant was more obvious in dark-pigmented Caucasians and Asians but not in Caucasian with white skin.

  13. Eukaryotic origin of a metabolic pathway in virus by horizontal gene transfer.

    PubMed

    Wu, Dong-Dong; Zhang, Ya-Ping

    2011-11-01

    Horizontal gene transfer, the movement of genetic materials across the normal mating barriers between organisms occurs frequently and contributes significantly to the evolution of both eukaryotic and prokaryotic genomes. However, few concurrent transfers of functionally related genes implemented in a pathway from eukaryotes to prokaryotes are observed. Here, we did phylogenetic analyses to support that the genes, i.e. dihydrofolate reductase, glycine hydroxymethyltransferase, and thymidylate synthase involved in thymidylate metabolism, in Hz-1 virus were obtained from insect genome recently by independent horizontal gene transfers. In addition, five other related genes in nucleotide metabolism show evidences of horizontal gene transfers. These genes demonstrate similar expression pattern, and they may have formatted a functionally related pathway (e.g. thymidylate synthesis, and DNA replication) in Hz-1 virus. In conclusion, we provide an example of horizontal gene transfer of functionally related genes in a pathway to prokaryote from eukaryote. Copyright © 2011 Elsevier Inc. All rights reserved.

  14. Quantitative gene-gene and gene-environment mapping for leaf shape variation using tree-based models

    USDA-ARS?s Scientific Manuscript database

    Leaf shape traits have long been a focus of many disciplines, but searching for complex genetic and environmental interactive mechanisms regulating leaf shape variation has not yet been well developed. The question of the respective roles of gene and environment and how they interplay to modulate l...

  15. Utilizing Gene Tree Variation to Identify Candidate Effector Genes in Zymoseptoria tritici.

    PubMed

    McDonald, Megan C; McGinness, Lachlan; Hane, James K; Williams, Angela H; Milgate, Andrew; Solomon, Peter S

    2016-04-07

    Zymoseptoria tritici is a host-specific, necrotrophic pathogen of wheat. Infection by Z. tritici is characterized by its extended latent period, which typically lasts 2 wks, and is followed by extensive host cell death, and rapid proliferation of fungal biomass. This work characterizes the level of genomic variation in 13 isolates, for which we have measured virulence on 11 wheat cultivars with differential resistance genes. Between the reference isolate, IPO323, and the 13 Australian isolates we identified over 800,000 single nucleotide polymorphisms, of which ∼10% had an effect on the coding regions of the genome. Furthermore, we identified over 1700 probable presence/absence polymorphisms in genes across the Australian isolates using de novo assembly. Finally, we developed a gene tree sorting method that quickly identifies groups of isolates within a single gene alignment whose sequence haplotypes correspond with virulence scores on a single wheat cultivar. Using this method, we have identified < 100 candidate effector genes whose gene sequence correlates with virulence toward a wheat cultivar carrying a major resistance gene.

  16. Analysis of White Adipose Tissue Gene Expression Reveals CREB1 Pathway Altered in Huntington's Disease.

    PubMed

    McCourt, Andrew Christopher; Parker, Jennifer; Silajdžić, Edina; Haider, Salman; Sethi, Huma; Tabrizi, Sarah J; Warner, Thomas T; Björkqvist, Maria

    2015-01-01

    In addition to classical neurological symptoms, Huntington's disease (HD) is complicated by peripheral pathology and both the mutant gene and the protein are found in cells and tissues throughout the body. Despite the adipose tissue gene expression alterations described in HD mouse models, adipose tissue and its gene expression signature have not been previously explored in human HD. We investigated gene expression signatures in subcutaneous adipose tissue obtained from control subjects, premanifest HD gene carriers and manifest HD subjects with the aim to identify gene expression changes and signalling pathway alterations in adipose tissue relevant to HD. Gene expression was assessed using Affymetrix GeneChip® Human Gene 1.0 ST Array. Target genes were technically validated using real-time quantitative PCR and the expression signature was validated in an independent subject cohort. In subcutaneous adipose tissue, more than 500 genes were significantly different in premanifest HD subjects as compared to healthy controls. Pathway analysis suggests that the differentially expressed genes found here in HD adipose tissue are involved in fatty acid metabolism pathways, angiotensin signalling pathways and immune pathways. Transcription factor analysis highlights CREB1. Using RT-qPCR, we found that MAL2, AGTR2, COBL and the transcription factor CREB1 were significantly upregulated, with CREB1 and AGT also being significantly upregulated in a separate cohort. Distinct gene expression profiles can be seen in HD subcutaneous adipose tissue, with CREB1 highlighted as a key transcription factor.

  17. Patterns of human genetic variation inferred from comparative analysis of allelic mutations in blood group antigen genes.

    PubMed

    Patnaik, Santosh Kumar; Blumenfeld, Olga O

    2011-03-01

    Comparative analysis of allelic variation of a gene sheds light on the pattern and process of its diversification at the population level. Gene families for which a large number of allelic forms have been verified by sequencing provide a useful resource for such studies. In this regard, human blood group-encoding genes are unique in that differences of cell surface traits among individuals and populations can be readily detected by serological screening, and correlation between the variant cell surface phenotype and the genotype is, in most cases, unequivocal. Here, we perform a comprehensive analysis of allelic forms, compiled in the Blood Group Antigen Gene Mutation database, of ABO, RHD/CE, GYPA/B/E and FUT1/2 gene families that encode the ABO, RH, MNS, and H/h blood group system antigens, respectively. These genes are excellent illustrative examples showing distinct mutational patterns among the alleles, and leading to speculation on how their origin may have been driven by recurrent but different molecular mechanisms. We illustrate how alignment of alleles of a gene may provide an additional insight into the DNA variation process and its pathways, and how this approach may serve to catalog alleles of a gene, simplifying the task and content of mutation databases.

  18. Genetic Variations in SLCO Transporter Genes Contributing to Racial Disparity in Aggressiveness of Prostate Cancer

    DTIC Science & Technology

    2016-10-01

    AWARD NUMBER: W81XWH-14-1-0453 TITLE: Genetic Variations in SLCO Transporter Genes Contributing to Racial Disparity in Aggressiveness of...Sep 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Genetic Variations in SLCO Transporter Genes Contributing to Racial Disparity in Aggressiveness...expected to (1) identify genetic variations in the genes of androgen transporters that are associated with the racial differences in prostate cancer

  19. Gene Regulatory Variation Mediates Flowering Responses to Vernalization along an Altitudinal Gradient in Arabidopsis1[W][OPEN

    PubMed Central

    Suter, Léonie; Rüegg, Marlene; Zemp, Niklaus

    2014-01-01

    Steep environmental gradients provide ideal settings for studies of potentially adaptive phenotypic and genetic variation in plants. The accurate timing of flowering is crucial for reproductive success and is regulated by several pathways, including the vernalization pathway. Among the numerous genes known to enable flowering in response to vernalization, the most prominent is FLOWERING LOCUS C (FLC). FLC and other genes of the vernalization pathway vary extensively among natural populations and are thus candidates for the adaptation of flowering time to environmental gradients such as altitude. We used 15 natural Arabidopsis (Arabidopsis thaliana) genotypes originating from an altitudinal gradient (800–2,700 m above sea level) in the Swiss Alps to test whether flowering time correlated with altitude under different vernalization scenarios. Additionally, we measured the expression of 12 genes of the vernalization pathway and its downstream targets. Flowering time correlated with altitude in a nonlinear manner for vernalized plants. Flowering time could be explained by the expression and regulation of the vernalization pathway, most notably by AGAMOUS LIKE19 (AGL19), FLOWERING LOCUS T (FT), and FLC. The expression of AGL19, FT, and VERNALIZATION INSENSITIVE3 was associated with altitude, and the regulation of MADS AFFECTING FLOWERING2 (MAF2) and MAF3 differed between low- and high-altitude genotypes. In conclusion, we found clinal variation across an altitudinal gradient both in flowering time and the expression and regulation of genes in the flowering time control network, often independent of FLC, suggesting that the timing of flowering may contribute to altitudinal adaptation. PMID:25339407

  20. The Pathway From Genes to Gene Therapy in Glaucoma: A Review of Possibilities for Using Genes as Glaucoma Drugs.

    PubMed

    Borrás, Teresa

    2017-01-01

    Treatment of diseases with gene therapy is advancing rapidly. The use of gene therapy has expanded from the original concept of re-placing the mutated gene causing the disease to the use of genes to con-trol nonphysiological levels of expression or to modify pathways known to affect the disease. Genes offer numerous advantages over conventional drugs. They have longer duration of action and are more specific. Genes can be delivered to the target site by naked DNA, cells, nonviral, and viral vectors. The enormous progress of the past decade in molecular bi-ology and delivery systems has provided ways for targeting genes to the intended cell/tissue and safe, long-term vectors. The eye is an ideal organ for gene therapy. It is easily accessible and it is an immune-privileged site. Currently, there are clinical trials for diseases affecting practically every tissue of the eye, including those to restore vision in patients with Leber congenital amaurosis. However, the number of eye trials compared with those for systemic diseases is quite low (1.8%). Nevertheless, judg-ing by the vast amount of ongoing preclinical studies, it is expected that such number will increase considerably in the near future. One area of great need for eye gene therapy is glaucoma, where a long-term gene drug would eliminate daily applications and compliance issues. Here, we review the current state of gene therapy for glaucoma and the possibilities for treating the trabecular meshwork to lower intraocular pressure and the retinal ganglion cells to protect them from neurodegeneration.

  1. Mapping toll-like receptor signaling pathway genes of Zhikong scallop ( Chlamys farreri) with FISH

    NASA Astrophysics Data System (ADS)

    Zhao, Bosong; Zhao, Liang; Liao, Huan; Cheng, Jie; Lian, Shanshan; Li, Xuan; Huang, Xiaoting; Bao, Zhenmin

    2015-12-01

    Toll-like receptor (TLR) signaling pathway plays a pivotal role in the innate immune system. Studies on TLR signaling pathway genes in Zhikong scallop ( Chlamys farreri) have mainly focused on sequence analysis and expression profiling, no research has been carried out on their localization. The chromosomal position of TLR signaling pathway genes can be valuable for assemblying scallop genome and analysizing gene regulatory networks. In the present study, five key TLR signaling pathway genes ( CfTLR, CfMyd88, CfTRAF6, CfNFκB, and CfIκB) containing bacterial artificial chromosomes (BACs) were isolated and physically mapped through fluorescence in situ hybridization on five non-homologous chromosome pairs, showing a similar distribution to another five model species. The isolation and mapping of these key immune genes of C. farreri will aid to the research on innate immunity, assignment of interested genes to chromosomes, and integration of physical, linkage and cytogenetic maps of this species.

  2. Pathway and gene ontology based analysis of gene expression in a rat model of cerebral ischemic tolerance.

    PubMed

    Feng, Zheng; Davis, Daniel P; Sásik, Roman; Patel, Hemal H; Drummond, John C; Patel, Piyush M

    2007-10-26

    Ischemic tolerance is a phenomenon whereby a sublethal ischemic insult [ischemic preconditioning (IPC)] provides robust protection against subsequent lethal ischemia. Activation of N-methyl-D-aspartate (NMDA) receptors and subsequent new gene transcription are required for tolerance. We utilized the NMDA antagonist, MK801, prior to the IPC stimulus to separate candidate genes from epiphenomenona. Rats were divided into four groups: vehicle/IPC (preconditioned), MK801/IPC (attenuated preconditioning), vehicle/sham (non-preconditioned), and MK801/sham (non-preconditioned). Hippocampi (5/group/time point) were harvested immediately after ischemia as well as 1, 4, and 24 h post-ischemia to profile gene expression patterns using microarray analyses. Extracted mRNAs were pooled and subsequently hybridized to Affymetrix arrays. In addition, groups of rats were sacrificed for Western blot analysis and histological studies. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology (GO) analyses were used to identify functionally related groups of genes whose modulation was statistically significant, while hierarchical cluster analysis was used to visualize the fold expression within these groups. Significantly modulated pathways included: MAP kinase signaling pathway, Toll receptor pathway, TGF-beta signaling pathways, and pathways associated with ribosome function and oxidative phosphorylation. Our data suggest that the tolerant brain responds to subsequent ischemic stress by partially downregulating inflammatory and upregulating protein synthesis and energy metabolism pathways.

  3. Integromic Analysis of Genetic Variation and Gene Expression Identifies Networks for Cardiovascular Disease Phenotypes

    PubMed Central

    Yao, Chen; Chen, Brian H.; Joehanes, Roby; Otlu, Burcak; Zhang, Xiaoling; Liu, Chunyu; Huan, Tianxiao; Tastan, Oznur; Cupples, L. Adrienne; Meigs, James B.; Fox, Caroline S.; Freedman, Jane E.; Courchesne, Paul; O’Donnell, Christopher J.; Munson, Peter J.; Keles, Sunduz; Levy, Daniel

    2015-01-01

    Background Cardiovascular disease (CVD) reflects a highly coordinated complex of traits. Although genome-wide association studies have reported numerous single nucleotide polymorphisms (SNPs) to be associated with CVD, the role of most of these variants in disease processes remains unknown. Methods and Results We built a CVD network using 1512 SNPs associated with 21 CVD traits in genome-wide association studies (at P≤5×10−8) and cross-linked different traits by virtue of their shared SNP associations. We then explored whole blood gene expression in relation to these SNPs in 5257 participants in the Framingham Heart Study. At a false discovery rate <0.05, we identified 370 cis-expression quantitative trait loci (eQTLs; SNPs associated with altered expression of nearby genes) and 44 trans-eQTLs (SNPs associated with altered expression of remote genes). The eQTL network revealed 13 CVD-related modules. Searching for association of eQTL genes with CVD risk factors (lipids, blood pressure, fasting blood glucose, and body mass index) in the same individuals, we found examples in which the expression of eQTL genes was significantly associated with these CVD phenotypes. In addition, mediation tests suggested that a subset of SNPs previously associated with CVD phenotypes in genome-wide association studies may exert their function by altering expression of eQTL genes (eg, LDLR and PCSK7), which in turn may promote interindividual variation in phenotypes. Conclusions Using a network approach to analyze CVD traits, we identified complex networks of SNP-phenotype and SNP-transcript connections. Integrating the CVD network with phenotypic data, we identified biological pathways that may provide insights into potential drug targets for treatment or prevention of CVD. PMID:25533967

  4. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes

    PubMed Central

    Glessner, Joseph T.; Wang, Kai; Cai, Guiqing; Korvatska, Olena; Kim, Cecilia E.; Wood, Shawn; Zhang, Haitao; Estes, Annette; Brune, Camille W.; Bradfield, Jonathan P.; Imielinski, Marcin; Frackelton, Edward C.; Reichert, Jennifer; Crawford, Emily L.; Munson, Jeffrey; Sleiman, Patrick M. A.; Chiavacci, Rosetta; Annaiah, Kiran; Thomas, Kelly; Hou, Cuiping; Glaberson, Wendy; Flory, James; Otieno, Frederick; Garris, Maria; Soorya, Latha; Klei, Lambertus; Piven, Joseph; Meyer, Kacie J.; Anagnostou, Evdokia; Sakurai, Takeshi; Game, Rachel M.; Rudd, Danielle S.; Zurawiecki, Danielle; McDougle, Christopher J.; Davis, Lea K.; Miller, Judith; Posey, David J.; Michaels, Shana; Kolevzon, Alexander; Silverman, Jeremy M.; Bernier, Raphael; Levy, Susan E.; Schultz, Robert T.; Dawson, Geraldine; Owley, Thomas; McMahon, William M.; Wassink, Thomas H.; Sweeney, John A.; Nurnberger, John I.; Coon, Hilary; Sutcliffe, James S.; Minshew, Nancy J.; Grant, Struan F. A.; Bucan, Maja; Cook, Edwin H.; Buxbaum, Joseph D.; Devlin, Bernie; Schellenberg, Gerard D.; Hakonarson, Hakon

    2010-01-01

    Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1–4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5–9. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ~550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10−3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10−3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10−6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD. PMID:19404257

  5. Association study between genes in Reelin signaling pathway and autism identifies DAB1 as a susceptibility gene in a Chinese Han population.

    PubMed

    Li, Jun; Liu, Jing; Zhao, Linnan; Ma, Yuanlin; Jia, Meixiang; Lu, Tianlan; Ruan, Yanyan; Li, Qizhai; Yue, Weihua; Zhang, Dai; Wang, Lifang

    2013-07-01

    Autism is a pervasive neurodevelopmental disorder diagnosed in early childhood. The genetic factors might play an important role in its pathogenesis. Previous studies revealed that Reelin (RELN) polymorphisms were associated with autism. However, the roles of genes in Reelin signaling pathway for autism are largely unknown. As several knockout mice models in which the Reelin pathway genes (i.e. DAB1, VLDLR/APOER2, FYN/SRC and CRK/CRKL) are deficient have the similar phenotype as the reeler mice (Reelin(-/-)), we hypothesized that the Reelin signaling pathway genes might play roles in the etiology of autism. Therefore, we conducted a family-based association study. Sixty-two tagged single nucleotide polymorphisms (SNPs) covering 15 genes in Reelin pathway were genotyped in 239 trios, and 14 significant SNPs were further investigated in the additional 188 trios. In the total 427 trios, we found significant genetic association between autism and four SNPs in DAB1 (rs12035887 G: p=0.0006; rs3738556 G: p=0.0044; rs1202773 A: p=0.0048; rs12740765 T: p=0.0196). After the Bonferroni correction, SNP rs12035887 remained significant. Furthermore, the haplotype constructed with rs1202773 and rs12023109 in DAB1 showed significant excess transmission in both individual and global haplotype analyses (p=0.0052 and 0.0279, respectively). Our findings suggested that variations in DAB1 involved in the Reelin signaling pathway might contribute to genetic susceptibility to autism with Chinese Han decent, supporting the defect in the Reelin signaling pathway as a predisposition factor for autism. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. The Regulated Secretory Pathway and Human Disease: Insights from Gene Variants and Single Nucleotide Polymorphisms

    PubMed Central

    Lin, Wei-Jye; Salton, Stephen R.

    2013-01-01

    The regulated secretory pathway provides critical control of peptide, growth factor, and hormone release from neuroendocrine and endocrine cells, and neurons, maintaining physiological homeostasis. Propeptides and prohormones are packaged into dense core granules (DCGs), where they frequently undergo tissue-specific processing as the DCG matures. Proteins of the granin family are DCG components, and although their function is not fully understood, data suggest they are involved in DCG formation and regulated protein/peptide secretion, in addition to their role as precursors of bioactive peptides. Association of gene variation, including single nucleotide polymorphisms (SNPs), with neuropsychiatric, endocrine, and metabolic diseases, has implicated specific secreted proteins and peptides in disease pathogenesis. For example, a SNP at position 196 (G/A) of the human brain-derived neurotrophic factor gene dysregulates protein processing and secretion and leads to cognitive impairment. This suggests more generally that variants identified in genes encoding secreted growth factors, peptides, hormones, and proteins involved in DCG biogenesis, protein processing, and the secretory apparatus, could provide insight into the process of regulated secretion as well as disorders that result when it is impaired. PMID:23964269

  7. The regulated secretory pathway and human disease: insights from gene variants and single nucleotide polymorphisms.

    PubMed

    Lin, Wei-Jye; Salton, Stephen R

    2013-01-01

    The regulated secretory pathway provides critical control of peptide, growth factor, and hormone release from neuroendocrine and endocrine cells, and neurons, maintaining physiological homeostasis. Propeptides and prohormones are packaged into dense core granules (DCGs), where they frequently undergo tissue-specific processing as the DCG matures. Proteins of the granin family are DCG components, and although their function is not fully understood, data suggest they are involved in DCG formation and regulated protein/peptide secretion, in addition to their role as precursors of bioactive peptides. Association of gene variation, including single nucleotide polymorphisms (SNPs), with neuropsychiatric, endocrine, and metabolic diseases, has implicated specific secreted proteins and peptides in disease pathogenesis. For example, a SNP at position 196 (G/A) of the human brain-derived neurotrophic factor gene dysregulates protein processing and secretion and leads to cognitive impairment. This suggests more generally that variants identified in genes encoding secreted growth factors, peptides, hormones, and proteins involved in DCG biogenesis, protein processing, and the secretory apparatus, could provide insight into the process of regulated secretion as well as disorders that result when it is impaired.

  8. Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes

    PubMed Central

    Dadgostar, Hajir; Zarnegar, Brian; Hoffmann, Alexander; Qin, Xiao-Feng; Truong, Uyen; Rao, Govinda; Baltimore, David; Cheng, Genhong

    2002-01-01

    CD40/CD40L interaction is essential for multiple biological events in T dependent humoral immune responses, including B cell survival and proliferation, germinal center and memory B cell formation, and antibody isotype switching and affinity maturation. By using high-density microarrays, we examined gene expression in primary mouse B lymphocytes after multiple time points of CD40L stimulation. In addition to genes involved in cell survival and growth, which are also induced by other mitogens such as lipopolysaccharide, CD40L specifically activated genes involved in germinal center formation and T cell costimulatory molecules that facilitate T dependent humoral immunity. Next, by examining the roles of individual CD40-activated signal transduction pathways, we dissected the overall CD40-mediated response into genes independently regulated by the individual pathways or collectively by all pathways. We also found that gene down-regulation is a significant part of the overall response and that the p38 pathway plays an important role in this process, whereas the NF-κB pathway is important for the up-regulation of primary response genes. Our finding of overlapping independent control of gene expression modules by different pathways suggests, in principle, that distinct biological behaviors that depend on distinct gene expression subsets can be manipulated by targeting specific signaling pathways. PMID:11830667

  9. Genetic Variation in the Histamine Production, Response, and Degradation Pathway Is Associated with Histamine Pharmacodynamic Response in Children with Asthma

    PubMed Central

    Jones, Bridgette L.; Sherwin, Catherine M. T.; Liu, Xiaoxi; Dai, Hongying; Vyhlidal, Carrie A.

    2017-01-01

    Introduction: There is growing knowledge of the wide ranging effects of histamine throughout the body therefore it is important to better understand the effects of this amine in patients with asthma. We aimed to explore the association between histamine pharmacodynamic (PD) response and genetic variation in the histamine pathway in children with asthma. Methods: Histamine Iontophoresis with Laser Doppler Monitoring (HILD) was performed in children with asthma and estimates for area under the effect curve (AUEC), maximal response over baseline (Emax), and time of Emax (Tmax) were calculated using non-compartmental analysis and non-linear mixed-effects model with a linked effect PK/PD model. DNA isolation and genotyping were performed among participants to detect known single nucleotide polymorphisms (SNPs) (n = 10) among genes (HDC, HNMT, ABP1, HRH1, HRH4) within the histamine pathway. General linear model was used to identify associations between histamine related genetic variants and measured histamine PD response parameters. Results: Genotyping and HILD response profiles were completed for 163 children. ABP1 47 C/T, ABP1 4107, and HNMT-1639 C/Twere associated with Emax (ABP1 47 CC genotype mean Emax 167.21 vs. CT/TT genotype mean Emax 139.20, p = 0.04; ABP1 4107 CC genotype mean Emax 141.72 vs. CG/GG genotype mean Emax 156.09, p = 0.005; HNMT-1639 CC genotype mean Emax 132.62 vs. CT/TT genotype mean Emax 155.3, p = 0.02). In a stratified analysis among African American children only, ABP1 and HNMT SNPs were also associated with PD response; HRH4 413 CC genotype was associated with lower Emax, p = 0.009. Conclusions: We show for the first time that histamine pathway genetic variation is associated with measureable changes in histamine response in children with asthma. The variability in histamine response and impact of histamine pathway genotype is important to further explore in patients with asthma so as to improve disease phenotyping leading to more

  10. Identification of gene variants related to the nitric oxide pathway in patients with acute coronary syndrome.

    PubMed

    Umman, B; Cakmakoglu, B; Cincin, Z B; Kocaaga, M; Emet, S; Tamer, S; Gokkusu, C

    2015-12-10

    Dysfunction of vascular endothelium is known to have an essential role in the atherosclerotic process by releasing mediators including nitric oxide (NO). Nitric oxide maintains endothelial balance by controlling cellular processes of vascular smooth muscle cells. Evidence suggests that variations in the NO pathway could include atherosclerotic events. The objective of this study was to determine the possible effects of genes on the nitric oxide pathway in the development of acute coronary syndrome (ACS). The blood samples of 100 patients with ACS and 100 controls were collected at Istanbul University, Department of Cardiology. DNA samples were genotyped by using Illumina Cyto-SNP-12 BeadChip. The additive model and Correlation/Trend Test were selected for association analysis. Afterwards, a Q-Q graphic was drawn to compare expected and obtained values. A Manhattan plot was produced to display p-values that were generated by -log10(P) function for each SNP. The p-values under 1×10(-4) were selected as statistically significant SNPs while p-values under 5×10(-2) were considered as suspicious biomarker candidates. Nitric oxide pathway analysis was then used to find the single nucleotide polymorphisms (SNPs) related to ACS. As a result, death-associated protein kinase 3 (DAPK) (rs10426955) was found to be most statistically significant SNP. The most suspicious biomarker candidates associated with the nitric oxide pathway analysis were vascular endothelial growth factor A (VEGFA), methionine sulfoxide reductase A (MSRA), nitric oxide synthase 1 (NOS1), and GTP cyclohydrolase I (GCH-1). Further studies with large sample groups are necessary to clarify the exact role of nitric oxide in the development of disease.

  11. Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function.

    PubMed

    Raychaudhuri, Soumya; Korn, Joshua M; McCarroll, Steven A; Altshuler, David; Sklar, Pamela; Purcell, Shaun; Daly, Mark J

    2010-09-09

    Investigators have linked rare copy number variation (CNVs) to neuropsychiatric diseases, such as schizophrenia. One hypothesis is that CNV events cause disease by affecting genes with specific brain functions. Under these circumstances, we expect that CNV events in cases should impact brain-function genes more frequently than those events in controls. Previous publications have applied "pathway" analyses to genes within neuropsychiatric case CNVs to show enrichment for brain-functions. While such analyses have been suggestive, they often have not rigorously compared the rates of CNVs impacting genes with brain function in cases to controls, and therefore do not address important confounders such as the large size of brain genes and overall differences in rates and sizes of CNVs. To demonstrate the potential impact of confounders, we genotyped rare CNV events in 2,415 unaffected controls with Affymetrix 6.0; we then applied standard pathway analyses using four sets of brain-function genes and observed an apparently highly significant enrichment for each set. The enrichment is simply driven by the large size of brain-function genes. Instead, we propose a case-control statistical test, cnv-enrichment-test, to compare the rate of CNVs impacting specific gene sets in cases versus controls. With simulations, we demonstrate that cnv-enrichment-test is robust to case-control differences in CNV size, CNV rate, and systematic differences in gene size. Finally, we apply cnv-enrichment-test to rare CNV events published by the International Schizophrenia Consortium (ISC). This approach reveals nominal evidence of case-association in neuronal-activity and the learning gene sets, but not the other two examined gene sets. The neuronal-activity genes have been associated in a separate set of schizophrenia cases and controls; however, testing in independent samples is necessary to definitively confirm this association. Our method is implemented in the PLINK software package.

  12. Pervasive gene content variation and copy number variation in maize and its undomesticated progenitor

    USDA-ARS?s Scientific Manuscript database

    Different individuals of the same species are generally thought to have very similar genomes. However, there is growing evidence that structural variation in the form of copy number variation (CNV) and presence-absence variation (PAV) can lead to variation in the genome content of individuals withi...

  13. Epilepsy-causing sequence variations in SIK1 disrupt synaptic activity response gene expression and affect neuronal morphology.

    PubMed

    Pröschel, Christoph; Hansen, Jeanne N; Ali, Adil; Tuttle, Emily; Lacagnina, Michelle; Buscaglia, Georgia; Halterman, Marc W; Paciorkowski, Alex R

    2017-02-01

    SIK1 syndrome is a newly described developmental epilepsy disorder caused by heterozygous mutations in the salt-inducible kinase SIK1. To better understand the pathophysiology of SIK1 syndrome, we studied the effects of SIK1 pathogenic sequence variations in human neurons. Primary human fetal cortical neurons were transfected with a lentiviral vector to overexpress wild-type and mutant SIK1 protein. We evaluated the transcriptional activity of known downstream gene targets in neurons expressing mutant SIK1 compared with wild type. We then assayed neuronal morphology by measuring neurite length, number and branching. Truncating SIK1 sequence variations were associated with abnormal MEF2C transcriptional activity and decreased MEF2C protein levels. Epilepsy-causing SIK1 sequence variations were associated with significantly decreased expression of ARC (activity-regulated cytoskeletal-associated) and other synaptic activity response element genes. Assay of mRNA levels for other MEF2C target genes NR4A1 (Nur77) and NRG1, found significantly, decreased the expression of these genes as well. The missense p.(Pro287Thr) SIK1 sequence variation was associated with abnormal neuronal morphology, with significant decreases in mean neurite length, mean number of neurites and a significant increase in proximal branches compared with wild type. Epilepsy-causing SIK1 sequence variations resulted in abnormalities in the MEF2C-ARC pathway of neuronal development and synapse activity response. This work provides the first insights into the mechanisms of pathogenesis in SIK1 syndrome, and extends the ARX-MEF2C pathway in the pathogenesis of developmental epilepsy.

  14. Genetic variation in the insulin, insulin-like growth factor, growth hormone, and leptin pathways in relation to breast cancer in African-American women: the AMBER consortium

    PubMed Central

    Ruiz-Narváez, Edward A; Lunetta, Kathryn L; Hong, Chi-Chen; Haddad, Stephen; Yao, Song; Cheng, Ting-Yuan David; Bensen, Jeannette T; Bandera, Elisa V; Haiman, Christopher A; Troester, Melissa A; Ambrosone, Christine B; Rosenberg, Lynn; Palmer, Julie R

    2016-01-01

    The insulin/insulin-like growth factor (IGF) system and related pathways such as growth hormone, and leptin signaling have a key role in cancer development. It is unclear how germline variation in these pathways affects breast cancer risk. We conducted gene-based analyses of 184 genes in the insulin/IGF, growth hormone, and leptin pathways to identify genetic variation associated with risk of breast cancer overall, and for estrogen receptor (ER) subtypes. Tag single-nucleotide polymorphisms (SNPs) for each gene were selected and genotyped on a customized Illumina SNP array. Imputation was carried out using 1000 Genomes haplotypes. The analysis included 91,627 SNPs genotyped or imputed in 3,663 breast cancer cases, (1,983 ER-positive and 1,098 ER-negative) and 4,687 controls from the African American Breast Cancer Epidemiology and Risk consortium, a collaborative project of four large studies of breast cancer in African-American women (Carolina Breast Cancer Study, Black Women's Health Study, Women's Circle of Health Study, and Multiethnic Cohort). We used a multi-locus adaptive joint test to determine the association of each gene with overall breast cancer and ER subtypes. The most significant gene associations (P ≤ 0.01) were BAIAP2 and CALM2 for overall breast cancer; BAIAP2 and CSNK2A1 for ER+ breast cancer; and BRAF, BAD, and MAPK3 for ER− breast cancer. The association of BAD with ER− breast cancer was explained by a two-SNP risk model; all other associations were best explained by one-SNP risk models. In total, six genes and seven SNPs had suggestive associations with overall breast cancer or ER subtypes in African-American women. PMID:27942580

  15. Pesticide exposure and inherited variants in vitamin D pathway genes in relation to prostate cancer

    PubMed Central

    Karami, Sara; Andreotti, Gabriella; Koutros, Stella; Barry, Kathryn Hughes; Moore, Lee E.; Han, Summer; Hoppin, Jane A.; Sandler, Dale P.; Lubin, Jay H.; Burdette, Laurie A.; Yuenger, Jeffrey; Yeager, Meredith; Beane Freeman, Laura E.; Blair, Aaron; Alavanja, Michael C.R.

    2013-01-01

    Background Vitamin D and its metabolites are believed to impede carcinogenesis by stimulating cell differentiation, inhibiting cell proliferation, and inducing apoptosis. Certain pesticides have been shown to deregulate vitamin D’s anti-carcinogenic properties. We hypothesize that certain pesticides may be linked to prostate cancer via an interaction with vitamin D genetic variants. Methods We evaluated interactions between 41 pesticides and 152 single nucleotide polymorphisms (SNPs) in nine vitamin D pathway genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of Caucasian pesticide applicators within the Agricultural Health Study. We assessed interaction P-values using likelihood ratio tests from unconditional logistic regression and a False Discovery Rate (FDR) to account for multiple comparisons. Results Five significant interactions (P<0.01) displayed a monotonic increase in prostate cancer risk with individual pesticide use in one genotype and no association in the other. These interactions involved parathion and terbufos use and three vitamin D genes (VDR, RXRB and GC). The exposure-response pattern among participants with increasing parathion use with the homozygous CC genotype for GC rs7041 compared to unexposed participants was noteworthy (low versus no exposure: odds ratio (OR)=2.58, 95% confidence interval (CI)=1.07–6.25; high versus no exposure: OR=3.09, 95%CI=1.10–8.68; P-interaction=3.8×10−3). Conclusions In this study, genetic variations in vitamin D pathway genes, particularly GC rs7041, a SNP previously linked to lower circulating vitamin D levels modified pesticide associations with prostate cancer risk. Impact Because our study is the first to examine this relationship, additional studies are needed to rule out chance findings. PMID:23833127

  16. Conceptual Variation or Incoherence? Textbook Discourse on Genes in Six Countries

    ERIC Educational Resources Information Center

    Gericke, Niklas M.; Hagberg, Mariana; dos Santos, Vanessa Carvalho; Joaquim, Leyla Mariane; El-Hani, Charbel N.

    2014-01-01

    The aim of this paper is to investigate in a systematic and comparative way previous results of independent studies on the treatment of genes and gene function in high school textbooks from six different countries. We analyze how the conceptual variation within the scientific domain of Genetics regarding gene function models and gene concepts is…

  17. Conceptual Variation or Incoherence? Textbook Discourse on Genes in Six Countries

    ERIC Educational Resources Information Center

    Gericke, Niklas M.; Hagberg, Mariana; dos Santos, Vanessa Carvalho; Joaquim, Leyla Mariane; El-Hani, Charbel N.

    2014-01-01

    The aim of this paper is to investigate in a systematic and comparative way previous results of independent studies on the treatment of genes and gene function in high school textbooks from six different countries. We analyze how the conceptual variation within the scientific domain of Genetics regarding gene function models and gene concepts is…

  18. The Effect of Genetic and Environmental Variation on Metabolic Gene Expression

    PubMed Central

    Scott, Cinda P.; Williams, Dean A.; Crawford, Douglas L.

    2009-01-01

    What is the relationship between genetic or environmental variation and the variation in mRNA expression? To address this, microarrays were used to examine the effect of genetic and environmental variation on cardiac mRNA expression for metabolic genes in three groups of Fundulus heteroclitus: (1) individuals sampled in the field (field), (2) field individuals acclimated for six months to laboratory conditions (acclimated) or (3) individuals bred for ten successive generations in a laboratory environment (G10). The G10 individuals have significantly less genetic variation than individuals obtained in the field and had a significantly lower variation in mRNA expression across all genes in comparison to the other two groups (p ≤ 0.001). When examining the gene specific variation, twenty-two genes had variation in expression that was significantly different among groups with lower variation in G10 individuals than in acclimated individuals. Additionally, there were fewer genes with significant differences in expression among G10 individuals versus either acclimated or field individuals: 66 genes have statistically different levels of expression versus 107 or 97 for Acclimated or Field groups. Based on the permutation of the data, these differences in the number of genes with significant differences among individuals within a group are unlikely to occur by chance (p < 0.01). Surprisingly, variation in mRNA expression in field individuals is lower than in acclimated individuals. Relative to the variation among individual within a group, few genes have significant differences in expression among groups (seven, 2.3%) and none of these are different between acclimated and field individuals. The results support the concept that genetic variation affects variation in mRNA expression and also suggests that temporal environmental variation associated with estuarine environments does not increase the variation among individuals or add to the differences among groups. PMID

  19. Cerebrospinal Fluid Aβ42 Levels and APP Processing Pathway Genes in Parkinson’s Disease

    PubMed Central

    Bekris, L.M.; Tsuang, D.W.; Peskind, E.R.; Yu, C.E.; Montine, T.J.; Zhang, J.; Zabetian, C.P.; Leverenz, J.B.

    2015-01-01

    Background Of recent interest is the finding that certain CSF biomarkers traditionally linked to Alzheimer’s disease (AD), specifically amyloid beta protein (Aβ), are abnormal in PD CSF. The aim of this exploratory investigation was to determine if genetic variation within the amyloid precursor protein (APP) processing pathway genes, correlate with cerebrospinal fluid (CSF) Aβ42 levels in Parkinson’s disease (PD). Method PD (n=86) and control (n=161) DNA were genotyped for 19 regulatory region tagging single nucleotide polymorphisms (SNPs) within nine genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN and APH1B) involved in the cleavage of APP. SNP genotypes were tested for their association with CSF biomarkers and PD risk while adjusting for age, gender, and APOE ε4 status. Results Significant correlation with CSF Aβ42 levels in PD was observed for two SNPs, (APP rs466448 and APH1B rs2068143). Conversely, significant correlation with CSF Aβ42 levels in controls was observed for three SNPs (APP rs214484 and rs2040273 and PSEN1 rs362344). Conclusion The results of this exploratory investigation suggest that an APP SNP and an APH1B SNP are marginally associated with PD CSF Aβ42 levels in APOE ε4 non-carriers. Further hypotheses generated include that decreased CSF Aβ42 levels are in part driven by genetic variation in APP processing genes. Additional investigation into the relationship between these findings and clinical characteristics of PD, including cognitive impairment, compared to other neurodegenerative diseases, such as AD, are warranted. PMID:25808939

  20. GeneFisher-P: variations of GeneFisher as processes in Bio-jETI

    PubMed Central

    Lamprecht, Anna-Lena; Margaria, Tiziana; Steffen, Bernhard; Sczyrba, Alexander; Hartmeier, Sven; Giegerich, Robert

    2008-01-01

    Background PCR primer design is an everyday, but not trivial task requiring state-of-the-art software. We describe the popular tool GeneFisher and explain its recent restructuring using workflow techniques. We apply a service-oriented approach to model and implement GeneFisher-P, a process-based version of the GeneFisher web application, as a part of the Bio-jETI platform for service modeling and execution. We show how to introduce a flexible process layer to meet the growing demand for improved user-friendliness and flexibility. Results Within Bio-jETI, we model the process using the jABC framework, a mature model-driven, service-oriented process definition platform. We encapsulate remote legacy tools and integrate web services using jETI, an extension of the jABC for seamless integration of remote resources as basic services, ready to be used in the process. Some of the basic services used by GeneFisher are in fact already provided as individual web services at BiBiServ and can be directly accessed. Others are legacy programs, and are made available to Bio-jETI via the jETI technology. The full power of service-based process orientation is required when more bioinformatics tools, available as web services or via jETI, lead to easy extensions or variations of the basic process. This concerns for instance variations of data retrieval or alignment tools as provided by the European Bioinformatics Institute (EBI). Conclusions The resulting service- and process-oriented GeneFisher-P demonstrates how basic services from heterogeneous sources can be easily orchestrated in the Bio-jETI platform and lead to a flexible family of specialized processes tailored to specific tasks. PMID:18460174

  1. IntPath--an integrated pathway gene relationship database for model organisms and important pathogens

    PubMed Central

    2012-01-01

    Background Pathway data are important for understanding the relationship between genes, proteins and many other molecules in living organisms. Pathway gene relationships are crucial information for guidance, prediction, reference and assessment in biochemistry, computational biology, and medicine. Many well-established databases--e.g., KEGG, WikiPathways, and BioCyc--are dedicated to collecting pathway data for public access. However, the effectiveness of these databases is hindered by issues such as incompatible data formats, inconsistent molecular representations, inconsistent molecular relationship representations, inconsistent referrals to pathway names, and incomprehensive data from different databases. Results In this paper, we overcome these issues through extraction, normalization and integration of pathway data from several major public databases (KEGG, WikiPathways, BioCyc, etc). We build a database that not only hosts our integrated pathway gene relationship data for public access but also maintains the necessary updates in the long run. This public repository is named IntPath (Integrated Pathway gene relationship database for model organisms and important pathogens). Four organisms--S. cerevisiae, M. tuberculosis H37Rv, H. Sapiens and M. musculus--are included in this version (V2.0) of IntPath. IntPath uses the "full unification" approach to ensure no deletion and no introduced noise in this process. Therefore, IntPath contains much richer pathway-gene and pathway-gene pair relationships and much larger number of non-redundant genes and gene pairs than any of the single-source databases. The gene relationships of each gene (measured by average node degree) per pathway are significantly richer. The gene relationships in each pathway (measured by average number of gene pairs per pathway) are also considerably richer in the integrated pathways. Moderate manual curation are involved to get rid of errors and noises from source data (e.g., the gene ID errors

  2. Hormonal Regulation and Expression Profiles of Wheat Genes Involved during Phytic Acid Biosynthesis Pathway

    PubMed Central

    Aggarwal, Sipla; Shukla, Vishnu; Bhati, Kaushal Kumar; Kaur, Mandeep; Sharma, Shivani; Singh, Anuradha; Mantri, Shrikant; Pandey, Ajay Kumar

    2015-01-01

    Phytic acid (PA) biosynthesis pathway genes were reported from multiple crop species. PA accumulation was enhanced during grain filling and at that time, hormones like Abscisic acid (ABA) and Gibberellic acid (GA3) interplay to control the process of seed development. Regulation of wheat PA pathway genes has not yet been reported in seeds. In an attempt to find the clues for the regulation by hormones, the promoter region of wheat PA pathway genes was analyzed for the presence of cis-elements. Multiple cis-elements of those known to be involved for ABA, GA3, salicylic acid (SA), and cAMP sensing were identified in the promoters of PA pathway genes. Eight genes (TaIMP, TaITPK1-4, TaPLC1, TaIPK2 and TaIPK1) involved in the wheat PA biosynthesis pathway were selected for the expression studies. The temporal expression response was studied in seeds treated with ABA and GA3 using quantitative real time PCR. Our results suggested that exogenous application of ABA induces few PA pathway genes in wheat grains. Comparison of expression profiles for PA pathway for GA3 and ABA suggested the antagonistic regulation of certain genes. Additionally, to reveal stress responses of wheat PA pathway genes, expression was also studied in the presence of SA and cAMP. Results suggested SA specific differential expression of few genes, whereas, overall repression of genes was observed in cAMP treated samples. This study is an effort to understand the regulation of PA biosynthesis genes in wheat. PMID:27135330

  3. Hormonal Regulation and Expression Profiles of Wheat Genes Involved during Phytic Acid Biosynthesis Pathway.

    PubMed

    Aggarwal, Sipla; Shukla, Vishnu; Bhati, Kaushal Kumar; Kaur, Mandeep; Sharma, Shivani; Singh, Anuradha; Mantri, Shrikant; Pandey, Ajay Kumar

    2015-06-11

    Phytic acid (PA) biosynthesis pathway genes were reported from multiple crop species. PA accumulation was enhanced during grain filling and at that time, hormones like Abscisic acid (ABA) and Gibberellic acid (GA₃) interplay to control the process of seed development. Regulation of wheat PA pathway genes has not yet been reported in seeds. In an attempt to find the clues for the regulation by hormones, the promoter region of wheat PA pathway genes was analyzed for the presence of cis-elements. Multiple cis-elements of those known to be involved for ABA, GA₃, salicylic acid (SA), and cAMP sensing were identified in the promoters of PA pathway genes. Eight genes (TaIMP, TaITPK1-4, TaPLC1, TaIPK2 and TaIPK1) involved in the wheat PA biosynthesis pathway were selected for the expression studies. The temporal expression response was studied in seeds treated with ABA and GA₃ using quantitative real time PCR. Our results suggested that exogenous application of ABA induces few PA pathway genes in wheat grains. Comparison of expression profiles for PA pathway for GA₃ and ABA suggested the antagonistic regulation of certain genes. Additionally, to reveal stress responses of wheat PA pathway genes, expression was also studied in the presence of SA and cAMP. Results suggested SA specific differential expression of few genes, whereas, overall repression of genes was observed in cAMP treated samples. This study is an effort to understand the regulation of PA biosynthesis genes in wheat.

  4. Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia.

    PubMed

    Gu, Fangyi; Zhang, Han; Hyland, Paula L; Berndt, Sonja; Gapstur, Susan M; Wheeler, William; Ellipse Consortium, The; Amos, Christopher I; Bezieau, Stephane; Bickeböller, Heike; Brenner, Hermann; Brennan, Paul; Chang-Claude, Jenny; Conti, David V; Doherty, Jennifer Anne; Gruber, Stephen B; Harrison, Tabitha A; Hayes, Richard B; Hoffmeister, Michael; Houlston, Richard S; Hung, Rayjean J; Jenkins, Mark A; Kraft, Peter; Lawrenson, Kate; McKay, James; Markt, Sarah; Mucci, Lorelei; Phelan, Catherine M; Qu, Conghui; Risch, Angela; Rossing, Mary Anne; Wichmann, H-Erich; Shi, Jianxin; Schernhammer, Eva; Yu, Kai; Landi, Maria Teresa; Caporaso, Neil E

    2017-11-01

    Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (ppathway  < 0.00625). The two most significant genes were NPAS2 (pgene  = 0.0062) and AANAT (pgene  = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (ppathway  = 0.021); this association was not confirmed in GECCO (ppathway  = 0.76) or the combined data (ppathway  = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.

  5. Transcriptomic analysis in the developing zebrafish embryo after compound exposure: individual gene expression and pathway regulation.

    PubMed

    Hermsen, Sanne A B; Pronk, Tessa E; van den Brandhof, Evert-Jan; van der Ven, Leo T M; Piersma, Aldert H

    2013-10-01

    The zebrafish embryotoxicity test is a promising alternative assay for developmental toxicity. Classically, morphological assessment of the embryos is applied to evaluate the effects of compound exposure. However, by applying differential gene expression analysis the sensitivity and predictability of the test may be increased. For defining gene expression signatures of developmental toxicity, we explored the possibility of using gene expression signatures of compound exposures based on commonly expressed individual genes as well as based on regulated gene pathways. Four developmental toxic compounds were tested in concentration-response design, caffeine, carbamazepine, retinoic acid and valproic acid, and two non-embryotoxic compounds, d-mannitol and saccharin, were included. With transcriptomic analyses we were able to identify commonly expressed genes, which were mostly development related, after exposure to the embryotoxicants. We also identified gene pathways regulated by the embryotoxicants, suggestive of their modes of action. Furthermore, whereas pathways may be regulated by all compounds, individual gene expression within these pathways can differ for each compound. Overall, the present study suggests that the use of individual gene expression signatures as well as pathway regulation may be useful starting points for defining gene biomarkers for predicting embryotoxicity.

  6. Transcriptome analysis reveals novel patterning and pigmentation genes underlying Heliconius butterfly wing pattern variation

    PubMed Central

    2012-01-01

    Background Heliconius butterfly wing pattern diversity offers a unique opportunity to investigate how natural genetic variation can drive the evolution of complex adaptive phenotypes. Positional cloning and candidate gene studies have identified a handful of regulatory and pigmentation genes implicated in Heliconius wing pattern variation, but little is known about the greater developmental networks within which these genes interact to pattern a wing. Here we took a large-scale transcriptomic approach to identify the network of genes involved in Heliconius wing pattern development and variation. This included applying over 140 transcriptome microarrays to assay gene expression in dissected wing pattern elements across a range of developmental stages and wing pattern morphs of Heliconius erato. Results We identified a number of putative early prepattern genes with color-pattern related expression domains. We also identified 51 genes differentially expressed in association with natural color pattern variation. Of these, the previously identified color pattern “switch gene” optix was recovered as the first transcript to show color-specific differential expression. Most differentially expressed genes were transcribed late in pupal development and have roles in cuticle formation or pigment synthesis. These include previously undescribed transporter genes associated with ommochrome pigmentation. Furthermore, we observed upregulation of melanin-repressing genes such as ebony and Dat1 in non-melanic patterns. Conclusions This study identifies many new genes implicated in butterfly wing pattern development and provides a glimpse into the number and types of genes affected by variation in genes that drive color pattern evolution. PMID:22747837

  7. Analysis of vascular endothelial dysfunction genes and related pathways in obesity through systematic bioinformatics.

    PubMed

    Zhang, Hui; Wang, Jing; Sun, Ling; Xu, Qiuqin; Hou, Miao; Ding, Yueyue; Huang, Jie; Chen, Ye; Cao, Lei; Zhang, Jianmin; Qian, Weiguo; Lv, Haitao

    2015-01-01

    Obesity has become an increasingly serious health problem and popular research topic. It is associated with many diseases, especially cardiovascular disease (CVD)-related endothelial dysfunction. This study analyzed genes related to endothelial dysfunction and obesity and then summarized their most significant signaling pathways. Genes related to vascular endothelial dysfunction and obesity were extracted from a PubMed database, and analyzed by STRING, DAVID, and Gene-Go Meta-Core software. 142 genes associated with obesity were found to play a role in endothelial dysfunction in PubMed. A significant pathway (Angiotensin system maturation in protein folding and maturation) associated with obesity and endothelial dysfunction was explored. The genes and the pathway explored may play an important role in obesity. Further studies about preventing vascular endothelial dysfunction obesity should be conducted through targeting these loci and pathways.

  8. A novel pathway-based distance score enhances assessment of disease heterogeneity in gene expression.

    PubMed

    Yan, Xiting; Liang, Anqi; Gomez, Jose; Cohn, Lauren; Zhao, Hongyu; Chupp, Geoffrey L

    2017-06-20

    Distance based unsupervised clustering of gene expression data is commonly used to identify heterogeneity in biologic samples. However, high noise levels in gene expression data and relatively high correlation between genes are often encountered, so traditional distances such as Euclidean distance may not be effective at discriminating the biological differences between samples. An alternative method to examine disease phenotypes is to use pre-defined biological pathways. These pathways have been shown to be perturbed in different ways in different subjects who have similar clinical features. We hypothesize that differences in the expressions of genes in a given pathway are more predictive of differences in biological differences compared to standard approaches and if integrated into clustering analysis will enhance the robustness and accuracy of the clustering method. To examine this hypothesis, we developed a novel computational method to assess the biological differences between samples using gene expression data by assuming that ontologically defined biological pathways in biologically similar samples have similar behavior. Pre-defined biological pathways were downloaded and genes in each pathway were used to cluster samples using the Gaussian mixture model. The clustering results across different pathways were then summarized to calculate the pathway-based distance score between samples. This method was applied to both simulated and real data sets and compared to the traditional Euclidean distance and another pathway-based clustering method, Pathifier. The results show that the pathway-based distance score performs significantly better than the Euclidean distance, especially when the heterogeneity is low and genes in the same pathways are correlated. Compared to Pathifier, we demonstrated that our approach achieves higher accuracy and robustness for small pathways. When the pathway size is large, by downsampling the pathways into smaller pathways, our

  9. Allelic diversity in an NLR gene BPH9 enables rice to combat planthopper variation

    PubMed Central

    Zhao, Yan; Huang, Jin; Wang, Zhizheng; Jing, Shengli; Wang, Yang; Ouyang, Yidan; Cai, Baodong; Xin, Xiu-Fang; Liu, Xin; Zhang, Chunxiao; Pan, Yufang; Ma, Rui; Li, Qiaofeng; Jiang, Weihua; Zeng, Ya; Shangguan, Xinxin; Wang, Huiying; Du, Bo; Zhu, Lili; Xu, Xun; Feng, Yu-Qi; He, Sheng Yang; Chen, Rongzhi; Zhang, Qifa; He, Guangcun

    2016-01-01

    Brown planthopper (BPH), Nilaparvata lugens Stål, is one of the most devastating insect pests of rice (Oryza sativa L.). Currently, 30 BPH-resistance genes have been genetically defined, most of which are clustered on specific chromosome regions. Here, we describe molecular cloning and characterization of a BPH-resistance gene, BPH9, mapped on the long arm of rice chromosome 12 (12L). BPH9 encodes a rare type of nucleotide-binding and leucine-rich repeat (NLR)-containing protein that localizes to the endomembrane system and causes a cell death phenotype. BPH9 activates salicylic acid- and jasmonic acid-signaling pathways in rice plants and confers both antixenosis and antibiosis to BPH. We further demonstrated that the eight BPH-resistance genes that are clustered on chromosome 12L, including the widely used BPH1, are allelic with each other. To honor the priority in the literature, we thus designated this locus as BPH1/9. These eight genes can be classified into four allelotypes, BPH1/9-1, -2, -7, and -9. These allelotypes confer varying levels of resistance to different biotypes of BPH. The coding region of BPH1/9 shows a high level of diversity in rice germplasm. Homologous fragments of the nucleotide-binding (NB) and leucine-rich repeat (LRR) domains exist, which might have served as a repository for generating allele diversity. Our findings reveal a rice plant strategy for modifying the genetic information to gain the upper hand in the struggle against insect herbivores. Further exploration of natural allelic variation and artificial shuffling within this gene may allow breeding to be tailored to control emerging biotypes of BPH. PMID:27791169

  10. Allelic diversity in an NLR gene BPH9 enables rice to combat planthopper variation.

    PubMed

    Zhao, Yan; Huang, Jin; Wang, Zhizheng; Jing, Shengli; Wang, Yang; Ouyang, Yidan; Cai, Baodong; Xin, Xiu-Fang; Liu, Xin; Zhang, Chunxiao; Pan, Yufang; Ma, Rui; Li, Qiaofeng; Jiang, Weihua; Zeng, Ya; Shangguan, Xinxin; Wang, Huiying; Du, Bo; Zhu, Lili; Xu, Xun; Feng, Yu-Qi; He, Sheng Yang; Chen, Rongzhi; Zhang, Qifa; He, Guangcun

    2016-10-24

    Brown planthopper (BPH), Nilaparvata lugens Stål, is one of the most devastating insect pests of rice (Oryza sativa L.). Currently, 30 BPH-resistance genes have been genetically defined, most of which are clustered on specific chromosome regions. Here, we describe molecular cloning and characterization of a BPH-resistance gene, BPH9, mapped on the long arm of rice chromosome 12 (12L). BPH9 encodes a rare type of nucleotide-binding and leucine-rich repeat (NLR)-containing protein that localizes to the endomembrane system and causes a cell death phenotype. BPH9 activates salicylic acid- and jasmonic acid-signaling pathways in rice plants and confers both antixenosis and antibiosis to BPH. We further demonstrated that the eight BPH-resistance genes that are clustered on chromosome 12L, including the widely used BPH1, are allelic with each other. To honor the priority in the literature, we thus designated this locus as BPH1/9 These eight genes can be classified into four allelotypes, BPH1/9-1, -2, -7, and -9 These allelotypes confer varying levels of resistance to different biotypes of BPH. The coding region of BPH1/9 shows a high level of diversity in rice germplasm. Homologous fragments of the nucleotide-binding (NB) and leucine-rich repeat (LRR) domains exist, which might have served as a repository for generating allele diversity. Our findings reveal a rice plant strategy for modifying the genetic information to gain the upper hand in the struggle against insect herbivores. Further exploration of natural allelic variation and artificial shuffling within this gene may allow breeding to be tailored to control emerging biotypes of BPH.

  11. No Association between Variation in Longevity Candidate Genes and Aging-related Phenotypes in Oldest-old Danes.

    PubMed

    Soerensen, Mette; Nygaard, Marianne; Debrabant, Birgit; Mengel-From, Jonas; Dato, Serena; Thinggaard, Mikael; Christensen, Kaare; Christiansen, Lene

    2016-06-01

    In this study we explored the association between aging-related phenotypes previously reported to predict survival in old age and variation in 77 genes from the DNA repair pathway, 32 genes from the growth hormone 1/ insulin-like growth factor 1/insulin (GH/IGF-1/INS) signalling pathway and 16 additional genes repeatedly considered as candidates for human longevity: APOE, APOA4, APOC3, ACE, CETP, HFE, IL6, IL6R, MTHFR, TGFB1, SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. Altogether, 1,049 single nucleotide polymorphisms (SNPs) were genotyped in 1,088 oldest-old (age 92-93 years) Danes and analysed with phenotype data on physical functioning (hand grip strength), cognitive functioning (mini mental state examination and a cognitive composite score), activity of daily living and self-rated health. Five SNPs showed association to one of the phenotypes; however, none of these SNPs were associated with a change in the relevant phenotype over time (7 years of follow-up) and none of the SNPs could be confirmed in a replication sample of 1,281 oldest-old Danes (age 94-100). Hence, our study does not support association between common variation in the investigated longevity candidate genes and aging-related phenotypes consistently shown to predict survival. It is possible that larger sample sizes are needed to robustly reveal associations with small effect sizes.

  12. Pathways analysis of differential gene expression induced by engrafting doses of total body irradiation for allogeneic bone marrow transplantation in mice.

    PubMed

    Chen, Xinjian; Wang, Yuanyuan; Li, Qiuxia; Tsai, Schickwann; Thomas, Alun; Shizuru, Judith A; Cao, Thai M

    2013-08-01

    A major challenge in allogeneic bone marrow (BM) transplantation is overcoming engraftment resistance to avoid the clinical problem of graft rejection. Identifying gene pathways that regulate BM engraftment may reveal molecular targets for overcoming engraftment barriers. Previously, we developed a mouse model of BM transplantation that utilizes recipient conditioning with non-myeloablative total body irradiation (TBI). We defined TBI doses that lead to graft rejection, that conversely are permissive for engraftment, and mouse strain variation with regards to the permissive TBI dose. We now report gene expression analysis, using Agilent Mouse 8x60K microarrays, in spleens of mice conditioned with varied TBI doses for correlation to the expected engraftment phenotype. The spleens of mice given engrafting doses of TBI, compared with non-engrafting TBI doses, demonstrated substantially broader gene expression changes, significant at the multiple testing-corrected P <0.05 level and with fold change ≥2. Functional analysis revealed significant enrichment for a down-regulated canonical pathway involving B-cell development. Genes enriched in this pathway suggest that suppressing donor antigen processing and presentation may be pivotal effects conferred by TBI to enable engraftment. Regardless of TBI dose and recipient mouse strain, pervasive genomic changes related to inflammation was observed and reflected by significant enrichment for canonical pathways and association with upstream regulators. These gene expression changes suggest that macrophage and complement pathways may be targeted to overcome engraftment barriers. These exploratory results highlight gene pathways that may be important in mediating BM engraftment resistance.

  13. The gene-gene interaction of INSIG-SCAP-SREBP pathway on the risk of obesity in Chinese children.

    PubMed

    Liu, Fang-Hong; Song, Jie-Yun; Shang, Xiao-Rui; Meng, Xiang-Rui; Ma, Jun; Wang, Hai-Jun

    2014-01-01

    Childhood obesity has become a global public health problem in recent years. This study aimed to explore the association of genetic variants in INSIG-SCAP-SREBP pathway with obesity in Chinese children. A case-control study was conducted, including 705 obese cases and 1,325 nonobese controls. We genotyped 15 single nucleotide polymorphisms (SNPs) of five genes in INSIG-SCAP-SREBP pathway, including insulin induced gene 1 (INSIG1), insulin induced gene 2 (INSIG2), SREBP cleavage-activating protein gene (SCAP), sterol regulatory element binding protein gene 1 (SREBP1), and sterol regulatory element binding protein gene 2 (SREBP2). We used generalized multifactor dimensionality reduction (GMDR) and logistic regression to investigate gene-gene interactions. Single polymorphism analyses showed that SCAP rs12487736 and rs12490383 were nominally associated with obesity. We identified a 3-locus interaction on obesity in GMDR analyses (P = 0.001), involving 3 genetic variants of INSIG2, SCAP, and SREBP2. The individuals in high-risk group of the 3-locus combinations had a 79.9% increased risk of obesity compared with those in low-risk group (OR = 1.799, 95% CI: 1.475-2.193, P = 6.61 × 10(-9)). We identified interaction of three genes in INSIG-SCAP-SREBP pathway on risk of obesity, revealing that these genes affect obesity more likely through a complex interaction pattern than single gene effect.

  14. Natural variation in cardiac metabolism and gene expression in Fundulus heteroclitus

    PubMed Central

    Oleksiak, Marjorie F; Roach, Jennifer L; Crawford, Douglas L

    2006-01-01

    Individual variation in gene expression is important for evolutionary adaptation1,2 and susceptibility to diseases and pathologies3,4. In this study, we address the functional importance of this variation by comparing cardiac metabolism to patterns of mRNA expression using microarrays. There is extensive variation in both cardiac metabolism and the expression of metabolic genes among individuals of the teleost fish Fundulus heteroclitus from natural outbred populations raised in a common environment: metabolism differed among individuals by a factor of more than 2, and expression levels of 94% of genes were significantly different (P < 0.01) between individuals in a population. This unexpectedly high variation in metabolic gene expression explains much of the variation in metabolism, suggesting that it is biologically relevant. The patterns of gene expression that are most important in explaining cardiac metabolism differ between groups of individuals. Apparently, the variation in metabolism seems to be related to different patterns of gene expression in the different groups of individuals. The magnitude of differences in gene expression in these groups is not important; large changes in expression have no greater predictive value than small changes. These data suggest that variation in physiological performance is related to the subtle variation in gene expression and that this relationship differs among individuals. PMID:15568023

  15. Global gene expression and functional network analysis of gastric cancer identify extended pathway maps and GPRC5A as a potential biomarker.

    PubMed

    Cheng, Lei; Yang, Sheng; Yang, Yanqing; Zhang, Wen; Xiao, Huasheng; Gao, Hengjun; Deng, Xiaxing; Zhang, Qinghua

    2012-12-29

    To get more understanding of the molecular mechanisms underlying gastric cancer, 25 paired samples were applied to gene expression microarray analysis. Here, expression microarray, quantitative reverse transcription-PCR (qRT-PCR) and immunohistochemical analysis indicated that GPRC5A was significantly elevated in gastric cancer tissues. The integrative network analysis of deregulated genes generated eight subnetworks. We also mapped copy number variations (CNVs) and associated mRNA expression changes into pathways and identified WNT, RTK-Ras-PI3K-AKT, NF-κB, and PLAU-JAK-STAT pathways involved in proliferation, evading apoptosis and sustained angiogenesis, respectively. Taken together, our results reveal several interesting genes including GPRC5A as potential biomarkers for gastric cancer, and highlight more systematical insight of deregulated genes in genetic pathways of gastric carcinogenesis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  16. RNAi pathway genes are resistant to small RNA mediated gene silencing in the protozoan parasite Entamoeba histolytica.

    PubMed

    Pompey, Justine M; Morf, Laura; Singh, Upinder

    2014-01-01

    The RNA interference pathway in the protist Entamoeba histolytica plays important roles in permanent gene silencing as well as in the regulation of virulence determinants. Recently, a novel RNA interference (RNAi)-based silencing technique was developed in this parasite that uses a gene endogenously silenced by small RNAs as a "trigger" to induce silencing of other genes that are fused to it. Fusion to a trigger gene induces the production of gene-specific antisense small RNAs, resulting in robust and permanent silencing of the cognate gene. This approach has silenced multiple genes including those involved in virulence and transcriptional regulation. We now demonstrate that all tested genes of the amebic RNAi pathway are unable to be silenced using the trigger approach, including Argonaute genes (Ago2-1, Ago2-2, and Ago2-3), RNaseIII, and RNA-dependent RNA polymerase (RdRP). In all situations (except for RdRP), fusion to a trigger successfully induces production of gene-specific antisense small RNAs to the cognate gene. These small RNAs are capable of silencing a target gene in trans, indicating that they are functional; despite this, however, they cannot silence the RNAi pathway genes. Interestingly, when a trigger is fused to RdRP, small RNA induction to RdRP does not occur, a unique phenotype hinting that either RdRP is highly resistant to being a target of small RNAs or that small RNA generation may be controlled by RdRP. The inability of the small RNA pathway to silence RNAi genes in E. histolytica, despite the generation of functional small RNAs to these loci suggest that epigenetic factors may protect certain genomic loci and thus determine susceptibility to small RNA mediated silencing.

  17. RNAi Pathway Genes Are Resistant to Small RNA Mediated Gene Silencing in the Protozoan Parasite Entamoeba histolytica

    PubMed Central

    Pompey, Justine M.; Morf, Laura; Singh, Upinder

    2014-01-01

    The RNA interference pathway in the protist Entamoeba histolytica plays important roles in permanent gene silencing as well as in the regulation of virulence determinants. Recently, a novel RNA interference (RNAi)-based silencing technique was developed in this parasite that uses a gene endogenously silenced by small RNAs as a “trigger” to induce silencing of other genes that are fused to it. Fusion to a trigger gene induces the production of gene-specific antisense small RNAs, resulting in robust and permanent silencing of the cognate gene. This approach has silenced multiple genes including those involved in virulence and transcriptional regulation. We now demonstrate that all tested genes of the amebic RNAi pathway are unable to be silenced using the trigger approach, including Argonaute genes (Ago2-1, Ago2-2, and Ago2-3), RNaseIII, and RNA-dependent RNA polymerase (RdRP). In all situations (except for RdRP), fusion to a trigger successfully induces production of gene-specific antisense small RNAs to the cognate gene. These small RNAs are capable of silencing a target gene in trans, indicating that they are functional; despite this, however, they cannot silence the RNAi pathway genes. Interestingly, when a trigger is fused to RdRP, small RNA induction to RdRP does not occur, a unique phenotype hinting that either RdRP is highly resistant to being a target of small RNAs or that small RNA generation may be controlled by RdRP. The inability of the small RNA pathway to silence RNAi genes in E. histolytica, despite the generation of functional small RNAs to these loci suggest that epigenetic factors may protect certain genomic loci and thus determine susceptibility to small RNA mediated silencing. PMID:25198343

  18. Looking on the bright side of serotonin transporter gene variation.

    PubMed

    Homberg, Judith R; Lesch, Klaus-Peter

    2011-03-15

    Converging evidence indicates an association of the short (s), low-expressing variant of the repeat length polymorphism, serotonin transporter-linked polymorphic region (5-HTTLPR), in the human serotonin transporter gene (5-HTT, SERT, SLC6A4) with anxiety-related traits and increased risk for depression in interaction with psychosocial adversity across the life span. However, genetically driven deficient serotonin transporter (5-HTT) function would not have been maintained throughout evolution if it only exerted negative effects without conveying any gain of function. Here, we review recent findings that humans and nonhuman primates carrying the s variant of the 5-HTTLPR outperform subjects carrying the long allele in an array of cognitive tasks and show increased social conformity. In addition, studies in 5-HTT knockout rodents are included that provide complementary insights in the beneficial effects of the 5-HTTLPR s-allele. We postulate that hypervigilance, mediated by hyperactivity in corticolimbic structures, may be the common denominator in the anxiety-related traits and (social) cognitive superiority of s-allele carriers and that environmental conditions determine whether a response will turn out to be negative (emotional) or positive (cognitive, in conformity with the social group). Taken together, these findings urge for a conceptual change in the current deficit-oriented connotation of the 5-HTTLPR variants. In fact, these factors may counterbalance or completely offset the negative consequences of the anxiety-related traits. This notion may not only explain the modest effect size of the 5-HTTLPR and inconsistent reports but may also lead to a more refined appreciation of allelic variation in 5-HTT function. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  19. Recursive random forest algorithm for constructing multilayered hierarchical gene regulatory networks that govern biological pathways

    PubMed Central

    Zhang, Kui; Busov, Victor; Wei, Hairong

    2017-01-01

    Background Present knowledge indicates a multilayered hierarchical gene regulatory network (ML-hGRN) often operates above a biological pathway. Although the ML-hGRN is very important for understanding how a pathway is regulated, there is almost no computational algorithm for directly constructing ML-hGRNs. Results A backward elimination random forest (BWERF) algorithm was developed for constructing the ML-hGRN operating above a biological pathway. For each pathway gene, the BWERF used a random forest model to calculate the importance values of all transcription factors (TFs) to this pathway gene recursively with a portion (e.g. 1/10) of least important TFs being excluded in each round of modeling, during which, the importance values of all TFs to the pathway gene were updated and ranked until only one TF was remained in the list. The above procedure, termed BWERF. After that, the importance values of a TF to all pathway genes were aggregated and fitted to a Gaussian mixture model to determine the TF retention for the regulatory layer immediately above the pathway layer. The acquired TFs at the secondary layer were then set to be the new bottom layer to infer the next upper layer, and this process was repeated until a ML-hGRN with the expected layers was obtained. Conclusions BWERF improved the accuracy for constructing ML-hGRNs because it used backward elimination to exclude the noise genes, and aggregated the individual importance values for determining the TFs retention. We validated the BWERF by using it for constructing ML-hGRNs operating above mouse pluripotency maintenance pathway and Arabidopsis lignocellulosic pathway. Compared to GENIE3, BWERF showed an improvement in recognizing authentic TFs regulating a pathway. Compared to the bottom-up Gaussian graphical model algorithm we developed for constructing ML-hGRNs, the BWERF can construct ML-hGRNs with significantly reduced edges that enable biologists to choose the implicit edges for experimental

  20. Dependence of PEI and PAMAM Gene Delivery on Clathrin- and Caveolin-Dependent Trafficking Pathways

    PubMed Central

    Hwang, Mark E.; Keswani, Rahul K.; Pack, Daniel W.

    2014-01-01

    Purpose Non-viral gene delivery vehicles such as polyethylenimine and polyamidoamine dendrimer effectively condense plasmid DNA, facilitate endocytosis, and deliver nucleic acid cargo to the nucleus in vitro. Better understanding of intracellular trafficking mechanisms involved in polymeric gene delivery is a prerequisite to clinical application. This study investigates the role of clathrin and caveolin endocytic pathways in cellular uptake and subsequent vector processing. Methods We formed 25-kD polyethylenimine (PEI) and generation 4 (G4) polyamidoamine (PAMAM) polyplexes at N/P 10 and evaluated internalization pathways and gene delivery in HeLa cells. Clathrin- and caveolin-dependent endocytosis inhibitors were used at varying concentrations to elucidate the roles of these important pathways. Results PEI and PAMAM polyplexes were internalized by both pathways. However, the amount of polyplex internalized poorly correlated with transgene expression. While the caveolin-dependent pathway generally led to effective gene delivery with both polymers, complete inhibition of the clathrin-dependent pathway was also deleterious to transfection with PEI polyplexes. Inhibition of one endocytic pathway may lead to an overall increase in uptake via unaffected pathways, suggesting the existence of compensatory endocytic mechanisms. Conclusions The well-studied clathrin- and caveolin-dependent endocytosis pathways are not necessarily independent, and perturbing one mechanism of trafficking influences the larger trafficking network. PMID:25511918

  1. Identification of hub genes and pathways associated with retinoblastoma based on co-expression network analysis.

    PubMed

    Wang, Q L; Chen, X; Zhang, M H; Shen, Q H; Qin, Z M

    2015-12-08

    The objective of this paper was to identify hub genes and pathways associated with retinoblastoma using centrality analysis of the co-expression network and pathway-enrichment analysis. The co-expression network of retinoblastoma was constructed by weighted gene co-expression network analysis (WGCNA) based on differentially expressed (DE) genes, and clusters were obtained through the molecular complex detection (MCODE) algorithm. Degree centrality analysis of the co-expression network was performed to explore hub genes present in retinoblastoma. Pathway-enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Validation of hub gene expression in retinoblastoma was performed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. The co-expression network based on 221 DE genes between retinoblastoma and normal controls consisted of 210 nodes and 3965 edges, and 5 clusters of the network were evaluated. By assessing the centrality analysis of the co-expression network, 21 hub genes were identified, such as SNORD115-41, RASSF2, and SNORD115-44. According to RT-PCR analysis, 16 of the 21 hub genes were differently expressed, including RASSF2 and CDCA7, and 5 were not differently expressed in retinoblastoma compared to normal controls. Pathway analysis showed that genes in 2 clusters were enriched in 3 pathways: purine metabolism, p53 signaling pathway, and melanogenesis. In this study, we successfully identified 16 hub genes and 3 pathways associated with retinoblastoma, which may be potential biomarkers for early detection and therapy for retinoblastoma.

  2. Screening essential genes of Mycobacterium tuberculosis with the pathway enrichment method.

    PubMed

    Xu, Guangyu; Ni, Zhaohui; Shi, Yue; Sun, Xiaoyu; Wang, Huaidong; Wei, Chengguo; Wang, Guoqing; Li, Fan

    2014-11-01

    The number of effective drugs for the prevention and control of tuberculosis is very limited. Therefore, high-throughput screening for Mycobacterium tuberculosis drug targets is critical. In addition, determining the essential gene cluster is important for both understanding a survival mechanism and finding novel molecular targets for anti-tuberculosis drugs. In this study, we applied the pathway enrichment method to perform high throughput screening of genes encoding key molecules for potential drug targets for M. tuberculosis. Our results indicated 122 genes that existed in more than three pathways, while four existed in 11 pathways. We predicted 55 genes that are potentially essential genes. Four of them, namely, Rv0363c, Rv0408, Rv0409 and Rv0794c, had the highest probability to be essential genes, and thus further experimental validation is warranted.

  3. NF-Y activates genes of metabolic pathways altered in cancer cells.

    PubMed

    Benatti, Paolo; Chiaramonte, Maria Luisa; Lorenzo, Mariangela; Hartley, John A; Hochhauser, Daniel; Gnesutta, Nerina; Mantovani, Roberto; Imbriano, Carol; Dolfini, Diletta

    2016-01-12

    The trimeric transcription factor NF-Y binds to the CCAAT box, an element enriched in promoters of genes overexpressed in tumors. Previous studies on the NF-Y regulome identified the general term metabolism as significantly enriched. We dissect here in detail the targeting of metabolic genes by integrating analysis of NF-Y genomic binding and profilings after inactivation of NF-Y subunits in different cell types. NF-Y controls de novo biosynthetic pathways of lipids, teaming up with the master SREBPs regulators. It activates glycolytic genes, but, surprisingly, is neutral or represses mitochondrial respiratory genes. NF-Y targets the SOCG (Serine, One Carbon, Glycine) and Glutamine pathways, as well as genes involved in the biosynthesis of polyamines and purines. Specific cancer-driving nodes are generally under NF-Y control. Altogether, these data delineate a coherent strategy to promote expression of metabolic genes fuelling anaerobic energy production and other anabolic pathways commonly altered in cancer cells.

  4. Variation in levels of enzymes related to energy metabolism in alternative developmental pathways of Blastocladiella emersonii.

    PubMed

    Ingebretsen, O C; Sanner, T

    1976-06-01

    The activities of phosphofructokinase (PFK), fructose diphosphatase (FDP), nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP)-linked isocitrate dehydrogenases (IDHNAD, IDHNADP), two NAD-linked glutamate dehydrogenases (GDH1, GDH2), and isocitrate lyase were studied during the development of the two phenotypes, ordinary colorless and resistant sporangia (OC and RS plants), of water mold Blastocladiella emersonii in synchronized liquid cultures. The OC plants had a generation time of about 12 h, whereas the RS plants required 3.5 days to reach maturity. All the enzymes were present throughout the development of both phenotypes. In zoospores, PFK, FDP, and GDH2 were localized in the cytosol. The IDHNADP activity was distributed with two-thirds in the soluble and one-third in the particulate fraction. GDH1 and IDHNAD showed the same distribution and were predominantly present in the particulate fraction, presumably in the mitochondria. Isocitrate lyase was found in the particulate fraction. The enzyme levels changed considerably during development. FDP and IDHNADP varied in a parallel manner. Similarly, the three enzymes PFK, IDHNAD and GDH1 showed parallel variations. The activity patterns for all enzymes were different for the OC and RS pathways. Isocitrate lyase exhibited the largest changes in activity during development. Thus, during OC plant formation, its activity decreased by a factor of 20. GDH2 varied similarly to PFK and IDHNADP during OC plant development, whereas it behaved like isocitrate lyase during RS plant development. The ratios between anabolic and catabolic enzymes were higher in mature plants than in zoospores and higher in RS plants than in OC plants. The results indicate that the variations in the enzyme levels are secondary to the critical changes involved in the transition from one developmental pathway to the other.

  5. Gene Loss Dominates As a Source of Genetic Variation within Clonal Pathogenic Bacterial Species.

    PubMed

    Bolotin, Evgeni; Hershberg, Ruth

    2015-07-10

    Some of the most dangerous pathogens such as Mycobacterium tuberculosis and Yersinia pestis evolve clonally. This means that little or no recombination occurs between strains belonging to these species. Paradoxically, although different members of these species show extreme sequence similarity of orthologous genes, some show considerable intraspecies phenotypic variation, the source of which remains elusive. To examine the possible sources of phenotypic variation within clonal pathogenic bacterial species, we carried out an extensive genomic and pan-genomic analysis of the sources of genetic variation available to a large collection of clonal and nonclonal pathogenic bacterial species. We show that while nonclonal species diversify through a combination of changes to gene sequences, gene loss and gene gain, gene loss completely dominates as a source of genetic variation within clonal species. Indeed, gene loss is so prevalent within clonal species as to lead to levels of gene content variation comparable to those found in some nonclonal species that are much more diverged in their gene sequences and that acquire a substantial number of genes horizontally. Gene loss therefore needs to be taken into account as a potential dominant source of phenotypic variation within clonal bacterial species.

  6. Potential hippocampal genes and pathways involved in Alzheimer's disease: a bioinformatic analysis.

    PubMed

    Zhang, L; Guo, X Q; Chu, J F; Zhang, X; Yan, Z R; Li, Y Z

    2015-06-29

    Alzheimer's disease (AD) is a neurodegenerative disor-der and the most common cause of dementia in elderly people. Nu-merous studies have focused on the dysregulated genes in AD, but the pathogenesis is still unknown. In this study, we explored critical hippocampal genes and pathways that might potentially be involved in the pathogenesis of AD. Four transcriptome datasets for the hip-pocampus of patients with AD were downloaded from ArrayExpress, and the gene signature was identified by integrated analysis of mul-tiple transcriptomes using novel genome-wide relative significance and genome-wide global significance models. A protein-protein interaction network was constructed, and five clusters were selected. The biologi-cal functions and pathways were identified by Gene Ontology and Kyo-to Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. A total of 6994 genes were screened, and the top 300 genes were subjected to further analysis. Four significant KEGG pathways were identified, including oxidative phosphorylation and Parkinson's disease, Huntington's disease, and Alzheimer's disease pathways. The hub network of cluster 1 with the highest average rank value was de-fined. The genes (NDUFB3, NDUFA9, NDUFV1, NDUFV2, NDUFS3, NDUFA10, COX7B, and UQCR1) were considered critical with high degree in cluster 1 as well as being shared by the four significant path-ways. The oxidative phosphorylation process was also involved in the other three pathways and is considered to be relevant to energy-related AD pathology in the hippocampus. This research provides a perspec-tive from which to explore critical genes and pathways for potential AD therapies.

  7. Characterization of Differentially Expressed Genes Involved in Pathways Associated with Gastric Cancer

    PubMed Central

    Li, Hao; Yu, Beiqin; Li, Jianfang; Su, Liping; Yan, Min; Zhang, Jun; Li, Chen; Zhu, Zhenggang; Liu, Bingya

    2015-01-01

    To explore the patterns of gene expression in gastric cancer, a total of 26 paired gastric cancer and noncancerous tissues from patients were enrolled for gene expression microarray analyses. Limma methods were applied to analyze the data, and genes were considered to be significantly differentially expressed if the False Discovery Rate (FDR) value was < 0.01, P-value was <0.01 and the fold change (FC) was >2. Subsequently, Gene Ontology (GO) categories were used to analyze the main functions of the differentially expressed genes. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we found pathways significantly associated with the differential genes. Gene-Act network and co-expression network were built respectively based on the relationships among the genes, proteins and compounds in the database. 2371 mRNAs and 350 lncRNAs considered as significantly differentially expressed genes were selected for the further analysis. The GO categories, pathway analyses and the Gene-Act network showed a consistent result that up-regulated genes were responsible for tumorigenesis, migration, angiogenesis and microenvironment formation, while down-regulated genes were involved in metabolism. These results of this study provide some novel findings on coding RNAs, lncRNAs, pathways and the co-expression network in gastric cancer which will be useful to guide further investigation and target therapy for this disease. PMID:25928635

  8. Pathways enrichment analysis for differentially expressed genes in squamous lung cancer.

    PubMed

    Qian, Liqiang; Luo, Qingquan; Zhao, Xiaojing; Huang, Jia

    2014-01-01

    Squamous lung cancer (SQLC) is a common type of lung cancer, but its oncogenesis mechanism is not so clear. The aim of this study was to screen the potential pathways changed in SQLC and elucidate the mechanism of it. Published microarray data of GSE3268 series was downloaded from Gene Expression Omnibus (GEO). Significance analysis of microarrays was performed using software R, and differentially expressed genes (DEGs) were harvested. The functions and pathways of DEGs were mapped in Gene Otology and KEGG pathway database, respectively. A total of 2961 genes were filtered as DEGs between normal and SQLC cells. Cell cycle and metabolism were the mainly changed functions of SQLC cells. Meanwhile genes such as MCM, RFC, FEN1, and POLD may induce SQLC through DNA replication pathway, and genes such as PTTG1, CCNB1, CDC6, and PCNA may be involved in SQLC through cell cycle pathway. It is demonstrated that pathway analysis is useful in the identification of target genes in SQLC.

  9. Genome wide transcriptome profiling reveals differential gene expression in secondary metabolite pathway of Cymbopogon winterianus

    PubMed Central

    Devi, Kamalakshi; Mishra, Surajit K.; Sahu, Jagajjit; Panda, Debashis; Modi, Mahendra K.; Sen, Priyabrata

    2016-01-01

    Advances in transcriptome sequencing provide fast, cost-effective and reliable approach to generate large expression datasets especially suitable for non-model species to identify putative genes, key pathway and regulatory mechanism. Citronella (Cymbopogon winterianus) is an aromatic medicinal grass used for anti-tumoral, antibacterial, anti-fungal, antiviral, detoxifying and natural insect repellent properties. Despite of having number of utilities, the genes involved in terpenes biosynthetic pathway is not yet clearly elucidated. The present study is a pioneering attempt to generate an exhaustive molecular information of secondary metabolite pathway and to increase genomic resources in Citronella. Using high-throughput RNA-Seq technology, root and leaf transcriptome was analysed at an unprecedented depth (11.7 Gb). Targeted searches identified majority of the genes associated with metabolic pathway and other natural product pathway viz. antibiotics synthesis along with many novel genes. Terpenoid biosynthesis genes comparative expression results were validated for 15 unigenes by RT-PCR and qRT-PCR. Thus the coverage of these transcriptome is comprehensive enough to discover all known genes of major metabolic pathways. This transcriptome dataset can serve as important public information for gene expression, genomics and function genomics studies in Citronella and shall act as a benchmark for future improvement of the crop. PMID:26877149

  10. Genome wide transcriptome profiling reveals differential gene expression in secondary metabolite pathway of Cymbopogon winterianus.

    PubMed

    Devi, Kamalakshi; Mishra, Surajit K; Sahu, Jagajjit; Panda, Debashis; Modi, Mahendra K; Sen, Priyabrata

    2016-02-15

    Advances in transcriptome sequencing provide fast, cost-effective and reliable approach to generate large expression datasets especially suitable for non-model species to identify putative genes, key pathway and regulatory mechanism. Citronella (Cymbopogon winterianus) is an aromatic medicinal grass used for anti-tumoral, antibacterial, anti-fungal, antiviral, detoxifying and natural insect repellent properties. Despite of having number of utilities, the genes involved in terpenes biosynthetic pathway is not yet clearly elucidated. The present study is a pioneering attempt to generate an exhaustive molecular information of secondary metabolite pathway and to increase genomic resources in Citronella. Using high-throughput RNA-Seq technology, root and leaf transcriptome was analysed at an unprecedented depth (11.7 Gb). Targeted searches identified majority of the genes associated with metabolic pathway and other natural product pathway viz. antibiotics synthesis along with many novel genes. Terpenoid biosynthesis genes comparative expression results were validated for 15 unigenes by RT-PCR and qRT-PCR. Thus the coverage of these transcriptome is comprehensive enough to discover all known genes of major metabolic pathways. This transcriptome dataset can serve as important public information for gene expression, genomics and function genomics studies in Citronella and shall act as a benchmark for future improvement of the crop.

  11. Association of Variants in Estrogen-Related Pathway Genes with Prostate Cancer Risk

    PubMed Central

    Holt, Sarah K.; Kwon, Erika M.; Fu, Rong; Kolb, Suzanne; Feng, Ziding; Ostrander, Elaine A.; Stanford, Janet L.

    2012-01-01

    Background Through mediation of estrogen receptors, estradiol has been shown to have both carcinogenic and anti-carcinogenic effects on the prostate. We performed a population-based case-control study to investigate variants in estrogen-related genes ESR1, ESR2, CYP19A1, CYP1A1, and CYP1B1 and the potential association with risk of prostate cancer. Materials and Methods We evaluated prostate cancer risk conferred by 73 single nucleotide polymorphisms in 1,304 incident prostate cancer cases and 1,266 age-matched controls. Analysis included stratification by clinical features and assessment of environmental modifiers. Results There was evidence of altered risk of developing prostate cancer for variants in ESR1, CYP1A1, and CYP1B1, however, only CYP1B1 rs1056836 retained significance after adjustment for multiple comparisons. An association with risk for more aggressive prostate cancer was observed for variants in ESR1, ESR2, and CYP19A1, but none was significant after adjustment for multiple comparisons. There was no effect modification by obesity. Conclusions Germline genetic variation of these estrogen pathway genes may contribute to risk of prostate cancer. Additional studies to validate these results and examine the functional consequence of validated variants are warranted. PMID:22549291

  12. The MORPH-R web server and software tool for predicting missing genes in biological pathways.

    PubMed

    Amar, David; Frades, Itziar; Diels, Tim; Zaltzman, David; Ghatan, Netanel; Hedley, Pete E; Alexandersson, Erik; Tzfadia, Oren; Shamir, Ron

    2015-09-01

    A biological pathway is the set of molecular entities involved in a given biological process and the interrelations among them. Even though biological pathways have been studied extensively, discovering missing genes in pathways remains a fundamental challenge. Here, we present an easy-to-use tool that allows users to run MORPH (MOdule-guided Ranking of candidate PatHway genes), an algorithm for revealing missing genes in biological pathways, and demonstrate its capabilities. MORPH supports the analysis in tomato, Arabidopsis and the two new species: rice and the newly sequenced potato genome. The new tool, called MORPH-R, is available both as a web server (at http://bioinformatics.psb.ugent.be/webtools/morph/) and as standalone software that can be used locally. In the standalone version, the user can apply the tool to new organisms using any proprietary and public data sources.

  13. Impact of microRNA regulation on variation in human gene expression

    PubMed Central

    Lu, Jian; Clark, Andrew G.

    2012-01-01

    MicroRNAs (miRNAs) are endogenously expressed small RNAs that regulate expression of mRNAs at the post-transcriptional level. The consequence of miRNA regulation is hypothesized to reduce the expression variation of target genes. However, it is possible that mutations in miRNAs and target sites cause rewiring of the miRNA regulatory networks resulting in increased variation in gene expression. By examining variation in gene expression patterns in human populations and between human and other primate species, we find that miRNAs have stabilized expression of a small number of target genes during primate evolution. Compared with genes not regulated by miRNAs, however, genes regulated by miRNAs overall have higher expression variation at the population level, and they display greater variation in expression among human ethnic groups or between human and other primate species. By integrating expression data with genotypes determined in the HapMap 3 and the 1000 Genomes Projects, we found that expression variation in miRNAs, genetic variants in miRNA loci, and mutations in miRNA target sites are important sources of elevated expression variation of miRNA target genes. A reasonable case can be made that natural selection is driving this pattern of variation. PMID:22456605

  14. Enhancing Automatic Biological Pathway Generation with GO-based Gene Similarity

    SciTech Connect

    Sanfilippo, Antonio P.; Baddeley, Robert L.; Beagley, Nathaniel; Riensche, Roderick M.; Gopalan, Banu

    2009-08-03

    One of the greatest challenges in today’s analysis of microarray gene expression data is to identify pathways across regulated genes that underlie structural and functional changes of living cells in specific pathologies. Most current approaches to pathway generation are based on a reverse engineering approach in which pathway plausibility is solely induced from observed pathway data. These approaches tend to lack in generality as they are too dependent on the pathway observables from which they are induced. By contrast, alternative approaches that rely on prior biological knowledge may err in the opposite direction as the prior knowledge is usually not sufficiently tuned to the pathology of focus. In this paper, we present a novel pathway generation approach which combines insights from the reverse engineering and knowledge-based approaches to increase the biological plausibility and specificity of induced regulatory networks.

  15. The Relationship between Gene Network Structure and Expression Variation among Individuals and Species

    PubMed Central

    Sears, Karen E.; Maier, Jennifer A.; Rivas-Astroza, Marcelo; Poe, Rachel; Zhong, Sheng; Kosog, Kari; Marcot, Jonathan D.; Behringer, Richard R.; Rasweiler, John J.; Rapti, Zoi

    2015-01-01

    Abstract Variation among individuals is a prerequisite of evolution by natural selection. As such, identifying the origins of variation is a fundamental goal of biology. We investigated the link between gene interactions and variation in gene expression among individuals and species using the mammalian limb as a model system. We first built interaction networks for key genes regulating early (outgrowth; E9.5–11) and late (expansion and elongation; E11-13) limb development in mouse. This resulted in an Early (ESN) and Late (LSN) Stage Network. Computational perturbations of these networks suggest that the ESN is more robust. We then quantified levels of the same key genes among mouse individuals and found that they vary less at earlier limb stages and that variation in gene expression is heritable. Finally, we quantified variation in gene expression levels among four mammals with divergent limbs (bat, opossum, mouse and pig) and found that levels vary less among species at earlier limb stages. We also found that variation in gene expression levels among individuals and species are correlated for earlier and later limb development. In conclusion, results are consistent with the robustness of the ESN buffering among-individual variation in gene expression levels early in mammalian limb development, and constraining the evolution of early limb development among mammalian species. PMID:26317994

  16. Pathway-Informed Classification System (PICS) for Cancer Analysis Using Gene Expression Data

    PubMed Central

    Young, Michael R; Craft, David L

    2016-01-01

    We introduce Pathway-Informed Classification System (PICS) for classifying cancers based on tumor sample gene expression levels. PICS is a computational method capable of expeditiously elucidating both known and novel biological pathway involvement specific to various cancers and uses that learned pathway information to separate patients into distinct classes. The method clearly separates a pan-cancer dataset by tissue of origin and also sub-classifies individual cancer datasets into distinct survival classes. Gene expression values are collapsed into pathway scores that reveal which biological activities are most useful for clustering cancer cohorts into subtypes. Variants of the method allow it to be used on datasets that do and do not contain noncancerous samples. Activity levels of all types of pathways, broadly grouped into metabolic, cellular processes and signaling, and immune system, are useful for separating the pan-cancer cohort. In the clustering of specific cancer types, certain pathway types become more valuable depending on the site being studied. For lung cancer, signaling pathways dominate; for pancreatic cancer, signaling and metabolic pathways dominate; and for melanoma, immune system pathways are the most useful. This work suggests the utility of pathway-level genomic analysis and points in the direction of using pathway classification for predicting the efficacy and side effects of drugs and radiation. PMID:27486299

  17. Integrative Analysis of Metabolomic, Proteomic and Genomic Data to Reveal Functional Pathways and Candidate Genes for Drip Loss in Pigs

    PubMed Central

    Welzenbach, Julia; Neuhoff, Christiane; Heidt, Hanna; Cinar, Mehmet Ulas; Looft, Christian; Schellander, Karl; Tholen, Ernst; Große-Brinkhaus, Christine

    2016-01-01

    The aim of this study was to integrate multi omics data to characterize underlying functional pathways and candidate genes for drip loss in pigs. The consideration of different omics levels allows elucidating the black box of phenotype expression. Metabolite and protein profiling was applied in Musculus longissimus dorsi samples of 97 Duroc × Pietrain pigs. In total, 126 and 35 annotated metabolites and proteins were quantified, respectively. In addition, all animals were genotyped with the porcine 60 k Illumina beadchip. An enrichment analysis resulted in 10 pathways, amongst others, sphingolipid metabolism and glycolysis/gluconeogenesis, with significant influence on drip loss. Drip loss and 22 metabolic components were analyzed as intermediate phenotypes within a genome-wide association study (GWAS). We detected significantly associated genetic markers and candidate genes for drip loss and for most of the metabolic components. On chromosome 18, a region with promising candidate genes was identified based on SNPs associated with drip loss, the protein “phosphoglycerate mutase 2” and the metabolite glycine. We hypothesize that association studies based on intermediate phenotypes are able to provide comprehensive insights in the genetic variation of genes directly involved in the metabolism of performance traits. In this way, the analyses contribute to identify reliable candidate genes. PMID:27589727

  18. Genome-Wide Prediction of Metabolic Enzymes, Pathways, and Gene Clusters in Plants1[OPEN

    PubMed Central

    Zhang, Peifen; Kim, Taehyong; Banf, Michael; Chavali, Arvind K.; Nilo-Poyanco, Ricardo; Bernard, Thomas

    2017-01-01

    Plant metabolism underpins many traits of ecological and agronomic importance. Plants produce numerous compounds to cope with their environments but the biosynthetic pathways for most of these compounds have not yet been elucidated. To engineer and improve metabolic traits, we need comprehensive and accurate knowledge of the organization and regulation of plant metabolism at the genome scale. Here, we present a computational pipeline to identify metabolic enzymes, pathways, and gene clusters from a sequenced genome. Using this pipeline, we generated metabolic pathway databases for 22 species and identified metabolic gene clusters from 18 species. This unified resource can be used to conduct a wide array of comparative studies of plant metabolism. Using the resource, we discovered a widespread occurrence of metabolic gene clusters in plants: 11,969 clusters from 18 species. The prevalence of metabolic gene clusters offers an intriguing possibility of an untapped source for uncovering new metabolite biosynthesis pathways. For example, more than 1,700 clusters contain enzymes that could generate a specialized metabolite scaffold (signature enzymes) and enzymes that modify the scaffold (tailoring enzymes). In four species with sufficient gene expression data, we identified 43 highly coexpressed clusters that contain signature and tailoring enzymes, of which eight were characterized previously to be functional pathways. Finally, we identified patterns of genome organization that implicate local gene duplication and, to a lesser extent, single gene transposition as having played roles in the evolution of plant metabolic gene clusters. PMID:28228535

  19. Variation in the PTH gene, hip fracture, and femoral neck geometry in elderly women.

    PubMed

    Tenne, M; McGuigan, F E; Ahlborg, H; Gerdhem, P; Akesson, K

    2010-05-01

    Parathyroid hormone (PTH) is a principal regulator of calcium homeostasis. Previously, we studied single-nucleotide polymorphisms present in the major genes in the PTH pathway (PTH, PTHrP, PTHR1, PTHR2) in relation to bone mineral density (BMD) and fracture incidence. We found that haplotypes of the PTH gene were associated with fracture risk independent of BMD. In the present study, we evaluated the relationship between PTH haplotypes and femoral neck bone size. Hip structure analysis and BMD of the femoral neck was assessed by DXA in elderly women from the Malmö Osteoporosis Prospective Risk Assessment study. Data on hip fracture, sustained as a result of low trauma, after the age of 45 years were also analyzed. Haplotypes derived from six polymorphisms in the PTH locus were analyzed in 750 women. Carriers of haplotype 9 had lower values for hip geometry parameters cross-sectional moment of inertia (P = 0.029), femoral neck width (P = 0.049), and section modulous (P = 0.06), suggestive of increased fracture risk at the hip. However, this did not translate into an increased incidence of hip fracture in the studied population. Women who suffered a hip fracture compared to those who had not had longer hip axis length (HAL) (P < 0.001). HAL was not significantly different among haplotypes. Polymorphisms in the PTH gene are associated with differences in aspects of femoral neck geometry in elderly women; however, the major predictor of hip fracture in our population was HAL, to which PTH gene variation does not contribute significantly.

  20. Inflammatory pathway genes associated with inter-individual variability in the trajectories of morning and evening fatigue in patients receiving chemotherapy.

    PubMed

    Wright, Fay; Hammer, Marilyn; Paul, Steven M; Aouizerat, Bradley E; Kober, Kord M; Conley, Yvette P; Cooper, Bruce A; Dunn, Laura B; Levine, Jon D; DEramo Melkus, Gail; Miaskowski, Christine

    2017-03-01

    Fatigue, a highly prevalent and distressing symptom during chemotherapy (CTX), demonstrates diurnal and interindividual variability in severity. Little is known about the associations between variations in genes involved in inflammatory processes and morning and evening fatigue severity during CTX. The purposes of this study, in a sample of oncology patients (N=543) with breast, gastrointestinal (GI), gynecological (GYN), or lung cancer who received two cycles of CTX, were to determine whether variations in genes involved in inflammatory processes were associated with inter-individual variability in initial levels as well as in the trajectories of morning and evening fatigue. Patients completed the Lee Fatigue Scale to determine morning and evening fatigue severity a total of six times over two cycles of CTX. Using a whole exome array, 309 single nucleotide polymorphisms SNPs among the 64 candidate genes that passed all quality control filters were evaluated using hierarchical linear modeling (HLM). Based on the results of the HLM analyses, the final SNPs were evaluated for their potential impact on protein function using two bioinformational tools. The following inflammatory pathways were represented: chemokines (3 genes); cytokines (12 genes); inflammasome (11 genes); Janus kinase/signal transducers and activators of transcription (JAK/STAT, 10 genes); mitogen-activated protein kinase/jun amino-terminal kinases (MAPK/JNK, 3 genes); nuclear factor-kappa beta (NFkB, 18 genes); and NFkB and MAP/JNK (7 genes). After controlling for self-reported and genomic estimates of race and ethnicity, polymorphisms in six genes from the cytokine (2 genes); inflammasome (2 genes); and NFkB (2 genes) pathways were associated with both morning and evening fatigue. Polymorphisms in six genes from the inflammasome (1 gene); JAK/STAT (1 gene); and NFkB (4 genes) pathways were associated with only morning fatigue. Polymorphisms in three genes from the inflammasome (2 genes) and the NFk

  1. Molecular variation and evolution of the tyrosine kinase domains of insulin receptor IRa and IRb genes in Cyprinidae.

    PubMed

    Kong, XiangHui; Wang, XuZhen; He, ShunPing

    2011-07-01

    The insulin receptor (IR) gene plays an important role in regulating cell growth, differentiation and development. In the present study, DNA sequences of insulin receptor genes, IRa and IRb, were amplified and sequenced from 37 representative species of the Cyprinidae and from five outgroup species from non-cyprinid Cypriniformes. Based on coding sequences (CDS) of tyrosine kinase regions of IRa and IRb, molecular evolution and phylogenetic relationships were analyzed to better understand the characteristics of IR gene divergence in the family Cyprinidae. IRa and IRb were clustered into one lineage in the gene tree of the IR gene family, reconstructed using the unweighted pair group method with arithmetic mean (UPGMA). IRa and IRb have evolved into distinct genes after IR gene duplication in Cyprinidae. For each gene, molecular evolution analyses showed that there was no significant difference among different groups in the reconstructed maximum parsimony (MP) tree of Cyprinidae; IRa and IRb have been subjected to similar evolutionary pressure among different lineages. Although the amino acid sequences of IRa and IRb tyrosine kinase regions were highly conserved, our analyses showed that there were clear sequence variations between the tyrosine kinase regions of IRa and IRb proteins. This indicates that IRa and IRb proteins might play different roles in the insulin signaling pathway.

  2. Detection of additional genes of the patulin biosynthetic pathway in Penicillium griseofulvum

    USDA-ARS?s Scientific Manuscript database

    Genes in the patulin biosynthetic pathway are likely to be arranged in a cluster as has been found for biosynthetic pathways of other mycotoxins. The mycotoxin patulin, common in apples and apple juice, is most often associated with Penicillium expansum. However, of 15 fungal species capable of sy...

  3. Discovering relationships between nuclear receptor signaling pathways, genes, and tissues in Transcriptomine.

    PubMed

    Becnel, Lauren B; Ochsner, Scott A; Darlington, Yolanda F; McOwiti, Apollo; Kankanamge, Wasula H; Dehart, Michael; Naumov, Alexey; McKenna, Neil J

    2017-04-25

    We previously developed a web tool, Transcriptomine, to explore expression profiling data sets involving small-molecule or genetic manipulations of nuclear receptor signaling pathways. We describe advances in biocuration, query interface design, and data visualization that enhance the discovery of uncharacterized biology in these pathways using this tool. Transcriptomine currently contains about 45 million data points encompassing more than 2000 experiments in a reference library of nearly 550 data sets retrieved from public archives and systematically curated. To make the underlying data points more accessible to bench biologists, we classified experimental small molecules and gene manipulations into signaling pathways and experimental tissues and cell lines into physiological systems and organs. Incorporation of these mappings into Transcriptomine enables the user to readily evaluate tissue-specific regulation of gene expression by nuclear receptor signaling pathways. Data points from animal and cell model experiments and from clinical data sets elucidate the roles of nuclear receptor pathways in gene expression events accompanying various normal and pathological cellular processes. In addition, data sets targeting non-nuclear receptor signaling pathways highlight transcriptional cross-talk between nuclear receptors and other signaling pathways. We demonstrate with specific examples how data points that exist in isolation in individual data sets validate each other when connected and made accessible to the user in a single interface. In summary, Transcriptomine allows bench biologists to routinely develop research hypotheses, validate experimental data, or model relationships between signaling pathways, genes, and tissues. Copyright © 2017, American Association for the Advancement of Science.

  4. Distribution and variation of NV genes in fish rhabdoviruses.

    PubMed

    Kurath, G; Higman, K H; Björklund, H V

    1997-01-01

    The fish rhabdovirus infectious haematopoietic necrosis virus (IHNV) contains a non-virion (NV) gene between the glycoprotein (G) and polymerase (L) genes on its RNA genome. The present study investigated three other fish rhabdovirus genomes and found that the NV gene of hirame rhabdovirus is closely related to the NV of IHNV, whereas the viral haemorrhagic septicemia NV gene showed evidence of significant divergence. Most importantly, spring viraemia of carp virus, the only vesiculovirus-like fish rhabdovirus examined, did not have an NV gene at its genomic RNA G-L junction. These results suggest that the presence of an NV gene is characteristic of the unassigned fish rhabdovirus subgroup previously classified as lyssaviruses, and that the NV gene is not essential for replication in fish cells per se, since it is absent in a vesiculovirus-like fish rhabdovirus.

  5. Distribution and variation of NV genes in fish rhabdoviruses

    USGS Publications Warehouse

    Kurath, G.; Higman, K.H.; Bjorklund, H.V.

    1997-01-01

    The fish rhabdovirus infectious haematopoietic necrosis virus (IHNV) contains a non-virion (NV) gene between the glycoprotein (G) and polymerase (L) genes on its RNA genome. The present study investigated three other fish rhabdovirus genomes and found that the NV gene of hirame rhabdovirus is closely related to the NV of IHNV, whereas the viral haemorrhagic septicemia NV gene showed evidence of significant divergence. Most importantly, spring viraemia of carp virus, the only vesiculovirus-like fish rhabdovirus examined, did not have an NV gene at its genomic RNA G-L junction. These results suggest that the presence of an NV gene is characteristic of the unassigned fish rhabdovirus subgroup previously classified as lyssaviruses, and that the NV gene is not essential for replication in fish cells per se, since it is absent in a vesiculovirus-like fish rhabdovirus.

  6. Rice Xa21 primed genes and pathways that are critical for combating bacterial blight infection.

    PubMed

    Peng, Hai; Chen, Zheng; Fang, Zhiwei; Zhou, Junfei; Xia, Zhihui; Gao, Lifen; Chen, Lihong; Li, Lili; Li, Tiantian; Zhai, Wenxue; Zhang, Weixiong

    2015-07-17

    Rice bacterial blight (BB) is a devastating rice disease. The Xa21 gene confers a broad and persistent resistance against BB. We introduced Xa21 into Oryza sativa L ssp indica (rice 9311), through multi-generation backcrossing, and generated a nearly isogenic, blight-resistant 9311/Xa21 rice. Using next-generation sequencing, we profiled the transcriptomes of both varieties before and within four days after infection of bacterium Xanthomonas oryzae pv. oryzae. The identified differentially expressed (DE) genes and signaling pathways revealed insights into the functions of Xa21. Surprisingly, before infection 1,889 genes on 135 of the 316 signaling pathways were DE between the 9311/Xa21 and 9311 plants. These Xa21-mediated basal pathways included mainly those related to the basic material and energy metabolisms and many related to phytohormones such as cytokinin, suggesting that Xa21 triggered redistribution of energy, phytohormones and resources among essential cellular activities before invasion. Counter-intuitively, after infection, the DE genes between the two plants were only one third of that before the infection; other than a few stress-related pathways, the affected pathways after infection constituted a small subset of the Xa21-mediated basal pathways. These results suggested that Xa21 primed critically important genes and signaling pathways, enhancing its resistance against bacterial infection.

  7. Framing Ethnic Variations in Alcohol Outcomes from Biological Pathways to Neighborhood Context

    PubMed Central

    Chartier, Karen G.; Scott, Denise M.; Wall, Tamara L.; Covault, Jonathan; Karriker-Jaffe, Katherine J.; Mills, Britain A.; Luczak, Susan E.; Caetano, Raul; Arroyo, Judith A.

    2013-01-01

    Health disparities research seeks to eliminate disproportionate negative health outcomes experienced in some racial/ethnic minority groups. This brief review presents findings on factors associated with drinking and alcohol-related problems in racial/ethnic groups. Those discussed are: 1) biological pathways to alcohol problems, 2) gene by stress interactions, 3) neighborhood disadvantage, stress, and access to alcohol, and 4) drinking cultures and contexts. These factors and their interrelationships are complex, requiring a multi-level perspective. The use of interdisciplinary teams and an epigenetic focus are suggested to move the research forward. The application of multi-level research to policy, prevention, and intervention programs may help prioritize combinations of the most promising intervention targets. PMID:24483624

  8. Framing ethnic variations in alcohol outcomes from biological pathways to neighborhood context.

    PubMed

    Chartier, Karen G; Scott, Denise M; Wall, Tamara L; Covault, Jonathan; Karriker-Jaffe, Katherine J; Mills, Britain A; Luczak, Susan E; Caetano, Raul; Arroyo, Judith A

    2014-03-01

    Health disparities research seeks to eliminate disproportionate negative health outcomes experienced in some racial/ethnic minority groups. This brief review presents findings on factors associated with drinking and alcohol-related problems in racial/ethnic groups. Those discussed are as follows: (i) biological pathways to alcohol problems, (ii) gene × stress interactions, (iii) neighborhood disadvantage, stress, and access to alcohol, and (iv) drinking cultures and contexts. These factors and their interrelationships are complex, requiring a multilevel perspective. The use of interdisciplinary teams and an epigenetic focus are suggested to move the research forward. The application of multilevel research to policy, prevention, and intervention programs may help prioritize combinations of the most promising intervention targets. Copyright © 2014 by the Research Society on Alcoholism.

  9. Along signal paths: an empirical gene set approach exploiting pathway topology

    PubMed Central

    Martini, Paolo; Sales, Gabriele; Massa, M. Sofia; Chiogna, Monica; Romualdi, Chiara

    2013-01-01

    Gene set analysis using biological pathways has become a widely used statistical approach for gene expression analysis. A biological pathway can be represented through a graph where genes and their interactions are, respectively, nodes and edges of the graph. From a biological point of view only some portions of a pathway are expected to be altered; however, few methods using pathway topology have been proposed and none of them tries to identify the signal paths, within a pathway, mostly involved in the biological problem. Here, we present a novel algorithm for pathway analysis clipper, that tries to fill in this gap. clipper implements a two-step empirical approach based on the exploitation of graph decomposition into a junction tree to reconstruct the most relevant signal path. In the first step clipper selects significant pathways according to statistical tests on the means and the concentration matrices of the graphs derived from pathway topologies. Then, it identifies within these pathways the signal paths having the greatest association with a specific phenotype. We test our approach on simulated and two real expression datasets. Our results demonstrate the efficacy of clipper in the identification of signal transduction paths totally coherent with the biological problem. PMID:23002139

  10. Association of Genes, Pathways, and Haplogroups of the Mitochondrial Genome with the Risk of Colorectal Cancer: The Multiethnic Cohort.

    PubMed

    Li, Yuqing; Beckman, Kenneth B; Caberto, Christian; Kazma, Remi; Lum-Jones, Annette; Haiman, Christopher A; Le Marchand, Loïc; Stram, Daniel O; Saxena, Richa; Cheng, Iona

    2015-01-01

    The mitochondrial genome encodes for the synthesis of 13 proteins that are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may influence cancer development through changes in mitochondrial proteins, altering the OXPHOS process, and promoting the production of reactive oxidative species. To investigate the role of the OXPHOS pathway and mitochondrial genes in colorectal cancer (CRC) risk, we tested 185 mitochondrial SNPs (mtSNPs), located in 13 genes that comprise four complexes of the OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,453 colorectal cancer cases and 11,930 controls from the Multiethnic Cohort Study. Using the sequence kernel association test, we examined the collective set of 185 mtSNPs, as well as subsets of mtSNPs grouped by mitochondrial pathways, complexes, and genes, adjusting for age, sex, principal components of global ancestry, and self-reported maternal race/ethnicity. We also tested for haplogroup associations using unconditional logistic regression, adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with CRC risk (P = 0.04). In mtSNP-subset analysis, the NADH dehydrogenase 2 (MT-ND2) gene in Complex I was associated with CRC risk at a P-value of 0.001 (q = 0.015). In addition, haplogroup T was associated with CRC risk (OR = 1.66, 95% CI: 1.19-2.33, P = 0.003). No significant mitochondrial pathway and gene associations were observed in the remaining four racial/ethnic groups--African Americans, Asian Americans, Latinos, and Native Hawaiians. In summary, our findings suggest that variations in the mitochondrial genome and particularly in the MT-ND2 gene may play a role in CRC risk among European Americans, but not in other maternal racial/ethnic groups. Further replication is warranted and future studies

  11. Coregulation of terpenoid pathway genes and prediction of isoprene production in Bacillus subtilis using transcriptomics

    SciTech Connect

    Hess, Becky M.; Xue, Junfeng; Markillie, Lye Meng; Taylor, Ronald C.; Wiley, H. S.; Ahring, Birgitte K.; Linggi, Bryan E.

    2013-06-19

    The isoprenoid pathway converts pyruvate to isoprene and related isoprenoid compounds in plants and some bacteria. Currently, this pathway is of great interest because of the critical role that isoprenoids play in basic cellular processes as well as the industrial value of metabolites such as isoprene. Although the regulation of several pathway genes has been described, there is a paucity of information regarding the system level regulation and control of the pathway. To address this limitation, we examined Bacillus subtilis grown under multiple conditions and then determined the relationship between altered isoprene production and the pattern of gene expression. We found that terpenoid genes appeared to fall into two distinct subsets with opposing correlations with respect to the amount of isoprene produced. The group whose expression levels positively correlated with isoprene production included dxs, the gene responsible for the commitment step in the pathway, as well as ispD, and two genes that participate in the mevalonate pathway, yhfS and pksG. The subset of terpenoid genes that inversely correlated with isoprene production included ispH, ispF, hepS, uppS, ispE, and dxr. A genome wide partial least squares regression model was created to identify other genes or pathways that contribute to isoprene production. This analysis showed that a subset of 213 regulated genes was sufficient to create a predictive model of isoprene production under different conditions and showed correlations at the transcriptional level. We conclude that gene expression levels alone are sufficiently informative about the metabolic state of a cell that produces increased isoprene and can be used to build a model which accurately predicts production of this secondary metabolite across many simulated environmental conditions.

  12. Natural variation and evolution of the avirulence genes in Magnaporthe oryzae

    USDA-ARS?s Scientific Manuscript database

    The avirulence genes in Magnaporthe oryzae are important determinants for the corresponding resistance genes in rice. In the present study, we analyzed DNA sequence variation of the five avirulence genes, AVR-Pita1, AVR-Pik, AVR-Piz(t), AVR-Pia and AVR-Pii in field blast isolates in order to unders...

  13. Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population.

    PubMed

    Li, Wen-Qing; Hu, Nan; Hyland, Paula L; Gao, Ying; Wang, Zhao-Ming; Yu, Kai; Su, Hua; Wang, Chao-Yu; Wang, Le-Min; Chanock, Stephen J; Burdett, Laurie; Ding, Ti; Qiao, You-Lin; Fan, Jin-Hu; Wang, Yuan; Xu, Yi; Shi, Jian-Xin; Gu, Fangyi; Wheeler, William; Xiong, Xiao-Qin; Giffen, Carol; Tucker, Margaret A; Dawsey, Sanford M; Freedman, Neal D; Abnet, Christian C; Goldstein, Alisa M; Taylor, Philip R

    2013-07-01

    The DNA repair pathways help to maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal cancer and gastric cancer (GC) but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and GC, using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases and 2111 controls from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank-truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P = 6.37 × 10(-4)), but not with GC (P = 0.20). The most significant gene in ESCC was CHEK2 (P = 2.00 × 10(-6)) and in GC was CLK2 (P = 3.02 × 10(-4)). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE and BRCA1) or GC risk (MRE11A, RAD54L and POLE) (P < 0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.

  14. Analysis of the aspartic acid metabolic pathway using mutant genes.

    PubMed

    Azevedo, R A

    2002-01-01

    Amino acid metabolism is a fundamental process for plant growth and development. Although a considerable amount of information is available, little is known about the genetic control of enzymatic steps or regulation of several pathways. Much of the information about biochemical pathways has arisen from the use of mutants lacking key enzymes. Although mutants were largely used already in the 60's, by bacterial and fungal geneticists, it took plant research a long time to catch up. The advance in this area was rapid in the 80's, which was followed in the 90's by the development of techniques of plant transformation. In this review we present an overview of the aspartic acid metabolic pathway, the key regulatory enzymes and the mutants and transgenic plants produced for lysine and threonine metabolism. We also discuss and propose a new study of high-lysine mutants.

  15. Association and gene-gene interactions study of reelin signaling pathway related genes with autism in the Han Chinese population.

    PubMed

    Shen, Yidong; Xun, Guanglei; Guo, Hui; He, Yiqun; Ou, Jianjun; Dong, Huixi; Xia, Kun; Zhao, Jingping

    2016-04-01

    Autism is a neurodevelopmental disorder with unclear etiology. Reelin had been proposed to participate in the etiology of autism due to its important role in brain development. The goal of this study was to explore the association and gene-gene interactions of reelin signaling pathway related genes (RELN, VLDLR, LRP8, DAB1, FYN, and CDK5) with autism in Han Chinese population. Genotyping data of the six genes were obtained from a recent genome-wide association study performed in 430 autistic children who fulfilled the DSM-IV-TR criteria for autistic disorder, and 1,074 healthy controls. Single marker case-control association analysis and haplotype case-control association analysis were conducted after the data was screened. Multifactor dimensionality reduction (MDR) was applied to further test gene-gene interactions. Neither the single marker nor the haplotype association tests found any significant difference between the autistic group and the control group after permutation test of 1,000 rounds. The 4-locus MDR model (comprising rs6143734, rs1858782, rs634500, and rs1924267 which belong to RELN and DAB1) was determined to be the model with the highest cross-validation consistency (CVC) and testing balanced accuracy. The results indicate that an interaction between RELN and DAB1 may increase the risk of autism in the Han Chinese population. Furthermore, it can also be inferred that the involvement of RELN in the etiology of autism would occur through interaction with DAB1. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

  16. Genes that integrate multiple adipogenic signaling pathways in human mesenchymal stem cells.

    PubMed

    Ito, Tomoya; Tsuruta, So; Tomita, Koki; Kikuchi, Kunio; Yokoi, Takahide; Aizawa, Yasunori

    2011-06-17

    Adipogenesis is a well-characterized cell differentiation process. A large body of evidence has revealed the core transcription factors and signaling pathways that govern adipogenesis, but cross-talks between these cellular signals and its functional consequences have not been thoroughly investigated. We, therefore, sought to identify genes that are regulated by multiple signaling pathways during adipogenesis of human mesenchymal stem cells. Focusing on the early stage of adipogenesis, microarray analysis and quantitative RT-PCR identified 12 genes whose transcription levels were dramatically affected by the complete adipogenic induction cocktail but not by the cocktail's individual components. Expression kinetics of these genes indicate diverse mechanisms of transcriptional regulation during adipogenesis. Functional relationships between these genes and adipogenic differentiation were frequently unknown. This study thus provided novel adipogenic gene candidates that likely mediate communications among multiple signaling pathways within human mesenchymal stem cells.

  17. Genetic variation in the TLR and NF-κB genetic pathways and cervical and vulvar cancer risk: a population-based case-control study

    PubMed Central

    Bodelon, Clara; Madeleine, Margaret M.; Johnson, Lisa G.; Du, Qin; Galloway, Denise A.; Malkki, Mari; Petersdorf, Effie W.; Schwartz, Stephen M.

    2013-01-01

    Genital infection with the oncogenic human papillomavirus (HPV) is the necessary cause of cervical cancer and of a large fraction of vulvar cancers. The toll-like receptor (TLR) and the nuclear factor κB (NF-κB) signaling pathways have been implicated in inflammation, autoimmune disease and cancer, but whether common nucleotide variation in these pathways is associated with the risk of cervical and vulvar cancers has received little study. Using data from a population-based case-control study of cervical and vulvar cancers, we genotyped 205 single nucleotide polymorphisms (SNPs) in and around 32 candidate gene regions within these pathways. Gene-based analyses were employed to estimate the associations between individual gene regions and the risk of cervical and vulvar cancers. Odds ratio (OR) and 95% confidence intervals (CI) were calculated to assess the risk of cervical and vulvar cancers for each SNP. P-values were adjusted for multiple testing. A total of 876 cervical cancer cases, 517 vulvar cancer cases and 1,100 controls were included in the analysis. The TNF region was significantly associated with the risks of cervical cancer (gene-based P-value: 2.0×10−4) and vulvar cancer (gene-based P-value: 1.0×10−4). The rare allele (A) of SNP rs2239704 in the 5′ UTR of the LTA gene was significantly associated with increased risks of cervical cancer (OR=1.31, 95% CI: 1.15–1.50; adjusted P-value: 0.013) and vulvar cancer (OR=1.51, 95% CI: 1.30–1.75; adjusted P-value: 1.9×10−5). These findings add to the evidence of the importance of the immune system in the etiology of cervical and vulvar cancers. PMID:23824834

  18. Vitamin B(12) synthesis and salvage pathways were acquired by horizontal gene transfer to the Thermotogales.

    PubMed

    Swithers, Kristen S; Petrus, Amanda K; Secinaro, Michael A; Nesbø, Camilla L; Gogarten, J Peter; Noll, Kenneth M; Butzin, Nicholas C

    2012-01-01

    The availability of genome sequences of Thermotogales species from across the order allows an examination of the evolutionary origins of phenotypic characteristics in this lineage. Several studies have shown that the Thermotogales have acquired large numbers of genes from distantly related lineages, particularly Firmicutes and Archaea. Here, we report the finding that some Thermotogales acquired the ability to synthesize vitamin B(12) by acquiring the requisite genes from these distant lineages. Thermosipho species, uniquely among the Thermotogales, contain genes that encode the means to synthesize vitamin B(12) de novo from glutamate. These genes are split into two gene clusters: the corrinoid synthesis gene cluster, that is unique to the Thermosipho and the cobinamide salvage gene cluster. The corrinoid synthesis cluster was acquired from the Firmicutes lineage, whereas the salvage pathway is an amalgam of bacteria- and archaea-derived proteins. The cobinamide salvage gene cluster has a patchy distribution among Thermotogales species, and ancestral state reconstruction suggests that this pathway was present in the common Thermotogales ancestor. We show that Thermosipho africanus can grow in the absence of vitamin B(12), so its de novo pathway is functional. We detected vitamin B(12) in the extracts of T. africanus cells to verify the synthetic pathway. Genes in T. africanus with apparent B(12) riboswitches were found to be down-regulated in the presence of vitamin B(12) consistent with their roles in B(12) synthesis and cobinamide salvage.

  19. Vitamin B12 Synthesis and Salvage Pathways Were Acquired by Horizontal Gene Transfer to the Thermotogales

    PubMed Central

    Swithers, Kristen S.; Petrus, Amanda K.; Secinaro, Michael A.; Nesbø, Camilla L.; Gogarten, J. Peter; Noll, Kenneth M.; Butzin, Nicholas C.

    2012-01-01

    The availability of genome sequences of Thermotogales species from across the order allows an examination of the evolutionary origins of phenotypic characteristics in this lineage. Several studies have shown that the Thermotogales have acquired large numbers of genes from distantly related lineages, particularly Firmicutes and Archaea. Here, we report the finding that some Thermotogales acquired the ability to synthesize vitamin B12 by acquiring the requisite genes from these distant lineages. Thermosipho species, uniquely among the Thermotogales, contain genes that encode the means to synthesize vitamin B12 de novo from glutamate. These genes are split into two gene clusters: the corrinoid synthesis gene cluster, that is unique to the Thermosipho and the cobinamide salvage gene cluster. The corrinoid synthesis cluster was acquired from the Firmicutes lineage, whereas the salvage pathway is an amalgam of bacteria- and archaea-derived proteins. The cobinamide salvage gene cluster has a patchy distribution among Thermotogales species, and ancestral state reconstruction suggests that this pathway was present in the common Thermotogales ancestor. We show that Thermosipho africanus can grow in the absence of vitamin B12, so its de novo pathway is functional. We detected vitamin B12 in the extracts of T. africanus cells to verify the synthetic pathway. Genes in T. africanus with apparent B12 riboswitches were found to be down-regulated in the presence of vitamin B12 consistent with their roles in B12 synthesis and cobinamide salvage. PMID:22798452

  20. Eight genes are highly associated with BMD variation in postmenopausal Caucasian women.

    PubMed

    Reppe, Sjur; Refvem, Hilde; Gautvik, Vigdis T; Olstad, Ole K; Høvring, Per I; Reinholt, Finn P; Holden, Marit; Frigessi, Arnoldo; Jemtland, Rune; Gautvik, Kaare M

    2010-03-01

    Low bone mineral density (BMD) is an important risk factor for skeletal fractures which occur in about 40% of women >/=50 years in the western world. We describe the transcriptional changes in 84 trans-iliacal bone biopsies associated with BMD variations in postmenopausal females (50 to 86 years), aiming to identify genetic determinants of bone structure. The women were healthy or having a primary osteopenic or osteoporotic status with or without low energy fractures. The total cohort of 91 unrelated women representing a wide range of BMDs, were consecutively registered and submitted to global gene Affymetrix microarray expression analysis or histomorphometry. Among almost 23,000 expressed transcripts, a set represented by ACSL3 (acyl-CoA synthetase long-chain family member 3), NIPSNAP3B (nipsnap homolog 3B), DLEU2 (Deleted in lymphocytic leukemia, 2), C1ORF61 (Chromosome 1 open reading frame 61), DKK1 (Dickkopf homolog 1), SOST (Sclerostin), ABCA8, (ATP-binding cassette, sub-family A, member 8), and uncharacterized (AFFX-M27830-M-at), was significantly correlated to total hip BMD (5% false discovery rate) explaining 62% of the BMD variation expressed as T-score, 53% when adjusting for the influence of age (Z-score) and 44% when further adjusting for body mass index (BMI). Only SOST was previously associated to BMD, and the majority of the genes have previously not been associated with a bone phenotype. In molecular network analyses, SOST shows a strong, positive correlation with DKK1, both being members of the Wnt signaling pathway. The results provide novel insight in the underlying biology of bone metabolism and osteoporosis which is the ultimate consequence of low BMD.

  1. Identification of mechanosensitive genes during skeletal development: alteration of genes associated with cytoskeletal rearrangement and cell signalling pathways

    PubMed Central

    2014-01-01

    Background Mechanical stimulation is necessary for regulating correct formation of the skeleton. Here we test the hypothesis that mechanical stimulation of the embryonic skeletal system impacts expre