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Sample records for candidate genetic analysis

  1. A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder.

    PubMed

    Ashbrook, David G; Williams, Robert W; Lu, Lu; Hager, Reinmar

    2015-01-01

    Bipolar disorder (BD) is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS) have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium's bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis. We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1, and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG, and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG, and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG, and TNR influence intercellular signaling in the striatum. PMID:26190982

  2. A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder

    PubMed Central

    Ashbrook, David G.; Williams, Robert W.; Lu, Lu; Hager, Reinmar

    2015-01-01

    Bipolar disorder (BD) is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS) have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium's bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis. We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1, and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG, and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG, and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG, and TNR influence intercellular signaling in the striatum. PMID:26190982

  3. Genetic analysis of dyslexia candidate genes in the European cross-linguistic NeuroDys cohort.

    PubMed

    Becker, Jessica; Czamara, Darina; Scerri, Tom S; Ramus, Franck; Csépe, Valéria; Talcott, Joel B; Stein, John; Morris, Andrew; Ludwig, Kerstin U; Hoffmann, Per; Honbolygó, Ferenc; Tóth, Dénes; Fauchereau, Fabien; Bogliotti, Caroline; Iannuzzi, Stéphanie; Chaix, Yves; Valdois, Sylviane; Billard, Catherine; George, Florence; Soares-Boucaud, Isabelle; Gérard, Christophe-Loïc; van der Mark, Sanne; Schulz, Enrico; Vaessen, Anniek; Maurer, Urs; Lohvansuu, Kaisa; Lyytinen, Heikki; Zucchelli, Marco; Brandeis, Daniel; Blomert, Leo; Leppänen, Paavo H T; Bruder, Jennifer; Monaco, Anthony P; Müller-Myhsok, Bertram; Kere, Juha; Landerl, Karin; Nöthen, Markus M; Schulte-Körne, Gerd; Paracchini, Silvia; Peyrard-Janvid, Myriam; Schumacher, Johannes

    2014-05-01

    Dyslexia is one of the most common childhood disorders with a prevalence of around 5-10% in school-age children. Although an important genetic component is known to have a role in the aetiology of dyslexia, we are far from understanding the molecular mechanisms leading to the disorder. Several candidate genes have been implicated in dyslexia, including DYX1C1, DCDC2, KIAA0319, and the MRPL19/C2ORF3 locus, each with reports of both positive and no replications. We generated a European cross-linguistic sample of school-age children - the NeuroDys cohort - that includes more than 900 individuals with dyslexia, sampled with homogenous inclusion criteria across eight European countries, and a comparable number of controls. Here, we describe association analysis of the dyslexia candidate genes/locus in the NeuroDys cohort. We performed both case-control and quantitative association analyses of single markers and haplotypes previously reported to be dyslexia-associated. Although we observed association signals in samples from single countries, we did not find any marker or haplotype that was significantly associated with either case-control status or quantitative measurements of word-reading or spelling in the meta-analysis of all eight countries combined. Like in other neurocognitive disorders, our findings underline the need for larger sample sizes to validate possibly weak genetic effects. PMID:24022301

  4. A candidate gene approach for the genetic analysis of susceptibility to tuberculosis

    SciTech Connect

    Morgan, K.; Liu, J.; Boothroyd, L.

    1994-09-01

    Tuberculosis is the most frequent and severe human disease caused by mycobacteria. In the mouse a candidate gene for innate resistance to mycobacteria (Bcg) was recently isolated and termed Nramp. We used SSCA and DNA sequencing to identify mutations in the human homologue, NRAMP, in chromosome region 2q35 in order to test if NRAMP contributes to susceptibility to tuberculosis. We have identified 16 sequence variants in or near NRAMP and defined haplotypes segregating in multiplex tuberculosis families from Canada, Columbia and Hong Kong. We defined a recessive susceptibility model for linkage analysis with four liability classes which take into account clinical status, age, exposure, and BCG vaccination. Our preliminary results support a role of NRAMP in tuberculosis susceptibility in an epidemic situation. This research was supported by grants from the Medical Research Council of Canada and the Canadian Genetic Diseases Network.

  5. A Comprehensive Analysis of Common Genetic Variation Around Six Candidate Loci for Intrahepatic Cholestasis of Pregnancy

    PubMed Central

    Dixon, Peter H; Wadsworth, Christopher A; Chambers, Jennifer; Donnelly, Jennifer; Cooley, Sharon; Buckley, Rebecca; Mannino, Ramona; Jarvis, Sheba; Syngelaki, Argyro; Geenes, Victoria; Paul, Priyadarshini; Sothinathan, Meera; Kubitz, Ralf; Lammert, Frank; Tribe, Rachel M; Ch'ng, Chin Lye; Marschall, Hanns-Ulrich; Glantz, Anna; Khan, Shahid A; Nicolaides, Kypros; Whittaker, John; Geary, Michael; Williamson, Catherine

    2014-01-01

    OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component. Heterozygous mutations of canalicular transporters occur in a subset of ICP cases and a population susceptibility allele (p.444A) has been identified in ABCB11. We sought to expand our knowledge of the detailed genetic contribution to ICP by investigation of common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19). METHODS: ICP patients (n=563) of white western European origin and controls (n=642) were analyzed in a case–control design. Single-nucleotide polymorphism (SNP) markers (n=83) were selected from the HapMap data set (Tagger, Haploview 4.1 (build 22)). Genotyping was performed by allelic discrimination assay on a robotic platform. Following quality control, SNP data were analyzed by Armitage's trend test. RESULTS: Cochran–Armitage trend testing identified six SNPs in ABCB11 together with six SNPs in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected P value for trend testing ABCB11 was 5.81×10−4 (rs3815676) and for ABCB4 it was 4.6×10−7(rs2109505). Conditional analysis of the two clusters of association signals suggested a single signal in ABCB4 but evidence for two independent signals in ABCB11. To confirm these findings, a second study was performed in a further 227 cases, which confirmed and strengthened the original findings. CONCLUSIONS: Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of ICP susceptibility. PMID:24366234

  6. Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms

    PubMed Central

    Ogata, Toru; Shibamura, Hidenori; Tromp, Gerard; Sinha, Moumita; Goddard, Katrina A. B.; Sakalihasan, Natzi; Limet, Raymond; MacKean, Gerald L.; Arthur, Claudette; Sueda, Taijiro; Land, Susan; Kuivaniemi, Helena

    2005-01-01

    Background Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study with polymorphisms in the genes for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and structural extracellular matrix molecules in AAA. Our hypothesis was that genetic variations in one or more of these genes contribute to greater or lesser activity of these gene products, and thereby contribute to susceptibility for developing AAAs. Methods DNA samples from 812 unrelated white subject (AAA, n = 387; controls, n = 425) were genotyped for 14 polymorphisms in 13 different candidate genes: MMP1(nt−1607), MMP2(nt−955), MMP3(nt−1612), MMP9(nt−1562), MMP10(nt+180), MMP12(nt−82), MMP13(nt−77), TIMP1(nt+434), TIMP1(rs2070584), TIMP2(rs2009196), TIMP3(nt−1296), TGFB1(nt−509), ELN(nt+422), and COL3A1(nt+581). Odds ratios and P values adjusted for gender and country of origin using logistic regression and stratified by family history of AAA were calculated to test for association between genotype and disease status. Haplotype analysis was carried out for the two TIMP1 polymorphisms in male subjects. Results Analyses with one polymorphism per test without interactions showed an association with the two TIMP1 gene polymorphisms (nt+434, P = .0047; rs2070584, P = .015) in male subjects without a family history of AAA. The association remained significant when analyzing TIMP1 haplotypes (χ2 P = .014 and empirical P = .009). In addition, we found a significant interaction between the polymorphism and gender for MMP10 (P = .037) in cases without a family history of AAA, as well as between the polymorphism and country of origin for ELN (P = .0169) and TIMP3 (P = .0023) in cases with a family history of AAA. Conclusions These

  7. Genetic linkage analysis of 14 candidate gene loci in a family with autosomal dominant osteoarthritis without dysplasia.

    PubMed Central

    Meulenbelt, I; Bijkerk, C; Breedveld, F C; Slagboom, P E

    1997-01-01

    The role of various gene loci was investigated in a family in which familial osteoarthritis (FOA), with onset at an early age, is transmitted as an autosomal dominant mendelian trait. The absence of clinical and radiographic signs of dysplasia and calcium pyrophosphate deposition disease (CPDD) indicates that the basic disease process in this family is osteoarthritis (OA). Genetic linkage analysis of 14 candidate genes resulted in the exclusion of 10 important genes (COL2A1, COL9A1, COL9A2, COL11A1, COL11A2, COMP, the CPDD region, CRTL-1, CRTM, and MMP3). Other relevant genes were not informative in this family. The candidate loci previously identified in FOA and heritable skeletal disorders associated with OA are clearly not involved in the development of the primary FOA phenotype in the family investigated, indicating genetic heterogeneity. Images PMID:9429149

  8. Analysis of genetic variants of dyslexia candidate genes KIAA0319 and DCDC2 in Indian population.

    PubMed

    Venkatesh, Shyamala K; Siddaiah, Anand; Padakannaya, Prakash; Ramachandra, Nallur B

    2013-08-01

    Developmental dyslexia (DD) is a heritable, complex genetic disorder associated with impairment in reading and writing skills despite having normal intellectual ability and appropriate educational opportunities. Chromosome 6p23-21.3 at DYX2 locus has showed the most consistent evidence of linkage for DD and two susceptible genes KIAA0319 and DCDC2 for DD at DYX2 locus showed significant association. Specific candidate gene-association studies have identified variants, risk haplotypes and microsatellites of KIAA0319 and DCDC2 correlated with wide range of reading-related traits. In this study, we used a case-control approach for analyzing single-nucleotide polymorphisms (SNPs) in KIAA0319 and DCDC2. Our study demonstrated the association of DD with SNP rs4504469 of KIAA0319 and not with any SNPs of DCDC2. PMID:23677054

  9. Candidate Gene Analysis Suggests Untapped Genetic Complexity in Melanin-Based Pigmentation in Birds.

    PubMed

    Bourgeois, Yann X C; Bertrand, Joris A M; Delahaie, Boris; Cornuault, Josselin; Duval, Thomas; Milá, Borja; Thébaud, Christophe

    2016-07-01

    Studies on melanin-based color variation in a context of natural selection have provided a wealth of information on the link between phenotypic and genetic variation. Here, we evaluated associations between melanic plumage patterns and genetic polymorphism in the Réunion grey white-eye (Zosterops borbonicus), a species in which mutations on MC1R do not seem to play any role in explaining melanic variation. This species exhibits 5 plumage color variants that can be grouped into 3 color forms which occupy discrete geographic regions in the lowlands of Réunion, and a fourth high-elevation form which comprises 2 color morphs (grey and brown) and represents a true color polymorphism. We conducted a comprehensive survey of sequence variation in 96 individuals at a series of 7 candidate genes other than MC1R that have been previously shown to influence melanin-based color patterns in vertebrates, including genes that have rarely been studied in a wild bird species before: POMC, Agouti, TYR, TYRP1, DCT, Corin, and SLC24A5 Of these 7 genes, 2 (Corin and TYRP1) displayed an interesting shift in allele frequencies between lowland and highland forms and a departure from mutation-drift equilibrium consistent with balancing selection in the polymorphic highland form only. Sequence variation at Agouti, a gene frequently involved in melanin-based pigmentation patterning, was not associated with color forms or morphs. Thus, we suggest that functionally important changes in loci other than those classically studied are involved in the color polymorphism exhibited by the Réunion grey white-eye and possibly many other nonmodel species. PMID:26995742

  10. Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test.

    PubMed

    Young, E E; Bryant, C D; Lee, S E; Peng, X; Cook, B; Nair, H K; Dreher, K J; Zhang, X; Palmer, A A; Chung, J M; Mogil, J S; Chesler, E J; Lariviere, W R

    2016-07-01

    Mechanical sensitivity is commonly affected in chronic pain and other neurological disorders. To discover mechanisms of individual differences in punctate mechanosensation, we performed quantitative trait locus (QTL) mapping of the response to von Frey monofilament stimulation in BXD recombinant inbred (BXD) mice. Significant loci were detected on mouse chromosome (Chr) 5 and 15, indicating the location of underlying polymorphisms that cause heritable variation in von Frey response. Convergent evidence from public gene expression data implicates candidate genes within the loci: von Frey thresholds were strongly correlated with baseline expression of Cacna2d1, Ift27 and Csnk1e in multiple brain regions of BXD strains. Systemic gabapentin and PF-670462, which target the protein products of Cacna2d1 and Csnk1e, respectively, significantly increased von Frey thresholds in a genotype-dependent manner in progenitors and BXD strains. Real-time polymerase chain reaction confirmed differential expression of Cacna2d1 and Csnk1e in multiple brain regions in progenitors and showed differential expression of Cacna2d1 and Csnk1e in the dorsal root ganglia of the progenitors and BXD strains grouped by QTL genotype. Thus, linkage mapping, transcript covariance and pharmacological testing suggest that genetic variation affecting Cacna2d1 and Csnk1e may contribute to individual differences in von Frey filament response. This study implicates Cacna2d1 and Ift27 in basal mechanosensation in line with their previously suspected role in mechanical hypersensitivity. Csnk1e is implicated for von Frey response for the first time. Further investigation is warranted to identify the specific polymorphisms involved and assess the relevance of these findings to clinical conditions of disturbed mechanosensation. PMID:27231153

  11. Candidate genetic analysis of plasma high-density lipoprotein-cholesterol and severity of coronary atherosclerosis

    PubMed Central

    Chen, Suet Nee; Cilingiroglu, Mehmet; Todd, Josh; Lombardi, Raffaella; Willerson, James T; Gotto, Antonio M; Ballantyne, Christie M; Marian, AJ

    2009-01-01

    Background Plasma level of high-density lipoprotein-cholesterol (HDL-C), a heritable trait, is an important determinant of susceptibility to atherosclerosis. Non-synonymous and regulatory single nucleotide polymorphisms (SNPs) in genes implicated in HDL-C synthesis and metabolism are likely to influence plasma HDL-C, apolipoprotein A-I (apo A-I) levels and severity of coronary atherosclerosis. Methods We genotyped 784 unrelated Caucasian individuals from two sets of populations (Lipoprotein and Coronary Atherosclerosis Study- LCAS, N = 333 and TexGen, N = 451) for 94 SNPs in 42 candidate genes by 5' nuclease assays. We tested the distribution of the phenotypes by the Shapiro-Wilk normality test. We used Box-Cox regression to analyze associations of the non-normally distributed phenotypes (plasma HDL-C and apo A-I levels) with the genotypes. We included sex, age, body mass index (BMI), diabetes mellitus (DM), and cigarette smoking as covariates. We calculated the q values as indicators of the false positive discovery rate (FDR). Results Plasma HDL-C levels were associated with sex (higher in females), BMI (inversely), smoking (lower in smokers), DM (lower in those with DM) and SNPs in APOA5, APOC2, CETP, LPL and LIPC (each q ≤0.01). Likewise, plasma apo A-I levels, available in the LCAS subset, were associated with SNPs in CETP, APOA5, and APOC2 as well as with BMI, sex and age (all q values ≤0.03). The APOA5 variant S19W was also associated with minimal lumen diameter (MLD) of coronary atherosclerotic lesions, a quantitative index of severity of coronary atherosclerosis (q = 0.018); mean number of coronary artery occlusions (p = 0.034) at the baseline and progression of coronary atherosclerosis, as indicated by the loss of MLD. Conclusion Putatively functional variants of APOA2, APOA5, APOC2, CETP, LPL, LIPC and SOAT2 are independent genetic determinants of plasma HDL-C levels. The non-synonymous S19W SNP in APOA5 is also an independent determinant of plasma

  12. Genetic analysis reveals candidate species in the Scinax catharinae clade (Amphibia: Anura) from Central Brazil

    PubMed Central

    Nogueira, Lídia; Solé, Mirco; Siqueira, Sérgio; Affonso, Paulo Roberto Antunes de Mello; Strüssmann, Christine; Sampaio, Iracilda

    2016-01-01

    Abstract Scinax (Anura: Hylidae) is a species-rich genus of amphibians (113 spp.), divided into five species groups by morphological features. Cladistic analyses however revealed only two monophyletic clades in these groups: Scinax catharinae and Scinax ruber. Most species from the S. catharinae clade are found in Atlantic rainforest, except for Scinax canastrensis,S. centralis, S. luizotavioi, S. machadoi,S. pombali and S. skaios. In the present work, specimens of Scinax collected in Chapada dos Guimarães, central Brazil, were morphologically compatible with species from theS. catharinae group. On the other hand, genetic analysis based on mitochondrial (16S and 12S) and nuclear (rhodopsin) sequences revealed a nucleotide divergence of 6 to 20% between Scinax sp. and other congeners from the Brazilian savannah (Cerrado). Accordingly, Bayesian inference placed Scinax sp. in the S. catharinae clade with high support values. Hence, these findings strongly indicate the presence of a new species in the S. catharinae clade from the southwestern portion of the Brazilian savannah. To be properly validated as a novel species, detailed comparative morphological and bioacustic studies with other taxa from Brazil such asS. canastrensis, S. centralis, S. luizotavioi, S. machadoi, S. pombali and S. skaios are required. PMID:27007898

  13. Genetic analysis reveals candidate species in the Scinax catharinae clade (Amphibia: Anura) from Central Brazil.

    PubMed

    Nogueira, Lídia; Solé, Mirco; Siqueira, Sérgio; Affonso, Paulo Roberto Antunes de Mello; Strüssmann, Christine; Sampaio, Iracilda

    2016-03-01

    Scinax (Anura: Hylidae) is a species-rich genus of amphibians (113 spp.), divided into five species groups by morphological features. Cladistic analyses however revealed only two monophyletic clades in these groups: Scinax catharinae and Scinax ruber. Most species from the S. catharinae clade are found in Atlantic rainforest, except for Scinax canastrensis,S. centralis, S. luizotavioi, S. machadoi,S. pombali and S. skaios. In the present work, specimens of Scinax collected in Chapada dos Guimarães, central Brazil, were morphologically compatible with species from theS. catharinae group. On the other hand, genetic analysis based on mitochondrial (16S and 12S) and nuclear (rhodopsin) sequences revealed a nucleotide divergence of 6 to 20% between Scinax sp. and other congeners from the Brazilian savannah (Cerrado). Accordingly, Bayesian inference placed Scinax sp. in the S. catharinae clade with high support values. Hence, these findings strongly indicate the presence of a new species in the S. catharinae clade from the southwestern portion of the Brazilian savannah. To be properly validated as a novel species, detailed comparative morphological and bioacustic studies with other taxa from Brazil such asS. canastrensis, S. centralis, S. luizotavioi, S. machadoi, S. pombali and S. skaios are required. PMID:27007898

  14. Stress-sensitive neurosignalling in depression: an integrated network biology approach to candidate gene selection for genetic association analysis

    PubMed Central

    van Eekelen, J. Anke M.; Ellis, Justine A.; Pennell, Craig E.; Craig, Jeff; Saffery, Richard; Mattes, Eugen; Olsson, Craig A.

    2012-01-01

    Genetic risk for depressive disorders is poorly understood despite consistent suggestions of a high heritable component. Most genetic studies have focused on risk associated with single variants, a strategy which has so far only yielded small (often non-replicable) risks for depressive disorders. In this paper we argue that more substantial risks are likely to emerge from genetic variants acting in synergy within and across larger neurobiological systems (polygenic risk factors). We show how knowledge of major integrated neurobiological systems provides a robust basis for defining and testing theoretically defensible polygenic risk factors. We do this by describing the architecture of the overall stress response. Maladaptation via impaired stress responsiveness is central to the aetiology of depression and anxiety and provides a framework for a systems biology approach to candidate gene selection. We propose principles for identifying genes and gene networks within the neurosystems involved in the stress response and for defining polygenic risk factors based on the neurobiology of stress-related behaviour. We conclude that knowledge of the neurobiology of the stress response system is likely to play a central role in future efforts to improve genetic prediction of depression and related disorders. PMID:25478122

  15. Genetic Determinants of Facial Clefting: Analysis of 357 Candidate Genes Using Two National Cleft Studies from Scandinavia

    PubMed Central

    Gjessing, Håkon Kristian; Lie, Rolv Terje; Wilcox, Allen James; Weinberg, Clarice Ring; Christensen, Kaare; Boyles, Abee Lowman; Daack-Hirsch, Sandra; Trung, Truc Nguyen; Bille, Camilla; Lidral, Andrew Carl; Murray, Jeffrey Clark

    2009-01-01

    Background Facial clefts are common birth defects with a strong genetic component. To identify fetal genetic risk factors for clefting, 1536 SNPs in 357 candidate genes were genotyped in two population-based samples from Scandinavia (Norway: 562 case-parent and 592 control-parent triads; Denmark: 235 case-parent triads). Methodology/Principal Findings We used two complementary statistical methods, TRIMM and HAPLIN, to look for associations across these two national samples. TRIMM tests for association in each gene by using multi-SNP genotypes from case-parent triads directly without the need to infer haplotypes. HAPLIN on the other hand estimates the full haplotype distribution over a set of SNPs and estimates relative risks associated with each haplotype. For isolated cleft lip with or without cleft palate (I-CL/P), TRIMM and HAPLIN both identified significant associations with IRF6 and ADH1C in both populations, but only HAPLIN found an association with FGF12. For isolated cleft palate (I-CP), TRIMM found associations with ALX3, MKX, and PDGFC in both populations, but only the association with PDGFC was identified by HAPLIN. In addition, HAPLIN identified an association with ETV5 that was not detected by TRIMM. Conclusion/Significance Strong associations with seven genes were replicated in the Scandinavian samples and our approach effectively replicated the strongest previously known association in clefting—with IRF6. Based on two national cleft cohorts of similar ancestry, two robust statistical methods and a large panel of SNPs in the most promising cleft candidate genes to date, this study identified a previously unknown association with clefting for ADH1C and provides additional candidates and analytic approaches to advance the field. PMID:19401770

  16. Genomic convergence: identifying candidate genes for Parkinson's disease by combining serial analysis of gene expression and genetic linkage.

    PubMed

    Hauser, Michael A; Li, Yi-Ju; Takeuchi, Satoshi; Walters, Robert; Noureddine, Maher; Maready, Melinda; Darden, Tiffany; Hulette, Christine; Martin, Eden; Hauser, Elizabeth; Xu, Hong; Schmechel, Don; Stenger, Judith E; Dietrich, Fred; Vance, Jeffery

    2003-03-15

    We present a multifactorial, multistep approach called genomic convergence that combines gene expression with genomic linkage analysis to identify and prioritize candidate susceptibility genes for Parkinson's disease (PD). To initiate this process, we used serial analysis of gene expression (SAGE) to identify genes expressed in two normal substantia nigras (SN) and adjacent midbrain tissue. This identified over 3700 transcripts, including the three most abundant SAGE tags, which did not correspond to any known genes or ESTs. We developed high-throughput bioinformatics methods to map the genes corresponding to these tags and identified 402 SN genes that lay within five large genomic linkage regions, previously identified in 174 multiplex PD families. These genes represent excellent candidates for PD susceptibility alleles and further genomic convergence and analyses. PMID:12620972

  17. Genetics of serum concentration of IL-6 and TNFα in systemic lupus erythematosus and rheumatoid arthritis: a candidate gene analysis.

    PubMed

    Solus, Joseph F; Chung, Cecilia P; Oeser, Annette; Li, Chun; Rho, Young Hee; Bradley, Kevin M; Kawai, Vivian K; Smith, Jeffrey R; Stein, C Michael

    2015-08-01

    Elevated concentrations of inflammatory mediators are characteristic of autoimmune disease accompanied by chronic or recurrent inflammation. We examined the hypothesis that mediators of inflammation known to be elevated in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are associated with genetic polymorphism previously identified in studies of inflammatory disease. Serum interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) concentrations in patients with SLE (n = 117) or RA (n = 164) and in inflammatory disease-free control subjects (n = 172) were measured by multiplex ELISA. Candidate genes were chosen from studies of autoimmune and inflammatory disease. Genotypes were determined for 345 SNP markers in 75 genes. Association between serum analytes and single alleles was tested by linear regression. Polymorphisms in several genes were associated with IL-6 levels (including IL10, TYK2, and CD40L in SLE and DRB1, NOD2, and CSF1 in RA) or with TNFα levels (including TNFSF4 and CSF2 in SLE and PTPN2, DRB1, and NOD2 in RA). Some associations were shared between disease and control groups or between IL-6 and TNFα within a group. In conclusion, variation in genes implicated in disease pathology is associated with serum IL-6 or TNFα concentration. Some genetic associations are more apparent in healthy controls than in SLE or RA, suggesting dysregulation of the principal mediators of chronic inflammation in disease. Susceptibility genes may affect inflammatory response with variable effect on disease etiology. PMID:25652333

  18. Nogo Receptor 1 (RTN4R) as a Candidate Gene for Schizophrenia: Analysis Using Human and Mouse Genetic Approaches

    PubMed Central

    Hsu, Ruby; Woodroffe, Abigail; Lai, Wen-Sung; Cook, Melloni N.; Mukai, Jun; Dunning, Jonathan P.; Swanson, Douglas J.; Roos, J. Louw; Abecasis, Gonçalo R.; Karayiorgou, Maria; Gogos, Joseph A.

    2007-01-01

    Background NOGO Receptor 1 (RTN4R) regulates axonal growth, as well as axon regeneration after injury. The gene maps to the 22q11.2 schizophrenia susceptibility locus and is thus a strong functional and positional candidate gene. Methodology/Principal Findings We evaluate evidence for genetic association between common RTN4R polymorphisms and schizophrenia in a large family sample of Afrikaner origin and screen the exonic sequence of RTN4R for rare variants in an independent sample from the U.S. We also employ animal model studies to assay a panel of schizophrenia-related behavioral tasks in an Rtn4r-deficient mouse model. We found weak sex-specific evidence for association between common RTN4R polymorphisms and schizophrenia in the Afrikaner patients. In the U.S. sample, we identified two novel non-conservative RTN4R coding variants in two patients with schizophrenia that were absent in 600 control chromosomes. In our complementary mouse model studies, we identified a haploinsufficient effect of Rtn4r on locomotor activity, but normal performance in schizophrenia-related behavioral tasks. We also provide evidence that Rtn4r deficiency can modulate the long-term behavioral effects of transient postnatal N-methyl-D-aspartate (NMDA) receptor hypofunction. Conclusions Our results do not support a major role of RTN4R in susceptibility to schizophrenia or the cognitive and behavioral deficits observed in individuals with 22q11 microdeletions. However, they suggest that RTN4R may modulate the genetic risk or clinical expression of schizophrenia in a subset of patients and identify additional studies that will be necessary to clarify the role of RTN4R in psychiatric phenotypes. In addition, our results raise interesting issues about evaluating the significance of rare genetic variants in disease and their role in causation. PMID:18043741

  19. Genetic markers: Potential candidates for cardiovascular disease.

    PubMed

    Rather, Riyaz Ahmad; Dhawan, Veena

    2016-10-01

    The effective prevention of cardiovascular disease depends upon the ability to recognize the high-risk individuals at an early stage of the disease or long before the development of adverse events. Evolving technologies in the fields of proteomics, metabolomics, and genomics have played a significant role in the discovery of cardiovascular biomarkers, but so far these methods have achieved the modest success. Hence, there is a crucial need for more reliable, suitable, and lasting diagnostic and therapeutic markers to screen the disease well in time to start the clinical aid to the patients. Gene polymorphisms associated with the cardiovascular disease play a decisive role in the disease onset. Therefore, the genetic marker evaluation to classify high-risk patients from low-risk patients trends an effective approach to patient management and care. Currently, there are no genetic markers available for extensive adoption as risk factors for coronary vascular disease, yet, there are numerous promising, biologically acceptable candidates. Many of these gene biomarkers, alone or in combination, can play an essential role in the prediction of cardiovascular risk. The present review highlights some putative emerging genetic biomarkers that could facilitate more authentic and fast diagnosis of CVD. This review also briefly describes few technological approaches employed in the biomarker search. PMID:27416153

  20. Genetics of osteoporosis: searching for candidate genes for bone fragility.

    PubMed

    Rocha-Braz, Manuela G M; Ferraz-de-Souza, Bruno

    2016-08-01

    The pathogenesis of osteoporosis, a common disease with great morbidity and mortality, comprises environmental and genetic factors. As with other complex disorders, the genetic basis of osteoporosis has been difficult to identify. Nevertheless, several approaches have been undertaken in the past decades in order to identify candidate genes for bone fragility, including the study of rare monogenic syndromes with striking bone phenotypes (e.g. osteogenesis imperfecta and osteopetroses), the analysis of individuals or families with extreme osteoporotic phenotypes (e.g. idiopathic juvenile and pregnancy-related osteoporosis), and, chiefly, genome-wide association studies (GWAS) in large populations. Altogether, these efforts have greatly increased the understanding of molecular mechanisms behind bone remodelling, which has rapidly translated into the development of novel therapeutic strategies, exemplified by the tales of cathepsin K (CTSK) and sclerostin (SOST). Additional biological evidence of involvement in bone physiology still lacks for several candidate genes arisen from GWAS, opening an opportunity for the discovery of new mechanisms regulating bone strength, particularly with the advent of high-throughput genomic technologies. In this review, candidate genes for bone fragility will be presented in comprehensive tables and discussed with regard to how their association with osteoporosis emerged, highlighting key players such as LRP5, WNT1 and PLS3. Current limitations in our understanding of the genetic contribution to osteoporosis, such as yet unidentified genetic modifiers, may be overcome in the near future with better genotypic and phenotypic characterisation of large populations and the detailed study of candidate genes in informative individuals with marked phenotype. PMID:27533615

  1. Genetic regulation of cholesterol homeostasis: chromosomal organization of candidate genes.

    PubMed

    Welch, C L; Xia, Y R; Shechter, I; Farese, R; Mehrabian, M; Mehdizadeh, S; Warden, C H; Lusis, A J

    1996-07-01

    As part of an effort to dissect the genetic factors involved in cholesterol homeostasis in the mouse model, we report the mapping of 12 new candidate genes using linkage analysis. The genes include: cytoplasmic HMG-CoA synthase (Hmgcs 1, Chr 13), mitochondrial synthase (Hmgcs 2, Chr 3), a synthase-related sequence (Hmgcs 1-rs, Chr 12), mevalonate kinase (Mvk, Chr 5), farnesyl diphosphate synthase (Fdps, Chr 3), squalene synthase (Fdft 1, Chr 14), acyl-CoA:cholesterol acyltransferase (Acact, Chr 1), sterol regulatory element binding protein-1 (Srebf1, Chr 8) and -2 (Srebf2, Chr 15), apolipoprotein A-I regulatory protein (Tcfcoup2, Chr 7), low density receptor-related protein-related sequence (Lrp-rs, Chr 10), and Lrp-associated protein (Lrpap 1, Chr 5). In addition, the map positions for several lipoprotein receptor genes were refined. These genes include: low density lipoprotein receptor (Ldlr, Chr 9), very low density lipoprotein receptor (Vldlr, Chr 19), and glycoprotein 330 (Gp330, Chr 2). Some of these candidate genes are located within previously defined chromosomal regions (quantitative trait loci, QTLs) contributing to plasma lipoprotein levels, and Acact maps near a mouse mutation, ald, resulting in depletion of cholesteryl esters in the adrenals. The combined use of QTL and candidate gene mapping provides a powerful means of dissecting complex traits such as cholesterol homeostasis. PMID:8827514

  2. Genetic influences on smoking: candidate genes.

    PubMed Central

    Rossing, M A

    1998-01-01

    Twin studies consistently indicate important genetic influences on multiple aspects of smoking behavior, including both initiation and cessation; however, knowledge regarding the role of specific genes is extremely limited. Habit-forming actions of nicotine appear to be triggered primarily at nicotinic receptors on the cell bodies of dopaminergic neurons in the mesolimbic "reward" system of the brain, a region implicated in addiction to other substances including cocaine, opiates, and alcohol. Important aspects of the dopaminergic pathway include synthesis of dopamine in dopaminergic neurons, release of dopamine by presynaptic neurons, receptor activation of postsynaptic neurons, dopamine re-uptake by presynaptic neurons, and metabolism of released dopamine. Research examining the role of allelic variation in genes involved in these functions is being actively pursued with respect to addictive behavior as well as personality traits and psycho- and neuropathologic conditions and has implications for smoking research. In addition, genetic differences in nicotinic receptors or nicotine metabolism might reasonably be hypothesized to play a role in smoking addiction. A role of dopaminergic or other genes in smoking cessation is of particular potential importance, as research in this area may lead to the identification of subgroups of individuals for whom pharmacologic cessation aids may be most effective. PMID:9647893

  3. Discovering candidate genes that regulate resin canal number in Pinus taeda stems by integrating genetic analysis across environments, ages, and populations

    SciTech Connect

    Westbrook, JW; Walker, AR; Neves, LG; Munoz, P; Resende, MFR; Neale, DB; Wegrzyn, JL; Huber, DA; Kirst, M; Davis, JM; Peter, GF

    2014-09-30

    Genetically improving constitutive resin canal development in Pinus stems may enhance the capacity to synthesize terpenes for bark beetle resistance, chemical feedstocks, and biofuels. To discover genes that potentially regulate axial resin canal number (RCN), single nucleotide polymorphisms (SNPs) in 4027 genes were tested for association with RCN in two growth rings and three environments in a complex pedigree of 520 Pinus taeda individuals (CCLONES). The map locations of associated genes were compared with RCN quantitative trait loci (QTLs) in a (P.taedaxPinuselliottii)xP.elliottii pseudo-backcross of 345 full-sibs (BC1). Resin canal number was heritable (h(2)0.12-0.21) and positively genetically correlated with xylem growth (r(g)0.32-0.72) and oleoresin flow (r(g)0.15-0.51). Sixteen well-supported candidate regulators of RCN were discovered in CCLONES, including genes associated across sites and ages, unidirectionally associated with oleoresin flow and xylem growth, and mapped to RCN QTLs in BC1. Breeding is predicted to increase RCN 11% in one generation and could be accelerated with genomic selection at accuracies of 0.45-0.52 across environments. There is significant genetic variation for RCN in loblolly pine, which can be exploited in breeding for elevated terpene content.

  4. Discovering candidate genes that regulate resin canal number in Pinus taeda stems by integrating genetic analysis across environments, ages, and populations.

    PubMed

    Westbrook, Jared W; Walker, Alejandro R; Neves, Leandro G; Munoz, Patricio; Resende, Marcio F R; Neale, David B; Wegrzyn, Jill L; Huber, Dudley A; Kirst, Matias; Davis, John M; Peter, Gary F

    2015-01-01

    Genetically improving constitutive resin canal development in Pinus stems may enhance the capacity to synthesize terpenes for bark beetle resistance, chemical feedstocks, and biofuels. To discover genes that potentially regulate axial resin canal number (RCN), single nucleotide polymorphisms (SNPs) in 4027 genes were tested for association with RCN in two growth rings and three environments in a complex pedigree of 520 Pinus taeda individuals (CCLONES). The map locations of associated genes were compared with RCN quantitative trait loci (QTLs) in a (P. taeda × Pinus elliottii) × P. elliottii pseudo-backcross of 345 full-sibs (BC1). Resin canal number was heritable (h(2) ˜ 0.12-0.21) and positively genetically correlated with xylem growth (rg ˜ 0.32-0.72) and oleoresin flow (rg ˜ 0.15-0.51). Sixteen well-supported candidate regulators of RCN were discovered in CCLONES, including genes associated across sites and ages, unidirectionally associated with oleoresin flow and xylem growth, and mapped to RCN QTLs in BC1. Breeding is predicted to increase RCN 11% in one generation and could be accelerated with genomic selection at accuracies of 0.45-0.52 across environments. There is significant genetic variation for RCN in loblolly pine, which can be exploited in breeding for elevated terpene content. PMID:25266813

  5. The Genetics of Reading Disabilities: From Phenotypes to Candidate Genes

    PubMed Central

    Raskind, Wendy H.; Peter, Beate; Richards, Todd; Eckert, Mark M.; Berninger, Virginia W.

    2013-01-01

    This article provides an overview of (a) issues in definition and diagnosis of specific reading disabilities at the behavioral level that may occur in different constellations of developmental and phenotypic profiles (patterns); (b) rapidly expanding research on genetic heterogeneity and gene candidates for dyslexia and other reading disabilities; (c) emerging research on gene-brain relationships; and (d) current understanding of epigenetic mechanisms whereby environmental events may alter behavioral expression of genetic variations. A glossary of genetic terms (denoted by bold font) is provided for readers not familiar with the technical terms. PMID:23308072

  6. NOD congenic strain analysis of autoimmune diabetes reveals genetic complexity of the Idd18 locus and identifies Vav3 as a candidate gene

    PubMed Central

    Fraser, Heather I.; Dendrou, Calliope A.; Healy, Barry; Rainbow, Daniel B.; Howlett, Sarah; Smink, Luc J.; Gregory, Simon; Steward, Charles A.; Todd, John A.; Peterson, Laurence B.; Wicker, Linda S.

    2010-01-01

    We have used the public sequencing and annotation of the mouse genome to delimit the previously resolved type 1 diabetes (T1D) Idd18 interval to a region on chromosome 3 that includes the immunologically relevant candidate gene, Vav3. To test the candidacy of Vav3, we developed a novel congenic strain which enabled the resolution of Idd18 to a 604 kb interval, designated Idd18.1, which contains only two annotated genes: the complete sequence of Vav3, and the last exon of the gene encoding NETRIN G1, Ntng1. Targeted sequencing of Idd18.1 in the NOD mouse strain revealed that allelic variation between NOD and C57BL/6J (B6) occurs in non-coding regions with 138 single nucleotide polymorphisms (SNPs) concentrated in the introns between exons 20 and 27, and immediately after the 3′ UTR. We observed differential expression of VAV3 RNA transcripts in thymocytes when comparing congenic mouse strains with B6 or NOD alleles at Idd18.1. The T1D protection associated with B6 alleles of Idd18.1/Vav3 requires the presence of B6 protective alleles at Idd3, which are correlated with increased IL-2 production and regulatory T cell function. In the absence of B6 protective alleles at Idd3, we detected a second T1D protective B6 locus, Idd18.3, which is closely linked to, but distinct from, Idd18.1. Therefore, genetic mapping, sequencing, and gene expression evidence indicate that alteration of VAV3 expression is an etiological factor in the development of autoimmune beta-cell destruction in NOD mice. This study also demonstrates that a congenic strain mapping approach can isolate closely linked susceptibility genes. PMID:20363978

  7. Genetics of intracerebral hemorrhage: Insights from candidate gene approaches.

    PubMed

    Liu, Baoqiong; Zhang, Le; Yang, Qidong

    2012-01-01

    Intracerebral hemorrhage (ICH) is a heterogeneous disease with genetic factors playing an important role. Association studies on a wide range of candidate pathways suggest a weak but significant effect for several alleles with ICH risk. Among the most widely investigated genes are those involved in the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme), coagulation pathway (e.g., Factor XIII, Factor VII, platelet-activating factor acetylhydrolase, Factor V Leiden, and beta1-tubulin), lipid metabolism (e.g., apolipoproteins (Apo)E, Apo(a), ApoH), homocysteine metabolism (e.g., methylenetetrahydrofolate reductase), inflammation (e.g., interleukin-6 and tumor necrosis-alpha) and other candidate pathways. To identify the robustness of the above associations with ICH, a search of Pubmed (1988 through December 2011) was performed, with searches limited to English-language studies conducted among adult human subjects. This article presents a review of the examined literature on the genetics of ICH. PMID:22406772

  8. Global genetic analysis.

    PubMed

    Elahi, Elahe; Kumm, Jochen; Ronaghi, Mostafa

    2004-01-31

    The introduction of molecular markers in genetic analysis has revolutionized medicine. These molecular markers are genetic variations associated with a predisposition to common diseases and individual variations in drug responses. Identification and genotyping a vast number of genetic polymorphisms in large populations are increasingly important for disease gene identification, pharmacogenetics and population-based studies. Among variations being analyzed, single nucleotide polymorphisms seem to be most useful in large-scale genetic analysis. This review discusses approaches for genetic analysis, use of different markers, and emerging technologies for large-scale genetic analysis where millions of genotyping need to be performed. PMID:14761299

  9. A candidate multimodal functional genetic network for thermal adaptation

    PubMed Central

    Pathak, Rachana; Prajapati, Indira; Bankston, Shannon; Thompson, Aprylle; Usher, Jaytriece; Isokpehi, Raphael D.

    2014-01-01

    Vertebrate ectotherms such as reptiles provide ideal organisms for the study of adaptation to environmental thermal change. Comparative genomic and exomic studies can recover markers that diverge between warm and cold adapted lineages, but the genes that are functionally related to thermal adaptation may be difficult to identify. We here used a bioinformatics genome-mining approach to predict and identify functions for suitable candidate markers for thermal adaptation in the chicken. We first established a framework of candidate functions for such markers, and then compiled the literature on genes known to adapt to the thermal environment in different lineages of vertebrates. We then identified them in the genomes of human, chicken, and the lizard Anolis carolinensis, and established a functional genetic interaction network in the chicken. Surprisingly, markers initially identified from diverse lineages of vertebrates such as human and fish were all in close functional relationship with each other and more associated than expected by chance. This indicates that the general genetic functional network for thermoregulation and/or thermal adaptation to the environment might be regulated via similar evolutionarily conserved pathways in different vertebrate lineages. We were able to identify seven functions that were statistically overrepresented in this network, corresponding to four of our originally predicted functions plus three unpredicted functions. We describe this network as multimodal: central regulator genes with the function of relaying thermal signal (1), affect genes with different cellular functions, namely (2) lipoprotein metabolism, (3) membrane channels, (4) stress response, (5) response to oxidative stress, (6) muscle contraction and relaxation, and (7) vasodilation, vasoconstriction and regulation of blood pressure. This network constitutes a novel resource for the study of thermal adaptation in the closely related nonavian reptiles and other

  10. A candidate multimodal functional genetic network for thermal adaptation.

    PubMed

    Wollenberg Valero, Katharina C; Pathak, Rachana; Prajapati, Indira; Bankston, Shannon; Thompson, Aprylle; Usher, Jaytriece; Isokpehi, Raphael D

    2014-01-01

    Vertebrate ectotherms such as reptiles provide ideal organisms for the study of adaptation to environmental thermal change. Comparative genomic and exomic studies can recover markers that diverge between warm and cold adapted lineages, but the genes that are functionally related to thermal adaptation may be difficult to identify. We here used a bioinformatics genome-mining approach to predict and identify functions for suitable candidate markers for thermal adaptation in the chicken. We first established a framework of candidate functions for such markers, and then compiled the literature on genes known to adapt to the thermal environment in different lineages of vertebrates. We then identified them in the genomes of human, chicken, and the lizard Anolis carolinensis, and established a functional genetic interaction network in the chicken. Surprisingly, markers initially identified from diverse lineages of vertebrates such as human and fish were all in close functional relationship with each other and more associated than expected by chance. This indicates that the general genetic functional network for thermoregulation and/or thermal adaptation to the environment might be regulated via similar evolutionarily conserved pathways in different vertebrate lineages. We were able to identify seven functions that were statistically overrepresented in this network, corresponding to four of our originally predicted functions plus three unpredicted functions. We describe this network as multimodal: central regulator genes with the function of relaying thermal signal (1), affect genes with different cellular functions, namely (2) lipoprotein metabolism, (3) membrane channels, (4) stress response, (5) response to oxidative stress, (6) muscle contraction and relaxation, and (7) vasodilation, vasoconstriction and regulation of blood pressure. This network constitutes a novel resource for the study of thermal adaptation in the closely related nonavian reptiles and other

  11. Genetic similarity between cancers and comorbid Mendelian diseases identifies candidate driver genes

    PubMed Central

    Melamed, Rachel D.; Emmett, Kevin J.; Madubata, Chioma; Rzhetsky, Andrey; Rabadan, Raul

    2015-01-01

    Despite large-scale cancer genomics studies, key somatic mutations driving cancer, and their functional roles, remain elusive. Here we propose that analysis of comorbidities of Mendelian diseases with cancers provides a novel, systematic way to discover new cancer genes. If germline genetic variation in Mendelian loci predisposes bearers to common cancers, the same loci may harbor cancer-associated somatic variation. Compilations of clinical records spanning over 100 million patients provide an unprecedented opportunity to assess clinical associations between Mendelian diseases and cancers. We systematically compare these comorbidities against recurrent somatic mutations from more than five thousand patients across many cancers. Using multiple measures of genetic similarity, we show that a Mendelian disease and comorbid cancer indeed have genetic alterations of significant functional similarity. This result provides a basis to identify candidate drivers in cancers including melanoma and glioblastoma. Some Mendelian diseases demonstrate “pan-cancer” comorbidity and shared genetics across cancers. PMID:25926297

  12. Testing for genetic associations in a spina bifida population: analysis of the HOX gene family and human candidate gene regions implicated by mouse models of neural tube defects.

    PubMed

    Volcik, K A; Blanton, S H; Kruzel, M C; Townsend, I T; Tyerman, G H; Mier, R J; Northrup, H

    2002-07-01

    Neural tube defects (NTDs) are among the most common severely disabling birth defects in the United States, affecting approximately 1-2 of every 1,000 live births. The etiology of NTDs is multifactorial, involving the combined action of both genetic and environmental factors. HOX genes play a central role in establishing the initial body plan by providing positional information along the anterior-posterior body and limb axis and have been implicated in neural tube closure. There are many mouse models that exhibit both naturally occurring NTDs in various mouse strains as well as NTDs that have been created by "knocking out" various genes. A nonparametric linkage method, the transmission disequilibrium test (TDT), was utilized to test the HOX gene family and human equivalents of genes (when known) or the syntenic region in humans to those in mouse models which could play a role in the formation of NTDs. DNA from 459 spina bifida (SB) affected individuals and their parents was tested for linkage and association utilizing polymorphic markers from within or very close to the HOXA, HOXB, HOXC, and HOXD genes as well as from within the genes/gene regions of eight mouse models that exhibit NTDs. No significant findings were obtained for the tested markers. PMID:12116226

  13. Worldwide population genetic analysis and natural selection in the Plasmodium vivax Generative Cell Specific 1 (PvGCS1) as a transmission-blocking vaccine candidate.

    PubMed

    Mehrizi, Akram Abouie; Dodangeh, Fatemeh; Zakeri, Sedigheh; Djadid, Navid Dinparast

    2016-09-01

    GENERATIVE CELL SPECIFIC 1 (GCS1) is one of the Transmission Blocking Vaccine (TBV) candidate antigens, which is expressed on the surface of male gametocytes and gametes of Plasmodium species. Since antigenic diversity could inhibit the successful development of a malaria vaccine, it is crucial to determine the diversity of gcs1 gene in global malaria-endemic areas. Therefore, gene diversity and selection of gcs1 gene were analyzed in Iranian Plasmodium vivax isolates (n=52) and compared with the corresponding sequences from worldwide clinical P. vivax isolates available in PlasmoDB database. Totally 12 SNPs were detected in the pvgcs1 sequences as compared to Sal-1 sequence. Five out of 12 SNPs including three synonymous (T797C, G1559A, and G1667T) and two amino acid replacements (Y133S and Q634P) were detected in Iranian pvgcs1 sequences. According to four amino acid replacements (Y133S, N575S, Q634P and D637N) observed in all world PvGCS1 sequences, totally 5 PvGCS1 haplotypes were detected in the world, that three of them observed in Iranian isolates including the PvGCS-A (133S/634Q, 92.3%), PvGCS-B (133Y/634Q, 5.8%), and PvGCS-C (133S/634P, 1.9%). The overall nucleotide diversity (π) for all 52 sequences of Iranian pvgcs1 gene was 0.00018±0.00006, and the value of dN-dS (-0.00031) were negative, however, it was not statistically significant. In comparison with global isolates, Iranian and PNG pvgcs1 sequences had the lowest nucleotide and haplotype diversity, while the highest nucleotide and haplotype diversity was observed in China population. Moreover, epitope prediction in this antigen showed that all B-cell epitopes were located in conserved regions. However, Q634P (in one Iranian isolate) and D637N (observed in Thailand, China, Vietnam and North Korea) mutations are involved in predicted IURs. The obtained results in this study could be used in development of PvGCS1 based malaria vaccine. PMID:27180894

  14. Immunogenicity of Novel Mumps Vaccine Candidates Generated by Genetic Modification

    PubMed Central

    Xu, Pei; Chen, Zhenhai; Phan, Shannon; Pickar, Adrian

    2014-01-01

    Mumps is a highly contagious human disease, characterized by lateral or bilateral nonsuppurative swelling of the parotid glands and neurological complications that can result in aseptic meningitis or encephalitis. A mumps vaccination program implemented since the 1960s reduced mumps incidence by more than 99% and kept the mumps case numbers as low as hundreds of cases per year in the United States before 2006. However, a large mumps outbreak occurred in vaccinated populations in 2006 and again in 2009 in the United States, raising concerns about the efficacy of the vaccination program. Previously, we have shown that clinical isolate-based recombinant mumps viruses lacking expression of either the V protein (rMuVΔV) or the SH protein (rMuVΔSH) are attenuated in a neurovirulence test using newborn rat brains (P. Xu et al., Virology 417:126–136, 2011, http://dx.doi.org/10.1016/j.virol.2011.05.003; P. Xu et al., J. Virol. 86:1768–1776, 2012, http://dx.doi.org/10.1128/JVI.06019-11) and may be good candidates for vaccine development. In this study, we examined immunity induced by rMuVΔSH and rMuVΔV in mice. Furthermore, we generated recombinant mumps viruses lacking expression of both the V protein and the SH protein (rMuVΔSHΔV). Analysis of rMuVΔSHΔV indicated that it was stable in tissue culture cell lines. Importantly, rMuVΔSHΔV was immunogenic in mice, indicating that it is a promising candidate for mumps vaccine development. PMID:24352450

  15. Candidate Gene Analysis in Israeli Soldiers With Stress Fractures

    PubMed Central

    Yanovich, Ran; Friedman, Eitan; Milgrom, Roni; Oberman, Bernice; Freedman, Laurence; Moran, Daniel S.

    2012-01-01

    To investigate the association of polymorphisms within candidate genes which we hypothesized may contribute to stress fracture predisposition, a case-control, cross- sectional study design was employed. Genotyping 268 Single Nucleotide Polymorphisms- SNPs within 17 genes in 385 Israeli young male and female recruits (182 with and 203 without stress fractures). Twenty-five polymorphisms within 9 genes (NR3C1, ANKH, VDR, ROR2, CALCR, IL6, COL1A2, CBG, and LRP4) showed statistically significant differences (p < 0.05) in the distribution between stress fracture cases and non stress fracture controls. Seventeen genetic variants were associated with an increased stress fracture risk, and eight variants with a decreased stress fracture risk. None of the SNP associations remained significant after correcting for multiple comparisons (false discovery rate- FDR). Our findings suggest that genes may be involved in stress fracture pathogenesis. Specifically, the CALCR and the VDR genes are intriguing candidates. The putative involvement of these genes in stress fracture predisposition requires analysis of more cases and controls and sequencing the relevant genomic regions, in order to define the specific gene mutations. Key pointsUnderstanding the possible contribution of genetic variants to stress fracture pathogenesis.There is a paucity of data on the involvement of polymorphisms in specific genes in active military personnel/athletes which may contribute to stress fractures development.The results from the current study should facilitate a more comprehensive look at the genetic component of stress fractures. PMID:24149131

  16. Saccharomyces cerevisiae Genetics Predicts Candidate Therapeutic Genetic Interactions at the Mammalian Replication Fork

    PubMed Central

    van Pel, Derek M.; Stirling, Peter C.; Minaker, Sean W.; Sipahimalani, Payal; Hieter, Philip

    2013-01-01

    The concept of synthetic lethality has gained popularity as a rational guide for predicting chemotherapeutic targets based on negative genetic interactions between tumor-specific somatic mutations and a second-site target gene. One hallmark of most cancers that can be exploited by chemotherapies is chromosome instability (CIN). Because chromosome replication, maintenance, and segregation represent conserved and cell-essential processes, they can be modeled effectively in simpler eukaryotes such as Saccharomyces cerevisiae. Here we analyze and extend genetic networks of CIN cancer gene orthologs in yeast, focusing on essential genes. This identifies hub genes and processes that are candidate targets for synthetic lethal killing of cancer cells with defined somatic mutations. One hub process in these networks is DNA replication. A nonessential, fork-associated scaffold, CTF4, is among the most highly connected genes. As Ctf4 lacks enzymatic activity, potentially limiting its development as a therapeutic target, we exploited its function as a physical interaction hub to rationally predict synthetic lethal interactions between essential Ctf4-binding proteins and CIN cancer gene orthologs. We then validated a subset of predicted genetic interactions in a human colorectal cancer cell line, showing that siRNA-mediated knockdown of MRE11A sensitizes cells to depletion of various replication fork-associated proteins. Overall, this work describes methods to identify, predict, and validate in cancer cells candidate therapeutic targets for tumors with known somatic mutations in CIN genes using data from yeast. We affirm not only replication stress but also the targeting of DNA replication fork proteins themselves as potential targets for anticancer therapeutic development. PMID:23390603

  17. Osteosarcoma Genetics and Epigenetics: Emerging Biology and Candidate Therapies

    PubMed Central

    Morrow, James J.; Khanna, Chand

    2016-01-01

    Osteosarcoma is the most common primary malignancy of bone, typically presenting in the first or second decade of life. Unfortunately, clinical outcomes for osteosarcoma patients have not substantially improved in over 30 years. This stagnation in therapeutic advances is perhaps explained by the genetic, epigenetic, and biological complexities of this rare tumor. In this review we provide a general background on the biology of osteosarcoma and the clinical status quo. We go on to enumerate the genetic and epigenetic defects identified in osteosarcoma. Finally, we discuss ongoing large-scale studies in the field and potential new therapies that are currently under investigation. PMID:26349415

  18. Osteosarcoma Genetics and Epigenetics: Emerging Biology and Candidate Therapies.

    PubMed

    Morrow, James J; Khanna, Chand

    2015-01-01

    Osteosarcoma is the most common primary malignancy of bone, typically presenting in the first or second decade of life. Unfortunately, clinical outcomes for osteosarcoma patients have not substantially improved in over 30 years. This stagnation in therapeutic advances is perhaps explained by the genetic, epigenetic, and biological complexities of this rare tumor. In this review we provide a general background on the biology of osteosarcoma and the clinical status quo. We go on to enumerate the genetic and epigenetic defects identified in osteosarcoma. Finally, we discuss ongoing large-scale studies in the field and potential new therapies that are currently under investigation. PMID:26349415

  19. Candidate-gene analysis of white matter hyperintensities on neuroimaging

    PubMed Central

    Tran, Theresa; Cotlarciuc, Ioana; Yadav, Sunaina; Hasan, Nazeeha; Bentley, Paul; Levi, Christopher; Worrall, Bradford B; Meschia, James F; Rost, Natalia; Sharma, Pankaj

    2016-01-01

    Background White matter hyperintensities (WMH) are a common radiographic finding and may be a useful endophenotype for small vessel diseases. Given high heritability of WMH, we hypothesised that certain genotypes may predispose individuals to these lesions and consequently, to an increased risk of stroke, dementia and death. We performed a meta-analysis of studies investigating candidate genes and WMH to elucidate the genetic susceptibility to WMH and tested associated variants in a new independent WMH cohort. We assessed a causal relationship of WMH to methylene tetrahydrofolate reductase (MTHFR). Methods Database searches through March 2014 were undertaken and studies investigating candidate genes in WMH were assessed. Associated variants were tested in a new independent ischaemic cohort of 1202 WMH patients. Mendelian randomization was undertaken to assess a causal relationship between WMH and MTHFR. Results We identified 43 case-control studies interrogating eight polymorphisms in seven genes covering 6,314 WMH cases and 15,461 controls. Fixed-effects meta-analysis found that the C-allele containing genotypes of the aldosterone synthase CYP11B2 T(−344)C gene polymorphism were associated with a decreased risk of WMH (OR=0.61; 95% CI, 0.44 to 0.84; p=0.003). Using mendelian randomisation the association among MTHFR C677T, homocysteine levels and WMH, approached, but did not reach, significance (expected OR=1.75; 95% CI, 0.90−3.41; observed OR=1.68; 95% CI, 0.97−2.94). Neither CYP11B2 T(−344)C nor MTHFR C677T were significantly associated when tested in a new independent cohort of 1202 patients with WMH. Conclusions There is a genetic basis to WMH but anonymous genome wide and exome studies are more likely to provide novel loci of interest. PMID:25835038

  20. Impact of Candidate Genetic Polymorphisms in Prostate Cancer: An Overview.

    PubMed

    Salvi, S; Conteduca, V; Gurioli, G; Calistri, D; Casadio, V; De Giorgi, U

    2016-02-01

    In the last few years, the presence of single nucleotide polymorphisms (SNPs) has been investigated in many tumors as predictor of disease aggressiveness and clinical outcome. We searched for relevant articles from 1998 to 2015 about the impact of SNPs in prostate cancer. Particularly, in this article, we review the pathogenetic, prognostic and predictive significance of gene polymorphisms in prostate tumor, providing a brief overview of studies in which the possible role of genetic variants was investigated in clinical settings. Because conflicting results often emerge about the impact of gene polymorphisms in prostate cancer, further larger studies are warranted in order to introduce gene polymorphism into clinical practice as biomarkers. PMID:26518421

  1. Molecular characterisation and genetic mapping of candidate genes for qualitative disease resistance in perennial ryegrass (Lolium perenne L.)

    PubMed Central

    Dracatos, Peter M; Cogan, Noel OI; Sawbridge, Timothy I; Gendall, Anthony R; Smith, Kevin F; Spangenberg, German C; Forster, John W

    2009-01-01

    Background Qualitative pathogen resistance in both dicotyledenous and monocotyledonous plants has been attributed to the action of resistance (R) genes, including those encoding nucleotide binding site – leucine rich repeat (NBS-LRR) proteins and receptor-like kinase enzymes. This study describes the large-scale isolation and characterisation of candidate R genes from perennial ryegrass. The analysis was based on the availability of an expressed sequence tag (EST) resource and a functionally-integrated bioinformatics database. Results Amplification of R gene sequences was performed using template EST data and information from orthologous candidate using a degenerate consensus PCR approach. A total of 102 unique partial R genes were cloned, sequenced and functionally annotated. Analysis of motif structure and R gene phylogeny demonstrated that Lolium R genes cluster with putative ortholoci, and evolved from common ancestral origins. Single nucleotide polymorphisms (SNPs) predicted through resequencing of amplicons from the parental genotypes of a genetic mapping family were validated, and 26 distinct R gene loci were assigned to multiple genetic maps. Clusters of largely non-related NBS-LRR genes were located at multiple distinct genomic locations and were commonly found in close proximity to previously mapped defence response (DR) genes. A comparative genomics analysis revealed the co-location of several candidate R genes with disease resistance quantitative trait loci (QTLs). Conclusion This study is the most comprehensive analysis to date of qualitative disease resistance candidate genes in perennial ryegrass. SNPs identified within candidate genes provide a valuable resource for mapping in various ryegrass pair cross-derived populations and further germplasm analysis using association genetics. In parallel with the use of specific pathogen virulence races, such resources provide the means to identify gene-for-gene mechanisms for multiple host pathogen

  2. Organ-Specific Quantitative Genetics and Candidate Genes of Phenylpropanoid Metabolism in Brassica oleracea

    PubMed Central

    Francisco, Marta; Ali, Mahmoud; Ferreres, Federico; Moreno, Diego A.; Velasco, Pablo; Soengas, Pilar

    2016-01-01

    Phenolic compounds are proving to be increasingly important for human health and in crop development, defense and adaptation. In spite of the economical importance of Brassica crops in agriculture, the mechanisms involved in the biosynthesis of phenolic compounds presents in these species remain unknown. The genetic and metabolic basis of phenolics accumulation was dissected through analysis of total phenolics concentration and its individual components in leaves, flower buds, and seeds of a double haploid (DH) mapping population of Brassica oleracea. The quantitative trait loci (QTL) that had an effect on phenolics concentration in each organ were integrated, resulting in 33 consensus QTLs controlling phenolics traits. Most of the studied compounds had organ-specific genomic regulation. Moreover, this information allowed us to propose candidate genes and to predict the function of genes underlying the QTL. A number of previously unknown potential regulatory regions involved in phenylpropanoid metabolism were identified and this study illustrates how plant ontogeny can affect a biochemical pathway. PMID:26858727

  3. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

    PubMed Central

    Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B.; Rudolph, Anja; Schmutzler, Rita K.; Simard, Jacques; Soucy, Penny; Eeles, Rosalind A.; Easton, Douglas F.; Hamann, Ute; Wilkening, Stefan; Chen, Bowang; Rookus, Matti A.; Schmidt, Marjanka K; van der Baan, Frederieke H.; Spurdle, Amanda B.; Walker, Logan C.; Lose, Felicity; Maia, Ana-Teresa; Montagna, Marco; Matricardi, Laura; Lubinski, Jan; Jakubowska, Anna; Gómez Garcia, Encarna B.; Olopade, Olufunmilayo I.; Nussbaum, Robert L.; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Arun, Banu K.; Karlan, Beth Y.; Orsulic, Sandra; Lester, Jenny; Chung, Wendy K.; Miron, Alex; Southey, Melissa C.; Goldgar, David E.; Buys, Saundra S.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Ding, Yuan Chun; Neuhausen, Susan L.; Hansen, Thomas V. O.; Gerdes, Anne-Marie; Ejlertsen, Bent; Jønson, Lars; Osorio, Ana; Martínez-Bouzas, Cristina; Benitez, Javier; Conway, Edye E.; Blazer, Kathleen R.; Weitzel, Jeffrey N.; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Barile, Monica; Ficarazzi, Filomena; Mariette, Frederique; Fortuzzi, Stefano; Viel, Alessandra; Giannini, Giuseppe; Papi, Laura; Martayan, Aline; Tibiletti, Maria Grazia; Radice, Paolo; Vratimos, Athanassios; Fostira, Florentia; Garber, Judy E.; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D. Gareth R.; Frost, Debra; Eccles, Diana; Brady, Angela; Cook, Jackie; Tischkowitz, Marc; Adlard, Julian; Barwell, Julian; Walker, Lisa; Izatt, Louise; Side, Lucy E.; Kennedy, M. John; Rogers, Mark T.; Porteous, Mary E.; Morrison, Patrick J.; Platte, Radka; Davidson, Rosemarie; Hodgson, Shirley V.; Ellis, Steve; Cole, Trevor; Godwin, Andrew K.; Claes, Kathleen; Van Maerken, Tom; Meindl, Alfons; Gehrig, Andrea; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Plendl, Hansjoerg; Kast, Karin; Rhiem, Kerstin; Ditsch, Nina; Arnold, Norbert; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Wang-Gohrke, Shan; Bressac-de Paillerets, Brigitte; Buecher, Bruno; Delnatte, Capucine; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Coupier, Isabelle; Barjhoux, Laure; Venat-Bouvet, Laurence; Golmard, Lisa; Boutry-Kryza, Nadia; Sinilnikova, Olga M.; Caron, Olivier; Pujol, Pascal; Mazoyer, Sylvie; Belotti, Muriel; Piedmonte, Marion; Friedlander, Michael L.; Rodriguez, Gustavo C.; Copeland, Larry J; de la Hoya, Miguel; Segura, Pedro Perez; Nevanlinna, Heli; Aittomäki, Kristiina; van Os, Theo A.M.; Meijers-Heijboer, Hanne E.J.; van der Hout, Annemarie H.; Vreeswijk, Maaike P.G.; Hoogerbrugge, Nicoline; Ausems, Margreet G.E.M.; van Doorn, Helena C.; Collée, J. Margriet; Olah, Edith; Diez, Orland; Blanco, Ignacio; Lazaro, Conxi; Brunet, Joan; Feliubadalo, Lidia; Cybulski, Cezary; Gronwald, Jacek; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Sukiennicki, Grzegorz; Arason, Adalgeir; Chiquette, Jocelyne; Teixeira, Manuel R.; Olswold, Curtis; Couch, Fergus J.; Lindor, Noralane M.; Wang, Xianshu; Szabo, Csilla I.; Offit, Kenneth; Corines, Marina; Jacobs, Lauren; Robson, Mark E.; Zhang, Liying; Joseph, Vijai; Berger, Andreas; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng M.; Phelan, Catherine M.; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Mulligan, Anna Marie; Glendon, Gord; Tchatchou, Sandrine; Andrulis, Irene L.; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Thomassen, Mads; Jensen, Uffe Birk; Laitman, Yael; Rantala, Johanna; von Wachenfeldt, Anna; Ehrencrona, Hans; Askmalm, Marie Stenmark; Borg, Åke; Kuchenbaecker, Karoline B.; McGuffog, Lesley; Barrowdale, Daniel; Healey, Sue; Lee, Andrew; Pharoah, Paul D.P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Friedman, Eitan

    2014-01-01

    Background BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. PMID:25336561

  4. Contamination analysis of SSF candidate materials

    NASA Technical Reports Server (NTRS)

    Johnson, R. Barry

    1991-01-01

    NASA's In Situ Contamination Effects Facility, Marshall Space Flight Center, has been used to test several candidate materials for use upon Space Station Freedom. Optical measurements were made in the vacuum ultraviolet (VUV) as test mirrors were contaminated by materials in a space-like environment. This was done to determine the effects of the contamination and subsequent exposure to VUV radiation upon optical components that will be used upon the space station.

  5. A Novel Candidate Region for Genetic Adaptation to High Altitude in Andean Populations

    PubMed Central

    Lippold, Sebastian; de Filippo, Cesare; Tang, Kun; López Herráez, David; Li, Jing; Stoneking, Mark

    2015-01-01

    Humans living at high altitude (≥2,500 meters above sea level) have acquired unique abilities to survive the associated extreme environmental conditions, including hypoxia, cold temperature, limited food availability and high levels of free radicals and oxidants. Long-term inhabitants of the most elevated regions of the world have undergone extensive physiological and/or genetic changes, particularly in the regulation of respiration and circulation, when compared to lowland populations. Genome scans have identified candidate genes involved in altitude adaption in the Tibetan Plateau and the Ethiopian highlands, in contrast to populations from the Andes, which have not been as intensively investigated. In the present study, we focused on three indigenous populations from Bolivia: two groups of Andean natives, Aymara and Quechua, and the low-altitude control group of Guarani from the Gran Chaco lowlands. Using pooled samples, we identified a number of SNPs exhibiting large allele frequency differences over 900,000 genotyped SNPs. A region in chromosome 10 (within the cytogenetic bands q22.3 and q23.1) was significantly differentiated between highland and lowland groups. We resequenced ~1.5 Mb surrounding the candidate region and identified strong signals of positive selection in the highland populations. A composite of multiple signals like test localized the signal to FAM213A and a related enhancer; the product of this gene acts as an antioxidant to lower oxidative stress and may help to maintain bone mass. The results suggest that positive selection on the enhancer might increase the expression of this antioxidant, and thereby prevent oxidative damage. In addition, the most significant signal in a relative extended haplotype homozygosity analysis was localized to the SFTPD gene, which encodes a surfactant pulmonary-associated protein involved in normal respiration and innate host defense. Our study thus identifies two novel candidate genes and associated pathways

  6. Genetic susceptibility to heroin addiction; a candidate-gene association study

    PubMed Central

    Levran, O.; Londono, D.; O’Hara, K.; Nielsen, D. A.; Peles, E.; Rotrosen, J.; Casadonte, P.; Linzy, S.; Randesi, M.; Ott, J.; Adelson, M.; Kreek, M. J.

    2010-01-01

    Heroin addiction is a chronic complex disease with a substantial genetic contribution. This study was designed to identify genetic variants that are associated with susceptibility to develop heroin addiction, by analyzing 1350 variants in 130 candidate genes. All subjects had Caucasian ancestry. The sample consisted of 412 former severe heroin addicts in methadone treatment, and 184 healthy controls with no history of drug abuse. Nine variants, in six genes, showed the lowest nominal P values in the association tests (P < 0.01). These variants were in non-coding regions of the genes encoding the mu (OPRM1; rs510769, rs3778151), kappa (OPRK1; rs6473797), and delta opioid receptors, (OPRD1; rs2236861, rs2236857 and rs3766951), the neuropeptide galanin (GAL; rs694066), the serotonin receptor subtype 3B (HTR3B; rs3758987) and the casein kinase 1 isoform epsilon (CSNK1E; rs1534891). Several haplotypes and multi-locus genotype patterns showed nominally significant associations (e.g. OPRM1; P = 0.0006 and CSNK1E; P = 0.0007). Analysis of a combined effect of OPRM1 and OPRD1 showed that rs510769 and rs2236861 increase the risk of heroin addiction (P = 0.0005). None of these associations remained significant after adjustment for multiple testing. This study suggests the involvement of several genes and variants in heroin addiction that is worthy of future study. PMID:18518925

  7. Genetic analysis of bleeding disorders.

    PubMed

    Edison, E; Konkle, B A; Goodeve, A C

    2016-07-01

    Molecular genetic analysis of inherited bleeding disorders has been practised for over 30 years. Technological changes have enabled advances, from analyses using extragenic linked markers to next-generation DNA sequencing and microarray analysis. Two approaches for genetic analysis are described, each suiting their environment. The Christian Medical Centre in Vellore, India, uses conformation-sensitive gel electrophoresis mutation screening of multiplexed PCR products to identify candidate mutations, followed by Sanger sequencing confirmation of variants identified. Specific analyses for F8 intron 1 and 22 inversions are also undertaken. The MyLifeOurFuture US project between the American Thrombosis and Hemostasis Network, the National Hemophilia Foundation, Bloodworks Northwest and Biogen uses molecular inversion probes (MIP) to capture target exons, splice sites plus 5' and 3' sequences and to detect F8 intron 1 and 22 inversions. This allows screening for all F8 and F9 variants in one sequencing run of multiple samples (196 or 392). Sequence variants identified are subsequently confirmed by a diagnostic laboratory. After having identified variants in genes of interest through these processes, a systematic procedure determining their likely pathogenicity should be applied. Several scientific societies have prepared guidelines. Systematic analysis of the available evidence facilitates reproducible scoring of likely pathogenicity. Documentation of frequency in population databases of variant prevalence and in locus-specific mutation databases can provide initial information on likely pathogenicity. Whereas null mutations are often pathogenic, missense and splice site variants often require in silico analyses to predict likely pathogenicity and using an accepted suite of tools can help standardize their documentation. PMID:27405681

  8. Mitochondrial DNA variant at HVI region as a candidate of genetic markers of type 2 diabetes

    NASA Astrophysics Data System (ADS)

    Gumilar, Gun Gun; Purnamasari, Yunita; Setiadi, Rahmat

    2016-02-01

    Mitochondrial DNA (mtDNA) is maternally inherited. mtDNA mutations which can contribute to the excess of maternal inheritance of type 2 diabetes. Due to the high mutation rate, one of the areas in the mtDNA that is often associated with the disease is the hypervariable region I (HVI). Therefore, this study was conducted to determine the genetic variants of human mtDNA HVI that related to the type 2 diabetes in four samples that were taken from four generations in one lineage. Steps being taken include the lyses of hair follicles, amplification of mtDNA HVI fragment using Polymerase Chain Reaction (PCR), detection of PCR products through agarose gel electrophoresis technique, the measurement of the concentration of mtDNA using UV-Vis spectrophotometer, determination of the nucleotide sequence via direct sequencing method and analysis of the sequencing results using SeqMan DNASTAR program. Based on the comparison between nucleotide sequence of samples and revised Cambridge Reference Sequence (rCRS) obtained six same mutations that these are C16147T, T16189C, C16193del, T16127C, A16235G, and A16293C. After comparing the data obtained to the secondary data from Mitomap and NCBI, it were found that two mutations, T16189C and T16217C, become candidates as genetic markers of type 2 diabetes even the mutations were found also in the generations of undiagnosed type 2 diabetes. The results of this study are expected to give contribution to the collection of human mtDNA database of genetic variants that associated to metabolic diseases, so that in the future it can be utilized in various fields, especially in medicine.

  9. Pathogenic Network Analysis Predicts Candidate Genes for Cervical Cancer

    PubMed Central

    Zhang, Yun-Xia

    2016-01-01

    Purpose. The objective of our study was to predicate candidate genes in cervical cancer (CC) using a network-based strategy and to understand the pathogenic process of CC. Methods. A pathogenic network of CC was extracted based on known pathogenic genes (seed genes) and differentially expressed genes (DEGs) between CC and normal controls. Subsequently, cluster analysis was performed to identify the subnetworks in the pathogenic network using ClusterONE. Each gene in the pathogenic network was assigned a weight value, and then candidate genes were obtained based on the weight distribution. Eventually, pathway enrichment analysis for candidate genes was performed. Results. In this work, a total of 330 DEGs were identified between CC and normal controls. From the pathogenic network, 2 intensely connected clusters were extracted, and a total of 52 candidate genes were detected under the weight values greater than 0.10. Among these candidate genes, VIM had the highest weight value. Moreover, candidate genes MMP1, CDC45, and CAT were, respectively, enriched in pathway in cancer, cell cycle, and methane metabolism. Conclusion. Candidate pathogenic genes including MMP1, CDC45, CAT, and VIM might be involved in the pathogenesis of CC. We believe that our results can provide theoretical guidelines for future clinical application. PMID:27034707

  10. Genotype relative risks: methods for design and analysis of candidate-gene association studies.

    PubMed Central

    Schaid, D J; Sommer, S S

    1993-01-01

    Design and analysis methods are presented for studying the association of a candidate gene with a disease by using parental data in place of nonrelated controls. This alternative design eliminates spurious differences in allele frequencies between cases and nonrelated controls resulting from different ethnic origins and population stratification for these two groups. We present analysis methods which are based on two genetic relative risks: (1) the relative risk of disease for homozygotes with two copies of the candidate gene versus homozygotes without the candidate gene and (2) the relative risk for heterozygotes with one copy of the candidate gene versus homozygotes without the candidate gene. In addition to estimating the magnitude of these relative risks, likelihood methods allow specific hypotheses to be tested, namely, a test for overall association of the candidate gene with disease, as well as specific genetic hypotheses, such as dominant or recessive inheritance. Two likelihood methods are presented: (1) a likelihood method appropriate when Hardy-Weinberg equilibrium holds and (2) a likelihood method in which we condition on parental genotype data when Hardy-Weinberg equilibrium does not hold. The results for the relative efficiency of these two methods suggest that the conditional approach may at times be preferable, even when equilibrium holds. Sample-size and power calculations are presented for a multitiered design. The purpose of tier 1 is to detect the presence of an abnormal sequence for a postulated candidate gene among a small group of cases. The purpose of tier 2 is to test for association of the abnormal variant with disease, such as by the likelihood methods presented. The purpose of tier 3 is to confirm positive results from tier 2. Results indicate that required sample sizes are smaller when expression of disease is recessive, rather than dominant, and that, for recessive disease and large relative risks, necessary sample sizes may be

  11. Network analysis of EtOH-related candidate genes.

    PubMed

    Guo, An-Yuan; Sun, Jingchun; Jia, Peilin; Zhao, Zhongming

    2010-05-01

    Recently, we collected many large-scale datasets for alcohol dependence and EtOH response in five organisms and deposited them in our EtOH-related gene resource database (ERGR, http://bioinfo.mc.vanderbilt.edu/ERGR/). Based on multidimensional evidence among these datasets, we prioritized 57 EtOH-related candidate genes. To explore their biological roles, and the molecular mechanisms of EtOH response and alcohol dependence, we examined the features of these genes by the Gene Ontology (GO) term-enrichment test and network/pathway analysis. Our analysis revealed that these candidate genes were highly enriched in alcohol dependence/alcoholism and highly expressed in brain or liver tissues. All the significantly enriched GO terms were related to neurotransmitter systems or EtOH metabolic processes. Using the Ingenuity Pathway Analysis system, we found that these genes were involved in networks of neurological disease, cardiovascular disease, inflammatory response, and small molecular metabolism. Many key genes in signaling pathways were in the central position of these networks. Furthermore, our protein-protein interaction (PPI) network analysis suggested some novel candidate genes which also had evidence in the ERGR database. This study demonstrated that our candidate gene selection is effective and our network/pathway analysis is useful for uncovering the molecular mechanisms of EtOH response and alcohol dependence. This approach can be applied to study the features of candidate genes of other complex traits/phenotypes. PMID:20491071

  12. Natural Genetic Variation and Candidate Genes for Morphological Traits in Drosophila melanogaster

    PubMed Central

    Carreira, Valeria Paula; Mensch, Julián; Hasson, Esteban; Fanara, Juan José

    2016-01-01

    Body size is a complex character associated to several fitness related traits that vary within and between species as a consequence of environmental and genetic factors. Latitudinal and altitudinal clines for different morphological traits have been described in several species of Drosophila and previous work identified genomic regions associated with such variation in D. melanogaster. However, the genetic factors that orchestrate morphological variation have been barely studied. Here, our main objective was to investigate genetic variation for different morphological traits associated to the second chromosome in natural populations of D. melanogaster along latitudinal and altitudinal gradients in Argentina. Our results revealed weak clinal signals and a strong population effect on morphological variation. Moreover, most pairwise comparisons between populations were significant. Our study also showed important within-population genetic variation, which must be associated to the second chromosome, as the lines are otherwise genetically identical. Next, we examined the contribution of different candidate genes to natural variation for these traits. We performed quantitative complementation tests using a battery of lines bearing mutated alleles at candidate genes located in the second chromosome and six second chromosome substitution lines derived from natural populations which exhibited divergent phenotypes. Results of complementation tests revealed that natural variation at all candidate genes studied, invected, Fasciclin 3, toucan, Reticulon-like1, jing and CG14478, affects the studied characters, suggesting that they are Quantitative Trait Genes for morphological traits. Finally, the phenotypic patterns observed suggest that different alleles of each gene might contribute to natural variation for morphological traits. However, non-additive effects cannot be ruled out, as wild-derived strains differ at myriads of second chromosome loci that may interact

  13. Natural Genetic Variation and Candidate Genes for Morphological Traits in Drosophila melanogaster.

    PubMed

    Carreira, Valeria Paula; Mensch, Julián; Hasson, Esteban; Fanara, Juan José

    2016-01-01

    Body size is a complex character associated to several fitness related traits that vary within and between species as a consequence of environmental and genetic factors. Latitudinal and altitudinal clines for different morphological traits have been described in several species of Drosophila and previous work identified genomic regions associated with such variation in D. melanogaster. However, the genetic factors that orchestrate morphological variation have been barely studied. Here, our main objective was to investigate genetic variation for different morphological traits associated to the second chromosome in natural populations of D. melanogaster along latitudinal and altitudinal gradients in Argentina. Our results revealed weak clinal signals and a strong population effect on morphological variation. Moreover, most pairwise comparisons between populations were significant. Our study also showed important within-population genetic variation, which must be associated to the second chromosome, as the lines are otherwise genetically identical. Next, we examined the contribution of different candidate genes to natural variation for these traits. We performed quantitative complementation tests using a battery of lines bearing mutated alleles at candidate genes located in the second chromosome and six second chromosome substitution lines derived from natural populations which exhibited divergent phenotypes. Results of complementation tests revealed that natural variation at all candidate genes studied, invected, Fasciclin 3, toucan, Reticulon-like1, jing and CG14478, affects the studied characters, suggesting that they are Quantitative Trait Genes for morphological traits. Finally, the phenotypic patterns observed suggest that different alleles of each gene might contribute to natural variation for morphological traits. However, non-additive effects cannot be ruled out, as wild-derived strains differ at myriads of second chromosome loci that may interact

  14. Genetic region characterization (Gene RECQuest) - software to assist in identification and selection of candidate genes from genomic regions

    PubMed Central

    Sadasivam, Rajani S; Sundar, Gayathri; Vaughan, Laura K; Tanik, Murat M; Arnett, Donna K

    2009-01-01

    Background The availability of research platforms like the web tools of the National Center for Biotechnology Information (NCBI) has transformed the time-consuming task of identifying candidate genes from genetic studies to an interactive process where data from a variety of sources are obtained to select likely genes for follow-up. This process presents its own set of challenges, as the genetic researcher has to interact with several tools in a time-intensive, manual, and cumbersome manner. We developed a method and implemented an effective software system to address these challenges by multidisciplinary efforts of professional software developers with domain experts. The method presented in this paper, Gene RECQuest, simplifies the interaction with existing research platforms through the use of advanced integration technologies. Findings Gene RECQuest is a web-based application that assists in the identification of candidate genes from linkage and association studies using information from Online Mendelian Inheritance in Man (OMIM) and PubMed. To illustrate the utility of Gene RECQuest we used it to identify genes physically located within a linkage region as potential candidate genes for a quantitative trait locus (QTL) for very low density lipoprotein (VLDL) response on chromosome 18. Conclusion Gene RECQuest provides a tool which enables researchers to easily identify and organize literature supporting their own expertise and make informed decisions. It is important to note that Gene RECQuest is a data acquisition and organization software, and not a data analysis method. PMID:19793396

  15. Genotype relative risks: Methods for design and analysis of candidate-gene association studies

    SciTech Connect

    Shaid, D.J.; Sommer, S.S. )

    1993-11-01

    Design and analysis methods are presented for studying the association of a candidate gene with a disease by using parental data in place of nonrelated controls. This alternating design eliminates spurious differences in allele frequencies between cases and nonrelated controls resulting from different ethnic origins and population stratification for these two groups. The authors present analysis methods which are based on two genetic relative risks: (1) the relative risk of disease for homozygotes with two copies of the candidate gene versus homozygotes without the candidate gene and (2) the relative risk for heterozygotes with one copy of the candidate gene versus homozygotes without the candidate gene. In addition to estimating the magnitude of these relative risks, likelihood methods allow specific hypotheses to be tested, namely, a test for overall association of the candidate gene with disease, as well as specific genetic hypotheses, such as dominant or recessive inheritance. Two likelihood methods are presented: (1) a likelihood method appropriate when Hardy-Weinberg equilibrium holds and (2) a likelihood method in which the authors condition on parental genotype data when Hardy-Weinberg equilibrium does not hold. The results for the relative efficiency of these two methods suggest that the conditional approach may at times be preferable, even when equilibrium holds. Sample-size and power calculations are presented for a multitiered design. Tier 1 detects the presence of an abnormal sequence for a postulated candidate gene among a small group of cases. Tier 2 tests for association of the abnormal variant with disease, such as by the likelihood methods presented. Tier 3 confirms positive results from tier 2. Results indicate that required sample sizes are smaller when expression of disease is recessive, rather than dominant, and that, for recessive disease and large relative risks, necessary sample sizes may be feasible. 19 refs., 2 figs., 2 tabs.

  16. PON1 as a model for integration of genetic, epigenetic, and expression data on candidate susceptibility genes

    PubMed Central

    Huen, Karen; Yousefi, Paul; Street, Kelly; Eskenazi, Brenda; Holland, Nina

    2016-01-01

    Recent genome- and epigenome-wide studies demonstrate that the DNA methylation is controlled in part by genetics, highlighting the importance of integrating genetic and epigenetic data. To better understand molecular mechanisms affecting gene expression, we used the candidate susceptibility gene paraoxonase 1 (PON1) as a model to assess associations of PON1 genetic polymorphisms with DNA methylation and arylesterase activity, a marker of PON1 expression. PON1 has been associated with susceptibility to obesity, cardiovascular disease, and pesticide exposure. In this study, we assessed DNA methylation in 18 CpG sites located along PON1 shores, shelves, and its CpG island in blood specimens collected from newborns and 9-year-old children participating (n = 449) in the CHAMACOS birth cohort study. The promoter polymorphism, PON1−108, was strongly associated with methylation, particularly for CpG sites located near the CpG island (P << 0.0005). Among newborns, these relationships were even more pronounced after adjusting for blood cell composition. We also observed significant decreases in arylesterase activity with increased methylation at the same nine CpG sites at both ages. Using causal mediation analysis, we found statistically significant indirect effects of methylation (β(95% confidence interval): 6.9(1.5, 12.4)) providing evidence that DNA methylation mediates the relationship between PON1−108 genotype and PON1 expression. Our findings show that integration of genetic, epigenetic, and expression data can shed light on the functional mechanisms involving genetic and epigenetic regulation of candidate susceptibility genes like PON1. PMID:26913202

  17. Integrative analysis to select cancer candidate biomarkers to targeted validation.

    PubMed

    Kawahara, Rebeca; Meirelles, Gabriela V; Heberle, Henry; Domingues, Romênia R; Granato, Daniela C; Yokoo, Sami; Canevarolo, Rafael R; Winck, Flavia V; Ribeiro, Ana Carolina P; Brandão, Thaís Bianca; Filgueiras, Paulo R; Cruz, Karen S P; Barbuto, José Alexandre; Poppi, Ronei J; Minghim, Rosane; Telles, Guilherme P; Fonseca, Felipe Paiva; Fox, Jay W; Santos-Silva, Alan R; Coletta, Ricardo D; Sherman, Nicholas E; Paes Leme, Adriana F

    2015-12-22

    Targeted proteomics has flourished as the method of choice for prospecting for and validating potential candidate biomarkers in many diseases. However, challenges still remain due to the lack of standardized routines that can prioritize a limited number of proteins to be further validated in human samples. To help researchers identify candidate biomarkers that best characterize their samples under study, a well-designed integrative analysis pipeline, comprising MS-based discovery, feature selection methods, clustering techniques, bioinformatic analyses and targeted approaches was performed using discovery-based proteomic data from the secretomes of three classes of human cell lines (carcinoma, melanoma and non-cancerous). Three feature selection algorithms, namely, Beta-binomial, Nearest Shrunken Centroids (NSC), and Support Vector Machine-Recursive Features Elimination (SVM-RFE), indicated a panel of 137 candidate biomarkers for carcinoma and 271 for melanoma, which were differentially abundant between the tumor classes. We further tested the strength of the pipeline in selecting candidate biomarkers by immunoblotting, human tissue microarrays, label-free targeted MS and functional experiments. In conclusion, the proposed integrative analysis was able to pre-qualify and prioritize candidate biomarkers from discovery-based proteomics to targeted MS. PMID:26540631

  18. Integrative analysis to select cancer candidate biomarkers to targeted validation

    PubMed Central

    Heberle, Henry; Domingues, Romênia R.; Granato, Daniela C.; Yokoo, Sami; Canevarolo, Rafael R.; Winck, Flavia V.; Ribeiro, Ana Carolina P.; Brandão, Thaís Bianca; Filgueiras, Paulo R.; Cruz, Karen S. P.; Barbuto, José Alexandre; Poppi, Ronei J.; Minghim, Rosane; Telles, Guilherme P.; Fonseca, Felipe Paiva; Fox, Jay W.; Santos-Silva, Alan R.; Coletta, Ricardo D.; Sherman, Nicholas E.; Paes Leme, Adriana F.

    2015-01-01

    Targeted proteomics has flourished as the method of choice for prospecting for and validating potential candidate biomarkers in many diseases. However, challenges still remain due to the lack of standardized routines that can prioritize a limited number of proteins to be further validated in human samples. To help researchers identify candidate biomarkers that best characterize their samples under study, a well-designed integrative analysis pipeline, comprising MS-based discovery, feature selection methods, clustering techniques, bioinformatic analyses and targeted approaches was performed using discovery-based proteomic data from the secretomes of three classes of human cell lines (carcinoma, melanoma and non-cancerous). Three feature selection algorithms, namely, Beta-binomial, Nearest Shrunken Centroids (NSC), and Support Vector Machine-Recursive Features Elimination (SVM-RFE), indicated a panel of 137 candidate biomarkers for carcinoma and 271 for melanoma, which were differentially abundant between the tumor classes. We further tested the strength of the pipeline in selecting candidate biomarkers by immunoblotting, human tissue microarrays, label-free targeted MS and functional experiments. In conclusion, the proposed integrative analysis was able to pre-qualify and prioritize candidate biomarkers from discovery-based proteomics to targeted MS. PMID:26540631

  19. The number of candidate variants in exome sequencing for Mendelian disease under no genetic heterogeneity.

    PubMed

    Nishino, Jo; Mano, Shuhei

    2013-01-01

    There has been recent success in identifying disease-causing variants in Mendelian disorders by exome sequencing followed by simple filtering techniques. Studies generally assume complete or high penetrance. However, there are likely many failed and unpublished studies due in part to incomplete penetrance or phenocopy. In this study, the expected number of candidate single-nucleotide variants (SNVs) in exome data for autosomal dominant or recessive Mendelian disorders was investigated under the assumption of "no genetic heterogeneity." All variants were assumed to be under the "null model," and sample allele frequencies were modeled using a standard population genetics theory. To investigate the properties of pedigree data, full-sibs were considered in addition to unrelated individuals. In both cases, particularly regarding full-sibs, the number of SNVs remained very high without controls. The high efficacy of controls was also confirmed. When controls were used with a relatively large total sample size (e.g., N = 20, 50), filtering incorporating of incomplete penetrance and phenocopy efficiently reduced the number of candidate SNVs. This suggests that filtering is useful when an assumption of no "genetic heterogeneity" is appropriate and could provide general guidelines for sample size determination. PMID:23762180

  20. Genetic diversity and population structure of genes encoding vaccine candidate antigens of Plasmodium vivax

    PubMed Central

    2012-01-01

    Background A major concern in malaria vaccine development is genetic polymorphisms typically observed among Plasmodium isolates in different geographical areas across the world. Highly polymorphic regions have been observed in Plasmodium falciparum and Plasmodium vivax antigenic surface proteins such as Circumsporozoite protein (CSP), Duffy-binding protein (DBP), Merozoite surface protein-1 (MSP-1), Apical membrane antigen-1 (AMA-1) and Thrombospondin related anonymous protein (TRAP). Methods Genetic variability was assessed in important polymorphic regions of various vaccine candidate antigens in P. vivax among 106 isolates from the Amazon Region of Loreto, Peru. In addition, genetic diversity determined in Peruvian isolates was compared to population studies from various geographical locations worldwide. Results The structured diversity found in P. vivax populations did not show a geographic pattern and haplotypes from all gene candidates were distributed worldwide. In addition, evidence of balancing selection was found in polymorphic regions of the trap, dbp and ama-1 genes. Conclusions It is important to have a good representation of the haplotypes circulating worldwide when implementing a vaccine, regardless of the geographic region of deployment since selective pressure plays an important role in structuring antigen diversity. PMID:22417572

  1. Bioinformatic analysis of expression data to identify effector candidates.

    PubMed

    Reid, Adam J; Jones, John T

    2014-01-01

    Pathogens produce effectors that manipulate the host to the benefit of the pathogen. These effectors are often secreted proteins that are upregulated during the early phases of infection. These properties can be used to identify candidate effectors from genomes and transcriptomes of pathogens. Here we describe commonly used bioinformatic approaches that (1) allow identification of genes encoding predicted secreted proteins within a genome and (2) allow the identification of genes encoding predicted secreted proteins that are upregulated at important stages of the life cycle. Other approaches for bioinformatic identification of effector candidates, including OrthoMCL analysis to identify expanded gene families, are also described. PMID:24643549

  2. Genetic analysis in translational medicine

    PubMed Central

    Patrinos, George P.; Innocenti, Federico; Cox, Nancy; Fortina, Paolo

    2013-01-01

    The 2010 GOLDEN HELIX Symposium ‘Genetic Analysis in Translational Medicine' was held in Athens, Greece, Athens, Greece, 1-4 December 2010. The scientific program covered all aspects of this discipline, including genome-wide association studies, genomics of cancer and human disorders, molecular cytogenetics, advances in genomic technology, next-generation sequencing applications, pharmacogenomics and bioinformatics. In addition, various topics on genetics and society and genetic analysis in clinical practice were discussed. Here, we provide an overview of the plenary lectures and the topics discussed in the symposium. PMID:21438074

  3. The genomic architecture and association genetics of adaptive characters using a candidate SNP approach in boreal black spruce

    PubMed Central

    2013-01-01

    Background The genomic architecture of adaptive traits remains poorly understood in non-model plants. Various approaches can be used to bridge this gap, including the mapping of quantitative trait loci (QTL) in pedigrees, and genetic association studies in non-structured populations. Here we present results on the genomic architecture of adaptive traits in black spruce, which is a widely distributed conifer of the North American boreal forest. As an alternative to the usual candidate gene approach, a candidate SNP approach was developed for association testing. Results A genetic map containing 231 gene loci was used to identify QTL that were related to budset timing and to tree height assessed over multiple years and sites. Twenty-two unique genomic regions were identified, including 20 that were related to budset timing and 6 that were related to tree height. From results of outlier detection and bulk segregant analysis for adaptive traits using DNA pool sequencing of 434 genes, 52 candidate SNPs were identified and subsequently tested in genetic association studies for budset timing and tree height assessed over multiple years and sites. A total of 34 (65%) SNPs were significantly associated with budset timing, or tree height, or both. Although the percentages of explained variance (PVE) by individual SNPs were small, several significant SNPs were shared between sites and among years. Conclusions The sharing of genomic regions and significant SNPs between budset timing and tree height indicates pleiotropic effects. Significant QTLs and SNPs differed quite greatly among years, suggesting that different sets of genes for the same characters are involved at different stages in the tree’s life history. The functional diversity of genes carrying significant SNPs and low observed PVE further indicated that a large number of polymorphisms are involved in adaptive genetic variation. Accordingly, for undomesticated species such as black spruce with natural populations

  4. Genetic Analysis in Neurology

    PubMed Central

    Pittman, Alan; Hardy, John

    2014-01-01

    In recent years, neurogenetics research had made some remarkable advances owing to the advent of genotyping arrays and next-generation sequencing. These improvements to the technology have allowed us to determine the whole-genome structure and its variation and to examine its effect on phenotype in an unprecedented manner. The identification of rare disease-causing mutations has led to the identification of new biochemical pathways and has facilitated a greater understanding of the etiology of many neurological diseases. Furthermore, genome-wide association studies have provided information on how common genetic variability impacts on the risk for the development of various complex neurological diseases. Herein, we review how these technological advances have changed the approaches being used to study the genetic basis of neurological disease and how the research findings will be translated into clinical utility. PMID:23571731

  5. Genetic Analysis of Xenopus tropicalis

    PubMed Central

    Geach, Timothy J.; Stemple, Derek L.; Zimmerman, Lyle B.

    2014-01-01

    The pipid frog Xenopus tropicalis has emerged as a powerful new model system for combining genetic and genomic analysis of tetrapod development with robust embryological, molecular and biochemical assays. Its early development closely resembles that of its well-understood relative X. laevis, from which techniques and reagents can be readily transferred. In contrast to the tetraploid X. laevis, X. tropicalis has a compact diploid genome with strong synteny to those of amniotes. Recently, advances in high-throughput sequencing together with solution-hybridization whole-exome enrichment technology offer powerful strategies for cloning novel mutations as well as reverse genetic identification of sequence lesions in specific genes of interest. Further advantages include the wide range of functional and molecular assays available, the large number of embryos/meioses produced, and the ease of haploid genetics and gynogenesis. The addition of these genetic tools to X. tropicalis provides a uniquely flexible platform for analysis of gene function in vertebrate development. PMID:22956083

  6. In silico identification of genetically attenuated vaccine candidate genes for Plasmodium liver stage.

    PubMed

    Kumar, Hirdesh; Frischknecht, Friedrich; Mair, Gunnar R; Gomes, James

    2015-12-01

    Genetically attenuated parasites (GAPs) that lack genes essential for the liver stage of the malaria parasite, and therefore cause developmental arrest, have been developed as live vaccines in rodent malaria models and recently been tested in humans. The genes targeted for deletion were often identified by trial and error. Here we present a systematic gene - protein and transcript - expression analyses of several Plasmodium species with the aim to identify candidate genes for the generation of novel GAPs. With a lack of liver stage expression data for human malaria parasites, we used data available for liver stage development of Plasmodium yoelii, a rodent malaria model, to identify proteins expressed in the liver stage but absent from blood stage parasites. An orthology-based search was then employed to identify orthologous proteins in the human malaria parasite Plasmodium falciparum resulting in a total of 310 genes expressed in the liver stage but lacking evidence of protein expression in blood stage parasites. Among these 310 possible GAP candidates, we further studied Plasmodium liver stage proteins by phyletic distribution and functional domain analyses and shortlisted twenty GAP-candidates; these are: fabB/F, fabI, arp, 3 genes encoding subunits of the PDH complex, dnaJ, urm1, rS5, ancp, mcp, arh, gk, lisp2, valS, palm, and four conserved Plasmodium proteins of unknown function. Parasites lacking one or several of these genes might yield new attenuated malaria parasites for experimental vaccination studies. PMID:26348884

  7. Candidate gene analysis of osteochondrosis in Spanish Purebred horses.

    PubMed

    Sevane, N; Dunner, S; Boado, A; Cañon, J

    2016-10-01

    Equine osteochondrosis (OC) is a frequent developmental orthopaedic disease with high economic impact on the equine industry and may lead to premature retirement of the animal as a result of chronic pain and lameness. The genetic background of OC includes different genes affecting several locations; however, these genetic associations have been tested in only one or few populations, lacking the validation in others. The aim of this study was to identify the genetic determinants of OC in the Spanish Purebred horse breed. For that purpose, we used a candidate gene approach to study the association between loci previously implicated in the onset and development of OC in other breeds and different OC locations using radiographic data from 144 individuals belonging to the Spanish Purebred horse breed. Of the 48 polymorphisms analysed, three single nucleotide polymorphisms (SNPs) located in the FAF1, FCN3 and COL1A2 genes were found to be associated with different locations of OC lesions. These data contribute insights into the complex gene networks underlying the multifactorial disease OC, and the associated SNPs could be used in a marker-assisted selection strategy to improve horse health, welfare and competitive lifespan. PMID:27422688

  8. Immunoproteomic Analysis of Potential Serum Biomarker Candidates in Human Glaucoma

    PubMed Central

    Tezel, Gülgün; Thornton, Ivey L.; Tong, Melissa G.; Luo, Cheng; Yang, Xiangjun; Cai, Jian; Powell, David W.; Soltau, Joern B.; Liebmann, Jeffrey M.; Ritch, Robert

    2012-01-01

    Purpose. Evidence supporting the immune system involvement in glaucoma includes increased titers of serum antibodies to retina and optic nerve proteins, although their pathogenic importance remains unclear. This study using an antibody-based proteomics approach aimed to identify disease-related antigens as candidate biomarkers of glaucoma. Methods. Serum samples were collected from 111 patients with primary open-angle glaucoma and an age-matched control group of 49 healthy subjects without glaucoma. For high-throughput characterization of antigens, serum IgG was eluted from five randomly selected glaucomatous samples and analyzed by linear ion trap mass spectrometry (LC-MS/MS). Serum titers of selected biomarker candidates were then measured by specific ELISAs in the whole sample pool (including an additional control group of diabetic retinopathy). Results. LC-MS/MS analysis of IgG elutes revealed a complex panel of proteins, including those detectable only in glaucomatous samples. Interestingly, many of these antigens corresponded to upregulated retinal proteins previously identified in glaucomatous donors (or that exhibited increased methionine oxidation). Moreover, additional analysis detected a greater immunoreactivity of the patient sera to glaucomatous retinal proteins (or to oxidatively stressed cell culture proteins), thereby suggesting the importance of disease-related protein modifications in autoantibody production/reactivity. As a narrowing-down strategy for selection of initial biomarker candidates, we determined the serum proteins overlapping with the retinal proteins known to be up-regulated in glaucoma. Four of the selected 10 candidates (AIF, cyclic AMP-responsive element binding protein, ephrin type-A receptor, and huntingtin) exhibited higher ELISA titers in the glaucomatous sera. Conclusions. A number of serum proteins identified by this immunoproteomic study of human glaucoma may represent diseased tissue-related antigens and serve as candidate

  9. Linkage analysis of candidate myelin genes in familial multiple sclerosis.

    PubMed

    Seboun, E; Oksenberg, J R; Rombos, A; Usuku, K; Goodkin, D E; Lincoln, R R; Wong, M; Pham-Dinh, D; Boesplug-Tanguy, O; Carsique, R; Fitoussi, R; Gartioux, C; Reyes, C; Ribierre, F; Faure, S; Fizames, C; Gyapay, G; Weissenbach, J; Dautigny, A; Rimmler, J B; Garcia, M E; Pericak-Vance, M A; Haines, J L; Hauser, S L

    1999-09-01

    Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. A complex genetic etiology is thought to underlie susceptibility to this disease. The present study was designed to analyze whether differences in genes that encode myelin proteins influence susceptibility to MS. We performed linkage analysis of MS to markers in chromosomal regions that include the genes encoding myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMGP), and myelin oligodendrocyte glycoprotein (MOG) in a well-characterized population of 65 multiplex MS families consisting of 399 total individuals, 169 affected with MS and 102 affected sibpairs. Physical mapping data permitted placement of MAG and PLP genes on the Genethon genetic map; all other genes were mapped on the Genethon genetic map by linkage analysis. For each gene, at least one marker within the gene and/or two tightly linked flanking markers were analyzed. Marker data analysis employed a combination of genetic trait model-dependent (parametric) and model-independent linkage methods. Results indicate that MAG, MBP, OMGP, and PLP genes do not have a significant genetic effect on susceptibility to MS in this population. As MOG resides within the MHC, a potential role of the MOG gene could not be excluded. PMID:10541588

  10. Analysis of candidate genes for macular telangiectasia type 2

    PubMed Central

    Parmalee, Nancy L.; Schubert, Carl; Merriam, Joanna E.; Allikmets, Kaija; Bird, Alan C.; Gillies, Mark C.; Peto, Tunde; Figueroa, Maria; Friedlander, Martin; Fruttiger, Marcus; Greenwood, John; Moss, Stephen E.; Smith, Lois E.H.; Toomes, Carmel; Inglehearn, Chris F.

    2010-01-01

    Purpose To find the gene(s) responsible for macular telangiectasia type 2 (MacTel) by a candidate-gene screening approach. Methods Candidate genes were selected based on the following criteria: those known to cause or be associated with diseases with phenotypes similar to MacTel, genes with known function in the retinal vasculature or macular pigment transport, genes that emerged from expression microarray data from mouse models designed to mimic MacTel phenotype characteristics, and genes expressed in the retina that are also related to diabetes or hypertension, which have increased prevalence in MacTel patients. Probands from eight families with at least two affected individuals were screened by direct sequencing of 27 candidate genes. Identified nonsynonymous variants were analyzed to determine whether they co-segregate with the disease in families. Allele frequencies were determined by TaqMan analysis of the large MacTel and control cohorts. Results We identified 23 nonsynonymous variants in 27 candidate genes in at least one proband. Of these, eight were known single nucleotide polymorphisms (SNPs) with allele frequencies of >0.05; these variants were excluded from further analyses. Three previously unidentified missense variants, three missense variants with reported disease association, and five rare variants were analyzed for segregation and/or allele frequencies. No variant fulfilled the criteria of being causal for MacTel. A missense mutation, p.Pro33Ser in frizzled homolog (Drosophila) 4 (FZD4), previously suggested as a disease-causing variant in familial exudative vitreoretinopathy, was determined to be a rare benign polymorphism. Conclusions We have ruled out the exons and flanking intronic regions in 27 candidate genes as harboring causal mutations for MacTel. PMID:21179236

  11. Genetic Epidemiology and Nonsyndromic Structural Birth Defects: From Candidate Genes to Epigenetics

    PubMed Central

    Hobbs, Charlotte A.; Chowdhury, Shimul; Cleves, Mario A.; Erickson, Stephen; MacLeod, Stewart L.; Shaw, Gary M.; Shete, Sanjay J.; Witte, John S.; Tycko, Benjamin

    2014-01-01

    Birth defects are a leading cause of infant morbidity and mortality worldwide. The vast majority of birth defects are nonsyndromic, and although their etiologies remain mostly unknown, evidence supports the hypothesis that they result from the complex interaction of genetic, epigenetic, environmental, and lifestyle factors. Since our last review published in 2002 describing the basic tools of genetic epidemiology used to study nonsyndromic structural birth defects, many new approaches have become available and have been used with varying success. Through rapid advances in genomic technologies, investigators are now able to interrogate large portions of the genome at a fraction of previous costs. With next generation sequencing (NGS), research has progressed from assessing a small percentage of single nucleotide polymorphisms (SNPs) to assessing the entire human protein-coding repertoire (exome) – an approach that is starting to uncover rare but informative mutations associated with nonsyndromic birth defects. Here we report on the current state of genetic epidemiology of birth defects and comment on future challenges and opportunities. We consider issues of study design, and we discuss common variant approaches including candidate gene studies and genome-wide association studies (GWAS). We also discuss the complexities embedded in exploring gene-environment interactions. We complete our review by describing new and promising NGS technologies and examining how the study of epigenetic mechanisms could become the key to unraveling the complex etiologies of nonsyndromic structural birth defects. PMID:24515445

  12. Combining case-control and case-trio data from the same population in genetic association analyses: overview of approaches and illustration with a candidate gene study.

    PubMed

    Infante-Rivard, Claire; Mirea, Lucia; Bull, Shelley B

    2009-09-01

    In genetic association studies, investigators compare allele or genotype frequencies in unrelated case and control subjects or examine preferential allele transmissions from parents to affected offspring. In many genetic case-control studies, the collection of DNA material extends to relatives such as parents of cases. Thus, case-control and case-parent trio association analyses are possible. Whereas the goal of collecting genetic information from family members in a study initially designed as a case-control study is to enrich the genetic analysis, increase power, or address concern about population structure bias, methods of combining genetic data from unrelated case and control subjects with genetic trio data from the same study population are not well known. A number of hybrid approaches have been developed that utilize such data together. In this paper, the authors describe key features of genetic case-control and case-parent trio studies and review commonly used methods of genetic analysis for case-parent trio designs. In addition, they provide a pragmatic review of statistical methods and available software for existing hybrid approaches that combine various components of case-control and genetic trio data. The application of all methods is illustrated using a candidate gene study of childhood leukemia that included case-control subjects and their parents. PMID:19635737

  13. Evaluation of a genetically modified foot-and-mouth disease virus vaccine candidate generated by reverse genetics

    PubMed Central

    2012-01-01

    . Thus, the full-length cDNA clone of FMDV can be a useful tool to develop genetically engineered FMDV vaccine candidates to help control porcinophilic FMD epidemics in China. PMID:22591597

  14. Identification of a strawberry flavor gene candidate using an integrated genetic-genomic-analytical chemistry approach

    PubMed Central

    2014-01-01

    Background There is interest in improving the flavor of commercial strawberry (Fragaria × ananassa) varieties. Fruit flavor is shaped by combinations of sugars, acids and volatile compounds. Many efforts seek to use genomics-based strategies to identify genes controlling flavor, and then designing durable molecular markers to follow these genes in breeding populations. In this report, fruit from two cultivars, varying for presence-absence of volatile compounds, along with segregating progeny, were analyzed using GC/MS and RNAseq. Expression data were bulked in silico according to presence/absence of a given volatile compound, in this case γ-decalactone, a compound conferring a peach flavor note to fruits. Results Computationally sorting reads in segregating progeny based on γ-decalactone presence eliminated transcripts not directly relevant to the volatile, revealing transcripts possibly imparting quantitative contributions. One candidate encodes an omega-6 fatty acid desaturase, an enzyme known to participate in lactone production in fungi, noted here as FaFAD1. This candidate was induced by ripening, was detected in certain harvests, and correlated with γ-decalactone presence. The FaFAD1 gene is present in every genotype where γ-decalactone has been detected, and it was invariably missing in non-producers. A functional, PCR-based molecular marker was developed that cosegregates with the phenotype in F1 and BC1 populations, as well as in many other cultivars and wild Fragaria accessions. Conclusions Genetic, genomic and analytical chemistry techniques were combined to identify FaFAD1, a gene likely controlling a key flavor volatile in strawberry. The same data may now be re-sorted based on presence/absence of any other volatile to identify other flavor-affecting candidates, leading to rapid generation of gene-specific markers. PMID:24742080

  15. Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma

    PubMed Central

    Yan, Fengting; Alinari, Lapo; Lustberg, Mark E.; Martin, Ludmila Katherine; Cordero-Nieves, Hector M.; Banasavadi-Siddegowda, Yeshavanth; Virk, Selene; Barnholtz-Sloan, Jill; Bell, Erica Hlavin; Wojton, Jeffrey; Jacob, Naduparambil K.; Chakravarti, Arnab; Nowicki, Michal O.; Wu, Xin; Lapalombella, Rosa; Datta, Jharna; Yu, Bo; Gordon, Kate; Haseley, Amy; Patton, John T.; Smith, Porsha L.; Ryu, John; Zhang, Xiaoli; Mo, Xiaokui; Marcucci, Guido; Nuovo, Gerard; Kwon, Chang-Hyuk; Byrd, John C.; Chiocca, E. Antonio; Li, Chenglong; Sif, Said; Jacob, Samson; Lawler, Sean; Kaur, Balveen; Baiocchi, Robert A.

    2014-01-01

    Glioblastoma (GBM) is the most common and aggressive histologic subtype of brain cancer with poor outcomes and limited treatment options. Here we report the selective overexpression of the protein arginine methyltransferase PRMT5 as a novel candidate theranostic target in this disease. PRMT5 silences the transcription of regulatory genes by catalyzing symmetric di-methylation of arginine residues on histone tails. PRMT5 overexpression in patient-derived primary tumors and cell lines correlated with cell line growth rate and inversely with overall patient survival. Genetic attenuation of PRMT5 led to cell cycle arrest, apoptosis and loss of cell migratory activity. Cell death was p53-independent but caspase-dependent and enhanced with temozolomide, a chemotherapeutic agent used as a present standard of care. Global gene profiling and chromatin immunoprecipitation identified the tumor suppressor ST7 as a key gene silenced by PRMT5. Diminished ST7 expression was associated with reduced patient survival. PRMT5 attenuation limited PRMT5 recruitment to the ST7 promoter, led to restored expression of ST7 and cell growth inhibition. Lastly, PRMT5 attenuation enhanced GBM cell survival in a mouse xenograft model of aggressive GBM. Together, our findings defined PRMT5 as a candidate prognostic factor and therapeutic target in GBM, offering a preclinical justification for targeting PRMT5-driven oncogenic pathways in this deadly disease. PMID:24453002

  16. Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech.

    PubMed

    Peter, Beate; Wijsman, Ellen M; Nato, Alejandro Q; Matsushita, Mark M; Chapman, Kathy L; Stanaway, Ian B; Wolff, John; Oda, Kaori; Gabo, Virginia B; Raskind, Wendy H

    2016-01-01

    Childhood apraxia of speech (CAS) is a severe and socially debilitating form of speech sound disorder with suspected genetic involvement, but the genetic etiology is not yet well understood. Very few known or putative causal genes have been identified to date, e.g., FOXP2 and BCL11A. Building a knowledge base of the genetic etiology of CAS will make it possible to identify infants at genetic risk and motivate the development of effective very early intervention programs. We investigated the genetic etiology of CAS in two large multigenerational families with familial CAS. Complementary genomic methods included Markov chain Monte Carlo linkage analysis, copy-number analysis, identity-by-descent sharing, and exome sequencing with variant filtering. No overlaps in regions with positive evidence of linkage between the two families were found. In one family, linkage analysis detected two chromosomal regions of interest, 5p15.1-p14.1, and 17p13.1-q11.1, inherited separately from the two founders. Single-point linkage analysis of selected variants identified CDH18 as a primary gene of interest and additionally, MYO10, NIPBL, GLP2R, NCOR1, FLCN, SMCR8, NEK8, and ANKRD12, possibly with additive effects. Linkage analysis in the second family detected five regions with LOD scores approaching the highest values possible in the family. A gene of interest was C4orf21 (ZGRF1) on 4q25-q28.2. Evidence for previously described causal copy-number variations and validated or suspected genes was not found. Results are consistent with a heterogeneous CAS etiology, as is expected in many neurogenic disorders. Future studies will investigate genome variants in these and other families with CAS. PMID:27120335

  17. Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech

    PubMed Central

    Wijsman, Ellen M.; Nato, Alejandro Q.; Matsushita, Mark M.; Chapman, Kathy L.; Stanaway, Ian B.; Wolff, John; Oda, Kaori; Gabo, Virginia B.; Raskind, Wendy H.

    2016-01-01

    Childhood apraxia of speech (CAS) is a severe and socially debilitating form of speech sound disorder with suspected genetic involvement, but the genetic etiology is not yet well understood. Very few known or putative causal genes have been identified to date, e.g., FOXP2 and BCL11A. Building a knowledge base of the genetic etiology of CAS will make it possible to identify infants at genetic risk and motivate the development of effective very early intervention programs. We investigated the genetic etiology of CAS in two large multigenerational families with familial CAS. Complementary genomic methods included Markov chain Monte Carlo linkage analysis, copy-number analysis, identity-by-descent sharing, and exome sequencing with variant filtering. No overlaps in regions with positive evidence of linkage between the two families were found. In one family, linkage analysis detected two chromosomal regions of interest, 5p15.1-p14.1, and 17p13.1-q11.1, inherited separately from the two founders. Single-point linkage analysis of selected variants identified CDH18 as a primary gene of interest and additionally, MYO10, NIPBL, GLP2R, NCOR1, FLCN, SMCR8, NEK8, and ANKRD12, possibly with additive effects. Linkage analysis in the second family detected five regions with LOD scores approaching the highest values possible in the family. A gene of interest was C4orf21 (ZGRF1) on 4q25-q28.2. Evidence for previously described causal copy-number variations and validated or suspected genes was not found. Results are consistent with a heterogeneous CAS etiology, as is expected in many neurogenic disorders. Future studies will investigate genome variants in these and other families with CAS. PMID:27120335

  18. Thermodynamic analysis of a kagome spin liquid candidate

    NASA Astrophysics Data System (ADS)

    Han, Tianheng; Bonnoit, Craig; Chisnell, Robin; Helton, Joel; Takano, Yasu; Lee, Young

    2013-03-01

    Herbertsmithite ZnCu3(OH)6Cl2-one of the most promising quantum spin liquid candidates-presents a promising system for studies of frustrated magnetism on an S =1/2 kagomé lattice. Following our recent success in crystal growth, specific heat has been measured at dilution fridge temperatures up to 18 T on a single crystal sample which gives further information on the low temperature phase. Additional analysis of the thermodynamic measurements on single crystal samples lends further hints on the intrinsic spin liquid physics.

  19. Genetic Associations with Diabetes: Meta-Analyses of 10 Candidate Polymorphisms

    PubMed Central

    Wang, Qinwen; Xu, Leiting; Bu, Shizhong; Huang, Yi; Zhang, Cheng; Ye, Huadan; Xu, Xuting; Liu, Qiong; Ye, Meng; Mai, Yifeng; Duan, Shiwei

    2013-01-01

    Aims The goal of our study is to investigate the combined contribution of 10 genetic variants to diabetes susceptibility. Methods Bibliographic databases were searched from 1970 to Dec 2012 for studies that reported on genetic association study of diabetes. After a comprehensive filtering procedure, 10 candidate gene variants with informative genotype information were collected for the current meta-anlayses. Using the REVMAN software, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the combined contribution of the selected genetic variants to diabetes. Results A total of 37 articles among 37,033 cases and 54,716 controls were involved in the present meta-analyses of 10 genetic variants. Three variants were found to be significantly associated with type 1 diabetes (T1D): NLRP1 rs12150220 (OR = 0.71, 95% CI = 0.55–0.92, P = 0.01), IL2RA rs11594656 (OR = 0.86, 95% CI = 0.82–0.91, P<0.00001), and CLEC16A rs725613 (OR = 0.71, 95% CI = 0.55–0.92, P = 0.01). APOA5 −1131T/C polymorphism was shown to be significantly associated with of type 2 diabetes (T2D, OR = 1.27, 95% CI = 1.03–1.57, P = 0.03). No association with diabetes was showed in the meta-analyses of other six genetic variants, including SLC2A10 rs2335491, ATF6 rs2070150, KLF11 rs35927125, CASQ1 rs2275703, GNB3 C825T, and IL12B 1188A/C. Conclusion Our results demonstrated that IL2RA rs11594656 and CLEC16A rs725613 are protective factors of T1D, while NLRP1 rs12150220 and APOA5 −1131T/C are risky factors of T1D and T2D, respectively. PMID:23922971

  20. Meta-analysis in psychiatric genetics.

    PubMed

    Levinson, Douglas F

    2005-04-01

    The article reviews literature on methods for meta-analysis of genetic linkage and association studies, and summarizes and comments on specific meta-analysis findings for psychiatric disorders. The Genome Scan Meta-Analysis and Multiple Scan Probability methods assess the evidence for linkage across studies. Multiple Scan Probability analysis suggested linkage of two chromosomal regions (13q and 22q) to schizophrenia and bipolar disorder, whereas Genome Scan Meta-Analysis on a larger sample identified at least 10 schizophrenia linkage regions, but none for bipolar disorder. Meta-analyses of pooled ORs support association of schizophrenia to the Ser311Cys polymorphism in DRD2 and the T102C polymorphism in HTR2A, and of attention deficit hyperactivity disorder to the 48-bp repeat in DRD4. The 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) may contribute to the risk of bipolar disorder, suicidal behavior, and neuroticism, but association to the lifetime risk of major depression has not been shown. Meta-analyses support linkage of schizophrenia to regions where replicable associations to candidate genes have been identified through positional cloning methods. There are additional supported regions where susceptibility genes are likely to be identified. Linkage meta-analysis has had less clear success for bipolar disorder based on a smaller dataset. Meta-analysis can guide the prioritization of regions for study, but proof of association requires biological confirmation of hypotheses about gene actions. Elucidation of causal mechanisms will require more comprehensive study of sequence variation in candidate genes, better statistical and meta-analytic methods to take all variation into account, and biological strategies for testing etiologic hypotheses. PMID:15802092

  1. Genetic basis of qualitative and quantitative resistance to powdery mildew in wheat: from consensus regions to candidate genes

    PubMed Central

    2013-01-01

    Background Powdery mildew (Blumeria graminis f. sp. tritici) is one of the most damaging diseases of wheat. The objective of this study was to identify the wheat genomic regions that are involved in the control of powdery mildew resistance through a quantitative trait loci (QTL) meta-analysis approach. This meta-analysis allows the use of collected QTL data from different published studies to obtain consensus QTL across different genetic backgrounds, thus providing a better definition of the regions responsible for the trait, and the possibility to obtain molecular markers that will be suitable for marker-assisted selection. Results Five QTL for resistance to powdery mildew were identified under field conditions in the durum-wheat segregating population Creso × Pedroso. An integrated map was developed for the projection of resistance genes/ alleles and the QTL from the present study and the literature, and to investigate their distribution in the wheat genome. Molecular markers that correspond to candidate genes for plant responses to pathogens were also projected onto the map, particularly considering NBS-LRR and receptor-like protein kinases. More than 80 independent QTL and 51 resistance genes from 62 different mapping populations were projected onto the consensus map using the Biomercator statistical software. Twenty-four MQTL that comprised 2–6 initial QTL that had widely varying confidence intervals were found on 15 chromosomes. The co-location of the resistance QTL and genes was investigated. Moreover, from analysis of the sequences of DArT markers, 28 DArT clones mapped on wheat chromosomes have been shown to be associated with the NBS-LRR genes and positioned in the same regions as the MQTL for powdery mildew resistance. Conclusions The results from the present study provide a detailed analysis of the genetic basis of resistance to powdery mildew in wheat. The study of the Creso × Pedroso durum-wheat population has revealed some QTL that had

  2. PCMDI analysis of candidate atmospheric models for CCSM

    SciTech Connect

    Wehner, M F; Taylor, K; Doutriaux, C; AchutaRao, K; Gleckler, P; Hnilo, J; Boyle, J

    2000-12-13

    This report is intended to give a summary analysis of the candidate model configurations under consideration by NCAR for the atmospheric component of next version of the Community Climate System Model (CCSM). Intercomparison results are presented for each of the models available prior to the Atmospheric Model Working Group (AMWG) meeting, December 12-14, 2000. We present four types of figures in this report. The traditional methods of viewing zonal mean surface fields, latitude-longitude maps and zonal mean latitude-height cross sections are straightforward. In each of these cases, we present DJF and JJA climatological averages and a difference from an observational or reanalysis data set. The fourth method of analyzing the candidates' model performance involves the use of ''performance portraits'' and is explained in detail on following pages. As stated by NCAR and the AMWG, the information included in this report should be considered proprietary to NCAR and is not to be cited, consistent with the disclaimer on the AMWG password protected web pages. We deliberately have deferred our conclusions in this printed report to our presentation. Rather, we encourage you to draw your own conclusions based on these figures and other information made available at the AMWG meeting.

  3. Genetic subdivision and candidate genes under selection in North American grey wolves.

    PubMed

    Schweizer, Rena M; vonHoldt, Bridgett M; Harrigan, Ryan; Knowles, James C; Musiani, Marco; Coltman, David; Novembre, John; Wayne, Robert K

    2016-01-01

    Previous genetic studies of the highly mobile grey wolf (Canis lupus) found population structure that coincides with habitat and phenotype differences. We hypothesized that these ecologically distinct populations (ecotypes) should exhibit signatures of selection in genes related to morphology, coat colour and metabolism. To test these predictions, we quantified population structure related to habitat using a genotyping array to assess variation in 42 036 single-nucleotide polymorphisms (SNPs) in 111 North American grey wolves. Using these SNP data and individual-level measurements of 12 environmental variables, we identified six ecotypes: West Forest, Boreal Forest, Arctic, High Arctic, British Columbia and Atlantic Forest. Next, we explored signals of selection across these wolf ecotypes through the use of three complementary methods to detect selection: FST /haplotype homozygosity bivariate percentilae, bayescan, and environmentally correlated directional selection with bayenv. Across all methods, we found consistent signals of selection on genes related to morphology, coat coloration, metabolism, as predicted, as well as vision and hearing. In several high-ranking candidate genes, including LEPR, TYR and SLC14A2, we found variation in allele frequencies that follow environmental changes in temperature and precipitation, a result that is consistent with local adaptation rather than genetic drift. Our findings show that local adaptation can occur despite gene flow in a highly mobile species and can be detected through a moderately dense genomic scan. These patterns of local adaptation revealed by SNP genotyping likely reflect high fidelity to natal habitats of dispersing wolves, strong ecological divergence among habitats, and moderate levels of linkage in the wolf genome. PMID:26333947

  4. [Candidate gene analysis of high quality merino sheep].

    PubMed

    Liu, Gui-Fen; Tian, Ke-Chuan; Zhang, En-Ping; Huang, Xi-Xia; Zhang, Yan-Hua

    2007-01-01

    Partial sequences of wool fiber constituent genes KAP1.1 and KAP1.3 and the exonic sequence of the KAP6.1 gene were chosen for polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis to assess their ability as candidate genes during indirect selection for fine wool traits. Results show that locus W08667 in the genes (KAP1.1, KAP1.3) which code the high sulfur protein associated-protein of keratin associated-protein family is significantly correlated with fine wool quality (P < 0.05). Among the high-glycine-tyrosine keratin associated- protein, the AA and BB genotypes of W06933 are also significantly correlated with fine wool quality (P < 0.05). PMID:17284427

  5. Optimisation of contribution of candidate parents to maximise genetic gain and restricting inbreeding using semidefinite programming (Open Access publication)

    PubMed Central

    Pong-Wong, Ricardo; Woolliams, John A

    2007-01-01

    An approach for optimising genetic contributions of candidates to control inbreeding in the offspring generation using semidefinite programming (SDP) was proposed. Formulations were done for maximising genetic gain while restricting inbreeding to a preset value and for minimising inbreeding without regard of gain. Adaptations to account for candidates with fixed contributions were also shown. Using small but traceable numerical examples, the SDP method was compared with an alternative based upon Lagrangian multipliers (RSRO). The SDP method always found the optimum solution that maximises genetic gain at any level of restriction imposed on inbreeding, unlike RSRO which failed to do so in several situations. For these situations, the expected gains from the solution obtained with RSRO were between 1.5–9% lower than those expected from the optimum solution found with SDP with assigned contributions varying widely. In conclusion SDP is a reliable and flexible method for solving contribution problems. PMID:17212945

  6. A Multiple Interaction Analysis Reveals ADRB3 as a Potential Candidate for Gallbladder Cancer Predisposition via a Complex Interaction with Other Candidate Gene Variations

    PubMed Central

    Rai, Rajani; Kim, Jong Joo; Misra, Sanjeev; Kumar, Ashok; Mittal, Balraj

    2015-01-01

    Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors. Previously, we demonstrated the association of several candidate gene variations with GBC risk. In this study, we aimed to identify the combination of gene variants and their possible interactions contributing towards genetic susceptibility of GBC. Here, we performed Multifactor-Dimensionality Reduction (MDR) and Classification and Regression Tree Analysis (CRT) to investigate the gene–gene interactions and the combined effect of 14 SNPs in nine genes (DR4 (rs20576, rs6557634); FAS (rs2234767); FASL (rs763110); DCC (rs2229080, rs4078288, rs7504990, rs714); PSCA (rs2294008, rs2978974); ADRA2A (rs1801253); ADRB1 (rs1800544); ADRB3 (rs4994); CYP17 (rs2486758)) involved in various signaling pathways. Genotyping was accomplished by PCR-RFLP or Taqman allelic discrimination assays. SPSS software version 16.0 and MDR software version 2.0 were used for all the statistical analysis. Single locus investigation demonstrated significant association of DR4 (rs20576, rs6557634), DCC (rs714, rs2229080, rs4078288) and ADRB3 (rs4994) polymorphisms with GBC risk. MDR analysis revealed ADRB3 (rs4994) to be crucial candidate in GBC susceptibility that may act either alone (p < 0.0001, CVC = 10/10) or in combination with DCC (rs714 and rs2229080, p < 0.0001, CVC = 9/10). Our CRT results are in agreement with the above findings. Further, in-silico results of studied SNPs advocated their role in splicing, transcriptional and/or protein coding regulation. Overall, our result suggested complex interactions amongst the studied SNPs and ADRB3 rs4994 as candidate influencing GBC susceptibility. PMID:26602921

  7. A Multiple Interaction Analysis Reveals ADRB3 as a Potential Candidate for Gallbladder Cancer Predisposition via a Complex Interaction with Other Candidate Gene Variations.

    PubMed

    Rai, Rajani; Kim, Jong Joo; Misra, Sanjeev; Kumar, Ashok; Mittal, Balraj

    2015-01-01

    Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors. Previously, we demonstrated the association of several candidate gene variations with GBC risk. In this study, we aimed to identify the combination of gene variants and their possible interactions contributing towards genetic susceptibility of GBC. Here, we performed Multifactor-Dimensionality Reduction (MDR) and Classification and Regression Tree Analysis (CRT) to investigate the gene-gene interactions and the combined effect of 14 SNPs in nine genes (DR4 (rs20576, rs6557634); FAS (rs2234767); FASL (rs763110); DCC (rs2229080, rs4078288, rs7504990, rs714); PSCA (rs2294008, rs2978974); ADRA2A (rs1801253); ADRB1 (rs1800544); ADRB3 (rs4994); CYP17 (rs2486758)) involved in various signaling pathways. Genotyping was accomplished by PCR-RFLP or Taqman allelic discrimination assays. SPSS software version 16.0 and MDR software version 2.0 were used for all the statistical analysis. Single locus investigation demonstrated significant association of DR4 (rs20576, rs6557634), DCC (rs714, rs2229080, rs4078288) and ADRB3 (rs4994) polymorphisms with GBC risk. MDR analysis revealed ADRB3 (rs4994) to be crucial candidate in GBC susceptibility that may act either alone (p < 0.0001, CVC = 10/10) or in combination with DCC (rs714 and rs2229080, p < 0.0001, CVC = 9/10). Our CRT results are in agreement with the above findings. Further, in-silico results of studied SNPs advocated their role in splicing, transcriptional and/or protein coding regulation. Overall, our result suggested complex interactions amongst the studied SNPs and ADRB3 rs4994 as candidate influencing GBC susceptibility. PMID:26602921

  8. A systems approach to the biology of mood disorders through network analysis of candidate genes.

    PubMed

    Detera-Wadleigh, S D; Akula, N

    2011-05-01

    Meta analysis of association data of mood disorders has shown evidence for the role of particular genes in genetic risk. Integration of association data from meta analysis with differential expression data in brains of mood disorder patients could heighten the level of support for specific genes. To identify molecular mechanisms that may be disrupted in disease, a systems approach that involves analysis of biological networks created by these selected genes was employed.Interaction networks of hierarchical groupings of selected genes were generated using the Michigan Molecular Interactions (MiMI) software. Large networks were deconvoluted into subclusters of core complexes by using a community clustering program, GLay. Network nodes were functionally annotated in DAVID Bioinformatics Resource to identify enriched pathways and functional clusters. MAPK and beta adrenergic receptor signaling pathways were significantly enriched in the ANK3 and CACNA1C network. The PBRM1 network bolstered the enrichment of chromatin remodeling and transcription regulation functional clusters. Lowering the stringency for inclusion of other genes in network seeds increased network complexity and expanded the recruitment of enriched pathways to include signaling by neurotransmitter and hormone receptors, neurotrophin, ErbB and the cell cycle. We present a strategy to interrogate mechanisms in the cellular system that might be perturbed in disease. Network analysis of meta analysis- generated candidate genes that exhibited differential expression in mood disorder brains identified signaling pathways and functional clusters that may be involved in genetic risk for mood disorders. PMID:21547870

  9. High volume molecular genetic identification of single nucleotide polymorphisms using Genetic Bit Analysis Application to human genetic diagnosis

    SciTech Connect

    Boyce-Jacino, M.T.; Reynolds, J.; Nikiforov, T.

    1994-09-01

    The most common type of genetic disease-associated mutation is the single nucleotide polymorphism (SNP). Because most genetic diseases can be caused by multiple SNPs in the same gene, effective routine diagnosis of complex genetic diseases is dependent on a simple and reliable method of interrogating SNP sites. Molecular Tool`s solid phase assay capable of direct genotyping (single base sequencing) of SNP sites, Genetic Bit Analysis (GBA), involves hybridization-capture of a single-stranded PCR product to a sequence-specific, microtiter plate-bound oligonucleotide primer. The captured PCR product then acts as template for single-base extension of the capture primer across the polymorphic site, enabling direct determination of the base composition of the polymorphism through a simple colormetric assay. Genotyping in a high volume, semi-automated, processing system with a current capacity of 100 SNP interrogations per technician per day enables the screening of candidate mutations rapidly and cost-effectively, critically important to comprehensive genetic diagnosis. Using this gel-free technology, we have developed prototype diagnostic tests for CFTR and ApoE polymorphisms which enable direct sequencing of the polymorphic base at each site of interest. Routine clinical diagnosis of genetically complex diseases such as cystic fibrosis is dependent on this combination of robust biochemistry and simple format. Additionally, the ability to transfer the format and biochemistry to any disease gene of interest enables the broad application of this technology to clinical diagnostics, especially for genetically complex diseases.

  10. Root Transcriptome Analysis of Wild Peanut Reveals Candidate Genes for Nematode Resistance.

    PubMed

    Guimaraes, Patricia M; Guimaraes, Larissa A; Morgante, Carolina V; Silva, Orzenil B; Araujo, Ana Claudia G; Martins, Andressa C Q; Saraiva, Mario A P; Oliveira, Thais N; Togawa, Roberto C; Leal-Bertioli, Soraya C M; Bertioli, David J; Brasileiro, Ana Cristina M

    2015-01-01

    Wild peanut relatives (Arachis spp.) are genetically diverse and were adapted to a range of environments during the evolution course, constituting an important source of allele diversity for resistance to biotic and abiotic stresses. The wild diploid A. stenosperma harbors high levels of resistance to a variety of pathogens, including the root-knot nematode (RKN) Meloidogyne arenaria, through the onset of the Hypersensitive Response (HR). In order to identify genes and regulators triggering this defense response, a comprehensive root transcriptome analysis during the first stages of this incompatible interaction was conducted using Illumina Hi-Seq. Overall, eight cDNA libraries were produced generating 28.2 GB, which were de novo assembled into 44,132 contigs and 37,882 loci. Differentially expressed genes (DEGs) were identified and clustered according to their expression profile, with the majority being downregulated at 6 DAI, which coincides with the onset of the HR. Amongst these DEGs, 27 were selected for further qRT-PCR validation allowing the identification of nematode-responsive candidate genes that are putatively related to the resistance response. Those candidates are engaged in the salycilic (NBS-LRR, lipocalins, resveratrol synthase) and jasmonic (patatin, allene oxidase cyclase) acids pathways, and also related to hormonal balance (auxin responsive protein, GH3) and cellular plasticity and signaling (tetraspanin, integrin, expansin), with some of them showing contrasting expression behavior between Arachis RKN-resistant and susceptible genotypes. As these candidate genes activate different defensive signaling systems, the genetic (HR) and the induced resistance (IR), their pyramidding in one genotype via molecular breeding or transgenic strategy might contribute to a more durable resistance, thus improving the long-term control of RKN in peanut. PMID:26488731

  11. Root Transcriptome Analysis of Wild Peanut Reveals Candidate Genes for Nematode Resistance

    PubMed Central

    Guimaraes, Patricia M.; Guimaraes, Larissa A.; Morgante, Carolina V.; Silva, Orzenil B.; Araujo, Ana Claudia G.; Martins, Andressa C. Q.; Saraiva, Mario A. P.; Oliveira, Thais N.; Togawa, Roberto C.; Leal-Bertioli, Soraya C. M.; Bertioli, David J.; Brasileiro, Ana Cristina M.

    2015-01-01

    Wild peanut relatives (Arachis spp.) are genetically diverse and were adapted to a range of environments during the evolution course, constituting an important source of allele diversity for resistance to biotic and abiotic stresses. The wild diploid A. stenosperma harbors high levels of resistance to a variety of pathogens, including the root-knot nematode (RKN) Meloidogyne arenaria, through the onset of the Hypersensitive Response (HR). In order to identify genes and regulators triggering this defense response, a comprehensive root transcriptome analysis during the first stages of this incompatible interaction was conducted using Illumina Hi-Seq. Overall, eight cDNA libraries were produced generating 28.2 GB, which were de novo assembled into 44,132 contigs and 37,882 loci. Differentially expressed genes (DEGs) were identified and clustered according to their expression profile, with the majority being downregulated at 6 DAI, which coincides with the onset of the HR. Amongst these DEGs, 27 were selected for further qRT-PCR validation allowing the identification of nematode-responsive candidate genes that are putatively related to the resistance response. Those candidates are engaged in the salycilic (NBS-LRR, lipocalins, resveratrol synthase) and jasmonic (patatin, allene oxidase cyclase) acids pathways, and also related to hormonal balance (auxin responsive protein, GH3) and cellular plasticity and signaling (tetraspanin, integrin, expansin), with some of them showing contrasting expression behavior between Arachis RKN-resistant and susceptible genotypes. As these candidate genes activate different defensive signaling systems, the genetic (HR) and the induced resistance (IR), their pyramidding in one genotype via molecular breeding or transgenic strategy might contribute to a more durable resistance, thus improving the long-term control of RKN in peanut. PMID:26488731

  12. Candidate gene analysis of GH1 for effects on growth and carcass composition of cattle.

    PubMed

    Taylor, J F; Coutinho, L L; Herring, K L; Gallagher, D S; Brenneman, R A; Burney, N; Sanders, J O; Turner, J W; Smith, S B; Miller, R K; Savell, J W; Davis, S K

    1998-06-01

    We present an approach to evaluate the support for candidate genes as quantitative trait loci (QTLs) within the context of genome-wide map-based cloning strategies. To establish candidacy, a bacterial artificial chromosome (BAC) clone containing a putative candidate gene is physically assigned to an anchored linkage map to localise the gene relative to an identified QTL effect. Microsatellite loci derived from BAC clones containing an established candidate gene are integrated into the linkage map facilitating the evaluation by interval analysis of the statistical support for QTL identity. Permutation analysis is employed to determine experiment-wise statistical support. The approach is illustrated for the growth hormone 1 (GH1) gene and growth and carcass phenotypes in cattle. Polymerase chain reaction (PCR) primers which amplify a 441 bp fragment of GH1 were used to systematically screen a bovine BAC library comprising 60,000 clones and with a 95% probability of containing a single copy sequence. The presence of GH1 in BAC-110R2C3 was confirmed by sequence analysis of the PCR product from this clone and by the physical assignment of BAC110R2C3 to bovine chromosome 19 (BTA19) band 22 by fluorescence in situ hybridisation (FISH). Microsatellite KHGH1 was isolated from BAC110R2C3 and scored in 529 reciprocal backcross and F2 fullsib progeny from 41 resource families derived from Angus (Bos taurus) and Brahman (Bos indicus). The microsatellite KHGH1 was incorporated into a framework genetic map of BTA19 comprising 12 microsatellite loci, the erythrocyte antigen T and a GH1-TaqI restriction fragment length polymorphism (RFLP). Interval analysis localised effects of taurus vs. indicus alleles on subcutaneous fat and the percentage of either extractable fat from the Iongissimus dorsi muscle to the region of BTA19 harbouring GH1. PMID:9720178

  13. Shared Pathways Among Autism Candidate Genes Determined by Co-expression Network Analysis of the Developing Human Brain Transcriptome.

    PubMed

    Mahfouz, Ahmed; Ziats, Mark N; Rennert, Owen M; Lelieveldt, Boudewijn P F; Reinders, Marcel J T

    2015-12-01

    Autism spectrum disorder (ASD) is a neurodevelopmental syndrome known to have a significant but complex genetic etiology. Hundreds of diverse genes have been implicated in ASD; yet understanding how many genes, each with disparate function, can all be linked to a single clinical phenotype remains unclear. We hypothesized that understanding functional relationships between autism candidate genes during normal human brain development may provide convergent mechanistic insight into the genetic heterogeneity of ASD. We analyzed the co-expression relationships of 455 genes previously implicated in autism using the BrainSpan human transcriptome database, across 16 anatomical brain regions spanning prenatal life through adulthood. We discovered modules of ASD candidate genes with biologically relevant temporal co-expression dynamics, which were enriched for functional ontologies related to synaptogenesis, apoptosis, and GABA-ergic neurons. Furthermore, we also constructed co-expression networks from the entire transcriptome and found that ASD candidate genes were enriched in modules related to mitochondrial function, protein translation, and ubiquitination. Hub genes central to these ASD-enriched modules were further identified, and their functions supported these ontological findings. Overall, our multi-dimensional co-expression analysis of ASD candidate genes in the normal developing human brain suggests the heterogeneous set of ASD candidates share transcriptional networks related to synapse formation and elimination, protein turnover, and mitochondrial function. PMID:26399424

  14. Molecular Mapping and Candidate Gene Analysis for Numerous Spines on the Fruit of Cucumber.

    PubMed

    Zhang, Shengping; Liu, Shulin; Miao, Han; Wang, Min; Liu, Panna; Wehner, Todd C; Gu, Xingfang

    2016-09-01

    Number of spines on the fruit is an important quality trait in cucumber. The inheritance and identification of molecular markers for fruit spine density gene can provide a basis for breeding and lay the foundation for gene cloning. Cucumber inbred lines NCG-122 with numerous spines and NCG-121 with few spines were used for genetic analysis and gene mapping in this study. Genetic analysis showed that the numerous spines trait in NCG-122 was qualitative, and a single recessive nuclear gene (ns) controlled this trait. The few spines trait was dominant over the numerous spines trait. In the preliminary genetic mapping of the ns gene, 8 SSR markers were found to be linked to ns, which mapped to chromosome 2 (Chr.2) of cucumber. The closest flanking markers SSR22338 and SSR11596 were linked to the ns gene, with genetic distances of 10.2 and 1.7cM, respectively. One-hundred and thirty pairs of new SSR primers and 28 pairs of Indel primers were developed based on sequence information in the preliminary mapping region of ns Fifteen SSR markers and 2 Indel markers were identified to be linked to the ns gene after analysis on the F2 mapping population using the new molecular markers. The 2 closest flanking markers, SSRns-127 and SSR04219, were 0.7 and 2.4 cM from ns, respectively. The physical distance between SSRns-127 and SSR04219 was 266.1kb, containing 27 predicted genes. Csa2G285390 was speculated as the probable candidate gene for numerous spines. The accuracy of the closest linked marker to the ns gene, SSRns-127, for MAS breeding was 95.0%. PMID:27317924

  15. A roadmap for the genetic analysis of renal aging.

    PubMed

    Noordmans, Gerda A; Hillebrands, Jan-Luuk; van Goor, Harry; Korstanje, Ron

    2015-10-01

    Several studies show evidence for the genetic basis of renal disease, which renders some individuals more prone than others to accelerated renal aging. Studying the genetics of renal aging can help us to identify genes involved in this process and to unravel the underlying pathways. First, this opinion article will give an overview of the phenotypes that can be observed in age-related kidney disease. Accurate phenotyping is essential in performing genetic analysis. For kidney aging, this could include both functional and structural changes. Subsequently, this article reviews the studies that report on candidate genes associated with renal aging in humans and mice. Several loci or candidate genes have been found associated with kidney disease, but identification of the specific genetic variants involved has proven to be difficult. CUBN, UMOD, and SHROOM3 were identified by human GWAS as being associated with albuminuria, kidney function, and chronic kidney disease (CKD). These are promising examples of genes that could be involved in renal aging, and were further mechanistically evaluated in animal models. Eventually, we will provide approaches for performing genetic analysis. We should leverage the power of mouse models, as testing in humans is limited. Mouse and other animal models can be used to explain the underlying biological mechanisms of genes and loci identified by human GWAS. Furthermore, mouse models can be used to identify genetic variants associated with age-associated histological changes, of which Far2, Wisp2, and Esrrg are examples. A new outbred mouse population with high genetic diversity will facilitate the identification of genes associated with renal aging by enabling high-resolution genetic mapping while also allowing the control of environmental factors, and by enabling access to renal tissues at specific time points for histology, proteomics, and gene expression. PMID:26219736

  16. A roadmap for the genetic analysis of renal aging

    PubMed Central

    Noordmans, Gerda A; Hillebrands, Jan-Luuk; van Goor, Harry; Korstanje, Ron

    2015-01-01

    Several studies show evidence for the genetic basis of renal disease, which renders some individuals more prone than others to accelerated renal aging. Studying the genetics of renal aging can help us to identify genes involved in this process and to unravel the underlying pathways. First, this opinion article will give an overview of the phenotypes that can be observed in age-related kidney disease. Accurate phenotyping is essential in performing genetic analysis. For kidney aging, this could include both functional and structural changes. Subsequently, this article reviews the studies that report on candidate genes associated with renal aging in humans and mice. Several loci or candidate genes have been found associated with kidney disease, but identification of the specific genetic variants involved has proven to be difficult. CUBN, UMOD, and SHROOM3 were identified by human GWAS as being associated with albuminuria, kidney function, and chronic kidney disease (CKD). These are promising examples of genes that could be involved in renal aging, and were further mechanistically evaluated in animal models. Eventually, we will provide approaches for performing genetic analysis. We should leverage the power of mouse models, as testing in humans is limited. Mouse and other animal models can be used to explain the underlying biological mechanisms of genes and loci identified by human GWAS. Furthermore, mouse models can be used to identify genetic variants associated with age-associated histological changes, of which Far2, Wisp2, and Esrrg are examples. A new outbred mouse population with high genetic diversity will facilitate the identification of genes associated with renal aging by enabling high-resolution genetic mapping while also allowing the control of environmental factors, and by enabling access to renal tissues at specific time points for histology, proteomics, and gene expression. PMID:26219736

  17. Using the PhenoGen Website for “In Silico” Analysis of Morphine-Induced Analgesia: Identifying Candidate Genes

    PubMed Central

    Hoffman, Paula L.; Bennett, Beth; Saba, Laura M.; Bhave, Sanjiv V.; Carosone-Link, Phyllis J.; Hornbaker, Cheryl K.; Kechris, Katerina J.; Williams, Robert W.; Tabakoff, Boris

    2010-01-01

    The identification of genes that contribute to polygenic (complex) behavioral phenotypes is a key goal of current genetic research. One approach to this goal is to combine gene expression information with genetic information, i.e., to map chromosomal regions that regulate gene expression levels. This approach has been termed “genetical genomics”, and, when used in conjunction with the identification of genomic regions (QTLs) that regulate the complex physiological trait under investigation, provides a strong basis for candidate gene discovery. In this paper, we describe the implementation of the genetical genomic/phenotypic approach to identify candidate genes for sensitivity to the analgesic effect of morphine in BXD recombinant inbred mice. Our analysis was performed “in silico”, using an online interactive resource called PhenoGen (http://phenogen.ucdenver.edu). We describe in detail the use of this resource, which identified a set of candidate genes, some of whose products regulate the cellular localization and activity of the mu opiate receptor. The results demonstrate how PhenoGen can be used to identify a novel set of genes that can be further investigated for their potential role in pain, morphine analgesia and/or morphine tolerance. PMID:21054686

  18. Placental Genome and Maternal-Placental Genetic Interactions: A Genome-Wide and Candidate Gene Association Study of Placental Abruption

    PubMed Central

    Denis, Marie; Enquobahrie, Daniel A.; Tadesse, Mahlet G.; Gelaye, Bizu; Sanchez, Sixto E.; Salazar, Manuel; Ananth, Cande V.; Williams, Michelle A.

    2014-01-01

    While available evidence supports the role of genetics in the pathogenesis of placental abruption (PA), PA-related placental genome variations and maternal-placental genetic interactions have not been investigated. Maternal blood and placental samples collected from participants in the Peruvian Abruptio Placentae Epidemiology study were genotyped using Illumina’s Cardio-Metabochip platform. We examined 118,782 genome-wide SNPs and 333 SNPs in 32 candidate genes from mitochondrial biogenesis and oxidative phosphorylation pathways in placental DNA from 280 PA cases and 244 controls. We assessed maternal-placental interactions in the candidate gene SNPS and two imprinted regions (IGF2/H19 and C19MC). Univariate and penalized logistic regression models were fit to estimate odds ratios. We examined the combined effect of multiple SNPs on PA risk using weighted genetic risk scores (WGRS) with repeated ten-fold cross-validations. A multinomial model was used to investigate maternal-placental genetic interactions. In placental genome-wide and candidate gene analyses, no SNP was significant after false discovery rate correction. The top genome-wide association study (GWAS) hits were rs544201, rs1484464 (CTNNA2), rs4149570 (TNFRSF1A) and rs13055470 (ZNRF3) (p-values: 1.11e-05 to 3.54e-05). The top 200 SNPs of the GWAS overrepresented genes involved in cell cycle, growth and proliferation. The top candidate gene hits were rs16949118 (COX10) and rs7609948 (THRB) (p-values: 6.00e-03 and 8.19e-03). Participants in the highest quartile of WGRS based on cross-validations using SNPs selected from the GWAS and candidate gene analyses had a 8.40-fold (95% CI: 5.8–12.56) and a 4.46-fold (95% CI: 2.94–6.72) higher odds of PA compared to participants in the lowest quartile. We found maternal-placental genetic interactions on PA risk for two SNPs in PPARG (chr3∶12313450 and chr3∶12412978) and maternal imprinting effects for multiple SNPs in the C19MC and IGF2/H19 regions

  19. Methods for genetic linkage analysis using trisomies

    SciTech Connect

    Feingold, E.; Lamb, N.E.; Sherman, S.L.

    1995-02-01

    Certain genetic disorders are rare in the general population, but more common in individuals with specific trisomies. Examples of this include leukemia and duodenal atresia in trisomy 21. This paper presents a linkage analysis method for using trisomic individuals to map genes for such traits. It is based on a very general gene-specific dosage model that posits that the trait is caused by specific effects of different alleles at one or a few loci and that duplicate copies of {open_quotes}susceptibility{close_quotes} alleles inherited from the nondisjoining parent give increased likelihood of having the trait. Our mapping method is similar to identity-by-descent-based mapping methods using affected relative pairs and also to methods for mapping recessive traits using inbred individuals by looking for markers with greater than expected homozygosity by descent. In the trisomy case, one would take trisomic individuals and look for markers with greater than expected homozygosity in the chromosomes inherited from the nondisjoining parent. We present statistical methods for performing such a linkage analysis, including a test for linkage to a marker, a method for estimating the distance from the marker to the trait gene, a confidence interval for that distance, and methods for computing power and sample sizes. We also resolve some practical issues involved in implementing the methods, including how to use partially informative markers and how to test candidate genes. 20 refs., 5 figs., 1 tab.

  20. Using a Candidate Gene-Based Genetic Linkage Map to Identify QTL for Winter Survival in Perennial Ryegrass.

    PubMed

    Paina, Cristiana; Byrne, Stephen L; Studer, Bruno; Rognli, Odd Arne; Asp, Torben

    2016-01-01

    Important agronomical traits in perennial ryegrass (Lolium perenne) breeding programs such as winter survival and heading date, are quantitative traits that are generally controlled by multiple loci. Individually, these loci have relatively small effects. The aim of this study was to develop a candidate gene based Illumina GoldenGate 1,536-plex assay, containing single nucleotide polymorphism markers designed from transcripts involved in response to cold acclimation, vernalization, and induction of flowering. The assay was used to genotype a mapping population that we have also phenotyped for winter survival to complement the heading date trait previously mapped in this population. A positive correlation was observed between strong vernalization requirement and winter survival, and some QTL for winter survival and heading date overlapped on the genetic map. Candidate genes were located in clusters along the genetic map, some of which co-localized with QTL for winter survival and heading date. These clusters of candidate genes may be used in candidate gene based association studies to identify alleles associated with winter survival and heading date. PMID:27010567

  1. Using a Candidate Gene-Based Genetic Linkage Map to Identify QTL for Winter Survival in Perennial Ryegrass

    PubMed Central

    Paina, Cristiana; Byrne, Stephen L.; Studer, Bruno; Rognli, Odd Arne; Asp, Torben

    2016-01-01

    Important agronomical traits in perennial ryegrass (Lolium perenne) breeding programs such as winter survival and heading date, are quantitative traits that are generally controlled by multiple loci. Individually, these loci have relatively small effects. The aim of this study was to develop a candidate gene based Illumina GoldenGate 1,536-plex assay, containing single nucleotide polymorphism markers designed from transcripts involved in response to cold acclimation, vernalization, and induction of flowering. The assay was used to genotype a mapping population that we have also phenotyped for winter survival to complement the heading date trait previously mapped in this population. A positive correlation was observed between strong vernalization requirement and winter survival, and some QTL for winter survival and heading date overlapped on the genetic map. Candidate genes were located in clusters along the genetic map, some of which co-localized with QTL for winter survival and heading date. These clusters of candidate genes may be used in candidate gene based association studies to identify alleles associated with winter survival and heading date. PMID:27010567

  2. Integrated analysis of genetic data with R

    PubMed Central

    2006-01-01

    Genetic data are now widely available. There is, however, an apparent lack of concerted effort to produce software systems for statistical analysis of genetic data compared with other fields of statistics. It is often a tremendous task for end-users to tailor them for particular data, especially when genetic data are analysed in conjunction with a large number of covariates. Here, R http://www.r-project.org, a free, flexible and platform-independent environment for statistical modelling and graphics is explored as an integrated system for genetic data analysis. An overview of some packages currently available for analysis of genetic data is given. This is followed by examples of package development and practical applications. With clear advantages in data management, graphics, statistical analysis, programming, internet capability and use of available codes, it is a feasible, although challenging, task to develop it into an integrated platform for genetic analysis; this will require the joint efforts of many researchers. PMID:16460651

  3. Association Analysis Suggests SOD2 as a Newly Identified Candidate Gene Associated With Leprosy Susceptibility.

    PubMed

    Ramos, Geovana Brotto; Salomão, Heloisa; Francio, Angela Schneider; Fava, Vinícius Medeiros; Werneck, Renata Iani; Mira, Marcelo Távora

    2016-08-01

    Genetic studies have identified several genes and genomic regions contributing to the control of host susceptibility to leprosy. Here, we test variants of the positional and functional candidate gene SOD2 for association with leprosy in 2 independent population samples. Family-based analysis revealed an association between leprosy and allele G of marker rs295340 (P = .042) and borderline evidence of an association between leprosy and alleles C and A of markers rs4880 (P = .077) and rs5746136 (P = .071), respectively. Findings were validated in an independent case-control sample for markers rs295340 (P = .049) and rs4880 (P = .038). These results suggest SOD2 as a newly identified gene conferring susceptibility to leprosy. PMID:27132285

  4. Rare genetic variant analysis on blood pressure in related samples

    PubMed Central

    2014-01-01

    The genetic variants associated with blood pressure identified so far explain only a small proportion of the total heritability of this trait. With recent advances in sequencing technology and statistical methodology, it becomes feasible to study the association between blood pressure and rare genetic variants. Using real baseline phenotype data and imputed dosage data from Genetic Analysis Workshop 18, we performed a candidate gene association analysis. We focused on 8 genes shown to be associated with either systolic or diastolic blood pressure to identify the association with both common and rare genetic variants, and then did a genome-wide rare-variant analysis on blood pressure. We performed association analysis for rare coding and splicing variants within each gene region and all rare variants in each sliding window, using either burden tests or sequence kernel association tests accounting for familial correlation. With a sample size of only 747, we failed to find any novel associated genetic loci. Consequently, we performed analyses on simulated data, with knowledge of the underlying simulating model, to evaluate the type I error rate and power for the methods used in real data analysis. PMID:25519320

  5. Genetic analysis of safflower domestication

    PubMed Central

    2014-01-01

    Background Safflower (Carthamus tinctorius L.) is an oilseed crop in the Compositae (a.k.a. Asteraceae) that is valued for its oils rich in unsaturated fatty acids. Here, we present an analysis of the genetic architecture of safflower domestication and compare our findings to those from sunflower (Helianthus annuus L.), an independently domesticated oilseed crop within the same family. We mapped quantitative trait loci (QTL) underlying 24 domestication-related traits in progeny from a cross between safflower and its wild progenitor, Carthamus palaestinus Eig. Also, we compared QTL positions in safflower against those that have been previously identified in cultivated x wild sunflower crosses to identify instances of colocalization. Results We mapped 61 QTL, the vast majority of which (59) exhibited minor or moderate phenotypic effects. The two large-effect QTL corresponded to one each for flower color and leaf spininess. A total of 14 safflower QTL colocalized with previously reported sunflower QTL for the same traits. Of these, QTL for three traits (days to flower, achene length, and number of selfed seed) had cultivar alleles that conferred effects in the same direction in both species. Conclusions As has been observed in sunflower, and unlike many other crops, our results suggest that the genetics of safflower domestication is quite complex. Moreover, our comparative mapping results indicate that safflower and sunflower exhibit numerous instances of QTL colocalization, suggesting that parallel trait transitions during domestication may have been driven, at least in part, by parallel genotypic evolution at some of the same underlying genes. PMID:24502326

  6. Genomic convergence to identify candidate genes for Parkinson disease: SAGE analysis of the substantia nigra.

    PubMed

    Noureddine, Maher A; Li, Yi-Ju; van der Walt, Joelle M; Walters, Robert; Jewett, Rita M; Xu, Hong; Wang, Tianyuan; Walter, Jeffrey W; Scott, Burton L; Hulette, Christine; Schmechel, Don; Stenger, Judith E; Dietrich, Fred; Vance, Jeffery M; Hauser, Michael A

    2005-10-01

    Genomic convergence is a multistep approach that combines gene expression with genomic linkage to identify and prioritize susceptibility genes for complex disease. As a first step, we previously performed linkage analysis on 174 multiplex Parkinson's disease (PD) families, identifying five peaks for PD risk and two for genes affecting age at onset (AAO) in PD [Hauser et al., Hum Mol Genet 2003;12:671-677]. We report here the next step: serial analysis of gene expression [SAGE; Scott et al., JAMA 2001;286:2239-2242] to analyze substantia nigra tissue from three PD patients and two age-matched controls. We find 933 differentially expressed genes (P<0.05) between PD and controls, but of these, only 50 genes represented by unique SAGE tags map within our previously described PD linkage regions. Furthermore, genes encoded by mitochondrial DNA are expressed 1.5-fold higher in PD patients versus controls, without an increase in the corresponding nuclear-encoded mitochondrial components, suggesting an increase in mtDNA genomes in PD or a disjunction with nuclear expression. The next step in the genomic convergence process will be to screen these 50 high-quality candidate genes for association with PD risk susceptibility and genetic effects on AAO. PMID:15966006

  7. A genetic predictive model for canine hip dysplasia: integration of Genome Wide Association Study (GWAS) and candidate gene approaches.

    PubMed

    Bartolomé, Nerea; Segarra, Sergi; Artieda, Marta; Francino, Olga; Sánchez, Elisenda; Szczypiorska, Magdalena; Casellas, Joaquim; Tejedor, Diego; Cerdeira, Joaquín; Martínez, Antonio; Velasco, Alfonso; Sánchez, Armand

    2015-01-01

    Canine hip dysplasia is one of the most prevalent developmental orthopedic diseases in dogs worldwide. Unfortunately, the success of eradication programs against this disease based on radiographic diagnosis is low. Adding the use of diagnostic genetic tools to the current phenotype-based approach might be beneficial. The aim of this study was to develop a genetic prognostic test for early diagnosis of hip dysplasia in Labrador Retrievers. To develop our DNA test, 775 Labrador Retrievers were recruited. For each dog, a blood sample and a ventrodorsal hip radiograph were taken. Dogs were divided into two groups according to their FCI hip score: control (A/B) and case (D/E). C dogs were not included in the sample. Genetic characterization combining a GWAS and a candidate gene strategy using SNPs allowed a case-control population association study. A mathematical model which included 7 SNPs was developed using logistic regression. The model showed a good accuracy (Area under the ROC curve = 0.85) and was validated in an independent population of 114 dogs. This prognostic genetic test represents a useful tool for choosing the most appropriate therapeutic approach once genetic predisposition to hip dysplasia is known. Therefore, it allows a more individualized management of the disease. It is also applicable during genetic selection processes, since breeders can benefit from the information given by this test as soon as a blood sample can be collected, and act accordingly. In the authors' opinion, a shift towards genomic screening might importantly contribute to reducing canine hip dysplasia in the future. In conclusion, based on genetic and radiographic information from Labrador Retrievers with hip dysplasia, we developed an accurate predictive genetic test for early diagnosis of hip dysplasia in Labrador Retrievers. However, further research is warranted in order to evaluate the validity of this genetic test in other dog breeds. PMID:25874693

  8. A Genetic Predictive Model for Canine Hip Dysplasia: Integration of Genome Wide Association Study (GWAS) and Candidate Gene Approaches

    PubMed Central

    Bartolomé, Nerea; Segarra, Sergi; Artieda, Marta; Francino, Olga; Sánchez, Elisenda; Szczypiorska, Magdalena; Casellas, Joaquim; Tejedor, Diego; Cerdeira, Joaquín; Martínez, Antonio; Velasco, Alfonso; Sánchez, Armand

    2015-01-01

    Canine hip dysplasia is one of the most prevalent developmental orthopedic diseases in dogs worldwide. Unfortunately, the success of eradication programs against this disease based on radiographic diagnosis is low. Adding the use of diagnostic genetic tools to the current phenotype-based approach might be beneficial. The aim of this study was to develop a genetic prognostic test for early diagnosis of hip dysplasia in Labrador Retrievers. To develop our DNA test, 775 Labrador Retrievers were recruited. For each dog, a blood sample and a ventrodorsal hip radiograph were taken. Dogs were divided into two groups according to their FCI hip score: control (A/B) and case (D/E). C dogs were not included in the sample. Genetic characterization combining a GWAS and a candidate gene strategy using SNPs allowed a case-control population association study. A mathematical model which included 7 SNPs was developed using logistic regression. The model showed a good accuracy (Area under the ROC curve = 0.85) and was validated in an independent population of 114 dogs. This prognostic genetic test represents a useful tool for choosing the most appropriate therapeutic approach once genetic predisposition to hip dysplasia is known. Therefore, it allows a more individualized management of the disease. It is also applicable during genetic selection processes, since breeders can benefit from the information given by this test as soon as a blood sample can be collected, and act accordingly. In the authors’ opinion, a shift towards genomic screening might importantly contribute to reducing canine hip dysplasia in the future. In conclusion, based on genetic and radiographic information from Labrador Retrievers with hip dysplasia, we developed an accurate predictive genetic test for early diagnosis of hip dysplasia in Labrador Retrievers. However, further research is warranted in order to evaluate the validity of this genetic test in other dog breeds. PMID:25874693

  9. Methods for genetic linkage analysis using trisomies

    SciTech Connect

    Feingold, E.; Lamb, N.E.; Sherman, S.L.

    1994-09-01

    Certain genetic disorders (e.g. congenital cataracts, duodenal atresia) are rare in the general population, but more common in people with Down`s syndrome. We present a method for using individuals with trisomy 21 to map genes for such traits. Our methods are analogous to methods for mapping autosomal dominant traits using affected relative pairs by looking for markers with greater than expected identity-by-descent. In the trisomy case, one would take trisomic individuals and look for markers with greater than expected reduction to homozygosity in the chromosomes inherited form the non-disjoining parent. We present statistical methods for performing such a linkage analysis, including a test for linkage to a marker, a method for estimating the distance from the marker to the gene, a confidence interval for that distance, and methods for computing power and sample sizes. The methods are described in the context of gene-dosage model for the etiology of the disorder, but can be extended to other models. We also resolve some practical issues involved in implementing the methods, including how to use partially informative markers, how to test candidate genes, and how to handle the effect of reduced recombination associated with maternal meiosis I non-disjunction.

  10. Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study

    PubMed Central

    Fox, Ervin R.; Young, J. Hunter; Li, Yali; Dreisbach, Albert W.; Keating, Brendan J.; Musani, Solomon K.; Liu, Kiang; Morrison, Alanna C.; Ganesh, Santhi; Kutlar, Abdullah; Ramachandran, Vasan S.; Polak, Josef F.; Fabsitz, Richard R.; Dries, Daniel L.; Farlow, Deborah N.; Redline, Susan; Adeyemo, Adebowale; Hirschorn, Joel N.; Sun, Yan V.; Wyatt, Sharon B.; Penman, Alan D.; Palmas, Walter; Rotter, Jerome I.; Townsend, Raymond R.; Doumatey, Ayo P.; Tayo, Bamidele O.; Mosley, Thomas H.; Lyon, Helen N.; Kang, Sun J.; Rotimi, Charles N.; Cooper, Richard S.; Franceschini, Nora; Curb, J. David; Martin, Lisa W.; Eaton, Charles B.; Kardia, Sharon L.R.; Taylor, Herman A.; Caulfield, Mark J.; Ehret, Georg B.; Johnson, Toby; Chakravarti, Aravinda; Zhu, Xiaofeng; Levy, Daniel; Munroe, Patricia B.; Rice, Kenneth M.; Bochud, Murielle; Johnson, Andrew D.; Chasman, Daniel I.; Smith, Albert V.; Tobin, Martin D.; Verwoert, Germaine C.; Hwang, Shih-Jen; Pihur, Vasyl; Vollenweider, Peter; O'Reilly, Paul F.; Amin, Najaf; Bragg-Gresham, Jennifer L.; Teumer, Alexander; Glazer, Nicole L.; Launer, Lenore; Zhao, Jing Hua; Aulchenko, Yurii; Heath, Simon; Sõber, Siim; Parsa, Afshin; Luan, Jian'an; Arora, Pankaj; Dehghan, Abbas; Zhang, Feng; Lucas, Gavin; Hicks, Andrew A.; Jackson, Anne U.; Peden, John F.; Tanaka, Toshiko; Wild, Sarah H.; Rudan, Igor; Igl, Wilmar; Milaneschi, Yuri; Parker, Alex N.; Fava, Cristiano; Chambers, John C.; Kumari, Meena; JinGo, Min; van der Harst, Pim; Kao, Wen Hong Linda; Sjögren, Marketa; Vinay, D.G.; Alexander, Myriam; Tabara, Yasuharu; Shaw-Hawkins, Sue; Whincup, Peter H.; Liu, Yongmei; Shi, Gang; Kuusisto, Johanna; Seielstad, Mark; Sim, Xueling; Nguyen, Khanh-Dung Hoang; Lehtimäki, Terho; Matullo, Giuseppe; Wu, Ying; Gaunt, Tom R.; Charlotte Onland-Moret, N.; Cooper, Matthew N.; Platou, Carl G.P.; Org, Elin; Hardy, Rebecca; Dahgam, Santosh; Palmen, Jutta; Vitart, Veronique; Braund, Peter S.; Kuznetsova, Tatiana; Uiterwaal, Cuno S.P.M.; Campbell, Harry; Ludwig, Barbara; Tomaszewski, Maciej; Tzoulaki, Ioanna; Palmer, Nicholette D.; Aspelund, Thor; Garcia, Melissa; Chang, Yen-Pei C.; O'Connell, Jeffrey R.; Steinle, Nanette I.; Grobbee, Diederick E.; Arking, Dan E.; Hernandez, Dena; Najjar, Samer; McArdle, Wendy L.; Hadley, David; Brown, Morris J.; Connell, John M.; Hingorani, Aroon D.; Day, Ian N.M.; Lawlor, Debbie A.; Beilby, John P.; Lawrence, Robert W.; Clarke, Robert; Collins, Rory; Hopewell, Jemma C.; Ongen, Halit; Bis, Joshua C.; Kähönen, Mika; Viikari, Jorma; Adair, Linda S.; Lee, Nanette R.; Chen, Ming-Huei; Olden, Matthias; Pattaro, Cristian; Hoffman Bolton, Judith A.; Köttgen, Anna; Bergmann, Sven; Mooser, Vincent; Chaturvedi, Nish; Frayling, Timothy M.; Islam, Muhammad; Jafar, Tazeen H.; Erdmann, Jeanette; Kulkarni, Smita R.; Bornstein, Stefan R.; Grässler, Jürgen; Groop, Leif; Voight, Benjamin F.; Kettunen, Johannes; Howard, Philip; Taylor, Andrew; Guarrera, Simonetta; Ricceri, Fulvio; Emilsson, Valur; Plump, Andrew; Barroso, Inês; Khaw, Kay-Tee; Weder, Alan B.; Hunt, Steven C.; Bergman, Richard N.; Collins, Francis S.; Bonnycastle, Lori L.; Scott, Laura J.; Stringham, Heather M.; Peltonen, Leena; Perola, Markus; Vartiainen, Erkki; Brand, Stefan-Martin; Staessen, Jan A.; Wang, Thomas J.; Burton, Paul R.; SolerArtigas, Maria; Dong, Yanbin; Snieder, Harold; Wang, Xiaoling; Zhu, Haidong; Lohman, Kurt K.; Rudock, Megan E.; Heckbert, Susan R.; Smith, Nicholas L.; Wiggins, Kerri L.; Shriner, Daniel; Veldre, Gudrun; Viigimaa, Margus; Kinra, Sanjay; Prabhakaran, Dorairajan; Tripathy, Vikal; Langefeld, Carl D.; Rosengren, Annika; Thelle, Dag S.; MariaCorsi, Anna; Singleton, Andrew; Forrester, Terrence; Hilton, Gina; McKenzie, Colin A.; Salako, Tunde; Iwai, Naoharu; Kita, Yoshikuni; Ogihara, Toshio; Ohkubo, Takayoshi; Okamura, Tomonori; Ueshima, Hirotsugu; Umemura, Satoshi; Eyheramendy, Susana; Meitinger, Thomas; Wichmann, H.-Erich; Cho, Yoon Shin; Kim, Hyung-Lae; Lee, Jong-Young; Scott, James; Sehmi, Joban S.; Zhang, Weihua; Hedblad, Bo; Nilsson, Peter; Smith, George Davey; Wong, Andrew; Narisu, Narisu; Stančáková, Alena; Raffel, Leslie J.; Yao, Jie; Kathiresan, Sekar; O'Donnell, Chris; Schwartz, Steven M.; Arfan Ikram, M.; Longstreth, Will T.; Seshadri, Sudha; Shrine, Nick R.G.; Wain, Louise V.; Morken, Mario A.; Swift, Amy J.; Laitinen, Jaana; Prokopenko, Inga; Zitting, Paavo; Cooper, Jackie A.; Humphries, Steve E.; Danesh, John; Rasheed, Asif; Goel, Anuj; Hamsten, Anders; Watkins, Hugh; Bakker, Stephan J.L.; van Gilst, Wiek H.; Janipalli, Charles S.; Radha Mani, K.; Yajnik, Chittaranjan S.; Hofman, Albert; Mattace-Raso, Francesco U.S.; Oostra, Ben A.; Demirkan, Ayse; Isaacs, Aaron; Rivadeneira, Fernando; Lakatta, Edward G.; Orru, Marco; Scuteri, Angelo; Ala-Korpela, Mika; Kangas, Antti J.; Lyytikäinen, Leo-Pekka; Soininen, Pasi; Tukiainen, Taru; Würz, Peter; Twee-Hee Ong, Rick; Dörr, Marcus; Kroemer, Heyo K.; Völker, Uwe; Völzke, Henry; Galan, Pilar; Hercberg, Serge; Lathrop, Mark; Zelenika, Diana; Deloukas, Panos; Mangino, Massimo; Spector, Tim D.; Zhai, Guangju; Meschia, James F.; Nalls, Michael A.; Sharma, Pankaj; Terzic, Janos; Kranthi Kumar, M.J.; Denniff, Matthew; Zukowska-Szczechowska, Ewa; Wagenknecht, Lynne E.; Fowkes, Gerald R.; Charchar, Fadi J.; Schwarz, Peter E.H.; Hayward, Caroline; Guo, Xiuqing; Bots, Michiel L.; Brand, Eva; Samani, Nilesh J.; Polasek, Ozren; Talmud, Philippa J.; Nyberg, Fredrik; Kuh, Diana; Laan, Maris; Hveem, Kristian; Palmer, Lyle J.; van der Schouw, Yvonne T.; Casas, Juan P.; Mohlke, Karen L.; Vineis, Paolo; Raitakari, Olli; Wong, Tien Y.; Shyong Tai, E.; Laakso, Markku; Rao, Dabeeru C.; Harris, Tamara B.; Morris, Richard W.; Dominiczak, Anna F.; Kivimaki, Mika; Marmot, Michael G.; Miki, Tetsuro; Saleheen, Danish; Chandak, Giriraj R.; Coresh, Josef; Navis, Gerjan; Salomaa, Veikko; Han, Bok-Ghee; Kooner, Jaspal S.; Melander, Olle; Ridker, Paul M.; Bandinelli, Stefania; Gyllensten, Ulf B.; Wright, Alan F.; Wilson, James F.; Ferrucci, Luigi; Farrall, Martin; Tuomilehto, Jaakko; Pramstaller, Peter P.; Elosua, Roberto; Soranzo, Nicole; Sijbrands, Eric J.G.; Altshuler, David; Loos, Ruth J.F.; Shuldiner, Alan R.; Gieger, Christian; Meneton, Pierre; Uitterlinden, Andre G.; Wareham, Nicholas J.; Gudnason, Vilmundur; Rettig, Rainer; Uda, Manuela; Strachan, David P.; Witteman, Jacqueline C.M.; Hartikainen, Anna-Liisa; Beckmann, Jacques S.; Boerwinkle, Eric; Boehnke, Michael; Larson, Martin G.; Järvelin, Marjo-Riitta; Psaty, Bruce M.; Abecasis, Gonçalo R.; Elliott, Paul; van Duijn , Cornelia M.; Newton-Cheh, Christopher

    2011-01-01

    The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity. PMID:21378095

  11. Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.

    PubMed

    Fox, Ervin R; Young, J Hunter; Li, Yali; Dreisbach, Albert W; Keating, Brendan J; Musani, Solomon K; Liu, Kiang; Morrison, Alanna C; Ganesh, Santhi; Kutlar, Abdullah; Ramachandran, Vasan S; Polak, Josef F; Fabsitz, Richard R; Dries, Daniel L; Farlow, Deborah N; Redline, Susan; Adeyemo, Adebowale; Hirschorn, Joel N; Sun, Yan V; Wyatt, Sharon B; Penman, Alan D; Palmas, Walter; Rotter, Jerome I; Townsend, Raymond R; Doumatey, Ayo P; Tayo, Bamidele O; Mosley, Thomas H; Lyon, Helen N; Kang, Sun J; Rotimi, Charles N; Cooper, Richard S; Franceschini, Nora; Curb, J David; Martin, Lisa W; Eaton, Charles B; Kardia, Sharon L R; Taylor, Herman A; Caulfield, Mark J; Ehret, Georg B; Johnson, Toby; Chakravarti, Aravinda; Zhu, Xiaofeng; Levy, Daniel

    2011-06-01

    The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity. PMID:21378095

  12. Genetic and Molecular Functional Characterization of Variants within TNFSF13B, a Positional Candidate Preeclampsia Susceptibility Gene on 13q

    PubMed Central

    Roten, Linda T.; Aas, Per A.; Forsmo, Siri; Klepper, Kjetil; East, Christine E.; Abraham, Lawrence J.; Blangero, John; Brennecke, Shaun P.; Austgulen, Rigmor; Moses, Eric K.

    2010-01-01

    Background Preeclampsia is a serious pregnancy complication, demonstrating a complex pattern of inheritance. The elucidation of genetic liability to preeclampsia remains a major challenge in obstetric medicine. We have adopted a positional cloning approach to identify maternal genetic components, with linkages previously demonstrated to chromosomes 2q, 5q and 13q in an Australian/New Zealand familial cohort. The current study aimed to identify potential functional and structural variants in the positional candidate gene TNFSF13B under the 13q linkage peak and assess their association status with maternal preeclampsia genetic susceptibility. Methodology/Principal Findings The proximal promoter and coding regions of the positional candidate gene TNFSF13B residing within the 13q linkage region was sequenced using 48 proband or founder individuals from Australian/New Zealand families. Ten sequence variants (nine SNPs and one single base insertion) were identified and seven SNPs were successfully genotyped in the total Australian/New Zealand family cohort (74 families/480 individuals). Borderline association to preeclampsia (p = 0.0153) was observed for three rare SNPs (rs16972194, rs16972197 and rs56124946) in strong linkage disequilibrium with each other. Functional evaluation by electrophoretic mobility shift assays showed differential nuclear factor binding to the minor allele of the rs16972194 SNP, residing upstream of the translation start site, making this a putative functional variant. The observed genetic associations were not replicated in a Norwegian case/control cohort (The Nord-Trøndelag Health Study (HUNT2), 851 preeclamptic and 1,440 non-preeclamptic women). Conclusion/Significance TNFSF13B has previously been suggested to contribute to the normal immunological adaption crucial for a successful pregnancy. Our observations support TNFSF13B as a potential novel preeclampsia susceptibility gene. We discuss a possible role for TNFSF13B in preeclampsia

  13. Large-Scale candidate gene analysis of spontaneous hepatitis C virus clearance

    PubMed Central

    Mosbruger, Timothy L; Duggal, Priya; Goedert, James J.; Kirk, Gregory D; Hoots, W. Keith; Tobler, Leslie H; Busch, Michael; Peters, Marion G.; Rosen, Hugo R; Thomas, David L; Thio, Chloe L

    2010-01-01

    Human genetic variation is a determinant of recovery from an acute hepatitis C virus (HCV) infection, but, to date, single nucleotide polymorphisms (SNPs) in a limited number of genes have been studied with respect to HCV clearance. We determined whether SNPs in 112 selected immune-response genes are important for HCV clearance by genotyping 1536 SNPs in a cohort of 343 persons with natural HCV clearance and 547 persons with HCV persistence. PLINK and Haploview software packages were used to perform association, permutation, and haplotype analyses stratified by African-American (AA) and European-American (EA) race. Of the 1536 SNPs tested, 1426 were successfully genotyped (92.8%). In AAs, we identified 18 SNPs located in 11 gene regions that were associated with HCV outcome (empirical p-value < 0.01). In EAs, there were 20 SNPs located in eight gene regions associated with HCV outcome. Four of the gene regions studied (TNFSF18, TANK, HAVCR1 and IL18BP) contained SNPs with empirical p-values < 0.01 in both of the race groups. Conclusion In this large-scale analysis of 1426 genotyped SNPs in 112 candidate genes, we identified four gene regions that are likely candidates for a role in HCV clearance or persistence in both AAs and EAs. PMID:20331378

  14. Integrative Analysis of Metabolomic, Proteomic and Genomic Data to Reveal Functional Pathways and Candidate Genes for Drip Loss in Pigs.

    PubMed

    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

  15. An Analysis of Changes in Voter Perception of Candidates' Positions.

    ERIC Educational Resources Information Center

    Anderson, James A.; And Others

    In an effort to discover the effects of mass media on viewer perception of candidates' positions, tests were administered to 10 to 12 families at each of five locations across the country immediately following each of the 1976 Carter-Ford debates. Sixteen statements were drawn from the presidential platform of each party and each statement was…

  16. The Use of Complex Case Analysis To Make Visible the Quality of Teacher Candidates.

    ERIC Educational Resources Information Center

    Denner, Peter; Miller, Terry; Newsome, Jack; Birdsong, Julie

    Faculty members at Idaho State University evaluated the use of case analysis as an accountability measure for demonstrating teacher candidates' abilities to meet targeted course, institutional, and state teaching standards for student motivation and classroom management. Thirty-four teacher candidates completed a case analysis assessment.…

  17. Transcriptomic Analysis Using Olive Varieties and Breeding Progenies Identifies Candidate Genes Involved in Plant Architecture.

    PubMed

    González-Plaza, Juan J; Ortiz-Martín, Inmaculada; Muñoz-Mérida, Antonio; García-López, Carmen; Sánchez-Sevilla, José F; Luque, Francisco; Trelles, Oswaldo; Bejarano, Eduardo R; De La Rosa, Raúl; Valpuesta, Victoriano; Beuzón, Carmen R

    2016-01-01

    Plant architecture is a critical trait in fruit crops that can significantly influence yield, pruning, planting density and harvesting. Little is known about how plant architecture is genetically determined in olive, were most of the existing varieties are traditional with an architecture poorly suited for modern growing and harvesting systems. In the present study, we have carried out microarray analysis of meristematic tissue to compare expression profiles of olive varieties displaying differences in architecture, as well as seedlings from their cross pooled on the basis of their sharing architecture-related phenotypes. The microarray used, previously developed by our group has already been applied to identify candidates genes involved in regulating juvenile to adult transition in the shoot apex of seedlings. Varieties with distinct architecture phenotypes and individuals from segregating progenies displaying opposite architecture features were used to link phenotype to expression. Here, we identify 2252 differentially expressed genes (DEGs) associated to differences in plant architecture. Microarray results were validated by quantitative RT-PCR carried out on genes with functional annotation likely related to plant architecture. Twelve of these genes were further analyzed in individual seedlings of the corresponding pool. We also examined Arabidopsis mutants in putative orthologs of these targeted candidate genes, finding altered architecture for most of them. This supports a functional conservation between species and potential biological relevance of the candidate genes identified. This study is the first to identify genes associated to plant architecture in olive, and the results obtained could be of great help in future programs aimed at selecting phenotypes adapted to modern cultivation practices in this species. PMID:26973682

  18. Transcriptomic Analysis Using Olive Varieties and Breeding Progenies Identifies Candidate Genes Involved in Plant Architecture

    PubMed Central

    González-Plaza, Juan J.; Ortiz-Martín, Inmaculada; Muñoz-Mérida, Antonio; García-López, Carmen; Sánchez-Sevilla, José F.; Luque, Francisco; Trelles, Oswaldo; Bejarano, Eduardo R.; De La Rosa, Raúl; Valpuesta, Victoriano; Beuzón, Carmen R.

    2016-01-01

    Plant architecture is a critical trait in fruit crops that can significantly influence yield, pruning, planting density and harvesting. Little is known about how plant architecture is genetically determined in olive, were most of the existing varieties are traditional with an architecture poorly suited for modern growing and harvesting systems. In the present study, we have carried out microarray analysis of meristematic tissue to compare expression profiles of olive varieties displaying differences in architecture, as well as seedlings from their cross pooled on the basis of their sharing architecture-related phenotypes. The microarray used, previously developed by our group has already been applied to identify candidates genes involved in regulating juvenile to adult transition in the shoot apex of seedlings. Varieties with distinct architecture phenotypes and individuals from segregating progenies displaying opposite architecture features were used to link phenotype to expression. Here, we identify 2252 differentially expressed genes (DEGs) associated to differences in plant architecture. Microarray results were validated by quantitative RT-PCR carried out on genes with functional annotation likely related to plant architecture. Twelve of these genes were further analyzed in individual seedlings of the corresponding pool. We also examined Arabidopsis mutants in putative orthologs of these targeted candidate genes, finding altered architecture for most of them. This supports a functional conservation between species and potential biological relevance of the candidate genes identified. This study is the first to identify genes associated to plant architecture in olive, and the results obtained could be of great help in future programs aimed at selecting phenotypes adapted to modern cultivation practices in this species. PMID:26973682

  19. GENETIC CHARACTERIZATION OF GONATOCERUS TUBERCULIFEMUR FROM SOUTH AMERICA UNCOVERS DIVERGENT CLADES: PROSPECTIVE EGG PARASITOID CANDIDATE AGENT FOR THE GLASSY-WINGED SHARPSHOOTER IN CALIFORNIA

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We genetically characterized the prospective South American egg parasitoid candidate agent, Gonatocerus tuberculifemur, of the glassy-winged sharsphooter (GWSS), Homalodisca vitripennis (Germar) [=H. coagulata (Say)] for a neoclassical biological control program in California. Two molecular methods...

  20. CANDID: Companion Analysis and Non-Detection in Interferometric Data

    NASA Astrophysics Data System (ADS)

    Gallenne, A.; Mérand, A.; Kervella, P.; Monnier, J. D.; Schaefer, G. H.; Baron, F.; Breitfelder, J.; Le Bouquin, J. B.; Roettenbacher, R. M.; Gieren, W.; Pietrzynski, G.; McAlister, H.; ten Brummelaar, T.; Sturmann, J.; Sturmann, L.; Turner, N.; Ridgway, S.; Kraus, S.

    2015-05-01

    CANDID finds faint companion around star in interferometric data in the OIFITS format. It allows systematically searching for faint companions in OIFITS data, and if not found, estimates the detection limit. The tool is based on model fitting and Chi2 minimization, with a grid for the starting points of the companion position. It ensures all positions are explored by estimating a-posteriori if the grid is dense enough, and provides an estimate of the optimum grid density.

  1. Genetic mapping of thirteen drought tolerance candidate genes in wheat (T. aestivum)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Drought is a severe abiotic stress that affects wheat production worldwide. In order to identify candidate genes for tolerance to water stress in wheat, sequences of 11 genes that have function of drought tolerance in other plant species were used to identify the wheat ortholog genes via homology se...

  2. Genetic reprogramming of human amniotic cells with episomal vectors: neural rosettes as sentinels in candidate selection for validation assays

    PubMed Central

    Payne, Tiffany

    2014-01-01

    The promise of genetic reprogramming has prompted initiatives to develop banks of induced pluripotent stem cells (iPSCs) from diverse sources. Sentinel assays for pluripotency could maximize available resources for generating iPSCs. Neural rosettes represent a primitive neural tissue that is unique to differentiating PSCs and commonly used to identify derivative neural/stem progenitors. Here, neural rosettes were used as a sentinel assay for pluripotency in selection of candidates to advance to validation assays. Candidate iPSCs were generated from independent populations of amniotic cells with episomal vectors. Phase imaging of living back up cultures showed neural rosettes in 2 of the 5 candidate populations. Rosettes were immunopositive for the Sox1, Sox2, Pax6 and Pax7 transcription factors that govern neural development in the earliest stage of development and for the Isl1/2 and Otx2 transcription factors that are expressed in the dorsal and ventral domains, respectively, of the neural tube in vivo. Dissociation of rosettes produced cultures of differentiation competent neural/stem progenitors that generated immature neurons that were immunopositive for βIII-tubulin and glia that were immunopositive for GFAP. Subsequent validation assays of selected candidates showed induced expression of endogenous pluripotency genes, epigenetic modification of chromatin and formation of teratomas in immunodeficient mice that contained derivatives of the 3 embryonic germ layers. Validated lines were vector-free and maintained a normal karyotype for more than 60 passages. The credibility of rosette assembly as a sentinel assay for PSCs is supported by coordinate loss of nuclear-localized pluripotency factors Oct4 and Nanog in neural rosettes that emerge spontaneously in cultures of self-renewing validated lines. Taken together, these findings demonstrate value in neural rosettes as sentinels for pluripotency and selection of promising candidates for advance to validation

  3. Genetic reprogramming of human amniotic cells with episomal vectors: neural rosettes as sentinels in candidate selection for validation assays.

    PubMed

    Wilson, Patricia G; Payne, Tiffany

    2014-01-01

    The promise of genetic reprogramming has prompted initiatives to develop banks of induced pluripotent stem cells (iPSCs) from diverse sources. Sentinel assays for pluripotency could maximize available resources for generating iPSCs. Neural rosettes represent a primitive neural tissue that is unique to differentiating PSCs and commonly used to identify derivative neural/stem progenitors. Here, neural rosettes were used as a sentinel assay for pluripotency in selection of candidates to advance to validation assays. Candidate iPSCs were generated from independent populations of amniotic cells with episomal vectors. Phase imaging of living back up cultures showed neural rosettes in 2 of the 5 candidate populations. Rosettes were immunopositive for the Sox1, Sox2, Pax6 and Pax7 transcription factors that govern neural development in the earliest stage of development and for the Isl1/2 and Otx2 transcription factors that are expressed in the dorsal and ventral domains, respectively, of the neural tube in vivo. Dissociation of rosettes produced cultures of differentiation competent neural/stem progenitors that generated immature neurons that were immunopositive for βIII-tubulin and glia that were immunopositive for GFAP. Subsequent validation assays of selected candidates showed induced expression of endogenous pluripotency genes, epigenetic modification of chromatin and formation of teratomas in immunodeficient mice that contained derivatives of the 3 embryonic germ layers. Validated lines were vector-free and maintained a normal karyotype for more than 60 passages. The credibility of rosette assembly as a sentinel assay for PSCs is supported by coordinate loss of nuclear-localized pluripotency factors Oct4 and Nanog in neural rosettes that emerge spontaneously in cultures of self-renewing validated lines. Taken together, these findings demonstrate value in neural rosettes as sentinels for pluripotency and selection of promising candidates for advance to validation

  4. Candidate gene analysis: severe intraventricular hemorrhage in inborn preterm neonates.

    PubMed

    Adén, Ulrika; Lin, Aiping; Carlo, Waldemar; Leviton, Alan; Murray, Jeffrey C; Hallman, Mikko; Lifton, Richard P; Zhang, Heping; Ment, Laura R

    2013-11-01

    Intraventricular hemorrhage (IVH) is a disorder of complex etiology. We analyzed genotypes for 7 genes from 224 inborn preterm neonates treated with antenatal steroids and grade 3-4 IVH and 389 matched controls. Only methylenetetrahydrofolate reductase was more prevalent in cases of IVH, emphasizing the need for more comprehensive genetic strategies. PMID:23896193

  5. Identification and Evolutionary Analysis of Potential Candidate Genes in a Human Eating Disorder

    PubMed Central

    Mullegama, Saman; Wyckoff, Gerald J.

    2016-01-01

    The purpose of this study was to find genes linked with eating disorders and associated with both metabolic and neural systems. Our operating hypothesis was that there are genetic factors underlying some eating disorders resting in both those pathways. Specifically, we are interested in disorders that may rest in both sleep and metabolic function, generally called Night Eating Syndrome (NES). A meta-analysis of the Gene Expression Omnibus targeting the mammalian nervous system, sleep, and obesity studies was performed, yielding numerous genes of interest. Through a text-based analysis of the results, a number of potential candidate genes were identified. VGF, in particular, appeared to be relevant both to obesity and, broadly, to brain or neural development. VGF is a highly connected protein that interacts with numerous targets via proteolytically digested peptides. We examined VGF from an evolutionary perspective to determine whether other available evidence supported a role for the gene in human disease. We conclude that some of the already identified variants in VGF from human polymorphism studies may contribute to eating disorders and obesity. Our data suggest that there is enough evidence to warrant eGWAS and GWAS analysis of these genes in NES patients in a case-control study. PMID:27088090

  6. Unravelling enzymatic discoloration in potato through a combined approach of candidate genes, QTL, and expression analysis.

    PubMed

    Werij, Jeroen S; Kloosterman, Bjorn; Celis-Gamboa, Carolina; de Vos, C H Ric; America, Twan; Visser, Richard G F; Bachem, Christian W B

    2007-07-01

    Enzymatic discoloration (ED) of potato tubers was investigated in an attempt to unravel the underlying genetic factors. Both enzyme and substrate concentration have been reported to influence the degree of discoloration and as such this trait can be regarded as polygenic. The diploid mapping population C x E, consisting of 249 individuals, was assayed for the degree of ED and levels of chlorogenic acid and tyrosine. Using this data, Quantitative Trait Locus (QTL) analysis was performed. Three QTLs for ED have been found on parental chromosomes C3, C8, E1, and E8. For chlorogenic acid a QTL has been identified on C2 and for tyrosine levels, a QTL has been detected on C8. None of the QTLs overlap, indicating the absence of genetic correlations between these components underlying ED, in contrast to earlier reports in literature. An obvious candidate gene for the QTL for ED on Chromosome 8 is polyphenol oxidase (PPO), which was previously mapped on chromosome 8. With gene-specific primers for PPO gene POT32 a CAPS marker was developed. Three different alleles (POT32-1, -2, and -3) could be discriminated. The segregating POT32 alleles were used to map the POT32 CAPS marker and QTL analysis was redone, showing that POT32 coincides with the QTL peak. A clear correlation between allele combinations and degree of discoloration was observed. In addition, analysis of POT32 gene expression in a subset of genotypes indicated a correlation between the level of gene expression and allele composition. On average, genotypes having two copies of allele 1 had both the highest degree of discoloration as well as the highest level of POT32 gene expression. PMID:17492422

  7. Unravelling enzymatic discoloration in potato through a combined approach of candidate genes, QTL, and expression analysis

    PubMed Central

    Kloosterman, Bjorn; Celis-Gamboa, Carolina; de Vos, C. H. Ric; America, Twan; Visser, Richard G. F.; Bachem, Christian W. B.

    2007-01-01

    Enzymatic discoloration (ED) of potato tubers was investigated in an attempt to unravel the underlying genetic factors. Both enzyme and substrate concentration have been reported to influence the degree of discoloration and as such this trait can be regarded as polygenic. The diploid mapping population C × E, consisting of 249 individuals, was assayed for the degree of ED and levels of chlorogenic acid and tyrosine. Using this data, Quantitative Trait Locus (QTL) analysis was performed. Three QTLs for ED have been found on parental chromosomes C3, C8, E1, and E8. For chlorogenic acid a QTL has been identified on C2 and for tyrosine levels, a QTL has been detected on C8. None of the QTLs overlap, indicating the absence of genetic correlations between these components underlying ED, in contrast to earlier reports in literature. An obvious candidate gene for the QTL for ED on Chromosome 8 is polyphenol oxidase (PPO), which was previously mapped on chromosome 8. With gene-specific primers for PPO gene POT32 a CAPS marker was developed. Three different alleles (POT32-1, -2, and -3) could be discriminated. The segregating POT32 alleles were used to map the POT32 CAPS marker and QTL analysis was redone, showing that POT32 coincides with the QTL peak. A clear correlation between allele combinations and degree of discoloration was observed. In addition, analysis of POT32 gene expression in a subset of genotypes indicated a correlation between the level of gene expression and allele composition. On average, genotypes having two copies of allele 1 had both the highest degree of discoloration as well as the highest level of POT32 gene expression. PMID:17492422

  8. Quantitative Trait Locus Mapping and Candidate Gene Analysis for Plant Architecture Traits Using Whole Genome Re-Sequencing in Rice

    PubMed Central

    Lim, Jung-Hyun; Yang, Hyun-Jung; Jung, Ki-Hong; Yoo, Soo-Cheul; Paek, Nam-Chon

    2014-01-01

    Plant breeders have focused on improving plant architecture as an effective means to increase crop yield. Here, we identify the main-effect quantitative trait loci (QTLs) for plant shape-related traits in rice (Oryza sativa) and find candidate genes by applying whole genome re-sequencing of two parental cultivars using next-generation sequencing. To identify QTLs influencing plant shape, we analyzed six traits: plant height, tiller number, panicle diameter, panicle length, flag leaf length, and flag leaf width. We performed QTL analysis with 178 F7 recombinant in-bred lines (RILs) from a cross of japonica rice line ‘SNUSG1’ and indica rice line ‘Milyang23’. Using 131 molecular markers, including 28 insertion/deletion markers, we identified 11 main- and 16 minor-effect QTLs for the six traits with a threshold LOD value > 2.8. Our sequence analysis identified fifty-four candidate genes for the main-effect QTLs. By further comparison of coding sequences and meta-expression profiles between japonica and indica rice varieties, we finally chose 15 strong candidate genes for the 11 main-effect QTLs. Our study shows that the whole-genome sequence data substantially enhanced the efficiency of polymorphic marker development for QTL fine-mapping and the identification of possible candidate genes. This yields useful genetic resources for breeding high-yielding rice cultivars with improved plant architecture. PMID:24599000

  9. A SYSTEMATIC ASSESSMENT OF LINKING GENE EXPRESSION WITH GENETIC VARIANTS FOR PRIORITIZING CANDIDATE TARGETS

    PubMed Central

    FAN-MINOGUE, HUA; CHEN, BIN; SIKORA-WOHLFELD, WERONIKA; SIROTA, MARINA; BUTTE, ATUL J

    2014-01-01

    Gene expression and disease-associated variants are often used to prioritize candidate genes for target validation. However, the success of these gene features alone or in combination in the discovery of therapeutic targets is uncertain. Here we evaluated the effectiveness of the differential expression (DE), the disease-associated single nucleotide polymorphisms (SNPs) and the combination of the two in recovering and predicting known therapeutic targets across 56 human diseases. We demonstrate that the performance of each feature varies across diseases and generally the features have more recovery power than predictive power. The combination of the two features, however, has significantly higher predictive power than each feature alone. Our study provides a systematic evaluation of two common gene features, DE and SNPs, for prioritization of candidate targets and identified an improved predictive power of coupling these two features. PMID:25592598

  10. A Novel Approach to Identify Candidate Prognostic Factors for Hepatitis C Treatment Response Integrating Clinical and Viral Genetic Data

    PubMed Central

    Amadoz, Alicia; González-Candelas, Fernando

    2015-01-01

    The combined therapy of pegylated interferon (IFN) plus ribavirin (RBV) has been for a long time the standard treatment for patients infected with hepatitis C virus (HCV). In the case of genotype 1, only 38%–48% of patients have a positive response to the combined treatment. In previous studies, viral genetic information has been occasionally included as a predictor. Here, we consider viral genetic variation in addition to 11 clinical and 19 viral populations and evolutionary parameters to identify candidate baseline prognostic factors that could be involved in the treatment outcome. We obtained potential prognostic models for HCV subtypes la and lb in combination as well as separately. We also found that viral genetic information is relevant for the combined treatment assessment of patients, as the potential prognostic model of joint subtypes includes 9 viral-related variables out of 11. Our proposed methodology fully characterizes viral genetic information and finds a combination of positions that modulate inter-patient variability. PMID:25780333

  11. Seeking signatures of reinforcement at the genetic level: a hitchhiking mapping and candidate gene approach in the house mouse

    PubMed Central

    Caminade, Pierre; Thoma, Marios; Latour, Yasmin; Roux, Camille; Thoss, Michaela; Penn, Dustin J.; Ganem, Guila; Boursot, Pierre

    2016-01-01

    Reinforcement is the process by which prezygotic isolation is strengthened as a response to selection against hybridisation. Most empirical support for reinforcement comes from the observation of its possible phenotypic signature: an accentuated degree of prezygotic isolation in the hybrid zone as compared to allopatry. Here, we implemented a novel approach to this question by seeking for the signature of reinforcement at the genetic level. In the house mouse, selection against hybrids and enhanced olfactory-based assortative mate preferences are observed in a hybrid zone between the two European subspecies Mus musculus musculus and M. m. domesticus, suggesting a possible recent reinforcement event. To test for the genetic signature of reinforcing selection and identify genes involved in sexual isolation, we adopted a hitchhiking mapping approach targeting genomic regions containing candidate genes for assortative mating in mice. We densely scanned these genomic regions in hybrid zone and allopatric samples using a large number of fast evolving microsatellite loci that allow the detection of recent selection events. We found a handful of loci showing the expected pattern of significant reduction of variability in populations close to the hybrid zone and showing assortative odour preference in mate choice experiments as compared to populations further away and displaying no such preference. These loci lie close to genes that we pinpoint as testable candidates for further investigation. PMID:26132782

  12. Seeking signatures of reinforcement at the genetic level: a hitchhiking mapping and candidate gene approach in the house mouse.

    PubMed

    Smadja, Carole M; Loire, Etienne; Caminade, Pierre; Thoma, Marios; Latour, Yasmin; Roux, Camille; Thoss, Michaela; Penn, Dustin J; Ganem, Guila; Boursot, Pierre

    2015-08-01

    Reinforcement is the process by which prezygotic isolation is strengthened as a response to selection against hybridization. Most empirical support for reinforcement comes from the observation of its possible phenotypic signature: an accentuated degree of prezygotic isolation in the hybrid zone as compared to allopatry. Here, we implemented a novel approach to this question by seeking for the signature of reinforcement at the genetic level. In the house mouse, selection against hybrids and enhanced olfactory-based assortative mate preferences are observed in a hybrid zone between the two European subspecies Mus musculus musculus and M. m. domesticus, suggesting a possible recent reinforcement event. To test for the genetic signature of reinforcing selection and identify genes involved in sexual isolation, we adopted a hitchhiking mapping approach targeting genomic regions containing candidate genes for assortative mating in mice. We densely scanned these genomic regions in hybrid zone and allopatric samples using a large number of fast evolving microsatellite loci that allow the detection of recent selection events. We found a handful of loci showing the expected pattern of significant reduction in variability in populations close to the hybrid zone, showing assortative odour preference in mate choice experiments as compared to populations further away and displaying no such preference. These loci lie close to genes that we pinpoint as testable candidates for further investigation. PMID:26132782

  13. Genetic Influences on Hand Osteoarthritis in Finnish Women – A Replication Study of Candidate Genes

    PubMed Central

    Hämäläinen, Satu; Solovieva, Svetlana; Vehmas, Tapio; Luoma, Katariina; Leino-Arjas, Päivi; Hirvonen, Ari

    2014-01-01

    Objectives Our aims were to replicate some previously reported associations of single nucleotide polymorphisms (SNPs) in five genes (A2BP1, COG5, GDF5, HFE, ESR1) with hand osteoarthritis (OA), and to examine whether genes (BCAP29, DIO2, DUS4L, DVWA, HLA, PTGS2, PARD3B, TGFB1 and TRIB1) associated with OA at other joint sites were associated with hand OA among Finnish women. Design We examined the bilateral hand radiographs of 542 occupationally active Finnish female dentists and teachers aged 45 to 63 and classified them according to the presence of OA by using reference images. Data regarding finger joint pain and other risk factors were collected using a questionnaire. We defined two hand OA phenotypes: radiographic OA in at least three joints (ROA) and symptomatic DIP OA. The genotypes were determined by PCR-based methods. In statistical analysis, we used SNPStats software, the chi-square test and logistic regression. Results Of the SNPs, rs716508 in A2BP1 was associated with ROA (OR = 0.7, 95% CI 0.5–0.9) and rs1800470 in TGFB1 with symptomatic DIP OA (1.8, 1.2–2.9). We found an interaction between ESR1 (rs9340799) and occupation: teachers with the minor allele were at an increased risk of symptomatic DIP OA (2.8, 1.3–6.5). We saw no association among the dentists. We also found that the carriage of the COG5 rs3757713 C allele increased the risk of ROA only among women with the BCAP29 rs10953541 CC genotype (2.6; 1.1–6.1). There was also a suggestive interaction between the HFE rs179945 and the ESR1 rs9340799, and the carriage of the minor allele of either of these SNPs was associated with an increased risk of symptomatic DIP OA (2.1, 1.3–2.5). Conclusions Our results support the earlier findings of A2BP1 and TBGF1 being OA susceptibility genes and provide evidence of a possible gene-gene interaction in the genetic influence on hand OA predisposition. PMID:24825461

  14. Genetic analysis in Bartter syndrome from India.

    PubMed

    Sharma, Pradeep Kumar; Saikia, Bhaskar; Sharma, Rachna; Ankur, Kumar; Khilnani, Praveen; Aggarwal, Vinay Kumar; Cheong, Hae

    2014-10-01

    Bartter syndrome is a group of inherited, salt-losing tubulopathies presenting as hypokalemic metabolic alkalosis with normotensive hyperreninemia and hyperaldosteronism. Around 150 cases have been reported in literature till now. Mutations leading to salt losing tubulopathies are not routinely tested in Indian population. The authors have done the genetic analysis for the first time in the Bartter syndrome on two cases from India. First case was antenatal Bartter syndrome presenting with massive polyuria and hyperkalemia. Mutational analysis revealed compound heterozygous mutations in KCNJ1(ROMK) gene [p(Leu220Phe), p(Thr191Pro)]. Second case had a phenotypic presentation of classical Bartter syndrome however, genetic analysis revealed only heterozygous novel mutation in SLC12A gene p(Ala232Thr). Bartter syndrome is a clinical diagnosis and genetic analysis is recommended for prognostication and genetic counseling. PMID:24696311

  15. Analysis: OB/GYN-Genetics.

    PubMed

    Fries, Melissa

    2016-01-01

    Ovarian salvage from a patient with brain death is not available and will not preserve viable ova for future reproduction. Previous interest in assisted reproductive technology is only the first step in this process, which requires careful assessment of maternal risks and potential for recurrent genetic disease. PMID:27045306

  16. Candidate loci reveal genetic differentiation between temporally divergent migratory runs of Chinook salmon (Oncorhynchus tshawytscha)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Local adaptation is a dynamic process driven by selection that can vary both in space and time. One important temporal adaptation for migratory animals is the timing of migration and breeding within a reproductive season. Anadromous salmon are excellent subjects for studying the genetic basis of t...

  17. Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence

    PubMed Central

    Yan, Jia; Aliev, Fazil; Webb, Bradley T; Kendler, Kenneth S; Williamson, Vernell S; Edenberg, Howard J; Agrawal, Arpana; Kos, Mark Z; Almasy, Laura; Nurnberger, John I; Schuckit, Marc A; Kramer, John R; Rice, John P; Kuperman, Samuel; Goate, Alison M; Tischfield, Jay A; Porjesz, Bernice; Dick, Danielle M

    2013-01-01

    Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared to family history information has not been reported. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we examined the aggregate impact of multiple single nucleotide polymorphisms (SNPs) on risk prediction. We created genetic sum scores by adding risk alleles associated in discovery samples, and then tested the scores for their ability to discriminate between cases and controls in validation samples. Genetic sum scores were assessed separately for SNPs associated with AD in candidate gene studies and SNPs from GWAS analyses that met varying p-value thresholds. Candidate gene sum scores did not exhibit significant predictive accuracy. Family history was a better classifier of case-control status, with a significant area under the receiver operating characteristic curve (AUC) of 0.686 in COGA and 0.614 in SAGE. SNPs that met less stringent p-value thresholds of 0.01 to 0.50 in GWAS analyses yielded significant AUC estimates, ranging from mean estimates of 0.549 for SNPs with p < 0.01 to 0.565 for SNPs with p < 0.50. This study suggests that SNPs currently have limited clinical utility, but there is potential for enhanced predictive ability with better understanding of the large number of variants that might contribute to risk. PMID:23362995

  18. QTL Analysis and Candidate Gene Mapping for the Polyphenol Content in Cider Apple

    PubMed Central

    Verdu, Cindy F.; Guyot, Sylvain; Childebrand, Nicolas; Bahut, Muriel; Celton, Jean-Marc; Gaillard, Sylvain; Lasserre-Zuber, Pauline; Troggio, Michela; Guilet, David; Laurens, François

    2014-01-01

    Polyphenols have favorable antioxidant potential on human health suggesting that their high content is responsible for the beneficial effects of apple consumption. They control the quality of ciders as they predominantly account for astringency, bitterness, color and aroma. In this study, we identified QTLs controlling phenolic compound concentrations and the average polymerization degree of flavanols in a cider apple progeny. Thirty-two compounds belonging to five groups of phenolic compounds were identified and quantified by reversed phase liquid chromatography on both fruit extract and juice, over three years. The average polymerization degree of flavanols was estimated in fruit by phloroglucinolysis coupled to HPLC. Parental maps were built using SSR and SNP markers and used for the QTL analysis. Sixty-nine and 72 QTLs were detected on 14 and 11 linkage groups of the female and male maps, respectively. A majority of the QTLs identified in this study are specific to this population, while others are consistent with previous studies. This study presents for the first time in apple, QTLs for the mean polymerization degree of procyanidins, for which the mechanisms involved remains unknown to this day. Identification of candidate genes underlying major QTLs was then performed in silico and permitted the identification of 18 enzymes of the polyphenol pathway and six transcription factors involved in the apple anthocyanin regulation. New markers were designed from sequences of the most interesting candidate genes in order to confirm their co-localization with underlying QTLs by genetic mapping. Finally, the potential use of these QTLs in breeding programs is discussed. PMID:25271925

  19. Genomic analysis identifies candidate pathogenic variants in 9 of 18 patients with unexplained West syndrome.

    PubMed

    Hino-Fukuyo, Naomi; Kikuchi, Atsuo; Arai-Ichinoi, Natsuko; Niihori, Tetsuya; Sato, Ryo; Suzuki, Tasuku; Kudo, Hiroki; Sato, Yuko; Nakayama, Tojo; Kakisaka, Yosuke; Kubota, Yuki; Kobayashi, Tomoko; Funayama, Ryo; Nakayama, Keiko; Uematsu, Mitsugu; Aoki, Yoko; Haginoya, Kazuhiro; Kure, Shigeo

    2015-06-01

    West syndrome, which is narrowly defined as infantile spasms that occur in clusters and hypsarrhythmia on EEG, is the most common early-onset epileptic encephalopathy (EOEE). Patients with West syndrome may have clear etiologies, including perinatal events, infections, gross chromosomal abnormalities, or cases followed by other EOEEs. However, the genetic etiology of most cases of West syndrome remains unexplained. DNA from 18 patients with unexplained West syndrome was subjected to microarray-based comparative genomic hybridization (array CGH), followed by trio-based whole-exome sequencing in 14 unsolved families. We identified candidate pathogenic variants in 50% of the patients (n = 9/18). The array CGH revealed candidate pathogenic copy number variations in four cases (22%, 4/18), including an Xq28 duplication, a 16p11.2 deletion, a 16p13.1 deletion and a 19p13.2 deletion disrupting CACNA1A. Whole-exome sequencing identified candidate mutations in known epilepsy genes in five cases (36%, 5/14). Three candidate de novo mutations were identified in three cases, with two mutations occurring in two new candidate genes (NR2F1 and CACNA2D1) (21%, 3/14). Hemizygous candidate mutations in ALG13 and BRWD3 were identified in the other two cases (14%, 2/14). Evaluating a panel of 67 known EOEE genes failed to identify significant mutations. Despite the heterogeneity of unexplained West syndrome, the combination of array CGH and whole-exome sequencing is an effective means of evaluating the genetic background in unexplained West syndrome. We provide additional evidence for NR2F1 as a causative gene and for CACNA2D1 and BRWD3 as candidate genes for West syndrome. PMID:25877686

  20. The genetics of multiple sclerosis: review of current and emerging candidates.

    PubMed

    Muñoz-Culla, Maider; Irizar, Haritz; Otaegui, David

    2013-01-01

    Multiple sclerosis (MS) is a complex disease in which environmental, genetic, and epigenetic factors determine the risk of developing the disease. The human leukocyte antigen region is the strongest susceptibility locus linked to MS, but it does not explain the whole heritability of the disease. To find other non-human leukocyte antigen loci associated with the disease, high-throughput genotyping, sequencing, and gene-expression studies have been performed, producing a valuable quantity of information. An overview of the genomic and expression studies is provided in this review, as well as microRNA-expression studies, highlighting the importance of combining all the layers of information in order to elucidate the causes or pathological mechanisms occurring in the disease. Genetics in MS is a promising field that is presumably going to be very productive in the next decade understanding the cross talk between all the factors contributing to the development of MS. PMID:24019748

  1. The genetics of multiple sclerosis: review of current and emerging candidates

    PubMed Central

    Muñoz-Culla, Maider; Irizar, Haritz; Otaegui, David

    2013-01-01

    Multiple sclerosis (MS) is a complex disease in which environmental, genetic, and epigenetic factors determine the risk of developing the disease. The human leukocyte antigen region is the strongest susceptibility locus linked to MS, but it does not explain the whole heritability of the disease. To find other non-human leukocyte antigen loci associated with the disease, high-throughput genotyping, sequencing, and gene-expression studies have been performed, producing a valuable quantity of information. An overview of the genomic and expression studies is provided in this review, as well as microRNA-expression studies, highlighting the importance of combining all the layers of information in order to elucidate the causes or pathological mechanisms occurring in the disease. Genetics in MS is a promising field that is presumably going to be very productive in the next decade understanding the cross talk between all the factors contributing to the development of MS. PMID:24019748

  2. AFLP Genome Scan to Detect Genetic Structure and Candidate Loci under Selection for Local Adaptation of the Invasive Weed Mikania micrantha

    PubMed Central

    Wang, Ting; Chen, Guopei; Zan, Qijie; Wang, Chunbo; Su, Ying-juan

    2012-01-01

    Why some species become successful invaders is an important issue in invasive biology. However, limited genomic resources make it very difficult for identifying candidate genes involved in invasiveness. Mikania micrantha H.B.K. (Asteraceae), one of the world's most invasive weeds, has adapted rapidly in response to novel environments since its introduction to southern China. In its genome, we expect to find outlier loci under selection for local adaptation, critical to dissecting the molecular mechanisms of invasiveness. An explorative amplified fragment length polymorphism (AFLP) genome scan was used to detect candidate loci under selection in 28 M. micrantha populations across its entire introduced range in southern China. We also estimated population genetic parameters, bottleneck signatures, and linkage disequilibrium. In binary characters, such as presence or absence of AFLP bands, if all four character combinations are present, it is referred to as a character incompatibility. Since character incompatibility is deemed to be rare in populations with extensive asexual reproduction, a character incompatibility analysis was also performed in order to infer the predominant mating system in the introduced M. micrantha populations. Out of 483 AFLP loci examined using stringent significance criteria, 14 highly credible outlier loci were identified by Dfdist and Bayescan. Moreover, remarkable genetic variation, multiple introductions, substantial bottlenecks and character compatibility were found to occur in M. micrantha. Thus local adaptation at the genome level indeed exists in M. micrantha, and may represent a major evolutionary mechanism of successful invasion. Interactions between genetic diversity, multiple introductions, and reproductive modes contribute to increase the capacity of adaptive evolution. PMID:22829939

  3. Laser hazard analysis for various candidate diode lasers associated with the high resolution pulsed scanner.

    SciTech Connect

    Augustoni, Arnold L.

    2004-10-01

    A laser hazard analysis and safety assessment was performed for each various laser diode candidates associated with the High Resolution Pulse Scanner based on the ANSI Standard Z136.1-2000, American National Standard for the Safe Use of Lasers. A theoretical laser hazard analysis model for this system was derived and an Excel{reg_sign} spreadsheet model was developed to answer the 'what if questions' associated with the various modes of operations for the various candidate diode lasers.

  4. A large-scale candidate gene analysis of mood disorders: evidence of neurotrophic tyrosine kinase receptor and opioid receptor signaling dysfunction

    PubMed Central

    Deo, Anthony J.; Huang, Yung-yu; Hodgkinson, Colin A.; Xin, Yurong; Oquendo, Maria A.; Dwork, Andrew J.; Arango, Victoria; Brent, David A.; Goldman, David; Mann, J. John; Haghighi, Fatemeh

    2013-01-01

    Background Despite proven heritability, little is known about the genetic architecture of mood disorders. Although a number of family and case–control studies have examined the genetics of mood disorders, none have carried out joint linkage-association studies and sought to validate the results with gene expression analyses in an independent cohort. Methods We present findings from a large candidate gene study that combines linkage and association analyses using families and singletons, providing a systematic candidate gene investigation of mood disorder. For this study, 876 individuals were recruited, including 83 families with 313 individuals and 563 singletons. This large-scale candidate gene analysis included 130 candidate genes implicated in addictive and other psychiatric disorders. These data showed significant genetic associations for 28 of these candidate genes, although none remained significant after correction for multiple testing. To evaluate the functional significance of these 28 candidate genes in mood disorders, we examined the transcriptional profiles of these genes within the dorsolateral prefrontal cortex and anterior cingulate for 21 cases with mood disorders and 25 nonpsychiatric controls, and carried out a pathway analysis to identify points of high connectivity suggestive of particular molecular pathways that may be dysregulated. Results Two primary gene candidates were supported by the linkage-association, gene expression profiling, and network analysis: neurotrophic tyrosine kinase receptor, type 2 (NTRK2), and the opioid receptor, κ1 (OPRK1). Conclusion This study supports a role for NTRK2 and OPRK1 signaling in the pathophysiology of mood disorder. The unique approach incorporating evidence from multiple experimental and computational modalities enhances confidence in these findings. PMID:23277131

  5. Integrating subpathway analysis to identify candidate agents for hepatocellular carcinoma

    PubMed Central

    Wang, Jiye; Li, Mi; Wang, Yun; Liu, Xiaoping

    2016-01-01

    Hepatocellular carcinoma (HCC) is the second most common cause of cancer-associated death worldwide, characterized by a high invasiveness and resistance to normal anticancer treatments. The need to develop new therapeutic agents for HCC is urgent. Here, we developed a bioinformatics method to identify potential novel drugs for HCC by integrating HCC-related and drug-affected subpathways. By using the RNA-seq data from the TCGA (The Cancer Genome Atlas) database, we first identified 1,763 differentially expressed genes between HCC and normal samples. Next, we identified 104 significant HCC-related subpathways. We also identified the subpathways associated with small molecular drugs in the CMap database. Finally, by integrating HCC-related and drug-affected subpathways, we identified 40 novel small molecular drugs capable of targeting these HCC-involved subpathways. In addition to previously reported agents (ie, calmidazolium), our method also identified potentially novel agents for targeting HCC. We experimentally verified that one of these novel agents, prenylamine, induced HCC cell apoptosis using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, an acridine orange/ethidium bromide stain, and electron microscopy. In addition, we found that prenylamine not only affected several classic apoptosis-related proteins, including Bax, Bcl-2, and cytochrome c, but also increased caspase-3 activity. These candidate small molecular drugs identified by us may provide insights into novel therapeutic approaches for HCC. PMID:27022281

  6. Integrating subpathway analysis to identify candidate agents for hepatocellular carcinoma.

    PubMed

    Wang, Jiye; Li, Mi; Wang, Yun; Liu, Xiaoping

    2016-01-01

    Hepatocellular carcinoma (HCC) is the second most common cause of cancer-associated death worldwide, characterized by a high invasiveness and resistance to normal anticancer treatments. The need to develop new therapeutic agents for HCC is urgent. Here, we developed a bioinformatics method to identify potential novel drugs for HCC by integrating HCC-related and drug-affected subpathways. By using the RNA-seq data from the TCGA (The Cancer Genome Atlas) database, we first identified 1,763 differentially expressed genes between HCC and normal samples. Next, we identified 104 significant HCC-related subpathways. We also identified the subpathways associated with small molecular drugs in the CMap database. Finally, by integrating HCC-related and drug-affected subpathways, we identified 40 novel small molecular drugs capable of targeting these HCC-involved subpathways. In addition to previously reported agents (ie, calmidazolium), our method also identified potentially novel agents for targeting HCC. We experimentally verified that one of these novel agents, prenylamine, induced HCC cell apoptosis using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, an acridine orange/ethidium bromide stain, and electron microscopy. In addition, we found that prenylamine not only affected several classic apoptosis-related proteins, including Bax, Bcl-2, and cytochrome c, but also increased caspase-3 activity. These candidate small molecular drugs identified by us may provide insights into novel therapeutic approaches for HCC. PMID:27022281

  7. TOPICAL REVIEW: Integrated genetic analysis microsystems

    NASA Astrophysics Data System (ADS)

    Lagally, Eric T.; Mathies, Richard A.

    2004-12-01

    With the completion of the Human Genome Project and the ongoing DNA sequencing of the genomes of other animals, bacteria, plants and others, a wealth of new information about the genetic composition of organisms has become available. However, as the demand for sequence information grows, so does the workload required both to generate this sequence and to use it for targeted genetic analysis. Microfabricated genetic analysis systems are well poised to assist in the collection and use of these data through increased analysis speed, lower analysis cost and higher parallelism leading to increased assay throughput. In addition, such integrated microsystems may point the way to targeted genetic experiments on single cells and in other areas that are otherwise very difficult. Concomitant with these advantages, such systems, when fully integrated, should be capable of forming portable systems for high-speed in situ analyses, enabling a new standard in disciplines such as clinical chemistry, forensics, biowarfare detection and epidemiology. This review will discuss the various technologies available for genetic analysis on the microscale, and efforts to integrate them to form fully functional robust analysis devices.

  8. Path analysis in genetic epidemiology: a critique.

    PubMed Central

    Karlin, S; Cameron, E C; Chakraborty, R

    1983-01-01

    Path analysis, a form of general linear structural equation models, is used in studies of human genetics data to discern genetic, environmental, and cultural factors contributing to familial resemblance. It postulates a set of linear and additive parametric relationships between phenotypes and genetic and cultural variables and then essentially uses the assumption of multivariate normality to estimate and perform tests of hypothesis on parameters. Such an approach has been advocated for the analysis of genetic epidemiological data by D. C. Rao, N. Morton, C. R. Cloninger, L. J. Eaves, and W. E. Nance, among others. This paper reviews and evaluates the formulations, assumptions, methodological procedures, interpretations, and applications of path analysis. To give perspective, we begin with a discussion of path analysis as it occurs in the form of general linear causal models in several disciplines of the social sciences. Several specific path analysis models applied to lipoprotein concentrations, IQ, and twin data are then reviewed to keep the presentation self-contained. The bulk of the critical discussion that follows is directed toward the following four facets of path analysis: (1) coherence of model specification and applicability to data; (2) plausibility of modeling assumptions; (3) interpretability and utility of the model; and (4) validity of statistical and computational procedures. In the concluding section, a brief discussion of the problem of appropriate model selection is presented, followed by a number of suggestions of essentially model-free alternative methods of use in the treatment of complex structured data such as occurs in genetic epidemiology. PMID:6349335

  9. A "candidate-interactome" aggregate analysis of genome-wide association data in multiple sclerosis.

    PubMed

    Mechelli, Rosella; Umeton, Renato; Policano, Claudia; Annibali, Viviana; Coarelli, Giulia; Ricigliano, Vito A G; Vittori, Danila; Fornasiero, Arianna; Buscarinu, Maria Chiara; Romano, Silvia; Salvetti, Marco; Ristori, Giovanni

    2013-01-01

    Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. PMID:23696811

  10. A “Candidate-Interactome” Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

    PubMed Central

    Policano, Claudia; Annibali, Viviana; Coarelli, Giulia; Ricigliano, Vito A. G.; Vittori, Danila; Fornasiero, Arianna; Buscarinu, Maria Chiara; Romano, Silvia; Salvetti, Marco; Ristori, Giovanni

    2013-01-01

    Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a “candidate interactome” (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. PMID:23696811

  11. Analysis of Genetically Complex Epilepsies

    PubMed Central

    Ottman, Ruth

    2006-01-01

    During the last decade, great progress has been made in the discovery of genes that influence risk for epilepsy. However, these gene discoveries have been in epilepsies with Mendelian modes of inheritance, which comprise only a tiny fraction of all epilepsy. Most people with epilepsy have no affected relatives, suggesting that the great majority of all epilepsies are genetically complex: multiple genes contribute to their etiology, none of which has a major effect on disease risk. Gene discovery in the genetically complex epilepsies is a formidable task. It is unclear which epilepsy phenotypes are most advantageous to study, and chromosomal localization and mutation detection are much more difficult than in Mendelian epilepsies. Association studies are very promising for the identification of complex epilepsy genes, but we are still in the earliest stages of their application in the epilepsies. Future studies should employ very large sample sizes to ensure adequate statistical power, clinical phenotyping methods of the highest quality, designs and analytic techniques that control for population stratification, and state-of-the-art molecular methods. Collaborative studies are essential to achieve these goals. PMID:16359464

  12. Characterization of genetically inactivated pertussis toxin mutants: candidates for a new vaccine against whooping cough.

    PubMed Central

    Nencioni, L; Pizza, M; Bugnoli, M; De Magistris, T; Di Tommaso, A; Giovannoni, F; Manetti, R; Marsili, I; Matteucci, G; Nucci, D

    1990-01-01

    the introduction of two amino acid substitutions within the enzymatically active subunit S1 of pertussis toxin (PT) abolishes its ADP-ribosyltransferase activity and toxicity on CHO cells (Pizza et al., Science 246:497-500, 1989). These genetically inactivated molecules are also devoid of other in vivo adverse reactions typical of PT, such as induction of leukocytosis, potentiation of anaphylaxis, stimulation of insulin secretion, and histamine sensitivity. However, the mutant PT molecules are indistinguishable from wild-type PT in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and maintain all the physical and chemical properties of PT, including affinity for toxin-neutralizing poly- and monoclonal antibodies. Either alone or stabilized with formaldehyde, PT mutants are able to induce high levels of neutralizing antibodies and to protect mice in a dose-dependent fashion against intracerebral challenge with virulent B. pertussis. These results clearly show that these genetically inactivated PT molecules are nontoxic but still immunogenic and justify their development as a component of a new, safer acellular vaccine against whooping cough. Images PMID:2323818

  13. Criteria for Identifying and Evaluating Candidate Sites for Open-Field Trials of Genetically Engineered Mosquitoes

    PubMed Central

    Brown, David M.; Alphey, Luke S.; McKemey, Andrew; Beech, Camilla

    2014-01-01

    Abstract Recent laboratory successes in the development of genetically engineered mosquitoes for controlling pathogen transmission have fostered the need for standardized procedures for advancing the technical achievements to practical tools. It is incumbent in many cases for the same scientists doing the in-laboratory discovery research to also take on the initial challenges of developing the pathway that will move the technologies to the field. One of these challenges is having a set of criteria for selecting collaborators and sites for efficacy and safety field trials that combine rigorous science with good ethical and legal practices. Specific site-selection criteria were developed in four categories—Scientific, Regulatory, Community Engagement, and Resources—in anticipation of open-field releases of a transgenic mosquito strain designed to suppress populations of the dengue vector mosquito, Aedes aegypti. The criteria are derived from previous published material, discussions, and personal experiences with the expectation of providing guidance to laboratory scientists for addressing the conceptual and operational considerations for identifying partner researchers and countries with whom to collaborate. These criteria are not intended to be prescriptive nor can they be applied to every circumstance where genetic approaches are proposed for deployment. However, we encourage those involved in the discovery phase of research to consider each criterion during project planning activities, and where appropriate, incorporate them into a “go/no-go” decision-making process for further development and testing of the technologies. PMID:24689963

  14. Criteria for identifying and evaluating candidate sites for open-field trials of genetically engineered mosquitoes.

    PubMed

    Brown, David M; Alphey, Luke S; McKemey, Andrew; Beech, Camilla; James, Anthony A

    2014-04-01

    Recent laboratory successes in the development of genetically engineered mosquitoes for controlling pathogen transmission have fostered the need for standardized procedures for advancing the technical achievements to practical tools. It is incumbent in many cases for the same scientists doing the in-laboratory discovery research to also take on the initial challenges of developing the pathway that will move the technologies to the field. One of these challenges is having a set of criteria for selecting collaborators and sites for efficacy and safety field trials that combine rigorous science with good ethical and legal practices. Specific site-selection criteria were developed in four categories-Scientific, Regulatory, Community Engagement, and Resources-in anticipation of open-field releases of a transgenic mosquito strain designed to suppress populations of the dengue vector mosquito, Aedes aegypti. The criteria are derived from previous published material, discussions, and personal experiences with the expectation of providing guidance to laboratory scientists for addressing the conceptual and operational considerations for identifying partner researchers and countries with whom to collaborate. These criteria are not intended to be prescriptive nor can they be applied to every circumstance where genetic approaches are proposed for deployment. However, we encourage those involved in the discovery phase of research to consider each criterion during project planning activities, and where appropriate, incorporate them into a "go/no-go" decision-making process for further development and testing of the technologies. PMID:24689963

  15. Assessment of Osteoarthritis Candidate Genes in a Meta-Analysis of Nine Genome-Wide Association Studies

    PubMed Central

    Rodriguez-Fontenla, Cristina; Calaza, Manuel; Evangelou, Evangelos; Valdes, Ana M; Arden, Nigel; Blanco, Francisco J; Carr, Andrew; Chapman, Kay; Deloukas, Panos; Doherty, Michael; Esko, Tõnu; Garcés Aletá, Carlos M; Gomez-Reino Carnota, Juan J; Helgadottir, Hafdis; Hofman, Albert; Jonsdottir, Ingileif; Kerkhof, Hanneke J M; Kloppenburg, Margreet; McCaskie, Andrew; Ntzani, Evangelia E; Ollier, William E R; Oreiro, Natividad; Panoutsopoulou, Kalliope; Ralston, Stuart H; Ramos, Yolande F; Riancho, Jose A; Rivadeneira, Fernando; Slagboom, P Eline; Styrkarsdottir, Unnur; Thorsteinsdottir, Unnur; Thorleifsson, Gudmar; Tsezou, Aspasia; Uitterlinden, André G; Wallis, Gillian A; Wilkinson, J Mark; Zhai, Guangju; Zhu, Yanyan; Felson, David T; Ioannidis, John P A; Loughlin, John; Metspalu, Andres; Meulenbelt, Ingrid; Stefansson, Kari; van Meurs, Joyce B; Zeggini, Eleftheria; Spector, Timothy D; Gonzalez, Antonio

    2014-01-01

    Objective To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA. Methods A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10−5 were considered significant. Results SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10−5, odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06−1.17) and rs1241164 (P = 1.47 × 10−5, OR 0.82, 95% CI 0.74−0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10−5, OR 0.87, 95% CI 0.82−0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10−5, OR 0.85, 95% CI 0.79−0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened. Conclusion Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated. PMID:24757145

  16. Patterns of genetic diversity and candidate genes for ecological divergence in a homoploid hybrid sunflower, Helianthus anomalus

    PubMed Central

    SAPIR, YUVAL; MOODY, MICHAEL L.; BROUILLETTE, LARRY C.; DONOVAN, LISA A.; RIESEBERG, LOREN H.

    2008-01-01

    Natural hybridization accompanied by a shift in niche preference by hybrid genotypes can lead to hybrid speciation. Natural selection may cause the fixation of advantageous alleles in the ecologically diverged hybrids, and the loci experiencing selection should exhibit a reduction in allelic diversity relative to neutral loci. Here, we analyzed patterns of genetic diversity at 59 microsatellite loci associated with expressed sequence tags (ESTs) in a homoploid hybrid sunflower species, Helianthus anomalus. We used two indices, ln RV and ln RH, to compare variation and heterozygosity (respectively) at each locus between the hybrid species and its two parental species, H. annuus and H. petiolaris. Mean values of ln RV and ln RH were significantly lower than zero, which implies that H. anomalus experienced a population bottleneck during its recent evolutionary history. After correcting for the apparent bottleneck, we found six loci with a significant reduction in variation or with heterozygosity in the hybrid species, compared to one or both of the parental species. These loci should be viewed as a ranked list of candidate loci, pending further sequencing and functional analyses. Sequence data were generated for two of the candidate loci, but population genetics tests failed to detect deviations from neutral evolution at either locus. Nonetheless, a greater than eight-fold excess of nonsynonymous substitutions was found near a putative N-myristoylation motif at the second locus (HT998), and likelihood-based models indicated that the protein has been under selection in H. anomalus in the past and, perhaps, in one or both parental species. Finally, our data suggest that selective sweeps may have united populations of H. anomalus isolated by a mountain range, indicating that even low gene-flow species may be held together by the spread of advantageous alleles. PMID:17944850

  17. A Killed, Genetically Engineered Derivative of a Wild-Type Extraintestinal Pathogenic E. coli strain is a Vaccine Candidate

    PubMed Central

    Russo, Thomas A.; Beanan, Janet M.; Olson, Ruth; Genagon, Stacy A.; MacDonald, Ulrike; Cope, John J.; Davidson, Bruce A.; Johnston, Brian; Johnson, James R.

    2007-01-01

    Infections due to extraintestinal pathogenic E. coli (ExPEC) result in significant morbidity, mortality and increased healthcare costs. An efficacious vaccine against ExPEC would be desirable. In this report we explore the use of killed-whole E. coli as a vaccine immunogen. Given the diversity of capsule and O-antigens in ExPEC we have hypothesized that alternative targets are viable vaccine candidates. We have also hypothesized that immunization with a genetically engineered strain that is deficient in the capsule and O-antigen will generate a greater immune response against antigens other than the capsular and O-antigen epitopes than a wild-type strain. Lastly, we hypothesize that mucosal immunization with killed E. coli has the potential to generate a significant immune response. In this study we demonstrated that nasal immunization with a formalin-killed ExPEC derivative deficient in capsule and O-antigen results in a significantly greater overall humoral response compared to its wild-type derivative (which demonstrates that capsule and/or the O-antigen impede the development of an optimal humoral immune response) and a significantly greater immune response against non-capsular and O-antigen epitopes. These antibodies also bound to a subset of heterologous ExPEC strains and enhanced neutrophil-mediated bactericidal activity against the homologous and a heterologous strain. Taken together these studies support the concept that formalin-killed genetically engineered ExPEC derivatives are whole cell vaccine candidates to prevent infections due to ExPEC. PMID:17306426

  18. Gene-gene interactions among genetic variants from obesity candidate genes for nonobese and obese populations in type 2 diabetes.

    PubMed

    Lin, Eugene; Pei, Dee; Huang, Yi-Jen; Hsieh, Chang-Hsun; Wu, Lawrence Shih-Hsin

    2009-08-01

    Recent studies indicate that obesity may play a key role in modulating genetic predispositions to type 2 diabetes (T2D). This study examines the main effects of both single-locus and multilocus interactions among genetic variants in Taiwanese obese and nonobese individuals to test the hypothesis that obesity-related genes may contribute to the etiology of T2D independently and/or through such complex interactions. We genotyped 11 single nucleotide polymorphisms for 10 obesity candidate genes including adrenergic beta-2-receptor surface, adrenergic beta-3-receptor surface, angiotensinogen, fat mass and obesity associated gene, guanine nucleotide binding protein beta polypeptide 3 (GNB3), interleukin 6 receptor, proprotein convertase subtilisin/kexin type 1 (PCSK1), uncoupling protein 1, uncoupling protein 2, and uncoupling protein 3. There were 389 patients diagnosed with T2D and 186 age- and sex-matched controls. Single-locus analyses showed significant main effects of the GNB3 and PCSK1 genes on the risk of T2D among the nonobese group (p = 0.002 and 0.047, respectively). Further, interactions involving GNB3 and PCSK1 were suggested among the nonobese population using the generalized multifactor dimensionality reduction method (p = 0.001). In addition, interactions among angiotensinogen, fat mass and obesity associated gene, GNB3, and uncoupling protein 3 genes were found in a significant four-locus generalized multifactor dimensionality reduction model among the obese population (p = 0.001). The results suggest that the single nucleotide polymorphisms from the obesity candidate genes may contribute to the risk of T2D independently and/or in an interactive manner according to the presence or absence of obesity. PMID:19594364

  19. A new web-based data mining tool for the identification of candidate genes for human genetic disorders.

    PubMed

    van Driel, Marc A; Cuelenaere, Koen; Kemmeren, Patrick P C W; Leunissen, Jack A M; Brunner, Han G

    2003-01-01

    To identify the gene underlying a human genetic disorder can be difficult and time-consuming. Typically, positional data delimit a chromosomal region that contains between 20 and 200 genes. The choice then lies between sequencing large numbers of genes, or setting priorities by combining positional data with available expression and phenotype data, contained in different internet databases. This process of examining positional candidates for possible functional clues may be performed in many different ways, depending on the investigator's knowledge and experience. Here, we report on a new tool called the GeneSeeker, which gathers and combines positional data and expression/phenotypic data in an automated way from nine different web-based databases. This results in a quick overview of interesting candidate genes in the region of interest. The GeneSeeker system is built in a modular fashion allowing for easy addition or removal of databases if required. Databases are searched directly through the web, which obviates the need for data warehousing. In order to evaluate the GeneSeeker tool, we analysed syndromes with known genesis. For each of 10 syndromes the GeneSeeker programme generated a shortlist that contained a significantly reduced number of candidate genes from the critical region, yet still contained the causative gene. On average, a list of 163 genes based on position alone was reduced to a more manageable list of 22 genes based on position and expression or phenotype information. We are currently expanding the tool by adding other databases. The GeneSeeker is available via the web-interface (http://www.cmbi.kun.nl/GeneSeeker/). PMID:12529706

  20. Application of Genomic and Quantitative Genetic Tools to Identify Candidate Resistance Genes for Brown Rot Resistance in Peach

    PubMed Central

    Martínez-García, Pedro J.; Parfitt, Dan E.; Bostock, Richard M.; Fresnedo-Ramírez, Jonathan; Vazquez-Lobo, Alejandra; Ogundiwin, Ebenezer A.; Gradziel, Thomas M.; Crisosto, Carlos H.

    2013-01-01

    The availability of a complete peach genome assembly and three different peach genome sequences created by our group provide new opportunities for application of genomic data and can improve the power of the classical Quantitative Trait Loci (QTL) approaches to identify candidate genes for peach disease resistance. Brown rot caused by Monilinia spp., is the most important fungal disease of stone fruits worldwide. Improved levels of peach fruit rot resistance have been identified in some cultivars and advanced selections developed in the UC Davis and USDA breeding programs. Whole genome sequencing of the Pop-DF parents lead to discovery of high-quality SNP markers for QTL genome scanning in this experimental population. Pop-DF created by crossing a brown rot moderately resistant cultivar ‘Dr. Davis’ and a brown rot resistant introgression line, ‘F8,1–42’, derived from an initial almond × peach interspecific hybrid, was evaluated for brown rot resistance in fruit of harvest maturity over three seasons. Using the SNP linkage map of Pop-DF and phenotypic data collected with inoculated fruit, a genome scan for QTL identified several SNP markers associated with brown rot resistance. Two of these QTLs were placed on linkage group 1, covering a large (physical) region on chromosome 1. The genome scan for QTL and SNP effects predicted several candidate genes associated with disease resistance responses in other host-pathogen systems. Two potential candidate genes, ppa011763m and ppa026453m, may be the genes primarily responsible for M. fructicola recognition in peach, activating both PAMP-triggered immunity (PTI) and effector-triggered immunity (ETI) responses. Our results provide a foundation for further genetic dissection, marker assisted breeding for brown rot resistance, and development of peach cultivars resistant to brown rot. PMID:24244329

  1. Neuregulin 1: a prime candidate for research into gene-environment interactions in schizophrenia? Insights from genetic rodent models

    PubMed Central

    Karl, Tim

    2013-01-01

    Schizophrenia is a multi-factorial disease characterized by a high heritability and environmental risk factors. In recent years, an increasing number of researchers worldwide have started investigating the “two-hit hypothesis” of schizophrenia predicting that genetic and environmental risk factors (GxE) interactively cause the development of the disorder. This work is starting to produce valuable new animal models and reveal novel insights into the pathophysiology of schizophrenia. This mini review will focus on recent advancements in the field made by challenging mutant and transgenic rodent models for the schizophrenia candidate gene neuregulin 1 (NRG1) with particular environmental factors. It will outline results obtained from mouse and rat models for various Nrg1 isoforms/isoform types (e.g., transmembrane domain Nrg1, Type II Nrg1), which have been exposed to different forms of stress (acute versus chronic, restraint versus social) and housing conditions (standard laboratory versus minimally enriched housing). These studies suggest Nrg1 as a prime candidate for GxE interactions in schizophrenia rodent models and that the use of rodent models will enable a better understanding of GxE interactions and the underlying mechanisms. PMID:23966917

  2. Candidate genes and their interactions with other genetic / environmental risk factors in the etiology of schizophrenia

    PubMed Central

    Prasad, KM; Talkowski, MT; Chowdari, KV; McClain, L; Yolken, RH

    2016-01-01

    Identification of causative factors for common, chronic disorders is a major focus of current human health science research. These disorders are likely to be caused by multiple etiological agents. Available evidence also suggests that interactions between the risk factors may explain some of their pathogenic effects. While progress in genomics and allied biological research has brought forth powerful analytic techniques, the predicted complexity poses daunting analytic challenges. The search for pathogenesis of schizophrenia shares most of these challenges. We have reviewed the analytic and logistic problems associated with the search for pathogenesis. Evidence for pathogenic interactions is presented for selected diseases and for schizophrenia. We end by suggesting ‘recursive analyses’ as a potential design to address these challenges. This scheme involves initial focused searches for interactions motivated by available evidence, typically involving identified individual risk factors, such as candidate gene variants. Putative interactions are tested rigorously for replication and for biological plausibility. Support for the interactions from statistical and functional analyses motivates a progressively larger array of interactants that are evaluated recursively. The risk explained by the interactions is assessed concurrently and further elaborate searches may be guided by the results of such analyses. By way of example, we summarize our ongoing analyses of dopaminergic polymorphisms, as well as infectious etiological factors in schizophrenia genesis to exemplify this approach. PMID:19729054

  3. Selection of neutrino burst candidates by pulse spatial distribution analysis

    NASA Astrophysics Data System (ADS)

    Ryasny, V. G.

    1996-02-01

    The method of analysis and possibilities of identification of neutrino bursts from collapsing stars using a spatial distribution of pulses in the multimodular installations, like the Large Volume Detector at the Gran Sasso Laboratory, Liquid Scintillation Detector (Mont Blanc) and Baksan Scintillation Telescope, are discussed. The method could be applicable for any position sensitive detector. By the spatial distribution analysis the burst imitation probability can be decreased by at least 2 orders of magnitude, without significant loss of sensitivity, for currently predicted number of the neutrino interactions.

  4. PLANETARY CANDIDATES OBSERVED BY KEPLER. III. ANALYSIS OF THE FIRST 16 MONTHS OF DATA

    SciTech Connect

    Batalha, Natalie M.; Rowe, Jason F.; Burke, Christopher J.; Caldwell, Douglas A.; Mullally, Fergal; Thompson, Susan E.; Barclay, Thomas; Dupree, Andrea K.; Latham, David W.; Quinn, Samuel N.; Ragozzine, Darin; Fabrycky, Daniel C.; Fortney, Jonathan J.; Ford, Eric B.; Gilliland, Ronald L.; Isaacson, Howard; Marcy, Geoffrey W.; and others

    2013-02-15

    New transiting planet candidates are identified in 16 months (2009 May-2010 September) of data from the Kepler spacecraft. Nearly 5000 periodic transit-like signals are vetted against astrophysical and instrumental false positives yielding 1108 viable new planet candidates, bringing the total count up to over 2300. Improved vetting metrics are employed, contributing to higher catalog reliability. Most notable is the noise-weighted robust averaging of multi-quarter photo-center offsets derived from difference image analysis that identifies likely background eclipsing binaries. Twenty-two months of photometry are used for the purpose of characterizing each of the candidates. Ephemerides (transit epoch, T {sub 0}, and orbital period, P) are tabulated as well as the products of light curve modeling: reduced radius (R {sub P}/R {sub *}), reduced semimajor axis (d/R {sub *}), and impact parameter (b). The largest fractional increases are seen for the smallest planet candidates (201% for candidates smaller than 2 R {sub Circled-Plus} compared to 53% for candidates larger than 2 R {sub Circled-Plus }) and those at longer orbital periods (124% for candidates outside of 50 day orbits versus 86% for candidates inside of 50 day orbits). The gains are larger than expected from increasing the observing window from 13 months (Quarters 1-5) to 16 months (Quarters 1-6) even in regions of parameter space where one would have expected the previous catalogs to be complete. Analyses of planet frequencies based on previous catalogs will be affected by such incompleteness. The fraction of all planet candidate host stars with multiple candidates has grown from 17% to 20%, and the paucity of short-period giant planets in multiple systems is still evident. The progression toward smaller planets at longer orbital periods with each new catalog release suggests that Earth-size planets in the habitable zone are forthcoming if, indeed, such planets are abundant.

  5. Monte Carlo methods in genetic analysis

    SciTech Connect

    Lin, Shili

    1996-12-31

    Many genetic analyses require computation of probabilities and likelihoods of pedigree data. With more and more genetic marker data deriving from new DNA technologies becoming available to researchers, exact computations are often formidable with standard statistical methods and computational algorithms. The desire to utilize as much available data as possible, coupled with complexities of realistic genetic models, push traditional approaches to their limits. These methods encounter severe methodological and computational challenges, even with the aid of advanced computing technology. Monte Carlo methods are therefore increasingly being explored as practical techniques for estimating these probabilities and likelihoods. This paper reviews the basic elements of the Markov chain Monte Carlo method and the method of sequential imputation, with an emphasis upon their applicability to genetic analysis. Three areas of applications are presented to demonstrate the versatility of Markov chain Monte Carlo for different types of genetic problems. A multilocus linkage analysis example is also presented to illustrate the sequential imputation method. Finally, important statistical issues of Markov chain Monte Carlo and sequential imputation, some of which are unique to genetic data, are discussed, and current solutions are outlined. 72 refs.

  6. Genetic variation at hair length candidate genes in elephants and the extinct woolly mammoth

    PubMed Central

    Roca, Alfred L; Ishida, Yasuko; Nikolaidis, Nikolas; Kolokotronis, Sergios-Orestis; Fratpietro, Stephen; Stewardson, Kristin; Hensley, Shannon; Tisdale, Michele; Boeskorov, Gennady; Greenwood, Alex D

    2009-01-01

    Background Like humans, the living elephants are unusual among mammals in being sparsely covered with hair. Relative to extant elephants, the extinct woolly mammoth, Mammuthus primigenius, had a dense hair cover and extremely long hair, which likely were adaptations to its subarctic habitat. The fibroblast growth factor 5 (FGF5) gene affects hair length in a diverse set of mammalian species. Mutations in FGF5 lead to recessive long hair phenotypes in mice, dogs, and cats; and the gene has been implicated in hair length variation in rabbits. Thus, FGF5 represents a leading candidate gene for the phenotypic differences in hair length notable between extant elephants and the woolly mammoth. We therefore sequenced the three exons (except for the 3' UTR) and a portion of the promoter of FGF5 from the living elephantid species (Asian, African savanna and African forest elephants) and, using protocols for ancient DNA, from a woolly mammoth. Results Between the extant elephants and the mammoth, two single base substitutions were observed in FGF5, neither of which alters the amino acid sequence. Modeling of the protein structure suggests that the elephantid proteins fold similarly to the human FGF5 protein. Bioinformatics analyses and DNA sequencing of another locus that has been implicated in hair cover in humans, type I hair keratin pseudogene (KRTHAP1), also yielded negative results. Interestingly, KRTHAP1 is a pseudogene in elephantids as in humans (although fully functional in non-human primates). Conclusion The data suggest that the coding sequence of the FGF5 gene is not the critical determinant of hair length differences among elephantids. The results are discussed in the context of hairlessness among mammals and in terms of the potential impact of large body size, subarctic conditions, and an aquatic ancestor on hair cover in the Proboscidea. PMID:19747392

  7. Molecular Genetic Analysis of Chlamydia Species.

    PubMed

    Sixt, Barbara S; Valdivia, Raphael H

    2016-09-01

    Species of Chlamydia are the etiologic agent of endemic blinding trachoma, the leading cause of bacterial sexually transmitted diseases, significant respiratory pathogens, and a zoonotic threat. Their dependence on an intracellular growth niche and their peculiar developmental cycle are major challenges to elucidating their biology and virulence traits. The last decade has seen tremendous advances in our ability to perform a molecular genetic analysis of Chlamydia species. Major achievements include the generation of large collections of mutant strains, now available for forward- and reverse-genetic applications, and the introduction of a system for plasmid-based transformation enabling complementation of mutations; expression of foreign, modified, or reporter genes; and even targeted gene disruptions. This review summarizes the current status of the molecular genetic toolbox for Chlamydia species and highlights new insights into their biology and new challenges in the nascent field of Chlamydia genetics. PMID:27607551

  8. Planetary Candidates Observed by Kepler, III: Analysis of the First 16 Months of Data

    SciTech Connect

    Batalha, Natalie M.; Rowe, Jason F.; Bryson, Stephen T.; Barclay, Thomas; Burke, Christopher J.; Caldwell, Douglas A.; Christiansen, Jessie L.; Mullally, Fergal; Thompson, Susan E.; Brown, Timothy M.; Dupree, Andrea K.; /Harvard-Smithsonian Ctr. Astrophys. /UC, Santa Cruz

    2012-02-01

    New transiting planet candidates are identified in sixteen months (May 2009 - September 2010) of data from the Kepler spacecraft. Nearly five thousand periodic transit-like signals are vetted against astrophysical and instrumental false positives yielding 1091 viable new planet candidates, bringing the total count up to over 2,300. Improved vetting metrics are employed, contributing to higher catalog reliability. Most notable is the noise-weighted robust averaging of multiquarter photo-center offsets derived from difference image analysis which identifies likely background eclipsing binaries. Twenty-two months of photometry are used for the purpose of characterizing each of the new candidates. Ephemerides (transit epoch, T{sub 0}, and orbital period, P) are tabulated as well as the products of light curve modeling: reduced radius (R{sub P}/R{sub {star}}), reduced semi-major axis (d/R{sub {star}}), and impact parameter (b). The largest fractional increases are seen for the smallest planet candidates (197% for candidates smaller than 2R{sub {circle_plus}} compared to 52% for candidates larger than 2R{sub {circle_plus}}) and those at longer orbital periods (123% for candidates outside of 50 day orbits versus 85% for candidates inside of 50 day orbits). The gains are larger than expected from increasing the observing window from thirteen months (Quarter 1 - Quarter 5) to sixteen months (Quarter 1 - Quarter 6). This demonstrates the benefit of continued development of pipeline analysis software. The fraction of all host stars with multiple candidates has grown from 17% to 20%, and the paucity of short-period giant planets in multiple systems is still evident. The progression toward smaller planets at longer orbital periods with each new catalog release suggests that Earth-size planets in the Habitable Zone are forthcoming if, indeed, such planets are abundant.

  9. Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene

    PubMed Central

    Okada, Yukinori; Diogo, Dorothee; Greenberg, Jeffrey D.; Mouassess, Faten; Achkar, Walid A. L.; Fulton, Robert S.; Denny, Joshua C.; Gupta, Namrata; Mirel, Daniel; Gabriel, Stacy; Li, Gang; Kremer, Joel M.; Pappas, Dimitrios A.; Carroll, Robert J.; Eyler, Anne E.; Trynka, Gosia; Stahl, Eli A.; Cui, Jing; Saxena, Richa; Coenen, Marieke J. H.; Guchelaar, Henk-Jan; Huizinga, Tom W. J.; Dieudé, Philippe; Mariette, Xavier; Barton, Anne; Canhão, Helena; Fonseca, João E.; de Vries, Niek; Tak, Paul P.; Moreland, Larry W.; Bridges, S. Louis; Miceli-Richard, Corinne; Choi, Hyon K.; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Raj, Towfique; De Jager, Philip L.; Raychaudhuri, Soumya; Worthington, Jane; Padyukov, Leonid; Klareskog, Lars; Siminovitch, Katherine A.; Gregersen, Peter K.; Mardis, Elaine R.; Arayssi, Thurayya; Kazkaz, Layla A.; Plenge, Robert M.

    2014-01-01

    Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10−6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. PMID:24520335

  10. Anti-candidal activity of genetically engineered histatin variants with multiple functional domains.

    PubMed

    Oppenheim, Frank G; Helmerhorst, Eva J; Lendenmann, Urs; Offner, Gwynneth D

    2012-01-01

    The human bodily defense system includes a wide variety of innate antimicrobial proteins. Histatins are small molecular weight proteins produced by the human salivary glands that exhibit antifungal and antibacterial activities. While evolutionarily old salivary proteins such as mucins and proline-rich proteins contain large regions of tandem repeats, relatively young proteins like histatins do not contain such repeated domains. Anticipating that domain duplications have a functional advantage, we genetically engineered variants of histatin 3 with one, two, three, or four copies of the functional domain by PCR and splice overlap. The resulting proteins, designated reHst3 1-mer, reHist3 2-mer, reHis3 3-mer and reHist3 4-mer, exhibited molecular weights of 4,062, 5,919, 7,777, and 9,634 Da, respectively. The biological activities of these constructs were evaluated in fungicidal assays toward Candida albicans blastoconidia and germinated cells. The antifungal activities per mole of protein increased concomitantly with the number of functional domains present. This increase, however, was higher than could be anticipated from the molar concentration of functional domains present in the constructs. The demonstrated increase in antifungal activity may provide an evolutionary explanation why such domain multiplication is a frequent event in human salivary proteins. PMID:23251551

  11. The Genetics of POAG in Black South Africans: A Candidate Gene Association Study

    PubMed Central

    Williams, Susan E. I.; Carmichael, Trevor R.; Allingham, R. Rand; Hauser, Michael; Ramsay, Michele

    2015-01-01

    Multiple loci have been associated with either primary open angle glaucoma (POAG) or heritable ocular quantitative traits associated with this condition. This study examined the association of these loci with POAG, with central corneal thickness (CCT), vertical cup-to-disc ratio (VCDR) and with diabetes mellitus in a group of black South Africans (215 POAG cases and 214 controls). The population was homogeneous and distinct from other African and European populations. Single SNPs in the MYOC, COL8A2, COL1A1 and ZNF469 gene regions showed marginal associations with POAG. No association with POAG was identified with tagging SNPs in TMCO1, CAV1/CAV2, CYP1B1, COL1A2, COL5A1, CDKN2B/CDKN2BAS-1, SIX1/SIX6 or the chromosome 2p16 regions and there were no associations with CCT or VCDR. However, SNP rs12522383 in WDR36 was associated with diabetes mellitus (p = 0.00008). This first POAG genetic association study in black South Africans has therefore identified associations that require additional investigation in this and other populations to determine their significance. This highlights the need for larger studies in this population if we are to achieve the goal of facilitating early POAG detection and ultimately preventing irreversible blindness from this condition. PMID:25669751

  12. The genetics of POAG in black South Africans: a candidate gene association study.

    PubMed

    Williams, Susan E I; Carmichael, Trevor R; Allingham, R Rand; Hauser, Michael; Ramsay, Michele

    2015-01-01

    Multiple loci have been associated with either primary open angle glaucoma (POAG) or heritable ocular quantitative traits associated with this condition. This study examined the association of these loci with POAG, with central corneal thickness (CCT), vertical cup-to-disc ratio (VCDR) and with diabetes mellitus in a group of black South Africans (215 POAG cases and 214 controls). The population was homogeneous and distinct from other African and European populations. Single SNPs in the MYOC, COL8A2, COL1A1 and ZNF469 gene regions showed marginal associations with POAG. No association with POAG was identified with tagging SNPs in TMCO1, CAV1/CAV2, CYP1B1, COL1A2, COL5A1, CDKN2B/CDKN2BAS-1, SIX1/SIX6 or the chromosome 2p16 regions and there were no associations with CCT or VCDR. However, SNP rs12522383 in WDR36 was associated with diabetes mellitus (p = 0.00008). This first POAG genetic association study in black South Africans has therefore identified associations that require additional investigation in this and other populations to determine their significance. This highlights the need for larger studies in this population if we are to achieve the goal of facilitating early POAG detection and ultimately preventing irreversible blindness from this condition. PMID:25669751

  13. Genetic Polymorphisms of Functional Candidate Genes and Recurrent Acute Otitis Media With or Without Tympanic Membrane Perforation.

    PubMed

    Esposito, Susanna; Marchisio, Paola; Orenti, Annalisa; Spena, Silvia; Bianchini, Sonia; Nazzari, Erica; Rosazza, Chiara; Zampiero, Alberto; Biganzoli, Elia; Principi, Nicola

    2015-10-01

    Evaluation of the genetic contribution to the development of recurrent acute otitis media (rAOM) remains challenging. This study aimed to evaluate the potential association between single nucleotide polymorphisms (SNPs) in selected genes and rAOM and to analyze whether genetic variations might predispose to the development of complicated recurrent cases, such as those with tympanic membrane perforation (TMP).A total of 33 candidate genes and 47 SNPs were genotyped in 200 children with rAOM (116 with a history of TMP) and in 200 healthy controls.INFγ rs 12369470CT was significantly less common in the children with rAOM than in healthy controls (odds ratio [OR] 0.5, 95% confidence interval [CI] 0.25-1, P = 0.04). Although not significant, interleukin (IL)-1β rs 1143627G and toll-like receptor (TLR)-4 rs2737191AG were less frequently detected in the children with rAOM than in controls. The opposite was true for IL-8 rs2227306CT, which was found more frequently in the children with rAOM than in healthy controls. The IL-10 rs1800896TC SNP and the IL-1α rs6746923A and AG SNPs were significantly more and less common, respectively, among children without a history of TMP than among those who suffered from this complication (OR 2.17, 95% CI 1.09-4.41, P = 0.02, and OR 0.42, 95% CI 0.21-0.84, P = 0.01).This study is the first report suggesting an association between variants in genes encoding for factors of innate or adaptive immunity and the occurrence of rAOM with or without TMP, which confirms the role of genetics in conditioning susceptibility to AOM. PMID:26496338

  14. Genetic Polymorphisms of Functional Candidate Genes and Recurrent Acute Otitis Media With or Without Tympanic Membrane Perforation

    PubMed Central

    Esposito, Susanna; Marchisio, Paola; Orenti, Annalisa; Spena, Silvia; Bianchini, Sonia; Nazzari, Erica; Rosazza, Chiara; Zampiero, Alberto; Biganzoli, Elia; Principi, Nicola

    2015-01-01

    Abstract Evaluation of the genetic contribution to the development of recurrent acute otitis media (rAOM) remains challenging. This study aimed to evaluate the potential association between single nucleotide polymorphisms (SNPs) in selected genes and rAOM and to analyze whether genetic variations might predispose to the development of complicated recurrent cases, such as those with tympanic membrane perforation (TMP). A total of 33 candidate genes and 47 SNPs were genotyped in 200 children with rAOM (116 with a history of TMP) and in 200 healthy controls. INFγ rs 12369470CT was significantly less common in the children with rAOM than in healthy controls (odds ratio [OR] 0.5, 95% confidence interval [CI] 0.25–1, P = 0.04). Although not significant, interleukin (IL)-1β rs 1143627G and toll-like receptor (TLR)-4 rs2737191AG were less frequently detected in the children with rAOM than in controls. The opposite was true for IL-8 rs2227306CT, which was found more frequently in the children with rAOM than in healthy controls. The IL-10 rs1800896TC SNP and the IL-1α rs6746923A and AG SNPs were significantly more and less common, respectively, among children without a history of TMP than among those who suffered from this complication (OR 2.17, 95% CI 1.09–4.41, P = 0.02, and OR 0.42, 95% CI 0.21–0.84, P = 0.01). This study is the first report suggesting an association between variants in genes encoding for factors of innate or adaptive immunity and the occurrence of rAOM with or without TMP, which confirms the role of genetics in conditioning susceptibility to AOM. PMID:26496338

  15. A Systematic Analysis of Candidate Genes Associated with Nicotine Addiction

    PubMed Central

    Liu, Meng; Li, Xia; Fan, Rui; Liu, Xinhua; Wang, Ju

    2015-01-01

    Nicotine, as the major psychoactive component of tobacco, has broad physiological effects within the central nervous system, but our understanding of the molecular mechanism underlying its neuronal effects remains incomplete. In this study, we performed a systematic analysis on a set of nicotine addiction-related genes to explore their characteristics at network levels. We found that NAGenes tended to have a more moderate degree and weaker clustering coefficient and to be less central in the network compared to alcohol addiction-related genes or cancer genes. Further, clustering of these genes resulted in six clusters with themes in synaptic transmission, signal transduction, metabolic process, and apoptosis, which provided an intuitional view on the major molecular functions of the genes. Moreover, functional enrichment analysis revealed that neurodevelopment, neurotransmission activity, and metabolism related biological processes were involved in nicotine addiction. In summary, by analyzing the overall characteristics of the nicotine addiction related genes, this study provided valuable information for understanding the molecular mechanisms underlying nicotine addiction. PMID:26097843

  16. A Systematic Analysis of Candidate Genes Associated with Nicotine Addiction.

    PubMed

    Liu, Meng; Li, Xia; Fan, Rui; Liu, Xinhua; Wang, Ju

    2015-01-01

    Nicotine, as the major psychoactive component of tobacco, has broad physiological effects within the central nervous system, but our understanding of the molecular mechanism underlying its neuronal effects remains incomplete. In this study, we performed a systematic analysis on a set of nicotine addiction-related genes to explore their characteristics at network levels. We found that NAGenes tended to have a more moderate degree and weaker clustering coefficient and to be less central in the network compared to alcohol addiction-related genes or cancer genes. Further, clustering of these genes resulted in six clusters with themes in synaptic transmission, signal transduction, metabolic process, and apoptosis, which provided an intuitional view on the major molecular functions of the genes. Moreover, functional enrichment analysis revealed that neurodevelopment, neurotransmission activity, and metabolism related biological processes were involved in nicotine addiction. In summary, by analyzing the overall characteristics of the nicotine addiction related genes, this study provided valuable information for understanding the molecular mechanisms underlying nicotine addiction. PMID:26097843

  17. Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence.

    PubMed

    Fernàndez-Castillo, N; Cabana-Domínguez, J; Soriano, J; Sànchez-Mora, C; Roncero, C; Grau-López, L; Ros-Cucurull, E; Daigre, C; van Donkelaar, M M J; Franke, B; Casas, M; Ribasés, M; Cormand, B

    2015-01-01

    Cocaine reward and reinforcing effects are mediated mainly by dopaminergic neurotransmission. In this study, we aimed at evaluating gene expression changes induced by acute cocaine exposure on SH-SY5Y-differentiated cells, which have been widely used as a dopaminergic neuronal model. Expression changes and a concomitant increase in neuronal activity were observed after a 5 μM cocaine exposure, whereas no changes in gene expression or in neuronal activity took place at 1 μM cocaine. Changes in gene expression were identified in a total of 756 genes, mainly related to regulation of transcription and gene expression, cell cycle, adhesion and cell projection, as well as mitogen-activeated protein kinase (MAPK), CREB, neurotrophin and neuregulin signaling pathways. Some genes displaying altered expression were subsequently targeted with predicted functional single-nucleotide polymorphisms (SNPs) in a case-control association study in a sample of 806 cocaine-dependent patients and 817 controls. This study highlighted associations between cocaine dependence and five SNPs predicted to alter microRNA binding at the 3'-untranslated region of the NFAT5 gene. The association of SNP rs1437134 with cocaine dependence survived the Bonferroni correction for multiple testing. A functional effect was confirmed for this variant by a luciferase reporter assay, with lower expression observed for the rs1437134G allele, which was more pronounced in the presence of hsa-miR-509. However, brain volumes in regions of relevance to addiction, as assessed with magnetic resonance imaging, did not correlate with NFAT5 variation. These results suggest that the NFAT5 gene, which is upregulated a few hours after cocaine exposure, may be involved in the genetic predisposition to cocaine dependence. PMID:26506053

  18. Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence

    PubMed Central

    Fernàndez-Castillo, N; Cabana-Domínguez, J; Soriano, J; Sànchez-Mora, C; Roncero, C; Grau-López, L; Ros-Cucurull, E; Daigre, C; van Donkelaar, M M J; Franke, B; Casas, M; Ribasés, M; Cormand, B

    2015-01-01

    Cocaine reward and reinforcing effects are mediated mainly by dopaminergic neurotransmission. In this study, we aimed at evaluating gene expression changes induced by acute cocaine exposure on SH-SY5Y-differentiated cells, which have been widely used as a dopaminergic neuronal model. Expression changes and a concomitant increase in neuronal activity were observed after a 5 μM cocaine exposure, whereas no changes in gene expression or in neuronal activity took place at 1 μM cocaine. Changes in gene expression were identified in a total of 756 genes, mainly related to regulation of transcription and gene expression, cell cycle, adhesion and cell projection, as well as mitogen-activeated protein kinase (MAPK), CREB, neurotrophin and neuregulin signaling pathways. Some genes displaying altered expression were subsequently targeted with predicted functional single-nucleotide polymorphisms (SNPs) in a case–control association study in a sample of 806 cocaine-dependent patients and 817 controls. This study highlighted associations between cocaine dependence and five SNPs predicted to alter microRNA binding at the 3′-untranslated region of the NFAT5 gene. The association of SNP rs1437134 with cocaine dependence survived the Bonferroni correction for multiple testing. A functional effect was confirmed for this variant by a luciferase reporter assay, with lower expression observed for the rs1437134G allele, which was more pronounced in the presence of hsa-miR-509. However, brain volumes in regions of relevance to addiction, as assessed with magnetic resonance imaging, did not correlate with NFAT5 variation. These results suggest that the NFAT5 gene, which is upregulated a few hours after cocaine exposure, may be involved in the genetic predisposition to cocaine dependence. PMID:26506053

  19. Molecular genetic analysis of six Dutch families with atrial fibrillation

    PubMed Central

    Entius, M.M.; Groenewegen, A.; Pronk, A.; van der Smagt, J.J; Loh, P.; Hauer, R.N.; Derksen, R.; van Gelder, I.C.; Lok, D.J.A.; Doevendans, P.A.

    2005-01-01

    Background Atrial fibrillation (AF), the most common cardiac arrhythmia, is characterised by rapid and irregular contraction of the atrium. The risk of AF increases with age and AF increases the risk of various heart disorders, stroke and mortality. AF can occur in a sporadic or familial form. The underlying mechanism leading to AF is not well known but genetic analysis can increase our insight into the molecular pathways in AF. Detailed information on the molecular mechanisms of a disorder increase options for diagnosis and treatment. Recently, a gain-of-function mutation in exon of the KCNQ1 gene located on chromosome 11 was identified in a large Chinese AF family. KCNQ1 associates with KCNE1 or KCNE2 (both located on chromosome 21) to form cardiac potassium channels. Subsequent analysis of Chinese families showed a KCNE2 mutation in two families. Other genetic studies show linkage to chromosome 6 and 10, indicating genetic heterogeneity. A number of studies have shown that altered expression of the atrial connexin40 protein is a risk factor for AF. Connexin genes encode gap-junction proteins that are important in cardiac conduction and for normal wave propagation. Objectives/methods In this study we analysed the role of KCNQ1, KCNE1 coding region and Cx40 promoter region in six Dutch AF families by sequence analysis. Conclusion No mutations were found in these genes. The absence of mutations indicates genetic heterogeneity in familial AF; however, further research is needed. Candidate genes are being sequenced, linkage analysis in a large family will be performed and additional AF families will be collected. ImagesFigure 1 PMID:25696507

  20. An integrated system for genetic analysis

    PubMed Central

    Fiddy, Simon; Cattermole, David; Xie, Dong; Duan, Xiao Yuan; Mott, Richard

    2006-01-01

    Background Large-scale genetic mapping projects require data management systems that can handle complex phenotypes and detect and correct high-throughput genotyping errors, yet are easy to use. Description We have developed an Integrated Genotyping System (IGS) to meet this need. IGS securely stores, edits and analyses genotype and phenotype data. It stores information about DNA samples, plates, primers, markers and genotypes generated by a genotyping laboratory. Data are structured so that statistical genetic analysis of both case-control and pedigree data is straightforward. Conclusion IGS can model complex phenotypes and contain genotypes from whole genome association studies. The database makes it possible to integrate genetic analysis with data curation. The IGS web site contains further information. PMID:16623936

  1. CFD Analysis of Emissions for a Candidate N+3 Combustor

    NASA Technical Reports Server (NTRS)

    Ajmani, Kumud

    2015-01-01

    An effort was undertaken to analyze the performance of a model Lean-Direct Injection (LDI) combustor designed to meet emissions and performance goals for NASA's N+3 program. Computational predictions of Emissions Index (EINOx) and combustor exit temperature were obtained for operation at typical power conditions expected of a small-core, high pressure-ratio (greater than 50), high T3 inlet temperature (greater than 950K) N+3 combustor. Reacting-flow computations were performed with the National Combustion Code (NCC) for a model N+3 LDI combustor, which consisted of a nine-element LDI flame-tube derived from a previous generation (N+2) thirteen-element LDI design. A consistent approach to mesh-optimization, spray-modeling and kinetics-modeling was used, in order to leverage the lessons learned from previous N+2 flame-tube analysis with the NCC. The NCC predictions for the current, non-optimized N+3 combustor operating indicated a 74% increase in NOx emissions as compared to that of the emissions-optimized, parent N+2 LDI combustor.

  2. CFD Analysis of Emissions for a Candidate N+3 Combustor

    NASA Technical Reports Server (NTRS)

    Ajmani, Kumud

    2015-01-01

    An effort was undertaken to analyze the performance of a model Lean-Direct Injection (LDI) combustor designed to meet emissions and performance goals for NASA's N+3 program. Computational predictions of Emissions Index (EINOx) and combustor exit temperature were obtained for operation at typical power conditions expected of a small-core, high pressure-ratio (greater than 50), high T3 inlet temperature (greater than 950K) N+3 combustor. Reacting-flow computations were performed with the National Combustion Code (NCC) for a model N+3 LDI combustor, which consisted of a nine-element LDI flame-tube derived from a previous generation (N+2) thirteen-element LDI design. A consistent approach to mesh-optimization, spraymodeling and kinetics-modeling was used, in order to leverage the lessons learned from previous N+2 flame-tube analysis with the NCC. The NCC predictions for the current, non-optimized N+3 combustor operating indicated a 74% increase in NOx emissions as compared to that of the emissions-optimized, parent N+2 LDI combustor.

  3. Quantitative DNA methylation analysis of candidate genes in cervical cancer.

    PubMed

    Siegel, Erin M; Riggs, Bridget M; Delmas, Amber L; Koch, Abby; Hakam, Ardeshir; Brown, Kevin D

    2015-01-01

    Aberrant DNA methylation has been observed in cervical cancer; however, most studies have used non-quantitative approaches to measure DNA methylation. The objective of this study was to quantify methylation within a select panel of genes previously identified as targets for epigenetic silencing in cervical cancer and to identify genes with elevated methylation that can distinguish cancer from normal cervical tissues. We identified 49 women with invasive squamous cell cancer of the cervix and 22 women with normal cytology specimens. Bisulfite-modified genomic DNA was amplified and quantitative pyrosequencing completed for 10 genes (APC, CCNA, CDH1, CDH13, WIF1, TIMP3, DAPK1, RARB, FHIT, and SLIT2). A Methylation Index was calculated as the mean percent methylation across all CpG sites analyzed per gene (~4-9 CpG site) per sequence. A binary cut-point was defined at >15% methylation. Sensitivity, specificity and area under ROC curve (AUC) of methylation in individual genes or a panel was examined. The median methylation index was significantly higher in cases compared to controls in 8 genes, whereas there was no difference in median methylation for 2 genes. Compared to HPV and age, the combination of DNA methylation level of DAPK1, SLIT2, WIF1 and RARB with HPV and age significantly improved the AUC from 0.79 to 0.99 (95% CI: 0.97-1.00, p-value = 0.003). Pyrosequencing analysis confirmed that several genes are common targets for aberrant methylation in cervical cancer and DNA methylation level of four genes appears to increase specificity to identify cancer compared to HPV detection alone. Alterations in DNA methylation of specific genes in cervical cancers, such as DAPK1, RARB, WIF1, and SLIT2, may also occur early in cervical carcinogenesis and should be evaluated. PMID:25826459

  4. Quantitative DNA Methylation Analysis of Candidate Genes in Cervical Cancer

    PubMed Central

    Siegel, Erin M.; Riggs, Bridget M.; Delmas, Amber L.; Koch, Abby; Hakam, Ardeshir; Brown, Kevin D.

    2015-01-01

    Aberrant DNA methylation has been observed in cervical cancer; however, most studies have used non-quantitative approaches to measure DNA methylation. The objective of this study was to quantify methylation within a select panel of genes previously identified as targets for epigenetic silencing in cervical cancer and to identify genes with elevated methylation that can distinguish cancer from normal cervical tissues. We identified 49 women with invasive squamous cell cancer of the cervix and 22 women with normal cytology specimens. Bisulfite-modified genomic DNA was amplified and quantitative pyrosequencing completed for 10 genes (APC, CCNA, CDH1, CDH13, WIF1, TIMP3, DAPK1, RARB, FHIT, and SLIT2). A Methylation Index was calculated as the mean percent methylation across all CpG sites analyzed per gene (~4-9 CpG site) per sequence. A binary cut-point was defined at >15% methylation. Sensitivity, specificity and area under ROC curve (AUC) of methylation in individual genes or a panel was examined. The median methylation index was significantly higher in cases compared to controls in 8 genes, whereas there was no difference in median methylation for 2 genes. Compared to HPV and age, the combination of DNA methylation level of DAPK1, SLIT2, WIF1 and RARB with HPV and age significantly improved the AUC from 0.79 to 0.99 (95% CI: 0.97–1.00, p-value = 0.003). Pyrosequencing analysis confirmed that several genes are common targets for aberrant methylation in cervical cancer and DNA methylation level of four genes appears to increase specificity to identify cancer compared to HPV detection alone. Alterations in DNA methylation of specific genes in cervical cancers, such as DAPK1, RARB, WIF1, and SLIT2, may also occur early in cervical carcinogenesis and should be evaluated. PMID:25826459

  5. Electron Microscopy Abrasion Analysis of Candidate Fabrics for Planetary Space Suit Protective Overgarment Application

    NASA Technical Reports Server (NTRS)

    Hennessy, Mary J.

    1992-01-01

    The Electron Microscopy Abrasion Analysis of Candidate Fabrics for Planetary Space Suit Protective Overgarment Application is in support of the Abrasion Resistance Materials Screening Test. The fundamental assumption made for the SEM abrasion analysis was that woven fabrics to be used as the outermost layer of the protective overgarment in the design of the future, planetary space suits perform best when new. It is the goal of this study to determine which of the candidate fabrics was abraded the least in the tumble test. The sample that was abraded the least will be identified at the end of the report as the primary candidate fabric for further investigation. In addition, this analysis will determine if the abrasion seen by the laboratory tumbled samples is representative of actual EVA Apollo abrasion.

  6. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

    PubMed Central

    Schumann, Gunter; Coin, Lachlan J.; Lourdusamy, Anbarasu; Charoen, Pimphen; Berger, Karen H.; Stacey, David; Desrivières, Sylvane; Aliev, Fazil A.; Khan, Anokhi A.; Amin, Najaf; Aulchenko, Yurii S.; Bakalkin, Georgy; Bakker, Stephan J.; Balkau, Beverley; Beulens, Joline W.; Bilbao, Ainhoa; de Boer, Rudolf A.; Beury, Delphine; Bots, Michiel L.; Breetvelt, Elemi J.; Cauchi, Stéphane; Cavalcanti-Proença, Christine; Chambers, John C.; Clarke, Toni-Kim; Dahmen, Norbert; de Geus, Eco J.; Dick, Danielle; Ducci, Francesca; Easton, Alanna; Edenberg, Howard J.; Esko, Tõnu; Fernández-Medarde, Alberto; Foroud, Tatiana; Freimer, Nelson B.; Girault, Jean-Antoine; Grobbee, Diederick E.; Guarrera, Simonetta; Gudbjartsson, Daniel F.; Hartikainen, Anna-Liisa; Heath, Andrew C.; Hesselbrock, Victor; Hofman, Albert; Hottenga, Jouke-Jan; Isohanni, Matti K.; Kaprio, Jaakko; Khaw, Kay-Tee; Kuehnel, Brigitte; Laitinen, Jaana; Lobbens, Stéphane; Luan, Jian'an; Mangino, Massimo; Maroteaux, Matthieu; Matullo, Giuseppe; McCarthy, Mark I.; Mueller, Christian; Navis, Gerjan; Numans, Mattijs E.; Núñez, Alejandro; Nyholt, Dale R.; Onland-Moret, Charlotte N.; Oostra, Ben A.; O'Reilly, Paul F.; Palkovits, Miklos; Penninx, Brenda W.; Polidoro, Silvia; Pouta, Anneli; Prokopenko, Inga; Ricceri, Fulvio; Santos, Eugenio; Smit, Johannes H.; Soranzo, Nicole; Song, Kijoung; Sovio, Ulla; Stumvoll, Michael; Surakk, Ida; Thorgeirsson, Thorgeir E.; Thorsteinsdottir, Unnur; Troakes, Claire; Tyrfingsson, Thorarinn; Tönjes, Anke; Uiterwaal, Cuno S.; Uitterlinden, Andre G.; van der Harst, Pim; van der Schouw, Yvonne T.; Staehlin, Oliver; Vogelzangs, Nicole; Vollenweider, Peter; Waeber, Gerard; Wareham, Nicholas J.; Waterworth, Dawn M.; Whitfield, John B.; Wichmann, Erich H.; Willemsen, Gonneke; Witteman, Jacqueline C.; Yuan, Xin; Zhai, Guangju; Zhao, Jing H.; Zhang, Weihua; Martin, Nicholas G.; Metspalu, Andres; Doering, Angela; Scott, James; Spector, Tim D.; Loos, Ruth J.; Boomsma, Dorret I.; Mooser, Vincent; Peltonen, Leena; Stefansson, Kari; van Duijn, Cornelia M.; Vineis, Paolo; Sommer, Wolfgang H.; Kooner, Jaspal S.; Spanagel, Rainer; Heberlein, Ulrike A.; Jarvelin, Marjo-Riitta; Elliott, Paul

    2011-01-01

    Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 × 10−8 to P = 4 × 10−9). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior. PMID:21471458

  7. High-Resolution Genetic Mapping in the Diversity Outbred Mouse Population Identifies Apobec1 as a Candidate Gene for Atherosclerosis

    PubMed Central

    Smallwood, Tangi L.; Gatti, Daniel M.; Quizon, Pamela; Weinstock, George M.; Jung, Kuo-Chen; Zhao, Liyang; Hua, Kunjie; Pomp, Daniel; Bennett, Brian J.

    2014-01-01

    Inbred mice exhibit strain-specific variation in susceptibility to atherosclerosis and dyslipidemia that renders them useful in dissecting the genetic architecture of these complex diseases. Traditional quantitative trait locus (QTL) mapping studies using inbred strains often identify large genomic regions, containing many genes, due to limited recombination and/or sample size. This hampers candidate gene identification and translation of these results into possible risk factors and therapeutic targets. An alternative approach is the use of multiparental outbred lines for genetic mapping, such as the Diversity Outbred (DO) mouse panel, which can be more informative than traditional two-parent crosses and can aid in the identification of causal genes and variants associated with QTL. We fed 292 female DO mice either a high-fat, cholesterol-containing (HFCA) diet, to induce atherosclerosis, or a low-fat, high-protein diet for 18 wk and measured plasma lipid levels before and after diet treatment. We measured markers of atherosclerosis in the mice fed the HFCA diet. The mice were genotyped on a medium-density single-nucleotide polymorphism array and founder haplotypes were reconstructed using a hidden Markov model. The reconstructed haplotypes were then used to perform linkage mapping of atherosclerotic lesion size as well as plasma total cholesterol, triglycerides, insulin, and glucose. Among our highly significant QTL we detected a ~100 kb QTL interval for atherosclerosis on Chromosome 6, as well as a 1.4 Mb QTL interval on Chromosome 9 for triglyceride levels at baseline and a coincident 22.2 Mb QTL interval on Chromosome 9 for total cholesterol after dietary treatment. One candidate gene within the Chromosome 6 peak region associated with atherosclerosis is Apobec1, the apolipoprotein B (ApoB) mRNA-editing enzyme, which plays a role in the regulation of ApoB, a critical component of low-density lipoprotein, by editing ApoB mRNA. This study demonstrates the value

  8. PEACE: pulsar evaluation algorithm for candidate extraction - a software package for post-analysis processing of pulsar survey candidates

    NASA Astrophysics Data System (ADS)

    Lee, K. J.; Stovall, K.; Jenet, F. A.; Martinez, J.; Dartez, L. P.; Mata, A.; Lunsford, G.; Cohen, S.; Biwer, C. M.; Rohr, M.; Flanigan, J.; Walker, A.; Banaszak, S.; Allen, B.; Barr, E. D.; Bhat, N. D. R.; Bogdanov, S.; Brazier, A.; Camilo, F.; Champion, D. J.; Chatterjee, S.; Cordes, J.; Crawford, F.; Deneva, J.; Desvignes, G.; Ferdman, R. D.; Freire, P.; Hessels, J. W. T.; Karuppusamy, R.; Kaspi, V. M.; Knispel, B.; Kramer, M.; Lazarus, P.; Lynch, R.; Lyne, A.; McLaughlin, M.; Ransom, S.; Scholz, P.; Siemens, X.; Spitler, L.; Stairs, I.; Tan, M.; van Leeuwen, J.; Zhu, W. W.

    2013-07-01

    Modern radio pulsar surveys produce a large volume of prospective candidates, the majority of which are polluted by human-created radio frequency interference or other forms of noise. Typically, large numbers of candidates need to be visually inspected in order to determine if they are real pulsars. This process can be labour intensive. In this paper, we introduce an algorithm called Pulsar Evaluation Algorithm for Candidate Extraction (PEACE) which improves the efficiency of identifying pulsar signals. The algorithm ranks the candidates based on a score function. Unlike popular machine-learning-based algorithms, no prior training data sets are required. This algorithm has been applied to data from several large-scale radio pulsar surveys. Using the human-based ranking results generated by students in the Arecibo Remote Command Center programme, the statistical performance of PEACE was evaluated. It was found that PEACE ranked 68 per cent of the student-identified pulsars within the top 0.17 per cent of sorted candidates, 95 per cent within the top 0.34 per cent and 100 per cent within the top 3.7 per cent. This clearly demonstrates that PEACE significantly increases the pulsar identification rate by a factor of about 50 to 1000. To date, PEACE has been directly responsible for the discovery of 47 new pulsars, 5 of which are millisecond pulsars that may be useful for pulsar timing based gravitational-wave detection projects.

  9. BAYESIAN ANALYSIS TO IDENTIFY NEW STAR CANDIDATES IN NEARBY YOUNG STELLAR KINEMATIC GROUPS

    SciTech Connect

    Malo, Lison; Doyon, Rene; Lafreniere, David; Artigau, Etienne; Gagne, Jonathan; Baron, Frederique; Riedel, Adric E-mail: doyon@astro.umontreal.ca E-mail: artigau@astro.umontreal.ca E-mail: baron@astro.umontreal.ca

    2013-01-10

    We present a new method based on a Bayesian analysis to identify new members of nearby young kinematic groups. The analysis minimally takes into account the position, proper motion, magnitude, and color of a star, but other observables can be readily added (e.g., radial velocity, distance). We use this method to find new young low-mass stars in the {beta} Pictoris and AB Doradus moving groups and in the TW Hydrae, Tucana-Horologium, Columba, Carina, and Argus associations. Starting from a sample of 758 mid-K to mid-M (K5V-M5V) stars showing youth indicators such as H{alpha} and X-ray emission, our analysis yields 214 new highly probable low-mass members of the kinematic groups analyzed. One is in TW Hydrae, 37 in {beta} Pictoris, 17 in Tucana-Horologium, 20 in Columba, 6 in Carina, 50 in Argus, 32 in AB Doradus, and the remaining 51 candidates are likely young but have an ambiguous membership to more than one association. The false alarm rate for new candidates is estimated to be 5% for {beta} Pictoris and TW Hydrae, 10% for Tucana-Horologium, Columba, Carina, and Argus, and 14% for AB Doradus. Our analysis confirms the membership of 58 stars proposed in the literature. Firm membership confirmation of our new candidates will require measurement of their radial velocity (predicted by our analysis), parallax, and lithium 6708 A equivalent width. We have initiated these follow-up observations for a number of candidates, and we have identified two stars (2MASSJ01112542+1526214, 2MASSJ05241914-1601153) as very strong candidate members of the {beta} Pictoris moving group and one strong candidate member (2MASSJ05332558-5117131) of the Tucana-Horologium association; these three stars have radial velocity measurements confirming their membership and lithium detections consistent with young age.

  10. Analysis of complex repeat sequences within the spinal muscular atrophy (SMA) candidate region in 5q13

    SciTech Connect

    Davies, K.E.; Morrison, K.E.; Daniels, R.I.

    1994-09-01

    We previously reported that the 400 kb interval flanked the polymorphic loci D5S435 and D5S557 contains blocks of a chromosome 5 specific repeat. This interval also defines the SMA candidate region by genetic analysis of recombinant families. A YAC contig of 2-3 Mb encompassing this area has been constructed and a 5.5 kb conserved fragment, isolated from a YAC end clone within the above interval, was used to obtain cDNAs from both fetal and adult brain libraries. We describe the identification of cDNAs with stretches of high DNA sequence homology to exons of {beta} glucuronidase on human chromosome 7. The cDNAs map both to the candidate region and to an area of 5p using FISH and deletion hybrid analysis. Hybridization to bacteriophage and cosmid clones from the YACs localizes the {beta} glucuronidase related sequences within the 400 kb region of the YAC contig. The cDNAs show a polymorphic pattern on hybridization to genomic BamH1 fragments in the size range of 10-250 kb. Further analysis using YAC fragmentation vectors is being used to determine how these {beta} glucuronidase related cDNAs are distributed within 5q13. Dinucleotide repeats within the region are being investigated to determine linkage disequilibrium with the disease locus.

  11. Meta-analysis in cancer genetics.

    PubMed

    Pabalan, Noel A

    2010-01-01

    Genetic association studies report potentially conflicting findings which meta-analysis seeks to quantify and objectively summarize. Attributing cancer to a single gene variant requires large sample sizes, which may strain resources in a primary study. Properly used, meta-analysis is a powerful tool for resolving discrepancies in genetic association studies given the exponential increase in sample sizes when data are combined. The several steps involved in this methodology require careful attention to critical issues in meta-analysis, heterogeneity and publication bias, evaluation of which can be graphical or statistical. Overall summary effects of a meta-analysis may or may not reflect similar associations when the component studies are sub grouped. Overall associations and that of the subgroups are evaluated for tenability using sensitivity analysis. The low association between a polymorphism and cancer is offset by detectable changes in cancer incidence in the general population making them an important issue from a public health point of view. Asian meta-analytic publications in cancer genetics come from six countries with an output that number from one to two. The exception is China, whose publication output has increased exponentially since 2008. PMID:20593927

  12. Transcriptome network analysis reveals potential candidate genes for squamous lung cancer.

    PubMed

    Bai, Jing; Hu, Sheng

    2012-01-01

    Squamous lung cancer is a common type of lung cancer; however, its mechanism of oncogenesis is still unknown. The aim of this study was to screen candidate genes of squamous lung cancer using a bioinformatics strategy and elucidate the mechanism of squamous lung cancer. Published microarray data of the GSE3268 series was obtained from Gene Expression Omnibus (GEO). Significance analysis of microarrays was performed using the software R, and differentially expressed genes by R analysis were harvested. The relationship between transcription factors and target genes in cancer were collected from the Transcriptional regulatory element database. A transcriptome network analysis method was used to construct gene regulation networks and select the candidate genes for squamous lung cancer. SPI1, FLI1, FOS, ETS2, EGR1 and PPARG were defined as candidate genes for squamous lung cancer by the transcriptome network analysis method. Among them, 5 genes had been reported to be involved in lung cancer, except SPI1 and FLI1. Effective recall on previous knowledge conferred strong confidence in these methods. It is demonstrated that transcriptome network analysis is useful in the identification of candidate genes in disease. PMID:21922129

  13. Genetic Diversity of the Malaria Vaccine Candidate Plasmodium falciparum Merozoite Surface Protein-3 in a Hypoendemic Transmission Environment

    PubMed Central

    Jordan, Stephen J.; Branch, OraLee H.; Castro, Jean Carlos; Oster, Robert A.; Rayner, Julian C.

    2009-01-01

    The N-terminal domain of Plasmodium falciparum merozoite surface protein-3 (PfMSP3) has been excluded from malaria vaccine development largely because of genetic diversity concerns. However, no study to date has followed N-terminal diversity over time. This study describes PfMSP3 variation in a hypoendemic longitudinal cohort in the Peruvian Amazon over the 2003-2006 transmission seasons. Polymerase chain reaction was used to amplify the N-terminal domain in 630 distinct P. falciparum infections, which were allele-typed by size and also screened for sequence variation using a new high-throughput technique, denaturing high performance liquid chromatography. PfMSP3 allele frequencies fluctuated significantly over the 4-year period, but sequence variation was very limited, with only 10 mutations being identified of 630 infections screened. The sequence of the PfMSP3 N-terminal domain is relatively stable over time in this setting, and further studies of its status as a vaccine candidate are therefore warranted. PMID:19270302

  14. Fetal-Adult Cardiac Transcriptome Analysis in Rats with Contrasting Left Ventricular Mass Reveals New Candidates for Cardiac Hypertrophy

    PubMed Central

    Grabowski, Katja; Riemenschneider, Mona; Schulte, Leonard; Witten, Anika; Schulz, Angela; Stoll, Monika; Kreutz, Reinhold

    2015-01-01

    Reactivation of fetal gene expression patterns has been implicated in common cardiac diseases in adult life including left ventricular (LV) hypertrophy (LVH) in arterial hypertension. Thus, increased wall stress and neurohumoral activation are discussed to induce the return to expression of fetal genes after birth in LVH. We therefore aimed to identify novel potential candidates for LVH by analyzing fetal-adult cardiac gene expression in a genetic rat model of hypertension, i.e. the stroke-prone spontaneously hypertensive rat (SHRSP). To this end we performed genome-wide transcriptome analysis in SHRSP to identify differences in expression patterns between day 20 of fetal development (E20) and adult animals in week 14 in comparison to a normotensive rat strain with contrasting low LV mass, i.e. Fischer (F344). 15232 probes were detected as expressed in LV tissue obtained from rats at E20 and week 14 (p < 0.05) and subsequently screened for differential expression. We identified 24 genes with SHRSP specific up-regulation and 21 genes with down-regulation as compared to F344. Further bioinformatic analysis presented Efcab6 as a new candidate for LVH that showed only in the hypertensive SHRSP rat differential expression during development (logFC = 2.41, p < 0.001) and was significantly higher expressed in adult SHRSP rats compared with adult F344 (+ 76%) and adult normotensive Wistar-Kyoto rats (+ 82%). Thus, it represents an interesting new target for further functional analyses and the elucidation of mechanisms leading to LVH. Here we report a new approach to identify candidate genes for cardiac hypertrophy by combining the analysis of gene expression differences between strains with a contrasting cardiac phenotype with a comparison of fetal-adult cardiac expression patterns. PMID:25646840

  15. Mutational analysis of the candidate tumor suppressor genes TEL and KIP1 in childhood acute lymphoblastic leukemia.

    PubMed

    Stegmaier, K; Takeuchi, S; Golub, T R; Bohlander, S K; Bartram, C R; Koeffler, H P

    1996-03-15

    We have shown previously that loss of heterozygosity at chromosome band 12p13 is among the most frequent genetic abnormalities identified in acute lymphoblastic leukemia (ALL) of childhood. Two known genes map within the critically deleted region of 12p: TEL, the gene encoding a new member of the ETS family of transcription factors, which is rearranged in a variety of hematological malignancies; and KIP1, the gene encoding the cyclin-dependent kinase inhibitor p27. Both genes are, therefore, excellent candidate tumor suppressor genes. In this report, we determined the exon organization of the TEL gene and performed mutational analysis of TEL and KIP1 in 33 childhood ALL patients known to have loss of heterozygosity at this locus. No mutations in either TEL or KIP1 were found; this suggest that neither TEL nor KIP1 is the critical 12p tumor suppressor gene in childhood ALL. PMID:8640833

  16. Quantitative trait locus linkage analysis in a large Amish pedigree identifies novel candidate loci for erythrocyte traits

    PubMed Central

    Hinckley, Jesse D; Abbott, Diana; Burns, Trudy L; Heiman, Meadow; Shapiro, Amy D; Wang, Kai; Di Paola, Jorge

    2013-01-01

    We characterized a large Amish pedigree and, in 384 pedigree members, analyzed the genetic variance components with covariate screen as well as genome-wide quantitative trait locus (QTL) linkage analysis of red blood cell count (RBC), hemoglobin (HB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), platelet count (PLT), and white blood cell count (WBC) using SOLAR. Age and gender were found to be significant covariates in many CBC traits. We obtained significant heritability estimates for RBC, MCV, MCH, MCHC, RDW, PLT, and WBC. We report four candidate loci with Logarithm of the odds (LOD) scores above 2.0: 6q25 (MCH), 9q33 (WBC), 10p12 (RDW), and 20q13 (MCV). We also report eleven candidate loci with LOD scores between 1.5 and <2.0. Bivariate linkage analysis of MCV and MCH on chromosome 20 resulted in a higher maximum LOD score of 3.14. Linkage signals on chromosomes 4q28, 6p22, 6q25, and 20q13 are concomitant with previously reported QTL. All other linkage signals reported herein represent novel evidence of candidate QTL. Interestingly rs1800562, the most common causal variant of hereditary hemochromatosis in HFE (6p22) was associated with MCH and MCHC in this family. Linkage studies like the one presented here will allow investigators to focus the search for rare variants amidst the noise encountered in the large amounts of data generated by whole-genome sequencing. PMID:24058921

  17. Genome-Wide Linkage Analysis of Global Gene Expression in Loin Muscle Tissue Identifies Candidate Genes in Pigs

    PubMed Central

    Steibel, Juan Pedro; Bates, Ronald O.; Rosa, Guilherme J. M.; Tempelman, Robert J.; Rilington, Valencia D.; Ragavendran, Ashok; Raney, Nancy E.; Ramos, Antonio Marcos; Cardoso, Fernando F.; Edwards, David B.; Ernst, Catherine W.

    2011-01-01

    Background Nearly 6,000 QTL have been reported for 588 different traits in pigs, more than in any other livestock species. However, this effort has translated into only a few confirmed causative variants. A powerful strategy for revealing candidate genes involves expression QTL (eQTL) mapping, where the mRNA abundance of a set of transcripts is used as the response variable for a QTL scan. Methodology/Principal Findings We utilized a whole genome expression microarray and an F2 pig resource population to conduct a global eQTL analysis in loin muscle tissue, and compared results to previously inferred phenotypic QTL (pQTL) from the same experimental cross. We found 62 unique eQTL (FDR <10%) and identified 3 gene networks enriched with genes subject to genetic control involved in lipid metabolism, DNA replication, and cell cycle regulation. We observed strong evidence of local regulation (40 out of 59 eQTL with known genomic position) and compared these eQTL to pQTL to help identify potential candidate genes. Among the interesting associations, we found aldo-keto reductase 7A2 (AKR7A2) and thioredoxin domain containing 12 (TXNDC12) eQTL that are part of a network associated with lipid metabolism and in turn overlap with pQTL regions for marbling, % intramuscular fat (% fat) and loin muscle area on Sus scrofa (SSC) chromosome 6. Additionally, we report 13 genomic regions with overlapping eQTL and pQTL involving 14 local eQTL. Conclusions/Significance Results of this analysis provide novel candidate genes for important complex pig phenotypes. PMID:21346809

  18. Candidate Genes Involved in the Biosynthesis of Triterpenoid Saponins in Platycodon grandiflorum Identified by Transcriptome Analysis

    PubMed Central

    Ma, Chun-Hua; Gao, Zheng-Jie; Zhang, Jia-Jin; Zhang, Wei; Shao, Jian-Hui; Hai, Mei-Rong; Chen, Jun-Wen; Yang, Sheng-Chao; Zhang, Guang-Hui

    2016-01-01

    Background: Platycodon grandiflorum is the only species in the genus Platycodon of the family Campanulaceae, which has been traditionally used as a medicinal plant for its lung-heat-clearing, antitussive, and expectorant properties in China, Japanese, and Korean. Oleanane-type triterpenoid saponins were the main chemical components of P. grandiflorum and platycodin D was the abundant and main bioactive component, but little is known about their biosynthesis in plants. Hence, P. grandiflorum is an ideal medicinal plant for studying the biosynthesis of Oleanane-type saponins. In addition, the genomic information of this important herbal plant is unavailable. Principal findings: A total of 58,580,566 clean reads were obtained, which were assembled into 34,053 unigenes, with an average length of 936 bp and N50 of 1,661 bp by analyzing the transcriptome data of P. grandiflorum. Among these 34,053 unigenes, 22,409 unigenes (65.80%) were annotated based on the information available from public databases, including Nr, NCBI, Swiss-Prot, KOG, and KEGG. Furthermore, 21 candidate cytochrome P450 genes and 17 candidate UDP-glycosyltransferase genes most likely involved in triterpenoid saponins biosynthesis pathway were discovered from the transcriptome sequencing of P. grandiflorum. In addition, 10,626 SSRs were identified based on the transcriptome data, which would provide abundant candidates of molecular markers for genetic diversity and genetic map for this medicinal plant. Conclusion: The genomic data obtained from P. grandiflorum, especially the identification of putative genes involved in triterpenoid saponins biosynthesis pathway, will facilitate our understanding of the biosynthesis of triterpenoid saponins at molecular level. PMID:27242873

  19. Genetic analysis for early diagnosis of otorhinolaryngeal diseases

    PubMed Central

    Propping, Peter

    2010-01-01

    Familiarity with the concepts and methods of human genetics is important in order to be able to perform genetic analysis. The grade of predictability of a genetic disease is partly given by formal genetics but also depends on the importance of the mutated gene for the phenotype. Possibilities for genetic analysis range from differential diagnosis to predictive diagnosis to prenatal diagnosis. After initial consultation in which the physician fully explains the procedure to the patient, it is mandatory that the patient give his full consent. This article summarises and evaluates current knowledge about genetic analysis of important otorhinolaryngeal diseases, including hereditary hearing disabilities, olfactory malfunction, hereditary tumorous diseases, hereditary syndromes and dysplasias. In addition, this article discusses genetic diseases that affect voice and speech, highlights the relevance of human genetic consultation and discusses the importance of embedding genetic analysis in medicine in general. PMID:22073089

  20. The IL-6 -634C/G polymorphism: a candidate genetic marker for the prediction of idiopathic recurrent pregnancy loss

    PubMed Central

    Rasti, Zarnegar; Nasiri, Mahboobeh; Kohan, Leila

    2016-01-01

    Background: Recurrent pregnancy loss (RPL) is defined as two or more miscarriages before the 20th week of gestation and its etiology is unknown in 50% of the cases. Interleukin 6 is an immune mediator, plays a regulatory role in embryo implantation and placental development. Objective: The purpose was to assess the association between IL-6 -634C/G polymorphism and, susceptibility to idiopathic RPL for the first time in Iran. Materials and Methods: In total 121 women with RPL and 121 healthy women as control group were enrolled in this case-control study. This study was performed from August 2013 to October 2014 in the Molecular Genetics Laboratory of Arsanjan University. Candidate polymorphism was evaluated by PCR-RFLP method on extracted genomic DNA. Data was analyzed using the statistical SPSS package. Results: Our results showed an increased risk of RPL in patients with GG + GC genotype (OR=5.1, 95%CI: 1.04-25.3, p=0.04) in comparison to CC genotype. The frequency of mutant allele G in patients and controls was 0.75 and 0.66 respectively. The mutant allele G predisposes women to miscarriage 1.5 times greater than controls (OR=1.5, 95%CI: 1.03-2.27, p=0.036). The mean number of live births in RPL women (1.3±2.3) was significantly lower compared to control women (4.8±2.3). Conclusion: This study indicated that the promoter polymorphism (-634C/G) of the IL-6 gene has likely influence on individual susceptibility to RPL. PMID:27200424

  1. Quantitative Trait Locus (QTL) meta-analysis and comparative genomics for candidate gene prediction in perennial ryegrass (Lolium perenne L.)

    PubMed Central

    2012-01-01

    Background In crop species, QTL analysis is commonly used for identification of factors contributing to variation of agronomically important traits. As an important pasture species, a large number of QTLs have been reported for perennial ryegrass based on analysis of biparental mapping populations. Further characterisation of those QTLs is, however, essential for utilisation in varietal improvement programs. Results A bibliographic survey of perennial ryegrass trait-dissection studies identified a total of 560 QTLs from previously published papers, of which 189, 270 and 101 were classified as morphology-, physiology- and resistance/tolerance-related loci, respectively. The collected dataset permitted a subsequent meta-QTL study and implementation of a cross-species candidate gene identification approach. A meta-QTL analysis based on use of the BioMercator software was performed to identify two consensus regions for pathogen resistance traits. Genes that are candidates for causal polymorphism underpinning perennial ryegrass QTLs were identified through in silico comparative mapping using rice databases, and 7 genes were assigned to the p150/112 reference map. Markers linked to the LpDGL1, LpPh1 and LpPIPK1 genes were located close to plant size, leaf extension time and heading date-related QTLs, respectively, suggesting that these genes may be functionally associated with important agronomic traits in perennial ryegrass. Conclusions Functional markers are valuable for QTL meta-analysis and comparative genomics. Enrichment of such genetic markers may permit further detailed characterisation of QTLs. The outcomes of QTL meta-analysis and comparative genomics studies may be useful for accelerated development of novel perennial ryegrass cultivars with desirable traits. PMID:23137269

  2. A generalized genetic random field method for the genetic association analysis of sequencing data.

    PubMed

    Li, Ming; He, Zihuai; Zhang, Min; Zhan, Xiaowei; Wei, Changshuai; Elston, Robert C; Lu, Qing

    2014-04-01

    With the advance of high-throughput sequencing technologies, it has become feasible to investigate the influence of the entire spectrum of sequencing variations on complex human diseases. Although association studies utilizing the new sequencing technologies hold great promise to unravel novel genetic variants, especially rare genetic variants that contribute to human diseases, the statistical analysis of high-dimensional sequencing data remains a challenge. Advanced analytical methods are in great need to facilitate high-dimensional sequencing data analyses. In this article, we propose a generalized genetic random field (GGRF) method for association analyses of sequencing data. Like other similarity-based methods (e.g., SIMreg and SKAT), the new method has the advantages of avoiding the need to specify thresholds for rare variants and allowing for testing multiple variants acting in different directions and magnitude of effects. The method is built on the generalized estimating equation framework and thus accommodates a variety of disease phenotypes (e.g., quantitative and binary phenotypes). Moreover, it has a nice asymptotic property, and can be applied to small-scale sequencing data without need for small-sample adjustment. Through simulations, we demonstrate that the proposed GGRF attains an improved or comparable power over a commonly used method, SKAT, under various disease scenarios, especially when rare variants play a significant role in disease etiology. We further illustrate GGRF with an application to a real dataset from the Dallas Heart Study. By using GGRF, we were able to detect the association of two candidate genes, ANGPTL3 and ANGPTL4, with serum triglyceride. PMID:24482034

  3. Genetic Predictors of Susceptibility to Cutaneous Fungal Infections: a pilot Genome Wide Association Study to Refine a Candidate Gene Search

    PubMed Central

    Abdel-Rahman, Susan M.; Preuett, Barry L.

    2012-01-01

    Background Trichophyton tonsurans is the foremost fungal pathogen of minority children in the U.S. Despite overwhelming infection rates, it does not appear that this fungus infects children in a non-specific manner. Objective This study was designed to identify genes that may predispose or protect a child from T. tonsurans infection. Methods Children participating in an earlier longitudinal study wherein infection rates could be reliably determined were eligible for inclusion. DNA from a subset (n=40) of these children at the population extremes underwent whole genome genotyping (WGG). Allele frequencies between cases and controls were examined and significant SNPs were used to develop a candidate gene list for which the remainder of the cohort (n=115) were genotyped. Cumulative infection rate was examined by genotype and the ability of selected genotypes to predict the likelihood of infection explored by multivariable analysis. Results 23 genes with a putative mechanistic role in cutaneous infection were selected for evaluation. Of these, 21 demonstrated significant differences in infection rate between genotypes. A risk index assigned to genotypes in the 21 genes accounted for over 60% of the variability observed in infection rate (adjusted r2=0.665, p<0.001). Among these, 8 appeared to account for the majority of variability that was observed (r2=0.603, p<0.001). These included genes involved in: leukocyte activation and migration, extracellular matrix integrity and remodeling, epidermal maintenance and wound repair, and cutaneous permeability. Conclusions Applying WGG to individuals at the extremes of phenotype can help to guide the selection of candidate genes in populations of small cohorts where disease etiology is likely polygenic in nature. PMID:22704677

  4. Functional Annotation and Identification of Candidate Disease Genes by Computational Analysis of Normal Tissue Gene Expression Data

    PubMed Central

    Miozzi, Laura; Piro, Rosario Michael; Rosa, Fabio; Ala, Ugo; Silengo, Lorenzo; Di Cunto, Ferdinando; Provero, Paolo

    2008-01-01

    Background High-throughput gene expression data can predict gene function through the “guilt by association” principle: coexpressed genes are likely to be functionally associated. Methodology/Principal Findings We analyzed publicly available expression data on normal human tissues. The analysis is based on the integration of data obtained with two experimental platforms (microarrays and SAGE) and of various measures of dissimilarity between expression profiles. The building blocks of the procedure are the Ranked Coexpression Groups (RCG), small sets of tightly coexpressed genes which are analyzed in terms of functional annotation. Functionally characterized RCGs are selected by means of the majority rule and used to predict new functional annotations. Functionally characterized RCGs are enriched in groups of genes associated to similar phenotypes. We exploit this fact to find new candidate disease genes for many OMIM phenotypes of unknown molecular origin. Conclusions/Significance We predict new functional annotations for many human genes, showing that the integration of different data sets and coexpression measures significantly improves the scope of the results. Combining gene expression data, functional annotation and known phenotype-gene associations we provide candidate genes for several genetic diseases of unknown molecular basis. PMID:18560577

  5. Genetic Dissection of Drought and Heat Tolerance in Chickpea through Genome-Wide and Candidate Gene-Based Association Mapping Approaches

    PubMed Central

    Thudi, Mahendar; Upadhyaya, Hari D.; Rathore, Abhishek; Gaur, Pooran Mal; Krishnamurthy, Lakshmanan; Roorkiwal, Manish; Nayak, Spurthi N.; Chaturvedi, Sushil Kumar; Basu, Partha Sarathi; Gangarao, N. V. P. R.; Fikre, Asnake; Kimurto, Paul; Sharma, Prakash C.; Sheshashayee, M. S.; Tobita, Satoshi; Kashiwagi, Junichi; Ito, Osamu; Killian, Andrzej; Varshney, Rajeev Kumar

    2014-01-01

    To understand the genetic basis of tolerance to drought and heat stresses in chickpea, a comprehensive association mapping approach has been undertaken. Phenotypic data were generated on the reference set (300 accessions, including 211 mini-core collection accessions) for drought tolerance related root traits, heat tolerance, yield and yield component traits from 1–7 seasons and 1–3 locations in India (Patancheru, Kanpur, Bangalore) and three locations in Africa (Nairobi, Egerton in Kenya and Debre Zeit in Ethiopia). Diversity Array Technology (DArT) markers equally distributed across chickpea genome were used to determine population structure and three sub-populations were identified using admixture model in STRUCTURE. The pairwise linkage disequilibrium (LD) estimated using the squared-allele frequency correlations (r2; when r2<0.20) was found to decay rapidly with the genetic distance of 5 cM. For establishing marker-trait associations (MTAs), both genome-wide and candidate gene-sequencing based association mapping approaches were conducted using 1,872 markers (1,072 DArTs, 651 single nucleotide polymorphisms [SNPs], 113 gene-based SNPs and 36 simple sequence repeats [SSRs]) and phenotyping data mentioned above employing mixed linear model (MLM) analysis with optimum compression with P3D method and kinship matrix. As a result, 312 significant MTAs were identified and a maximum number of MTAs (70) was identified for 100-seed weight. A total of 18 SNPs from 5 genes (ERECTA, 11 SNPs; ASR, 4 SNPs; DREB, 1 SNP; CAP2 promoter, 1 SNP and AMDH, 1SNP) were significantly associated with different traits. This study provides significant MTAs for drought and heat tolerance in chickpea that can be used, after validation, in molecular breeding for developing superior varieties with enhanced drought and heat tolerance. PMID:24801366

  6. Genetic dissection of drought and heat tolerance in chickpea through genome-wide and candidate gene-based association mapping approaches.

    PubMed

    Thudi, Mahendar; Upadhyaya, Hari D; Rathore, Abhishek; Gaur, Pooran Mal; Krishnamurthy, Lakshmanan; Roorkiwal, Manish; Nayak, Spurthi N; Chaturvedi, Sushil Kumar; Basu, Partha Sarathi; Gangarao, N V P R; Fikre, Asnake; Kimurto, Paul; Sharma, Prakash C; Sheshashayee, M S; Tobita, Satoshi; Kashiwagi, Junichi; Ito, Osamu; Killian, Andrzej; Varshney, Rajeev Kumar

    2014-01-01

    To understand the genetic basis of tolerance to drought and heat stresses in chickpea, a comprehensive association mapping approach has been undertaken. Phenotypic data were generated on the reference set (300 accessions, including 211 mini-core collection accessions) for drought tolerance related root traits, heat tolerance, yield and yield component traits from 1-7 seasons and 1-3 locations in India (Patancheru, Kanpur, Bangalore) and three locations in Africa (Nairobi, Egerton in Kenya and Debre Zeit in Ethiopia). Diversity Array Technology (DArT) markers equally distributed across chickpea genome were used to determine population structure and three sub-populations were identified using admixture model in STRUCTURE. The pairwise linkage disequilibrium (LD) estimated using the squared-allele frequency correlations (r2; when r2<0.20) was found to decay rapidly with the genetic distance of 5 cM. For establishing marker-trait associations (MTAs), both genome-wide and candidate gene-sequencing based association mapping approaches were conducted using 1,872 markers (1,072 DArTs, 651 single nucleotide polymorphisms [SNPs], 113 gene-based SNPs and 36 simple sequence repeats [SSRs]) and phenotyping data mentioned above employing mixed linear model (MLM) analysis with optimum compression with P3D method and kinship matrix. As a result, 312 significant MTAs were identified and a maximum number of MTAs (70) was identified for 100-seed weight. A total of 18 SNPs from 5 genes (ERECTA, 11 SNPs; ASR, 4 SNPs; DREB, 1 SNP; CAP2 promoter, 1 SNP and AMDH, 1SNP) were significantly associated with different traits. This study provides significant MTAs for drought and heat tolerance in chickpea that can be used, after validation, in molecular breeding for developing superior varieties with enhanced drought and heat tolerance. PMID:24801366

  7. Bayesian Analysis to Identify New Star Candidates in Nearby Young Stellar Kinematic Groups

    NASA Astrophysics Data System (ADS)

    Malo, Lison; Doyon, René; Lafrenière, David; Artigau, Étienne; Gagné, Jonathan; Baron, Frédérique; Riedel, Adric

    2013-01-01

    We present a new method based on a Bayesian analysis to identify new members of nearby young kinematic groups. The analysis minimally takes into account the position, proper motion, magnitude, and color of a star, but other observables can be readily added (e.g., radial velocity, distance). We use this method to find new young low-mass stars in the β Pictoris and AB Doradus moving groups and in the TW Hydrae, Tucana-Horologium, Columba, Carina, and Argus associations. Starting from a sample of 758 mid-K to mid-M (K5V-M5V) stars showing youth indicators such as Hα and X-ray emission, our analysis yields 214 new highly probable low-mass members of the kinematic groups analyzed. One is in TW Hydrae, 37 in β Pictoris, 17 in Tucana-Horologium, 20 in Columba, 6 in Carina, 50 in Argus, 32 in AB Doradus, and the remaining 51 candidates are likely young but have an ambiguous membership to more than one association. The false alarm rate for new candidates is estimated to be 5% for β Pictoris and TW Hydrae, 10% for Tucana-Horologium, Columba, Carina, and Argus, and 14% for AB Doradus. Our analysis confirms the membership of 58 stars proposed in the literature. Firm membership confirmation of our new candidates will require measurement of their radial velocity (predicted by our analysis), parallax, and lithium 6708 Å equivalent width. We have initiated these follow-up observations for a number of candidates, and we have identified two stars (2MASSJ01112542+1526214, 2MASSJ05241914-1601153) as very strong candidate members of the β Pictoris moving group and one strong candidate member (2MASSJ05332558-5117131) of the Tucana-Horologium association; these three stars have radial velocity measurements confirming their membership and lithium detections consistent with young age. Based on observations obtained at the Canada-France-Hawaii Telescope (CFHT) which is operated by the National Research Council of Canada, the Institut National des Sciences de l'Univers of the Centre

  8. Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney

    PubMed Central

    Westland, Rik; Verbitsky, Miguel; Vukojevic, Katarina; Perry, Brittany J.; Fasel, David A.; Zwijnenburg, Petra J.G.; Bökenkamp, Arend; Gille, Johan J.P.; Saraga-Babic, Mirna; Ghiggeri, Gian Marco; D’Agati, Vivette D.; Schreuder, Michiel F.; Gharavi, Ali G.; van Wijk, Joanna A.E.; Sanna-Cherchi, Simone

    2016-01-01

    Copy number variations associate with different developmental phenotypes and represent a major cause of congenital anomalies of the kidney and urinary tract (CAKUT). Because rare pathogenic copy number variations are often large and contain multiple genes, identification of the underlying genetic drivers has proven to be difficult. Here we studied the role of rare copy number variations in 80 patients from the KIMONO-study cohort for which pathogenic mutations in three genes commonly implicated in CAKUT were excluded. In total, 13 known or novel genomic imbalances in 11 of 80 patients were absent or extremely rare in 23,362 population controls. To identify the most likely genetic drivers for the CAKUT phenotype underlying these rare copy number variations, we used a systematic in silico approach based on frequency in a large dataset of controls, annotation with publicly available databases for developmental diseases, tolerance and haploinsufficiency scores, and gene expression profile in the developing kidney and urinary tract. Five novel candidate genes for CAKUT were identified that showed specific expression in the human and mouse developing urinary tract. Among these genes, DLG1 and KIF12 are likely novel susceptibility genes for CAKUT in humans. Thus, there is a significant role of genomic imbalance in the determination of kidney developmental phenotypes. Additionally, we defined a systematic strategy to identify genetic drivers underlying rare copy number variations. PMID:26352300

  9. Generalizability and Validity of the Use of a Case Analysis Assessment To Make Visible the Quality of Teacher Candidates.

    ERIC Educational Resources Information Center

    Denner, Peter R.; Miller, Terry L.; Newsome, Jack D.; Birdsong, Julie R.

    2002-01-01

    Evaluated the use of case analysis as an accountability measure for demonstrating teacher candidates' abilities to meet targeted course, institutional, and state teaching standards for student motivation and classroom management. Findings for 34 teacher candidates support the generalizability of case analysis ratings, which were shown to…

  10. Genetic analysis of interspecific incompatibility in Brassica rapa.

    PubMed

    Udagawa, H; Ishimaru, Y; Li, F; Sato, Y; Kitashiba, H; Nishio, T

    2010-08-01

    In interspecific pollination of Brassica rapa stigmas with Brassica oleracea pollen grains, pollen tubes cannot penetrate stigma tissues. This trait, called interspecific incompatibility, is similar to self-incompatibility in pollen tube behaviors of rejected pollen grains. Since some B. rapa lines have no interspecific incompatibility, genetic analysis of interspecific incompatibility was performed using two F(2) populations. Analysis with an F(2) population between an interspecific-incompatible line and a self-compatible cultivar 'Yellow sarson' having non-functional alleles of S-locus genes and MLPK, the stigmas of which are compatible with B. oleracea pollen grains, revealed no involvement of the S locus and MLPK in the difference of their interspecific incompatibility phenotypes. In QTL analysis of the strength of interspecific incompatibility, three peaks of LOD scores were found, but their LOD scores were as high as the threshold value, and the variance explained by each QTL was small. QTL analysis using another F(2) population derived from selected parents having the highest and lowest levels of interspecific incompatibility revealed five QTLs with high LOD scores, which did not correspond to those found in the former population. The QTL having the highest LOD score was found in linkage group A02. The effect of this QTL on interspecific incompatibility was confirmed by analyzing backcrossed progeny. Based on synteny of this QTL region with Arabidopsis thaliana chromosome 5, a possible candidate gene, which might be involved in interspecific incompatibility, is discussed. PMID:20414635

  11. Classification and analysis of candidate impact crater-hosted closed-basin lakes on Mars

    NASA Astrophysics Data System (ADS)

    Goudge, Timothy A.; Aureli, Kelsey L.; Head, James W.; Fassett, Caleb I.; Mustard, John F.

    2015-11-01

    We present a new catalog of 205 candidate closed-basin lakes contained within impact craters across the surface of Mars. These basins have an inlet valley that incises the crater rim and flows into the basin but no visible outlet valley, and are considered candidate closed-basin lakes; the presence of a valley flowing into a basin does not necessitate the formation of a standing body of water. The major geomorphic distinction within our catalog of candidate paleolakes is the length of the inlet valley(s), with two major classes - basins with long (>20 km) inlet valleys (30 basins), and basins with short (<20 km) inlet valleys (175 basins). We identify 55 basins that contain sedimentary fan deposits at the mouths of their inlet valleys, of which nine are fed by long inlet valleys and 46 are fed by short inlet valleys. Analysis of the mineralogy of these fan deposits suggests that they are primarily composed of detrital material. Additionally, we find no evidence for widespread evaporite deposit formation within our catalog of candidate closed-basin lakes, which we conclude is indicative of a general transience for any lakes that did form within these basins. Morphometric characteristics for our catalog indicate that as an upper limit, these basins represent a volume of water equivalent to a ∼1.2 m global equivalent layer (GEL) of water spread evenly across the martian surface; this is a small fraction of the modern water ice reservoir on Mars. Our catalog offers a broader context within which results from the Mars Science Laboratory Curiosity rover can be interpreted, as Gale crater is a candidate closed-basin lake contained within our catalog. Gale is also one of 12 closed-basin lakes fed by both long and short inlet valleys, and so in␣situ analyses by Curiosity can shed light on the relative importance of these two types of inlets for any lacustrine activity within the basin.

  12. Exclusion of linkage between hypokalemic periodic paralysis and a candidate region in 1q31-32 suggests genetic heterogeneity

    SciTech Connect

    Sillen, A.; Wadelius, C.; Gustabson, K.H.

    1994-09-01

    Familial hypokalemic periodic paralysis (HOKPP) is an autosomal dominant disease with attacks of paralysis of varying severity. The attacks occur at intervals of days to years in otherwise healthy people combined with hypokalemia during attacks. The paralysis attacks are precipitated by a number of different factors, like carbohydrate-rich meals, cold, exercise and mental stress. Recently linkage for HOKPP was shown for chromosome 1q31-32 and the disease was mapped between D1S413 and D1S249. The gene for the calcium channel alfa1-subunit (CACNL 1A3) maps to this interval and in two families no recombination was found between a polymorphism in the CACNL 1A3 gene and the disease. This gene is therefore considered to be a candidate for HOKPP. The analysis of a large Danish family excludes linkage to this region and to the CACNL 1A3 gene. In each direction from D1S413, 18.8 cM could be excluded and for D1S249, 14.9 cM. The present study clearly excludes the possibility that the gene causing HOKPP in a large Danish family is located in the region 1q31-32. This result shows that HOKPP is a heterogenous disease, with only one mapped gene so far.

  13. Association analysis of GWAS and candidate gene loci in a Pakistani population with psoriasis.

    PubMed

    Munir, Saeeda; ber Rahman, Simeen; Rehman, Sadia; Saba, Nusrat; Ahmad, Wasim; Nilsson, Staffan; Mazhar, Kehkashan; Naluai, Åsa Torinsson

    2015-03-01

    Psoriasis is a common inflammatory and hyper proliferative condition of the skin and a serious chronic systemic autoimmune disease. We undertook an association study to investigate the genetic etiology of psoriasis in a Pakistani population by genotyping single-nucleotide polymorphisms (SNPs) previously reported to be associated in genome-wide association (GWAS) or in candidate gene studies of psoriasis. Fifty seven single-nucleotide polymorphisms (SNPs) from 42 loci were genotyped in 533 psoriasis patients and 373 controls. Our results showed genome wide significant association of the MHC region (rs1265181 being the most significant from five SNPs used with overall OR=3.38; p=2.97E-18), as well as nominally significant associations at ten other loci (p<0.05) in the Pakistani population (LCE3B, REL, IL13/IL4, TNIP1, IL12B, TRAF3IP2, ZC3H12C, NOS2 and RNF114 from GWAS and PRR9 from a previous candidate gene study). Overall, only nine SNPs out of the 42 GWAS loci, displayed an odds ratio in the opposite allelic direction and only three did not reach similar odds ratio within 95% confidence interval as previously reported (SLC45A1/TNFRSF9, ELMO1 and IL28RA). This indicates similar genetic risk factors and molecular mechanisms behind disease in Pakistani psoriasis patients as in other populations. In addition, we show that the MHC and TNIP1 regions are significantly different in patients with psoriasis onset before the age of 40 (type I) compared to after 40 years of age (type II). MHC being associated mainly with type I while TNIP1 with type II patients. PMID:25481369

  14. Genomic Analysis of Differentiation between Soil Types Reveals Candidate Genes for Local Adaptation in Arabidopsis lyrata

    PubMed Central

    Turner, Thomas L.; von Wettberg, Eric J.; Nuzhdin, Sergey V.

    2008-01-01

    Serpentine soil, which is naturally high in heavy metal content and has low calcium to magnesium ratios, comprises a difficult environment for most plants. An impressive number of species are endemic to serpentine, and a wide range of non-endemic plant taxa have been shown to be locally adapted to these soils. Locating genomic polymorphisms which are differentiated between serpentine and non-serpentine populations would provide candidate loci for serpentine adaptation. We have used the Arabidopsis thaliana tiling array, which has 2.85 million probes throughout the genome, to measure genetic differentiation between populations of Arabidopsis lyrata growing on granitic soils and those growing on serpentinic soils. The significant overrepresentation of genes involved in ion transport and other functions provides a starting point for investigating the molecular basis of adaptation to soil ion content, water retention, and other ecologically and economically important variables. One gene in particular, calcium-exchanger 7, appears to be an excellent candidate gene for adaptation to low Ca∶Mg ratio in A. lyrata. PMID:18784841

  15. QTL Mapping by SLAF-seq and Expression Analysis of Candidate Genes for Aphid Resistance in Cucumber

    PubMed Central

    Liang, Danna; Chen, Minyang; Qi, Xiaohua; Xu, Qiang; Zhou, Fucai; Chen, Xuehao

    2016-01-01

    Cucumber, a very important vegetable crop worldwide, is easily damaged by pests. Aphid is one of the most serious cucumber pests and frequently cause severe damage to commercially produced crops. Understanding the genetic mechanisms underlying pest resistance is important for aphid-resistant cucumber varieties breeding. In this study, two parental cucumber lines, JY30 (aphid susceptible) and EP6392 (aphid resistant), and pools of resistant and susceptible (n = 50 each) plants from 1000 F2 individuals derived from crossing JY30 with EP6392, were used to detect genomic regions associated with aphid resistance in cucumbers. The analysis was performed using specific length amplified fragment sequencing (SLAF-seq), bulked segregant analysis (BSA), and single nucleotide polymorphism index (SNP-index) methods. A main effect QTL (quantitative trait locus) of 0.31 Mb on Chr5, including 43 genes, was identified by association analysis. Sixteen of the 43 genes were identified as potentially associated with aphid resistance through gene annotation analysis. The effect of aphid infestation on the expression of these candidate genes screened by SLAF-seq was investigated in EP6392 plants by qRT-PCR. The results indicated that seven genes including encoding transcription factor MYB59-like (Csa5M641610.1), auxin transport protein BIG-like (Csa5M642140.1), F-box/kelch-repeat protein At5g15710-like (Csa5M642160.1), transcription factor HBP-1a-like (Csa5M642710.1), beta-glucan-binding protein (Csa5M643380.1), endo-1,3(4)-beta-glucanase 1-like (Csa5M643880.1), and proline-rich receptor-like protein kinase PERK10-like (Csa5M643900.1), out of the 16 genes were down regulated after aphid infestation, whereas 5 genes including encoding probable leucine-rich repeat (LRR) receptor-like serine/threonine-protein kinase At5g15730-like (Csa5M642150.1), Stress-induced protein KIN2 (Csa5M643240.1 and Csa5M643260.1), F-box family protein (Csa5M643280.1), F-box/kelch-repeat protein (Csa5M643290

  16. QTL Mapping by SLAF-seq and Expression Analysis of Candidate Genes for Aphid Resistance in Cucumber.

    PubMed

    Liang, Danna; Chen, Minyang; Qi, Xiaohua; Xu, Qiang; Zhou, Fucai; Chen, Xuehao

    2016-01-01

    Cucumber, a very important vegetable crop worldwide, is easily damaged by pests. Aphid is one of the most serious cucumber pests and frequently cause severe damage to commercially produced crops. Understanding the genetic mechanisms underlying pest resistance is important for aphid-resistant cucumber varieties breeding. In this study, two parental cucumber lines, JY30 (aphid susceptible) and EP6392 (aphid resistant), and pools of resistant and susceptible (n = 50 each) plants from 1000 F2 individuals derived from crossing JY30 with EP6392, were used to detect genomic regions associated with aphid resistance in cucumbers. The analysis was performed using specific length amplified fragment sequencing (SLAF-seq), bulked segregant analysis (BSA), and single nucleotide polymorphism index (SNP-index) methods. A main effect QTL (quantitative trait locus) of 0.31 Mb on Chr5, including 43 genes, was identified by association analysis. Sixteen of the 43 genes were identified as potentially associated with aphid resistance through gene annotation analysis. The effect of aphid infestation on the expression of these candidate genes screened by SLAF-seq was investigated in EP6392 plants by qRT-PCR. The results indicated that seven genes including encoding transcription factor MYB59-like (Csa5M641610.1), auxin transport protein BIG-like (Csa5M642140.1), F-box/kelch-repeat protein At5g15710-like (Csa5M642160.1), transcription factor HBP-1a-like (Csa5M642710.1), beta-glucan-binding protein (Csa5M643380.1), endo-1,3(4)-beta-glucanase 1-like (Csa5M643880.1), and proline-rich receptor-like protein kinase PERK10-like (Csa5M643900.1), out of the 16 genes were down regulated after aphid infestation, whereas 5 genes including encoding probable leucine-rich repeat (LRR) receptor-like serine/threonine-protein kinase At5g15730-like (Csa5M642150.1), Stress-induced protein KIN2 (Csa5M643240.1 and Csa5M643260.1), F-box family protein (Csa5M643280.1), F-box/kelch-repeat protein (Csa5M643290

  17. Candidate gene association study in pediatric acute lymphoblastic leukemia evaluated by Bayesian network based Bayesian multilevel analysis of relevance

    PubMed Central

    2012-01-01

    Background We carried out a candidate gene association study in pediatric acute lymphoblastic leukemia (ALL) to identify possible genetic risk factors in a Hungarian population. Methods The results were evaluated with traditional statistical methods and with our newly developed Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method. We collected genomic DNA and clinical data from 543 children, who underwent chemotherapy due to ALL, and 529 healthy controls. Altogether 66 single nucleotide polymorphisms (SNPs) in 19 candidate genes were genotyped. Results With logistic regression, we identified 6 SNPs in the ARID5B and IKZF1 genes associated with increased risk to B-cell ALL, and two SNPs in the STAT3 gene, which decreased the risk to hyperdiploid ALL. Because the associated SNPs were in linkage in each gene, these associations corresponded to one signal per gene. The odds ratio (OR) associated with the tag SNPs were: OR = 1.69, P = 2.22x10-7 for rs4132601 (IKZF1), OR = 1.53, P = 1.95x10-5 for rs10821936 (ARID5B) and OR = 0.64, P = 2.32x10-4 for rs12949918 (STAT3). With the BN-BMLA we confirmed the findings of the frequentist-based method and received additional information about the nature of the relations between the SNPs and the disease. E.g. the rs10821936 in ARID5B and rs17405722 in STAT3 showed a weak interaction, and in case of T-cell lineage sample group, the gender showed a weak interaction with three SNPs in three genes. In the hyperdiploid patient group the BN-BMLA detected a strong interaction among SNPs in the NOTCH1, STAT1, STAT3 and BCL2 genes. Evaluating the survival rate of the patients with ALL, the BN-BMLA showed that besides risk groups and subtypes, genetic variations in the BAX and CEBPA genes might also influence the probability of survival of the patients. Conclusions In the present study we confirmed the roles of genetic variations in ARID5B and IKZF1 in the susceptibility to B-cell ALL

  18. Genetic analysis of haemophilia A in Bulgaria

    PubMed Central

    Petkova, Rumena; Chakarov, Stoian; Kremensky, Ivo

    2004-01-01

    Background Haemophilias are the most common hereditary severe disorders of blood clotting. In families afflicted with heamophilia, genetic analysis provides opportunities to prevent recurrence of the disease. This study establishes a diagnostical strategy for carriership determination and prenatal diagnostics of haemophilia A in Bulgarian haemophilic population. Methods A diagnostical strategy consisting of screening for most common mutations in the factor VIII gene and analysis of a panel of eight linked to the factor VIII gene locus polymorphisms was established. Results Polymorphic analysis for carrier status determination of haemophilia A was successful in 30 families out of 32 (94%). Carrier status was determined in 25 of a total of 28 women at risk (89%). Fourteen prenatal diagnoses in women at high risk of having a haemophilia A – affected child were performed, resulting in 6 healthy boys and 5 girls. Conclusion The compound approach proves to be a highly informative and cost-effective strategy for prevention of recurrence of haemophilia A in Bulgaria. DNA analysis facilitates carriership determination and subsequent prenatal diagnosis in the majority of Bulgarian families affected by haemophilia A. PMID:15035673

  19. Warped Universe: Analysis of Strong Lens Candidates from Early Dark Energy Survey Data

    NASA Astrophysics Data System (ADS)

    Nord, Brian; Buckley-Geer, Elizabeth J.; Lin, Huan; Diehl, H. Thomas; Gaitsch, Hallie

    2015-01-01

    Over five observing seasons, which started in August 2013, the Dark Energy Survey (DES) will carry out a wide field survey of 5000 square degrees of the Southern Galactic Cap. As much of the wide-field area has not yet been systematically surveyed, we expect to discover many new strongly lensed galaxies and quasars.DES has identified 24 strong lens candidate objects (galaxy- and galaxy clusters-scale) in data from the Science Verification season and has performed spectroscopic follow-up on a subset of these candidates as part of a Gemini Large and Long program. We present the current state of progress on the photometric and spectroscopic analysis of the lens candidate systems.One of the main objectives of the strong lensing science program in DES is to derive constraints on dark energy. The two major components of this part of the program will be exploiting (1) lenses with background sources at multiple redshifts and (2) lensed quasars. In addition to cosmology, we will use the cluster-scale lens sample to study dark matter mass profile, along with the large sample of sources at varying redshifts to study of galaxy evolution and substructure.To obtain precise lens and source positions and to verify the candidate system as a lensing system, we must obtain spectroscopic redshifts. In order to model the lens potential to the required level of precision, we also require high-resolution imaging, both available at the Gemini South facility.To select lenses with arc-like features we use a combination of automated arc-finders, catalog searches and visual scans. We carry out these searches on the annual DES data release. The first target list of 24 candidates comes from the Science Verification season, which was undertaken during the 2012/2013 observing season and is about 300 square degrees. Using the upgraded GMOS spectrographs at Gemini South, we have begun spectroscopic observations through the Gemini Large and Long program, awarded to PI Liz Buckley-Geer to follow

  20. A model-based approach for analysis of spatial structure in genetic data.

    PubMed

    Yang, Wen-Yun; Novembre, John; Eskin, Eleazar; Halperin, Eran

    2012-06-01

    Characterizing genetic diversity within and between populations has broad applications in studies of human disease and evolution. We propose a new approach, spatial ancestry analysis, for the modeling of genotypes in two- or three-dimensional space. In spatial ancestry analysis (SPA), we explicitly model the spatial distribution of each SNP by assigning an allele frequency as a continuous function in geographic space. We show that the explicit modeling of the allele frequency allows individuals to be localized on the map on the basis of their genetic information alone. We apply our SPA method to a European and a worldwide population genetic variation data set and identify SNPs showing large gradients in allele frequency, and we suggest these as candidate regions under selection. These regions include SNPs in the well-characterized LCT region, as well as at loci including FOXP2, OCA2 and LRP1B. PMID:22610118

  1. Effects of GWAS-Associated Genetic Variants on lncRNAs within IBD and T1D Candidate Loci

    PubMed Central

    Brorsson, Caroline A.; Pociot, Flemming

    2014-01-01

    Long non-coding RNAs are a new class of non-coding RNAs that are at the crosshairs in many human diseases such as cancers, cardiovascular disorders, inflammatory and autoimmune disease like Inflammatory Bowel Disease (IBD) and Type 1 Diabetes (T1D). Nearly 90% of the phenotype-associated single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) lie outside of the protein coding regions, and map to the non-coding intervals. However, the relationship between phenotype-associated loci and the non-coding regions including the long non-coding RNAs (lncRNAs) is poorly understood. Here, we systemically identified all annotated IBD and T1D loci-associated lncRNAs, and mapped nominally significant GWAS/ImmunoChip SNPs for IBD and T1D within these lncRNAs. Additionally, we identified tissue-specific cis-eQTLs, and strong linkage disequilibrium (LD) signals associated with these SNPs. We explored sequence and structure based attributes of these lncRNAs, and also predicted the structural effects of mapped SNPs within them. We also identified lncRNAs in IBD and T1D that are under recent positive selection. Our analysis identified putative lncRNA secondary structure-disruptive SNPs within and in close proximity (+/−5 kb flanking regions) of IBD and T1D loci-associated candidate genes, suggesting that these RNA conformation-altering polymorphisms might be associated with diseased-phenotype. Disruption of lncRNA secondary structure due to presence of GWAS SNPs provides valuable information that could be potentially useful for future structure-function studies on lncRNAs. PMID:25144376

  2. Cost/benefit analysis of advanced materials technology candidates for the 1980's, part 2

    NASA Technical Reports Server (NTRS)

    Dennis, R. E.; Maertins, H. F.

    1980-01-01

    Cost/benefit analyses to evaluate advanced material technologies projects considered for general aviation and turboprop commuter aircraft through estimated life-cycle costs, direct operating costs, and development costs are discussed. Specifically addressed is the selection of technologies to be evaluated; development of property goals; assessment of candidate technologies on typical engines and aircraft; sensitivity analysis of the changes in property goals on performance and economics, cost, and risk analysis for each technology; and ranking of each technology by relative value. The cost/benefit analysis was applied to a domestic, nonrevenue producing, business-type jet aircraft configured with two TFE731-3 turbofan engines, and to a domestic, nonrevenue producing, business type turboprop aircraft configured with two TPE331-10 turboprop engines. In addition, a cost/benefit analysis was applied to a commercial turboprop aircraft configured with a growth version of the TPE331-10.

  3. Genetic analysis of glutamatergic function in Drosophila

    SciTech Connect

    Chase, B.A.; Kankel, D.R.

    1987-01-01

    Neurotransmitters are essential for communication between neurons and hence are vital in the overall integrative functioning of the nervous system. Previous work on acetylcholine metabolism in the fruit fly, Drosophila melanogaster, has also raised the possibility that transmitter metabolism may play a prominent role in either the achievement or maintenance of the normal structure of the central nervous system in this species. Unfortunately, acetylcholine is rather poorly characterized as a neurotransmitter in Drosophila; consequently, we have begun an analysis of the role of glutamate (probably the best characterized transmitter in this organism) in the formation and/or maintenance of nervous system structure. We present here the results of a series of preliminary analyses. To suggest where glutamatergic function may be localized, an examination of the spatial distribution of high affinity (/sup 3/H)-glutamate binding sites are presented. We present the results of an analysis of the spatial and temporal distribution of enzymatic activities thought to be important in the regulation of transmitter-glutamate pools (i.e., glutamate oxaloacetic transaminase, glutaminase, and glutamate dehydrogenase). To begin to examine whether mutations in any of these functions are capable of affecting glutamatergic activity, we present the results of an initial genetic analysis of one enzymatic function, glutamate oxaloacetic transaminase (GOT), chosen because of its differential distribution within the adult central nervous system and musculature.

  4. Meta-analysis of association studies between five candidate genes and type 2 diabetes in Chinese Han population.

    PubMed

    Jing, Chen; Xueyao, Han; Linong, Ji

    2012-10-01

    The multiple small-scale association studies of candidate genes for type 2 diabetes mellitus in the Chinese Han population have shown inconsistent results. Here, we performed a meta-analysis to evaluate the contribution of five candidate genes to the pathogenesis of type 2 diabetes in the Chinese Han population. We searched for relevant published papers and used STATA v.11.0 to perform a meta-analysis on six single-nucleotide polymorphisms in five genes-ADIPOQ-rs2241766 (SNP45) and -rs1501299 (SNP276), ADRB3-rs4994 (Trp64Arg), CAPN10-rs3792267 (SNP43), ENPP1-rs1044498 (K121Q), and PPARGC1A-rs8192678 (Gly482Ser)-in the Chinese Han population under an additive genetic model. The pooled odds ratios (95% confidence intervals and P-values) were 0.71 (0.60-0.83; P < 0.001) for ADIPOQ-rs2241766, 0.79 (0.64-0.97; P = 0.027) for ADIPOQ-rs1501299, 1.27 (1.07-1.51; P = 0.006) for ADRB3-rs4994, 0.79 (0.57-1.10; P = 0.163) for CAPN10-rs3792267, 1.41 (1.13-1.76; P = 0.003) for ENPP1-rs1044498, and 1.54 (1.34-1.81; P < 0.001) for PPARGC1A-rs8192678. There was high heterogeneity for ADIPOQ-rs2241766, ADIPOQ-rs1501299, and CAPN10-rs3792267 (I² = 74.9, 69.4, and 75.8%, respectively), but not for ADRB3-rs4994, ENPP1-rs1044498, and PPARGC1A-rs8192678 (I² = 0.0, 43.4, and 23.3%, respectively). Under an additive genetic model, the C allele of ADRB3-rs4994, the C allele of ENPP1-rs1044498, and the A allele of PPARGC1A-rs8192678 increase the risk of type 2 diabetes in the Chinese Han population. PMID:22391941

  5. Analysis of Surface Charging for a Candidate Solar Sail Mission Using Nascap-2k

    NASA Technical Reports Server (NTRS)

    Neergaard, Linda F.; Davis, Victoria A.; Gardner, Barbara; Mandell, Myron; Minow, Joseph I.

    2004-01-01

    The characterization of the electromagnetic interaction for a solar sail in the solar wind environment, and identification of viable charging mitigation strategies, is a critical solar sail mission design task, as spacecraft charging has important implications both for science applications and for sail lifetime. To that end, we have pexformed some preliminary surface charging calculations of a candidate 150 meter class solar sail spacecraft for the 0.5 AU solar polar orbit and a 1.0 AU L1 orbit. We construct a model of the spacecraft with candidate materials having appropriate electrical properties using Object Toolkit and perform the spacecraft charging analysis using Nascap-2k, the NASA/AFRL sponsored spacecraft charging analysis tool. We use mean and extreme solar wind environments appropriate for the 0.5 AU and 1.0 AU missions to establish current collection of solar wind ions and electrons. In addition, we include a geostationary orbit case to demonstrate a bounding example of extreme (negative) charging of a solar sail spacecraft in the geostationary orbit environment. Results from the charging analysis demonstrate that minimal differential potentials (and resulting threat of electrostatic discharge) occur when the spacecraft is constructed entirely of conducting materials, as expected. Examples with dielectric materials exposed to the space environment exhibit differential potentials ranging from a few volts to extreme potentials in the kilovolt range. Recommendations for further analyses include calculations of wake effects, surface current densities, and environments effects on conductivities.

  6. Analysis Of Surface Charging For A Candidate Solar Sail Mission Using Nascap-2k

    NASA Technical Reports Server (NTRS)

    Minow, Joseph; Parker, Linda Neergaard; Davis, Victoria

    2005-01-01

    The characterization of the electromagnetic interaction for a solar sail in the solar wind environment, and identification of viable charging mitigation strategies, is a critical solar sail mission design task, as spacecraft charging has important implications both for science applications and for sail lifetime. To that end, we have performed surface charging calculations of a candidate 150-meter-class solar sail spacecraft for the 0.5 solar polar orbit and a 1.0 AU L1 orbit. We construct a model of the spacecraft with candidate materials having appropriate electrical properties using Object Toolkit and perform the spacecraft charging analysis using NASCAP-2k, the NASA/AFRL sponsored spacecraft charging analysis tool. We use nominal and atypical solar wind environments appropriate for the 0.5 AU and 1.0 AU missions to establish current collection of solar wind ions and electrons. In addition, we include a geostationary orbit case to demonstrate a bounding example of extreme (negative) charging of a solar sail spacecraft in the geostationary orbit environment. Results form the charging analysis demonstrate that minimal differential potentials (and resulting threat of electrostatic discharge) occur when the spacecraft is constructed entirely of conducting materials, as expected. Examples with dielectric materials exposed to the space environment exhibit differential potentials ranging from a few volts to extreme potentials in the kilovolt range.

  7. Analysis of Surface Charging for a Candidate Solar Sail Mission Using NASCAP-2K

    NASA Technical Reports Server (NTRS)

    Parker, Linda Neergaard; Minow, Joseph I.; Davis, V. A.; Gardner, Barbara; Mandell, Myron

    2004-01-01

    The characterization of the electromagnetic interaction for a solar sail in the solar wind environment, and identification of viable charging mitigation strategies, is a critical solar sail mission design task, as spacecraft charging has important implications both for science applications and for sail lifetime. To that end, we have performed surface charging calculations of a candidate 150-meter-class solar sail spacecraft for the 0.5 AU solar polar orbit and a 1.0 AU L1 orbit. We construct a model of the spacecraft with candidate materials having appropriate electrical properties using Object Toolkit and perform the spacecraft charging analysis using NASCAP-2k, the NASA/AFRL sponsored spacecraft charging analysis tool. We use nominal and atypical solar wind environments appropriate for the 0.5 AU and 1.0 AU missions to establish current collection of solar wind ions and electrons. In addition, we include a geostationary orbit case to demonstrate a bounding example of extreme (negative) charging of a solar sail spacecraft in the geostationary orbit environment. Results from the charging analysis demonstrate that minimal differential potentials (and resulting threat of electrostatic discharge) occur when the spacecraft is constructed entirely of conducting materials, as expected. Examples with dielectric materials exposed to the space environment exhibit differential potentials ranging from a few volts to extreme potentials in the kilovolt range.

  8. Analysis of Lunar Surface Charging for a Candidate Spacecraft Using NASCAP-2K

    NASA Technical Reports Server (NTRS)

    Parker, Linda; Minow, Joseph; Blackwell, William, Jr.

    2007-01-01

    The characterization of the electromagnetic interaction for a spacecraft in the lunar environment, and identification of viable charging mitigation strategies, is a critical lunar mission design task, as spacecraft charging has important implications both for science applications and for astronaut safety. To that end, we have performed surface charging calculations of a candidate lunar spacecraft for lunar orbiting and lunar landing missions. We construct a model of the spacecraft with candidate materials having appropriate electrical properties using Object Toolkit and perform the spacecraft charging analysis using Nascap-2k, the NASA/AFRL sponsored spacecraft charging analysis tool. We use nominal and atypical lunar environments appropriate for lunar orbiting and lunar landing missions to establish current collection of lunar ions and electrons. In addition, we include a geostationary orbit case to demonstrate a bounding example of extreme (negative) charging of a lunar spacecraft in the geostationary orbit environment. Results from the charging analysis demonstrate that minimal differential potentials (and resulting threat of electrostatic discharge) occur when the spacecraft is constructed entirely of conducting materials, as expected. We compare charging results to data taken during previous lunar orbiting or lunar flyby spacecraft missions.

  9. Genetic variation and effects of candidate-gene polymorphisms on coagulation properties, curd firmness modeling and acidity in milk from Brown Swiss cows.

    PubMed

    Cecchinato, A; Chessa, S; Ribeca, C; Cipolat-Gotet, C; Bobbo, T; Casellas, J; Bittante, G

    2015-07-01

    The aims of this study were to estimate the genetic variation of traditional milk coagulation properties (MCPs), milk acidity, curd firmness (CF) modeled on time t (CF(t) ; comprising: RCT(eq), rennet coagulation time estimated from the equation; CF(P), the asymptotic potential curd firmness; k(CF), the curd firming instant rate constant; and k(SR), the syneresis instant rate constant) and maximum CF traits (MCF; comprising CF(max), the maximum CF value; and tmax, the time of attainment). Furthermore, we investigated 96 single nucleotide polymorphisms (SNPs) from 54 candidate genes, testing their associations with the above-listed traits. Milk and blood samples were collected from 1271 cows (each sampled once) from 85 herds. Genotyping was performed using a custom Illumina VeraCode GoldenGate approach. A Bayesian linear animal model (including the effects of herd, days in milk, parity and additive polygenic effects) was used to estimate the genetic parameters of the studied traits. The same model with the addition of the SNP genotype effect was used for our association analysis. The heritability estimates of CF t and the MCF traits (RCT(eq)=0.258; k(CF)=0.230; CF(max)=0.191; t(max)=0.278) were similar to those obtained using traditional MCPs (0.187 to 0.267), except for the lower estimates for CF(P) (0.064) and k(SR) (0.077). A total of 13 of the 51 tested SNPs had relevant additive effects on at least one trait. We observed associations between MCPs and SNPs in the genes encoding ATP-binding cassette sub-family G member 2 (ABCG2), chemokine ligand 2 (CCL2), growth hormone 1 (GH1), prolactin (PRL) and toll-like receptor 2 (TLR2). Whereas, CF(t) and the MCF traits were associated with polymorphisms in the α-s1-casein (CSN1S1), β-casein (CSN2), GH1, oxidized low-density lipoprotein receptor 1 (OLR1), phospholipase C β1 (PLCB1), PRL and signal transducer and activator of transcription 5A (STAT5A) genes. PMID:25823422

  10. RNA-Seq Analysis Reveals Candidate Genes for Ontogenic Resistance in Malus-Venturia Pathosystem

    PubMed Central

    Gusberti, Michele; Gessler, Cesare; Broggini, Giovanni A. L.

    2013-01-01

    Ontogenic scab resistance in apple leaves and fruits is a horizontal resistance against the plant pathogen Venturia inaequalis and is expressed as a decrease in disease symptoms and incidence with the ageing of the leaves. Several studies at the biochemical level tried to unveil the nature of this resistance; however, no conclusive results were reported. We decided therefore to investigate the genetic origin of this phenomenon by performing a full quantitative transcriptome sequencing and comparison of young (susceptible) and old (ontogenic resistant) leaves, infected or not with the pathogen. Two time points at 72 and 96 hours post-inoculation were chosen for RNA sampling and sequencing. Comparison between the different conditions (young and old leaves, inoculated or not) should allow the identification of differentially expressed genes which may represent different induced plant defence reactions leading to ontogenic resistance or may be the cause of a constitutive (uninoculated with the pathogen) shift toward resistance in old leaves. Differentially expressed genes were then characterised for their function by homology to A. thaliana and other plant genes, particularly looking for genes involved in pathways already suspected of appertaining to ontogenic resistance in apple or other hosts, or to plant defence mechanisms in general. In this work, five candidate genes putatively involved in the ontogenic resistance of apple were identified: a gene encoding an “enhanced disease susceptibility 1 protein” was found to be down-regulated in both uninoculated and inoculated old leaves at 96 hpi, while the other four genes encoding proteins (metallothionein3-like protein, lipoxygenase, lipid transfer protein, and a peroxidase 3) were found to be constitutively up-regulated in inoculated and uninoculated old leaves. The modulation of the five candidate genes has been validated using the real-time quantitative PCR. Thus, ontogenic resistance may be the result of the

  11. Linkage between stature and a region on chromosome 20 and analysis of a candidate gene, bone morphogenetic protein 2

    SciTech Connect

    Thompson, D.B.; Ossowski, V.; Janssen, R.C.; Knowler, W.C.; Bogardus, C.

    1995-12-04

    Sib-pair linkage analysis of the quantitative trait, stature, in over 500 Pima Indians indicates that a genetic determinant of governing stature is located on chromosome 20. Analysis of 10 short tandem repeat polymorphisms localized this linkage to a 3. cM region that includes D20S98 and D20S66. Using all possible sib-pair combinations, linkage was detected to both stature (P = 0.0001) and to leg length (P = 0.001), but not to sitting height. Single-strand conformational polymorphism analysis of exon 3 of the bone morphogenetic protein 2 (BMP2) gene, a candidate gene in this region, in genomic DNA of 20 of the tallest and 20 of the shortest individuals did not show any consistent differences associated with leg length or height. Sequence analysis of the region encoding the mature protein revealed a single nucleotide substitution, a T to G transversion, not detected by single-strand conformational polymorphism (SSCP) analysis. This transversion results in a conservative amino acid substitution of glycine for valine at codon 80 of BMP2. The frequency of this allele was 0.23 in the sample. No significant differences in height were noted in persons carrying either allele. This indicates that this structural alteration in the mature BMP2 protein does not contribute to the differences in stature observed in the Pima Indians, nor is this structural change in the mature protein likely to be responsible for the linkage observed with stature on chromosome 20. 33 refs., 2 figs., 2 tabs.

  12. Cloned cDNA of A/swine/Iowa/15/1930 internal genes as a candidate backbone for reverse genetics vaccine against influenza A viruses

    PubMed Central

    Lekcharoensuk, Porntippa; Wiriyarat, Witthawat; Petcharat, Nuntawan; Lekcharoensuk, Chalermpol; Auewarakul, Prasert; Richt, Juergen A

    2012-01-01

    Reverse genetics viruses for influenza vaccine production usually utilize the internal genes of the egg-adapted A/Puerto Rico/8/34 (PR8) strain. This egg-adapted strain provides high production yield in embryonated eggs but does not necessarily give the best yield in mammalian cell culture. In order to generate a reverse genetics viral backbone that is well-adapted to high growth in mammalian cell culture, a swine influenza isolate (A/swine/Iowa/15/30 (H1N1) (rg1930) that was shown to give high yield in Madin-Darby Canine Kidney (MDCK) cells was used as the internal gene donor for reverse genetics plasmids. In this report, the internal genes from rg1930 were used for construction of reverse genetics viruses carrying a cleavage site-modified hemagglutinin (HA) gene and neuraminidase (NA) gene from a highly pathogenic H5N1 virus. The resulting virus (rg1930H5N1) was low pathogenic in vivo. Inactivated rg1930H5N1 vaccine completely protected chickens from morbidity and mortality after challenge with highly pathogenic H5N1. Protective immunity was obtained when chickens were immunized with an inactivated vaccine consisting of at least 29 HA units of the rg1930H5N1 virus. In comparison to the PR8-based reverse genetics viruses carrying the same HA and NA genes from an H5N1 virus, rg1930 based viruses yielded higher viral titers in MDCK and Vero cells. In addition, the reverse genetics derived H3N2 and H5N2 viruses with the rg1930 backbone replicated in MDCK cells better than the cognate viruses with the rgPR8 backbone. It is concluded that this newly established reverse genetics backbone system could serve as a candidate for a master donor strain for development of inactivated influenza vaccines in cell-based systems. PMID:22230579

  13. GENETIC ANALYSIS OF ABSCISIC ACID BIOSYNTHESIS

    SciTech Connect

    MCCARTY D R

    2012-01-10

    The carotenoid cleavage dioxygenases (CCD) catalyze synthesis of a variety of apo-carotenoid secondary metabolites in plants, animals and bacteria. In plants, the reaction catalyzed by the 11, 12, 9-cis-epoxy carotenoid dioxygenase (NCED) is the first committed and key regulated step in synthesis of the plant hormone, abscisic acid (ABA). ABA is a key regulator of plant stress responses and has critical functions in normal root and seed development. The molecular mechanisms responsible for developmental control of ABA synthesis in plant tissues are poorly understood. Five of the nine CCD genes present in the Arabidopsis genome encode NCED's involved in control of ABA synthesis in the plant. This project is focused on functional analysis of these five AtNCED genes as a key to understanding developmental regulation of ABA synthesis and dissecting the role of ABA in plant development. For this purpose, the project developed a comprehensive set of gene knockouts in the AtNCED genes that facilitate genetic dissection of ABA synthesis. These mutants were used in combination with key molecular tools to address the following specific objectives: (1) the role of ABA synthesis in root development; (2) developmental control of ABA synthesis in seeds; (3) analysis of ATNCED over-expressers; (4) preliminary crystallography of the maize VP14 protein.

  14. Genetic analysis of plant height in wheat.

    PubMed

    Halloran, G M

    1974-01-01

    Genetic studies of plant height were made of 8 wheats and the 28 crosses between them using the diallel method of analysis. The inheritance of plant height in a glasshouse-grown F1 diallel set in which vernalization and photoperiodic responses had been removed, indicated close to complete dominance in its expression. A similar F1 set of crosses in the field environment indicated non-allelic interaction in its expression, attributable mainly to the cultivar Chile 1B generally in its crosses with the other 7 wheats. Its removal gave close to complete average dominance in the inheritance of plant height.In the F2 generation in the field its inheritance was again subject to non-allelic interaction, attributed mainly to Chile 1B which, on removal, gave a situation of average partial dominance in height expression.Standardized deviations of Yr and (Wr + Vr) for plant height for the diallels indicated a resonably close association of tallness with dominance and shortness with recessiveness.Frequency distributions of plant height in the F1 and F2 of two crosses from the diallel confirmed certain findings of the diallel analysis.At least two groups of dominant genes were found to influence plant height expression in the crosses of the diallel ; this number must be regarded as a minimal estimate of the number of genes influencing plant height in wheat. PMID:24419549

  15. Genetic Variants Associated with Breast Cancer Risk: Comprehensive Field Synopsis, Meta-Analysis, and Epidemiologic Evidence

    PubMed Central

    Zhang, Ben; Beeghly-Fadiel, Alicia; Long, Jirong; Zheng, Wei

    2011-01-01

    SUMMARY Background Over 1,000 reports have been published during the past two decades on associations between genetic variants in candidate genes and breast cancer risk. Results have been generally inconsistent. We conducted literature searches and meta-analyses to provide a field synopsis of the current understanding of the genetic architecture of breast cancer risk. Methods Systematic literature searches for candidate gene association studies of breast cancer risk were conducted in two stages using PubMed on or before February 28, 2010. A total of 24,500 publications were identified, of which, 1,059 were deemed eligible for inclusion. Meta-analyses were conducted for 279 genetic variants in 128 candidate genes or chromosomal loci that had a minimum of three data sources available. Variants with significant associations by meta-analysis were assessed using the Venice criteria and scored as having strong, moderate, or weak cumulative evidence for an association with breast cancer risk. Findings Fifty-one variants in 40 genes showed statistically significant associations with breast cancer risk. Cumulative epidemiologic evidence for an association with breast cancer risk was graded as strong for 10 variants in six genes (ATM, CASP8, CHEK2, CTLA4, NBN, and TP53), moderate for four variants in four genes (ATM, CYP19A1, TERT, and XRCC3), and weak for 37 additional variants. Additionally, in meta-analyses that included a minimum of 10,000 cases and 10,000 controls, convincing evidence of no association with breast cancer risk was identified for 45 variants in 37 genes. Interpretation While most genetic variants evaluated in previous candidate gene studies showed no association with breast cancer risk in meta-analyses, 14 variants in 9 genes were found to have moderate to strong evidence for an association with breast cancer risk. Further evaluation of these variants is warranted. PMID:21514219

  16. Genetic analysis of albuminuria in collaborative cross and multiple mouse intercross populations.

    PubMed

    Thaisz, Jill; Tsaih, Shirng-Wern; Feng, Minjie; Philip, Vivek M; Zhang, Yunyu; Yanas, Liane; Sheehan, Susan; Xu, Lingfei; Miller, Darla R; Paigen, Beverly; Chesler, Elissa J; Churchill, Gary A; Dipetrillo, Keith

    2012-10-01

    Albuminuria is an important marker of nephropathy that increases the risk of progressive renal and chronic cardiovascular diseases. The genetic basis of kidney disease is well-established in humans and rodent models, but the causal genes remain to be identified. We applied several genetic strategies to map and refine genetic loci affecting albuminuria in mice and translated the findings to human kidney disease. First, we measured albuminuria in mice from 33 inbred strains, used the data for haplotype association mapping (HAM), and detected 10 genomic regions associated with albuminuria. Second, we performed eight F(2) intercrosses between genetically diverse strains to identify six loci underlying albuminuria, each of which was concordant to kidney disease loci in humans. Third, we used the Oak Ridge National Laboratory incipient Collaborative Cross subpopulation to detect an additional novel quantitative trait loci (QTL) underlying albuminuria. We also performed a ninth intercross, between genetically similar strains, that substantially narrowed an albuminuria QTL on Chromosome 17 to a region containing four known genes. Finally, we measured renal gene expression in inbred mice to detect pathways highly correlated with albuminuria. Expression analysis also identified Glcci1, a gene known to affect podocyte structure and function in zebrafish, as a strong candidate gene for the albuminuria QTL on Chromosome 6. Overall, these findings greatly enhance our understanding of the genetic basis of albuminuria in mice and may guide future studies into the genetic basis of kidney disease in humans. PMID:22859403

  17. Array-CGH Analysis Suggests Genetic Heterogeneity in Rhombencephalosynapsis

    PubMed Central

    Démurger, F.; Pasquier, L.; Dubourg, C.; Dupé, V.; Gicquel, I.; Evain, C.; Ratié, L.; Jaillard, S.; Beri, M.; Leheup, B.; Lespinasse, J.; Martin-Coignard, D.; Mercier, S.; Quelin, C.; Loget, P.; Marcorelles, P.; Laquerrière, A.; Bendavid, C.; Odent, S.; David, V.

    2013-01-01

    Rhombencephalosynapsis is an uncommon, but increasingly recognized, cerebellar malformation defined as vermian agenesis with fusion of the hemispheres. The embryologic and genetic mechanisms involved are still unknown, and to date, no animal models are available. In the present study, we used Agilent oligonucleotide arrays in a large series of 57 affected patients to detect candidate genes. Four different unbalanced rearrangements were detected: a 16p11.2 deletion, a 14q12q21.2 deletion, an unbalanced translocation t(2p;10q), and a 16p13.11 microdeletion containing 2 candidate genes. These genes were further investigated by sequencing and in situ hybridization. This first microarray screening of a rhombencephalosynapsis series suggests that there may be heterogeneous genetic causes. PMID:24167461

  18. Analysis of Surface Charging for a Candidate Solar Sail Mission Using NASCAP-2K

    NASA Technical Reports Server (NTRS)

    Parker, Linda Neergaard; Minow, Joseph L.; Davis, V. A.; Mandell, Myron; Gardner, Barbara

    2005-01-01

    The characterization of the electromagnetic interaction for a solar sail in the solar wind environment and identification of viable charging mitigation strategies are critical solar sail mission design tasks. Spacecraft charging has important implications both for science applications and for lifetime and reliability issues of sail propulsion systems. To that end, surface charging calculations of a candidate 150-meter-class solar sail spacecraft for the 0.5 AU solar polar and 1.9 AU LI solar wind environments are performed. A model of the spacecraft with candidate materials having appropriate electrical properties is constructed using Object Toolkit. The spacecraft charging analysis is performed using Nascap-2k. the NASA/AFRL sponsored spacecraft charging analysis tool. Nominal and atypical solar wind environments appropriate for the 0.5 AU and 1.0 AU missions are used to establish current collection of solar wind ions and electrons. Finally, a geostationary orbit environment case is included to demonstrate a bounding example of extreme (negative) charging of a solar sail spacecraft. Results from the charging analyses demonstrate that minimal differential potentials (and resulting threat of electrostatic discharge) occur when the spacecraft is constructed entirely of conducting materials, as anticipated from standard guidelines for mitigation of spacecraft charging issues. Examples with dielectric materials exposed to the space environment exhibit differential potentials ranging from a few volts to extreme potentials in the kilovolt range.

  19. Analysis of Surface Charging for a Candidate Solar Sail Mission Using Nascap-2k

    NASA Technical Reports Server (NTRS)

    Parker, Linda Neergaard; Minow, Joseph I.; Davis, Victoria; Mandell, Myron; Gardner, Barbara

    2005-01-01

    The characterization of the electromagnetic interaction for a solar sail in the solar wind environment and identification of viable charging mitigation strategies are critical solar sail mission design task. Spacecraft charging has important implications both for science applications and for lifetime and reliability issues of sail propulsion systems. To that end, surface charging calculations of a candidate 150-meter-class solar sail spacecraft for the 0.5 AU solar polar and 1.0 AU L1 solar wind environments are performed. A model of the spacecraft with candidate materials having appropriate electrical properties is constructed using Object Toolkit. The spacecraft charging analysis is performed using Nascap-2k, the NASA/AFRL sponsored spacecraft charging analysis tool. Nominal and atypical solar wind environments appropriate for the 0.5 AU and 1.0 AU missions are used to establish current collection of solar wind ions and electrons. Finally, a geostationary orbit environment case is included to demonstrate a bounding example of extreme (negative) charging of a solar sail spacecraft. Results from the charging analyses demonstrate that minimal differential potentials (and resulting threat of electrostatic discharge) occur when the spacecraft is constructed entirely of conducting materials, as anticipated from standard guidelines for mitigation of spacecraft charging issues. Examples with dielectric materials exposed to the space environment exhibit differential potentials ranging from a few volts to extreme potentials in the kilovolt range.

  20. CHARACTERISTICS OF PLANETARY CANDIDATES OBSERVED BY KEPLER. II. ANALYSIS OF THE FIRST FOUR MONTHS OF DATA

    SciTech Connect

    Borucki, William J.; Koch, David G.; Bryson, Stephen T.; Lissauer, Jack J.; Basri, Gibor; Marcy, Geoffrey W.; Batalha, Natalie; Brown, Timothy M.; Caldwell, Douglas; DeVore, Edna; Jenkins, Jon M.; Christensen-Dalsgaard, Joergen; Cochran, William D.; Dunham, Edward W.; Gautier, Thomas N.; Geary, John C.; Latham, David W.; Gilliland, Ronald; Gould, Alan; Howell, Steve B. E-mail: Martin.Still@nasa.gov

    2011-07-20

    On 2011 February 1 the Kepler mission released data for 156,453 stars observed from the beginning of the science observations on 2009 May 2 through September 16. There are 1235 planetary candidates with transit-like signatures detected in this period. These are associated with 997 host stars. Distributions of the characteristics of the planetary candidates are separated into five class sizes: 68 candidates of approximately Earth-size (R{sub p} < 1.25 R{sub +}), 288 super-Earth-size (1.25 R{sub +} {<=} R{sub p} < 2 R{sub +}), 662 Neptune-size (2 R{sub +} {<=} R{sub p} < 6 R{sub +}), 165 Jupiter-size (6 R{sub +} {<=} R{sub p} < 15 R{sub +}), and 19 up to twice the size of Jupiter (15 R{sub +} {<=} R{sub p} < 22 R{sub +}). In the temperature range appropriate for the habitable zone, 54 candidates are found with sizes ranging from Earth-size to larger than that of Jupiter. Six are less than twice the size of the Earth. Over 74% of the planetary candidates are smaller than Neptune. The observed number versus size distribution of planetary candidates increases to a peak at two to three times the Earth-size and then declines inversely proportional to the area of the candidate. Our current best estimates of the intrinsic frequencies of planetary candidates, after correcting for geometric and sensitivity biases, are 5% for Earth-size candidates, 8% for super-Earth-size candidates, 18% for Neptune-size candidates, 2% for Jupiter-size candidates, and 0.1% for very large candidates; a total of 0.34 candidates per star. Multi-candidate, transiting systems are frequent; 17% of the host stars have multi-candidate systems, and 34% of all the candidates are part of multi-candidate systems.

  1. Candidate Gene Association Analysis of Neuroblastoma in Chinese Children Strengthens the Role of LMO1

    PubMed Central

    Wang, Huanmin; Jin, Yaqiong; Han, Shujing; Han, Wei; Tai, Jun; Guo, Yongli; Ni, Xin

    2015-01-01

    Neuroblastoma (NB) is the most common extra-cranial solid tumor in children and the most frequently diagnosed cancer in the first year of life. Previous genome-wide association studies (GWAS) of Caucasian and African populations have shown that common single nucleotide polymorphisms (SNPs) in several genes are associated with the risk of developing NB, while few studies have been performed on Chinese children. Herein, we examined the association between the genetic polymorphisms in candidate genes and the risk of NB in Chinese children. In total, 127 SNPs in nine target genes, revealed by GWAS studies of other ethnic groups and four related lincRNAs, were genotyped in 549 samples (244 NB patients and 305 healthy controls). After adjustment for gender and age, there were 21 SNPs associated with NB risk at the two-sided P < 0.05 level, 11 of which were located in LMO1. After correction for multiple comparisons, only rs204926 in LMO1 remained significantly different between cases and controls (OR = 0.45, 95% CI: 0.31–0.65, adjusted P = 0.003). In addition, 16 haplotypes in four separate genes were significantly different between case and control groups at an unadjusted P value < 0.05, 11 of which were located in LMO1. A major haplotype, ATC, containing rs204926, rs110420, and rs110419, conferred a significant increase in risk for NB (OR = 1.82, 95% CI: 1.41–2.36, adjusted P < 0.001). The major finding of our study was obtained for risk alleles within the LMO1 gene. Our data suggest that genetic variants in LMO1 are associated with increased NB risk in Chinese children. PMID:26030754

  2. Candidate Gene Association Analysis of Neuroblastoma in Chinese Children Strengthens the Role of LMO1.

    PubMed

    Lu, Jie; Chu, Ping; Wang, Huanmin; Jin, Yaqiong; Han, Shujing; Han, Wei; Tai, Jun; Guo, Yongli; Ni, Xin

    2015-01-01

    Neuroblastoma (NB) is the most common extra-cranial solid tumor in children and the most frequently diagnosed cancer in the first year of life. Previous genome-wide association studies (GWAS) of Caucasian and African populations have shown that common single nucleotide polymorphisms (SNPs) in several genes are associated with the risk of developing NB, while few studies have been performed on Chinese children. Herein, we examined the association between the genetic polymorphisms in candidate genes and the risk of NB in Chinese children. In total, 127 SNPs in nine target genes, revealed by GWAS studies of other ethnic groups and four related lincRNAs, were genotyped in 549 samples (244 NB patients and 305 healthy controls). After adjustment for gender and age, there were 21 SNPs associated with NB risk at the two-sided P < 0.05 level, 11 of which were located in LMO1. After correction for multiple comparisons, only rs204926 in LMO1 remained significantly different between cases and controls (OR = 0.45, 95% CI: 0.31-0.65, adjusted P = 0.003). In addition, 16 haplotypes in four separate genes were significantly different between case and control groups at an unadjusted P value < 0.05, 11 of which were located in LMO1. A major haplotype, ATC, containing rs204926, rs110420, and rs110419, conferred a significant increase in risk for NB (OR = 1.82, 95% CI: 1.41-2.36, adjusted P < 0.001). The major finding of our study was obtained for risk alleles within the LMO1 gene. Our data suggest that genetic variants in LMO1 are associated with increased NB risk in Chinese children. PMID:26030754

  3. An analysis of a candidate control algorithm for a ride quality augmentation system

    NASA Technical Reports Server (NTRS)

    Suikat, Reiner; Donaldson, Kent; Downing, David R.

    1987-01-01

    This paper presents a detailed analysis of a candidate algorithm for a ride quality augmentation system. The algorithm consists of a full-state feedback control law based on optimal control output weighting, estimators for angle of attack and sideslip, and a maneuvering algorithm. The control law is shown to perform well by both frequency and time domain analysis. The rms vertical acceleration is reduced by about 40 percent over the whole mission flight envelope. The estimators for the angle of attack and sideslip avoid the often inaccurate or costly direct measurement of those angles. The maneuvering algorithm will allow the augmented airplane to respond to pilot inputs. The design characteristics and performance are documented by the closed-loop eigenvalues; rms levels of vertical, lateral, and longitudinal acceleration; and representative time histories and frequency response.

  4. Comparative Genomics Analysis of Mycobacterium ulcerans for the Identification of Putative Essential Genes and Therapeutic Candidates

    PubMed Central

    Tahir, Shifa; Tong, Yigang

    2012-01-01

    Mycobacterium ulcerans, the causative agent of Buruli ulcer, is the third most common mycobacterial disease after tuberculosis and leprosy. The present treatment options are limited and emergence of treatment resistant isolates represents a serious concern and a need for better therapeutics. Conventional drug discovery methods are time consuming and labor-intensive. Unfortunately, the slow growing nature of M. ulcerans in experimental conditions is also a barrier for drug discovery and development. In contrast, recent advancements in complete genome sequencing, in combination with cheminformatics and computational biology, represent an attractive alternative approach for the identification of therapeutic candidates worthy of experimental research. A computational, comparative genomics workflow was defined for the identification of novel therapeutic candidates against M. ulcerans, with the aim that a selected target should be essential to the pathogen, and have no homology in the human host. Initially, a total of 424 genes were predicted as essential from the M. ulcerans genome, via homology searching of essential genome content from 20 different bacteria. Metabolic pathway analysis showed that the most essential genes are associated with carbohydrate and amino acid metabolism. Among these, 236 proteins were identified as non-host and essential, and could serve as potential drug and vaccine candidates. Several drug target prioritization parameters including druggability were also calculated. Enzymes from several pathways are discussed as potential drug targets, including those from cell wall synthesis, thiamine biosynthesis, protein biosynthesis, and histidine biosynthesis. It is expected that our data will facilitate selection of M. ulcerans proteins for successful entry into drug design pipelines. PMID:22912793

  5. Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes.

    PubMed

    Pers, Tune H; Timshel, Pascal; Ripke, Stephan; Lent, Samantha; Sullivan, Patrick F; O'Donovan, Michael C; Franke, Lude; Hirschhorn, Joel N

    2016-03-15

    Over 100 associated genetic loci have been robustly associated with schizophrenia. Gene prioritization and pathway analysis have focused on a priori hypotheses and thus may have been unduly influenced by prior assumptions and missed important causal genes and pathways. Using a data-driven approach, we show that genes in associated loci: (1) are highly expressed in cortical brain areas; (2) are enriched for ion channel pathways (false discovery rates <0.05); and (3) contain 62 genes that are functionally related to each other and hence represent promising candidates for experimental follow up. We validate the relevance of the prioritized genes by showing that they are enriched for rare disruptive variants and de novo variants from schizophrenia sequencing studies (odds ratio 1.67, P = 0.039), and are enriched for genes encoding members of mouse and human postsynaptic density proteomes (odds ratio 4.56, P = 5.00 × 10(-4); odds ratio 2.60, P = 0.049).The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Author. PMID:26755824

  6. Genetic variants determining survival and fertility in an adverse African environment: a population-based large-scale candidate gene association study

    PubMed Central

    Koopman, Jacob J.E.; Pijpe, Jeroen; Böhringer, Stefan; van Bodegom, David; Eriksson, Ulrika K.; Sanchez-Faddeev, Hernando; Ziem, Juventus B.; Zwaan, Bas; Slagboom, P. Eline; de Knijff, Peter; Westendorp, Rudi G.J.

    2016-01-01

    Human survival probability and fertility decline strongly with age. These life history traits have been shaped by evolution. However, research has failed to uncover a consistent genetic determination of variation in survival and fertility. As an explanation, such genetic determinants have been selected in adverse environments, in which humans have lived during most of their history, but are almost exclusively studied in populations in modern affluent environments. Here, we present a large-scale candidate gene association study in a rural African population living in an adverse environment. In 4387 individuals, we studied 4052 SNPs in 148 genes that have previously been identified as possible determinants of survival or fertility in animals or humans. We studied their associations with survival comparing newborns, middle-age adults, and old individuals. In women, we assessed their associations with reported and observed numbers of children. We found no statistically significant associations of these SNPs with survival between the three age groups nor with women's reported and observed fertility. Population stratification was unlikely to explain these results. Apart from a lack of power, we hypothesise that genetic heterogeneity of complex phenotypes and gene-environment interactions prevent the identification of genetic variants explaining variation in survival and fertility in humans. PMID:27356285

  7. Longitudinal Genetic Analysis of Anxiety Sensitivity

    ERIC Educational Resources Information Center

    Zavos, Helena M. S.; Gregory, Alice M.; Eley, Thalia C.

    2012-01-01

    Anxiety sensitivity is associated with both anxiety and depression and has been shown to be heritable. Little, however, is known about the role of genetic influence on continuity and change of symptoms over time. The authors' aim was to examine the stability of anxiety sensitivity during adolescence. By using a genetically sensitive design, the…

  8. Genetic analysis of embryo dormancy. Final report

    SciTech Connect

    Galau, G.

    1998-09-01

    Primary dormancy is the inability of mature seed to immediately germinate until specific environmental stimuli are perceived that predict that future conditions will support plant growth and seed set. The analysis of abscisic acid deficient and insensitive mutants, in particular in Arabidopsis, suggests that embryo abscisic acid may be directly involved in the development of primary dormancy. Other studies implicate the continued accumulation of LEA proteins as inhibiting germination in dormant embryos. The results of these physiological, molecular and genetic approaches are complex and equivocal. There is a real need for approaches that test the separate nature of vivipary inhibition and primary dormancy and deliberately seed to decouple and dissect them. These approaches should be of help in understanding both late embryo development and primary dormancy. The approach taken here is to directly isolate mutants of Arabidopsis that appear to be deficient only in primary dormancy, that is fresh seed that germinate rapidly without the normally-required cold-stratification. The authors have isolated at least 8 independent, rapidly germinating RGM mutants of Arabidopsis. All others aspects of plant growth and development appear normal in these lines, suggesting that the rgm mutants are defective only in the establishment or maintenance of primary dormancy. At least one of these may be tagged with T-DNA. In addition, about 50 RGM isolates have been recovered from EMS-treated seed.

  9. Genetic analysis of Vibrio parahaemolyticus intestinal colonization.

    PubMed

    Hubbard, Troy P; Chao, Michael C; Abel, Sören; Blondel, Carlos J; Abel Zur Wiesch, Pia; Zhou, Xiaohui; Davis, Brigid M; Waldor, Matthew K

    2016-05-31

    Vibrio parahaemolyticus is the most common cause of seafood-borne gastroenteritis worldwide and a blight on global aquaculture. This organism requires a horizontally acquired type III secretion system (T3SS2) to infect the small intestine, but knowledge of additional factors that underlie V. parahaemolyticus pathogenicity is limited. We used transposon-insertion sequencing to screen for genes that contribute to viability of V. parahaemolyticus in vitro and in the mammalian intestine. Our analysis enumerated and controlled for the host infection bottleneck, enabling robust assessment of genetic contributions to in vivo fitness. We identified genes that contribute to V. parahaemolyticus colonization of the intestine independent of known virulence mechanisms in addition to uncharacterized components of T3SS2. Our study revealed that toxR, an ancestral locus in Vibrio species, is required for V. parahaemolyticus fitness in vivo and for induction of T3SS2 gene expression. The regulatory mechanism by which V. parahaemolyticus ToxR activates expression of T3SS2 resembles Vibrio cholerae ToxR regulation of distinct virulence elements acquired via lateral gene transfer. Thus, disparate horizontally acquired virulence systems have been placed under the control of this ancestral transcription factor across independently evolved human pathogens. PMID:27185914

  10. Genetic etiology of renal agenesis: fine mapping of Renag1 and identification of Kit as the candidate functional gene.

    PubMed

    Samanas, Nyssa Becker; Commers, Tessa W; Dennison, Kirsten L; Harenda, Quincy Eckert; Kurz, Scott G; Lachel, Cynthia M; Wavrin, Kristen Leland; Bowler, Michael; Nijman, Isaac J; Guryev, Victor; Cuppen, Edwin; Hubner, Norbert; Sullivan, Ruth; Vezina, Chad M; Shull, James D

    2015-01-01

    Congenital anomalies of the kidney and urogenital tract (CAKUT) occur in approximately 0.5% of live births and represent the most frequent cause of end-stage renal disease in neonates and children. The genetic basis of CAKUT is not well defined. To understand more fully the genetic basis of one type of CAKUT, unilateral renal agenesis (URA), we are studying inbred ACI rats, which spontaneously exhibit URA and associated urogenital anomalies at an incidence of approximately 10%. URA is inherited as an incompletely dominant trait with incomplete penetrance in crosses between ACI and Brown Norway (BN) rats and a single responsible genetic locus, designated Renag1, was previously mapped to rat chromosome 14 (RNO14). The goals of this study were to fine map Renag1, identify the causal genetic variant responsible for URA, confirm that the Renag1 variant is the sole determinant of URA in the ACI rat, and define the embryologic basis of URA in this rat model. Data presented herein localize Renag1 to a 379 kilobase (kb) interval that contains a single protein coding gene, Kit (v-kit Hardy-Zukerman 4 feline sarcoma viral oncogene homolog); identify an endogenous retrovirus-derived long terminal repeat located within Kit intron 1 as the probable causal variant; demonstrate aberrant development of the nephric duct in the anticipated number of ACI rat embryos; and demonstrate expression of Kit and Kit ligand (Kitlg) in the nephric duct. Congenic rats that harbor ACI alleles at Renag1 on the BN genetic background exhibit the same spectrum of urogenital anomalies as ACI rats, indicating that Renag1 is necessary and sufficient to elicit URA and associated urogenital anomalies. These data reveal the first genetic link between Kit and URA and illustrate the value of the ACI rat as a model for defining the mechanisms and cell types in which Kit functions during urogenital development. PMID:25693193

  11. Genetic Etiology of Renal Agenesis: Fine Mapping of Renag1 and Identification of Kit as the Candidate Functional Gene

    PubMed Central

    Samanas, Nyssa Becker; Commers, Tessa W.; Dennison, Kirsten L.; Harenda, Quincy Eckert; Kurz, Scott G.; Lachel, Cynthia M.; Wavrin, Kristen Leland; Bowler, Michael; Nijman, Isaac J.; Guryev, Victor; Cuppen, Edwin; Hubner, Norbert; Sullivan, Ruth; Vezina, Chad M.; Shull, James D.

    2015-01-01

    Congenital anomalies of the kidney and urogenital tract (CAKUT) occur in approximately 0.5% of live births and represent the most frequent cause of end-stage renal disease in neonates and children. The genetic basis of CAKUT is not well defined. To understand more fully the genetic basis of one type of CAKUT, unilateral renal agenesis (URA), we are studying inbred ACI rats, which spontaneously exhibit URA and associated urogenital anomalies at an incidence of approximately 10%. URA is inherited as an incompletely dominant trait with incomplete penetrance in crosses between ACI and Brown Norway (BN) rats and a single responsible genetic locus, designated Renag1, was previously mapped to rat chromosome 14 (RNO14). The goals of this study were to fine map Renag1, identify the causal genetic variant responsible for URA, confirm that the Renag1 variant is the sole determinant of URA in the ACI rat, and define the embryologic basis of URA in this rat model. Data presented herein localize Renag1 to a 379 kilobase (kb) interval that contains a single protein coding gene, Kit (v-kit Hardy-Zukerman 4 feline sarcoma viral oncogene homolog); identify an endogenous retrovirus-derived long terminal repeat located within Kit intron 1 as the probable causal variant; demonstrate aberrant development of the nephric duct in the anticipated number of ACI rat embryos; and demonstrate expression of Kit and Kit ligand (Kitlg) in the nephric duct. Congenic rats that harbor ACI alleles at Renag1 on the BN genetic background exhibit the same spectrum of urogenital anomalies as ACI rats, indicating that Renag1 is necessary and sufficient to elicit URA and associated urogenital anomalies. These data reveal the first genetic link between Kit and URA and illustrate the value of the ACI rat as a model for defining the mechanisms and cell types in which Kit functions during urogenital development. PMID:25693193

  12. An Analysis of the Candidate Teachers' Beliefs Related to Knowledge, Learning and Teaching

    ERIC Educational Resources Information Center

    Bay, Erdal; Vural, Ömer Faruk; Demir, Servet; Bagceci, Birsen

    2015-01-01

    Candidate teachers have several beliefs related to their knowledge, learning and teaching. The purpose of this study is to analyze the beliefs of candidate teachers about knowledge, learning and teaching. Candidate teachers were assigned a scale and from the answers "belief points" were obtained based on their attitudes about these three…

  13. Early developability screen of therapeutic antibody candidates using Taylor dispersion analysis and UV area imaging detection.

    PubMed

    Lavoisier, Alexandra; Schlaeppi, Jean-Marc

    2015-01-01

    Therapeutic antibodies represent one of the fastest growing segments in the pharmaceutical market. They are used in a broad range of disease fields, such as autoimmune diseases, cancer, inflammation and infectious diseases. The growth of the segment has necessitated development of new analytical platforms for faster and better antibody selection and characterization. Early quality control and risk assessment of biophysical parameters help prevent failure in later stages of antibody development, and thus can reduce costs and save time. Critical parameters such as aggregation, conformational stability, colloidal stability and hydrophilicity, are measured during the early phase of antibody generation and guide the selection process of the best lead candidates in terms of technical developability. We report on the use of a novel instrument (ActiPix/Viscosizer) for measuring both the hydrodynamic radius and the absolute viscosity of antibodies based on Taylor dispersion analysis and UV area imaging. The looped microcapillary-based method combines low sample consumption, fast throughput and high precision compared to other conventional methods. From a random panel of 130 antibodies in the early selection process, we identified some with large hydrodynamic radius outside the normal distribution and others with non-Gaussian Taylor dispersion profiles. The antibodies with such abnormal properties were confirmed later in the selection process to show poor developability profiles. Moreover, combining these results with those of the viscosity measurements at high antibody concentrations allows screening, with limited amounts of materials, candidates with potential issues in pre-formulation development. PMID:25514497

  14. Comparative analysis of SNP candidates in disparate milk yielding river buffaloes using targeted sequencing

    PubMed Central

    2016-01-01

    River buffalo (Bubalus bubalis) milk plays an important role in economy and nutritious diet in several developing countries. However, reliable milk-yield genomic markers and their functional insights remain unexposed. Here, we have used a target capture sequencing approach in three economically important buffalo breeds namely: Banni, Jafrabadi and Mehsani, belonging to either high or low milk-yield group. Blood samples were collected from the milk-yield/breed balanced group of 12 buffaloes, and whole exome sequencing was performed using Roche 454 GS-FLX Titanium sequencer. Using an innovative approach namely, MultiCom; we have identified high-quality SNPs specific for high and low-milk yield buffaloes. Almost 70% of the reported genes in QTL regions of milk-yield and milk-fat in cattle were present among the buffalo milk-yield gene candidates. Functional analysis highlighted transcriptional regulation category in the low milk-yield group, and several new pathways in the two groups. Further, the discovered SNP candidates may account for more than half of mammary transcriptome changes in high versus low-milk yielding cattle. Thus, starting from the design of a reliable strategy, we identified reliable genomic markers specific for high and low-milk yield buffalo breeds and addressed possible downstream effects. PMID:27441113

  15. Comparative analysis of epitope predictions: proposed library of putative vaccine candidates for HIV.

    PubMed

    Gupta, Arun; Chaukiker, Dinesh; Singh, Tiratha Raj

    2011-01-01

    Designing a vaccine for a disease is one of the crucial tasks that involve millions and billions of dollars, several decades and yet there is no guarantee of successful results. Several pharmaceutical companies are investing their money and time in such activities. Computational biology could be of great help in these activities by proving a library of plausible candidates that might actually show some positive responses. MHC binding peptide prediction is one such area where the immense power of computers could be used to get a breakthrough. In this direction several databases and servers have been developed by many labs to predict the MHC binding peptides. These short peptides on the antigen surface are recognized by the MHC molecule and are presented to the receptors of T-cells for further immune response. Peptides that bind to a given MHC molecule share sequence similarity. Here we present a comparative study of servers that can predict the MHC binding peptides in a given protein sequence of the antigen. Based on this comparative analysis on HIV data, we are able to propose a library of putative vaccine candidates for the env GP-160 protein of HIV-1. PMID:21383906

  16. Single-cell analysis reveals a novel uncultivated magnetotactic bacterium within the candidate division OP3.

    PubMed

    Kolinko, Sebastian; Jogler, Christian; Katzmann, Emanuel; Wanner, Gerhard; Peplies, Jörg; Schüler, Dirk

    2012-07-01

    Magnetotactic bacteria (MTB) are a diverse group of prokaryotes that orient along magnetic fields using membrane-coated magnetic nanocrystals of magnetite (Fe(3) O(4) ) or greigite (Fe(3) S(4) ), the magnetosomes. Previous phylogenetic analysis of MTB has been limited to few cultivated species and most abundant members of natural populations, which were assigned to Proteobacteria and the Nitrospirae phyla. Here, we describe a single cell-based approach that allowed the targeted phylogenetic and ultrastructural analysis of the magnetotactic bacterium SKK-01, which was low abundant in sediments of Lake Chiemsee. Morphologically conspicuous single cells of SKK-01 were micromanipulated from magnetically collected multi-species MTB populations, which was followed by whole genome amplification and ultrastructural analysis of sorted cells. Besides intracellular sulphur inclusions, the large ovoid cells of SKK-01 harbour ∼175 bullet-shaped magnetosomes arranged in multiple chains that consist of magnetite as revealed by TEM and EDX analysis. Sequence analysis of 16 and 23S rRNA genes from amplified genomic DNA as well as fluorescence in situ hybridization assigned SKK-01 to the candidate division OP3, which so far lacks any cultivated representatives. SKK-01 represents the first morphotype that can be assigned to the OP3 group as well as the first magnetotactic member of the PVC superphylum. PMID:22003954

  17. Academic performance of ethnic minority candidates and discrimination in the MRCGP examinations between 2010 and 2012: analysis of data

    PubMed Central

    Roberts, Chris

    2013-01-01

    Objective To determine the difference in failure rates in the postgraduate examination of the Royal College of General Practitioners (MRCGP) by ethnic or national background, and to identify factors associated with pass rates in the clinical skills assessment component of the examination. Design Analysis of data provided by the Royal College of General Practitioners and the General Medical Council. Participants Cohort of 5095 candidates sitting the applied knowledge test and clinical skills assessment components of the MRCGP examination between November 2010 and November 2012. A further analysis was carried out on 1175 candidates not trained in the United Kingdom, who sat an English language capability test (IELTS) and the Professional and Linguistic Assessment Board (PLAB) examination (as required for full medical registration), controlling for scores on these examinations and relating them to pass rates of the clinical skills assessment. Setting United Kingdom. Results After controlling for age, sex, and performance in the applied knowledge test, significant differences persisted between white UK graduates and other candidate groups. Black and minority ethnic graduates trained in the UK were more likely to fail the clinical skills assessment at their first attempt than their white UK colleagues (odds ratio 3.536 (95% confidence interval 2.701 to 4.629), P<0.001; failure rate 17% v 4.5%). Black and minority ethnic candidates who trained abroad were also more likely to fail the clinical skills assessment than white UK candidates (14.741 (11.397 to 19.065), P<0.001; 65% v 4.5%). For candidates not trained in the UK, black or minority ethnic candidates were more likely to fail than white candidates, but this difference was no longer significant after controlling for scores in the applied knowledge test, IELTS, and PLAB examinations (adjusted odds ratio 1.580 (95% confidence interval 0.878 to 2.845), P=0.127). Conclusions Subjective bias due to racial discrimination

  18. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients.

    PubMed

    Sadovnick, A Dessa; Traboulsee, Anthony L; Bernales, Cecily Q; Ross, Jay P; Forwell, Amanda L; Yee, Irene M; Guillot-Noel, Lena; Fontaine, Bertrand; Cournu-Rebeix, Isabelle; Alcina, Antonio; Fedetz, Maria; Izquierdo, Guillermo; Matesanz, Fuencisla; Hilven, Kelly; Dubois, Bénédicte; Goris, An; Astobiza, Ianire; Alloza, Iraide; Antigüedad, Alfredo; Vandenbroeck, Koen; Akkad, Denis A; Aktas, Orhan; Blaschke, Paul; Buttmann, Mathias; Chan, Andrew; Epplen, Joerg T; Gerdes, Lisa-Ann; Kroner, Antje; Kubisch, Christian; Kümpfel, Tania; Lohse, Peter; Rieckmann, Peter; Zettl, Uwe K; Zipp, Frauke; Bertram, Lars; Lill, Christina M; Fernandez, Oscar; Urbaneja, Patricia; Leyva, Laura; Alvarez-Cermeño, Jose Carlos; Arroyo, Rafael; Garagorri, Aroa M; García-Martínez, Angel; Villar, Luisa M; Urcelay, Elena; Malhotra, Sunny; Montalban, Xavier; Comabella, Manuel; Berger, Thomas; Fazekas, Franz; Reindl, Markus; Schmied, Mascha C; Zimprich, Alexander; Vilariño-Güell, Carles

    2016-01-01

    Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93-1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility. PMID:27194806

  19. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients

    PubMed Central

    Sadovnick, A. Dessa; Traboulsee, Anthony L.; Bernales, Cecily Q.; Ross, Jay P.; Forwell, Amanda L.; Yee, Irene M.; Guillot-Noel, Lena; Fontaine, Bertrand; Cournu-Rebeix, Isabelle; Alcina, Antonio; Fedetz, Maria; Izquierdo, Guillermo; Matesanz, Fuencisla; Hilven, Kelly; Dubois, Bénédicte; Goris, An; Astobiza, Ianire; Alloza, Iraide; Antigüedad, Alfredo; Vandenbroeck, Koen; Akkad, Denis A.; Aktas, Orhan; Blaschke, Paul; Buttmann, Mathias; Chan, Andrew; Epplen, Joerg T.; Gerdes, Lisa-Ann; Kroner, Antje; Kubisch, Christian; Kümpfel, Tania; Lohse, Peter; Rieckmann, Peter; Zettl, Uwe K.; Zipp, Frauke; Bertram, Lars; Lill, Christina M; Fernandez, Oscar; Urbaneja, Patricia; Leyva, Laura; Alvarez-Cermeño, Jose Carlos; Arroyo, Rafael; Garagorri, Aroa M.; García-Martínez, Angel; Villar, Luisa M.; Urcelay, Elena; Malhotra, Sunny; Montalban, Xavier; Comabella, Manuel; Berger, Thomas; Fazekas, Franz; Reindl, Markus; Schmied, Mascha C.; Zimprich, Alexander; Vilariño-Güell, Carles

    2016-01-01

    Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility. PMID:27194806

  20. Genetic analysis of abdominal aortic aneurysms (AAA)

    SciTech Connect

    St. Jean, P.L.; Hart, B.K.; Zhang, X.C.

    1994-09-01

    The association between AAA and gender, smoking (SM), hypertension (HTN) and inguinal herniation (IH) was examined in 141 AAA probands and 139 of their 1st degree relatives with aortic exam (36 affected, 103 unaffected). There was no significant difference between age at diagnosis of affecteds and age at exam of unaffecteds. Of 181 males, 142 had AAA; of 99 females, 35 had AAA. Using log-linear modeling AAA was significantly associated at the 5% level with gender, SM and HTN but not IH. The association of AAA with SM and HTN held when males and females were analyzed separately. HTN was -1.5 times more common in both affected males and females, while SM was 1.5 and 2 times more common in affected males and females, respectively. Tests of association and linkage analyses were performed with relevant candidate genes: 3 COL3A1 polymorphisms (C/T, ALA/THR, AvaII), 2 ELN polymorphisms (SER/GLY, (CA)n), FBN1(TAAA)n, 2 APOB polymorphisms (Xbal,Ins/Del), CLB4B (CA)n, PI and markers D1S243 (CA)n, HPR (CA)n and MFD23(CA)n. The loci were genotyped in > 100 AAA probands and > 95 normal controls. No statistically significant evidence of association at the 5% level was obtained for any of the loci using chi-square test of association. 28 families with 2 or more affecteds were analyzed using the affected pedigree member method (APM) and lod-score analyses. There was no evidence for linkage with any loci using APM. Lod-score analysis under an autosomal recessive model resulted in excluding linkage (lod score < -2) of all loci to AAA at {theta}=0.0. Under an autosomal dominant model, linkage was excluded at {theta}=0.0 to ELN, APOB, CLG4B, D1S243, HPR and MFD23. The various genes previously proposed in AAA pathogenesis are neither associated nor casually related in our study population.

  1. Accelerator-Based PIXE and STIM Analysis of Candidate Solar Sail Materials

    SciTech Connect

    Hollerman, W.A.; Stanaland, T.L.; Boudreaux, P.; Elberson, L.; Fontenot, J.; Gates, E.; Greco, R.; McBride, M.; Woodward, A.; Edwards, D.

    2003-08-26

    Solar sailing is a unique form of propulsion where a spacecraft gains momentum from incident photons. A totally reflective sail experiences a pressure of 9.1 {mu}Pa at a distance of 1 AU from the Sun. Since sails are not limited by reaction mass, they provide continual acceleration, reduced only by the lifetime of the lightweight film in the space environment and the distance to the Sun. Practical solar sails can expand the number of possible missions, enabling new concepts that are difficult by conventional means. One of the current challenges is to develop strong, lightweight, and radiation resistant sail materials. This paper will discuss initial results from a Particle Induced X-Ray Emission (PIXE) and Scanning Transmission Ion Microscopy (STIM) analysis of candidate solar sail materials.

  2. Genetic algorithms and supernovae type Ia analysis

    SciTech Connect

    Bogdanos, Charalampos; Nesseris, Savvas E-mail: nesseris@nbi.dk

    2009-05-15

    We introduce genetic algorithms as a means to analyze supernovae type Ia data and extract model-independent constraints on the evolution of the Dark Energy equation of state w(z) {identical_to} P{sub DE}/{rho}{sub DE}. Specifically, we will give a brief introduction to the genetic algorithms along with some simple examples to illustrate their advantages and finally we will apply them to the supernovae type Ia data. We find that genetic algorithms can lead to results in line with already established parametric and non-parametric reconstruction methods and could be used as a complementary way of treating SNIa data. As a non-parametric method, genetic algorithms provide a model-independent way to analyze data and can minimize bias due to premature choice of a dark energy model.

  3. Antimicrobial Protein Candidates from the Thermophilic Geobacillus sp. Strain ZGt-1: Production, Proteomics, and Bioinformatics Analysis

    PubMed Central

    Alkhalili, Rawana N.; Bernfur, Katja; Dishisha, Tarek; Mamo, Gashaw; Schelin, Jenny; Canbäck, Björn; Emanuelsson, Cecilia; Hatti-Kaul, Rajni

    2016-01-01

    A thermophilic bacterial strain, Geobacillus sp. ZGt-1, isolated from Zara hot spring in Jordan, was capable of inhibiting the growth of the thermophilic G. stearothermophilus and the mesophilic Bacillus subtilis and Salmonella typhimurium on a solid cultivation medium. Antibacterial activity was not observed when ZGt-1 was cultivated in a liquid medium; however, immobilization of the cells in agar beads that were subjected to sequential batch cultivation in the liquid medium at 60 °C showed increasing antibacterial activity up to 14 cycles. The antibacterial activity was lost on protease treatment of the culture supernatant. Concentration of the protein fraction by ammonium sulphate precipitation followed by denaturing polyacrylamide gel electrophoresis separation and analysis of the gel for antibacterial activity against G. stearothermophilus showed a distinct inhibition zone in 15–20 kDa range, suggesting that the active molecule(s) are resistant to denaturation by SDS. Mass spectrometric analysis of the protein bands around the active region resulted in identification of 22 proteins with molecular weight in the range of interest, three of which were new and are here proposed as potential antimicrobial protein candidates by in silico analysis of their amino acid sequences. Mass spectrometric analysis also indicated the presence of partial sequences of antimicrobial enzymes, amidase and dd-carboxypeptidase. PMID:27548162

  4. Homogeneity study of a corn flour laboratory reference material candidate for inorganic analysis.

    PubMed

    Dos Santos, Ana Maria Pinto; Dos Santos, Liz Oliveira; Brandao, Geovani Cardoso; Leao, Danilo Junqueira; Bernedo, Alfredo Victor Bellido; Lopes, Ricardo Tadeu; Lemos, Valfredo Azevedo

    2015-07-01

    In this work, a homogeneity study of a corn flour reference material candidate for inorganic analysis is presented. Seven kilograms of corn flour were used to prepare the material, which was distributed among 100 bottles. The elements Ca, K, Mg, P, Zn, Cu, Fe, Mn and Mo were quantified by inductively coupled plasma optical emission spectrometry (ICP OES) after acid digestion procedure. The method accuracy was confirmed by analyzing the rice flour certified reference material, NIST 1568a. All results were evaluated by analysis of variance (ANOVA) and principal component analysis (PCA). In the study, a sample mass of 400mg was established as the minimum mass required for analysis, according to the PCA. The between-bottle test was performed by analyzing 9 bottles of the material. Subsamples of a single bottle were analyzed for the within-bottle test. No significant differences were observed for the results obtained through the application of both statistical methods. This fact demonstrates that the material is homogeneous for use as a laboratory reference material. PMID:25704713

  5. Antimicrobial Protein Candidates from the Thermophilic Geobacillus sp. Strain ZGt-1: Production, Proteomics, and Bioinformatics Analysis.

    PubMed

    Alkhalili, Rawana N; Bernfur, Katja; Dishisha, Tarek; Mamo, Gashaw; Schelin, Jenny; Canbäck, Björn; Emanuelsson, Cecilia; Hatti-Kaul, Rajni

    2016-01-01

    A thermophilic bacterial strain, Geobacillus sp. ZGt-1, isolated from Zara hot spring in Jordan, was capable of inhibiting the growth of the thermophilic G. stearothermophilus and the mesophilic Bacillus subtilis and Salmonella typhimurium on a solid cultivation medium. Antibacterial activity was not observed when ZGt-1 was cultivated in a liquid medium; however, immobilization of the cells in agar beads that were subjected to sequential batch cultivation in the liquid medium at 60 °C showed increasing antibacterial activity up to 14 cycles. The antibacterial activity was lost on protease treatment of the culture supernatant. Concentration of the protein fraction by ammonium sulphate precipitation followed by denaturing polyacrylamide gel electrophoresis separation and analysis of the gel for antibacterial activity against G. stearothermophilus showed a distinct inhibition zone in 15-20 kDa range, suggesting that the active molecule(s) are resistant to denaturation by SDS. Mass spectrometric analysis of the protein bands around the active region resulted in identification of 22 proteins with molecular weight in the range of interest, three of which were new and are here proposed as potential antimicrobial protein candidates by in silico analysis of their amino acid sequences. Mass spectrometric analysis also indicated the presence of partial sequences of antimicrobial enzymes, amidase, and dd-carboxypeptidase. PMID:27548162

  6. Genetic Risk Score Modelling for Disease Progression in New-Onset Type 1 Diabetes Patients: Increased Genetic Load of Islet-Expressed and Cytokine-Regulated Candidate Genes Predicts Poorer Glycemic Control.

    PubMed

    Brorsson, Caroline A; Nielsen, Lotte B; Andersen, Marie Louise; Kaur, Simranjeet; Bergholdt, Regine; Hansen, Lars; Mortensen, Henrik B; Pociot, Flemming; Størling, Joachim

    2016-01-01

    Genome-wide association studies (GWAS) have identified over 40 type 1 diabetes risk loci. The clinical impact of these loci on β-cell function during disease progression is unknown. We aimed at testing whether a genetic risk score could predict glycemic control and residual β-cell function in type 1 diabetes (T1D). As gene expression may represent an intermediate phenotype between genetic variation and disease, we hypothesized that genes within T1D loci which are expressed in islets and transcriptionally regulated by proinflammatory cytokines would be the best predictors of disease progression. Two-thirds of 46 GWAS candidate genes examined were expressed in human islets, and 11 of these significantly changed expression levels following exposure to proinflammatory cytokines (IL-1β + IFNγ + TNFα) for 48 h. Using the GWAS single nucleotide polymorphisms (SNPs) from each locus, we constructed a genetic risk score based on the cumulative number of risk alleles carried in children with newly diagnosed T1D. With each additional risk allele carried, HbA1c levels increased significantly within first year after diagnosis. Network and gene ontology (GO) analyses revealed that several of the 11 candidate genes have overlapping biological functions and interact in a common network. Our results may help predict disease progression in newly diagnosed children with T1D which can be exploited for optimizing treatment. PMID:26904692

  7. A storied-identity analysis approach to teacher candidates learning to teach in an urban setting

    NASA Astrophysics Data System (ADS)

    Ibourk, Amal

    highlighted his struggle with navigating talkativeness in the class, but also his struggle being an authority figure in his classroom. At present, only Becky and Ashley pursued teaching in a high needs setting. A storied identity analysis provided as well an insight into their storied strategies, or the teaching strategies shaped by the stories the interns told about how they made sense of the challenges they faced in their teaching practice. There were five teaching strategies the interns named that were important in supporting their learning to teach were (1) building relationships with their students, (2) being resourceful and creative when faced with limited lab materials, (3) making science relevant to their students, (4) scaffolding their students in their learning, and (5) having a network of people as resources in helping them be better teachers and helping their students learn. Out of these five teaching strategies, I called those they named and highlighted as helping them teach in ways they valued and that connected back to their storied identity of science learning their storied strategies. Implications for further pushing storied identities as a tool for teacher educators to help pinpoint priorities that surface in teacher candidates' practice are discussed. An insight into the priorities that teacher candidates highlight in their practice as well as the storied strategies they name and use to deal with challenges that surface in their practice has potential in better helping teacher candidates navigate their developing practice.

  8. Heritability and genetic association analysis of cognition in the Diabetes Heart Study.

    PubMed

    Cox, Amanda J; Hugenschmidt, Christina E; Raffield, Laura M; Langefeld, Carl D; Freedman, Barry I; Williamson, Jeff D; Hsu, Fang-Chi; Bowden, Donald W

    2014-08-01

    Cognitive performance is an important component of healthy aging. Type 2 diabetes (T2D) is associated with negative outcomes for the brain and cognition, although causal mechanisms have not been definitely determined. Genetic risk factors warrant further consideration in this context. This study examined the heritability of cognitive function as assessed by (1) the Digit Symbol Substitution Task; (2) the Modified Mini-Mental State Examination; (3) the Stroop Task; (4) the Rey Auditory-Verbal Learning Task; and (5) the Controlled Oral Word Association Task for Phonemic and Semantic Fluency, in the family-based, T2D-enriched, Diabetes Heart Study sample (n = 550 participants from 257 families). The genetic basis of these cognitive measures was further evaluated by association analysis with candidate single-nucleotide polymorphisms (SNPs) and genome-wide SNP data. Measures of cognitive function were significantly heritable (hˆ(2) = 0.28-0.62) following adjustment for age, gender, and education. A total of 31 SNPs (from 26 genes/regions) selected to form an a priori set of candidate SNPs showed limited evidence of association with cognitive function when applying conservative metrics of significance. Genome-wide assessment of both noncoding and coding variants revealed suggestive evidence of association for several coding variants including rs139509083 in CNST (p = 4.9 × 10(-9)), rs199968569 in PLAA (p = 4.9 × 10(-9)) and rs138487371 in PCDH8 (p = 3.7 × 10(-8)). The identification of a heritable component to cognitive performance in T2D suggests a role for genetic contributors to cognitive performance even in the presence of metabolic disease and other associated comorbidities and is supported by the identification of genetic association signals in functionally plausible candidates. PMID:24684796

  9. Molecular genetic analysis of Down syndrome.

    PubMed

    Patterson, David

    2009-07-01

    Down syndrome (DS) is caused by trisomy of all or part of human chromosome 21 (HSA21) and is the most common genetic cause of significant intellectual disability. In addition to intellectual disability, many other health problems, such as congenital heart disease, Alzheimer's disease, leukemia, hypotonia, motor disorders, and various physical anomalies occur at an elevated frequency in people with DS. On the other hand, people with DS seem to be at a decreased risk of certain cancers and perhaps of atherosclerosis. There is wide variability in the phenotypes associated with DS. Although ultimately the phenotypes of DS must be due to trisomy of HSA21, the genetic mechanisms by which the phenotypes arise are not understood. The recent recognition that there are many genetically active elements that do not encode proteins makes the situation more complex. Additional complexity may exist due to possible epigenetic changes that may act differently in DS. Numerous mouse models with features reminiscent of those seen in individuals with DS have been produced and studied in some depth, and these have added considerable insight into possible genetic mechanisms behind some of the phenotypes. These mouse models allow experimental approaches, including attempts at therapy, that are not possible in humans. Progress in understanding the genetic mechanisms by which trisomy of HSA21 leads to DS is the subject of this review. PMID:19526251

  10. Meta-analysis and genome-wide interpretation of genetic susceptibility to drug addiction

    PubMed Central

    2011-01-01

    Background Classical genetic studies provide strong evidence for heritable contributions to susceptibility to developing dependence on addictive substances. Candidate gene and genome-wide association studies (GWAS) have sought genes, chromosomal regions and allelic variants likely to contribute to susceptibility to drug addiction. Results Here, we performed a meta-analysis of addiction candidate gene association studies and GWAS to investigate possible functional mechanisms associated with addiction susceptibility. From meta-data retrieved from 212 publications on candidate gene association studies and 5 GWAS reports, we linked a total of 843 haplotypes to addiction susceptibility. We mapped the SNPs in these haplotypes to functional and regulatory elements in the genome and estimated the magnitude of the contributions of different molecular mechanisms to their effects on addiction susceptibility. In addition to SNPs in coding regions, these data suggest that haplotypes in gene regulatory regions may also contribute to addiction susceptibility. When we compared the lists of genes identified by association studies and those identified by molecular biological studies of drug-regulated genes, we observed significantly higher participation in the same gene interaction networks than expected by chance, despite little overlap between the two gene lists. Conclusions These results appear to offer new insights into the genetic factors underlying drug addiction. PMID:21999673

  11. PLANET HUNTERS: NEW KEPLER PLANET CANDIDATES FROM ANALYSIS OF QUARTER 2

    SciTech Connect

    Lintott, Chris J.; Schwamb, Megan E.; Schwainski, Kevin; and others

    2013-06-15

    We present new planet candidates identified in NASA Kepler Quarter 2 public release data by volunteers engaged in the Planet Hunters citizen science project. The two candidates presented here survive checks for false positives, including examination of the pixel offset to constrain the possibility of a background eclipsing binary. The orbital periods of the planet candidates are 97.46 days (KIC 4552729) and 284.03 (KIC 10005758) days and the modeled planet radii are 5.3 and 3.8 R{sub Circled-Plus }. The latter star has an additional known planet candidate with a radius of 5.05 R{sub Circled-Plus} and a period of 134.49 days, which was detected by the Kepler pipeline. The discovery of these candidates illustrates the value of massively distributed volunteer review of the Kepler database to recover candidates which were otherwise uncataloged.

  12. Quantitative Genetic Analysis of Sleep in Drosophila melanogaster

    PubMed Central

    Harbison, Susan T.; Sehgal, Amita

    2008-01-01

    Although intensively studied, the biological purpose of sleep is not known. To identify candidate genes affecting sleep, we assayed 136 isogenic P-element insertion lines of Drosophila melanogaster. Since sleep has been negatively correlated with energy reserves across taxa, we measured energy stores (whole-body protein, glycogen, and triglycerides) in these lines as well. Twenty-one insertions with known effects on physiology, development, and behavior affect 24-hr sleep time. Thirty-two candidate insertions significantly impact energy stores. Mutational genetic correlations among sleep parameters revealed that the genetic basis of the transition between sleep and waking states in males and females may be different. Furthermore, sleep bout number can be decoupled from waking activity in males, but not in females. Significant genetic correlations are present between sleep phenotypes and glycogen stores in males, while sleep phenotypes are correlated with triglycerides in females. Differences observed in male and female sleep behavior in flies may therefore be related to sex-specific differences in metabolic needs. Sleep thus emerges as a complex trait that exhibits extensive pleiotropy and sex specificity. The large mutational target that we observed implicates genes functioning in a variety of biological processes, suggesting that sleep may serve a number of different functions rather than a single purpose. PMID:18430954

  13. Analysis of swing voter in the Indonesian election of 2014 presidential candidates using Twitter data

    NASA Astrophysics Data System (ADS)

    Alfarisy, Muhammad Salman; Putra, Rizki M.; Liong, The Houw; Purqon, Acep

    2015-09-01

    Ahead of the 2014 elections would be interesting to predict which candidate will hold the highest authority in the Republic of Indonesia. Entering the 2014 presidential election there is no infidelity tendency of voters who initially settled on a party or a candidate then choose another party or candidate in the next election. Changes in the tendency to make the condition of society in a state that has not been to given the choice of a candidate is commonly called swing voters. On this occasion, an examination of the swing voters who use social media twitter. By utilizing the advanced search facility to collect data from the response of tweeps (twitter users) on the twitter to Indonesian presidential candidate. The data will be used to describe how much the popularity of a candidate among tweeps, knowing the candidates who have the largest positive response and negative response, as well as the growing popularity of the candidate. The data is expected to predict the RI presidential candidate in 2014.

  14. Integration of gene-based markers in a pearl millet genetic map for identification of candidate genes underlying drought tolerance quantitative trait loci

    PubMed Central

    2012-01-01

    Background Identification of genes underlying drought tolerance (DT) quantitative trait loci (QTLs) will facilitate understanding of molecular mechanisms of drought tolerance, and also will accelerate genetic improvement of pearl millet through marker-assisted selection. We report a map based on genes with assigned functional roles in plant adaptation to drought and other abiotic stresses and demonstrate its use in identifying candidate genes underlying a major DT-QTL. Results Seventy five single nucleotide polymorphism (SNP) and conserved intron spanning primer (CISP) markers were developed from available expressed sequence tags (ESTs) using four genotypes, H 77/833-2, PRLT 2/89-33, ICMR 01029 and ICMR 01004, representing parents of two mapping populations. A total of 228 SNPs were obtained from 30.5 kb sequenced region resulting in a SNP frequency of 1/134 bp. The positions of major pearl millet linkage group (LG) 2 DT-QTLs (reported from crosses H 77/833-2 × PRLT 2/89-33 and 841B × 863B) were added to the present consensus function map which identified 18 genes, coding for PSI reaction center subunit III, PHYC, actin, alanine glyoxylate aminotransferase, uridylate kinase, acyl-CoA oxidase, dipeptidyl peptidase IV, MADS-box, serine/threonine protein kinase, ubiquitin conjugating enzyme, zinc finger C- × 8-C × 5-C × 3-H type, Hd3, acetyl CoA carboxylase, chlorophyll a/b binding protein, photolyase, protein phosphatase1 regulatory subunit SDS22 and two hypothetical proteins, co-mapping in this DT-QTL interval. Many of these candidate genes were found to have significant association with QTLs of grain yield, flowering time and leaf rolling under drought stress conditions. Conclusions We have exploited available pearl millet EST sequences to generate a mapped resource of seventy five new gene-based markers for pearl millet and demonstrated its use in identifying candidate genes underlying a major DT-QTL in this species. The reported gene-based markers represent

  15. Identification of Candidate Adherent-Invasive E. coli Signature Transcripts by Genomic/Transcriptomic Analysis

    PubMed Central

    Zhang, Yuanhao; Rowehl, Leahana; Krumsiek, Julia M.; Orner, Erika P.; Shaikh, Nurmohammad; Tarr, Phillip I.; Sodergren, Erica; Weinstock, George M.; Boedeker, Edgar C.; Xiong, Xuejian; Parkinson, John; Frank, Daniel N.; Li, Ellen; Gathungu, Grace

    2015-01-01

    Adherent-invasive Escherichia coli (AIEC) strains are detected more frequently within mucosal lesions of patients with Crohn’s disease (CD). The AIEC phenotype consists of adherence and invasion of intestinal epithelial cells and survival within macrophages of these bacteria in vitro. Our aim was to identify candidate transcripts that distinguish AIEC from non-invasive E. coli (NIEC) strains and might be useful for rapid and accurate identification of AIEC by culture-independent technology. We performed comparative RNA-Sequence (RNASeq) analysis using AIEC strain LF82 and NIEC strain HS during exponential and stationary growth. Differential expression analysis of coding sequences (CDS) homologous to both strains demonstrated 224 and 241 genes with increased and decreased expression, respectively, in LF82 relative to HS. Transition metal transport and siderophore metabolism related pathway genes were up-regulated, while glycogen metabolic and oxidation-reduction related pathway genes were down-regulated, in LF82. Chemotaxis related transcripts were up-regulated in LF82 during the exponential phase, but flagellum-dependent motility pathway genes were down-regulated in LF82 during the stationary phase. CDS that mapped only to the LF82 genome accounted for 747 genes. We applied an in silico subtractive genomics approach to identify CDS specific to AIEC by incorporating the genomes of 10 other previously phenotyped NIEC. From this analysis, 166 CDS mapped to the LF82 genome and lacked homology to any of the 11 human NIEC strains. We compared these CDS across 13 AIEC, but none were homologous in each. Four LF82 gene loci belonging to clustered regularly interspaced short palindromic repeats region (CRISPR)—CRISPR-associated (Cas) genes were identified in 4 to 6 AIEC and absent from all non-pathogenic bacteria. As previously reported, AIEC strains were enriched for pdu operon genes. One CDS, encoding an excisionase, was shared by 9 AIEC strains. Reverse transcription

  16. [Genetic background in common forms of obesity - from studies on identical twins to candidate genes of obesity].

    PubMed

    Bendlová, Běla; Lukášová, Petra; Vaňková, Markéta; Vejražková, Daniela; Bradnová, Olga; Včelák, Josef; Stanická, Soňa; Zamrazilová, Hana; Aldhoon-Hainerová, Irena; Dušátková, Lenka; Kunešová, Marie; Hainer, Vojtěch

    2014-01-01

    Common obesity is a result of interaction between genes and environmental/lifestyle factors, with heritability estimates 40-70%. Not only the susceptibility to obesity but also the success of weight management depends on the genetic background of each individual. This paper summarizes the up-to-date knowledge on genetic causes of common obesities. Introduction of genome-wide association studies (GWAS) led to an identification of a total of 32 variants associated with obesity/BMI and 14 with body fat distribution. Further, a great progress in revealing the mechanisms regulating the energy balance was also noted. However, the proportion of explained variance for BMI is still low, suggesting other mechanisms such as gene-gene and gene-environment interactions, rare gene variants, copy number variants polymorphisms, or epigenetic modifications and microRNAs regulating gene transcription. In summary, we present results of our studies on obesity risk variants in Czech adults, children and adolescents including those evaluating the influence of selected gene variants on the outcomes of weight management. PMID:25199545

  17. Development of a full-length cDNA-derived enterovirus A71 vaccine candidate using reverse genetics technology.

    PubMed

    Yang, Ya-Ting; Chow, Yen-Hung; Hsiao, Kuang-Nan; Hu, Kai-Chieh; Chiang, Jen-Ron; Wu, Suh-Chin; Chong, Pele; Liu, Chia-Chyi

    2016-08-01

    Enterovirus A71 (EV-A71) is responsible for epidemics of hand, foot and mouth disease (HFMD) in young children. To circumvent difficulties in obtaining clinical enterovirus isolates that might be contaminated with other viruses, a platform technology was developed to quickly generate vaccine virus strains based on the published enterovirus genomic sequences. A recombinant plasmid containing the full-length infectious cDNA clone of EV-A71 vaccine strain E59 was directly generated after transfecting the recombinant plasmid into Vero, RD or HEK293A cells, and phenotypic characteristics similar to the parental strain were observed. The cDNA-derived infectious EV-A71 virus grown in Vero cells produced relatively stable virus titers in both T-flasks and microcarrier culture systems. To evaluate the genetic stability of the cDNA-derived EV-A71 viruses, the immunodominant structural proteins, VP1 and VP2, of the recombinant EV-A71 viruses were sequenced and analyzed. The cDNA-derived EV-A71 virus showed weak pathogenicity in a human SCARB2 mouse model. These results show the successful generation of a recombinant virus derived from a published viral genomic sequence that demonstrated good genetic stability and viral yields, which could represent an efficient and safe vaccine strain for cGMP-grade manufacturing. PMID:27387826

  18. The CarbonSat Earth Explorer 8 candidate mission: Error analysis for carbon dioxide and methane

    NASA Astrophysics Data System (ADS)

    Buchwitz, Michael; Bovensmann, Heinrich; Reuter, Maximilian; Gerilowski, Konstantin; Meijer, Yasjka; Sierk, Bernd; Caron, Jerome; Loescher, Armin; Ingmann, Paul; Burrows, John P.

    2015-04-01

    CarbonSat is one of two candidate missions for ESA's Earth Explorer 8 (EE8) satellite to be launched around 2022. The main goal of CarbonSat is to advance our knowledge on the natural and man-made sources and sinks of the two most important anthropogenic greenhouse gases (GHGs) carbon dioxide (CO2) and methane (CH4) on various temporal and spatial scales (e.g., regional, city and point source scale), as well as related climate feedbacks. CarbonSat will be the first satellite mission optimised to detect emission hot spots of CO2 (e.g., cities, industrialised areas, power plants) and CH4 (e.g., oil and gas fields) and to quantify their emissions. Furthermore, CarbonSat will deliver a number of important by-products such as Vegetation Chlorophyll Fluorescence (VCF, also called Solar Induced Fluorescence (SIF)) at 755 nm. These applications require appropriate retrieval algorithms which are currently being optimized and used for error analysis. The status of this error analysis will be presented based on the latest version of the CO2 and CH4 retrieval algorithm and taking the current instrument specification into account. An overview will be presented focusing on nadir observations over land. Focus will be on specific issues such as errors of the CO2 and CH4 products due to residual polarization related errors and errors related to inhomogeneous ground scenes.

  19. Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes.

    PubMed

    Tucker, Tracy; Zahir, Farah R; Griffith, Malachi; Delaney, Allen; Chai, David; Tsang, Erica; Lemyre, Emmanuelle; Dobrzeniecka, Sylvia; Marra, Marco; Eydoux, Patrice; Langlois, Sylvie; Hamdan, Fadi F; Michaud, Jacques L; Friedman, Jan M

    2014-06-01

    Intellectual disability affects about 3% of individuals globally, with∼50% idiopathic. We designed an exonic-resolution array targeting all known submicroscopic chromosomal intellectual disability syndrome loci, causative genes for intellectual disability, and potential candidate genes, all genes encoding glutamate receptors and epigenetic regulators. Using this platform, we performed chromosomal microarray analysis on 165 intellectual disability trios (affected child and both normal parents). We identified and independently validated 36 de novo copy-number changes in 32 trios. In all, 67% of the validated events were intragenic, involving only exon 1 (which includes the promoter sequence according to our design), exon 1 and adjacent exons, or one or more exons excluding exon 1. Seventeen of the 36 copy-number variants involve genes known to cause intellectual disability. Eleven of these, including seven intragenic variants, are clearly pathogenic (involving STXBP1, SHANK3 (3 patients), IL1RAPL1, UBE2A, NRXN1, MEF2C, CHD7, 15q24 and 9p24 microdeletion), two are likely pathogenic (PI4KA, DCX), two are unlikely to be pathogenic (GRIK2, FREM2), and two are unclear (ARID1B, 15q22 microdeletion). Twelve individuals with genomic imbalances identified by our array were tested with a clinical microarray, and six had a normal result. We identified de novo copy-number variants within genes not previously implicated in intellectual disability and uncovered pathogenic variation of known intellectual disability genes below the detection limit of standard clinical diagnostic chromosomal microarray analysis. PMID:24253858

  20. Cloning and sequence analysis of candidate human natural killer-enhancing factor genes

    SciTech Connect

    Shau, H.; Butterfield, L.H.; Chiu, R.; Kim, A.

    1994-12-31

    A cytosol factor from human red blood cells enhances natural killer (NK) activity. This factor, termed NK-enhancing factor (NKEF), is a protein of 44000 M{sub r} consisting of two subunits of equal size linked by disulfide bonds. NKEF is expressed in the NK-sensitive erythroleukemic cell line K562. Using an antibody specific for NKEF as a probe for immunoblot screening, we isolated several clones from a {lambda}gt11 cDNA library of K562. Additional subcloning and sequencing revealed that the candidate NKEF cDNAs fell into one of two categories of closely related but non-identical genes, referred to as NKEF A and B. They are 88% identical in amino acid sequence and 71% identical in nucleotide sequence. Southern blot analysis suggests that there are two to three NKEF family members in the genome. Analysis of predicted amino acid sequences indicates that both NKEF A and B are cytosol proteins with several phosphorylation sites each, but that they have no glycosylation sites. They are significantly homologous to several other proteins from a wide variety of organisms ranging from prokaryotes to mammals, especially with regard to several well-conserved motifs within the amino acid sequences. The biological functions of these proteins in other species are mostly unknown, but some of them were reported to be induced by oxidative stress. Therefore, as well as for immunoregulation of NK activity, NKEF may be important for cells in coping with oxidative insults. 32 refs., 3 figs.

  1. Genetic Analysis of Human Preimplantation Embryos.

    PubMed

    Garcia-Herrero, S; Cervero, A; Mateu, E; Mir, P; Póo, M E; Rodrigo, L; Vera, M; Rubio, C

    2016-01-01

    Preimplantation development comprises the initial stages of mammalian development, before the embryo implants into the mother's uterus. In normal conditions, after fertilization the embryo grows until reaching blastocyst stage. The blastocyst grows as the cells divide and the cavity expands, until it arrives at the uterus, where it "hatches" from the zona pellucida to implant into the uterine wall. Nevertheless, embryo quality and viability can be affected by chromosomal abnormalities, most of which occur during gametogenesis and early embryo development; human embryos produced in vitro are especially vulnerable. Therefore, the selection of chromosomally normal embryos for transfer in assisted reproduction can improve outcomes in poor-prognosis patients. Additionally, in couples with an inherited disorder, early diagnosis could prevent pregnancy with an affected child and would, thereby, avoid the therapeutic interruption of pregnancy. These concerns have prompted advancements in the use of preimplantation genetic diagnosis (PGD). Genetic testing is applied in two different scenarios: in couples with an inherited genetic disorder or carriers of a structural chromosomal abnormality, it is termed PGD; in infertile couples with increased risk of generating embryos with de novo chromosome abnormalities, it is termed preimplantation genetic screening, or PGS. PMID:27475859

  2. Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains.

    PubMed

    Bennett, Brian J; Davis, Richard C; Civelek, Mete; Orozco, Luz; Wu, Judy; Qi, Hannah; Pan, Calvin; Packard, René R Sevag; Eskin, Eleazar; Yan, Mujing; Kirchgessner, Todd; Wang, Zeneng; Li, Xinmin; Gregory, Jill C; Hazen, Stanley L; Gargalovic, Peter S; Lusis, Aldons J

    2015-12-01

    Common forms of atherosclerosis involve multiple genetic and environmental factors. While human genome-wide association studies have identified numerous loci contributing to coronary artery disease and its risk factors, these studies are unable to control environmental factors or examine detailed molecular traits in relevant tissues. We now report a study of natural variations contributing to atherosclerosis and related traits in over 100 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP). The mice were made hyperlipidemic by transgenic expression of human apolipoprotein E-Leiden (APOE-Leiden) and human cholesteryl ester transfer protein (CETP). The mice were examined for lesion size and morphology as well as plasma lipid, insulin and glucose levels, and blood cell profiles. A subset of mice was studied for plasma levels of metabolites and cytokines. We also measured global transcript levels in aorta and liver. Finally, the uptake of acetylated LDL by macrophages from HMDP mice was quantitatively examined. Loci contributing to the traits were mapped using association analysis, and relationships among traits were examined using correlation and statistical modeling. A number of conclusions emerged. First, relationships among atherosclerosis and the risk factors in mice resemble those found in humans. Second, a number of trait-loci were identified, including some overlapping with previous human and mouse studies. Third, gene expression data enabled enrichment analysis of pathways contributing to atherosclerosis and prioritization of candidate genes at associated loci in both mice and humans. Fourth, the data provided a number of mechanistic inferences; for example, we detected no association between macrophage uptake of acetylated LDL and atherosclerosis. Fifth, broad sense heritability for atherosclerosis was much larger than narrow sense heritability, indicating an important role for gene-by-gene interactions. Sixth, stepwise linear regression

  3. Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains

    PubMed Central

    Bennett, Brian J.; Davis, Richard C.; Civelek, Mete; Orozco, Luz; Wu, Judy; Qi, Hannah; Pan, Calvin; Packard, René R. Sevag; Eskin, Eleazar; Yan, Mujing; Kirchgessner, Todd; Wang, Zeneng; Li, Xinmin; Gregory, Jill C.; Hazen, Stanley L.; Gargalovic, Peter S.; Lusis, Aldons J.

    2015-01-01

    Common forms of atherosclerosis involve multiple genetic and environmental factors. While human genome-wide association studies have identified numerous loci contributing to coronary artery disease and its risk factors, these studies are unable to control environmental factors or examine detailed molecular traits in relevant tissues. We now report a study of natural variations contributing to atherosclerosis and related traits in over 100 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP). The mice were made hyperlipidemic by transgenic expression of human apolipoprotein E-Leiden (APOE-Leiden) and human cholesteryl ester transfer protein (CETP). The mice were examined for lesion size and morphology as well as plasma lipid, insulin and glucose levels, and blood cell profiles. A subset of mice was studied for plasma levels of metabolites and cytokines. We also measured global transcript levels in aorta and liver. Finally, the uptake of acetylated LDL by macrophages from HMDP mice was quantitatively examined. Loci contributing to the traits were mapped using association analysis, and relationships among traits were examined using correlation and statistical modeling. A number of conclusions emerged. First, relationships among atherosclerosis and the risk factors in mice resemble those found in humans. Second, a number of trait-loci were identified, including some overlapping with previous human and mouse studies. Third, gene expression data enabled enrichment analysis of pathways contributing to atherosclerosis and prioritization of candidate genes at associated loci in both mice and humans. Fourth, the data provided a number of mechanistic inferences; for example, we detected no association between macrophage uptake of acetylated LDL and atherosclerosis. Fifth, broad sense heritability for atherosclerosis was much larger than narrow sense heritability, indicating an important role for gene-by-gene interactions. Sixth, stepwise linear regression

  4. Using Wikis with Teacher Candidates: Promoting Collaborative Practice and Contextual Analysis

    ERIC Educational Resources Information Center

    Wake, Donna Glenn; Modla, Virginia B.

    2012-01-01

    This article examines a collaborative study that two teacher educators conducted across two sites. Participants included teacher candidates implementing a digital language experience approach project with elementary learners. The teacher candidates collaborated across sites, building joint wikis to examine their processes and products. The wikis…

  5. The Effect of Candidate Gender on Electoral Outcomes: A Six-State Analysis.

    ERIC Educational Resources Information Center

    Welch, Susan; And Others

    Voter behavior is assessed toward female candidates for state legislatures in six states during 1970 to 1980. The sample consisted of 4,910 female and male candidates in state legislative elections to the lower house in Iowa, Missouri, Nebraska, New Mexico, Oklahoma, and Wyoming. The relationship of party, incumbency, and urban or rural residency…

  6. Candidate-Gene Screening and Association Analysis at the Autism-Susceptibility Locus on Chromosome 16p: Evidence of Association at GRIN2A and ABAT

    PubMed Central

    Barnby, Gabrielle; Abbott, Aaron; Sykes, Nuala; Morris, Andrew; Weeks, Daniel E.; Mott, Richard; Lamb, Janine; Bailey, Anthony J.; Monaco, Anthony P.

    2005-01-01

    Autism is a highly heritable neurodevelopmental disorder whose underlying genetic causes have yet to be identified. To date, there have been eight genome screens for autism, two of which identified a putative susceptibility locus on chromosome 16p. In the present study, 10 positional candidate genes that map to 16p11-13 were examined for coding variants: A2BP1, ABAT, BFAR, CREBBP, EMP2, GRIN2A, MRTF-B, SSTR5, TBX6, and UBN1. Screening of all coding and regulatory regions by denaturing high-performance liquid chromatography identified seven nonsynonymous changes. Five of these mutations were found to cosegregate with autism, but the mutations are not predicted to have deleterious effects on protein structure and are unlikely to represent significant etiological variants. Selected variants from candidate genes were genotyped in the entire International Molecular Genetics Study of Autism Consortium collection of 239 multiplex families and were tested for association with autism by use of the pedigree disequilibrium test. Additionally, genotype frequencies were compared between 239 unrelated affected individuals and 192 controls. Patterns of linkage disequilibrium were investigated, and the transmission of haplotypes across candidate genes was tested for association. Evidence of single-marker association was found for variants in ABAT, CREBBP, and GRIN2A. Within these genes, 12 single-nucleotide polymorphisms (SNPs) were subsequently genotyped in 91 autism trios (one affected individual and two unaffected parents), and the association was replicated within GRIN2A (Fisher's exact test, P<.0001). Logistic regression analysis of SNP data across GRIN2A and ABAT showed a trend toward haplotypic differences between cases and controls. PMID:15830322

  7. Genetic and Informatic Analyses Implicate Kif12 as a Candidate Gene within the Mpkd2 Locus That Modulates Renal Cystic Disease Severity in the Cys1cpk Mouse

    PubMed Central

    Mrug, Michal; Zhou, Juling; Yang, Chaozhe; Aronow, Bruce J.; Cui, Xiangqin; Schoeb, Trenton R.; Siegal, Gene P.; Yoder, Bradley K; Guay-Woodford, Lisa M.

    2015-01-01

    We have previously mapped the interval on Chromosome 4 for a major polycystic kidney disease modifier (Mpkd) of the B6(Cg)-Cys1cpk/J mouse model of recessive polycystic kidney disease (PKD). Informatic analyses predicted that this interval contains at least three individual renal cystic disease severity-modulating loci (Mpkd1-3). In the current study, we provide further validation of these predicted effects using a congenic mouse line carrying the entire CAST/EiJ (CAST)-derived Mpkd1-3 interval on the C57BL/6J background. We have also generated a derivative congenic line with a refined CAST-derived Mpkd1-2 interval and demonstrated its dominantly-acting disease-modulating effects (e.g., 4.2-fold increase in total cyst area; p<0.001). The relative strength of these effects allowed the use of recombinants from these crosses to fine map the Mpkd2 effects to a <14 Mbp interval that contains 92 RefSeq sequences. One of them corresponds to the previously described positional Mpkd2 candidate gene, Kif12. Among the positional Mpkd2 candidates, only expression of Kif12 correlates strongly with the expression pattern of Cys1 across multiple anatomical nephron structures and developmental time points. Also, we demonstrate that Kif12 encodes a primary cilium-associated protein. Together, these data provide genetic and informatic validation of the predicted renal cystic disease-modulating effects of Mpkd1-3 loci and implicate Kif12 as the candidate locus for Mpkd2. PMID:26295839

  8. Computational analysis of TRAPPC9: candidate gene for autosomal recessive non-syndromic mental retardation.

    PubMed

    Khattak, Naureen Aslam; Mir, Asif

    2014-01-01

    Mental retardation (MR)/ intellectual disability (ID) is a neuro-developmental disorder characterized by a low intellectual quotient (IQ) and deficits in adaptive behavior related to everyday life tasks such as delayed language acquisition, social skills or self-help skills with onset before age 18. To date, a few genes (PRSS12, CRBN, CC2D1A, GRIK2, TUSC3, TRAPPC9, TECR, ST3GAL3, MED23, MAN1B1, NSUN1) for autosomal-recessive forms of non syndromic MR (NS-ARMR) have been identified and established in various families with ID. The recently reported candidate gene TRAPPC9 was selected for computational analysis to explore its potentially important role in pathology as it is the only gene for ID reported in more than five different familial cases worldwide. YASARA (12.4.1) was utilized to generate three dimensional structures of the candidate gene TRAPPC9. Hybrid structure prediction was employed. Crystal Structure of a Conserved Metalloprotein From Bacillus Cereus (3D19-C) was selected as best suitable template using position-specific iteration-BLAST. Template (3D19-C) parameters were based on E-value, Z-score and resolution and quality score of 0.32, -1.152, 2.30°A and 0.684 respectively. Model reliability showed 93.1% residues placed in the most favored region with 96.684 quality factor, and overall 0.20 G-factor (dihedrals 0.06 and covalent 0.39 respectively). Protein-Protein docking analysis demonstrated that TRAPPC9 showed strong interactions of the amino acid residues S(253), S(251), Y(256), G(243), D(131) with R(105), Q(425), W(226), N(255), S(233), its functional partner 1KBKB. Protein-protein interacting residues could facilitate the exploration of structural and functional outcomes of wild type and mutated TRAPCC9 protein. Actively involved residues can be used to elucidate the binding properties of the protein, and to develop drug therapy for NS-ARMR patients. PMID:24040793

  9. Refining the locus for Best vitelliform macular dystrophy and mutation analysis of the candidate gene ROM1

    SciTech Connect

    Nichols, B.E.; Stone, E.M.; Sheffield, V.C. ); McInnes, R.; Bascom, R. ); Litt, M. )

    1994-01-01

    Vitelliform macular dystrophy (Best disease) is an autosomal dominant macular dystrophy which shares important clinical features with age-related macular degeneration, the most common cause of legal blindness in the elderly. Unfortunately, understanding and treatment for this common age-related disorder is limited. Discovery of the gene which causes Best disease has the potential to increase the understanding of the pathogenesis of all types of macular degeneration, including the common age-related form. Best disease has recently been mapped to chromosome 11q13. The photoreceptor-specific protein ROM1 has also been recently mapped to this location, and the ROM1 gene is a candidate gene for Best disease. Using highly polymorphic markers, the authors have narrowed the genetic region which contains the Best disease gene to the 10-cM region between markers D11S871 and PYGM. Marker D11S956 demonstrated no recombinants with Best disease in three large families and resulted in a lod score of 18.2. In addition, a polymorphism within the ROM1 gene also demonstrated no recombinants and resulted in a lod score of 10.0 in these same three families. The authors used a combination of SSCP analysis, denaturing gradient gel electrophoresis, and DNA sequencing to screen the entire coding region of the ROM1 gene in 11 different unrelated patients affected with Best disease. No nucleotide changes were found in the coding sequence of any affected patient, indicating that mutations within the coding sequence are unlikely to cause Best disease. 28 refs., 3 figs., 2 tabs.

  10. Refining the locus for Best vitelliform macular dystrophy and mutation analysis of the candidate gene ROM1.

    PubMed Central

    Nichols, B. E.; Bascom, R.; Litt, M.; McInnes, R.; Sheffield, V. C.; Stone, E. M.

    1994-01-01

    Vitelliform macular dystrophy (Best disease) is an autosomal dominant macular dystrophy which shares important clinical features with age-related macular degeneration, the most common cause of legal blindness in the elderly. Unfortunately, our understanding and treatment for this common age-related disorder is limited. Discovery of the gene which causes Best disease has the potential to increase our understanding of the pathogenesis of all types of macular degeneration, including the common age-related form. Best disease has recently been mapped to chromosome 11q13. The photoreceptor-specific protein ROM1 has also been recently mapped to this location, and the ROM1 gene is a candidate gene for Best disease. Using highly polymorphic markers, we have narrowed the genetic region which contains the Best disease gene to the 10-cM region between markers D11S871 and PYGM. Marker D11S956 demonstrated no recombinants with Best disease in three large families and resulted in a lod score of 18.2. In addition, a polymorphism within the ROM1 gene also demonstrated no recombinants and resulted in a lod score of 10.0 in these same three families. We used a combination of SSCP analysis, denaturing gradient gel electrophoresis, and DNA sequencing to screen the entire coding region of the ROM1 gene in 11 different unrelated patients affected with Best disease. No nucleotide changes were found in the coding sequence of any affected patient, indicating that mutations within the coding sequence are unlikely to cause Best disease. Images Figure 2 PMID:8279475

  11. Refining the locus for Best vitelliform macular dystrophy and mutation analysis of the candidate gene ROM1.

    PubMed

    Nichols, B E; Bascom, R; Litt, M; McInnes, R; Sheffield, V C; Stone, E M

    1994-01-01

    Vitelliform macular dystrophy (Best disease) is an autosomal dominant macular dystrophy which shares important clinical features with age-related macular degeneration, the most common cause of legal blindness in the elderly. Unfortunately, our understanding and treatment for this common age-related disorder is limited. Discovery of the gene which causes Best disease has the potential to increase our understanding of the pathogenesis of all types of macular degeneration, including the common age-related form. Best disease has recently been mapped to chromosome 11q13. The photoreceptor-specific protein ROM1 has also been recently mapped to this location, and the ROM1 gene is a candidate gene for Best disease. Using highly polymorphic markers, we have narrowed the genetic region which contains the Best disease gene to the 10-cM region between markers D11S871 and PYGM. Marker D11S956 demonstrated no recombinants with Best disease in three large families and resulted in a lod score of 18.2. In addition, a polymorphism within the ROM1 gene also demonstrated no recombinants and resulted in a lod score of 10.0 in these same three families. We used a combination of SSCP analysis, denaturing gradient gel electrophoresis, and DNA sequencing to screen the entire coding region of the ROM1 gene in 11 different unrelated patients affected with Best disease. No nucleotide changes were found in the coding sequence of any affected patient, indicating that mutations within the coding sequence are unlikely to cause Best disease. PMID:8279475

  12. Candidate gene association analysis for milk yield, composition, urea nitrogen and somatic cell scores in Brown Swiss cows.

    PubMed

    Cecchinato, A; Ribeca, C; Chessa, S; Cipolat-Gotet, C; Maretto, F; Casellas, J; Bittante, G

    2014-07-01

    The aim of this study was to investigate 96 single-nucleotide polymorphisms (SNPs) from 54 candidate genes, and test the associations of the polymorphic SNPs with milk yield, composition, milk urea nitrogen (MUN) content and somatic cell score (SCS) in individual milk samples from Italian Brown Swiss cows. Milk and blood samples were collected from 1271 cows sampled once from 85 herds. Milk production, quality traits (i.e. protein, casein, fat and lactose percentages), MUN and SCS were measured for each milk sample. Genotyping was performed using a custom Illumina VeraCode GoldenGate approach. A Bayesian linear animal model that considered the effects of herd, days in milk, parity, SNP genotype and additive polygenic effect was used for the association analysis. Our results showed that 14 of the 51 polymorphic SNPs had relevant additive effects on at least one of the aforementioned traits. Polymorphisms in the glucocorticoid receptor DNA-binding factor 1 (GRLF1), prolactin receptor (PRLR) and chemokine ligand 2 (CCL2) were associated with milk yield; an SNP in the stearoyl-CoA desaturase (SCD-1) was related to fat content; SNPs in the caspase recruitment domain 15 protein (CARD15) and lipin 1 (LPIN1) affected the protein and casein contents; SNPs in growth hormone 1 (GH1), lactotransferrin (LTF) and SCD-1 were relevant for casein number; variants in beta casein (CSN2), GH1, GRLF1 and LTF affected lactose content; SNPs in beta-2 adrenergic receptor (ADRB2), serpin peptidase inhibitor (PI) and SCD-1 were associated with MUN; and SNPs in acetyl-CoA carboxylase alpha (ACACA) and signal transducer and activator of transcription 5A (STAT5A) were relevant in explaining the variation of SCS. Although further research is needed to validate these SNPs in other populations and breeds, the association between these markers and milk yield, composition, MUN and SCS could be exploited in gene-assisted selection programs for genetic improvement purposes. PMID:24804775

  13. Evolutionary analysis suggests that AMTN is enamel-specific and a candidate for AI.

    PubMed

    Gasse, B; Silvent, J; Sire, J-Y

    2012-11-01

    Molecular evolutionary analysis is an efficient method to predict and/or validate amino acid substitutions that could lead to a genetic disease and to highlight residues and motifs that could play an important role in the protein structure and/or function. We have applied such analysis to amelotin (AMTN), a recently identified enamel protein in the rat, mouse, and humans. An in silico search for AMTN provided 42 new mammalian sequences that were added to the 3 published sequences with which we performed the analysis using a dataset representative of all lineages (circa 220 million years of evolution), including 2 enamel-less species, sloth and armadillo. During evolution, of the 209 residues of human AMTN, 17 were unchanged and 34 had conserved their chemical properties. Substituting these important residues could lead to amelogenesis imperfecta (AI). Also, AMTN possesses a well-conserved signal peptide, 2 conserved motifs whose function is certainly important but unknown, and a putative phosphorylation site (SXE). In addition, the sequences of the 2 enamel-less species display mutations revealing that AMTN underwent pseudogenization, which suggests that AMTN is an enamel-specific protein. PMID:22968158

  14. Thrombophilia and venous thromboembolism in pregnancy: a meta-analysis of genetic risk.

    PubMed

    Ziakas, Panayiotis D; Poulou, Loukia S; Pavlou, Matthaios; Zintzaras, Elias

    2015-08-01

    Three common polymorphic variants, namely Factor V Leiden (FVL), Prothrombin G20210A (PT G20210A) and Methylenetetrahydrofolate Reductase (MTHFR) C677T are candidate genes for venous thromboembolism (VTE) in pregnancy. We performed a literature review and meta-analysis of pertinent genetic association studies (GAS) in pregnancy, to quantify the genetic risk of VTE in pregnancy. We used the model-free approach of generalized odds ratio (ORG) to estimate gene-to-disease association and explored the mode of inheritance using the degree of dominance h index. Twelve case-control GAS studies provided the full genotype distributions for at least one candidate gene to assess the genetic risk. FVL was associated with a significant risk of VTE in pregnancy (ORG 7.28; 95% confidence interval 5.53-9.58) and a dominant mode of inheritance (h=0.76), that is the effect of heterozygous carriers will lie close to the homozygous mutant genotype. PT G20210A mutation was also associated with a significant VTE risk (ORG 5.43; 95% CI 3.66-8.03) and had an over-dominant mode of inheritance (h=1.5), suggesting that the effect of heterozygous carriers may exceed that of homozygous mutant. MTHFR C677T had no association with VTE risk in pregnancy (ORG 1.24; 95% CI 0.88-1.73). Our analysis provided robust data on VTE in pregnancy, relative to FVL and PT G20210A status and suggested that the genetic effects of heterozygous over homozygous carriers do not justify stratification of heterozygous as "lower risk" over homozygous mutants. On clinical grounds this may impact decisions to preferentially exclude heterozygous from anticoagulation prophylaxis. PMID:26115054

  15. Fine mapping and candidate gene analysis of an anthocyanin-rich gene, BnaA.PL1, conferring purple leaves in Brassica napus L.

    PubMed

    Li, Haibo; Zhu, Lixia; Yuan, Gaigai; Heng, Shuangping; Yi, Bin; Ma, Chaozhi; Shen, Jinxiong; Tu, Jinxing; Fu, Tingdong; Wen, Jing

    2016-08-01

    Because of the advantages of anthocyanins, the genetics and breeding of crops rich in anthocyanins has become a hot research topic. However, due to the lack of anthocyanin-related mutants, no regulatory genes have been mapped in Brassica napus. In this study, we first report the characterization of a B. napus line with purple leaves and the fine mapping and candidate screening of the BnaA.PL1 gene. The amount of anthocyanins in the purple leaf line was six times higher than that in a green leaf line. A genetic analysis indicated that the purple character was controlled by an incomplete dominant gene. Through map-based cloning, we localized the BnaA.PL1 gene to a 99-kb region at the end of B. napus chromosome A03. Transcriptional analysis of 11 genes located in the target region revealed that the expression level of only the BnAPR2 gene in seedling leaves decreased from purple to reddish green to green individuals, a finding that was consistent with the measured anthocyanin accumulation levels. Molecular cloning and sequence analysis of BnAPR2 showed that the purple individual-derived allele contained 17 variants. Markers co-segregating with BnaA.PL1 were developed from the sequence of BnAPR2 and were validated in the BC4P2 population. These results suggested that BnAPR2, which encodes adenosine 5'-phosphosulfate reductase, is likely to be a valuable candidate gene. This work may lay the foundation for the marker-assisted selection of B. napus vegetables that are rich in anthocyanins and for an improved understanding of the molecular mechanisms controlling anthocyanin accumulation in Brassica. PMID:27003438

  16. Estimation of the minimum uncertainty of DNA concentration in a genetically modified maize sample candidate certified reference material.

    PubMed

    Prokisch, J; Zeleny, R; Trapmann, S; Le Guern, L; Schimmel, H; Kramer, G N; Pauwels, J

    2001-08-01

    Homogeneity testing and the determination of minimum sample mass are an important part of the certification of reference materials. The smallest theoretically achievable uncertainty of certified concentration values is limited by the concentration distribution of analyte in the different particle size fractions of powdered biological samples. This might be of special importance if the reference material is prepared by dry mixing, a dilution technique which is used for the production of the new and third generation of genetically modified (GMO) plant certified reference materials. For the production of dry mixed PMON 810 maize reference material a computer program was developed to calculate the theoretically smallest uncertainty for a selected sample intake. This model was used to compare three differently milled maize samples, and the effect of dilution on the uncertainty of the DNA content of GMO maize was estimated as well. In the case of a 50-mg sample mass the lowest achievable standard deviation was 2% for the sample containing 0.1% GMO and the minimum deviation was less than 0.5% for the sample containing 5% GMO. PMID:11569879

  17. A genetically attenuated malaria vaccine candidate based on P. falciparum b9/slarp gene-deficient sporozoites.

    PubMed

    van Schaijk, Ben C L; Ploemen, Ivo H J; Annoura, Takeshi; Vos, Martijn W; Foquet, Lander; van Gemert, Geert-Jan; Chevalley-Maurel, Severine; van de Vegte-Bolmer, Marga; Sajid, Mohammed; Franetich, Jean-Francois; Lorthiois, Audrey; Leroux-Roels, Geert; Meuleman, Philip; Hermsen, Cornelius C; Mazier, Dominique; Hoffman, Stephen L; Janse, Chris J; Khan, Shahid M; Sauerwein, Robert W

    2014-01-01

    A highly efficacious pre-erythrocytic stage vaccine would be an important tool for the control and elimination of malaria but is currently unavailable. High-level protection in humans can be achieved by experimental immunization with Plasmodium falciparum sporozoites attenuated by radiation or under anti-malarial drug coverage. Immunization with genetically attenuated parasites (GAP) would be an attractive alternative approach. In this study, we present data on safety and protective efficacy using sporozoites with deletions of two genes, that is the newly identified b9 and slarp, which govern independent and critical processes for successful liver-stage development. In the rodent malaria model, PbΔb9ΔslarpGAP was completely attenuated showing no breakthrough infections while efficiently inducing high-level protection. The human PfΔb9ΔslarpGAP generated without drug resistance markers were infective to human hepatocytes in vitro and to humanized mice engrafted with human hepatocytes in vivo but completely aborted development after infection. These findings support the clinical development of a PfΔb9ΔslarpSPZ vaccine. PMID:25407681

  18. A Single Transcriptome of a Green Toad (Bufo viridis) Yields Candidate Genes for Sex Determination and -Differentiation and Non-Anonymous Population Genetic Markers.

    PubMed

    Gerchen, Jörn F; Reichert, Samuel J; Röhr, Johannes T; Dieterich, Christoph; Kloas, Werner; Stöck, Matthias

    2016-01-01

    Large genome size, including immense repetitive and non-coding fractions, still present challenges for capacity, bioinformatics and thus affordability of whole genome sequencing in most amphibians. Here, we test the performance of a single transcriptome to understand whether it can provide a cost-efficient resource for species with large unknown genomes. Using RNA from six different tissues from a single Palearctic green toad (Bufo viridis) specimen and Hiseq2000, we obtained 22,5 Mio reads and publish >100,000 unigene sequences. To evaluate efficacy and quality, we first use this data to identify green toad specific candidate genes, known from other vertebrates for their role in sex determination and differentiation. Of a list of 37 genes, the transcriptome yielded 32 (87%), many of which providing the first such data for this non-model anuran species. However, for many of these genes, only fragments could be retrieved. In order to allow also applications to population genetics, we further used the transcriptome for the targeted development of 21 non-anonymous microsatellites and tested them in genetic families and backcrosses. Eleven markers were specifically developed to be located on the B. viridis sex chromosomes; for eight markers we can indeed demonstrate sex-specific transmission in genetic families. Depending on phylogenetic distance, several markers, which are sex-linked in green toads, show high cross-amplification success across the anuran phylogeny, involving nine systematic anuran families. Our data support the view that single transcriptome sequencing (based on multiple tissues) provides a reliable genomic resource and cost-efficient method for non-model amphibian species with large genome size and, despite limitations, should be considered as long as genome sequencing remains unaffordable for most species. PMID:27232626

  19. A Single Transcriptome of a Green Toad (Bufo viridis) Yields Candidate Genes for Sex Determination and -Differentiation and Non-Anonymous Population Genetic Markers

    PubMed Central

    Gerchen, Jörn F.; Reichert, Samuel J.; Röhr, Johannes T.; Dieterich, Christoph; Kloas, Werner

    2016-01-01

    Large genome size, including immense repetitive and non-coding fractions, still present challenges for capacity, bioinformatics and thus affordability of whole genome sequencing in most amphibians. Here, we test the performance of a single transcriptome to understand whether it can provide a cost-efficient resource for species with large unknown genomes. Using RNA from six different tissues from a single Palearctic green toad (Bufo viridis) specimen and Hiseq2000, we obtained 22,5 Mio reads and publish >100,000 unigene sequences. To evaluate efficacy and quality, we first use this data to identify green toad specific candidate genes, known from other vertebrates for their role in sex determination and differentiation. Of a list of 37 genes, the transcriptome yielded 32 (87%), many of which providing the first such data for this non-model anuran species. However, for many of these genes, only fragments could be retrieved. In order to allow also applications to population genetics, we further used the transcriptome for the targeted development of 21 non-anonymous microsatellites and tested them in genetic families and backcrosses. Eleven markers were specifically developed to be located on the B. viridis sex chromosomes; for eight markers we can indeed demonstrate sex-specific transmission in genetic families. Depending on phylogenetic distance, several markers, which are sex-linked in green toads, show high cross-amplification success across the anuran phylogeny, involving nine systematic anuran families. Our data support the view that single transcriptome sequencing (based on multiple tissues) provides a reliable genomic resource and cost-efficient method for non-model amphibian species with large genome size and, despite limitations, should be considered as long as genome sequencing remains unaffordable for most species. PMID:27232626

  20. Candidate pathway-based genetic association study of Platinum and Platinum-Taxane Related Toxicity in a Cohort of Primary Lung Cancer Patients

    PubMed Central

    Johnson, Cassandra; Pankratz, Vernon S.; Velazquez, Ana I.; Aakre, Jeremiah A.; Loprinzi, Charles L.; Staff, Nathan P.; Windebank, Anthony J.; Yang, Ping

    2015-01-01

    Background Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity secondary to chemotherapy. Genetic factors may be important in predisposing patients to this adverse effect. Patients and Methods We studied 950 primary lung cancer patients, who received platinum or platinum-combination drug chemotherapy and who had DNA available for study. We analyzed epidemiological risk factors in 279 CIPN patients and 456 non-CIPN patients and genetic risk factors in 141 CIPN patients and 259 non-CIPN patients. The risk factors studied included demographic, diagnostic, and treatment data, as well as 174 tag SNPs (single nucleotide polymorphisms) across 43 candidate genes in the glutathione, cell cycle, DNA repair, cell signaling, and apoptosis pathways. Results Patients who had diabetes mellitus were more likely to have CIPN (p=0.0002). Other epidemiologic risk factors associated with CIPN included number of cycles (p=0.0004) and type of concurrent chemotherapy (p<0.001) . SNPs most associated with CIPN were in glutathione peroxidase 7 (GPX7) gene (p values 0.0015 and 0.0028, unadjusted and adjusted) and in ATP-binding cassette sub-family C member 4 (ABCC4) gene (p values 0.037 and 0.006, unadjusted and adjusted). We also found other suggestive associations in methyl-o-guanine-methyl-transferase (MGMT) and glutathione-S-transferase (GST) isoforms. Conclusions Epidemiological and genetic risk factors associated with CIPN in this cohort, included the type of chemotherapy drug, intensity of chemotherapy treatment, and genes known to be associated with chemotherapy resistance. These findings suggest that differentiating between cytotoxic and neurotoxic mechanisms of chemotherapy drugs is challenging but represents an important step toward individualized therapy and improving quality of life for patients. PMID:25586538

  1. Microarray analysis identifies candidate genes for key roles in coral development

    PubMed Central

    Grasso, Lauretta C; Maindonald, John; Rudd, Stephen; Hayward, David C; Saint, Robert; Miller, David J; Ball, Eldon E

    2008-01-01

    Background Anthozoan cnidarians are amongst the simplest animals at the tissue level of organization, but are surprisingly complex and vertebrate-like in terms of gene repertoire. As major components of tropical reef ecosystems, the stony corals are anthozoans of particular ecological significance. To better understand the molecular bases of both cnidarian development in general and coral-specific processes such as skeletogenesis and symbiont acquisition, microarray analysis was carried out through the period of early development – when skeletogenesis is initiated, and symbionts are first acquired. Results Of 5081 unique peptide coding genes, 1084 were differentially expressed (P ≤ 0.05) in comparisons between four different stages of coral development, spanning key developmental transitions. Genes of likely relevance to the processes of settlement, metamorphosis, calcification and interaction with symbionts were characterised further and their spatial expression patterns investigated using whole-mount in situ hybridization. Conclusion This study is the first large-scale investigation of developmental gene expression for any cnidarian, and has provided candidate genes for key roles in many aspects of coral biology, including calcification, metamorphosis and symbiont uptake. One surprising finding is that some of these genes have clear counterparts in higher animals but are not present in the closely-related sea anemone Nematostella. Secondly, coral-specific processes (i.e. traits which distinguish corals from their close relatives) may be analogous to similar processes in distantly related organisms. This first large-scale application of microarray analysis demonstrates the potential of this approach for investigating many aspects of coral biology, including the effects of stress and disease. PMID:19014561

  2. A Latent Class Analysis of Teacher Candidates' Goal Orientation, Perception of Classroom Structure, Motivation, and Self-Regulation

    ERIC Educational Resources Information Center

    Bembenutty, Hefer

    2010-01-01

    The purpose of this study was to examine whether teacher candidates with mastery- and performance-approach orientations would perceived their education courses as depicting a goal structure consistent with their personal orientations, use of self-regulatory strategies, and motivation for learning. A latent class analysis procedure was used to…

  3. Genetics of murine craniofacial morphology: diallel analysis of the eight founders of the Collaborative Cross.

    PubMed

    Percival, Christopher J; Liberton, Denise K; Pardo-Manuel de Villena, Fernando; Spritz, Richard; Marcucio, Ralph; Hallgrímsson, Benedikt

    2016-01-01

    Using eight inbred founder strains of the mouse Collaborative Cross (CC) project and their reciprocal F1 hybrids, we quantified variation in craniofacial morphology across mouse strains, explored genetic contributions to craniofacial variation that distinguish the founder strains, and tested whether specific or summary measures of craniofacial shape display stronger additive genetic contributions. This study thus provides critical information about phenotypic diversity among CC founder strains and about the genetic contributions to this phenotypic diversity, which is relevant to understanding the basis of variation in standard laboratory strains and natural populations. Craniofacial shape was quantified as a series of size-adjusted linear dimensions (RDs) and by principal components (PC) analysis of morphological landmarks captured from computed tomography images from 62 of the 64 reciprocal crosses of the CC founder strains. We first identified aspects of skull morphology that vary between these phenotypically 'normal' founder strains and that are defining characteristics of these strains. We estimated the contributions of additive and various non-additive genetic factors to phenotypic variation using diallel analyses of a subset of these strongly differing RDs and the first eight PCs of skull shape variation. We find little difference in the genetic contributions to RD measures and PC scores, suggesting fundamental similarities in the magnitude of genetic contributions to both specific and summary measures of craniofacial phenotypes. Our results indicate that there are stronger additive genetic effects associated with defining phenotypic characteristics of specific founder strains, suggesting these distinguishing measures are good candidates for use in genotype-phenotype association studies of CC mice. Our results add significantly to understanding of genotype-phenotype associations in the skull, which serve as a foundation for modeling the origins of medically

  4. Polyglot Programming in Applications Used for Genetic Data Analysis

    PubMed Central

    Nowak, Robert M.

    2014-01-01

    Applications used for the analysis of genetic data process large volumes of data with complex algorithms. High performance, flexibility, and a user interface with a web browser are required by these solutions, which can be achieved by using multiple programming languages. In this study, I developed a freely available framework for building software to analyze genetic data, which uses C++, Python, JavaScript, and several libraries. This system was used to build a number of genetic data processing applications and it reduced the time and costs of development. PMID:25197633

  5. Polyglot programming in applications used for genetic data analysis.

    PubMed

    Nowak, Robert M

    2014-01-01

    Applications used for the analysis of genetic data process large volumes of data with complex algorithms. High performance, flexibility, and a user interface with a web browser are required by these solutions, which can be achieved by using multiple programming languages. In this study, I developed a freely available framework for building software to analyze genetic data, which uses C++, Python, JavaScript, and several libraries. This system was used to build a number of genetic data processing applications and it reduced the time and costs of development. PMID:25197633

  6. Statistical Analysis in Genetic Studies of Mental Illnesses

    PubMed Central

    Zhang, Heping

    2011-01-01

    Identifying the risk factors for mental illnesses is of significant public health importance. Diagnosis, stigma associated with mental illnesses, comorbidity, and complex etiologies, among others, make it very challenging to study mental disorders. Genetic studies of mental illnesses date back at least a century ago, beginning with descriptive studies based on Mendelian laws of inheritance. A variety of study designs including twin studies, family studies, linkage analysis, and more recently, genomewide association studies have been employed to study the genetics of mental illnesses, or complex diseases in general. In this paper, I will present the challenges and methods from a statistical perspective and focus on genetic association studies. PMID:21909187

  7. Systems genetics analysis of body weight and energy metabolism traits in Drosophila melanogaster

    PubMed Central

    2010-01-01

    Background Obesity and phenotypic traits associated with this condition exhibit significant heritability in natural populations of most organisms. While a number of genes and genetic pathways have been implicated to play a role in obesity associated traits, the genetic architecture that underlies the natural variation in these traits is largely unknown. Here, we used 40 wild-derived inbred lines of Drosophila melanogaster to quantify genetic variation in body weight, the content of three major metabolites (glycogen, triacylglycerol, and glycerol) associated with obesity, and metabolic rate in young flies. We chose these lines because they were previously screened for variation in whole-genome transcript abundance and in several adult life-history traits, including longevity, resistance to starvation stress, chill-coma recovery, mating behavior, and competitive fitness. This enabled us not only to identify candidate genes and transcriptional networks that might explain variation for energy metabolism traits, but also to investigate the genetic interrelationships among energy metabolism, behavioral, and life-history traits that have evolved in natural populations. Results We found significant genetically based variation in all traits. Using a genome-wide association screen for single feature polymorphisms and quantitative trait transcripts, we identified 337, 211, 237, 553, and 152 novel candidate genes associated with body weight, glycogen content, triacylglycerol storage, glycerol levels, and metabolic rate, respectively. Weighted gene co-expression analyses grouped transcripts associated with each trait in significant modules of co-expressed genes and we interpreted these modules in terms of their gene enrichment based on Gene Ontology analysis. Comparison of gene co-expression modules for traits in this study with previously determined modules for life-history traits identified significant modular pleiotropy between glycogen content, body weight, competitive

  8. Analysis of Line Candidates in Gamma-Ray Bursts Observed by BATSE

    NASA Technical Reports Server (NTRS)

    Briggs, M. S.; Band, D. L.; Preece, R. D.; Paciesas, W. S.; Pendleton, G. N.

    1999-01-01

    A comprehensive search of BATSE Spectroscopy Detector data from 117 Gamma Ray Bursts (GRBs) has uncovered 13 statistically significant line candidates. The case of a candidate in GRB-930916 is discussed. In the data of SD-2 there appears to be a emission line at 46 keV, however the line is not seen in the data of SD-7. Simulations indicate that the lack of agreement between the results from SD-2 and SD-7 is implausible but not impossible.

  9. In silico analysis of an envelope domain III-based multivalent fusion protein as a potential dengue vaccine candidate

    PubMed Central

    2016-01-01

    Purpose Dengue virus infection is now a global problem. Currently, there is no licensed vaccine or proven antiviral treatment against this virus. All four serotypes (1-4) of dengue virus can infect human. An effective dengue vaccine should be tetravalent to induce protective immune responses against all four serotypes. Most of dengue vaccine candidates are monovalent, or in the form of physically mixed multivalent formulations. Recently envelope protein domain III of virus is considered as a vaccine candidate, which plays critical roles in the most important viral activities. Development of a tetravalent protein subunit vaccine is very important for equal induction of immune system and prevention of unbalanced immunity. Here, we have presented and used a rational approach to design a tetravalent dengue vaccine candidate. Materials and Methods We designed a multi domain antigen by fusing four consensus domain III sequences together with appropriate hydrophobic linkers and used several types of bioinformatics software and neural networks to predict structural and immunological properties of the designed tetravalent antigen. Results We designed a tetravalent protein (EDIIIF) based on domain III of dengue virus envelope protein. According to the results of the bioinformatics analysis, the constructed models for EDIIIF protein were structurally stable and potentially immunogenic. Conclusion The designed tetravalent protein can be considered as a potential dengue vaccine candidate. The presented approach can be used for rational design and in silico evaluation of chimeric dengue vaccine candidates. PMID:26866023

  10. Molecular Genetic Analysis of Phototropism in Arabidopsis

    PubMed Central

    Sakai, Tatsuya; Haga, Ken

    2012-01-01

    Plant life is strongly dependent on the environment, and plants regulate their growth and development in response to many different environmental stimuli. One of the regulatory mechanisms involved in these responses is phototropism, which allows plants to change their growth direction in response to the location of the light source. Since the study of phototropism by Darwin, many physiological studies of this phenomenon have been published. Recently, molecular genetic analyses of Arabidopsis have begun to shed light on the molecular mechanisms underlying this response system, including phototropin blue light photoreceptors, phototropin signaling components, auxin transporters, auxin action mechanisms and others. This review highlights some of the recent progress that has been made in further elucidating the phototropic response, with particular emphasis on mutant phenotypes. PMID:22864452

  11. Proteomic analysis of synovial fluid as an analytical tool to detect candidate biomarkers for knee osteoarthritis

    PubMed Central

    Liao, Weixiong; Li, Zhongli; Zhang, Hao; Li, Ji; Wang, Ketao; Yang, Yimeng

    2015-01-01

    We conducted research to detect the proteomic profiles in synovial fluid (SF) from knee osteoarthritis (OA) patients to better understand the pathogenesis and aetiology of OA. Our long-term goal is to identify reliable candidate biomarkers for OA in SF. The SF proteins obtained from 10 knee OA patients and 10 non-OA patients (9 of whom were patients with a meniscus injury in the knee; 1 had a discoid meniscus in the knee, and all exhibited intact articular cartilage) were separated by two-dimensional electrophoresis (2-DE). The repeatability of the obtained protein spots regarding their intensity was tested via triplicate 2-DE of selected samples. The observed protein expression patterns were subjected to statistical analysis, and differentially expressed protein spots were identified via matrix-assisted laser desorption/ionisation-time of flight/time of flight mass spectrometry (MALDI-TOF/TOF MS). Our analyses showed low intrasample variability and clear intersample variation. Among the protein spots observed on the gels, there were 29 significant differences, of which 22 corresponded to upregulation and 7 to downregulation in the OA group. One of the upregulated protein spots was confirmed to be haptoglobin by mass spectrometry, and the levels of haptoglobin in SF are positively correlated with the severity of OA (r = 0.89, P < 0.001). This study showed that 2-DE could be used under standard conditions to screen SF samples and identify a small subset of proteins in SF that are potential markers associated with OA. Spots of interest identified by mass spectrometry, such as haptoglobin, may be associated with OA severity. PMID:26617706

  12. Proteome analysis reveals protein candidates involved in early stages of brain regeneration of teleost fish.

    PubMed

    Ilieş, I; Zupanc, M M; Zupanc, G K H

    2012-09-01

    Exploration of the molecular dynamics underlying regeneration in the central nervous system of regeneration-competent organisms has received little attention thus far. By combining a cerebellar lesion paradigm with differential proteome analysis at a post-lesion survival time of 30 min, we screened for protein candidates involved in the early stages of regeneration in the cerebellum of such an organism, the teleost fish Apteronotus leptorhynchus. Out of 769 protein spots, the intensity of 26 spots was significantly increased by a factor of at least 1.5 in the lesioned hemisphere, relative to the intact hemisphere. The intensity of 9 protein spots was significantly reduced by a factor of at least 1.5. The proteins associated with 15 of the spots were identified by peptide mass fingerprinting and/or tandem mass spectrometry, resulting in the identification of a total of 11 proteins. Proteins whose abundance was significantly increased include: erythrocyte membrane protein 4.1N, fibrinogen gamma polypeptide, fructose-biphosphate aldolase C, alpha-internexin neuronal intermediate filament protein, major histocompatibility complex class I heavy chain, 26S proteasome non-ATPase regulatory subunit 8, tubulin alpha-1C chain, and ubiquitin-specific protease 5. Proteins with significantly decreased levels of abundance include: brain glycogen phosphorylase, neuron-specific calcium-binding protein hippocalcin, and spectrin alpha 2. We hypothesize that these proteins are involved in energy metabolism, blood clotting, electron transfer in oxidative reactions, cytoskeleton degradation, apoptotic cell death, synaptic plasticity, axonal regeneration, and promotion of mitotic activity. PMID:22659563

  13. Analysis of SSH library of rice variety Aganni reveals candidate gall midge resistance genes.

    PubMed

    Divya, Dhanasekar; Singh, Y Tunginba; Nair, Suresh; Bentur, J S

    2016-03-01

    The Asian rice gall midge, Orseolia oryzae, is a serious insect pest causing extensive yield loss. Interaction between the gall midge and rice genotypes is known to be on a gene-for-gene basis. Here, we report molecular basis of HR- (hypersensitive reaction-negative) type of resistance in Aganni (an indica rice variety possessing gall midge resistance gene Gm8) through the construction and analysis of a suppressive subtraction hybridization (SSH) cDNA library. In all, 2,800 positive clones were sequenced and analyzed. The high-quality ESTs were assembled into 448 non-redundant gene sequences. Homology search with the NCBI databases, using BlastX and BlastN, revealed that 73% of the clones showed homology to genes with known function and majority of ESTs belonged to the gene ontology category 'biological process'. Validation of 27 putative candidate gall midge resistance genes through real-time PCR, following gall midge infestation, in contrasting parents and their derived pre-NILs (near isogenic lines) revealed induction of specific genes related to defense and metabolism. Interestingly, four genes, belonging to families of leucine-rich repeat (LRR), heat shock protein (HSP), pathogenesis related protein (PR), and NAC domain-containing protein, implicated in conferring HR+ type of resistance, were found to be up-regulated in Aganni. Two of the reactive oxygen intermediates (ROI)-scavenging-enzyme-coding genes Cytosolic Ascorbate Peroxidase1, 2 (OsAPx1 and OsAPx2) were found up-regulated in Aganni in incompatible interaction possibly suppressing HR. We suggest that Aganni has a deviant form of inducible, salicylic acid (SA)-mediated resistance but without HR. PMID:26801786

  14. In Silico Analysis of the Metabolic Potential and Niche Specialization of Candidate Phylum "Latescibacteria" (WS3).

    PubMed

    Youssef, Noha H; Farag, Ibrahim F; Rinke, Christian; Hallam, Steven J; Woyke, Tanja; Elshahed, Mostafa S

    2015-01-01

    The "Latescibacteria" (formerly WS3), member of the Fibrobacteres-Chlorobi-Bacteroidetes (FCB) superphylum, represents a ubiquitous candidate phylum found in terrestrial, aquatic, and marine ecosystems. Recently, single-cell amplified genomes (SAGs) representing the "Latescibacteria" were obtained from the anoxic monimolimnion layers of Sakinaw Lake (British Columbia, Canada), and anoxic sediments of a coastal lagoon (Etoliko lagoon, Western Greece). Here, we present a detailed in-silico analysis of the four SAGs to gain some insights on their metabolic potential and apparent ecological roles. Metabolic reconstruction suggests an anaerobic fermentative mode of metabolism, as well as the capability to degrade multiple polysaccharides and glycoproteins that represent integral components of green (Charophyta and Chlorophyta) and brown (Phaeophycaea) algae cell walls (pectin, alginate, ulvan, fucan, hydroxyproline-rich glycoproteins), storage molecules (starch and trehalose), and extracellular polymeric substances (EPSs). The analyzed SAGs also encode dedicated transporters for the uptake of produced sugars and amino acids/oligopeptides, as well as an extensive machinery for the catabolism of all transported sugars, including the production of a bacterial microcompartment (BMC) to sequester propionaldehyde, a toxic intermediate produced during fucose and rhamnose metabolism. Finally, genes for the formation of gas vesicles, flagella, type IV pili, and oxidative stress response were found, features that could aid in cellular association with algal detritus. Collectively, these results indicate that the analyzed "Latescibacteria" mediate the turnover of multiple complex organic polymers of algal origin that reach deeper anoxic/microoxic habitats in lakes and lagoons. The implications of such process on our understanding of niche specialization in microbial communities mediating organic carbon turnover in stratified water bodies are discussed. PMID:26039074

  15. In Silico Analysis of the Metabolic Potential and Niche Specialization of Candidate Phylum "Latescibacteria" (WS3)

    PubMed Central

    Youssef, Noha H.; Farag, Ibrahim F.; Rinke, Christian; Hallam, Steven J.; Woyke, Tanja; Elshahed, Mostafa S.

    2015-01-01

    The “Latescibacteria” (formerly WS3), member of the Fibrobacteres–Chlorobi–Bacteroidetes (FCB) superphylum, represents a ubiquitous candidate phylum found in terrestrial, aquatic, and marine ecosystems. Recently, single-cell amplified genomes (SAGs) representing the “Latescibacteria” were obtained from the anoxic monimolimnion layers of Sakinaw Lake (British Columbia, Canada), and anoxic sediments of a coastal lagoon (Etoliko lagoon, Western Greece). Here, we present a detailed in-silico analysis of the four SAGs to gain some insights on their metabolic potential and apparent ecological roles. Metabolic reconstruction suggests an anaerobic fermentative mode of metabolism, as well as the capability to degrade multiple polysaccharides and glycoproteins that represent integral components of green (Charophyta and Chlorophyta) and brown (Phaeophycaea) algae cell walls (pectin, alginate, ulvan, fucan, hydroxyproline-rich glycoproteins), storage molecules (starch and trehalose), and extracellular polymeric substances (EPSs). The analyzed SAGs also encode dedicated transporters for the uptake of produced sugars and amino acids/oligopeptides, as well as an extensive machinery for the catabolism of all transported sugars, including the production of a bacterial microcompartment (BMC) to sequester propionaldehyde, a toxic intermediate produced during fucose and rhamnose metabolism. Finally, genes for the formation of gas vesicles, flagella, type IV pili, and oxidative stress response were found, features that could aid in cellular association with algal detritus. Collectively, these results indicate that the analyzed “Latescibacteria” mediate the turnover of multiple complex organic polymers of algal origin that reach deeper anoxic/microoxic habitats in lakes and lagoons. The implications of such process on our understanding of niche specialization in microbial communities mediating organic carbon turnover in stratified water bodies are discussed. PMID

  16. Low Luminosity States of the Black Hole Candidate GX 339-4. 2; Timing Analysis

    NASA Technical Reports Server (NTRS)

    Nowak, Michael A.; Wilms, Joern; Dove, James B.

    1999-01-01

    Here we present timing analysis of a set of eight Rossi X-ray Timing Explorer (RXTE) observations of the black hole candidate GX 339-4 that were taken during its hard/low state. On long time scales, the RXTE All Sky Monitor data reveal evidence of a 240 day periodicity, comparable to timescales expected from warped, precessing accretion disks. On short timescales all observations save one show evidence of a persistent f(qpo approximately equals 0.3 Hz quasi-periodic oscillations (QPO)). The broad band (10 (exp -3) to 10 (exp2) Hz) power appears to be dominated by two independent processes that can be modeled as very broad Lorentzians with Q approximately less than - 1. The coherence function between soft and hard photon variability shows that if these are truly independent processes, then they are individually coherent, but they are incoherent with one another. This is evidenced by the fact that the coherence function between the hard and soft variability is near unity between 5 x 10 (exp -3) but shows evidence of a dip at f approximately equals 1 Hz. This is the region of overlap between the broad Lorentzian fits to the Power Spectral Density (PSD). Similar to Cyg X-1, the coherence also drops dramatically at frequencies approximately greater than 1O Hz. Also similar to Cyg X-1, the hard photon variability is seen to lag the soft photon variability with the lag time increasing with decreasing Fourier frequency. The magnitude of this time lag appears to be positively correlated with the flux of GX 339-4. We discuss all of these observations in light of current theoretical models of both black hole spectra and temporal variability.

  17. Promoting Utilization of Saccharum spp. Genetic Resources through Genetic Diversity Analysis and Core Collection Construction

    PubMed Central

    Pathak, Bhuvan; Ayala-Silva, Tomas; Yang, Xiping; Todd, James; Glynn, Neil C.; Kuhn, David N.; Glaz, Barry; Gilbert, Robert A.; Comstock, Jack C.; Wang, Jianping

    2014-01-01

    Sugarcane (Saccharum spp.) and other members of Saccharum spp. are attractive biofuel feedstocks. One of the two World Collections of Sugarcane and Related Grasses (WCSRG) is in Miami, FL. This WCSRG has 1002 accessions, presumably with valuable alleles for biomass, other important agronomic traits, and stress resistance. However, the WCSRG has not been fully exploited by breeders due to its lack of characterization and unmanageable population. In order to optimize the use of this genetic resource, we aim to 1) genotypically evaluate all the 1002 accessions to understand its genetic diversity and population structure and 2) form a core collection, which captures most of the genetic diversity in the WCSRG. We screened 36 microsatellite markers on 1002 genotypes and recorded 209 alleles. Genetic diversity of the WCSRG ranged from 0 to 0.5 with an average of 0.304. The population structure analysis and principal coordinate analysis revealed three clusters with all S. spontaneum in one cluster, S. officinarum and S. hybrids in the second cluster and mostly non-Saccharum spp. in the third cluster. A core collection of 300 accessions was identified which captured the maximum genetic diversity of the entire WCSRG which can be further exploited for sugarcane and energy cane breeding. Sugarcane and energy cane breeders can effectively utilize this core collection for cultivar improvement. Further, the core collection can provide resources for forming an association panel to evaluate the traits of agronomic and commercial importance. PMID:25333358

  18. Promoting utilization of Saccharum spp. genetic resources through genetic diversity analysis and core collection construction.

    PubMed

    Nayak, Spurthi N; Song, Jian; Villa, Andrea; Pathak, Bhuvan; Ayala-Silva, Tomas; Yang, Xiping; Todd, James; Glynn, Neil C; Kuhn, David N; Glaz, Barry; Gilbert, Robert A; Comstock, Jack C; Wang, Jianping

    2014-01-01

    Sugarcane (Saccharum spp.) and other members of Saccharum spp. are attractive biofuel feedstocks. One of the two World Collections of Sugarcane and Related Grasses (WCSRG) is in Miami, FL. This WCSRG has 1002 accessions, presumably with valuable alleles for biomass, other important agronomic traits, and stress resistance. However, the WCSRG has not been fully exploited by breeders due to its lack of characterization and unmanageable population. In order to optimize the use of this genetic resource, we aim to 1) genotypically evaluate all the 1002 accessions to understand its genetic diversity and population structure and 2) form a core collection, which captures most of the genetic diversity in the WCSRG. We screened 36 microsatellite markers on 1002 genotypes and recorded 209 alleles. Genetic diversity of the WCSRG ranged from 0 to 0.5 with an average of 0.304. The population structure analysis and principal coordinate analysis revealed three clusters with all S. spontaneum in one cluster, S. officinarum and S. hybrids in the second cluster and mostly non-Saccharum spp. in the third cluster. A core collection of 300 accessions was identified which captured the maximum genetic diversity of the entire WCSRG which can be further exploited for sugarcane and energy cane breeding. Sugarcane and energy cane breeders can effectively utilize this core collection for cultivar improvement. Further, the core collection can provide resources for forming an association panel to evaluate the traits of agronomic and commercial importance. PMID:25333358

  19. SYNAPTONEMAL COMPLEX ANALYSIS IN GENETIC TOXICOLOGY

    EPA Science Inventory

    Synaptonemal complex analysis provides a unique means of visualizing the behavior of meiotic chromosomes. he technique has been applied to the study of normal karyotypes and mutant stocks of mice. ecent work demonstrating the usefulness of SC analysis for the detection of chromos...

  20. Toward the identification of the gene for Batten disease (CLN3) in 16p12 by physical mapping and analysis of candidate genes

    SciTech Connect

    Mole, S.E.; Jevelae, I.E.; Mitchison, H.M.

    1994-09-01

    CLN3 has been mapped genetically to 16p12, to the interval between D16S288 and D16S383, a sex-averaged genetic distance of 2.1 cM. Analysis of disease haplotypes from 134 families and four microsatellite markers in this interval, D16S288, D16S299, D16S298 and SPN, revealed significant allelic association between one allele at each of these loci and CLN3. All four of the associated markers have been used as nucleation sites in the isolation of genomic clones (YACs). A contig of approximately 860 Kb was assembled which contained three of the four associated markers and which confirmed the relative order of these markers. The distance between D16S288 and D16S299 is 430 Kb; that between D16S299 and D16S298 is less than 200 Kb. Marker D16S272 has been located on the physical map between D16S288 and D16S299. The YAC contig has now been extended towards the fourth associated marker. A detailed restriction map has revealed the location of possible CpG islands. Four cosmid contigs have been localized onto the physical map. Two genes, STP and STPM, have been mapped on the YAC contig proximal to D16S298 and are therefore candidates for CLN3. Sequence analysis of the coding region of these genes so far reveals no mutations.

  1. Analysis of Variance Components for Genetic Markers with Unphased Genotypes

    PubMed Central

    Wang, Tao

    2016-01-01

    An ANOVA type general multi-allele (GMA) model was proposed in Wang (2014) on analysis of variance components for quantitative trait loci or genetic markers with phased or unphased genotypes. In this study, by applying the GMA model, we further examine estimation of the genetic variance components for genetic markers with unphased genotypes based on a random sample from a study population. In one locus and two loci cases, we first derive the least square estimates (LSE) of model parameters in fitting the GMA model. Then we construct estimators of the genetic variance components for one marker locus in a Hardy-Weinberg disequilibrium population and two marker loci in an equilibrium population. Meanwhile, we explore the difference between the classical general linear model (GLM) and GMA based approaches in association analysis of genetic markers with quantitative traits. We show that the GMA model can retain the same partition on the genetic variance components as the traditional Fisher's ANOVA model, while the GLM cannot. We clarify that the standard F-statistics based on the partial reductions in sums of squares from GLM for testing the fixed allelic effects could be inadequate for testing the existence of the variance component when allelic interactions are present. We point out that the GMA model can reduce the confounding between the allelic effects and allelic interactions at least for independent alleles. As a result, the GMA model could be more beneficial than GLM for detecting allelic interactions. PMID:27468297

  2. Quantitative genetic analysis of injury liability in infants and toddlers

    SciTech Connect

    Phillips, K.; Matheny, A.P. Jr.

    1995-02-27

    A threshold model of latent liability was applied to infant and toddler twin data on total count of injuries sustained during the interval from birth to 36 months of age. A quantitative genetic analysis of estimated twin correlations in injury liability indicated strong genetic dominance effects, but no additive genetic variance was detected. Because interpretations involving overdominance have little research support, the results may be due to low order epistasis or other interaction effects. Boys had more injuries than girls, but this effect was found only for groups whose parents were prompted and questioned in detail about their children`s injuries. Activity and impulsivity are two behavioral predictors of childhood injury, and the results are discussed in relation to animal research on infant and adult activity levels, and impulsivity in adult humans. Genetic epidemiological approaches to childhood injury should aid in targeting higher risk children for preventive intervention. 30 refs., 4 figs., 3 tabs.

  3. Fine Mapping and Candidate Gene Analysis of the Leaf-Color Gene ygl-1 in Maize.

    PubMed

    Guan, Haiying; Xu, Xiangbo; He, Chunmei; Liu, Chunxiao; Liu, Qiang; Dong, Rui; Liu, Tieshan; Wang, Liming

    2016-01-01

    A novel yellow-green leaf mutant yellow-green leaf-1 (ygl-1) was isolated in self-pollinated progenies from the cross of maize inbred lines Ye478 and Yuanwu02. The mutant spontaneously showed yellow-green character throughout the lifespan. Meanwhile, the mutant reduced contents of chlorophyll and Car, arrested chloroplast development and lowered the capacity of photosynthesis compared with the wild-type Lx7226. Genetic analysis revealed that the mutant phenotype was controlled by a recessive nuclear gene. The ygl-1 locus was initially mapped to an interval of about 0.86 Mb in bin 1.01 on the short arm of chromosome 1 using 231 yellow-green leaf individuals of an F2 segregating population from ygl-1/Lx7226. Utilizing four new polymorphic SSR markers, the ygl-1 locus was narrowed down to a region of about 48 kb using 2930 and 2247 individuals of F2 and F3 mapping populations, respectively. Among the three predicted genes annotated within this 48 kb region, GRMZM2G007441, which was predicted to encode a cpSRP43 protein, had a 1-bp nucleotide deletion in the coding region of ygl-1 resulting in a frame shift mutation. Semi-quantitative RT-PCR analysis revealed that YGL-1 was constitutively expressed in all tested tissues and its expression level was not significantly affected in the ygl-1 mutant from early to mature stages, while light intensity regulated its expression both in the ygl-1 mutant and wild type seedlings. Furthermore, the mRNA levels of some genes involved in chloroplast development were affected in the six-week old ygl-1 plants. These findings suggested that YGL-1 plays an important role in chloroplast development of maize. PMID:27100184

  4. Fine Mapping and Candidate Gene Analysis of the Leaf-Color Gene ygl-1 in Maize

    PubMed Central

    Guan, Haiying; Xu, Xiangbo; He, Chunmei; Liu, Chunxiao; Liu, Qiang; Dong, Rui; Liu, Tieshan; Wang, Liming

    2016-01-01

    A novel yellow-green leaf mutant yellow-green leaf-1 (ygl-1) was isolated in self-pollinated progenies from the cross of maize inbred lines Ye478 and Yuanwu02. The mutant spontaneously showed yellow-green character throughout the lifespan. Meanwhile, the mutant reduced contents of chlorophyll and Car, arrested chloroplast development and lowered the capacity of photosynthesis compared with the wild-type Lx7226. Genetic analysis revealed that the mutant phenotype was controlled by a recessive nuclear gene. The ygl-1 locus was initially mapped to an interval of about 0.86 Mb in bin 1.01 on the short arm of chromosome 1 using 231 yellow-green leaf individuals of an F2 segregating population from ygl-1/Lx7226. Utilizing four new polymorphic SSR markers, the ygl-1 locus was narrowed down to a region of about 48 kb using 2930 and 2247 individuals of F2 and F3 mapping populations, respectively. Among the three predicted genes annotated within this 48 kb region, GRMZM2G007441, which was predicted to encode a cpSRP43 protein, had a 1-bp nucleotide deletion in the coding region of ygl-1 resulting in a frame shift mutation. Semi-quantitative RT-PCR analysis revealed that YGL-1 was constitutively expressed in all tested tissues and its expression level was not significantly affected in the ygl-1 mutant from early to mature stages, while light intensity regulated its expression both in the ygl-1 mutant and wild type seedlings. Furthermore, the mRNA levels of some genes involved in chloroplast development were affected in the six-week old ygl-1 plants. These findings suggested that YGL-1 plays an important role in chloroplast development of maize. PMID:27100184

  5. Seeking genetic signature of radiosensitivity - a novel method for data analysis in case of small sample sizes

    PubMed Central

    2014-01-01

    Background The identification of polymorphisms and/or genes responsible for an organism's radiosensitivity increases the knowledge about the cell cycle and the mechanism of the phenomena themselves, possibly providing the researchers with a better understanding of the process of carcinogenesis. Aim The aim of the study was to develop a data analysis strategy capable of discovering the genetic background of radiosensitivity in the case of small sample size studies. Results Among many indirect measures of radiosensitivity known, the level of radiation-induced chromosomal aberrations was used in the study. Mathematical modelling allowed the transformation of the yield-time curve of radiation-induced chromosomal aberrations into the exponential curve with limited number of parameters, while Gaussian mixture models applied to the distributions of these parameters provided the criteria for mouse strain classification. A detailed comparative analysis of genotypes between the obtained subpopulations of mice followed by functional validation provided a set of candidate polymorphisms that might be related to radiosensitivity. Among 1857 candidate relevant SNPs, that cluster in 28 genes, eight SNPs were detected nonsynonymous (nsSNP) on protein function. Two of them, rs48840878 (gene Msh3) and rs5144199 (gene Cc2d2a), were predicted as having increased probability of a deleterious effect. Additionally, rs48840878 is capable of disordering phosphorylation with 14 PKs. In silico analysis of candidate relevant SNP similarity score distribution among 60 CGD mouse strains allowed for the identification of SEA/GnJ and ZALENDE/EiJ mouse strains (95.26% and 86.53% genetic consistency respectively) as the most similar to radiosensitive subpopulation Conclusions A complete step-by-step strategy for seeking the genetic signature of radiosensitivity in the case of small sample size studies conducted on mouse models was proposed. It is shown that the strategy, which is a combination of

  6. Efficient set tests for the genetic analysis of correlated traits.

    PubMed

    Casale, Francesco Paolo; Rakitsch, Barbara; Lippert, Christoph; Stegle, Oliver

    2015-08-01

    Set tests are a powerful approach for genome-wide association testing between groups of genetic variants and quantitative traits. We describe mtSet (http://github.com/PMBio/limix), a mixed-model approach that enables joint analysis across multiple correlated traits while accounting for population structure and relatedness. mtSet effectively combines the benefits of set tests with multi-trait modeling and is computationally efficient, enabling genetic analysis of large cohorts (up to 500,000 individuals) and multiple traits. PMID:26076425

  7. Comparing G: multivariate analysis of genetic variation in multiple populations.

    PubMed

    Aguirre, J D; Hine, E; McGuigan, K; Blows, M W

    2014-01-01

    The additive genetic variance-covariance matrix (G) summarizes the multivariate genetic relationships among a set of traits. The geometry of G describes the distribution of multivariate genetic variance, and generates genetic constraints that bias the direction of evolution. Determining if and how the multivariate genetic variance evolves has been limited by a number of analytical challenges in comparing G-matrices. Current methods for the comparison of G typically share several drawbacks: metrics that lack a direct relationship to evolutionary theory, the inability to be applied in conjunction with complex experimental designs, difficulties with determining statistical confidence in inferred differences and an inherently pair-wise focus. Here, we present a cohesive and general analytical framework for the comparative analysis of G that addresses these issues, and that incorporates and extends current methods with a strong geometrical basis. We describe the application of random skewers, common subspace analysis, the 4th-order genetic covariance tensor and the decomposition of the multivariate breeders equation, all within a Bayesian framework. We illustrate these methods using data from an artificial selection experiment on eight traits in Drosophila serrata, where a multi-generational pedigree was available to estimate G in each of six populations. One method, the tensor, elegantly captures all of the variation in genetic variance among populations, and allows the identification of the trait combinations that differ most in genetic variance. The tensor approach is likely to be the most generally applicable method to the comparison of G-matrices from any sampling or experimental design. PMID:23486079

  8. Genetic diversity analysis of common beans based on molecular markers.

    PubMed

    Gill-Langarica, Homar R; Muruaga-Martínez, José S; Vargas-Vázquez, M L Patricia; Rosales-Serna, Rigoberto; Mayek-Pérez, Netzahualcoyotl

    2011-10-01

    A core collection of the common bean (Phaseolus vulgaris L.), representing genetic diversity in the entire Mexican holding, is kept at the INIFAP (Instituto Nacional de Investigaciones Forestales, Agricolas y Pecuarias, Mexico) Germplasm Bank. After evaluation, the genetic structure of this collection (200 accessions) was compared with that of landraces from the states of Oaxaca, Chiapas and Veracruz (10 genotypes from each), as well as a further 10 cultivars, by means of four amplified fragment length polymorphisms (AFLP) +3/+3 primer combinations and seven simple sequence repeats (SSR) loci, in order to define genetic diversity, variability and mutual relationships. Data underwent cluster (UPGMA) and molecular variance (AMOVA) analyses. AFLP analysis produced 530 bands (88.5% polymorphic) while SSR primers amplified 174 alleles, all polymorphic (8.2 alleles per locus). AFLP indicated that the highest genetic diversity was to be found in ten commercial-seed classes from two major groups of accessions from Central Mexico and Chiapas, which seems to be an important center of diversity in the south. A third group included genotypes from Nueva Granada, Mesoamerica, Jalisco and Durango races. Here, SSR analysis indicated a reduced number of shared haplotypes among accessions, whereas the highest genetic components of AMOVA variation were found within accessions. Genetic diversity observed in the common-bean core collection represents an important sample of the total Phaseolus genetic variability at the main Germplasm Bank of INIFAP. Molecular marker strategies could contribute to a better understanding of the genetic structure of the core collection as well as to its improvement and validation. PMID:22215964

  9. Genetic diversity analysis of common beans based on molecular markers

    PubMed Central

    Gill-Langarica, Homar R.; Muruaga-Martínez, José S.; Vargas-Vázquez, M.L. Patricia; Rosales-Serna, Rigoberto; Mayek-Pérez, Netzahualcoyotl

    2011-01-01

    A core collection of the common bean (Phaseolus vulgaris L.), representing genetic diversity in the entire Mexican holding, is kept at the INIFAP (Instituto Nacional de Investigaciones Forestales, Agricolas y Pecuarias, Mexico) Germplasm Bank. After evaluation, the genetic structure of this collection (200 accessions) was compared with that of landraces from the states of Oaxaca, Chiapas and Veracruz (10 genotypes from each), as well as a further 10 cultivars, by means of four amplified fragment length polymorphisms (AFLP) +3/+3 primer combinations and seven simple sequence repeats (SSR) loci, in order to define genetic diversity, variability and mutual relationships. Data underwent cluster (UPGMA) and molecular variance (AMOVA) analyses. AFLP analysis produced 530 bands (88.5% polymorphic) while SSR primers amplified 174 alleles, all polymorphic (8.2 alleles per locus). AFLP indicated that the highest genetic diversity was to be found in ten commercial-seed classes from two major groups of accessions from Central Mexico and Chiapas, which seems to be an important center of diversity in the south. A third group included genotypes from Nueva Granada, Mesoamerica, Jalisco and Durango races. Here, SSR analysis indicated a reduced number of shared haplotypes among accessions, whereas the highest genetic components of AMOVA variation were found within accessions. Genetic diversity observed in the common-bean core collection represents an important sample of the total Phaseolus genetic variability at the main Germplasm Bank of INIFAP. Molecular marker strategies could contribute to a better understanding of the genetic structure of the core collection as well as to its improvement and validation. PMID:22215964

  10. Combining genetic mapping with genome-wide expression in experimental autoimmune encephalomyelitis highlights a gene network enriched for T cell functions and candidate genes regulating autoimmunity

    PubMed Central

    Thessen Hedreul, Melanie; Möller, Steffen; Stridh, Pernilla; Gupta, Yask; Gillett, Alan; Daniel Beyeen, Amennai; Öckinger, Johan; Flytzani, Sevasti; Diez, Margarita; Olsson, Tomas; Jagodic, Maja

    2013-01-01

    The experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease of the central nervous system commonly used to study multiple sclerosis (MS). We combined clinical EAE phenotypes with genome-wide expression profiling in spleens from 150 backcross rats between susceptible DA and resistant PVG rat strains during the chronic EAE phase. This enabled correlation of transcripts with genotypes, other transcripts and clinical EAE phenotypes and implicated potential genetic causes and pathways in EAE. We detected 2285 expression quantitative trait loci (eQTLs). Sixty out of 599 cis-eQTLs overlapped well-known EAE QTLs and constitute positional candidate genes, including Ifit1 (Eae7), Atg7 (Eae20-22), Klrc3 (eEae22) and Mfsd4 (Eae17). A trans-eQTL that overlaps Eae23a regulated a large number of small RNAs and implicates a master regulator of transcription. We defined several disease-correlated networks enriched for pathways involved in cell-mediated immunity. They include C-type lectins, G protein coupled receptors, mitogen-activated protein kinases, transmembrane proteins, suppressors of transcription (Jundp2 and Nr1d1) and STAT transcription factors (Stat4) involved in interferon signaling. The most significant network was enriched for T cell functions, similar to genetic findings in MS, and revealed both established and novel gene interactions. Transcripts in the network have been associated with T cell proliferation and differentiation, the TCR signaling and regulation of regulatory T cells. A number of network genes and their family members have been associated with MS and/or other autoimmune diseases. Combining disease and genome-wide expression phenotypes provides a link between disease risk genes and distinct molecular pathways that are dysregulated during chronic autoimmune inflammation. PMID:23900079

  11. Genetics

    MedlinePlus

    Homozygous; Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of ...

  12. Genetics

    MedlinePlus

    ... Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of ...

  13. Fine mapping and candidate gene analysis of hwh1 and hwh2, a set of complementary genes controlling hybrid breakdown in rice.

    PubMed

    Jiang, Wenzhu; Chu, Sang-Ho; Piao, Rihua; Chin, Joong-Hyoun; Jin, Yong-Mei; Lee, Joohyun; Qiao, Yongli; Han, Longzhi; Piao, Zongze; Koh, Hee-Jong

    2008-05-01

    Hybrid breakdown (HB), a phenomenon of reduced viability or fertility accompanied with retarded growth in hybrid progenies, often arises in the offspring of intersubspecific hybrids between indica and japonica in rice. We detected HB plants in F8 recombinant inbred lines derived from the cross between an indica variety, Milyang 23, and a japonica variety, Tong 88-7. HB plants showed retarded growth, with fewer tillers and spikelets. Genetic analysis revealed that HB was controlled by the complementary action of two recessive genes, hwh1 and hwh2, originating from each of both parents, which were fine-mapped on the short arm of chromosome 2 and on the near centromere region of the long arm of chromosome 11, respectively. A comparison of the sequences of candidate genes among both parents and HB plants revealed that hwh1 encoded a putative glucose-methanol-choline oxidoreductase with one amino acid change compared to Hwh1 and that hwh2 probably encoded a putative hexose transporter with a six amino acid insertion compared to Hwh2. Investigation of the distribution of these alleles among 54 japonica and indica cultivars using candidate gene-based markers suggested that the two loci might be involved in developing reproductive barriers between two subspecies. PMID:18335199

  14. RNA-seq analysis reveals new candidate genes for drip loss in a Pietrain × Duroc × Landrace × Yorkshire population.

    PubMed

    Li, Bojiang; Liu, Kaiqing; Weng, Qiannan; Li, Pinghua; Wei, Wei; Li, Qifa; Chen, Jie; Huang, Ruihua; Wu, Wangjun; Liu, Honglin

    2016-04-01

    Drip loss, one of the most important meat quality traits, is characterized by low heritability. To date, the genetic factors affecting the drip loss trait have not been clearly elucidated. The objective of this study was to identify critical candidate genes affecting drip loss. First, we generated a Pietrain × Duroc × Landrace × Yorkshire commercial pig population and obtained phenotypic values for the drip loss trait. Furthermore, we constructed two RNA libraries from pooled samples of longissimus dorsi muscles with the highest (H group) and lowest (L group) drip loss and identified the differentially expressed genes (DEGs) between these extreme phenotypes using RNA-seq technology. In total, 25 883 genes were detected in the H and L group libraries, and none was specifically expressed in only one library. Comparative analysis of gene expression levels found that 150 genes were differentially expressed, of which 127 were upregulated and 23 were downregulated in the H group relative to the L group. In addition, 68 drip loss quantitative trait loci (QTL) overlapping with 63 DEGs were identified, and these QTL were distributed mainly on chromosomes 1, 2, 5 and 6. Interestingly, the triadin (TRDN) gene, which is involved in muscle contraction and fat deposition, and the myostatin (MSTN) gene, which has a role in muscle growth, were localized to more than two drip loss QTL, suggesting that both are critical candidate genes responsible for drip loss. PMID:26873330

  15. The population genetics of familial mediterranean fever: a meta-analysis study.

    PubMed

    Papadopoulos, V P; Giaglis, S; Mitroulis, I; Ritis, K

    2008-11-01

    Our aim was to construct a Familial Mediterranean Fever (FMF) cumulative database and to propose a MEFV based phylogenetic tree. Data were collected from published studies. A meta-analysis based on 16,756 chromosomes from FMF patients and normal individuals from 14 affected populations was performed. Arlequin 2.0 and Phylip 3.2 software were used for population genetics analysis and phylogenetic tree construction. We have shown that MEFV mutations are distributed non-uniformly along the Mediterranean Sea area. The most frequent mutations detected in FMF patients are M694V (39.6%), V726A (13.9%), M680I (11.4%), E148Q (3.4%), and M694I (2.9%), while 28.8% of chromosomes carry unidentified or no mutations, especially in Western Europeans. The mean overall carrier rate is 0.186 with peak values in Arabs, Armenians, Jews, and Turks. Only V726A obeys the Hardy-Weinberg law in FMF patients implying that this mutation is the most ancient. Jews present the most intense genetic isolation and drift; thus they might have nested de novo mutations and accelerated evolution. Besides Jews, three population groups might follow distinct evolutionary lines (Asia Minor, Eastern European, and Western European). In conclusion, the MEFV mutation pattern is non-uniform regarding distribution, phenotypic expression, neutrality and population genetics characteristics. Jews are the candidate population for founder effects in MEFV. PMID:18691160

  16. Receiver Operating Characteristic Curve Analysis of Wechsler Memory Scale-Revised Scores in Epilepsy Surgery Candidates.

    ERIC Educational Resources Information Center

    Barr, William B.

    1997-01-01

    Wechsler Memory Scale-Revised (WMS-R) scores were analyzed for 82 epilepsy surgery candidates and used in combination with receiver operating characteristic curves to classify patients with left (LTL) and right (RTL) temporal lobe seizure onset. Results indicate that WMS-R scores used alone or in combination provide relatively poor discrimination…

  17. A Candidate Gene Analysis of Methylphenidate Response in Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    McGough, James J.; McCracken, James T.; Loo, Sandra K.; Manganiello, Marc; Leung, Michael C.; Tietjens, Jeremy R.; Trinh, Thao; Baweja, Shilpa; Suddath, Robert; Smalley, Susan L.; Hellemann, Gerhard; Sugar, Catherine A.

    2009-01-01

    Objective: This study examines the potential role of candidate genes in moderating treatment effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD). Method: Eighty-two subjects with ADHD aged 6 to 17 years participated in a prospective, double-blind, placebo-controlled, multiple-dose, crossover titration trial of…

  18. An Analysis of Mathematics Teacher Candidates' Critical Thinking Dispositions and Their Logical Thinking Skills

    ERIC Educational Resources Information Center

    Incikabi, Lutfi; Tuna, Abdulkadir; Biber, Abdullah Cagri

    2013-01-01

    This study aimed to investigate the existence of the relationship between mathematics teacher candidates' critical thinking skills and their logical thinking dispositions in terms of the variables of grade level in college, high school type, and gender. The current study utilized relational survey model and included a total of 99 mathematics…

  19. The Analysis of the Understanding Levels of Teacher Candidates in Different Departments about Basic Astronomy Concepts

    ERIC Educational Resources Information Center

    Durukan, Ümmü Gülsüm; Saglam-Arslan, Aysegül

    2015-01-01

    Learners face a variety of concepts during the instructional process they experience. These concepts are mostly introduced by teachers; thus, the competences of teachers in terms of teaching concepts are vitally important. The aim of this study is to detect the understanding levels of teacher candidates about basic astronomy concepts. The method…

  20. A genetic analysis of Adh1 regulation

    SciTech Connect

    Freeling, M.

    1992-01-01

    The overall goal of our research proposal is to understand the meaning of the various cis-acting sites responsible for AdH1 expression in the entire maize plant. Progress is reported in the following areas: Studies on the TATA box and analysis of revertants of the Adh1-3F1124 allele; screening for more different mutants that affect Adh1 expression differentially; studies on cis-acting sequences required for root-specific Adh1 expression; refinement of the use of the particle gun; and functional analysis of a non- glycolytic anaerobic protein.

  1. Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from Meta-analysis.

    PubMed

    Webster, Jennifer; Reiman, Eric M; Zismann, Victoria L; Joshipura, Keta D; Pearson, John V; Hu-Lince, Diane; Huentelman, Matthew J; Craig, David W; Coon, Keith D; Beach, Thomas; Rohrer, Kristen C; Zhao, Alice S; Leung, Doris; Bryden, Leslie; Marlowe, Lauren; Kaleem, Mona; Mastroeni, Diego; Grover, Andrew; Rogers, Joseph; Heun, Reinhard; Jessen, Frank; Kölsch, Heike; Heward, Christopher B; Ravid, Rivka; Hutton, Michael L; Melquist, Stacey; Petersen, Ron C; Caselli, Richard J; Papassotiropoulos, Andreas; Stephan, Dietrich A; Hardy, John; Myers, Amanda

    2010-01-01

    For late onset Alzheimer's disease (LOAD), the only confirmed, genetic association is with the apolipoprotein E (APOE) locus on chromosome 19. Meta-analysis is often employed to sort the true associations from the false positives. LOAD research has the advantage of a continuously updated meta-analysis of candidate gene association studies in the web-based AlzGene database. The top 30 AlzGene loci on May 1(st), 2007 were investigated in our whole genome association data set consisting of 1411 LOAD cases and neuropathoiogicaiiy verified controls genotyped at 312,316 SNPs using the Affymetrix 500K Mapping Platform. Of the 30 "top AlzGenes", 32 SNPs in 24 genes had odds ratios (OR) whose 95% confidence intervals that did not include 1. Of these 32 SNPs, six were part of the Affymetrix 500K Mapping panel and another ten had proxies on the Affymetrix array that had >80% power to detect an association with α=0.001. Two of these 16 SNPs showed significant association with LOAD in our sample series. One was rs4420638 at the APOE locus (uncorrected p-value=4.58E-37) and the other was rs4293, located in the angiotensin converting enzyme (ACE) locus (uncorrected p-value=0.014). Since this result was nominally significant, but did not survive multiple testing correction for 16 independent tests, this association at rs4293 was verified in a geographically distinct German cohort (p-value=0.03). We present the results of our ACE replication aiongwith a discussion of the statistical limitations of multiple test corrections in whole genome studies. PMID:21537449

  2. Identification of candidates for cyclotide biosynthesis and cyclisation by expressed sequence tag analysis of Oldenlandia affinis

    PubMed Central

    2010-01-01

    Background Cyclotides are a family of circular peptides that exhibit a range of biological activities, including anti-bacterial, cytotoxic, anti-HIV activities, and are proposed to function in plant defence. Their high stability has motivated their development as scaffolds for the stabilisation of peptide drugs. Oldenlandia affinis is a member of the Rubiaceae (coffee) family from which 18 cyclotides have been sequenced to date, but the details of their processing from precursor proteins have only begun to be elucidated. To increase the speed at which genes involved in cyclotide biosynthesis and processing are being discovered, an expressed sequence tag (EST) project was initiated to survey the transcript profile of O. affinis and to propose some future directions of research on in vivo protein cyclisation. Results Using flow cytometry the holoploid genome size (1C-value) of O. affinis was estimated to be 4,210 - 4,284 Mbp, one of the largest genomes of the Rubiaceae family. High-quality ESTs were identified, 1,117 in total, from leaf cDNAs and assembled into 502 contigs, comprising 202 consensus sequences and 300 singletons. ESTs encoding the cyclotide precursors for kalata B1 (Oak1) and kalata B2 (Oak4) were among the 20 most abundant ESTs. In total, 31 ESTs encoded cyclotide precursors, representing a distinct commitment of 2.8% of the O. affinis transcriptome to cyclotide biosynthesis. The high expression levels of cyclotide precursor transcripts are consistent with the abundance of mature cyclic peptides in O. affinis. A new cyclotide precursor named Oak5 was isolated and represents the first cDNA for the bracelet class of cyclotides in O. affinis. Clones encoding enzymes potentially involved in processing cyclotides were also identified and include enzymes involved in oxidative folding and proteolytic processing. Conclusion The EST library generated in this study provides a valuable resource for the study of the cyclisation of plant peptides. Further analysis

  3. Discovery of candidate genes for muscle traits based on GWAS supported by eQTL-analysis.

    PubMed

    Ponsuksili, Siriluck; Murani, Eduard; Trakooljul, Nares; Schwerin, Manfred; Wimmers, Klaus

    2014-01-01

    Biochemical and biophysical processes that take place in muscle under relaxed and stressed conditions depend on the abundance and activity of gene products of metabolic and structural pathways. In livestock at post-mortem, these muscle properties determine aspects of meat quality and are measurable. The conversion of muscle to meat mimics pathological processes associated with muscle ischemia, injury or damage in humans and it is an economic factor in pork production. Linkage, association, and expression analyses independently contributed to the identification of trait-associated molecular pathways and genes. We aim at providing multiple evidences for the role of specific genes in meat quality by integrating a genome-wide association study (GWAS) for meat quality traits and the detection of eQTL based on trait-correlated expressed genes and trait-associated markers. The GWAS revealed 51 and 200 SNPs significantly associated with meat quality in a crossbred Pietrain×(German Landrace×Large White) (Pi×(GL×LW)) and a purebred German Landrace (GL) population, respectively. Most significant SNPs in Pi×(GL×LW) were located on chromosomes (SSC) 4 and 6. The data of 47,836 eQTLs at a significance level of p<10(-5) were used to scale down the number candidate genes located in these regions. These SNPs on SSC4 showed association with expression levels of ZNF704, IMPA1, and OXSR1; SSC6 SNPs were associated with expression of SIGLEC10 and PIH1D1. Most significant SNPs in GL were located on SSC6 and associated with expression levels of PIH1D1, SIGLEC10, TBCB, LOC100518735, KIF1B, LOC100514845, and two unknown genes. The abundance of transcripts of these genes in muscle, in turn, is significantly correlated with meat quality traits. We identified several genes with evidence for their candidacy for meat quality arising from the integrative approach of a genome-wide association study and eQTL analysis. PMID:24643240

  4. A scalable, knowledge-based analysis framework for genetic association studies

    PubMed Central

    2013-01-01

    Background Testing for marginal associations between numerous genetic variants and disease may miss complex relationships among variables (e.g., gene-gene interactions). Bayesian approaches can model multiple variables together and offer advantages over conventional model building strategies, including using existing biological evidence as modeling priors and acknowledging that many models may fit the data well. With many candidate variables, Bayesian approaches to variable selection rely on algorithms to approximate the posterior distribution of models, such as Markov-Chain Monte Carlo (MCMC). Unfortunately, MCMC is difficult to parallelize and requires many iterations to adequately sample the posterior. We introduce a scalable algorithm called PEAK that improves the efficiency of MCMC by dividing a large set of variables into related groups using a rooted graph that resembles a mountain peak. Our algorithm takes advantage of parallel computing and existing biological databases when available. Results By using graphs to manage a model space with more than 500,000 candidate variables, we were able to improve MCMC efficiency and uncover the true simulated causal variables, including a gene-gene interaction. We applied PEAK to a case-control study of childhood asthma with 2,521 genetic variants. We used an informative graph for oxidative stress derived from Gene Ontology and identified several variants in ERBB4, OXR1, and BCL2 with strong evidence for associations with childhood asthma. Conclusions We introduced an extremely flexible analysis framework capable of efficiently performing Bayesian variable selection on many candidate variables. The PEAK algorithm can be provided with an informative graph, which can be advantageous when considering gene-gene interactions, or a symmetric graph, which simply divides the model space into manageable regions. The PEAK framework is compatible with various model forms, allowing for the algorithm to be configured for different

  5. Analysis of genetic diversity of Lactarius hatsudake in south China.

    PubMed

    He, Li; Liang, Guo; Guoying, Zhou; Jun-ang, Liu

    2011-08-01

    Lactarius hatsudake is a type of ectomycorrhizal fungus that significantly influences the growth of pine trees. It is widely prevalent in Asian countries and has a high economic value. Artificial cultivation of this fungus has not been achieved as yet; therefore, excessive manual harvesting may cause serious damages to the site of its production. In this study, we analyzed 41 samples of L. hatsudake from south China using internal transcribed spacer (ITS) sequences. By comparing the differences among ITS sequences to identify the haplotype diversity within each population, the relationships among local populations, the relationship between the level of genetic differentiation and geographical separation, and the contributions of local and regional geographical separations to the overall ITS haplotype variation were analyzed. Genetic analysis indicates that ITS sequences obtained from these 41 L. hatsudake samples could be identified as 18 haplotypes, of which 13 haplotypes were contained in only a single sample, whereas the remaining sequence types all were contained in two or more samples. The most common sequence type, haplotype 6, was found in 16 samples and was distributed across nearly every region. The Mantel test demonstrated that there is no significant linear relationship between geographical distance and the F(ST) value of genetic difference. Results of this research illustrates that there exists a certain degree of genetic intermixing among natural populations of L. hatsudake. From the group genetic analysis, it appears that there exists genetic differentiation of lower frequencies in natural populations of L. hatsudake; however, the linear relationship between the degree of genetic differentiation and geographical distance is not distinctly apparent. PMID:21815833

  6. Genetic diversity of popcorn genotypes using molecular analysis.

    PubMed

    Resh, F S; Scapim, C A; Mangolin, C A; Machado, M F P S; do Amaral, A T; Ramos, H C C; Vivas, M

    2015-01-01

    In this study, we analyzed dominant molecular markers to estimate the genetic divergence of 26 popcorn genotypes and evaluate whether using various dissimilarity coefficients with these dominant markers influences the results of cluster analysis. Fifteen random amplification of polymorphic DNA primers produced 157 amplified fragments, of which 65 were monomorphic and 92 were polymorphic. To calculate the genetic distances among the 26 genotypes, the complements of the Jaccard, Dice, and Rogers and Tanimoto similarity coefficients were used. A matrix of Dij values (dissimilarity matrix) was constructed, from which the genetic distances among genotypes were represented in a more simplified manner as a dendrogram generated using the unweighted pair-group method with arithmetic average. Clusters determined by molecular analysis generally did not group material from the same parental origin together. The largest genetic distance was between varieties 17 (UNB-2) and 18 (PA-091). In the identification of genotypes with the smallest genetic distance, the 3 coefficients showed no agreement. The 3 dissimilarity coefficients showed no major differences among their grouping patterns because agreement in determining the genotypes with large, medium, and small genetic distances was high. The largest genetic distances were observed for the Rogers and Tanimoto dissimilarity coefficient (0.74), followed by the Jaccard coefficient (0.65) and the Dice coefficient (0.48). The 3 coefficients showed similar estimations for the cophenetic correlation coefficient. Correlations among the matrices generated using the 3 coefficients were positive and had high magnitudes, reflecting strong agreement among the results obtained using the 3 evaluated dissimilarity coefficients. PMID:26345916

  7. Molecular analysis of genetic diseases: an overview for clinicians.

    PubMed

    Javed, A A; Huang, Y; Bombard, A T

    1995-01-01

    The identification of fetal genetic disease has, for the most part, relied on examination of an end product, such as analysis of factor VIII levels obtained from cord blood in fetuses at risk for hemophilia. Advances in molecular genetics have shifted our focus in prenatal diagnosis away from protein product analysis toward etiology, making new discoveries gleaned from the Human Genome Project relevant to clinicians. This review discusses the basic principles involved in gene-based diagnosis, highlighting the complexities of current approaches to molecular diagnosis of fetal genetic disease. Given an understanding of both the theory and practice of genetic analysis, the review covers the fundamental principles of molecular biology (structure, function, packaging, and regulation) and discusses recombinant DNA techniques presently used for the analysis of mutations. Clinical examples are presented to introduce the techniques most commonly employed in service laboratories: direct detection assays, where the specific mutation is recognized, and indirect detection assays, useful for the deduction of an inheritance pattern where the actual mutation or its gene is not known but may be closely linked to known DNA polymorphisms. PMID:7858372

  8. Multivariate Genetic Analysis of Learning and Early Reading Development

    ERIC Educational Resources Information Center

    Byrne, Brian; Wadsworth, Sally; Boehme, Kristi; Talk, Andrew C.; Coventry, William L.; Olson, Richard K.; Samuelsson, Stefan; Corley, Robin

    2013-01-01

    The genetic factor structure of a range of learning measures was explored in twin children, recruited in preschool and followed to Grade 2 ("N"?=?2,084). Measures of orthographic learning and word reading were included in the analyses to determine how these patterned with the learning processes. An exploratory factor analysis of the…

  9. Understanding genetics: Analysis of secondary students' conceptual status

    NASA Astrophysics Data System (ADS)

    Tsui, Chi-Yan; Treagust, David F.

    2007-02-01

    This article explores the conceptual change of students in Grades 10 and 12 in three Australian senior high schools when the teachers included computer multimedia to a greater or lesser extent in their teaching of a genetics course. The study, underpinned by a multidimensional conceptual-change framework, used an interpretive approach and a case-based design with multiple data collection methods. Over 4-8 weeks, the students learned genetics in classroom lessons that included BioLogica activities, which feature multiple representations. Results of the online tests and interview tasks revealed that most students improved their understanding of genetics as evidenced in the development of genetics reasoning. However, using Thorley's (1990) status analysis categories, a cross-case analysis of the gene conceptions of 9 of the 26 students interviewed indicated that only 4 students' postinstructional conceptions were intelligible-plausible-fruitful. Students' conceptual change was consistent with classroom teaching and learning. Findings suggested that multiple representations supported conceptual understanding of genetics but not in all students. It was also shown that status can be a viable hallmark enabling researchers to identify students' conceptual change that would otherwise be less accessible. Thorley's method for analyzing conceptual status is discussed.

  10. Castor Bean Organelle Genome Sequencing and Worldwide Genetic Diversity Analysis

    PubMed Central

    Chan, Agnes P.; Williams, Amber L.; Rice, Danny W.; Liu, Xinyue; Melake-Berhan, Admasu; Huot Creasy, Heather; Puiu, Daniela; Rosovitz, M. J.; Khouri, Hoda M.; Beckstrom-Sternberg, Stephen M.; Allan, Gerard J.; Keim, Paul; Ravel, Jacques; Rabinowicz, Pablo D.

    2011-01-01

    Castor bean is an important oil-producing plant in the Euphorbiaceae family. Its high-quality oil contains up to 90% of the unusual fatty acid ricinoleate, which has many industrial and medical applications. Castor bean seeds also contain ricin, a highly toxic Type 2 ribosome-inactivating protein, which has gained relevance in recent years due to biosafety concerns. In order to gain knowledge on global genetic diversity in castor bean and to ultimately help the development of breeding and forensic tools, we carried out an extensive chloroplast sequence diversity analysis. Taking advantage of the recently published genome sequence of castor bean, we assembled the chloroplast and mitochondrion genomes extracting selected reads from the available whole genome shotgun reads. Using the chloroplast reference genome we used the methylation filtration technique to readily obtain draft genome sequences of 7 geographically and genetically diverse castor bean accessions. These sequence data were used to identify single nucleotide polymorphism markers and phylogenetic analysis resulted in the identification of two major clades that were not apparent in previous population genetic studies using genetic markers derived from nuclear DNA. Two distinct sub-clades could be defined within each major clade and large-scale genotyping of castor bean populations worldwide confirmed previously observed low levels of genetic diversity and showed a broad geographic distribution of each sub-clade. PMID:21750729

  11. GENETIC ASSOCIATION ANALYSIS OF COPY NUMBER VARIATION (CNVs) IN HUMAN DISEASE PATHOGENESIS

    PubMed Central

    Ionita-Laza, Iuliana; Rogers, Angela J.; Lange, Christoph; Raby, Benjamin A.; Lee, Charles

    2009-01-01

    Structural genetic variation, including copy number variation (CNV), constitutes a substantial fraction of total genetic variability and the importance of structural genetic variants in modulating human disease is increasingly being recognized. Early successes in identifying disease-associated CNVs via a candidate gene approach mandate that future disease association studies need to include structural genetic variation. Such analyses should not rely on previously developed methodologies that were designed to evaluate single nucleotide polymorphisms (SNPs). Instead, development of novel technical, statistical, and epidemiologic methods will be necessary to optimally capture this newly-appreciated form of genetic variation in a meaningful manner. PMID:18822366

  12. A genetic analysis of Adhl regulation

    SciTech Connect

    Freeling, M.

    1992-01-01

    Several separate but related studies are reported on the mechanism of alcohol dehydrogenase (Adh-1) are reported. A study of a deletion mutation in the TATA box region which resulted in an increase from 6--60% of wildtype Adh-1 expression in the revertant has led to a focus on trans-acting protein factors that bind the TATA box. Analysis of another revertant has led to study of cis-acting sequences in Adh-1 expression. Screening efforts aimed at defining different mutants affecting Adh-1 expression are reported.

  13. Identifying disease candidate genes via large-scale gene network analysis.

    PubMed

    Kim, Haseong; Park, Taesung; Gelenbe, Erol

    2014-01-01

    Gene Regulatory Networks (GRN) provide systematic views of complex living systems, offering reliable and large-scale GRNs to identify disease candidate genes. A reverse engineering technique, Bayesian Model Averaging-based Networks (BMAnet), which ensembles all appropriate linear models to tackle uncertainty in model selection that integrates heterogeneous biological data sets is introduced. Using network evaluation metrics, we compare the networks that are thus identified. The metric 'Random walk with restart (Rwr)' is utilised to search for disease genes. In a simulation our method shows better performance than elastic-net and Gaussian graphical models, but topological quantities vary among the three methods. Using real-data, brain tumour gene expression samples consisting of non-tumour, grade III and grade IV are analysed to estimate networks with a total of 4422 genes. Based on these networks, 169 brain tumour-related candidate genes were identified and some were found to relate to 'wound', 'apoptosis', and 'cell death' processes. PMID:25796737

  14. Microstructural analysis of candidate steels pre-selected for new advanced reactor systems

    NASA Astrophysics Data System (ADS)

    Zeman, A.; Debarberis, L.; Kočík, J.; Slugeň, V.; Keilová, E.

    2007-05-01

    Many of candidate materials for Generation IV concept have been developed in past, however they have not been tested yet for new conditions and therefore, a huge effort must be carried out for their characterization and validation in the R&D phase. Moreover, the issue concerning the structural integrity of materials is going to have a more and more dominant role due to the degradation mechanisms, as hardening, thermal fatigue, creep, swelling, phase instability and embrittlement, which must be understood in order to estimate the component lifetime. This paper presents some interesting results on few candidate materials selected for Generation IV reactor concepts. The study is based on application of non-destructive spectroscopic techniques to investigate materials as EUROFER'97, P91 and T91.

  15. Transcriptomic Identification of ADH1B as a Novel Candidate Gene for Obesity and Insulin Resistance in Human Adipose Tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES)

    PubMed Central

    Winnier, Deidre A.; Fourcaudot, Marcel; Norton, Luke; Abdul-Ghani, Muhammad A.; Hu, Shirley L.; Farook, Vidya S.; Coletta, Dawn K.; Kumar, Satish; Puppala, Sobha; Chittoor, Geetha; Dyer, Thomas D.; Arya, Rector; Carless, Melanie; Lehman, Donna M.; Curran, Joanne E.; Cromack, Douglas T.; Tripathy, Devjit; Blangero, John; Duggirala, Ravindranath; Göring, Harald H. H.; DeFronzo, Ralph A.; Jenkinson, Christopher P.

    2015-01-01

    Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR ≤ 10-4) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10-60) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10-9), BMI (5.4 x 10-6), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits. PMID:25830378

  16. Transcriptomic identification of ADH1B as a novel candidate gene for obesity and insulin resistance in human adipose tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES).

    PubMed

    Winnier, Deidre A; Fourcaudot, Marcel; Norton, Luke; Abdul-Ghani, Muhammad A; Hu, Shirley L; Farook, Vidya S; Coletta, Dawn K; Kumar, Satish; Puppala, Sobha; Chittoor, Geetha; Dyer, Thomas D; Arya, Rector; Carless, Melanie; Lehman, Donna M; Curran, Joanne E; Cromack, Douglas T; Tripathy, Devjit; Blangero, John; Duggirala, Ravindranath; Göring, Harald H H; DeFronzo, Ralph A; Jenkinson, Christopher P

    2015-01-01

    Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR ≤ 10(-4)) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10(-60)) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10(-9)), BMI (5.4 x 10(-6)), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits. PMID:25830378

  17. The future of genetic analysis of neurological disorders.

    PubMed

    Hardy, J; Singleton, A

    2000-04-01

    Molecular genetic analysis has allowed the elucidation of the etiology of many single-gene, neurodegenerative syndromes. However, as yet, it has had little direct impact on our understanding of the etiology in cases with more complex modes of inheritance. With the completion of the sequence of the human genome, it should be possible to start to attack these more complex problems. In this article, we review the genetic methods that may be used to dissect the etiologies of these diseases and outline what types of clinical samples will be needed for this quest. PMID:10783291

  18. Methods for the survey and genetic analysis of populations

    DOEpatents

    Ashby, Matthew

    2003-09-02

    The present invention relates to methods for performing surveys of the genetic diversity of a population. The invention also relates to methods for performing genetic analyses of a population. The invention further relates to methods for the creation of databases comprising the survey information and the databases created by these methods. The invention also relates to methods for analyzing the information to correlate the presence of nucleic acid markers with desired parameters in a sample. These methods have application in the fields of geochemical exploration, agriculture, bioremediation, environmental analysis, clinical microbiology, forensic science and medicine.

  19. X-Shooter GTO: chemical analysis of a sample of EMP candidates

    NASA Astrophysics Data System (ADS)

    Caffau, E.; Bonifacio, P.; François, P.; Spite, M.; Spite, F.; Zaggia, S.; Ludwig, H.-G.; Monaco, L.; Sbordone, L.; Cayrel, R.; Hammer, F.; Randich, S.; Hill, V.; Molaro, P.

    2011-10-01

    Context. Extremely metal-poor stars (EMP) are very rare objects that hold in their atmospheres the fossil record of the chemical composition of the early phases of Galactic evolution. Finding these objects and determining their chemical composition provides important constraints on these early phases. Aims: Using a carefully designed selection method, we chose a sample of candidate EMP stars from the low resolution spectra of the Sloan Digital Sky Survey and observed them with X-Shooter at the VLT to confirm their metallicities and determine abundances for as many elements as possible. Methods: The X-Shooter spectra are analysed by means of one-dimensional, plane-parallel, hydrostatic model atmospheres. Corrections for the granulation effects are computed using CO5BOLD hydrodynamical simulations. Results: All the candidates are confirmed to be EMP stars, proving the efficiency of our selection method within about 0.5 dex. The chemical composition of this sample is compatible with those of brighter samples, suggesting that the stars in the Galactic halo are well mixed. Conclusions: These observations show that it is feasible to observe, in a limited amount of time, a large sample of about one hundred stars among EMP candidates selected from the SDSS. Such a size of sample will allow us, in particular, to confirm or refute the existence of a vertical drop in the Galactic halo metallicity distribution function around [Fe/H] ~ -3.5. Based on observations obtained at ESO Paranal Observatory, GTO programme 086.D-0094.

  20. Localization of cDNAs to a region poorly represented in the CEPH chromosome 21 YAC contig: Candidate genes for genetic diseases mapped to 21q22.3

    SciTech Connect

    Gardiner, K.; Patterson, D.; Ichikawa, H.; Ohki, Misao; Cheng, Jan-Fang

    1995-11-20

    Fifty-three cDNA fragments previously obtained by hybridization selection from random clones in the chromosome 21 cosmid library LL21CNO2 failed to identify clones in the chromosome 21 YAC contig described. Using an expanded panel of somatic cell hybrids, we have verified that the majority of these cDNAs map to chromosome 21 and that in particular a very high proportion, {approximately}85%, localize to a 5-Mb region of distal 21q22.3. Pulsed-field analysis coupled with information from the NotI restriction map of the region further indicate that 17 cDNA fragments map within 650 kb of the PFKL gene and thus may be candidates for genetic diseases linked to this gene. This work helps to characterize a region poorly represented in the CEPH YAC contig and adds to the number of cDNAs useful in analysis of chromosome 21-associated diseases. 4 refs., 3 figs., 1 tab.

  1. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

    PubMed Central

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

    2015-01-01

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P<1.4 × 10−3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10−10 for risk variants (P<10−4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC. PMID:26391404

  2. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

    PubMed

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

    2015-01-01

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC. PMID:26391404

  3. Evaluating Historical Candidate Genes for Schizophrenia

    PubMed Central

    Farrell, Martilias; Werge, Thomas; Sklar, Pamela; Owen, Michael J.; Ophoff, Roel; O’Donovan, Michael; Corvin, Aiden; Cichon, Sven; Sullivan, Patrick F

    2015-01-01

    Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (e.g., COMT, DISC1, DTNBP1, and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia. PMID:25754081

  4. Evaluating historical candidate genes for schizophrenia.

    PubMed

    Farrell, M S; Werge, T; Sklar, P; Owen, M J; Ophoff, R A; O'Donovan, M C; Corvin, A; Cichon, S; Sullivan, P F

    2015-05-01

    Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia. PMID:25754081

  5. Genetic diversity analysis in Piper species (Piperaceae) using RAPD markers.

    PubMed

    Sen, Sandeep; Skaria, Reby; Abdul Muneer, P M

    2010-09-01

    The genetic diversity of eight species of Piper (Piperaceae) viz., P. nigrum, P. longum, P. betle, P. chaba, P. argyrophyllum, P. trichostachyon, P. galeatum, and P. hymenophyllum from Kerala state, India were analyzed by Random amplified polymorphic DNA (RAPD). Out of 22 10-mer RAPD primers screened, 11 were selected for comparative analysis of different species of Piper. High genetic variations were found among different Piper species studied. Among the total of 149 RAPD fragments amplified, 12 bands (8.05%) were found monomorphic in eight species. The remaining 137 fragments were found polymorphic (91.95%). Species-specific bands were found in all eight species studied. The average gene diversity or heterozygosity (H) was 0.33 across all the species, genetic distances ranged from 0.21 to 0.69. The results of this study will facilitate germplasm identification, management, and conservation. PMID:20383613

  6. Molecular population genetic analysis of emerged bacterial pathogens: selected insights.

    PubMed Central

    Musser, J. M.

    1996-01-01

    Research in bacterial population genetics has increased in the last 10 years. Population genetic theory and tools and related strategies have been used to investigate bacterial pathogens that have contributed to recent episodes of temporal variation in disease frequency and severity. A common theme demonstrated by these analyses is that distinct bacterial clones are responsible for disease outbreaks and increases in infection frequency. Many of these clones are characterized by unique combinations of virulence genes or alleles of virulence genes. Because substantial interclonal variance exists in relative virulence, molecular population genetic studies have led to the concept that the unit of bacterial pathogenicity is the clone or cell line. Continued new insights into host parasite interactions at the molecular level will be achieved by combining clonal analysis of bacterial pathogens with large-scale comparative sequencing of virulence genes. PMID:8903193

  7. [Screening of peafowl microsatellite primers and analysis of genetic diversity].

    PubMed

    Bao, Wen-Bin; Chen, Guo-Hong; Shu, Jing-Ting; Xu, Qi; Li, Hui-Fang

    2006-10-01

    The applicability of chicken microsatellite primers to peafowl population was analyzed in the present paper, and the results showed 14 of 29 pairs of microsatellite primers from chicken could amplify peafowl DNA and produce specific allele patterns. A mean of 1.71 alleles was found for each locus. Seven pairs were highly polymorphic, and MCW0080 and MCW0098 were ideal markers for peafowl. Genetic diversity analysis within and between the green peafowl and the blue peafowl populations demonstrated that the expected heterozygosity of two peafowl populations were 0.2482 and 0.2744, respectively. The inbreeding index (FST), Reynolds' genetic distance and gene flow between the two populations were 0.078, 0.0603 and 3.896 respectively. These results indicate that the heterozygosity and the genetic diversity of these two peafowl populations were very low, and suggest a tendency towards intermixing. PMID:17035182

  8. Frequency Analysis Techniques for Identification of Viral Genetic Data

    PubMed Central

    Trifonov, Vladimir; Rabadan, Raul

    2010-01-01

    Environmental metagenomic samples and samples obtained as an attempt to identify a pathogen associated with the emergence of a novel infectious disease are important sources of novel microorganisms. The low costs and high throughput of sequencing technologies are expected to allow for the genetic material in those samples to be sequenced and the genomes of the novel microorganisms to be identified by alignment to those in a database of known genomes. Yet, for various biological and technical reasons, such alignment might not always be possible. We investigate a frequency analysis technique which on one hand allows for the identification of genetic material without relying on alignment and on the other hand makes possible the discovery of nonoverlapping contigs from the same organism. The technique is based on obtaining signatures of the genetic data and defining a distance/similarity measure between signatures. More precisely, the signatures of the genetic data are the frequencies of k-mers occurring in them, with k being a natural number. We considered an entropy-based distance between signatures, similar to the Kullback-Leibler distance in information theory, and investigated its ability to categorize negative-sense single-stranded RNA (ssRNA) viral genetic data. Our conclusion is that in this viral context, the technique provides a viable way of discovering genetic relationships without relying on alignment. We envision that our approach will be applicable to other microbial genetic contexts, e.g., other types of viruses, and will be an important tool in the discovery of novel microorganisms. PMID:20824103

  9. Molecular genetic analysis of plant gravitropism

    NASA Technical Reports Server (NTRS)

    Lomax, T. L.

    1997-01-01

    The analysis of mutants is a powerful approach for elucidating the components of complex biological processes. A growing number of mutants have been isolated which affect plant gravitropism and the classes of mutants found thus far provide important information about the gravity response mechanism. The wide variety of mutants isolated, especially in Arabidopsis, indicates that gravitropism is a complex, multi-step process. The existence of mutants altered in either root gravitropism alone, shoot gravitropism alone, or both indicates that the root and shoot gravitropic mechanisms have both separate and common steps. Reduced starch mutants have confirmed the role of amyloplasts in sensing the gravity signal. The hormone auxin is thought to act as the transducing signal between the sites of gravity perception (the starch parenchyma cells surrounding the vascular tissue in shoots and the columella cells of root caps) and asymmetric growth (the epidermal cells of the elongation zone(s) of each organ). To date, all mutants that are resistant to high concentrations of auxin have also been found to exhibit a reduced gravitropic response, thus supporting the role of auxin. Not all gravitropic mutants are auxin-resistant, however, indicating that there are additional steps which do not involve auxin. Studies with mutants of tomato which exhibit either reduced or reversed gravitropic responses further support the role of auxin redistribution in gravitropism and suggest that both red light and cytokinin interact with gravitropism through controlling lateral auxin transport. Plant responses to gravity thus likely involve changes in both auxin transport and sensitivity.

  10. Genetic analysis of two Taiwanese bluetongue viruses.

    PubMed

    Lee, Fan; Ting, Lu-Jen; Lee, Ming-Shiuh; Chang, Wei-Ming; Wang, Fun-In

    2011-03-24

    BTV2/KM/2003 and BTV12/PT/2003 are the first identified bluetongue viruses in Taiwan. The prototype virus BTV2/KM/2003 was previously characterized in various respects as low virulent. In the present study, nucleotide sequences of the ten genome segments and their coding regions of the Taiwan strains were determined and analyzed. The two strains had >96.8% nucleotide and >97.9% deduced amino acid identities to each other, except for the VP2 genes. Their genome sequences, except for NS1 and VP2 genes, clustered overall in the Asian lineage, and were closely related to strains from China, India, Indonesia, and Japan. The phylogenetic trees and nucleotide identities of six BTV genes were suggestive of the geographical origin of the bluetongue virus strains analyzed, with a few exceptions. To examine which genes better distinguished strains from different origins (topography), the distribution of and the levels of differences in nucleotide identities were analyzed, revealing that VP3, NS2, and NS3 genes were more suitable for topotyping of BTVs. Analysis of ratios of non-synonymous/synonymous substitutions (dN/dS values) between putative ancestry and their descendant strains suggested that most BTV genes evolved under a negative selection, whereas the VP7 gene evolved under positive selection, and its non-synonymous substitutions accumulated more rapidly in strains from the Mediterranean region. PMID:20855174

  11. COL5A1: Fine genetic mapping, intron/exon organization, and exclusion as candidate gene in families with tuberous sclerosis complex 1, hereditary hemorrhagic telangiectasia, and Ehlers-Danlos syndrome type II

    SciTech Connect

    Greenspan, D.S.; Papenberg, K.A.; Marchuk, D.A.

    1994-09-01

    Type V collagen is the only fibrillar collagen which has yet to be implicated in the pathogenesis of genetic diseases in humans or mice. To begin examining the possible role of type V collagen in genetic disease, we have previously mapped COL5A1, the gene for the {alpha}1 chain of type V collagen, to 9q23.2{r_arrow}q34.3 and described two restriction site polymorphisms which allowed us to exclude COL5A1 as candidate gene for nail-patella syndrome. We have now used these polymorphisms to exclude COL5A1 as candidate gene for tuberous sclerosis complex 1 and Ehlers-Danlos syndrome type II. In addition, we describe a CA repeat, with observed heterozygosity of about 0.5, in a COL5A1 intron, which has allowed us to exclude COL5A1 as a candidate gene in hereditary hemorrhagic telangiectasia and to place COL5A1 on the CEPH family genetic map between markers D9S66 and D9S67. We have also determined the entire intron/exon organization of COL5A1, which will facilitate characterization of mutations in genetic diseases with which COL5A1 may be linked in future studies.

  12. Comparative genomic analysis of Lactobacillus plantarum ZJ316 reveals its genetic adaptation and potential probiotic profiles* #

    PubMed Central

    Li, Ping; Li, Xuan; Gu, Qing; Lou, Xiu-yu; Zhang, Xiao-mei; Song, Da-feng; Zhang, Chen

    2016-01-01

    Objective: In previous studies, Lactobacillus plantarum ZJ316 showed probiotic properties, such as antimicrobial activity against various pathogens and the capacity to significantly improve pig growth and pork quality. The purpose of this study was to reveal the genes potentially related to its genetic adaptation and probiotic profiles based on comparative genomic analysis. Methods: The genome sequence of L. plantarum ZJ316 was compared with those of eight L. plantarum strains deposited in GenBank. BLASTN, Mauve, and MUMmer programs were used for genome alignment and comparison. CRISPRFinder was applied for searching the clustered regularly interspaced short palindromic repeats (CRISPRs). Results: We identified genes that encode proteins related to genetic adaptation and probiotic profiles, including carbohydrate transport and metabolism, proteolytic enzyme systems and amino acid biosynthesis, CRISPR adaptive immunity, stress responses, bile salt resistance, ability to adhere to the host intestinal wall, exopolysaccharide (EPS) biosynthesis, and bacteriocin biosynthesis. Conclusions: Comparative characterization of the L. plantarum ZJ316 genome provided the genetic basis for further elucidating the functional mechanisms of its probiotic properties. ZJ316 could be considered a potential probiotic candidate. PMID:27487802

  13. QTL mapping and candidate gene analysis of telomere length control factors in maize (Zea mays L.)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Telomere length is under genetic control and important for essential telomere functions. Failure to regulate telomere length homeostasis contributes to cancers and aging-related diseases in animals, but the effects of telomere length defects in plants remains poorly understood. To learn more about t...

  14. Rising Cellular Immune Response after Injection of pVax/iutA: A Genetic DNA Cassette as Candidate Vaccine against Urinary Tract Infection

    PubMed Central

    BAKHTIARI, Ronak; AHMADIAN, Shahin; FALLAH MEHRABADI, Jalil

    2016-01-01

    Background: Uropathogenic Escherichia coli (UPEC) are major bacterial agent of Urinary Tract Infection (UTI). This infection is more prevalent among women because approximately half of all women will experience a UTI in their life-time and near a quarter of them will have a recurrent infection within 6–12 months. IutA protein has a major role during UPEC pathogenesis and consequently infection. Therefore, the aim of current study was assessment of IutA protein roles as a potential candidate antigen based for vaccine designing. Methods: This survey was conducted during 2014–2015 at the University of Tehran, Iran. Chromosomal DNA extracted from E. coli 35218 and iutA gene amplified by PCR. The amplicon cloned to pVax.1 eukaryotic expression vector and recombinant vector confirmed by sequencing. The iutA gene expression in genetic cassette of pVax/iutA was evaluated in COS7 cell line by RT-PCR. Then, injected to mouse model, which divided to three groups: injected with pVax vector, PBS and pVax/iutA cassette respectively in two stages (d 1 and 14). One week after the second injection, bleeding from immunized mouse was performed and IFN-gamma was measured. Results: The mice immunized with pVax/iutA showed increased interferon-γ responses significantly higher than two non-immunized groups (P<0.05). Conclusion: Cellular immune response has a main protective role against UTI. Raising this kind of immune response is important to preventing of recurrent infection. Moreover, the current DNA cassette will be valuable for more trying to prepare a new vaccine against UTI. PMID:27516995

  15. A systems genetic analysis of alcohol drinking by mice, rats and men: influence of brain GABAergic transmission.

    PubMed

    Saba, Laura M; Bennett, Beth; Hoffman, Paula L; Barcomb, Kelsey; Ishii, Takao; Kechris, Katerina; Tabakoff, Boris

    2011-06-01

    Genetic influences on the predisposition to complex behavioral or physiological traits can reflect genetic polymorphisms that lead to altered gene product function, and/or variations in gene expression levels. We have explored quantitative variations in an animal's alcohol consumption, using a genetical genomic/phenomic approach. In our studies, gene expression is correlated with amount of alcohol consumed, and genomic regions that regulate the alcohol consumption behavior and the quantitative levels of gene expression (behavioral and expression quantitative trait loci [QTL]) are determined and used as a filter to identify candidate genes predisposing the behavior. We determined QTLs for alcohol consumption using the LXS panel of recombinant inbred mice. We then identified genes that were: 1) differentially expressed between five high and five low alcohol-consuming lines or strains of mice; and 2) were physically located in, or had an expression QTL (eQTL) within the alcohol consumption QTLs. Comparison of mRNA and protein levels in brains of high and low alcohol consuming mice led us to a bioinformatic examination of potential regulation by microRNAs of an identified candidate transcript, Gnb1 (G protein beta subunit 1). We combined our current analysis with our earlier work identifying candidate genes for the alcohol consumption trait in mice, rats and humans. Our overall analysis leads us to postulate that the activity of the GABAergic system, and in particular GABA release and GABA receptor trafficking and signaling, which involves G protein function, contributes significantly to genetic variation in the predisposition to varying levels of alcohol consumption. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID:21185315

  16. Genome-wide association and pathway analysis of feed efficiency in pigs reveal candidate genes and pathways for residual feed intake

    PubMed Central

    Do, Duy N.; Strathe, Anders B.; Ostersen, Tage; Pant, Sameer D.; Kadarmideen, Haja N.

    2014-01-01

    Residual feed intake (RFI) is a complex trait that is economically important for livestock production; however, the genetic and biological mechanisms regulating RFI are largely unknown in pigs. Therefore, the study aimed to identify single nucleotide polymorphisms (SNPs), candidate genes and biological pathways involved in regulating RFI using Genome-wide association (GWA) and pathway analyses. A total of 596 Yorkshire boars with phenotypes for two different measures of RFI (RFI1 and 2) and 60k genotypic data was used. GWA analysis was performed using a univariate mixed model and 12 and 7 SNPs were found to be significantly associated with RFI1 and RFI2, respectively. Several genes such as xin actin-binding repeat-containing protein 2 (XIRP2),tetratricopeptide repeat domain 29 (TTC29),suppressor of glucose, autophagy associated 1 (SOGA1),MAS1,G-protein-coupled receptor (GPCR) kinase 5 (GRK5),prospero-homeobox protein 1 (PROX1),GPCR 155 (GPR155), and FYVE domain containing the 26 (ZFYVE26) were identified as putative candidates for RFI based on their genomic location in the vicinity of these SNPs. Genes located within 50 kbp of SNPs significantly associated with RFI and RFI2 (q-value ≤ 0.2) were subsequently used for pathway analyses. These analyses were performed by assigning genes to biological pathways and then testing the association of individual pathways with RFI using a Fisher’s exact test. Metabolic pathway was significantly associated with both RFIs. Other biological pathways regulating phagosome, tight junctions, olfactory transduction, and insulin secretion were significantly associated with both RFI traits when relaxed threshold for cut-off p-value was used (p ≤ 0.05). These results implied porcine RFI is regulated by multiple biological mechanisms, although the metabolic processes might be the most important. Olfactory transduction pathway controlling the perception of feed via smell, insulin pathway controlling food intake might be important

  17. Genetic analysis of jumbled spine and ribs (Jsr) mutation affecting the vertebral development in mice.

    PubMed

    Okano, Shinya; Asano, Atsushi; Kon, Yasuhiro; Miyoshi, Hiroyuki; Watanabe, Tomomasa

    2002-10-01

    The jumbled spine and ribs (Jsr) mouse was derived from a spontaneous mutation. As the phenotype, a shortened trunk and kinky tail are characteristic Jsr traits. In this study, on high resolution mapping it was found that Lunatic fringe (Lfng) mapped at the same position as Jsr. Lfng was identified as the candidate gene for Jsr, but sequence analysis of this gene revealed no substitution in the coding region of cDNA. Therefore, we adopted the strategy of positional cloning for Jsr using a mouse bacterial artificial chromosome (BAC) library. A BAC contig was constructed from three BAC clones showing positive signals of Lfng and 11MMHAP75FRD8.seq near the Jsr locus on chromosome 5. Based on the genetic mapping of both T7 and sp6 ends of a clone of BAC382-O-7 (BAC382), the Jsr gene was considered to exist in BAC382 and to be positioned near the sp6 side. PMID:12392169

  18. Random amplified polymorphic DNA analysis of genetically modified organisms.

    PubMed

    Yoke-Kqueen, Cheah; Radu, Son

    2006-12-15

    Randomly amplified polymorphic DNA (RAPD) was used to analyzed 78 samples comprises of certified reference materials (soya and maize powder), raw seeds (soybean and maize), processed food and animal feed. Combination assay of two arbitrary primers in the RAPD analysis enable to distinguish genetically modified organism (GMO) reference materials from the samples tested. Dendrogram analysis revealed 13 clusters at 45% similarity from the RAPD. RAPD analysis showed that the maize and soybean samples were clustered differently besides the GMO and non-GMO products. PMID:16860900

  19. Genetic Analysis of Arrhythmogenic Diseases in the Era of NGS: The Complexity of Clinical Decision-Making in Brugada Syndrome

    PubMed Central

    Allegue, Catarina; Coll, Mònica; Mates, Jesus; Campuzano, Oscar; Iglesias, Anna; Sobrino, Beatriz; Brion, Maria; Amigo, Jorge; Carracedo, Angel; Brugada, Pedro; Brugada, Josep; Brugada, Ramon

    2015-01-01

    Background The use of next-generation sequencing enables a rapid analysis of many genes associated with sudden cardiac death in diseases like Brugada Syndrome. Genetic variation is identified and associated with 30–35% of cases of Brugada Syndrome, with nearly 20–25% attributable to variants in SCN5A, meaning many cases remain undiagnosed genetically. To evaluate the role of genetic variants in arrhythmogenic diseases and the utility of next-generation sequencing, we applied this technology to resequence 28 main genes associated with arrhythmogenic disorders. Materials and Methods A cohort of 45 clinically diagnosed Brugada Syndrome patients classified as SCN5A-negative was analyzed using next generation sequencing. Twenty-eight genes were resequenced: AKAP9, ANK2, CACNA1C, CACNB2, CASQ2, CAV3, DSC2, DSG2, DSP, GPD1L, HCN4, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ5, KCNQ1, NOS1AP, PKP2, RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SNTA1, and TMEM43. A total of 85 clinically evaluated relatives were also genetically analyzed to ascertain familial segregation. Results and Discussion Twenty-two patients carried 30 rare genetic variants in 12 genes, only 4 of which were previously associated with Brugada Syndrome. Neither insertion/deletion nor copy number variation were detected. We identified genetic variants in novel candidate genes potentially associated to Brugada Syndrome. These include: 4 genetic variations in AKAP9 including a de novo genetic variation in 3 positive cases; 5 genetic variations in ANK2 detected in 4 cases; variations in KCNJ2 together with CASQ2 in 1 case; genetic variations in RYR2, including a de novo genetic variation and desmosomal proteins encoding genes including DSG2, DSP and JUP, detected in 3 of the cases. Larger gene panels or whole exome sequencing should be considered to identify novel genes associated to Brugada Syndrome. However, application of approaches such as whole exome sequencing would difficult the interpretation for clinical

  20. Stardust Interstellar Preliminary Examination III: Infrared spectroscopic analysis of interstellar dust candidates

    NASA Astrophysics Data System (ADS)

    Bechtel, Hans A.; Flynn, George J.; Allen, Carlton; Anderson, David; Ansari, Asna; Bajt, SašA.; Bastien, Ron K.; Bassim, Nabil; Borg, Janet; Brenker, Frank E.; Bridges, John; Brownlee, Donald E.; Burchell, Mark; Burghammer, Manfred; Butterworth, Anna L.; Changela, Hitesh; Cloetens, Peter; Davis, Andrew M.; Doll, Ryan; Floss, Christine; Frank, David R.; Gainsforth, Zack; Grün, Eberhard; Heck, Philipp R.; Hillier, Jon K.; Hoppe, Peter; Hudson, Bruce; Huth, Joachim; Hvide, Brit; Kearsley, Anton; King, Ashley J.; Lai, Barry; Leitner, Jan; Lemelle, Laurence; Leroux, Hugues; Leonard, Ariel; Lettieri, Robert; Marchant, William; Nittler, Larry R.; Ogliore, Ryan; Ong, Wei Ja; Postberg, Frank; Price, Mark C.; Sandford, Scott A.; Tresseras, Juan-Angel Sans; Schmitz, Sylvia; Schoonjans, Tom; Silversmit, Geert; Simionovici, Alexandre S.; Solé, Vicente A.; Srama, Ralf; Stadermann, Frank J.; Stephan, Thomas; Sterken, Veerle J.; Stodolna, Julien; Stroud, Rhonda M.; Sutton, Steven; Trieloff, Mario; Tsou, Peter; Tsuchiyama, Akira; Tyliszczak, Tolek; Vekemans, Bart; Vincze, Laszlo; von Korff, Joshua; Westphal, Andrew J.; Wordsworth, Naomi; Zevin, Daniel; Zolensky, Michael E.

    2014-09-01

    Under the auspices of the Stardust Interstellar Preliminary Examination, picokeystones extracted from the Stardust Interstellar Dust Collector were examined with synchrotron Fourier transform infrared (FTIR) microscopy to establish whether they contained extraterrestrial organic material. The picokeystones were found to be contaminated with varying concentrations and speciation of organics in the native aerogel, which hindered the search for organics in the interstellar dust candidates. Furthermore, examination of the picokeystones prior to and post X-ray microprobe analyses yielded evidence of beam damage in the form of organic deposition or modification, particularly with hard X-ray synchrotron X-ray fluorescence. From these results, it is clear that considerable care must be taken to interpret any organics that might be in interstellar dust particles. For the interstellar candidates examined thus far, however, there is no clear evidence of extraterrestrial organics associated with the track and/or terminal particles. However, we detected organic matter associated with the terminal particle in Track 37, likely a secondary impact from the Al-deck of the sample return capsule, demonstrating the ability of synchrotron FTIR to detect organic matter in small particles within picokeystones from the Stardust interstellar dust collector.

  1. PLANETARY TRANSIT CANDIDATES IN THE CSTAR FIELD: ANALYSIS OF THE 2008 DATA

    SciTech Connect

    Wang, Songhu; Zhang, Hui; Zhou, Ji-Lin; Yang, Ming; Liu, Huigen; Meng, Zeyang; Zhou, Xu; Fan, Zhou; Liu, Qiang; Ma, Jun; Wang, Lifan; Feng, Long-Long; Bayliss, D.; Zhou, G.; Ashley, M. C. B.; Lawrence, J. S.; Luong-Van, D. M.; Storey, J. W. V.; Wittenmyer, R. A.; Gong, Xuefei E-mail: zhouxu@bao.ac.cn; and others

    2014-04-01

    The Chinese Small Telescope ARray (CSTAR) is a group of four identical, fully automated, static 14.5 cm telescopes. CSTAR is located at Dome A, Antarctica and covers 20 deg{sup 2} of sky around the South Celestial Pole. The installation is designed to provide high-cadence photometry for the purpose of monitoring the quality of the astronomical observing conditions at Dome A and detecting transiting exoplanets. CSTAR has been operational since 2008, and has taken a rich and high-precision photometric data set of 10,690 stars. In the first observing season, we obtained 291,911 qualified science frames with 20 s integrations in the i band. Photometric precision reaches ∼4 mmag at 20 s cadence at i = 7.5 and is ∼20 mmag at i = 12. Using robust detection methods, 10 promising exoplanet candidates were found. Four of these were found to be giants using spectroscopic follow-up. All of these transit candidates are presented here along with the discussion of their detailed properties as well as the follow-up observations.

  2. Proteomic analysis of Brucella abortus cell envelope and identification of immunogenic candidate proteins for vaccine development.

    PubMed

    Connolly, Joseph P; Comerci, Diego; Alefantis, Timothy G; Walz, Alexander; Quan, Marian; Chafin, Ryan; Grewal, Paul; Mujer, Cesar V; Ugalde, Rodolfo A; DelVecchio, Vito G

    2006-07-01

    Brucella abortus is the etiologic agent of bovine brucellosis and causes a chronic disease in humans known as undulant fever. In livestock the disease is characterized by abortion and sterility. Live, attenuated vaccines such as S19 and RB51 have been used to control the spread of the disease in animals; however, they are considered unsafe for human use and they induce abortion in pregnant cattle. For the development of a safer and equally efficacious vaccine, immunoproteomics was utilized to identify novel candidate proteins from B. abortus cell envelope (CE). A total of 163 proteins were identified using 2-DE with MALDI-TOF MS and LC-MS/MS. Some of the major protein components include outer-membrane protein (OMP) 25, OMP31, Omp2b porin, and 60 kDa chaperonin GroEL. 2-DE Western blot analyses probed with antiserum from bovine and a human patient infected with Brucella identified several new immunogenic proteins such as fumarate reductase flavoprotein subunit, F0F1-type ATP synthase alpha subunit, and cysteine synthase A. The elucidation of the immunome of B. abortus CE identified a number of candidate proteins for developing vaccines against Brucella infection in bovine and humans. PMID:16739129

  3. Genetic analysis of advanced glycation end products in the DHS MIND study.

    PubMed

    Adams, Jeremy N; Raffield, Laura M; Martelle, Susan E; Freedman, Barry I; Langefeld, Carl D; Carr, J Jeffrey; Cox, Amanda J; Bowden, Donald W

    2016-06-15

    Advanced glycation end-products (AGEs) are a diverse group of molecules produced by the non-enzymatic addition of glucose to proteins, lipids, and nucleic acids. AGE levels have been associated with hyperglycemia and diabetic complications, especially in animal models, but less clearly in human studies. We measured total serum AGEs using an enzyme linked immunosorbant assay (ELISA) in 506 subjects from 246 families in the Diabetes Heart Study (DHS)/DHS MIND Study (n=399 type 2 diabetes (T2D)-affected). Single nucleotide polymorphisms (SNPs) in several candidate genes, including known AGE receptors, were tested for their influence on circulating AGE levels. The genetic analysis was expanded to include an exploratory genome-wide association study (GWAS) and exome chip analysis of AGEs (≈440,000 SNPs). AGEs were found to be highly heritable (h(2)=0.628, p=8.96 × 10(-10)). While no SNPs from candidate genes were significantly associated after Bonferroni correction, rs1035798 in the gene AGER was the most significantly associated (p=0.007). Additionally, rs7198427, in MT1A, showed a nominally significant p-value (p=0.0099). No SNPs from the GWAS or exome studies were identified after correction for multiple comparisons; however, rs17054480 in the PALLD2 gene on chromosome 4 showed the strongest association (p=7.77 × 10(-7)). Five SNPs at two loci (ISCA2/NPC2 and FBXO33) had p-values of less than 2.0 × 10(-5) and three additional SNPs (rs716326 in MACROD2, and rs6795197 and rs6765857 in ZBTB38) showed a nominal association with p-values of less than 1.0 × 10(-5).These findings provide a foundation for further investigation into the genetic component of circulating AGEs. PMID:26915486

  4. A Genetic Relationship between Phosphorus Efficiency and Photosynthetic Traits in Soybean As Revealed by QTL Analysis Using a High-Density Genetic Map

    PubMed Central

    Li, Hongyan; Yang, Yuming; Zhang, Hengyou; Chu, Shanshan; Zhang, Xingguo; Yin, Dongmei; Yu, Deyue; Zhang, Dan

    2016-01-01

    Plant productivity relies on photosynthesis, and the photosynthetic process relies on phosphorus (P). The genetic basis of photosynthesis and P efficiency (PE) affecting yield has been separately characterized in various crop plants. However, the genetic relationship between PE and photosynthesis remains to be elucidated. In this study, we used a combined analysis of phenotypic correlation, linkage mapping, and expression analysis to dissect the relationship between PE and photosynthesis. We found significant phenotypic correlations between PE and photosynthetic related traits, particularly under low P stress. A total of 172 QTLs for both traits were detected and classified into 29 genomic regions. 12 (41.4%) of 29 regions were detected to be associated with both PE and photosynthetic related traits. Three major QTLs, q14-2, q15-2, and q19-2, were found to be associated with both traits and explained 6.6–58.9% of phenotypic variation. A photosynthetic-specific QTL cluster, q12-1, was detected under both normal and low P conditions, suggesting that genes responsible for this region were less effected by low P stress, and could be used in high photosynthetic efficiency breeding programs. In addition, several candidate genes with significantly differential expression upon low P stress, such as a purple acid phosphatase gene (Glyma.19G193900) within q19-2 region, were considered as promising candidates involved in regulating both soybean PE and photosynthetic capacity. Our results reveal a significant genetic relationship between PE and photosynthetic traits, and uncover several major genomic regions specific or common to these traits. The markers linked closely to these major QTLs may be used for selection of soybean varieties with improved P efficiency and photosynthetic capacity. PMID:27446154

  5. A Genetic Relationship between Phosphorus Efficiency and Photosynthetic Traits in Soybean As Revealed by QTL Analysis Using a High-Density Genetic Map.

    PubMed

    Li, Hongyan; Yang, Yuming; Zhang, Hengyou; Chu, Shanshan; Zhang, Xingguo; Yin, Dongmei; Yu, Deyue; Zhang, Dan

    2016-01-01

    Plant productivity relies on photosynthesis, and the photosynthetic process relies on phosphorus (P). The genetic basis of photosynthesis and P efficiency (PE) affecting yield has been separately characterized in various crop plants. However, the genetic relationship between PE and photosynthesis remains to be elucidated. In this study, we used a combined analysis of phenotypic correlation, linkage mapping, and expression analysis to dissect the relationship between PE and photosynthesis. We found significant phenotypic correlations between PE and photosynthetic related traits, particularly under low P stress. A total of 172 QTLs for both traits were detected and classified into 29 genomic regions. 12 (41.4%) of 29 regions were detected to be associated with both PE and photosynthetic related traits. Three major QTLs, q14-2, q15-2, and q19-2, were found to be associated with both traits and explained 6.6-58.9% of phenotypic variation. A photosynthetic-specific QTL cluster, q12-1, was detected under both normal and low P conditions, suggesting that genes responsible for this region were less effected by low P stress, and could be used in high photosynthetic efficiency breeding programs. In addition, several candidate genes with significantly differential expression upon low P stress, such as a purple acid phosphatase gene (Glyma.19G193900) within q19-2 region, were considered as promising candidates involved in regulating both soybean PE and photosynthetic capacity. Our results reveal a significant genetic relationship between PE and photosynthetic traits, and uncover several major genomic regions specific or common to these traits. The markers linked closely to these major QTLs may be used for selection of soybean varieties with improved P efficiency and photosynthetic capacity. PMID:27446154

  6. Genetic analysis in the Collaborative Cross breeding population

    SciTech Connect

    Philip, Vivek; Sokoloff, Greta; Ackert-Bicknell, Cheryl; Striz, Martin; Branstetter, Lisa R; Beckmann, Melissa; Spence, Jason S; Jackson, Barbara L; Galloway, Leslie D; Barker, Gene; Wymore, Ann M; Hunsicker, Patricia R; Durtschi, David W; Shaw, Ginger S; Shinpock, Sarah G; Manly, Kenneth F; Miller, Darla R; Donahue, Kevin; Culiat, Cymbeline T; Churchill, Gary A; Lariviere, William R; Palmer, Abraham; O'Hara, Bruce; Voy, Brynn H; Chesler, Elissa J

    2011-01-01

    Genetic reference populations in model organisms are critical resources for systems genetic analysis of disease related phenotypes. The breeding history of these inbred panels may influence detectable allelic and phenotypic diversity. The existing panel of common inbred strains reflects historical selection biases, and existing recombinant inbred panels have low allelic diversity. All such populations may be subject to consequences of inbreeding depression. The Collaborative Cross (CC) is a mouse reference population with high allelic diversity that is being constructed using a randomized breeding design that systematically outcrosses eight founder strains, followed by inbreeding to obtain new recombinant inbred strains. Five of the eight founders are common laboratory strains, and three are wild-derived. Since its inception, the partially inbred CC has been characterized for physiological, morphological, and behavioral traits. The construction of this population provided a unique opportunity to observe phenotypic variation as new allelic combinations arose through intercrossing and inbreeding to create new stable genetic combinations. Processes including inbreeding depression and its impact on allelic and phenotypic diversity were assessed. Phenotypic variation in the CC breeding population exceeds that of existing mouse genetic reference populations due to both high founder genetic diversity and novel epistatic combinations. However, some focal evidence of allele purging was detected including a suggestive QTL for litter size in a location of changing allele frequency. Despite these inescapable pressures, high diversity and precision for genetic mapping remain. These results demonstrate the potential of the CC population once completed and highlight implications for development of related populations. Supplementary material consists of Supplementary Table 1 Phenotypic means, variances, ranges and heritabilities for all traits and generations, Supplementary Table

  7. Genetic Analysis of Rough Sheath1 Developmental Mutants of Maize

    PubMed Central

    Becraft, P. W.; Freeling, M.

    1994-01-01

    Maize Rough sheath1 (Rs1) mutants are dominant and cause a proliferation of sheath-like tissue at the base of the blade and throughout the ligular region. They also cause ligule displacement, a chaotic pattern of vasculature and abnormal cellular structure of vascular bundles. The affected region of Rs1-O leaves displays genetic and morphological attributes of both sheath and auricle, suggesting an overlap of these genetic programs. The rs1 locus maps approximately 26 map units distal to opaque2 (o2) on chromosome 7S, defining a new distal-most locus on the genetic map. Three mutant alleles, Rs1-O, Rs1-1025 and Rs1-Z, all display similar phenotypes. The mutations are completely dominant and the Rs1-O phenotype is not affected by dosage of the chromosome arm carrying the rs1(+) allele, indicating that these alleles are neomorphic. Analysis of genetic mosaics showed that the Rs1-O phenotype is non-cell-autonomous, suggesting that intercellular signals convey the phenotype. Rs1 mutant phenotypes are affected by modifiers present in particular genetic backgrounds. An enhancer of Rs1-O was identified; segregation data imply a single recessive gene, ers1. Rs1 mutants were also found to enhance the expression of unlinked rs2 and Rs4 mutants, suggesting that these mutations affect similar developmental processes. We discuss the phenotypic and genetic similarities between Rs1 and Knotted1 (Kn1) mutants that led to the identification of rs1 as a kn1-like homeobox gene (unpublished data). PMID:8138166

  8. Validation of Kepler's multiple planet candidates. III. Light curve analysis and announcement of hundreds of new multi-planet systems

    SciTech Connect

    Rowe, Jason F.; Bryson, Stephen T.; Lissauer, Jack J.; Jontof-Hutter, Daniel; Mullally, Fergal; Howell, Steve B.; Borucki, William J.; Haas, Michael; Huber, Daniel; Thompson, Susan E.; Quintana, Elisa; Barclay, Thomas; Still, Martin; Marcy, Geoffrey W.; Issacson, Howard; Gilliland, Ronald L.; Ford, Eric; Steffen, Jason H.; Gautier, T. N. III; and others

    2014-03-20

    The Kepler mission has discovered more than 2500 exoplanet candidates in the first two years of spacecraft data, with approximately 40% of those in candidate multi-planet systems. The high rate of multiplicity combined with the low rate of identified false positives indicates that the multiplanet systems contain very few false positive signals due to other systems not gravitationally bound to the target star. False positives in the multi-planet systems are identified and removed, leaving behind a residual population of candidate multi-planet transiting systems expected to have a false positive rate less than 1%. We present a sample of 340 planetary systems that contain 851 planets that are validated to substantially better than the 99% confidence level; the vast majority of these have not been previously verified as planets. We expect ∼two unidentified false positives making our sample of planet very reliable. We present fundamental planetary properties of our sample based on a comprehensive analysis of Kepler light curves, ground-based spectroscopy, and high-resolution imaging. Since we do not require spectroscopy or high-resolution imaging for validation, some of our derived parameters for a planetary system may be systematically incorrect due to dilution from light due to additional stars in the photometric aperture. Nonetheless, our result nearly doubles the number verified exoplanets.

  9. Validation of Kepler's Multiple Planet Candidates. III. Light Curve Analysis and Announcement of Hundreds of New Multi-planet Systems

    NASA Astrophysics Data System (ADS)

    Rowe, Jason F.; Bryson, Stephen T.; Marcy, Geoffrey W.; Lissauer, Jack J.; Jontof-Hutter, Daniel; Mullally, Fergal; Gilliland, Ronald L.; Issacson, Howard; Ford, Eric; Howell, Steve B.; Borucki, William J.; Haas, Michael; Huber, Daniel; Steffen, Jason H.; Thompson, Susan E.; Quintana, Elisa; Barclay, Thomas; Still, Martin; Fortney, Jonathan; Gautier, T. N., III; Hunter, Roger; Caldwell, Douglas A.; Ciardi, David R.; Devore, Edna; Cochran, William; Jenkins, Jon; Agol, Eric; Carter, Joshua A.; Geary, John

    2014-03-01

    The Kepler mission has discovered more than 2500 exoplanet candidates in the first two years of spacecraft data, with approximately 40% of those in candidate multi-planet systems. The high rate of multiplicity combined with the low rate of identified false positives indicates that the multiplanet systems contain very few false positive signals due to other systems not gravitationally bound to the target star. False positives in the multi-planet systems are identified and removed, leaving behind a residual population of candidate multi-planet transiting systems expected to have a false positive rate less than 1%. We present a sample of 340 planetary systems that contain 851 planets that are validated to substantially better than the 99% confidence level; the vast majority of these have not been previously verified as planets. We expect ~two unidentified false positives making our sample of planet very reliable. We present fundamental planetary properties of our sample based on a comprehensive analysis of Kepler light curves, ground-based spectroscopy, and high-resolution imaging. Since we do not require spectroscopy or high-resolution imaging for validation, some of our derived parameters for a planetary system may be systematically incorrect due to dilution from light due to additional stars in the photometric aperture. Nonetheless, our result nearly doubles the number verified exoplanets.

  10. Describing the genetic architecture of epilepsy through heritability analysis.

    PubMed

    Speed, Doug; O'Brien, Terence J; Palotie, Aarno; Shkura, Kirill; Marson, Anthony G; Balding, David J; Johnson, Michael R

    2014-10-01

    Epilepsy is a disease with substantial missing heritability; despite its high genetic component, genetic association studies have had limited success detecting common variants which influence susceptibility. In this paper, we reassess the role of common variants on epilepsy using extensions of heritability analysis. Our data set consists of 1258 UK patients with epilepsy, of which 958 have focal epilepsy, and 5129 population control subjects, with genotypes recorded for over 4 million common single nucleotide polymorphisms. Firstly, we show that on the liability scale, common variants collectively explain at least 26% (standard deviation 5%) of phenotypic variation for all epilepsy and 27% (standard deviation 5%) for focal epilepsy. Secondly we provide a new method for estimating the number of causal variants for complex traits; when applied to epilepsy, our most optimistic estimate suggests that at least 400 variants influence disease susceptibility, with potentially many thousands. Thirdly, we use bivariate analysis to assess how similar the genetic architecture of focal epilepsy is to that of non-focal epilepsy; we demonstrate both significant differences (P = 0.004) and significant similarities (P = 0.01) between the two subtypes, indicating that although the clinical definition of focal epilepsy does identify a genetically distinct epilepsy subtype, there is also scope to improve the classification of epilepsy by incorporating genotypic information. Lastly, we investigate the potential value in using genetic data to diagnose epilepsy following a single epileptic seizure; we find that a prediction model explaining 10% of phenotypic variation could have clinical utility for deciding which single-seizure individuals are likely to benefit from immediate anti-epileptic drug therapy. PMID:25063994

  11. Discovery and characterization of antibody variants using mass spectrometry-based comparative analysis for biosimilar candidates of monoclonal antibody drugs.

    PubMed

    Li, Wenhua; Yang, Bin; Zhou, Dongmei; Xu, Jun; Ke, Zhi; Suen, Wen-Chen

    2016-07-01

    Liquid chromatography mass spectrometry (LC-MS) is the most commonly used technique for the characterization of antibody variants. MAb-X and mAb-Y are two approved IgG1 subtype monoclonal antibody drugs recombinantly produced in Chinese hamster ovary (CHO) cells. We report here that two unexpected and rare antibody variants have been discovered during cell culture process development of biosimilars for these two approved drugs through intact mass analysis. We then used comprehensive mass spectrometry-based comparative analysis including reduced light, heavy chains, and domain-specific mass as well as peptide mapping analysis to fully characterize the observed antibody variants. The "middle-up" mass comparative analysis demonstrated that the antibody variant from mAb-X biosimilar candidate was caused by mass variation of antibody crystalline fragment (Fc), whereas a different variant with mass variation in antibody antigen-binding fragment (Fab) from mAb-Y biosimilar candidate was identified. Endoproteinase Lys-C digested peptide mapping and tandem mass spectrometry analysis further revealed that a leucine to glutamine change in N-terminal 402 site of heavy chain was responsible for the generation of mAb-X antibody variant. Lys-C and trypsin coupled non-reduced and reduced peptide mapping comparative analysis showed that the formation of the light-heavy interchain trisulfide bond resulted in the mAb-Y antibody variant. These two cases confirmed that mass spectrometry-based comparative analysis plays a critical role for the characterization of monoclonal antibody variants, and biosimilar developers should start with a comprehensive structural assessment and comparative analysis to decrease the risk of the process development for biosimilars. PMID:27214604

  12. [Genetic analysis of Streptomyces erythreus heteroclones. II. Determination of the distances between genetic loci on the map].

    PubMed

    Pencheva, R; Todorov, T

    1989-01-01

    As a result of recombination experiments between auxotrophic mutants of S. erythreus BTCC2 haploid recombinants and heteroclones were isolated. A genetic map of S. erythreus, including 15 auxotrophic loci was constructed by genetic analysis of the segregants of the heteroclones obtained. The genetic distances between 7 key loci on the map were determined and the entire length of the map of about 105 standard recombination units was calculated. PMID:2624163

  13. Genetic analysis of first lactation production traits in Kankrej cattle

    PubMed Central

    Ankuya, K. J.; Pareek, N. K.; Patel, M. P.; Rathod, B. S.; Prajapati, K. B.; Patel, J. B.

    2016-01-01

    Aim: The aim was to estimate genetic factors affecting the first lactation milk production traits in Kankrej cattle of North Gujarat. Materials and Methods: The 475 first lactation records of Kankrej cows that were maintained at the Livestock Research Station, Sardarkrushinagar Dantiwada Agricultural University, Sardarkrushinagar, Gujarat, over a period of 35 years from 1980 to 2014 were studied. The least squares maximum likelihood program was used to estimate genetic parameters of first lactation traits. Heritability was estimated through paternal half-sib analysis in adjusted data. Results: The heritability estimate for production traits was 0.40±0.17, 0.45±0.17, 0.35±0.18, and 0.20±0.14 for standard 300 days milk yield (F300Y), total lactation milk yield (FLY), wet average (FWA), and lactation length (FLL), respectively, in the first parity. All the genetic and phenotypic correlations among different production efficiency traits were high and positive. Genetic correlations between F300Y and FLY, FLL, and FWA were 0.80±0.20, 0.59±0.16, and 0.81±0.32, where as the phenotypic correlations were 0.969, 0.688, and 0.868, respectively. Genetic correlations of FLY with FLL and FWA were 0.60±0.13 and 0.79±0.20, whereas the phenotypic correlations were 0.777 and 0.817, respectively. Genetic and phenotypic correlation between FLL and FWA was 0.63±0.28 and 0.31, respectively. Conclusion: The heritability estimate of all first parity lactation traits waslow to medium (0.20-0.45) indicated the scope for further improvement in this trait through selection as well as managemental practice. Higher genetic and phenotypic correlation between thefirst lactation milk production traits gives theidea that genetic gain due to selection for one trait also givesmorecorrelated response of selection for other traits which is economically advantageous. PMID:27397993

  14. Space shuttle post-entry and landing analysis. Volume 1: Candidate system evaluations

    NASA Technical Reports Server (NTRS)

    Crawford, B. S.; Duiven, E. M.

    1973-01-01

    The general purpose of this study is to aid in the evaluation and design of multi-sensor navigation schemes proposed for the orbiter. The scope of the effort is limited to the post-entry, energy management, and approach and landing mission phases. One candidate system based on conventional navigation aids is illustrated including two DME (Distance Measuring Equipment) stations and ILS (Instrument Landing System) glide slope and localizer antennas. Some key elements of the system not shown are the onboard IMUs (Inertial Measurement Units), altimeters, and a computer. The latter is programmed to mix together (filter) the IMU data and the externally-derived data. A completely automatic, all-weather landing capability is required. Since no air-breathing engines will be carried on orbital flights, there will be no chance to go around and try again following a missed approach.

  15. Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells.

    PubMed

    Nowakowski, Tomasz J; Pollen, Alex A; Di Lullo, Elizabeth; Sandoval-Espinosa, Carmen; Bershteyn, Marina; Kriegstein, Arnold R

    2016-05-01

    The recent outbreak of Zika virus (ZIKV) in Brazil has been linked to substantial increases in fetal abnormalities and microcephaly. However, information about the underlying molecular and cellular mechanisms connecting viral infection to these defects remains limited. In this study we have examined the expression of receptors implicated in cell entry of several enveloped viruses including ZIKV across diverse cell types in the developing brain. Using single-cell RNA-seq and immunohistochemistry, we found that the candidate viral entry receptor AXL is highly expressed by human radial glial cells, astrocytes, endothelial cells, and microglia in developing human cortex and by progenitor cells in developing retina. We also show that AXL expression in radial glia is conserved in developing mouse and ferret cortex and in human stem cell-derived cerebral organoids, highlighting multiple experimental systems that could be applied to study mechanisms of ZIKV infectivity and effects on brain development. PMID:27038591

  16. Analysis of UV protection requirements and testing of candidate attenuators for the Haloe optical instrument

    NASA Technical Reports Server (NTRS)

    Nealy, J. E.; Goad, W. K.; Heath, D. M.

    1981-01-01

    Results of calculations are presented which simulate photolytic processes occurring in HALOE gas calibration cells exposed to extra-terrestrial solar ultraviolet photons. These calculations indicate that significant photolysis takes place in two of the sapphire-enclosed cells over the exposure periods of the proposed mission. A subsequent laboratory investigation is also described in which a high-voltage discharge hydrogen light source is used in conjunction with a vacuum ultraviolet spectrograph. The UV emission from this lamp was used to expose two candidate UV attenuators (ZnSe and coated Ge) to ascertain their suitability as UV filters while maintaining original infrared optical properties. Both materials were found to be effectively opaque to vacuum UV radiaton and suffered no adverse effects regarding their infrared transmissivity.

  17. Expression analysis of 13 ovine immune response candidate genes in Visna/Maedi disease progression.

    PubMed

    Larruskain, Amaia; Bernales, Irantzu; Luján, Lluis; de Andrés, Damián; Amorena, Beatriz; Jugo, Begoña M

    2013-07-01

    Visna/Maedi virus (VMV) is a lentivirus that infects cells of the monocyte/macrophage lineage in sheep. Infection with VMV may lead to Visna/Maedi (VM) disease, which causes a multisystemic inflammatory disorder causing pneumonia, encephalitis, mastitis and arthritis. The role of ovine immune response genes in the development of VM disease is not fully understood. In this work, sheep of the Rasa Aragonesa breed were divided into two groups depending on the presence/absence of VM-characteristic clinical lesions in the aforementioned organs and the relative levels of candidate gene expression, including cytokines and innate immunity loci were measured by qPCR in the lung and udder. Sheep with lung lesions showed differential expression in five target genes: CCR5, TLR7, and TLR8 were up regulated and IL2 and TNFα down regulated. TNFα up regulation was detected in the udder. PMID:23582860

  18. Forward and reverse genetic analysis of microtubule motors in Chlamydomonas.

    PubMed

    Pazour, G J; Witman, G B

    2000-12-01

    The ability to integrate biochemical, cell biological, and genetic approaches makes Chlamydomonas reinhardtii the premier model organism for studies of the eukaryotic flagellum and its associated molecular motors. Hundreds of motility mutations have been identified in Chlamydomonas, including many that affect dyneins and kinesins. These mutations have yielded much information on the structure and function of the motors as well as the roles of individual subunits within the motors. The development of insertional mutagenesis has opened the door to powerful new approaches for genetic analysis in Chlamydomonas. Insertional mutants are created by transforming cells with DNA-containing selectable markers. The DNA is randomly integrated throughout the genome and usually deletes part of the chromosome at the site of insertion, thereby creating mutations that are marked by the integrated DNA. These mutations can be used for forward genetic approaches where one characterizes a mutant phenotype and then clones the relevant gene using the integrated DNA as a tag. The insertional mutants also may be used in a reverse genetic approach in which mutants lacking a gene of interest are identified by DNA hybridization. We describe methods to generate and characterize insertional mutants, using mutations that affect the outer dynein arm as examples. PMID:11133235

  19. Association genetics and transcriptome analysis reveal a gibberellin-responsive pathway involved in regulating photosynthesis.

    PubMed

    Xie, Jianbo; Tian, Jiaxing; Du, Qingzhang; Chen, Jinhui; Li, Ying; Yang, Xiaohui; Li, Bailian; Zhang, Deqiang

    2016-05-01

    Gibberellins (GAs) regulate a wide range of important processes in plant growth and development, including photosynthesis. However, the mechanism by which GAs regulate photosynthesis remains to be understood. Here, we used multi-gene association to investigate the effect of genes in the GA-responsive pathway, as constructed by RNA sequencing, on photosynthesis, growth, and wood property traits, in a population of 435 Populus tomentosa By analyzing changes in the transcriptome following GA treatment, we identified many key photosynthetic genes, in agreement with the observed increase in measurements of photosynthesis. Regulatory motif enrichment analysis revealed that 37 differentially expressed genes related to photosynthesis shared two essential GA-related cis-regulatory elements, the GA response element and the pyrimidine box. Thus, we constructed a GA-responsive pathway consisting of 47 genes involved in regulating photosynthesis, including GID1, RGA, GID2, MYBGa, and 37 photosynthetic differentially expressed genes. Single nucleotide polymorphism (SNP)-based association analysis showed that 142 SNPs, representing 40 candidate genes in this pathway, were significantly associated with photosynthesis, growth, and wood property traits. Epistasis analysis uncovered interactions between 310 SNP-SNP pairs from 37 genes in this pathway, revealing possible genetic interactions. Moreover, a structural gene-gene matrix based on a time-course of transcript abundances provided a better understanding of the multi-gene pathway affecting photosynthesis. The results imply a functional role for these genes in mediating photosynthesis, growth, and wood properties, demonstrating the potential of combining transcriptome-based regulatory pathway construction and genetic association approaches to detect the complex genetic networks underlying quantitative traits. PMID:27091876

  20. Markov Logic Networks in the Analysis of Genetic Data

    PubMed Central

    Sakhanenko, Nikita A.

    2010-01-01

    Abstract Complex, non-additive genetic interactions are common and can be critical in determining phenotypes. Genome-wide association studies (GWAS) and similar statistical studies of linkage data, however, assume additive models of gene interactions in looking for genotype-phenotype associations. These statistical methods view the compound effects of multiple genes on a phenotype as a sum of influences of each gene and often miss a substantial part of the heritable effect. Such methods do not use any biological knowledge about underlying mechanisms. Modeling approaches from the artificial intelligence (AI) field that incorporate deterministic knowledge into models to perform statistical analysis can be applied to include prior knowledge in genetic analysis. We chose to use the most general such approach, Markov Logic Networks (MLNs), for combining deterministic knowledge with statistical analysis. Using simple, logistic regression-type MLNs we can replicate the results of traditional statistical methods, but we also show that we are able to go beyond finding independent markers linked to a phenotype by using joint inference without an independence assumption. The method is applied to genetic data on yeast sporulation, a complex phenotype with gene interactions. In addition to detecting all of the previously identified loci associated with sporulation, our method identifies four loci with smaller effects. Since their effect on sporulation is small, these four loci were not detected with methods that do not account for dependence between markers due to gene interactions. We show how gene interactions can be detected using more complex models, which can be used as a general framework for incorporating systems biology with genetics. PMID:20958249

  1. Genetic analysis of hispanic individuals with cystic fibrosis

    SciTech Connect

    Grebe, T.A.; Doane, W.W.; Norman, R.A.; Rhodes, S.N. ); Seltzer, W.K. ); DeMarchi, J.; Silva, D.K.; Gozal, D.; Bowman, C.M.; Accurso, F.J.; Jain, K.D. )

    1994-03-01

    The authors have performed molecular genetic analysis of Hispanic individuals with cystic fibrosis (CF) in the southwestern United States. Of 129 CF chromosomes analyzed, oly 46% (59/129) carry [Delta]F508. The G542X mutation was found on 5% (7/129) of CF chromosomes. The 3849+10kbC[yields]T mutation, detected primarily in Ashkenazi Jews, was present on 2% (3/129). R1162X and R334W, mutations identified in Spain and Italy, each occurred on 1.6% (2/129) of CF chromosomes. W1282X and R553X were each detected once. G551D and N1303K were not found. Overall, screening for 22 or more mutations resulted in detection of only 58% of CF transmembrane conductance regulator gene mutations among Hispanic individuals. Analysis of KM19/XV2c haplotypes revealed an unusual distribution. Although the majority of [Delta]508 mutations are on chromosomes of B haplotypes, the other CF mutations are on A and C haplotypes at higher-than-expected frequencies. These genetic analysis demonstrate significant differences between Hispanic individuals with CF and those of the general North American population. Assessment of carrier/affected risk in Hispanic CF individuals cannot, therefore, be based on the mutation frequencies found through studies of the general population but must be adjusted to better reflect the genetic makeup of this ethnic group. Further studies are necessary to identify the causative mutation(s) in this population and to better delineate genotype/phenotype correlations. These will enable counselors to provide more accurate genetic counseling. 22 refs., 2 tabs.

  2. Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases

    PubMed Central

    Li, Yun R; Li, Jin; Zhao, Sihai D; Bradfield, Jonathan P; Mentch, Frank D; Maggadottir, S Melkorka; Hou, Cuiping; Abrams, Debra J; Chang, Diana; Gao, Feng; Guo, Yiran; Wei, Zhi; Connolly, John J; Cardinale, Christopher J; Bakay, Marina; Glessner, Joseph T; Li, Dong; Kao, Charlly; Thomas, Kelly A; Qiu, Haijun; Chiavacci, Rosetta M; Kim, Cecilia E; Wang, Fengxiang; Snyder, James; Richie, Marylyn D; Flatø, Berit; Førre, Øystein; Denson, Lee A; Thompson, Susan D; Becker, Mara L; Guthery, Stephen L; Latiano, Anna; Perez, Elena; Resnick, Elena; Russell, Richard K; Wilson, David C; Silverberg, Mark S; Annese, Vito; Lie, Benedicte A; Punaro, Marilynn; Dubinsky, Marla C; Monos, Dimitri S; Strisciuglio, Caterina; Staiano, Annamaria; Miele, Erasmo; Kugathasan, Subra; Ellis, Justine A; Munro, Jane E; Sullivan, Kathleen E; Wise, Carol A; Chapel, Helen; Cunningham-Rundles, Charlotte; Grant, Struan F A; Orange, Jordan S; Sleiman, Patrick M A; Behrens, Edward M; Griffiths, Anne M; Satsangi, Jack; Finkel, Terri H; Keinan, Alon; Prak, Eline T Luning; Polychronakos, Constantin; Baldassano, Robert N; Li, Hongzhe; Keating, Brendan J; Hakonarson, Hakon

    2016-01-01

    Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ2 meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico–replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases. PMID:26301688

  3. Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.

    PubMed

    Li, Yun R; Li, Jin; Zhao, Sihai D; Bradfield, Jonathan P; Mentch, Frank D; Maggadottir, S Melkorka; Hou, Cuiping; Abrams, Debra J; Chang, Diana; Gao, Feng; Guo, Yiran; Wei, Zhi; Connolly, John J; Cardinale, Christopher J; Bakay, Marina; Glessner, Joseph T; Li, Dong; Kao, Charlly; Thomas, Kelly A; Qiu, Haijun; Chiavacci, Rosetta M; Kim, Cecilia E; Wang, Fengxiang; Snyder, James; Richie, Marylyn D; Flatø, Berit; Førre, Øystein; Denson, Lee A; Thompson, Susan D; Becker, Mara L; Guthery, Stephen L; Latiano, Anna; Perez, Elena; Resnick, Elena; Russell, Richard K; Wilson, David C; Silverberg, Mark S; Annese, Vito; Lie, Benedicte A; Punaro, Marilynn; Dubinsky, Marla C; Monos, Dimitri S; Strisciuglio, Caterina; Staiano, Annamaria; Miele, Erasmo; Kugathasan, Subra; Ellis, Justine A; Munro, Jane E; Sullivan, Kathleen E; Wise, Carol A; Chapel, Helen; Cunningham-Rundles, Charlotte; Grant, Struan F A; Orange, Jordan S; Sleiman, Patrick M A; Behrens, Edward M; Griffiths, Anne M; Satsangi, Jack; Finkel, Terri H; Keinan, Alon; Prak, Eline T Luning; Polychronakos, Constantin; Baldassano, Robert N; Li, Hongzhe; Keating, Brendan J; Hakonarson, Hakon

    2015-09-01

    Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases. PMID:26301688

  4. Systematic Review and Meta-analysis of Candidate Gene Association Studies of Lower Urinary Tract Symptoms in Men☆

    PubMed Central

    Cartwright, Rufus; Mangera, Altaf; Tikkinen, Kari A.O.; Rajan, Prabhakar; Pesonen, Jori; Kirby, Anna C.; Thiagamoorthy, Ganesh; Ambrose, Chris; Gonzalez-Maffe, Juan; Bennett, Phillip R.; Palmer, Tom; Walley, Andrew; Järvelin, Marjo-Riitta; Khullar, Vik; Chapple, Chris

    2014-01-01

    Context Although family studies have shown that male lower urinary tract symptoms (LUTS) are highly heritable, no systematic review exists of genetic polymorphisms tested for association with LUTS. Objective To systematically review and meta-analyze studies assessing candidate polymorphisms/genes tested for an association with LUTS, and to assess the strength, consistency, and potential for bias among pooled associations. Evidence acquisition A systematic search of the PubMed and HuGE databases as well as abstracts of major urologic meetings was performed through to January 2013. Case-control studies reporting genetic associations in men with LUTS were included. Reviewers independently and in duplicate screened titles, abstracts, and full texts to determine eligibility, abstracted data, and assessed the credibility of pooled associations according to the interim Venice criteria. Authors were contacted for clarifications if needed. Meta-analyses were performed for variants assessed in more than two studies. Evidence synthesis We identified 74 eligible studies containing data on 70 different genes. A total of 35 meta-analyses were performed with statistical significance in five (ACE, ELAC2, GSTM1, TERT, and VDR). The heterogeneity was high in three of these meta-analyses. The rs731236 variant of the vitamin D receptor had a protective effect for LUTS (odds ratio: 0.64; 95% confidence interval, 0.49–0.83) with moderate heterogeneity (I2 = 27.2%). No evidence for publication bias was identified. Limitations include wide-ranging phenotype definitions for LUTS and limited power in most meta-analyses to detect smaller effect sizes. Conclusions Few putative genetic risk variants have been reliably replicated across populations. We found consistent evidence of a reduced risk of LUTS associated with the common rs731236 variant of the vitamin D receptor gene in our meta-analyses. Patient summary Combining the results from all previous studies of genetic variants that may

  5. Comparative Transcriptome Analysis Identifies Candidate Genes Related to Skin Color Differentiation in Red Tilapia.

    PubMed

    Zhu, Wenbin; Wang, Lanmei; Dong, Zaijie; Chen, Xingting; Song, Feibiao; Liu, Nian; Yang, Hui; Fu, Jianjun

    2016-01-01

    Red tilapia is becoming more popular for aquaculture production in China in recent years. However, the pigmentation differentiation in genetic breeding is the main problem limiting its development of commercial red tilapia culture and the genetic basis of skin color variation is still unknown. In this study, we conducted Illumina sequencing of transcriptome on three color variety red tilapia. A total of 224,895,758 reads were generated, resulting in 160,762 assembled contigs that were used as reference contigs. The contigs of red tilapia transcriptome had hits in the range of 53.4% to 86.7% of the unique proteins of zebrafish, fugu, medaka, three-spined stickleback and tilapia. And 44,723 contigs containing 77,423 simple sequence repeats (SSRs) were identified, with 16,646 contigs containing more than one SSR. Three skin transcriptomes were compared pairwise and the results revealed that there were 148 common significantly differentially expressed unigenes and several key genes related to pigment synthesis, i.e. tyr, tyrp1, silv, sox10, slc24a5, cbs and slc7a11, were included. The results will facilitate understanding the molecular mechanisms of skin pigmentation differentiation in red tilapia and accelerate the molecular selection of the specific strain with consistent skin colors. PMID:27511178

  6. Comparative Transcriptome Analysis Identifies Candidate Genes Related to Skin Color Differentiation in Red Tilapia

    PubMed Central

    Zhu, Wenbin; Wang, Lanmei; Dong, Zaijie; Chen, Xingting; Song, Feibiao; Liu, Nian; Yang, Hui; Fu, Jianjun

    2016-01-01

    Red tilapia is becoming more popular for aquaculture production in China in recent years. However, the pigmentation differentiation in genetic breeding is the main problem limiting its development of commercial red tilapia culture and the genetic basis of skin color variation is still unknown. In this study, we conducted Illumina sequencing of transcriptome on three color variety red tilapia. A total of 224,895,758 reads were generated, resulting in 160,762 assembled contigs that were used as reference contigs. The contigs of red tilapia transcriptome had hits in the range of 53.4% to 86.7% of the unique proteins of zebrafish, fugu, medaka, three-spined stickleback and tilapia. And 44,723 contigs containing 77,423 simple sequence repeats (SSRs) were identified, with 16,646 contigs containing more than one SSR. Three skin transcriptomes were compared pairwise and the results revealed that there were 148 common significantly differentially expressed unigenes and several key genes related to pigment synthesis, i.e. tyr, tyrp1, silv, sox10, slc24a5, cbs and slc7a11, were included. The results will facilitate understanding the molecular mechanisms of skin pigmentation differentiation in red tilapia and accelerate the molecular selection of the specific strain with consistent skin colors. PMID:27511178

  7. High-throughput analysis of candidate imprinted genes and allele-specific gene expression in the human term placenta

    PubMed Central

    2010-01-01

    Background Imprinted genes show expression from one parental allele only and are important for development and behaviour. This extreme mode of allelic imbalance has been described for approximately 56 human genes. Imprinting status is often disrupted in cancer and dysmorphic syndromes. More subtle variation of gene expression, that is not parent-of-origin specific, termed 'allele-specific gene expression' (ASE) is more common and may give rise to milder phenotypic differences. Using two allele-specific high-throughput technologies alongside bioinformatics predictions, normal term human placenta was screened to find new imprinted genes and to ascertain the extent of ASE in this tissue. Results Twenty-three family trios of placental cDNA, placental genomic DNA (gDNA) and gDNA from both parents were tested for 130 candidate genes with the Sequenom MassArray system. Six genes were found differentially expressed but none imprinted. The Illumina ASE BeadArray platform was then used to test 1536 SNPs in 932 genes. The array was enriched for the human orthologues of 124 mouse candidate genes from bioinformatics predictions and 10 human candidate imprinted genes from EST database mining. After quality control pruning, a total of 261 informative SNPs (214 genes) remained for analysis. Imprinting with maternal expression was demonstrated for the lymphocyte imprinted gene ZNF331 in human placenta. Two potential differentially methylated regions (DMRs) were found in the vicinity of ZNF331. None of the bioinformatically predicted candidates tested showed imprinting except for a skewed allelic expression in a parent-specific manner observed for PHACTR2, a neighbour of the imprinted PLAGL1 gene. ASE was detected for two or more individuals in 39 candidate genes (18%). Conclusions Both Sequenom and Illumina assays were sensitive enough to study imprinting and strong allelic bias. Previous bioinformatics approaches were not predictive of new imprinted genes in the human term

  8. Genome wide analysis indicates genes for basement membrane and cartilage matrix proteins as candidates for hip dysplasia in Labrador Retrievers.

    PubMed

    Lavrijsen, Ineke C M; Leegwater, Peter A J; Martin, Alan J; Harris, Stephen J; Tryfonidou, Marianna A; Heuven, Henri C M; Hazewinkel, Herman A W

    2014-01-01

    Hip dysplasia, an abnormal laxity of the hip joint, is seen in humans as well as dogs and is one of the most common skeletal disorders in dogs. Canine hip dysplasia is considered multifactorial and polygenic, and a variety of chromosomal regions have been associated with the disorder. We performed a genome-wide association study in Dutch Labrador Retrievers, comparing data of nearly 18,000 single nucleotide polymorphisms (SNPs) in 48 cases and 30 controls using two different statistical methods. An individual SNP analysis based on comparison of allele frequencies with a χ(2) statistic was used, as well as a simultaneous SNP analysis based on Bayesian variable selection. Significant association with canine hip dysplasia was observed on chromosome 8, as well as suggestive association on chromosomes 1, 5, 15, 20, 25 and 32. Next-generation DNA sequencing of the exons of genes of seven regions identified multiple associated alleles on chromosome 1, 5, 8, 20, 25 and 32 (p<0.001). Candidate genes located in the associated regions on chromosomes 1, 8 and 25 included LAMA2, LRR1 and COL6A3, respectively. The associated region on CFA20 contained candidate genes GDF15, COMP and CILP2. In conclusion, our study identified candidate genes that might affect susceptibility to canine hip dysplasia. These genes are involved in hypertrophic differentiation of chondrocytes and extracellular matrix integrity of basement membrane and cartilage. The functions of the genes are in agreement with the notion that disruptions in endochondral bone formation in combination with soft tissue defects are involved in the etiology of hip dysplasia. PMID:24498183

  9. Genome Wide Analysis Indicates Genes for Basement Membrane and Cartilage Matrix Proteins as Candidates for Hip Dysplasia in Labrador Retrievers

    PubMed Central

    Lavrijsen, Ineke C. M.; Leegwater, Peter A. J.; Martin, Alan J.; Harris, Stephen J.; Tryfonidou, Marianna A.; Heuven, Henri C. M.; Hazewinkel, Herman A. W.

    2014-01-01

    Hip dysplasia, an abnormal laxity of the hip joint, is seen in humans as well as dogs and is one of the most common skeletal disorders in dogs. Canine hip dysplasia is considered multifactorial and polygenic, and a variety of chromosomal regions have been associated with the disorder. We performed a genome-wide association study in Dutch Labrador Retrievers, comparing data of nearly 18,000 single nucleotide polymorphisms (SNPs) in 48 cases and 30 controls using two different statistical methods. An individual SNP analysis based on comparison of allele frequencies with a χ2 statistic was used, as well as a simultaneous SNP analysis based on Bayesian variable selection. Significant association with canine hip dysplasia was observed on chromosome 8, as well as suggestive association on chromosomes 1, 5, 15, 20, 25 and 32. Next-generation DNA sequencing of the exons of genes of seven regions identified multiple associated alleles on chromosome 1, 5, 8, 20, 25 and 32 (p<0.001). Candidate genes located in the associated regions on chromosomes 1, 8 and 25 included LAMA2, LRR1 and COL6A3, respectively. The associated region on CFA20 contained candidate genes GDF15, COMP and CILP2. In conclusion, our study identified candidate genes that might affect susceptibility to canine hip dysplasia. These genes are involved in hypertrophic differentiation of chondrocytes and extracellular matrix integrity of basement membrane and cartilage. The functions of the genes are in agreement with the notion that disruptions in endochondral bone formation in combination with soft tissue defects are involved in the etiology of hip dysplasia. PMID:24498183

  10. Transdominant genetic analysis of a growth control pathway

    PubMed Central

    Caponigro, Giordano; Abedi, Majid R.; Hurlburt, Anthony P.; Maxfield, Andrew; Judd, Weston; Kamb, Alexander

    1998-01-01

    Genetic selections that use proteinaceous transdominant inhibitors encoded by DNA libraries to cause mutant phenocopies may facilitate genetic analysis in traditionally nongenetic organisms. We performed a selection for random short peptides and larger protein fragments (collectively termed “perturbagens”) that inhibit the yeast pheromone response pathway. Peptide and protein fragment perturbagens that permit cell division in the presence of pheromone were recovered. Two perturbagens were derived from proteins required for pheromone response, and an additional two were derived from proteins that may negatively influence the pheromone response pathway. Furthermore, three known components of the pathway were identified as probable perturbagen targets based on physical interaction assays. Thus, by selection for transdominant inhibitors of pheromone response, multiple pathway components were identified either directly as gene fragments or indirectly as the likely targets of specific perturbagens. These results, combined with the results of previous work [Holzmayer, T. A., Pestov, D. G. & Roninson, I. B. (1992) Nucl. Acids. Res. 20, 711–717; Whiteway, M., Dignard, D. & Thomas, D. Y. (1992) Proc. Natl. Acad. Sci. USA 89, 9410–9414; and Gudkov, A. V., Kazarov, A. R., Thimmapaya, R., Axenovich, S. A., Mazo, I. A. & Roninson, I. B. (1994) Proc. Natl. Acad. Sci. USA 91, 3744–3748], suggest that transdominant genetic analysis of the type described here will be broadly applicable. PMID:9636180

  11. Genetic diversity and recombination analysis of sweepoviruses from Brazil

    PubMed Central

    2012-01-01

    Background Monopartite begomoviruses (genus Begomovirus, family Geminiviridae) that infect sweet potato (Ipomoea batatas) around the world are known as sweepoviruses. Because sweet potato plants are vegetatively propagated, the accumulation of viruses can become a major constraint for root production. Mixed infections of sweepovirus species and strains can lead to recombination, which may contribute to the generation of new recombinant sweepoviruses. Results This study reports the full genome sequence of 34 sweepoviruses sampled from a sweet potato germplasm bank and commercial fields in Brazil. These sequences were compared with others from public nucleotide sequence databases to provide a comprehensive overview of the genetic diversity and patterns of genetic exchange in sweepoviruses isolated from Brazil, as well as to review the classification and nomenclature of sweepoviruses in accordance with the current guidelines proposed by the Geminiviridae Study Group of the International Committee on Taxonomy of Viruses (ICTV). Co-infections and extensive recombination events were identified in Brazilian sweepoviruses. Analysis of the recombination breakpoints detected within the sweepovirus dataset revealed that most recombination events occurred in the intergenic region (IR) and in the middle of the C1 open reading frame (ORF). Conclusions The genetic diversity of sweepoviruses was considerably greater than previously described in Brazil. Moreover, recombination analysis revealed that a genomic exchange is responsible for the emergence of sweepovirus species and strains and provided valuable new information for understanding the diversity and evolution of sweepoviruses. PMID:23082767

  12. Quantitative genetic analysis of the metabolic syndrome in Hispanic children.

    PubMed

    Butte, Nancy F; Comuzzie, Anthony G; Cole, Shelley A; Mehta, Nitesh R; Cai, Guowen; Tejero, Maria; Bastarrachea, Raul; Smith, E O'Brian

    2005-12-01

    Childhood obesity is associated with a constellation of metabolic derangements including glucose intolerance, hypertension, and dyslipidemia, referred to as metabolic syndrome. The purpose of this study was to investigate genetic and environmental factors contributing to the metabolic syndrome in Hispanic children. Metabolic syndrome, defined as having three or more metabolic risk components, was determined in 1030 Hispanic children, ages 4-19 y, from 319 families enrolled in the VIVA LA FAMILIA study. Anthropometry, body composition by dual energy x-ray absorptiometry, clinical signs, and serum biochemistries were measured using standard techniques. Risk factor analysis and quantitative genetic analysis were performed. Of the overweight children, 20%, or 28% if abnormal liver function is included in the definition, presented with the metabolic syndrome. Odds ratios for the metabolic syndrome were significantly increased by body mass index z-score and fasting serum insulin; independent effects of sex, age, puberty, and body composition were not seen. Heritabilities +/- SE for waist circumference, triglycerides (TG), HDL, systolic blood pressure (SBP), glucose, and alanine aminotransferase (ALT) were highly significant. Pleiotropy (a common set of genes affecting two traits) detected between SBP and waist circumference, SBP and glucose, HDL and waist circumference, ALT and waist circumference, and TG and ALT may underlie the clustering of the components of the metabolic syndrome. Significant heritabilities and pleiotropy seen for the components of the metabolic syndrome indicate a strong genetic contribution to the metabolic syndrome in overweight Hispanic children. PMID:16306201

  13. Transcriptome Analysis Reveals Candidate Genes involved in Blister Blight defense in Tea (Camellia sinensis (L) Kuntze)

    NASA Astrophysics Data System (ADS)

    Jayaswall, Kuldip; Mahajan, Pallavi; Singh, Gagandeep; Parmar, Rajni; Seth, Romit; Raina, Aparnashree; Swarnkar, Mohit Kumar; Singh, Anil Kumar; Shankar, Ravi; Sharma, Ram Kumar

    2016-07-01

    To unravel the molecular mechanism of defense against blister blight (BB) disease caused by an obligate biotrophic fungus, Exobasidium vexans, transcriptome of BB interaction with resistance and susceptible tea genotypes was analysed through RNA-seq using Illumina GAIIx at four different stages during ~20-day disease cycle. Approximately 69 million high quality reads were assembled de novo, yielding 37,790 unique transcripts with more than 55% being functionally annotated. Differentially expressed, 149 defense related transcripts/genes, namely defense related enzymes, resistance genes, multidrug resistant transporters, transcription factors, retrotransposons, metacaspases and chaperons were observed in RG, suggesting their role in defending against BB. Being present in the major hub, putative master regulators among these candidates were identified from predetermined protein-protein interaction network of Arabidopsis thaliana. Further, confirmation of abundant expression of well-known RPM1, RPS2 and RPP13 in quantitative Real Time PCR indicates salicylic acid and jasmonic acid, possibly induce synthesis of antimicrobial compounds, required to overcome the virulence of E. vexans. Compendiously, the current study provides a comprehensive gene expression and insights into the molecular mechanism of tea defense against BB to serve as a resource for unravelling the possible regulatory mechanism of immunity against various biotic stresses in tea and other crops.

  14. Proteomic analysis of a segregant population reveals candidate proteins linked to mealiness in peach.

    PubMed

    Almeida, Andréa Miyasaka; Urra, Claudio; Moraga, Carol; Jego, Marcela; Flores, Alejandra; Meisel, Lee; González, Mauricio; Infante, Rodrigo; Defilippi, Bruno G; Campos-Vargas, Reinaldo; Orellana, Ariel

    2016-01-10

    Peaches are stored at low temperatures to delay ripening and increase postharvest life. However some varieties are susceptible to chilling injury,which leads to fruit mealiness, browning and flesh bleeding. In order to identify potentialmarkers associated with chilling injury,we performed proteomic analyses on a segregating population with contrasting susceptibility to chilling-induced mealiness. Chilling-induced mealiness was assessed by measuring juiciness in fruits that have been stored in cold and then allowed to ripen. Fruitmesocarp and leaf proteome from contrasting segregants were analyzed using 2-DE gels. Comparison of protein abundance between segregants revealed 133 spots from fruit mesocarp and 36 from leaf. Thirty four fruit mesocarp proteins were identified from these spots. Most of these proteins were related to ethylene synthesis, ABA response and stress response. Leaf protein analyses identified 22 proteins, most of which related to energy metabolism. Some of the genes that code for these proteins have been previously correlated with chilling injury through transcript analyses and co-segregation with mealiness QTLs. The results from this study, further deciphers the molecular mechanisms associated with chilling response in peach fruit, and identifies candidate proteins linked to mealiness in peach which may be used as putative markers for this trait. PMID:26459401

  15. Transcriptome Analysis Reveals Candidate Genes involved in Blister Blight defense in Tea (Camellia sinensis (L) Kuntze)

    PubMed Central

    Jayaswall, Kuldip; Mahajan, Pallavi; Singh, Gagandeep; Parmar, Rajni; Seth, Romit; Raina, Aparnashree; Swarnkar, Mohit Kumar; Singh, Anil Kumar; Shankar, Ravi; Sharma, Ram Kumar

    2016-01-01

    To unravel the molecular mechanism of defense against blister blight (BB) disease caused by an obligate biotrophic fungus, Exobasidium vexans, transcriptome of BB interaction with resistance and susceptible tea genotypes was analysed through RNA-seq using Illumina GAIIx at four different stages during ~20-day disease cycle. Approximately 69 million high quality reads were assembled de novo, yielding 37,790 unique transcripts with more than 55% being functionally annotated. Differentially expressed, 149 defense related transcripts/genes, namely defense related enzymes, resistance genes, multidrug resistant transporters, transcription factors, retrotransposons, metacaspases and chaperons were observed in RG, suggesting their role in defending against BB. Being present in the major hub, putative master regulators among these candidates were identified from predetermined protein-protein interaction network of Arabidopsis thaliana. Further, confirmation of abundant expression of well-known RPM1, RPS2 and RPP13 in quantitative Real Time PCR indicates salicylic acid and jasmonic acid, possibly induce synthesis of antimicrobial compounds, required to overcome the virulence of E. vexans. Compendiously, the current study provides a comprehensive gene expression and insights into the molecular mechanism of tea defense against BB to serve as a resource for unravelling the possible regulatory mechanism of immunity against various biotic stresses in tea and other crops. PMID:27465480

  16. A New Analysis of the Bidelman & MacConnell Low-Metallicity Candidates

    NASA Astrophysics Data System (ADS)

    Krugler, J. A.; Frank, D.; Beers, T. C.; Norris, J. E.; Chiba, M.

    2004-12-01

    A new set of very high signal-to-noise ( > 100/1), medium-resolution (1 Å ) spectra have been obtained at Siding Springs Observatory for the sample of candidate low-metallicity stars originally selected by Bidelman & MacConnell, and reported on two decades ago by Norris, Bessell, & Pickles (1985). The sample has been supplemented with newly available proper motions from a variety of sources, as well as with JHK photometry from the 2MASS Point Source Catalog. Based on these data, we measure improved radial velocities, re-determine estimates of [Fe/H], provide new estimates of [C/Fe], and obtain full space motions for the majority of the stars in this catalog. Associations of these stars with various recognized stellar populations (the thin disk, thick disk, metal-weak thick disk, and halo) are discussed. This work received partial funding support from grant PHY 02-16783, Physics Frontier Centers/JINA: Joint Institute for Nuclear Astrophysics, awarded by the US National Science Foundation.

  17. Transcriptome Analysis Reveals Candidate Genes involved in Blister Blight defense in Tea (Camellia sinensis (L) Kuntze).

    PubMed

    Jayaswall, Kuldip; Mahajan, Pallavi; Singh, Gagandeep; Parmar, Rajni; Seth, Romit; Raina, Aparnashree; Swarnkar, Mohit Kumar; Singh, Anil Kumar; Shankar, Ravi; Sharma, Ram Kumar

    2016-01-01

    To unravel the molecular mechanism of defense against blister blight (BB) disease caused by an obligate biotrophic fungus, Exobasidium vexans, transcriptome of BB interaction with resistance and susceptible tea genotypes was analysed through RNA-seq using Illumina GAIIx at four different stages during ~20-day disease cycle. Approximately 69 million high quality reads were assembled de novo, yielding 37,790 unique transcripts with more than 55% being functionally annotated. Differentially expressed, 149 defense related transcripts/genes, namely defense related enzymes, resistance genes, multidrug resistant transporters, transcription factors, retrotransposons, metacaspases and chaperons were observed in RG, suggesting their role in defending against BB. Being present in the major hub, putative master regulators among these candidates were identified from predetermined protein-protein interaction network of Arabidopsis thaliana. Further, confirmation of abundant expression of well-known RPM1, RPS2 and RPP13 in quantitative Real Time PCR indicates salicylic acid and jasmonic acid, possibly induce synthesis of antimicrobial compounds, required to overcome the virulence of E. vexans. Compendiously, the current study provides a comprehensive gene expression and insights into the molecular mechanism of tea defense against BB to serve as a resource for unravelling the possible regulatory mechanism of immunity against various biotic stresses in tea and other crops. PMID:27465480

  18. Genetic analysis of incurvata mutants reveals three independent genetic operations at work in Arabidopsis leaf morphogenesis.

    PubMed Central

    Serrano-Cartagena, J; Candela, H; Robles, P; Ponce, M R; Pérez-Pérez, J M; Piqueras, P; Micol, J L

    2000-01-01

    In an attempt to identify genes involved in the control of leaf morphogenesis, we have studied 13 Arabidopsis thaliana mutants with curled, involute leaves, a phenotype herein referred to as Incurvata (Icu), which were isolated by G. Röbbelen and belong to the Arabidopsis Information Service Form Mutants collection. The Icu phenotype was inherited as a single recessive trait in 10 mutants, with semidominance in 2 mutants and with complete dominance in the remaining 1. Complementation analyses indicated that the studied mutations correspond to five genes, representative alleles of which were mapped relative to polymorphic microsatellites. Although most double-mutant combinations displayed additivity of the Icu phenotypes, those of icu1 icu2 and icu3 icu4 double mutants were interpreted as synergistic, which suggests that the five genes studied represent three independent genetic operations that are at work for the leaf to acquire its final form at full expansion. We have shown that icu1 mutations are alleles of the Polycomb group gene CURLY LEAF (CLF) and that the leaf phenotype of the icu2 mutant is suppressed in an agamous background, as is known for clf mutants. In addition, we have tested by means of multiplex RT-PCR the transcription of several floral genes in Icu leaves. Ectopic expression of AGAMOUS and APETALA3 was observed in clf and icu2, but not in icu3, icu4, and icu5 mutants. Taken together, these results suggest that CLF and ICU2 play related roles, the latter being a candidate to belong to the Polycomb group of regulatory genes. We propose that, as flowers evolved, a new major class of genes, including CLF and ICU2, may have been recruited to prevent the expression of floral homeotic genes in the leaves. PMID:11063708

  19. Analysis of genetic traits for drought tolerance in maize.

    PubMed

    Muhammad, R W; Qayyum, A; Hamza, A; Ahmad, M Q; Naseer, N S; Liaqat, S; Ahmad, B; Malik, W; Noor, E

    2015-01-01

    Fifty-four genotypes of maize were crossed and evaluated in the field during the crop season in February 2012 under both normal and water stress conditions. To identify the major parameters responsible for variation among genotypes, single linkage cluster analysis and principle component analysis (PCA) were carried out. Thirteen characters were studied. The PCA showed that the first six components, with eigen values >1, contributed 82.30% of the variability among the genotypes under normal field irrigation conditions while other PCs (7-13) had eigen values less than 1. Under drought conditions, the first four PCs, with eigen values >1, contributed 64.79% of the variability among genotypes while the other PCs (5-13) had eigen values less than 1. In the absence of water stress, heritability ranged from 68% (sucrose content) to 99% (plant height) and genetic advance ranged between 158.43% for stomatal frequency and 0.87 for biological yield. Under drought conditions, the coefficient of variability (CV) was 1.43-7.79, whereas estimates of heritability ranged between 68% and 99% for sucrose content and leaf area, respectively. The values of genetic advance ranged between 153.41 for stomatal frequency and 0.47 for nitrogen content. CV was 1.52-7.38 under drought conditions. The results indicated that the plant characters studied were under the control of additive genetic effects and suggested that selection should lead to fast genetic improvements. Clusters with superior agronomic types were identified and could be exploited for the transfer of desirable genes to improve the yield potential of the maize crop. PMID:26535668

  20. The geography of genetics: an analysis of referral patterns to a cancer genetics service

    PubMed Central

    Iredale, Rachel; Higgs, Gary

    2008-01-01

    This study uses a geographical information system (GIS) and statistical analysis to look for patterns in referrals to a British cancer genetics service. In this case, familial cancers are taken to be those that can develop when an individual inherits DNA mutations that cause an increased risk of cancer. Between 1998 and 2006 the Cancer Genetics Service for Wales received nearly 11,000 referrals for patients resident in Wales and it is the service database recording those referrals which is the subject of this secondary analysis. Using postcodes to match referred patients to areas, deprivation scores were assigned. Referral rates per 10,000 head of population across the 8-year study period by unitary authority are presented, as is information on referrals from primary and secondary care sources by year. Each patient referred has their family history of cancer recorded and is assigned to a risk category; high, medium or average. There are correlations between number of GPs (General Practitioners) in a practice, number of patients referred from a practice, and deprivation as measured by the overall Welsh Index of Multiple Deprivation 2005, such that the two former factors increase as deprivation decreases. Over time there were changes in referral sources, with referrals from primary care overtaking those from secondary care in percentage and absolute terms. There were also changes in the types of cancer referred, risk categories seen and to which centre referrals were made. Referral patterns reveal an inverse relationship between deprivation and health service availability and use. PMID:18923938

  1. Comparative mRNA analysis of behavioral and genetic mouse models of aggression.

    PubMed

    Malki, Karim; Tosto, Maria G; Pain, Oliver; Sluyter, Frans; Mineur, Yann S; Crusio, Wim E; de Boer, Sietse; Sandnabba, Kenneth N; Kesserwani, Jad; Robinson, Edward; Schalkwyk, Leonard C; Asherson, Philip

    2016-04-01

    Mouse models of aggression have traditionally compared strains, most notably BALB/cJ and C57BL/6. However, these strains were not designed to study aggression despite differences in aggression-related traits and distinct reactivity to stress. This study evaluated expression of genes differentially regulated in a stress (behavioral) mouse model of aggression with those from a recent genetic mouse model aggression. The study used a discovery-replication design using two independent mRNA studies from mouse brain tissue. The discovery study identified strain (BALB/cJ and C57BL/6J) × stress (chronic mild stress or control) interactions. Probe sets differentially regulated in the discovery set were intersected with those uncovered in the replication study, which evaluated differences between high and low aggressive animals from three strains specifically bred to study aggression. Network analysis was conducted on overlapping genes uncovered across both studies. A significant overlap was found with the genetic mouse study sharing 1,916 probe sets with the stress model. Fifty-one probe sets were found to be strongly dysregulated across both studies mapping to 50 known genes. Network analysis revealed two plausible pathways including one centered on the UBC gene hub which encodes ubiquitin, a protein well-known for protein degradation, and another on P38 MAPK. Findings from this study support the stress model of aggression, which showed remarkable molecular overlap with a genetic model. The study uncovered a set of candidate genes including the Erg2 gene, which has previously been implicated in different psychopathologies. The gene networks uncovered points at a Redox pathway as potentially being implicated in aggressive related behaviors. © 2016 Wiley Periodicals, Inc. PMID:26888158

  2. Mining, genetic mapping and expression analysis of EST-derived resistance gene homologs (RGHs) in cotton

    PubMed Central

    2014-01-01

    Background Cotton is the dominant textile crop and also serves as an important oil crop. An estimated 15% economic loss associated with cotton production in China has been caused by diseases, and no resistance genes have been cloned in this crop. Molecular markers developed from resistance gene homologues (RGHs) might be tightly linked with target genes and could be used for marker-assisted selection (MAS) or gene cloning. Results To genetically map expressed RGHs, 100 potential pathogenesis-related proteins (PRPs) and 215 resistance gene analogs (RGAs) were identified in the cotton expressed sequence tag database, and 347 specific primers were developed. Meanwhile, 61 cotton genome-derived RGA markers and 24 resistance gene analog polymorphism (RGAP) markers from published papers were included to view their genomic distribution. As a result, 38 EST-derived and 17 genome-derived RGH markers were added to our interspecific genetic map. These 55 markers were distributed on 18 of the 26 cotton chromosomes, with 34 markers on 6 chromosomes (Chr03, Chr04, Chr11, Chr17, Chr19 and Chr26). Homologous RGHs tended to be clustered; RGH clusters appeared on 9 chromosomes, with larger clusters on Chr03, Chr04 and Chr19, which suggests that RGH clusters are widely distributed in the cotton genome. Expression analysis showed that 19 RGHs were significantly altered after inoculation with the V991 stain of Verticillium dahliae. Comparative mapping showed that four RGH markers were linked with mapped loci for Verticillium wilt resistance. Conclusions The genetic mapping of RGHs confirmed their clustering in cotton genome. Expression analysis and comparative mapping suggest that EST-derived RGHs participate in cotton resistance. RGH markers are seemed to be useful tools to detected resistance loci and identify candidate resistance genes in cotton. PMID:25064562

  3. Genetic Geostatistical Framework for Spatial Analysis of Fine-Scale Genetic Heterogeneity in Modern Populations: Results from the KORA Study.

    PubMed

    Diaz-Lacava, A N; Walier, M; Holler, D; Steffens, M; Gieger, C; Furlanello, C; Lamina, C; Wichmann, H E; Becker, T

    2015-01-01

    Aiming to investigate fine-scale patterns of genetic heterogeneity in modern humans from a geographic perspective, a genetic geostatistical approach framed within a geographic information system is presented. A sample collected for prospective studies in a small area of southern Germany was analyzed. None indication of genetic heterogeneity was detected in previous analysis. Socio-demographic and genotypic data of German citizens were analyzed (212 SNPs; n = 728). Genetic heterogeneity was evaluated with observed heterozygosity (H O ). Best-fitting spatial autoregressive models were identified, using socio-demographic variables as covariates. Spatial analysis included surface interpolation and geostatistics of observed and predicted patterns. Prediction accuracy was quantified. Spatial autocorrelation was detected for both socio-demographic and genetic variables. Augsburg City and eastern suburban areas showed higher H O values. The selected model gave best predictions in suburban areas. Fine-scale patterns of genetic heterogeneity were observed. In accordance to literature, more urbanized areas showed higher levels of admixture. This approach showed efficacy for detecting and analyzing subtle patterns of genetic heterogeneity within small areas. It is scalable in number of loci, even up to whole-genome analysis. It may be suggested that this approach may be applicable to investigate the underlying genetic history that is, at least partially, embedded in geographic data. PMID:26258132

  4. Genetic Geostatistical Framework for Spatial Analysis of Fine-Scale Genetic Heterogeneity in Modern Populations: Results from the KORA Study

    PubMed Central

    Diaz-Lacava, A. N.; Walier, M.; Holler, D.; Steffens, M.; Gieger, C.; Furlanello, C.; Lamina, C.; Wichmann, H. E.; Becker, T.

    2015-01-01

    Aiming to investigate fine-scale patterns of genetic heterogeneity in modern humans from a geographic perspective, a genetic geostatistical approach framed within a geographic information system is presented. A sample collected for prospective studies in a small area of southern Germany was analyzed. None indication of genetic heterogeneity was detected in previous analysis. Socio-demographic and genotypic data of German citizens were analyzed (212 SNPs; n = 728). Genetic heterogeneity was evaluated with observed heterozygosity (HO). Best-fitting spatial autoregressive models were identified, using socio-demographic variables as covariates. Spatial analysis included surface interpolation and geostatistics of observed and predicted patterns. Prediction accuracy was quantified. Spatial autocorrelation was detected for both socio-demographic and genetic variables. Augsburg City and eastern suburban areas showed higher HO values. The selected model gave best predictions in suburban areas. Fine-scale patterns of genetic heterogeneity were observed. In accordance to literature, more urbanized areas showed higher levels of admixture. This approach showed efficacy for detecting and analyzing subtle patterns of genetic heterogeneity within small areas. It is scalable in number of loci, even up to whole-genome analysis. It may be suggested that this approach may be applicable to investigate the underlying genetic history that is, at least partially, embedded in geographic data. PMID:26258132

  5. Rheology Analysis of Thermosetting Resin Candidates for Use in Fuel Compacting

    SciTech Connect

    Trammell, Michael P.

    2012-06-01

    The AGR-1 and AGR-2 overcoating and compacting method utilized a wet mixing process where liquid resin (Hexion Durite SC-1008) was blended with natural and synthetic graphite to produce a graphite/resin matrix for overcoating. The matrix production method specified in the scale-up plan is a co-grinding jet mill process where powdered resin and graphite are fed at the same time into a jet mill. Because of the change in matrix production style, SC-1008 cannot be used in the jet milling process because it is a liquid. Also, attempts to dry out matrix made with SC-1008 for use in the overcoating process at B&W had mixed results. The SC-1008 resin became tacky when dried which caused the matrix to build up inside the overcoater. The scale- up jet milling/mixing and overcoating processes required that a suite of solid or powdered resins be identified. Suitable resins candidates were down selected to two resins, specifically Plenco 14838 and Hexion SD-1708. These resins are referred to as novolac or “two-stage” resins because they require the addition of a curing agent such as hexamethylenetetramine (Hexa) to promote an increased level of cross linking. The overcoating matrix is made of 3 components; natural graphite, synthetic graphite, and resin. The most influential component of the compacting process is the resin component and how it behaves with regards to time, temperature, and pressure. The selected scale-up resins are considered fast curing which means that the increase in molecular weight (curing) occurs over a relatively short period of time, ranging from a few seconds to several minutes depending on the temperature. To find the optimal compacting conditions it is useful to quantify this behavior. In this report, rheology is used to investigate viscosity as a function of time at specific temperatures for the previously mentioned resins.

  6. Expression analysis of candidate genes regulating successional tooth formation in the human embryo

    PubMed Central

    Olley, Ryan; Xavier, Guilherme M.; Seppala, Maisa; Volponi, Ana A.; Geoghegan, Fin; Sharpe, Paul T.; Cobourne, Martyn T.

    2014-01-01

    Human dental development is characterized by formation of primary teeth, which are subsequently replaced by the secondary dentition. The secondary dentition consists of incisors, canines, and premolars, which are derived from the successional dental lamina of the corresponding primary tooth germs; and molar teeth, which develop as a continuation of the dental lamina. Currently, very little is known about the molecular regulation of human successional tooth formation. Here, we have investigated expression of three candidate regulators for human successional tooth formation; the Fibroblast Growth Factor-antagonist SPROUTY2, the Hedgehog co-receptor GAS1 and the RUNT-related transcription factor RUNX2. At around 8 weeks of development, only SPROUTY2 showed strong expression in both epithelium and mesenchyme of the early bud. During the cap stage between 12–14 weeks, SPROUTY2 predominated in the dental papilla and inner enamel epithelium of the developing tooth. No specific expression was seen in the successional dental lamina. GAS1 was expressed in dental papilla and follicle, and associated with mesenchyme adjacent to the primary dental lamina during the late cap stage. In addition, GAS1 was identifiable in mesenchyme adjacent to the successional lamina, particularly in the developing primary first molar. For RUNX2, expression predominated in the dental papilla and follicle. Localized expression was seen in mesenchyme adjacent to the primary dental lamina at the late cap stage; but surprisingly, not in the early successional lamina at these stages. These findings confirm that SPROUTY2, GAS1, and RUNX2 are all expressed during early human tooth development. The domains of GAS1 and RUNX2 are consistent with a role influencing function of the primary dental lamina but only GAS1 transcripts were identifiable in the successional lamina at these early stages of development. PMID:25484868

  7. Gene Co-Expression Analysis Predicts Genetic Variants Associated with Drug Responsiveness in Lung Cancer

    PubMed Central

    Shroff, Sanaya; Zhang, Jie; Huang, Kun

    2016-01-01

    Responsiveness to drugs is an important concern in designing personalized treatment for cancer patients. Currently genetic markers are often used to guide targeted therapy. However, deeper understanding of the molecular basis for drug responses and discovery of new predictive biomarkers for drug sensitivity are much needed. In this paper, we present a workflow for identifying condition-specific gene co-expression networks associated with responses to the tyrosine kinase inhibitor, Erlotinib, in lung adenocarcinoma cell lines using data from the Cancer Cell Line Encyclopedia by combining network mining and statistical analysis. Particularly, we have identified multiple gene modules specifically co-expressed in the drug responsive cell lines but not in the unresponsive group. Interestingly, most of these modules are enriched on specific cytobands, suggesting potential copy number variation events on these loci. Our results therefore imply that there are multiple genetic loci with copy number variations associated with the Erlotinib responses. The existence of CNVs in these loci is also confirmed in lung cancer tissue samples using the TCGA data. Since these structural variations are inferred from functional genomics data, these CNVs are functional variations. These results suggest the condition specific gene co- expression network mining approach is an effective approach in predicting candidate biomarkers for drug responses. PMID:27570645

  8. Analysis of protein-coding genetic variation in 60,706 humans.

    PubMed

    Lek, Monkol; Karczewski, Konrad J; Minikel, Eric V; Samocha, Kaitlin E; Banks, Eric; Fennell, Timothy; O'Donnell-Luria, Anne H; Ware, James S; Hill, Andrew J; Cummings, Beryl B; Tukiainen, Taru; Birnbaum, Daniel P; Kosmicki, Jack A; Duncan, Laramie E; Estrada, Karol; Zhao, Fengmei; Zou, James; Pierce-Hoffman, Emma; Berghout, Joanne; Cooper, David N; Deflaux, Nicole; DePristo, Mark; Do, Ron; Flannick, Jason; Fromer, Menachem; Gauthier, Laura; Goldstein, Jackie; Gupta, Namrata; Howrigan, Daniel; Kiezun, Adam; Kurki, Mitja I; Moonshine, Ami Levy; Natarajan, Pradeep; Orozco, Lorena; Peloso, Gina M; Poplin, Ryan; Rivas, Manuel A; Ruano-Rubio, Valentin; Rose, Samuel A; Ruderfer, Douglas M; Shakir, Khalid; Stenson, Peter D; Stevens, Christine; Thomas, Brett P; Tiao, Grace; Tusie-Luna, Maria T; Weisburd, Ben; Won, Hong-Hee; Yu, Dongmei; Altshuler, David M; Ardissino, Diego; Boehnke, Michael; Danesh, John; Donnelly, Stacey; Elosua, Roberto; Florez, Jose C; Gabriel, Stacey B; Getz, Gad; Glatt, Stephen J; Hultman, Christina M; Kathiresan, Sekar; Laakso, Markku; McCarroll, Steven; McCarthy, Mark I; McGovern, Dermot; McPherson, Ruth; Neale, Benjamin M; Palotie, Aarno; Purcell, Shaun M; Saleheen, Danish; Scharf, Jeremiah M; Sklar, Pamela; Sullivan, Patrick F; Tuomilehto, Jaakko; Tsuang, Ming T; Watkins, Hugh C; Wilson, James G; Daly, Mark J; MacArthur, Daniel G

    2016-08-18

    Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes. PMID:27535533

  9. Association Between Six Genetic Polymorphisms and Colorectal Cancer: A Meta-Analysis

    PubMed Central

    Chen, Cheng; Wang, Lingyan; Liao, Qi; Xu, Leiting; Huang, Yi; Zhang, Cheng; Ye, Huadan; Xu, Xuting

    2014-01-01

    Objective: The aim of this study was to determine whether six genetic polymorphisms confer susceptibility to colorectal cancer (CRC). Methods: A systematic search for candidate genes of CRC was performed among several online databases, including PubMed, Embase, Web of Science, the Cochrane Library, CNKI, and Wanfang online libraries. After a comprehensive filtering procedure, we harvested five genes, including MGMT (rs12917 and rs2308321), ADH1B (rs1229984), SOD2 (rs4880), XPC (rs2228001), and PPARG (rs1801282). Using the REVMAN and Stata software, six meta-analyses were conducted for associations between CRC and the just-mentioned genetic variants. Results: A total of 34 comparative studies among 17,289 cases and 54,927 controls were involved in our meta-analyses. Significant association was found between ADH1B rs1229984 polymorphism and CRC (p=0.03, odds ratio [OR]=1.18, 95% confidence interval [CI]=1.01–1.36). We also found significant association between PPARG rs1801282 polymorphism and CRC (p=0.004, OR=1.498, 95% CI=1.139–1.970), and this significant association is specific in Caucasians (p=0.004, OR=1.603, 95% CI=1.165–2.205). Conclusions: The current meta-analysis has established that ADH1B (rs1229984) and PPARG (rs1801282) are two risk variants of CRC. PMID:24552298

  10. Gene Co-Expression Analysis Predicts Genetic Variants Associated with Drug Responsiveness in Lung Cancer.

    PubMed

    Shroff, Sanaya; Zhang, Jie; Huang, Kun

    2016-01-01

    Responsiveness to drugs is an important concern in designing personalized treatment for cancer patients. Currently genetic markers are often used to guide targeted therapy. However, deeper understanding of the molecular basis for drug responses and discovery of new predictive biomarkers for drug sensitivity are much needed. In this paper, we present a workflow for identifying condition-specific gene co-expression networks associated with responses to the tyrosine kinase inhibitor, Erlotinib, in lung adenocarcinoma cell lines using data from the Cancer Cell Line Encyclopedia by combining network mining and statistical analysis. Particularly, we have identified multiple gene modules specifically co-expressed in the drug responsive cell lines but not in the unresponsive group. Interestingly, most of these modules are enriched on specific cytobands, suggesting potential copy number variation events on these loci. Our results therefore imply that there are multiple genetic loci with copy number variations associated with the Erlotinib responses. The existence of CNVs in these loci is also confirmed in lung cancer tissue samples using the TCGA data. Since these structural variations are inferred from functional genomics data, these CNVs are functional variations. These results suggest the condition specific gene co- expression network mining approach is an effective approach in predicting candidate biomarkers for drug responses. PMID:27570645

  11. Global analysis of WRKY transcription factor superfamily in Setaria identifies potential candidates involved in abiotic stress signaling

    PubMed Central

    Muthamilarasan, Mehanathan; Bonthala, Venkata S.; Khandelwal, Rohit; Jaishankar, Jananee; Shweta, Shweta; Nawaz, Kashif; Prasad, Manoj

    2015-01-01

    Transcription factors (TFs) are major players in stress signaling and constitute an integral part of signaling networks. Among the major TFs, WRKY proteins play pivotal roles in regulation of transcriptional reprogramming associated with stress responses. In view of this, genome- and transcriptome-wide identification of WRKY TF family was performed in the C4model plants, Setaria italica (SiWRKY) and S. viridis (SvWRKY), respectively. The study identified 105 SiWRKY and 44 SvWRKY proteins that were computationally analyzed for their physicochemical properties. Sequence alignment and phylogenetic analysis classified these proteins into three major groups, namely I, II, and III with majority of WRKY proteins belonging to group II (53 SiWRKY and 23 SvWRKY), followed by group III (39 SiWRKY and 11 SvWRKY) and group I (10 SiWRKY and 6 SvWRKY). Group II proteins were further classified into 5 subgroups (IIa to IIe) based on their phylogeny. Domain analysis showed the presence of WRKY motif and zinc finger-like structures in these proteins along with additional domains in a few proteins. All SiWRKY genes were physically mapped on the S. italica genome and their duplication analysis revealed that 10 and 8 gene pairs underwent tandem and segmental duplications, respectively. Comparative mapping of SiWRKY and SvWRKY genes in related C4 panicoid genomes demonstrated the orthologous relationships between these genomes. In silico expression analysis of SiWRKY and SvWRKY genes showed their differential expression patterns in different tissues and stress conditions. Expression profiling of candidate SiWRKY genes in response to stress (dehydration and salinity) and hormone treatments (abscisic acid, salicylic acid, and methyl jasmonate) suggested the putative involvement of SiWRKY066 and SiWRKY082 in stress and hormone signaling. These genes could be potential candidates for further characterization to delineate their functional roles in abiotic stress signaling. PMID:26635818

  12. Global analysis of WRKY transcription factor superfamily in Setaria identifies potential candidates involved in abiotic stress signaling.

    PubMed

    Muthamilarasan, Mehanathan; Bonthala, Venkata S; Khandelwal, Rohit; Jaishankar, Jananee; Shweta, Shweta; Nawaz, Kashif; Prasad, Manoj

    2015-01-01

    Transcription factors (TFs) are major players in stress signaling and constitute an integral part of signaling networks. Among the major TFs, WRKY proteins play pivotal roles in regulation of transcriptional reprogramming associated with stress responses. In view of this, genome- and transcriptome-wide identification of WRKY TF family was performed in the C4model plants, Setaria italica (SiWRKY) and S. viridis (SvWRKY), respectively. The study identified 105 SiWRKY and 44 SvWRKY proteins that were computationally analyzed for their physicochemical properties. Sequence alignment and phylogenetic analysis classified these proteins into three major groups, namely I, II, and III with majority of WRKY proteins belonging to group II (53 SiWRKY and 23 SvWRKY), followed by group III (39 SiWRKY and 11 SvWRKY) and group I (10 SiWRKY and 6 SvWRKY). Group II proteins were further classified into 5 subgroups (IIa to IIe) based on their phylogeny. Domain analysis showed the presence of WRKY motif and zinc finger-like structures in these proteins along with additional domains in a few proteins. All SiWRKY genes were physically mapped on the S. italica genome and their duplication analysis revealed that 10 and 8 gene pairs underwent tandem and segmental duplications, respectively. Comparative mapping of SiWRKY and SvWRKY genes in related C4 panicoid genomes demonstrated the orthologous relationships between these genomes. In silico expression analysis of SiWRKY and SvWRKY genes showed their differential expression patterns in different tissues and stress conditions. Expression profiling of candidate SiWRKY genes in response to stress (dehydration and salinity) and hormone treatments (abscisic acid, salicylic acid, and methyl jasmonate) suggested the putative involvement of SiWRKY066 and SiWRKY082 in stress and hormone signaling. These genes could be potential candidates for further characterization to delineate their functional roles in abiotic stress signaling. PMID:26635818

  13. Analysis of Over 10,000 Cases Finds No Association between Previously-Reported Candidate Polymorphisms and Ovarian Cancer Outcome

    PubMed Central

    White, Kristin L.; Vierkant, Robert A.; Fogarty, Zachary C.; Charbonneau, Bridget; Block, Matthew S.; Pharoah, Paul D.P.; Chenevix-Trench, Georgia; Rossing, Mary Anne; Cramer, Daniel W.; Pearce, C. Leigh; Schildkraut, Joellen M.; Menon, Usha; Kjaer, Susanne Kruger; Levine, Douglas A.; Gronwald, Jacek; Culver, Hoda Anton; Whittemore, Alice S.; Karlan, Beth Y.; Lambrechts, Diether; Wentzensen, Nicolas; Kupryjanczyk, Jolanta; Chang-Claude, Jenny; Bandera, Elisa V.; Hogdall, Estrid; Heitz, Florian; Kaye, Stanley B.; Fasching, Peter A.; Campbell, Ian; Goodman, Marc T.; Pejovic, Tanja; Bean, Yukie; Lurie, Galina; Eccles, Diana; Hein, Alexander; Beckmann, Matthias W.; Ekici, Arif B.; Paul, James; Brown, Robert; Flanagan, James; Harter, Philipp; du Bois, Andreas; Schwaab, Ira; Hogdall, Claus K.; Lundvall, Lene; Olson, Sara H.; Orlow, Irene; Paddock, Lisa E.; Rudolph, Anja; Eilber, Ursula; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K.; Ziolkowska-Seta, Izabela; Brinton, Louise; Yang, Hannah; Garcia-Closas, Montserrat; Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace; Walsh, Christine; Lester, Jenny; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H.; Ziogas, Argyrios; Lubiński, Jan; Cybulski, Cezary; Menkiszak, Janusz; Jensen, Allan; Gayther, Simon A.; Ramus, Susan J.; Gentry-Maharaj, Aleksandra; Berchuck, Andrew; Wu, Anna H.; Pike, Malcolm C.; Van Den Berg, David; Terry, Kathryn L.; Vitonis, Allison F.; Doherty, Jennifer A.; Johnatty, Sharon; deFazio, Anna; Song, Honglin; Tyrer, Jonathan; Sellers, Thomas A.; Phelan, Catherine M.; Kalli, Kimberly R.; Cunningham, Julie M.; Fridley, Brooke L.; Goode, Ellen L.

    2013-01-01

    Background Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNPs) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000 observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. PMID:23513043

  14. Genetic Analysis of Oncorhynchus Nerka : Life History and Genetic Analysis of Redfish Lake Oncorhynchus Nerka, 1993-1994 Completion Report.

    SciTech Connect

    Brannon, E.L.; Thorgaard, G.H.; Cummings, S.A.

    1994-10-01

    The study has shown through life history examination and DNA analysis that three forms of O. nerka are present in Redfish Lake. The three forms are closely related, but may be sufficiently different to be considered three separate stocks. Fishhook Creek kokanee are temporally isolated from the beach spawners, and may represent the gene pool most similar to the historic sockeye population that once spawned there. Fishhook Creek offers the best spawning area available in the lake system, and should be considered for use in reestablishing an anadromous Fishhook Creek sockeye swain. The resident beach spawning strain of O. nerka is likewise the most similar genetic form of the companion anadromous beach spawning O. nerka, and needs to be considered the most appropriate genetic source to help minimize reduced fitness of the sockeye from inbreeding.

  15. Genetic Analysis of Craniofacial Traits in the Medaka

    PubMed Central

    Kimura, Tetsuaki; Shimada, Atsuko; Sakai, Noriyoshi; Mitani, Hiroshi; Naruse, Kiyoshi; Takeda, Hiroyuki; Inoko, Hidetoshi; Tamiya, Gen; Shinya, Minori

    2007-01-01

    Family and twin studies suggest that a substantial genetic component underlies individual differences in craniofacial morphology. In the current study, we quantified 444 craniofacial traits in 100 individuals from two inbred medaka (Oryzias latipes) strains, HNI and Hd-rR. Relative distances between defined landmarks were measured in digital images of the medaka head region. A total of 379 traits differed significantly between the two strains, indicating that many craniofacial traits are controlled by genetic factors. Of these, 89 traits were analyzed via interval mapping of 184 F2 progeny from an intercross between HNI and Hd-rR. We identified quantitative trait loci for 66 craniofacial traits. The highest logarithm of the odds score was 6.2 for linkage group (LG) 9 and 11. Trait L33, which corresponds to the ratio of head length to head height at eye level, mapped to LG9; trait V15, which corresponds to the ratio of snout length to head width measured behind the eyes, mapped to LG11. Our initial results confirm the potential of the medaka as a model system for the genetic analysis of complex traits such as craniofacial morphology. PMID:18073435

  16. Genetic aspect of Alzheimer disease: Results of complex segregation analysis

    SciTech Connect

    Sadonvick, A.D.; Lee, I.M.L.; Bailey-Wilson, J.E.

    1994-09-01

    The study was designed to evaluate the possibility that a single major locus will explain the segregation of Alzheimer disease (AD). The data were from the population-based AD Genetic Database and consisted of 402 consecutive, unrelated probands, diagnosed to have either `probable` or `autopsy confirmed` AD and their 2,245 first-degree relatives. In this analysis, a relative was considered affected with AD only when there were sufficient medical/autopsy data to support diagnosis of AD being the most likely cause of the dementia. Transmission probability models allowing for a genotype-dependent and logistically distributed age-of-onset were used. The program REGTL in the S.A.G.E. computer program package was used for a complex segregation analysis. The models included correction for single ascertainment. Regressive familial effects were not estimated. The data were analyzed to test for single major locus (SML), random transmission and no transmission (environmental) hypotheses. The results of the complex segregation analysis showed that (1) the SML was the best fit, and (2) the non-genetic models could be rejected.

  17. Population genetic analysis of Enterocytozoon bieneusi in humans.

    PubMed

    Li, Wei; Cama, Vitaliano; Feng, Yaoyu; Gilman, Robert H; Bern, Caryn; Zhang, Xichen; Xiao, Lihua

    2012-01-01

    Genotyping based on sequence analysis of the ribosomal internal transcribed spacer has revealed significant genetic di