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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 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

  2. 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.

  3. Genetic analysis of candidate SNPs for metabolic syndrome in obstructive sleep apnea (OSA).

    PubMed

    Grilo, Antonio; Ruiz-Granados, Elena S; Moreno-Rey, Concha; Rivera, Jose M; Ruiz, Agustin; Real, Luis M; Sáez, Maria E

    2013-05-25

    Obstructive sleep apnea (OSA) is a common disorder characterized by the reduction or complete cessation in airflow resulting from an obstruction of the upper airway. Several studies have observed an increased risk for cardiovascular morbidity and mortality among OSA patients. Metabolic syndrome (MetS), a cluster of cardiovascular risk factors characterized by the presence of insulin resistance, is often found in patients with OSA, but the complex interplay between these two syndromes is not well understood. In this study, we present the results of a genetic association analysis of 373 candidate SNPs for MetS selected in a previous genome wide association analysis (GWAS). The 384 selected SNPs were genotyped using the Illumina VeraCode Technology in 387 subjects retrospectively assessed at the Internal Medicine Unit of the "Virgen de Valme" University Hospital (Seville, Spain). In order to increase the power of this study and to validate our findings in an independent population, we used data from the Framingham Sleep Study which comprises 368 individuals. Only the rs11211631 polymorphism was associated with OSA in both populations, with an estimated OR=0.57 (0.42-0.79) in the joint analysis (p=7.21×10(-4)). This SNP was selected in the previous GWAS for MetS components using a digenic approach, but was not significant in the monogenic study. We have also identified two SNPs (rs2687855 and rs4299396) with a protective effect from OSA only in the subpopulation with abdominal obesity. As a whole, our study does not support the idea that OSA and MetS share major genetic determinants, although both syndromes share common epidemiological and clinical features. PMID:23524009

  4. Genetic analysis of candidate SNPs for metabolic syndrome in obstructive sleep apnea (OSA)

    PubMed Central

    Grilo, Antonio; Ruiz-Granados, Elena S.; Moreno-Rey, Concha; Rivera, Jose M.; Ruiz, Agustin; Real, Luis M.; Sáez, Maria E.

    2014-01-01

    Obstructive sleep apnea (OSA) is a common disorder characterized by the reduction or complete cessation in airflow resulting from an obstruction of the upper airway. Several studies have observed an increased risk for cardiovascular morbidity and mortality among OSA patients. Metabolic syndrome (MetS), a cluster of cardiovascular risk factors characterized by the presence of insulin resistance, is often found in patients with OSA, but the complex interplay between these two syndromes is not well understood. In this study, we present the results of a genetic association analysis of 373 candidate SNPs for MetS selected in a previous genome wide association analysis (GWAS). The 384 selected SNPs were genotyped using the Illumina VeraCode Technology in 387 subjects retrospectively assessed at the Internal Medicine Unit of the “Virgen de Valme” University Hospital (Seville, Spain). In order to increase the power of this study and to validate our findings in an independent population, we used data from the Framingham Sleep study which comprises 368 individuals. Only the rs11211631 polymorphism was associated with OSA in both populations, with an estimated OR=0.57 (0.42-0.79) in the joint analysis (p=7.21 × 10-4). This SNP was selected in the previous GWAS for MetS components using a digenic approach, but was not significant in the monogenic study. We have also identified two SNPs (rs2687855 and rs4299396) with a protective effect from OSA only in the abdominal obese subpopulation. As a whole, our study does not support that OSA and MetS share major genetic determinants, although both syndromes share common epidemiological and clinical features. PMID:23524009

  5. Genetic analysis of GABRB3 as a candidate gene of autism spectrum disorders

    PubMed Central

    2014-01-01

    Background GABRB3 is a position candidate gene at chromosome 15q12 that has been implicated in the neurobiology of autism spectrum disorders (ASD). The aim of this study was to examine the genetic association of GABRB3 with ASD. Methods The sample consisted of 356 patients with clinical diagnosis of ASD according to the DSM-IV diagnostic criteria and confirmed by the Autism Diagnostic Interview-Revised and 386 unrelated controls. We searched for mutations at all the exonic regions and 1.6 Kb of the 5′ region of GABRB3 in the genomic DNA of all the participants using the Sanger sequencing. We implemented a case-control association analysis of variants detected in this sample, and conducted a reporter gene assay to assess the functional impact of variants at the 5′ regulatory region. Results We detected six known common SNPs; however, they were not associated with ASD. Besides, a total of 22 rare variants (12 at 5′ regulatory, 4 at intronic, and 6 at exonic regions) were detected in 18 patients and 6 controls. The frequency of rare variants was significantly higher in the patient group than in the control group (18/356 versus 6/386, odds ratio = 3.37, P = 0.007). All the 12 rare variants at the 5′ regulatory region were only detected in 7 patients, but not in any of the controls (7/356 versus 0/386, Fisher’s exact test, P = 0.006). Two patients carried multiple rare variants. Family studies showed that most of these rare variants were transmitted from their parents. Reporter gene assays revealed that four rare variants at the 5′ regulatory region and 1 at exon 1a untranslated region had elevated reporter gene activities compared to two wild type alleles. Conclusions Our data suggest rare variants of GABRB3 might be associated with ASD, and increased GABRB3 expression may contribute to the pathogenesis of ASD in some patients. Trial registration Clinical trial registration Identifier: NCT00494754 PMID:24999380

  6. 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

  7. 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

  8. Photoreceptor dysplasia (pd) in miniature schnauzer dogs: evaluation of candidate genes by molecular genetic analysis.

    PubMed

    Zhang, Q; Baldwin, V J; Acland, G M; Parshall, C J; Haskel, J; Aguirre, G D; Ray, K

    1999-01-01

    Photoreceptor dysplasia (pd) is one of a group of at least six distinct autosomal and one X-linked retinal disorders identified in dogs which are collectively known as progressive retinal atrophy (PRA). It is an early onset retinal disease identified in miniature schnauzer dogs, and pedigree analysis and breeding studies have established autosomal recessive inheritance of the disease. Using a gene-based approach, a number of retina-expressed genes, including some members of the phototransduction pathway, have been causally implicated in retinal diseases of humans and other animals. Here we examined seven such potential candidate genes (opsin, RDS/peripherin, ROM1, rod cGMP-gated cation channel alpha-subunit, and three subunits of transducin) for their causal association with the pd locus by testing segregation of intragenic markers with the disease locus, or, in the absence of informative polymorphisms, sequencing of the coding regions of the genes. Based on these results, we have conclusively excluded four photoreceptor-specific genes as candidates for pd by linkage analysis. For three other photoreceptor-specific genes, we did not find any mutation in the coding sequences of the genes and have excluded them provisionally. Formal exclusion would require investigation of the levels of expression of the candidate genes in pd-affected dogs relative to age-matched controls. At present we are building suitable informative pedigrees for the disease locus with a sufficient number of meiosis to be useful for genomewide screening. This should identify markers linked to the disease locus and eventually permit progress toward the identification of the photoreceptor dysplasia gene and the disease-causing mutation.

  9. Genomic analysis of Meckel-Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes.

    PubMed

    Shaheen, Ranad; Faqeih, Eissa; Alshammari, Muneera J; Swaid, Abdulrahman; Al-Gazali, Lihadh; Mardawi, Elham; Ansari, Shinu; Sogaty, Sameera; Seidahmed, Mohammed Z; AlMotairi, Muhammed I; Farra, Chantal; Kurdi, Wesam; Al-Rasheed, Shatha; Alkuraya, Fowzan S

    2013-07-01

    Meckel-Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n=12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis-van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population.

  10. 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.

  11. 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

  12. 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

  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. 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

  15. 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

  16. 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.

  17. Molecular genetic analysis of the candidate gene for MOD, a locus required for self-incompatibility in Brassica rapa.

    PubMed

    Fukai, E; Nishio, T; Nasrallah, M E

    2001-05-01

    The MIP-MOD (for MOD-locus associated Major Intrinsic Protein) gene encodes an aquaporin-like product, and has been reported to be a candidate for the MOD gene which is required for the self-incompatibility response in Brassica rapa. In an antisense suppression experiment designed to investigate the role of MIP-MOD, we found that levels of MIP-MOD mRNA in the stigmas of fourteen antisense transgenics, as well as in the self-incompatible cultivar Osome (Osm), were much lower than in the stigmas of the self-incompatible S8 homozygous (S8) strain. Therefore, we analyzed the molecular structure of the MIP-MOD gene in three B. rapa strains: S8, Osm, and the self-compatible var. Yellow Sarson (YS). Nucleotide sequence analysis of the MIP-MOD genes isolated from the three strains revealed that all three encode the same amino acid sequence and that YS and Osm contain the same MIP-MOD allele, designated MIP-MOD(YS). Analysis of other self-incompatible B. rapa strains that are homozygous for the MIP-MOD(YS) allele indicated that high levels of MIP-MOD transcripts are not essential for the self-incompatibility response. Furthermore, a MOD mutant generated by gamma-irradiation was found to contain a wild-type MIP-MOD gene that is expressed at normal levels. These data suggest that MIP-MOD is not MOD itself. We suggest that this gene should be renamed MLM (for MIP gene linked to MOD).

  18. 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

  19. Functional-mixed effects models for candidate genetic mapping in imaging genetic studies.

    PubMed

    Lin, Ja-An; Zhu, Hongtu; Mihye, Ahn; Sun, Wei; Ibrahim, Joseph G

    2014-12-01

    The aim of this paper is to develop a functional-mixed effects modeling (FMEM) framework for the joint analysis of high-dimensional imaging data in a large number of locations (called voxels) of a three-dimensional volume with a set of genetic markers and clinical covariates. Our FMEM is extremely useful for efficiently carrying out the candidate gene approaches in imaging genetic studies. FMEM consists of two novel components including a mixed effects model for modeling nonlinear genetic effects on imaging phenotypes by introducing the genetic random effects at each voxel and a jumping surface model for modeling the variance components of the genetic random effects and fixed effects as piecewise smooth functions of the voxels. Moreover, FMEM naturally accommodates the correlation structure of the genetic markers at each voxel, while the jumping surface model explicitly incorporates the intrinsically spatial smoothness of the imaging data. We propose a novel two-stage adaptive smoothing procedure to spatially estimate the piecewise smooth functions, particularly the irregular functional genetic variance components, while preserving their edges among different piecewise-smooth regions. We develop weighted likelihood ratio tests and derive their exact approximations to test the effect of the genetic markers across voxels. Simulation studies show that FMEM significantly outperforms voxel-wise approaches in terms of higher sensitivity and specificity to identify regions of interest for carrying out candidate genetic mapping in imaging genetic studies. Finally, FMEM is used to identify brain regions affected by three candidate genes including CR1, CD2AP, and PICALM, thereby hoping to shed light on the pathological interactions between these candidate genes and brain structure and function.

  20. 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

  1. 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.

  2. 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.

  3. Genetics and anorexia nervosa: a review of candidate genes.

    PubMed

    Gorwood, P; Bouvard, M; Mouren-Siméoni, M C; Kipman, A; Adès, J

    1998-01-01

    Anorexia nervosa is a severe disorder which seems likely to have a multifactorial aetiology. However, several studies have stressed that genetic factors play a significant role. Epidemiological studies have shown that the lifetime risk for first-degree relatives of a patient with an eating disorder is 6% compared to 1% among relatives of controls, and a twin study performed on 34 pairs of twins has shown a higher concordance rate in monozygotic twins (55%) compared to dizygotic twins (7%). The vulnerability component of anorexia nervosa that can be attributed to genetic influences has been estimated from twin studies to be around 70%. Despite this, few genetic studies have been performed testing the role of candidate genes which code for proteins potentially implicated in the aetiopathogenesis of the disorder. In this review, genes encoding components of the dopamine, serotonin, opiate, and noradrenaline systems are assessed for their role in anorexia nervosa. Attention is paid to psychological dimensions, clinical symptoms, co-morbidity frequency, pharmacological data, and biological measures that characterize anorexia nervosa.

  4. 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

  5. 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

  6. Pseudomonas putida CSV86: A Candidate Genome for Genetic Bioaugmentation

    PubMed Central

    Paliwal, Vasundhara; Raju, Sajan C.; Modak, Arnab; Phale, Prashant S.; Purohit, Hemant J.

    2014-01-01

    Pseudomonas putida CSV86, a plasmid-free strain possessing capability to transfer the naphthalene degradation property, has been explored for its metabolic diversity through genome sequencing. The analysis of draft genome sequence of CSV86 (6.4 Mb) revealed the presence of genes involved in the degradation of naphthalene, salicylate, benzoate, benzylalcohol, p-hydroxybenzoate, phenylacetate and p-hydroxyphenylacetate on the chromosome thus ensuring the stability of the catabolic potential. Moreover, genes involved in the metabolism of phenylpropanoid and homogentisate, as well as heavy metal resistance, were additionally identified. Ability to grow on vanillin, veratraldehyde and ferulic acid, detection of inducible homogentisate dioxygenase and growth on aromatic compounds in the presence of heavy metals like copper, cadmium, cobalt and arsenic confirm in silico observations reflecting the metabolic versatility. In silico analysis revealed the arrangement of genes in the order: tRNAGly, integrase followed by nah operon, supporting earlier hypothesis of existence of a genomic island (GI) for naphthalene degradation. Deciphering the genomic architecture of CSV86 for aromatic degradation pathways and identification of elements responsible for horizontal gene transfer (HGT) suggests that genetic bioaugmentation strategies could be planned using CSV86 for effective bioremediation. PMID:24475028

  7. 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

  8. Genetic diversity of vaccine candidate antigens in Plasmodium falciparum isolates from the Amazon basin of Peru

    PubMed Central

    Chenet, Stella M; Branch, OraLee H; Escalante, Ananias A; Lucas, Carmen M; Bacon, David J

    2008-01-01

    Background Several of the intended Plasmodium falciparum vaccine candidate antigens are highly polymorphic and could render a vaccine ineffective if their antigenic sites were not represented in the vaccine. In this study, characterization of genetic variability was performed in major B and T-cell epitopes within vaccine candidate antigens in isolates of P. falciparum from Peru. Methods DNA sequencing analysis was completed on 139 isolates of P. falciparum collected from endemic areas of the Amazon basin in Loreto, Peru from years 1998 to 2006. Genetic diversity was determined in immunological important regions in circumsporozoite protein (CSP), merozoite surface protein-1 (MSP-1), apical membrane antigen-1 (AMA-1), liver stage antigen-1 (LSA-1) and thrombospondin-related anonymous protein (TRAP). Alleles identified by DNA sequencing were aligned with the vaccine strain 3D7 and DNA polymorphism analysis and FST study-year pairwise comparisons were done using the DnaSP software. Multilocus analysis (MLA) was performed and average of expected heterozygosity was calculated for each loci and haplotype over time. Results Three different alleles for CSP, seven for MSP-1 Block 2, one for MSP-1 Block 17, three for AMA-1 and for LSA-1 each and one for TRAP were identified. There were 24 different haplotypes in 125 infections with complete locus typing for each gene. Conclusion Characterization of the genetic diversity in Plasmodium isolates from the Amazon Region of Peru showed that P. falciparum T and B cell epitopes in these antigens have polymorphisms more similar to India than to Africa. These findings are helpful in the formulation of a vaccine considering restricted repertoire populations. PMID:18505558

  9. 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

  10. 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

  11. 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

  12. 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

  13. Large-Scale Candidate Gene Analysis of HDL Particle Features

    PubMed Central

    Kaess, Bernhard M.; Tomaszewski, Maciej; Braund, Peter S.; Stark, Klaus; Rafelt, Suzanne; Fischer, Marcus; Hardwick, Robert; Nelson, Christopher P.; Debiec, Radoslaw; Huber, Fritz; Kremer, Werner; Kalbitzer, Hans Robert; Rose, Lynda M.; Chasman, Daniel I.; Hopewell, Jemma; Clarke, Robert; Burton, Paul R.; Tobin, Martin D.

    2011-01-01

    Background HDL cholesterol (HDL-C) is an established marker of cardiovascular risk with significant genetic determination. However, HDL particles are not homogenous, and refined HDL phenotyping may improve insight into regulation of HDL metabolism. We therefore assessed HDL particles by NMR spectroscopy and conducted a large-scale candidate gene association analysis. Methodology/Principal Findings We measured plasma HDL-C and determined mean HDL particle size and particle number by NMR spectroscopy in 2024 individuals from 512 British Caucasian families. Genotypes were 49,094 SNPs in >2,100 cardiometabolic candidate genes/loci as represented on the HumanCVD BeadChip version 2. False discovery rates (FDR) were calculated to account for multiple testing. Analyses on classical HDL-C revealed significant associations (FDR<0.05) only for CETP (cholesteryl ester transfer protein; lead SNP rs3764261: p = 5.6*10−15) and SGCD (sarcoglycan delta; rs6877118: p = 8.6*10−6). In contrast, analysis with HDL mean particle size yielded additional associations in LIPC (hepatic lipase; rs261332: p = 6.1*10−9), PLTP (phospholipid transfer protein, rs4810479: p = 1.7*10−8) and FBLN5 (fibulin-5; rs2246416: p = 6.2*10−6). The associations of SGCD and Fibulin-5 with HDL particle size could not be replicated in PROCARDIS (n = 3,078) and/or the Women's Genome Health Study (n = 23,170). Conclusions We show that refined HDL phenotyping by NMR spectroscopy can detect known genes of HDL metabolism better than analyses on HDL-C. PMID:21283740

  14. Molecular genetic gene-environment studies using candidate genes in schizophrenia: a systematic review.

    PubMed

    Modinos, Gemma; Iyegbe, Conrad; Prata, Diana; Rivera, Margarita; Kempton, Matthew J; Valmaggia, Lucia R; Sham, Pak C; van Os, Jim; McGuire, Philip

    2013-11-01

    The relatively high heritability of schizophrenia suggests that genetic factors play an important role in the etiology of the disorder. On the other hand, a number of environmental factors significantly influence its incidence. As few direct genetic effects have been demonstrated, and there is considerable inter-individual heterogeneity in the response to the known environmental factors, interactions between genetic and environmental factors may be important in determining whether an individual develops the disorder. To date, a considerable number of studies of gene-environment interactions (G×E) in schizophrenia have employed a hypothesis-based molecular genetic approach using candidate genes, which have led to a range of different findings. This systematic review aims to summarize the results from molecular genetic candidate studies and to review challenges and opportunities of this approach in psychosis research. Finally, we discuss the potential of future prospects, such as new studies that combine hypothesis-based molecular genetic candidate approaches with agnostic genome-wide association studies in determining schizophrenia risk.

  15. 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

  16. Defining a new candidate gene for amelogenesis imperfecta: from molecular genetics to biochemistry.

    PubMed

    Urzúa, Blanca; Ortega-Pinto, Ana; Morales-Bozo, Irene; Rojas-Alcayaga, Gonzalo; Cifuentes, Víctor

    2011-02-01

    Amelogenesis imperfecta is a group of genetic conditions that affect the structure and clinical appearance of tooth enamel. The types (hypoplastic, hypocalcified, and hypomature) are correlated with defects in different stages of the process of enamel synthesis. Autosomal dominant, recessive, and X-linked types have been previously described. These disorders are considered clinically and genetically heterogeneous in etiology, involving a variety of genes, such as AMELX, ENAM, DLX3, FAM83H, MMP-20, KLK4, and WDR72. The mutations identified within these causal genes explain less than half of all cases of amelogenesis imperfecta. Most of the candidate and causal genes currently identified encode proteins involved in enamel synthesis. We think it is necessary to refocus the search for candidate genes using biochemical processes. This review provides theoretical evidence that the human SLC4A4 gene (sodium bicarbonate cotransporter) may be a new candidate gene.

  17. Candidate Locus Analysis for PHACE Syndrome

    PubMed Central

    Mitchell, Sheri; Siegel, Dawn H.; Shieh, Joseph T.; Stevenson, David A.; Grimmer, J. Fredrik; Lewis, Tracey; Metry, Denise; Frieden, Ilona; Blei, Francine; Kayserili, Hulya; Drolet, Beth A.; Bayrak-Toydemir, Pinar

    2012-01-01

    PHACE syndrome (OMIM #606519) is a neurocutaneous syndrome of unknown etiology and pathogenesis. We report on an individual with PHACE syndrome with a complete deletion of SLC35B4 on 7q33. In order to further analyze this region, SLC35B4 was sequenced for 33 individuals with PHACE syndrome and one parental set. Common polymorphisms with a possible haplotype but no disease causing mutation were identified. Sixteen of 33 samples of the PHACE syndrome patients were also analyzed for copy number variations using high resolution oligo-Comparative Genomic Hybridization (CGH) microarray. A second individual in this cohort had a 26.5kb deletion approximately 80kb upstream of SLC35B4 with partial deletion of the AKR1B1 on 7q33. The deletions observed on 7q33 are not likely the singular cause of PHACE syndrome; however, it is possible that this region provides a genetic susceptibility to phenotypic expression with other confounding genetic or environmental factors. PMID:22544659

  18. 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.

  19. 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

  20. 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.

  1. 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

  2. The Candidate Cancer Gene Database: a database of cancer driver genes from forward genetic screens in mice.

    PubMed

    Abbott, Kenneth L; Nyre, Erik T; Abrahante, Juan; Ho, Yen-Yi; Isaksson Vogel, Rachel; Starr, Timothy K

    2015-01-01

    Identification of cancer driver gene mutations is crucial for advancing cancer therapeutics. Due to the overwhelming number of passenger mutations in the human tumor genome, it is difficult to pinpoint causative driver genes. Using transposon mutagenesis in mice many laboratories have conducted forward genetic screens and identified thousands of candidate driver genes that are highly relevant to human cancer. Unfortunately, this information is difficult to access and utilize because it is scattered across multiple publications using different mouse genome builds and strength metrics. To improve access to these findings and facilitate meta-analyses, we developed the Candidate Cancer Gene Database (CCGD, http://ccgd-starrlab.oit.umn.edu/). The CCGD is a manually curated database containing a unified description of all identified candidate driver genes and the genomic location of transposon common insertion sites (CISs) from all currently published transposon-based screens. To demonstrate relevance to human cancer, we performed a modified gene set enrichment analysis using KEGG pathways and show that human cancer pathways are highly enriched in the database. We also used hierarchical clustering to identify pathways enriched in blood cancers compared to solid cancers. The CCGD is a novel resource available to scientists interested in the identification of genetic drivers of cancer.

  3. 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

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. Silver-Russell syndrome: a dissection of the genetic aetiology and candidate chromosomal regions

    PubMed Central

    Hitchins, M.; Stanier, P.; Preece, M.; Moore, G.

    2001-01-01

    The main features of Silver-Russell syndrome (SRS) are pre- and postnatal growth restriction and a characteristic small, triangular face. SRS is also accompanied by other dysmorphic features including fifth finger clinodactyly and skeletal asymmetry. The disorder is clinically and genetically heterogeneous, and various modes of inheritance and abnormalities involving chromosomes 7, 8, 15, 17, and 18 have been associated with SRS and SRS-like cases. However, only chromosomes 7 and 17 have been consistently implicated in patients with a strict clinical diagnosis of SRS. Two cases of balanced translocations with breakpoints in 17q23.3-q25 and two cases with a hemizygous deletion of the chorionic somatomammatropin gene (CSH1) on 17q24.1 have been associated with SRS, strongly implicating this region. Maternal uniparental disomy for chromosome 7 (mUPD(7)) occurs in up to 10% of SRS patients, with disruption of genomic imprinting underlying the disease status in these cases. Recently, two SRS patients with a maternal duplication of 7p11.2-p13, and a single proband with segmental mUPD for the region 7q31-qter, were described. These key patients define two separate candidate regions for SRS on both the p and q arms of chromosome 7. Both the 7p11.2-p13 and 7q31-qter regions are subject to genomic imprinting and the homologous regions in the mouse are associated with imprinted growth phenotypes. This review provides an overview of the genetics of SRS, and focuses on the newly defined candidate regions on chromosome 7. The analyses of imprinted candidate genes within 7p11.2-p13 and 7q31-qter, and gene candidates on distal 17q, are discussed.


Keywords: Silver-Russell syndrome; imprinting; mUPD(7); candidates PMID:11748303

  9. A possible genetic association with chronic fatigue in primary Sjögren's syndrome: a candidate gene study.

    PubMed

    Norheim, Katrine Brække; Le Hellard, Stephanie; Nordmark, Gunnel; Harboe, Erna; Gøransson, Lasse; Brun, Johan G; Wahren-Herlenius, Marie; Jonsson, Roland; Omdal, Roald

    2014-02-01

    Fatigue is prevalent and disabling in primary Sjögren's syndrome (pSS). Results from studies in chronic fatigue syndrome (CFS) indicate that genetic variation may influence fatigue. The aim of this study was to investigate single nucleotide polymorphism (SNP) variations in pSS patients with high and low fatigue. A panel of 85 SNPs in 12 genes was selected based on previous studies in CFS. A total of 207 pSS patients and 376 healthy controls were genotyped. One-hundred and ninety-three patients and 70 SNPs in 11 genes were available for analysis after quality control. Patients were dichotomized based on fatigue visual analogue scale (VAS) scores, with VAS <50 denominated "low fatigue" (n = 53) and VAS ≥50 denominated "high fatigue" (n = 140). We detected signals of association with pSS for one SNP in SLC25A40 (unadjusted p = 0.007) and two SNPs in PKN1 (both p = 0.03) in our pSS case versus control analysis. The association with SLC25A40 was stronger when only pSS high fatigue patients were analysed versus controls (p = 0.002). One SNP in PKN1 displayed an association in the case-only analysis of pSS high fatigue versus pSS low fatigue (p = 0.005). This candidate gene study in pSS did reveal a trend for associations between genetic variation in candidate genes and fatigue. The results will need to be replicated. More research on genetic associations with fatigue is warranted, and future trials should include larger cohorts and multicentre collaborations with sharing of genetic material to increase the statistical power.

  10. 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

  11. 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

  12. 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

  13. 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.

  14. 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

  15. 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.

  16. Meta-analyses between 18 candidate genetic markers and overweight/obesity

    PubMed Central

    2014-01-01

    Aims The goal of our study is to investigate the associations between 18 candidate genetic markers and overweight/obesity. Methods A total of 72 eligible articles were retrieved from literature databases including PubMed, Embase, SpingerLink, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang. Meta-analyses of 18 genetic markers among 56,738 controls and 48,148 overweight/obese persons were done by Review Manager 5.0. Results Our results showed that SH2B1 rs7498665 polymorphism was significantly associated with the risk of overweight/obesity (overall odds ratio (OR) = 1.21, 95% confidence interval (CI) = 1.09-1.34, P = 0.0004). Increased risk of overweight/obesity was also observed in FAIM2 rs7138803 polymorphism (overall OR = 1.11, 95% CI = 1.01-1.22, P = 0.04). Conclusion Our meta-analyses have shown the important role of 2 polymorphisms (SH2B1 rs7498665 and FAIM2 rs7138803) in the development of overweight/obesity. This study highlighted the importance of above two candidate genes (SH2B1 and FAIM2) in the risk of overweight/obesity. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2785487401176182. PMID:24621099

  17. 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

  18. 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

  19. 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

  20. The cognitive genetics of attention deficit hyperactivity disorder (ADHD): sustained attention as a candidate phenotype.

    PubMed

    Bellgrove, Mark A; Hawi, Ziarih; Gill, Michael; Robertson, Ian H

    2006-08-01

    Here we describe the application of cognitive genetics to the study of attention deficit hyperactivity disorder (ADHD). Cognitive genetics owes much to the pioneering work of cognitive neuropsychologists such as John Marshall, whose careful observations of cognitive dissociations between brain-lesioned patients greatly advanced the theoretical understanding of normal cognitive function. These theories have in turn helped to constrain linkages between candidate genes and cognitive processes and thus help to drive the relatively new field of cognitive genetics in a hypothesis-driven fashion. We examined the relationship between sustained attention deficits in ADHD and genetic variation in a catecholamine-related gene, dopamine beta hydroxylase (DbetaH). DBH encodes the enzyme that converts dopamine to noradrenaline and is crucial to catecholamine regulation. A polymorphism with the DBH gene has been associated with ADHD. In fifty-two children with ADHD, we examined whether variation in the Taq I DBH gene polymorphism was related to sustained attention performance. Participants performed the Sustained Attention to Response Test (SART). Performance on the SART discriminates ADHD from control children, and in imaging work, is associated with right frontoparietal activation. A significant effect of DBH genotype was found on SART performance measures. Children possessing two copies of the ADHD-associated risk allele (A2) had significantly poorer sustained attention than those ADHD children who did not possess this allele or a non-genotyped control group. The DBH gene may contribute to the susceptibility for ADHD, in part because of its varying effects on the development of brain mechanisms mediating sustained attention.

  1. 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

  2. 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

  3. A candidate region for Nevoid Basal Cell Carcinoma Syndrome defined by genetic and physical mapping

    SciTech Connect

    Wainwright, B.; Negus, K.; Berkman, J.

    1994-09-01

    Nevoid Basal Cell Carcinoma Syndrome (NBCCS, or Gorlin`s syndrome) is a cancer predisposition syndrome charcterized by multiple basal cell carcinomas (BCCs) and diverse developmental defects. The gene responsible for NBCCS, which is most likely to be a tumor suppressor gene, has previously been mapped to 9q22.3-q31 in a 12 cM interval between the microsatellite marker loci D9S12 and D9S109. Combined multipoint and haplotype analyses of Australian pedigrees has further refined the localization to a 2 cM interval between markers D9S196 and D9S180. Our loss of heterozygosity (LOH) studies from sporadic (n= 58) and familial (n=41) BCCs indicate that 50% have deletions within the NBCCS candidate region. All LOH is consistent with the genetic mapping of the NBCCS locus. Additionally, one sporadic tumor indicates that the smallest region of overlap in the deletions is within the interval D9S287 (proximal) and D9S180 (distal). A series of YAC clones from within this region has been mapped by FISH to examine chimerism. These clones, which have been mapped with respect to one another, form a contig which encompasses the candidate region from D9S196 to D9S180.

  4. 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

  5. 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

  6. Genetic variants implicated in personality: a review of the more promising candidates.

    PubMed

    Savitz, Jonathan B; Ramesar, Rajkumar S

    2004-11-15

    Alleles of the serotonin transporter gene (SERT) and the dopamine 4 receptor gene (DRD4) were first associated with anxiety-related and novelty-seeking personality traits, respectively, in 1996. These early successes precipitated a flood of research into the genetic basis of personality; a quest that has yet to yield decisive answers. Here, both the theoretical and the empirical evidence implicating specific loci-in particular SERT and DRD4-in the development of personality is evaluated. Despite a paucity of statistically significant results following post-hoc analysis, and an excess of positive results derived from studies with small sample sizes, the existence of a genuine effect is argued for: a gene-personality relationship rendered periodically latent through genetic epistasis, gene-environment interactions, variation in genetic background, and the presence of other confounding variables.

  7. 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

  8. 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.

  9. 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

  10. Genetic analysis of intracellular aminoglycerophospholipid traffic.

    PubMed

    Voelker, Dennis R

    2004-02-01

    Inter- and intramembrane phospholipid transport processes are central features of membrane biogenesis and homeostasis. Relatively recent successes in the molecular genetic analysis of aminoglycerophospholipid transport processes in both yeast and mammalian cells are now providing important new information defining specific protein and lipid components that participate in these reactions. Studies focused on phosphatidylserine (PtdSer) transport to the mitochondria reveal that the process is regulated by ubiquitination. In addition, a specific mutation disrupts PtdSer transport between mitochondrial membranes. Analysis of PtdSer transport from the endoplasmic reticulum to the locus of PtdSer decarboxylase 2 demonstrates the requirement for a phosphatidylinositol-4-kinase, a phosphatidylinositol-binding protein, and the C2 domain of the decarboxylase. Examination of NBD-phosphatidylcholine transport demonstrates the involvement of the prevacuolar compartment and a requirement for multiple genes involved in regulating vacuolar protein sorting for transport of the lipid to the vacuole. In intramembrane transport, multiple genes are now identified including those encoding multidrug resistant protein family members, DNF family members, ATP binding cassette transporters, and pleiotropic drug resistance family members. The scramblase family constitutes a collection of putative transmembrane transporters that function in an ATP-independent manner. The genetic analysis of lipid traffic is uncovering new molecules involved in all aspects of the regulation and execution of the transport steps and also providing essential tools to critically test the involvement of numerous candidate molecules.

  11. 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

  12. EST-SNP discovery and dense genetic mapping in lentil (Lens culinaris Medik.) enable candidate gene selection for boron tolerance.

    PubMed

    Kaur, Sukhjiwan; Cogan, Noel O I; Stephens, Amber; Noy, Dianne; Butsch, Mirella; Forster, John W; Materne, Michael

    2014-03-01

    Large-scale SNP discovery and dense genetic mapping in a lentil intraspecific cross permitted identification of a single chromosomal region controlling tolerance to boron toxicity, an important breeding objective. Lentil (Lens culinaris Medik.) is a highly nutritious food legume crop that is cultivated world-wide. Until recently, lentil has been considered a genomic 'orphan' crop, limiting the feasibility of marker-assisted selection strategies in breeding programs. The present study reports on the identification of single-nucleotide polymorphisms (SNPs) from transcriptome sequencing data, utilisation of expressed sequence tag (EST)-derived simple sequence repeat (SSR) and SNP markers for construction of a gene-based genetic linkage map, and identification of markers in close linkage to major QTLs for tolerance to boron (B) toxicity. A total of 2,956 high-quality SNP markers were identified from a lentil EST database. Sub-sets of 546 SSRs and 768 SNPs were further used for genetic mapping of an intraspecific mapping population (Cassab × ILL2024) that exhibits segregation for B tolerance. Comparative analysis of the lentil linkage map with the sequenced genomes of Medicago truncatula Gaertn., soybean (Glycine max [L.] Merr.) and Lotus japonicus L. indicated blocks of conserved macrosynteny, as well as a number of rearrangements. A single genomic region was found to be associated with variation for B tolerance in lentil, based on evaluation performed over 2 years. Comparison of flanking markers to genome sequences of model species (M. truncatula, soybean and Arabidopsis thaliana) identified candidate genes that are functionally associated with B tolerance, and could potentially be used for diagnostic marker development in lentil.

  13. 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

  14. Collaborative Meta-analysis: Associations of 150 Candidate Genes With Osteoporosis and Osteoporotic Fracture

    PubMed Central

    Richards, J. Brent; Kavvoura, Fotini K.; Rivadeneira, Fernando; Styrkársdóttir, Unnur; Estrada, Karol; Halldórsson, Bjarni V.; Hsu, Yi-Hsiang; Zillikens, M. Carola; Wilson, Scott G.; Mullin, Benjamin H.; Amin, Najaf; Aulchenko, Yurii S.; Cupples, L. Adrienne; Deloukas, Panagiotis; Demissie, Serkalem; Hofman, Albert; Kong, Augustine; Karasik, David; van Meurs, Joyce B.; Oostra, Ben A.; Pols, Huibert A.P.; Sigurdsson, Gunnar; Thorsteinsdottir, Unnur; Soranzo, Nicole; Williams, Frances M.K.; Zhou, Yanhua; Ralston, Stuart H.; Thorleifsson, Gudmar; van Duijn, Cornelia M.; Kiel, Douglas P.; Stefansson, Kari; Uitterlinden, André G.; Ioannidis, John P.A.; Spector, Tim D.

    2010-01-01

    genes could not be excluded. Conclusion In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD. Primary Funding Source European Union, Netherlands Organisation for Scientific Research, Research Institute for Diseases in the Elderly, Netherlands Genomics Initiative, Wellcome Trust, National Institutes of Health, deCODE Genetics, and Canadian Institutes of Health Research. PMID:19841454

  15. 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

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. Prioritization of Genetic Variants in the microRNA Regulome as Functional Candidates in Genome-Wide Association Studies

    PubMed Central

    Bulik-Sullivan, Brendan; Selitsky, Sara; Sethupathy, Praveen

    2013-01-01

    Comprehensive analyses of results from genome-wide association studies (GWAS) have demonstrated that complex disease/trait-associated loci are enriched in gene regulatory regions of the genome. The search for causal regulatory variation has focused primarily on transcriptional elements, such as promoters and enhancers. microRNAs (miRNAs) are now widely appreciated as critical posttranscriptional regulators of gene expression and are thought to impart stability to biological systems. Naturally occurring genetic variation in the miRNA regulome is likely an important contributor to phenotypic variation in the human population. However, the extent to which polymorphic miRNA-mediated gene regulation underlies GWAS signals remains unclear. In this study, we have developed the most comprehensive bioinformatic analysis pipeline to date for cataloging and prioritizing variants in the miRNA regulome as functional candidates in GWAS. We highlight specific findings, including a variant in the promoter of the miRNA let-7 that may contribute to human height variation. We also provide a discussion of how our approach can be expanded in the future. Overall, we believe that the results of this study will be valuable for researchers interested in determining whether GWAS signals implicate the miRNA regulome in their disease/trait of interest. PMID:23595788

  3. Incorporating alternative splicing and mRNA editing into the genetic analysis of complex traits

    PubMed Central

    Hassan, Musa A.; Saeij, Jeroen P.J.

    2014-01-01

    The nomination of candidate genes underlying complex traits is often focused on genetic variations that alter mRNA abundance or result in non-conservative changes in amino acids. Although inconspicuous in complex trait analysis, genetic variants that affect splicing or RNA editing can also generate proteomic diversity and impact genetic traits. Indeed it is known that splicing and RNA editing modulate several traits in humans and model organisms. Using high-throughput RNA sequencing (RNA-seq) analysis, it is now possible to integrate the genetics of transcript abundance, alternative splicing and editing with the analysis of complex traits. We recently demonstrated that both alternative splicing and mRNA editing are modulated by genetic and environmental factors, and potentially engender phenotypic diversity in a genetically segregating mouse population. Therefore, the analysis of splicing and RNA editing will expand not only the regulatory landscape of transcriptome and proteome complexity, but also the repertoire of candidate genes for complex traits. PMID:25171292

  4. 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.

  5. 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

  6. 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

  7. 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.

  8. Mosaic zebrafish transgenesis for functional genomic analysis of candidate cooperative genes in tumor pathogenesis.

    PubMed

    Ung, Choong Yong; Guo, Feng; Zhang, Xiaoling; Zhu, Zhihui; Zhu, Shizhen

    2015-01-01

    Comprehensive genomic analysis has uncovered surprisingly large numbers of genetic alterations in various types of cancers. To robustly and efficiently identify oncogenic "drivers" among these tumors and define their complex relationships with concurrent genetic alterations during tumor pathogenesis remains a daunting task. Recently, zebrafish have emerged as an important animal model for studying human diseases, largely because of their ease of maintenance, high fecundity, obvious advantages for in vivo imaging, high conservation of oncogenes and their molecular pathways, susceptibility to tumorigenesis and, most importantly, the availability of transgenic techniques suitable for use in the fish. Transgenic zebrafish models of cancer have been widely used to dissect oncogenic pathways in diverse tumor types. However, developing a stable transgenic fish model is both tedious and time-consuming, and it is even more difficult and more time-consuming to dissect the cooperation of multiple genes in disease pathogenesis using this approach, which requires the generation of multiple transgenic lines with overexpression of the individual genes of interest followed by complicated breeding of these stable transgenic lines. Hence, use of a mosaic transient transgenic approach in zebrafish offers unique advantages for functional genomic analysis in vivo. Briefly, candidate transgenes can be coinjected into one-cell-stage wild-type or transgenic zebrafish embryos and allowed to integrate together into each somatic cell in a mosaic pattern that leads to mixed genotypes in the same primarily injected animal. This permits one to investigate in a faster and less expensive manner whether and how the candidate genes can collaborate with each other to drive tumorigenesis. By transient overexpression of activated ALK in the transgenic fish overexpressing MYCN, we demonstrate here the cooperation of these two oncogenes in the pathogenesis of a pediatric cancer, neuroblastoma that has

  9. Microsatellite data analysis for population genetics.

    PubMed

    Kim, Kyung Seok; Sappington, Thomas W

    2013-01-01

    Theories and analytical tools of population genetics have been widely applied for addressing various questions in the fields of ecological genetics, conservation biology, and any context where the role of dispersal or gene flow is important. Underlying much of population genetics is the analysis of variation at selectively neutral marker loci, and microsatellites continue to be a popular choice of marker. In recent decades, software programs to estimate population genetics parameters have been developed at an increasing pace as computational science and theoretical knowledge advance. Numerous population genetics software programs are presently available to analyze microsatellite genotype data, but only a handful are commonly employed for calculating parameters such as genetic variation, genetic structure, patterns of spatial and temporal gene flow, population demography, individual population assignment, and genetic relationships within and between populations. In this chapter, we introduce statistical analyses and relevant population genetic software programs that are commonly employed in the field of population genetics and molecular ecology.

  10. 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.

  11. 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

  12. 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

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

    PubMed Central

    Welzenbach, Julia; Neuhoff, Christiane; Heidt, Hanna; Cinar, Mehmet Ulas; Looft, Christian; Schellander, Karl; Tholen, Ernst; Große-Brinkhaus, Christine

    2016-01-01

    The aim of this study was to integrate multi omics data to characterize underlying functional pathways and candidate genes for drip loss in pigs. The consideration of different omics levels allows elucidating the black box of phenotype expression. Metabolite and protein profiling was applied in Musculus longissimus dorsi samples of 97 Duroc × Pietrain pigs. In total, 126 and 35 annotated metabolites and proteins were quantified, respectively. In addition, all animals were genotyped with the porcine 60 k Illumina beadchip. An enrichment analysis resulted in 10 pathways, amongst others, sphingolipid metabolism and glycolysis/gluconeogenesis, with significant influence on drip loss. Drip loss and 22 metabolic components were analyzed as intermediate phenotypes within a genome-wide association study (GWAS). We detected significantly associated genetic markers and candidate genes for drip loss and for most of the metabolic components. On chromosome 18, a region with promising candidate genes was identified based on SNPs associated with drip loss, the protein “phosphoglycerate mutase 2” and the metabolite glycine. We hypothesize that association studies based on intermediate phenotypes are able to provide comprehensive insights in the genetic variation of genes directly involved in the metabolism of performance traits. In this way, the analyses contribute to identify reliable candidate genes. PMID:27589727

  14. 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.…

  15. 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

  16. 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.

  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. Dynamic QTL Analysis and Candidate Gene Mapping for Waterlogging Tolerance at Maize Seedling Stage

    PubMed Central

    Osman, Khalid A.; Tang, Bin; Wang, Yaping; Chen, Juanhua; Yu, Feng; Li, Liu; Han, Xuesong; Zhang, Zuxin; Yan, Jianbin; Zheng, Yonglian; Yue, Bing; Qiu, Fazhan

    2013-01-01

    Soil waterlogging is one of the major abiotic stresses adversely affecting maize growth and yield. To identify dynamic expression of genes or quantitative trait loci (QTL), QTL associated with plant height, root length, root dry weight, shoot dry weight and total dry weight were identified via conditional analysis in a mixed linear model and inclusive composite interval mapping method at three respective periods under waterlogging and control conditions. A total of 13, 19 and 23 QTL were detected at stages 3D|0D (the period during 0–3 d of waterlogging), 6D|3D and 9D|6D, respectively. The effects of each QTL were moderate and distributed over nine chromosomes, singly explaining 4.14–18.88% of the phenotypic variation. Six QTL (ph6-1, rl1-2, sdw4-1, sdw7-1, tdw4-1 and tdw7-1) were identified at two consistent stages of seedling development, which could reflect a continuous expression of genes; the remaining QTL were detected at only one stage. Thus, expression of most QTL was influenced by the developmental status. In order to provide additional evidence regarding the role of corresponding genes in waterlogging tolerance, mapping of Expressed Sequence Tags markers and microRNAs were conducted. Seven candidate genes were observed to co-localize with the identified QTL on chromosomes 1, 4, 6, 7 and 9, and may be important candidate genes for waterlogging tolerance. These results are a good starting point for understanding the genetic basis for selectively expressing of QTL in different stress periods and the common genetic control mechanism of the co-localized traits. PMID:24244474

  20. Linkage analysis of candidate obesity genes among the Mexican-American population of Starr County, Texas.

    PubMed

    Bray, M S; Boerwinkle, E; Hanis, C L

    1999-01-01

    Recent advances in the molecular basis of body fat regulation have identified several genes in which genetic variation may influence obesity and related measures in human populations. Genes that have been shown to have a regulatory function in the control of body fat utilization, eating behavior, and/or metabolic rate in rodent models of obesity include leptin (LEP), leptin receptor (LEPR), neuropeptide Y (NPY), NPY Y1 receptor (NPYY1), glucagon-like peptide-1 (GLP-1), GLP-1 receptor (GLP1R), and uncoupling protein 1 (UCP1). We have typed microsatellite markers located within or near these seven candidate obesity genes in 302 non-diabetic individuals from 59 Mexican-American families from Starr County, Texas. Sib pair linkage analysis was used to examine linkage between these genes and obesity status (obese siblings only; n = 170 pairs) and several obesity-related quantitative variables (all siblings; n = 545 total sibling pairs). Significant linkage (P = 0.042) was found between obesity and NPY within the obese sibling pairs. No other candidate gene was linked to obesity status in this subsample. Consistent with the obese sib pair linkage results, NPY showed evidence of linkage to body weight (P = 0.020), abdominal circumference (P = 0.031), hip circumference (P = 0.012), diastolic blood pressure (P = 0.005), and a composite measure of body mass and size (P = 0.048) in the entire sibling sample. Other significant linkages observed were between LEP and waist/hip ratio (P = 0.010), total cholesterol (P = 0.030), and HDL cholesterol (P = 0.026) and between LEPR and fasting blood glucose (P = 0.018) and diastolic blood pressure (P = 0.003). These results support further investigation of NPY, LEP, and LEPR to identify genetic variation that may influence obesity status, glucose and lipid metabolism, and blood pressure in Mexican Americans. PMID:10207720

  1. 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

  2. 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.

  3. Microsatellite data analysis for population genetics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Theories and analytical tools of population genetics have been widely applied for addressing various questions in the fields of ecological genetics, conservation biology, and any context where the role of dispersal or gene flow is important. Underlying much of population genetics is the analysis of ...

  4. 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.

  5. 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.

  6. 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

  7. 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

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

    PubMed

    Sabbagh, Ubadah; 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.

  9. 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

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

    PubMed

    Sabbagh, Ubadah; 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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...

  19. 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

  20. QTL analysis and candidate gene mapping for the polyphenol content in cider apple.

    PubMed

    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

  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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

  6. Analysis of 34 candidate genes in bupropion and placebo remission.

    PubMed

    Tiwari, Arun K; Zai, Clement C; Sajeev, Gautam; Arenovich, Tamara; Müller, Daniel J; Kennedy, James L

    2013-05-01

    There is considerable variability in the rate of response and remission following treatment with antidepressant drugs or placebo in depression patients. No pharmacogenetic studies of bupropion response have been done. We investigated 532 tagging single nucleotide polymorphisms (SNPs) in 34 candidate genes for association with remission and response to either bupropion (n=319) or placebo (n=257) in patients with major depressive disorder. Analyses were performed using conditional logistic regression. Significant association (gene-wide correction) was observed for remission following treatment with bupropion for a SNP within the serotonin receptor 2A gene (HTR2A rs2770296, p(corrected)=0.02). Response to bupropion treatment was significantly associated with a SNP in the dopamine transporter gene (rs6347, p(corrected)=0.013). Among the patients who received placebo, marginal association for remission was observed between a SNP in HTR2A (rs2296972, p(corrected)=0.055) as well as in the serotonin transporter gene (5-HTT or SLC6A4 rs4251417, p(corrected)=0.050). Placebo response was associated with SNPs in the glucocorticoid receptor gene (NR3C1; rs1048261, p(corrected)=0.040) and monoamine oxidase A gene (MAOA; rs6609257, p corrected=0.046). Although the above observations were significant after gene-wide corrections, none of these would be significant after a more conservative study-wide correction for multiple tests. These results suggest a possible role for HTR2A in remission to bupropion treatment. In accordance with bupropion pharmacology, dopamine transporter may play a role in response. The MAOA gene may be involved in placebo response.

  7. Genetic Determinants for Promoter Hypermethylation in the Lungs of Smokers: A Candidate Gene-Based Study

    PubMed Central

    Leng, Shuguang; Stidley, Christine A.; Liu, Yushi; Edlund, Christopher K.; Willink, Randall P.; Han, Younghun; Landi, Maria Teresa; Thun, Michael; Picchi, Maria A.; Bruse, Shannon E.; Crowell, Richard E.; Van Den Berg, David; Caporaso, Neil E.; Amos, Christopher I.; Siegfried, Jill M.; Tesfaigzi, Yohannes; Gilliland, Frank D.; Belinsky, Steven A.

    2011-01-01

    The detection of tumor suppressor gene promoter methylation in sputum-derived exfoliated cells predicts early lung cancer. Here we identified genetic determinants for this epigenetic process and examined their biological effects on gene regulation. A two-stage approach involving discovery and replication was employed to assess the association between promoter hypermethylation of a 12-gene panel and common variation in 40 genes involved in carcinogen metabolism, regulation of methylation, and DNA damage response in members of the Lovelace Smokers Cohort (n=1434). Molecular validation of three identified variants was conducted using primary bronchial epithelial cells. Association of study-wide significance (P<8.2×10−5) was identified for rs1641511, rs3730859, and rs1883264 in TP53, LIG1, and BIK, respectively. These SNPs were significantly associated with altered expression of the corresponding genes in primary bronchial epithelial cells. In addition, rs3730859 in LIG1 was also moderately associated with increased risk for lung cancer among Caucasian smokers. Together, our findings suggest that genetic variation in DNA replication and apoptosis pathways impacts the propensity for gene promoter hypermethylation in the aerodigestive tract of smokers. The incorporation of genetic biomarkers for gene promoter hypermethylation with clinical and somatic markers may improve risk assessment models for lung cancer. PMID:22139380

  8. 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

  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.

  10. 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

  11. Genetic mapping of natural variation in a shade avoidance response: ELF3 is the candidate gene for a QTL in hypocotyl growth regulation

    PubMed Central

    Coluccio, M. Paula; Sanchez, Sabrina E.; Kasulin, Luciana; Yanovsky, Marcelo J.; Botto, Javier F.

    2011-01-01

    When plants become shaded by neighbouring plants, they perceive a decrease in the red/far-red (R/FR) ratio of the light environment, which provides an early and unambiguous warning of the presence of competing vegetation. The mechanistic bases of the natural genetic variation in response to shade signals remain largely unknown. This study demonstrates that a wide range of genetic variation for hypocotyl elongation in response to an FR pulse at the end of day (EOD), a light signal that simulates natural shade, exists between Arabidopsis accessions. A quantitative trait locus (QTL) mapping analysis was done in the Bayreuth×Shahdara recombinant inbred line population. EODINDEX1 is the most significant QTL identified in response to EOD. The Shahdara alleles at EODINDEX1 caused a reduced response to shade as a consequence of an impaired hypocotyl inhibition under white light, and an accelerated leaf movement rhythm, which correlated positively with the pattern of circadian expression of clock genes such as PRR7 and PRR9. Genetic and quantitative complementation analyses demonstrated that ELF3 is the most likely candidate gene underlying natural variation at EODINDEX1. In conclusion, ELF3 is proposed as a component of the shade avoidance signalling pathway responsible for the phenotypic differences between Arabidopsis populations in relation to adaptation in a changing light environment. PMID:20713464

  12. Novel Biomarker Candidates for Colorectal Cancer Metastasis: A Meta-analysis of In Vitro Studies

    PubMed Central

    Long, Nguyen Phuoc; Lee, Wun Jun; Huy, Nguyen Truong; Lee, Seul Ji; Park, Jeong Hill; Kwon, Sung Won

    2016-01-01

    Colorectal cancer (CRC) is one of the most common and lethal cancers. Although numerous studies have evaluated potential biomarkers for early diagnosis, current biomarkers have failed to reach an acceptable level of accuracy for distant metastasis. In this paper, we performed a gene set meta-analysis of in vitro microarray studies and combined the results from this study with previously published proteomic data to validate and suggest prognostic candidates for CRC metastasis. Two microarray data sets included found 21 significant genes. Of these significant genes, ALDOA, IL8 (CXCL8), and PARP4 had strong potential as prognostic candidates. LAMB2, MCM7, CXCL23A, SERPINA3, ABCA3, ALDH3A2, and POLR2I also have potential. Other candidates were more controversial, possibly because of the biologic heterogeneity of tumor cells, which is a major obstacle to predicting metastasis. In conclusion, we demonstrated a meta-analysis approach and successfully suggested ten biomarker candidates for future investigation.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. 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

  18. 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

  19. 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

  20. 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.

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

    PubMed

    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. The genetics of neuroendocrine prostate cancers: a review of current and emerging candidates.

    PubMed

    Ather, M Hammad; Siddiqui, Tahmeena

    2012-01-01

    Prostate cancer (PC) displays a strong familial link and genetic factors; genes regulating inflammation may have a pivotal role in the disease. Epigenetic changes control chromosomal integrity, gene functions, and, ultimately, carcinogenesis. The most widely studied epigenetic event in PC is aberrant DNA methylation (hypo- and hypermethylation); besides this, chromatin remodeling and micro RNA (miRNA) are other studied alterations in PC. These all lead to genomic instability and inappropriate gene expression. Causative dysfunction of histone modifying enzymes results in generic and locus-specific changes in chromatin remodeling. miRNA deregulation also contributes to prostate carcinogenesis, including interference with androgen-receptor signaling and apoptosis. These epigenetic alterations have the potential to act as biomarkers for PC for screening and diagnosis as well as prognosis and follow-up. The variable biological potential for a newly diagnosed PC is one of the biggest challenges. The other major clinical problem is in the management of castration-resistant PC. Neuroendocrine (NE) differentiation is one of the putative explanations for the development of castration-resistant disease. Most advanced and poorly differentiated cancer does not produce prostate-specific antigen (PSA) in response to disease progression. Circulating and tissue biomarkers like chromogranin A (CgA) thus become important tools. There is the potential to use various genetic and epigenetic alterations and NE differentiation as therapeutic targets in the management of PC. However, we are still some distance from developing clinically effective tools. Valuable insights into the nature of NE differentiation in PC have been gained in the last decades, but additional understanding of its pathogenetic mechanisms is needed. This will help in devising novel therapeutic strategies to develop targeted therapies. CgA has the potential to become an important marker of advanced castration

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

    PubMed Central

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

    2009-01-01

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

  4. 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

  5. Genetic mapping of male pheromone response in the European corn borer identifies candidate genes regulating neurogenesis

    PubMed Central

    Dekker, Teun; Heckel, David G.

    2016-01-01

    The sexual pheromone communication system of moths is a model system for studies of the evolution of reproductive isolation. Females emit a blend of volatile components that males detect at a distance. Species differences in female pheromone composition and male response directly reinforce reproductive isolation in nature, because even slight variations in the species-specific pheromone blend are usually rejected by the male. The mechanisms by which a new pheromone signal–response system could evolve are enigmatic, because any deviation from the optimally attractive blend should be selected against. Here we investigate the genetic mechanisms enabling a switch in male response. We used a quantitative trait locus-mapping approach to identify the genetic basis of male response in the two pheromone races of the European corn borer, Ostrinia nubilalis. Male response to a 99:1 vs. a 3:97 ratio of the E and Z isomers of the female pheromone is governed by a single, sex-linked locus. We found that the chromosomal region most tightly linked to this locus contains genes involved in neurogenesis but, in accordance with an earlier study, does not contain the odorant receptors expressed in the male antenna that detect the pheromone. This finding implies that differences in the development of neuronal pathways conveying information from the antenna, not differences in pheromone detection by the odorant receptors, are primarily responsible for the behavioral response differences among the males in this system. Comparison with other moth species reveals a previously unexplored mechanism by which male pheromone response can change in evolution. PMID:27698145

  6. Combining gene expression and genetic analyses to identify candidate genes involved in cold responses in pea.

    PubMed

    Legrand, Sylvain; Marque, Gilles; Blassiau, Christelle; Bluteau, Aurélie; Canoy, Anne-Sophie; Fontaine, Véronique; Jaminon, Odile; Bahrman, Nasser; Mautord, Julie; Morin, Julie; Petit, Aurélie; Baranger, Alain; Rivière, Nathalie; Wilmer, Jeroen; Delbreil, Bruno; Lejeune-Hénaut, Isabelle

    2013-09-01

    Cold stress affects plant growth and development. In order to better understand the responses to cold (chilling or freezing tolerance), we used two contrasted pea lines. Following a chilling period, the Champagne line becomes tolerant to frost whereas the Terese line remains sensitive. Four suppression subtractive hybridisation libraries were obtained using mRNAs isolated from pea genotypes Champagne and Terese. Using quantitative polymerase chain reaction (qPCR) performed on 159 genes, 43 and 54 genes were identified as differentially expressed at the initial time point and during the time course study, respectively. Molecular markers were developed from the differentially expressed genes and were genotyped on a population of 164 RILs derived from a cross between Champagne and Terese. We identified 5 candidate genes colocalizing with 3 different frost damage quantitative trait loci (QTL) intervals and a protein quantity locus (PQL) rich region previously reported. This investigation revealed the role of constitutive differences between both genotypes in the cold responses, in particular with genes related to glycine degradation pathway that could confer to Champagne a better frost tolerance. We showed that freezing tolerance involves a decrease of expression of genes related to photosynthesis and the expression of a gene involved in the production of cysteine and methionine that could act as cryoprotectant molecules. Although it remains to be confirmed, this study could also reveal the involvement of the jasmonate pathway in the cold responses, since we observed that two genes related to this pathway were mapped in a frost damage QTL interval and in a PQL rich region interval, respectively.

  7. Genetic Association Analysis of Drusen Progression

    PubMed Central

    Hoffman, Joshua D.; van Grinsven, Mark J. J. P.; Li, Chun; Brantley, Milam; McGrath, Josephine; Agarwal, Anita; Scott, William K.; Schwartz, Stephen G.; Kovach, Jaclyn; Pericak-Vance, Margaret; Sanchez, Clara I.; Haines, Jonathan L.

    2016-01-01

    Purpose Age-related macular degeneration is a common form of vision loss affecting older adults. The etiology of AMD is multifactorial and is influenced by environmental and genetic risk factors. In this study, we examine how 19 common risk variants contribute to drusen progression, a hallmark of AMD pathogenesis. Methods Exome chip data was made available through the International AMD Genomics Consortium (IAMDGC). Drusen quantification was carried out with color fundus photographs using an automated drusen detection and quantification algorithm. A genetic risk score (GRS) was calculated per subject by summing risk allele counts at 19 common genetic risk variants weighted by their respective effect sizes. Pathway analysis of drusen progression was carried out with the software package Pathway Analysis by Randomization Incorporating Structure. Results We observed significant correlation with drusen baseline area and the GRS in the age-related eye disease study (AREDS) dataset (ρ = 0.175, P = 0.006). Measures of association were not statistically significant between drusen progression and the GRS (P = 0.54). Pathway analysis revealed the cell adhesion molecules pathway as the most highly significant pathway associated with drusen progression (corrected P = 0.02). Conclusions In this study, we explored the potential influence of known common AMD genetic risk factors on drusen progression. Our results from the GRS analysis showed association of increasing genetic burden (from 19 AMD associated loci) to baseline drusen load but not drusen progression in the AREDS dataset while pathway analysis suggests additional genetic contributors to AMD risk. PMID:27116550

  8. Development of RGA-CAPS markers and genetic mapping of candidate genes for sugarcane mosaic virus resistance in maize.

    PubMed

    Quint, M.; Mihaljevic, R.; Dussle, M.; Xu, L.; Melchinger, E.; Lübberstedt, T.

    2002-08-01

    Three previously published resistance gene analogues (RGAs), pic13, pic21 and pic19, were mapped in relation to sugarcane mosaic virus (SCMV) resistance genes ( Scmv1, Scmv2) in maize. We cloned these RGAs from six inbreds including three SCMV-resistant lines (D21, D32, FAP1360A) and three SCMV-susceptible lines (D145, D408, F7). Pairwise sequence alignments among the six inbreds revealed a frequency of one single nucleotide polymorphism (SNP) per 33 bp for the three RGAs, indicating a high degree of polymorphism and a high probability of success in converting RGAs into codominant cleaved amplified polymorphic sequence (CAPS) markers compared to other sequences. SNPs were used to develop CAPS markers for mapping of the three RGAs in relation to Scmv1 (chromosome 6) and Scmv2 (chromosome 3), and for pedigree analyses of resistant inbred lines. By genetic mapping pic21 was shown to be different from Scmv2, whereas pic19 and pic13 are still candidates for Scmv1 and Scmv2, respectively, due to genetic mapping and consistent restriction patterns of ancestral lines.

  9. Measuring Coping Behavior in Liver Transplant Candidates: A Psychometric Analysis of the Brief COPE.

    PubMed

    Amoyal, Nicole; Fernandez, Anne C; Ng, Reuben; Fehon, Dwain C

    2016-09-01

    Liver transplant candidates must cope with significant physiological and psychological challenges. The Brief COPE is a frequently used measure of coping behavior; however, knowledge of the scale's factor structure and construct validity is limited with regard to liver transplant candidates. This study assessed the validity of the Brief COPE in 120 liver transplant candidates using exploratory factor analysis. Results revealed a 6-factor solution, only 2 of which were consistent with the original scale assignments. Construct validity of the 6 Brief COPE scales yielded in this study was demonstrated. The results indicate that the Brief COPE is valid, reliable, and can be meaningfully interpreted in liver transplant patients. Future research should confirm this factor structure and examine its predictive validity prior to widespread use among liver transplant patients. Suggestions are presented for enhancing the care of transplant candidates by promoting the use of adaptive coping mechanisms to manage distress.

  10. 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.

  11. 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.

  12. 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

    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.

  13. 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

  14. 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.

  15. 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.

  16. 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

  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. 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.

  19. An integrated approach of comparative genomics and heritability analysis of pig and human on obesity trait: evidence for candidate genes on human chromosome 2

    PubMed Central

    2012-01-01

    Background Traditional candidate gene approach has been widely used for the study of complex diseases including obesity. However, this approach is largely limited by its dependence on existing knowledge of presumed biology of the phenotype under investigation. Our combined strategy of comparative genomics and chromosomal heritability estimate analysis of obesity traits, subscapular skinfold thickness and back-fat thickness in Korean cohorts and pig (Sus scrofa), may overcome the limitations of candidate gene analysis and allow us to better understand genetic predisposition to human obesity. Results We found common genes including FTO, the fat mass and obesity associated gene, identified from significant SNPs by association studies of each trait. These common genes were related to blood pressure and arterial stiffness (P = 1.65E-05) and type 2 diabetes (P = 0.00578). Through the estimation of variance of genetic component (heritability) for each chromosome by SNPs, we observed a significant positive correlation (r = 0.479) between genetic contributions of human and pig to obesity traits. Furthermore, we noted that human chromosome 2 (syntenic to pig chromosomes 3 and 15) was most important in explaining the phenotypic variance for obesity. Conclusions Obesity genetics still awaits further discovery. Navigating syntenic regions suggests obesity candidate genes on chromosome 2 that are previously known to be associated with obesity-related diseases: MRPL33, PARD3B, ERBB4, STK39, and ZNF385B. PMID:23253381

  20. 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.

  1. 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

  2. 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.

  3. A Stratified Transcriptomics Analysis of Polygenic Fat and Lean Mouse Adipose Tissues Identifies Novel Candidate Obesity Genes

    PubMed Central

    Morton, Nicholas M.; Nelson, Yvonne B.; Michailidou, Zoi; Di Rollo, Emma M.; Ramage, Lynne; Hadoke, Patrick W. F.; Seckl, Jonathan R.; Bunger, Lutz; Horvat, Simon; Kenyon, Christopher J.; Dunbar, Donald R.

    2011-01-01

    Background Obesity and metabolic syndrome results from a complex interaction between genetic and environmental factors. In addition to brain-regulated processes, recent genome wide association studies have indicated that genes highly expressed in adipose tissue affect the distribution and function of fat and thus contribute to obesity. Using a stratified transcriptome gene enrichment approach we attempted to identify adipose tissue-specific obesity genes in the unique polygenic Fat (F) mouse strain generated by selective breeding over 60 generations for divergent adiposity from a comparator Lean (L) strain. Results To enrich for adipose tissue obesity genes a ‘snap-shot’ pooled-sample transcriptome comparison of key fat depots and non adipose tissues (muscle, liver, kidney) was performed. Known obesity quantitative trait loci (QTL) information for the model allowed us to further filter genes for increased likelihood of being causal or secondary for obesity. This successfully identified several genes previously linked to obesity (C1qr1, and Np3r) as positional QTL candidate genes elevated specifically in F line adipose tissue. A number of novel obesity candidate genes were also identified (Thbs1, Ppp1r3d, Tmepai, Trp53inp2, Ttc7b, Tuba1a, Fgf13, Fmr) that have inferred roles in fat cell function. Quantitative microarray analysis was then applied to the most phenotypically divergent adipose depot after exaggerating F and L strain differences with chronic high fat feeding which revealed a distinct gene expression profile of line, fat depot and diet-responsive inflammatory, angiogenic and metabolic pathways. Selected candidate genes Npr3 and Thbs1, as well as Gys2, a non-QTL gene that otherwise passed our enrichment criteria were characterised, revealing novel functional effects consistent with a contribution to obesity. Conclusions A focussed candidate gene enrichment strategy in the unique F and L model has identified novel adipose tissue-enriched genes

  4. Genetic and Molecular Network Analysis of Behavior

    PubMed Central

    Williams, Robert W.; Mulligan, Megan K.

    2014-01-01

    This chapter provides an introduction into the genetic control and analysis of behavioral variation using powerful online resources. We introduce you to the new field of systems genetics using "case studies" drawn from the world of behavioral genetics that exploit populations of genetically diverse lines of mice. These lines differ very widely in patterns of gene and protein expression in the brain and in patterns of behavior. In this chapter we address the following set of related questions: (1) Can we combine massive genomic data sets with large aggregates of precise quantitative data on behavior? (2) Can we map causal relations between gene variants and behavioral differences? (3) Can we simultaneously use these highly coherent data sets to understand more about the underlying molecular and cellular basis of behavior? PMID:23195314

  5. 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

  6. Genetic basis of delay discounting in frequent gamblers: examination of a priori candidates and exploration of a panel of dopamine-related loci

    PubMed Central

    Gray, Joshua C; MacKillop, James

    2014-01-01

    Introduction Delay discounting is a behavioral economic index of impulsivity that reflects preferences for small immediate rewards relative to larger delayed rewards. It has been consistently linked to pathological gambling and other forms of addictive behavior, and has been proposed to be a behavioral characteristic that may link genetic variation and risk of developing addictive disorders (i.e., an endophenotype). Studies to date have revealed significant associations with polymorphisms associated with dopamine neurotransmission. The current study examined associations between delay discounting and both previously linked variants and a novel panel of dopamine-related variants in a sample of frequent gamblers. Methods Participants were 175 weekly gamblers of European ancestry who completed the Monetary Choice Questionnaire to assess delay discounting preferences and provided a DNA via saliva. Results In a priori tests, two loci previously associated with delayed reward discounting (rs1800497 and rs4680) were not replicated, however, the long form of DRD4 VNTR was significantly associated with lower discounting of delayed rewards. Exploratory analysis of the dopamine-related panel revealed 11 additional significant associations in genes associated with dopamine synthesis, breakdown, reuptake, and receptor function (DRD3, SLC6A3, DDC, DBH, and SLC18A2). An aggregate genetic risk score from the nominally significant loci accounted for 17% of the variance in discounting. Mediational analyses largely supported the presence of indirect effects between the associated loci, delay discounting, and pathological gambling severity. Conclusions These findings do not replicate previously reported associations but identify several novel candidates and provide preliminary support for a systems biology approach to understand the genetic basis of delay discounting. PMID:25365808

  7. A genetic association study of maternal and fetal candidate genes that predispose to preterm prelabor rupture of membranes (PROM)

    PubMed Central

    ROMERO, Roberto; FRIEL, Lara A.; EDWARDS, Digna R. VELEZ; KUSANOVIC, Juan Pedro; HASSAN, Sonia S.; MAZAKI-TOVI, Shali; VAISBUCH, Edi; KIM, Chong Jai; EREZ, Offer; CHAIWORAPONGSA, Tinnakorn; PEARCE, Brad D.; BARTLETT, Jacquelaine; SALISBURY, Benjamin A.; ANANT, Madan Kumar; VOVIS, Gerald F.; LEE, Min Seob; GOMEZ, Ricardo; BEHNKE, Ernesto; OYARZUN, Enrique; TROMP, Gerard; WILLIAMS, Scott M.; MENON, Ramkumar

    2010-01-01

    Objective To determine whether maternal/fetal SNPs in candidate genes are associated with preterm prelabor rupture of membranes (pPROM). Study Design A case-control study was conducted in patients with pPROM (225 mothers and 155 fetuses) and 599 mothers and 628 fetuses with a normal pregnancy; 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; FDR was used to correct for multiple testing (q*=0.15)]. Results 1) A SNP in TIMP2 in mothers was significantly associated with pPROM(OR=2.12 95% CI [1.47-3.07], p = 0.000068), and this association remained significant after correction for multiple comparisons; 2) Haplotypes for COL4A3 in the mother were associated with pPROM (global p = 0.003); 3) Multilocus analysis identified a three locus model, which included maternal SNPs in COL1A2, DEFA5, and EDN1. Conclusion DNA variants in a maternal gene involved in extracellular matrix metabolism doubled the risk of pPROM. PMID:20673868

  8. 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

  9. Strategies in analysis of the genetic component of multifactorial diseases; biostatistical aspects.

    PubMed

    Barnetche, Thomas; Gourraud, Pierre-Antoine; Cambon-Thomsen, Anne

    2005-08-01

    Complex polygenic and multifactorial diseases remain a challenge for human geneticists. Here we aim to remind basic definitions of multifactorial diseases and the genetic related concepts underlying classical methods. Knowledge on pathophysiological process and the genetic information available conditions the design of study. The choice of methodology, between candidate gene approach and genome scan approach, between linkage and association studies, is the most important step. Both methods, linkage analysis and association studies are usually considered as complementary approaches for a given disease. For this reason, in this article, we present the most important classical methodologies in genetic epidemiology of complex disorders. References and examples are given to illustrate.

  10. Protein expression analysis of chromosome 12 candidate genes in chronic lymphocytic leukemia (CLL).

    PubMed

    Winkler, D; Schneider, C; Kröber, A; Pasqualucci, L; Lichter, P; Döhner, H; Stilgenbauer, S

    2005-07-01

    The pathogenic role of trisomy 12 in chronic lymphocytic leukemia (CLL) remains unresolved, but recently an upregulated RNA expression level has been observed for chromosome 12 candidate genes. In the current study, the protein expression of chromosome 12 candidate genes was characterized by comparing CLL cases with (n=58) or without (n=16) trisomy 12, CD19+-B-cells and cell lines (JVM-2, EHEB, JURKAT). Immunoblotting was performed to quantify the levels of AID, APAF-1, ARF3, CCND2, CDK2, CKD4, GLI, MDM-2, p27, Smac/DIABLO and STAT6 (signal transducer and activator of transcription 6). The cell lines showed distinct expression patterns for CCND2, MDM-2, p27, Smac/DIABLO and STAT6, and displayed higher levels of CDK2 and CDK4 than the CLL cases. JURKAT and the CLL cases expressed uniformly high levels of p27, but low levels of CCND2. AID expression in the CLL cases was weak with slight variations regardless of the subgroup affiliation. The expression of the investigated proteins was independent of the trisomy 12 status as well as of the VH mutation status. The comparison of CD19+-B-cells with CLL revealed higher protein levels in CLL for CDK4, p27, Smac/DIABLO and STAT6. Further studies including protein expression experiments in genetic high-risk subgroups of CLL have to elucidate whether these proteins qualify as candidates for targeted CLL therapies. PMID:15902296

  11. Profiling candidate genes involved in wax biosynthesis in Arabidopsis thaliana by microarray analysis.

    PubMed

    Costaglioli, Patricia; Joubès, Jérôme; Garcia, Christel; Stef, Marianne; Arveiler, Benoît; Lessire, René; Garbay, Bertrand

    2005-06-01

    Plant epidermal wax forms a hydrophobic layer covering aerial plant organs which constitutes a barrier against uncontrolled water loss and biotic stresses. Wax biosynthesis requires the coordinated activity of a large number of enzymes for the formation of saturated very-long-chain fatty acids and their further transformation in several aliphatic compounds. We found in the available database 282 candidate genes that may play a role in wax synthesis, regulation and transport. To identify the most interesting candidates, we measured the level of expression of 204 genes in the aerial parts of 15-day-old Arabidopsis seedlings by performing microarray experiments. We showed that only 25% of the putative candidates were expressed to significant levels in our samples, thus significantly reducing the number of genes which will be worth studying using reverse genetics to demonstrate their involvement in wax accumulation. We identified a beta-keto acyl-CoA synthase gene, At5g43760, which is co-regulated with the wax gene CER6 in a number of conditions and organs. By contrast, we showed that neither the fatty acyl-CoA reductase genes nor the wax synthase genes were expressed in 15-day-old leaves and stems, raising questions about the identity of the enzymes involved in the acyl-reduction pathway that accounts for 20% of the total wax amount. PMID:15914083

  12. 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

  13. Novel Biomarker Candidates for Colorectal Cancer Metastasis: A Meta-analysis of In Vitro Studies.

    PubMed

    Long, Nguyen Phuoc; Lee, Wun Jun; Huy, Nguyen Truong; Lee, Seul Ji; Park, Jeong Hill; Kwon, Sung Won

    2016-01-01

    Colorectal cancer (CRC) is one of the most common and lethal cancers. Although numerous studies have evaluated potential biomarkers for early diagnosis, current biomarkers have failed to reach an acceptable level of accuracy for distant metastasis. In this paper, we performed a gene set meta-analysis of in vitro microarray studies and combined the results from this study with previously published proteomic data to validate and suggest prognostic candidates for CRC metastasis. Two microarray data sets included found 21 significant genes. Of these significant genes, ALDOA, IL8 (CXCL8), and PARP4 had strong potential as prognostic candidates. LAMB2, MCM7, CXCL23A, SERPINA3, ABCA3, ALDH3A2, and POLR2I also have potential. Other candidates were more controversial, possibly because of the biologic heterogeneity of tumor cells, which is a major obstacle to predicting metastasis. In conclusion, we demonstrated a meta-analysis approach and successfully suggested ten biomarker candidates for future investigation. PMID:27688707

  14. Novel Biomarker Candidates for Colorectal Cancer Metastasis: A Meta-analysis of In Vitro Studies

    PubMed Central

    Long, Nguyen Phuoc; Lee, Wun Jun; Huy, Nguyen Truong; Lee, Seul Ji; Park, Jeong Hill; Kwon, Sung Won

    2016-01-01

    Colorectal cancer (CRC) is one of the most common and lethal cancers. Although numerous studies have evaluated potential biomarkers for early diagnosis, current biomarkers have failed to reach an acceptable level of accuracy for distant metastasis. In this paper, we performed a gene set meta-analysis of in vitro microarray studies and combined the results from this study with previously published proteomic data to validate and suggest prognostic candidates for CRC metastasis. Two microarray data sets included found 21 significant genes. Of these significant genes, ALDOA, IL8 (CXCL8), and PARP4 had strong potential as prognostic candidates. LAMB2, MCM7, CXCL23A, SERPINA3, ABCA3, ALDH3A2, and POLR2I also have potential. Other candidates were more controversial, possibly because of the biologic heterogeneity of tumor cells, which is a major obstacle to predicting metastasis. In conclusion, we demonstrated a meta-analysis approach and successfully suggested ten biomarker candidates for future investigation. PMID:27688707

  15. Role of salivary and candidal proteins in denture stomatitis: an exploratory proteomic analysis.

    PubMed

    Byrd, Warren C; Schwartz-Baxter, Sarah; Carlson, Jim; Barros, Silvana; Offenbacher, Steven; Bencharit, Sompop

    2014-07-29

    Denture stomatitis, inflammation and redness beneath a denture, affects nearly half of all denture wearers. Candidal organisms, the presence of a denture, saliva, and host immunity are the key etiological factors for the condition. The role of salivary proteins in denture stomatitis is not clear. In this study 30 edentulous subjects wearing a maxillary complete denture were recruited. Unstimulated whole saliva from each subject was collected and pooled into two groups (n = 15 each), healthy and stomatitis (Newton classification II and III). Label-free multidimensional liquid chromatography/tandem mass spectrometry (2D-LC-MS/MS) proteomics on two mass spectrometry platforms were used to determine peptide mass differences between control and stomatitis groups. Cluster analysis and principal component analysis were used to determine the differential expression among the groups. The two proteomic platforms identified 97 and 176 proteins (ANOVA; p < 0.01) differentially expressed among the healthy, type 2 and 3 stomatitis groups. Three proteins including carbonic anhydrase 6, cystatin C, and cystatin SN were found to be the same as previous study. Salivary proteomic profiles of patients with denture stomatitis were found to be uniquely different from controls. Analysis of protein components suggests that certain salivary proteins may predispose some patients to denture stomatitis while others are believed to be involved in the reaction to fungal infection. Analysis of candidal proteins suggests that multiple species of candidal organisms play a role in denture stomatitis.

  16. 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…

  17. 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

  18. Physical mapping of the major early-onset familial Alzheimer`s disease locus on chromosome 14 and analysis of candidate gene sequences

    SciTech Connect

    Tanzi, R.E.; Romano, D.M.; Crowley, A.C.

    1994-09-01

    Genetic studies of kindreds displaying evidence for familial AD (FAD) have led to the localization of gene defects responsible for this disorder on chromosomes 14, 19, and 21. A minor early-onset FAD gene on chromosome 21 has been identified to enode the amyloid precursor protein (APP), and the late-onset FAD susceptibility locus on chromosome 19 has been shown to be in linkage disequilibrium with the E4 allele of the APOE gene. Meanwhile, the locus responsible for the major form of early-onset FAD on chromosome 14q24 has not yet been identified. By recombinational analysis, we have refined the minimal candidate region containing the gene defect to approximately 3 megabases in 14q24. We will describe our laboratory`s progress on attempts to finely localize this locus, as well as test known candidate genes from this region for either inclusion in the minimal candidate region or the presence of pathogenic mutations. Candidate genes that have been tested so far include cFOS, heat shock protein 70 member (HSF2A), transforming growth factor beta (TGFB3), the trifunctional protein C1-THF synthase (MTHFD), bradykinin receptor (BR), and the E2k component of a-ketoglutarate dehydrogenase. HSP2A, E2k, MTHFD, and BR do not map to the current defined minimal candidate region; however, sequence analysis must be performed to confirm exclusion of these genes as true candidates. Meanwhile, no pathogenic mutations have yet been found in cFOS or TGFB3. We have also isolated a large number of novel transcribed sequences from the minimal candidate region in the form of {open_quotes}trapped exons{close_quotes} from cosmids identified by hybridization to select YAC clones; we are currently in the process of searching for pathogenic mutations in these exons in affected individuals from FAD families.

  19. 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

  20. 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.

  1. Bayesian semiparametric meta-analysis for genetic association studies.

    PubMed

    De Iorio, Maria; Newcombe, Paul J; Tachmazidou, Ioanna; Verzilli, Claudio J; Whittaker, John C

    2011-07-01

    We present a Bayesian semiparametric model for the meta-analysis of candidate gene studies with a binary outcome. Such studies often report results from association tests for different, possibly study-specific and non-overlapping genetic markers in the same genetic region. Meta-analyses of the results at each marker in isolation are seldom appropriate as they ignore the correlation that may exist between markers due to linkage disequilibrium (LD) and cannot assess the relative importance of variants at each marker. Also such marker-wise meta-analyses are restricted to only those studies that have typed the marker in question, with a potential loss of power. A better strategy is one which incorporates information about the LD between markers so that any combined estimate of the effect of each variant is corrected for the effect of other variants, as in multiple regression. Here we develop a Bayesian semiparametric model which models the observed genotype group frequencies conditional to the case/control status and uses pairwise LD measurements between markers as prior information to make posterior inference on adjusted effects. The approach allows borrowing of strength across studies and across markers. The analysis is based on a mixture of Dirichlet processes model as the underlying semiparametric model. Full posterior inference is performed through Markov chain Monte Carlo algorithms. The approach is demonstrated on simulated and real data. PMID:21400586

  2. Identification of Single Nucleotide Polymorphisms and analysis of Linkage Disequilibrium in sunflower elite inbred lines using the candidate gene approach

    PubMed Central

    Fusari, Corina M; Lia, Verónica V; Hopp, H Esteban; Heinz, Ruth A; Paniego, Norma B

    2008-01-01

    Background Association analysis is a powerful tool to identify gene loci that may contribute to phenotypic variation. This includes the estimation of nucleotide diversity, the assessment of linkage disequilibrium structure (LD) and the evaluation of selection processes. Trait mapping by allele association requires a high-density map, which could be obtained by the addition of Single Nucleotide Polymorphisms (SNPs) and short insertion and/or deletions (indels) to SSR and AFLP genetic maps. Nucleotide diversity analysis of randomly selected candidate regions is a promising approach for the success of association analysis and fine mapping in the sunflower genome. Moreover, knowledge of the distance over which LD persists, in agronomically meaningful sunflower accessions, is important to establish the density of markers and the experimental design for association analysis. Results A set of 28 candidate genes related to biotic and abiotic stresses were studied in 19 sunflower inbred lines. A total of 14,348 bp of sequence alignment was analyzed per individual. In average, 1 SNP was found per 69 nucleotides and 38 indels were identified in the complete data set. The mean nucleotide polymorphism was moderate (θ = 0.0056), as expected for inbred materials. The number of haplotypes per region ranged from 1 to 9 (mean = 3.54 ± 1.88). Model-based population structure analysis allowed detection of admixed individuals within the set of accessions examined. Two putative gene pools were identified (G1 and G2), with a large proportion of the inbred lines being assigned to one of them (G1). Consistent with the absence of population sub-structuring, LD for G1 decayed more rapidly (r2 = 0.48 at 643 bp; trend line, pooled data) than the LD trend line for the entire set of 19 individuals (r2 = 0.64 for the same distance). Conclusion Knowledge about the patterns of diversity and the genetic relationships between breeding materials could be an invaluable aid in crop improvement

  3. Network-centric Analysis of Genetic Predisposition in Diabetic Nephropathy

    PubMed Central

    Ntemka, A; Iliadis, F; Papanikolaou, NA; Grekas, D

    2011-01-01

    Diabetic nephropathy is a serious, long-term complication of diabetes and the leading cause of end-stage renal disease throughout the world. Although this disease is progressively imposing a heavier burden on the health care system, in many aspects it remains poorly understood. In addition to environmental influences, there is abundant evidence in support of genetic susceptibility to microvascular complications of nephropathy in diabetic patients. Familial clustering of phenotypes such as end-stage renal disease, albuminuria and kidney disease have been reported in large scale population studies throughout the world demonstrating strong contribution of inherited factors. Recent genome-wide linkage scans identified several chromosomal regions that are likely to contain diabetic nephropathy susceptibility genes, and association analyses have evaluated positional candidate genes under linkage peaks. In this review we have extracted from the literature the most promising candidate genes thought to confer susceptibility to diabetic nephropathy and mapped them to affected pathways by using network-centric analysis. Several of the top susceptibility genes have been identified as network hubs and bottlenecks suggesting that they might be important agents in the onset of diabetic nephropathy. PMID:22435020

  4. An Association Analysis of Murine Anxiety Genes in Humans Implicates Novel Candidate Genes for Anxiety Disorders

    PubMed Central

    Donner, Jonas; Pirkola, Sami; Silander, Kaisa; Kananen, Laura; Terwilliger, Joseph D.; Lönnqvist, Jouko; Peltonen, Leena; Hovatta, Iiris

    2008-01-01

    Background Human anxiety disorders are complex diseases with largely unknown etiology. We have taken a cross-species approach to identify genes that regulate anxiety-like behavior with inbred mouse strains that differ in their innate anxiety levels as a model. We previously identified 17 genes with expression levels that correlate with anxiety behavior across the studied strains. In the present study, we tested their 13 known human homologues as candidate genes for human anxiety disorders with a genetic association study. Methods We describe an anxiety disorder study sample derived from a Finnish population-based cohort and consisting of 321 patients and 653 carefully matched control subjects, all interviewed to obtain DSM-IV diagnoses. We genotyped altogether 208 single nucleotide polymorphisms (SNPs) (all non-synonymous SNPs, SNPs that alter potential microRNA binding sites, and gap-filling SNPs selected on the basis of HapMap information) from the investigated anxiety candidate genes. Results Specific alleles and haplotypes of six of the examined genes revealed some evidence for association (p ≤ .01). The most significant evidence for association with different anxiety disorder subtypes were: p = .0009 with ALAD (δ-aminolevulinate dehydratase) in social phobia, p = .009 with DYNLL2 (dynein light chain 2) in generalized anxiety disorder, and p = .004 with PSAP (prosaposin) in panic disorder. Conclusions Our findings suggest that variants in these genes might predispose to specific human anxiety disorders. These results illustrate the potential utility of cross-species approaches in identification of candidate genes for psychiatric disorders. PMID:18639233

  5. Analysis of the VAV3 as candidate gene for schizophrenia: evidences from voxel-based morphometry and mutation screening.

    PubMed

    Aleksic, Branko; Kushima, Itaru; Hashimoto, Ryota; Ohi, Kazutaka; Ikeda, Masashi; Yoshimi, Akira; Nakamura, Yukako; Ito, Yoshihito; Okochi, Tomo; Fukuo, Yasuhisa; Yasuda, Yuka; Fukumoto, Motoyuki; Yamamori, Hidenaga; Ujike, Hiroshi; Suzuki, Michio; Inada, Toshiya; Takeda, Masatoshi; Kaibuchi, Kozo; Iwata, Nakao; Ozaki, Norio

    2013-05-01

    In recently completed Japanese genome-wide association studies (GWAS) of schizophrenia (JPN_GWAS) one of the top association signals was detected in the region of VAV3, a gene that maps to the chromosome 1p13.3. In order to complement JPN_GWAS findings, we tested the association of rs1410403 with brain structure in healthy individuals and schizophrenic patients and performed exon resequencing of VAV3. We performed voxel-based morphometry (VBM) and mutation screening of VAV3. Four independent samples were used in the present study: (1) for VBM analysis, we used case-control sample comprising 100 patients with schizophrenia and 264 healthy controls, (2) mutation analysis was performed on a total of 321 patients suffering from schizophrenia, and 2 case-control samples (3) 729 unrelated patients with schizophrenia and 564 healthy comparison subjects, and (4) sample comprising 1511 cases and 1517 healthy comparison subjects and were used for genetic association analysis of novel coding variants with schizophrenia. The VBM analysis suggests that rs1410403 might affect the volume of the left superior and middle temporal gyri (P=.011 and P=.013, respectively), which were reduced in patients with schizophrenia compared with healthy subjects. Moreover, 4 rare novel missense variants were detected. The mutations were followed-up in large independent sample, and one of the novel variants (Glu741Gly) was associated with schizophrenia (P=.02). These findings demonstrate that VAV3 can be seen as novel candidate gene for schizophrenia in which both rare and common variants may be related to increased genetic risk for schizophrenia in Japanese population.

  6. 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.

  7. 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

  8. Genetic association analysis using weighted false discovery rate approach on Genetic Analysis Workshop 18 data.

    PubMed

    Qiu, Xin; Shen, Xiaowei; Espin-Garcia, Osvaldo; Azad, Abul Kalam; Liu, Geoffrey; Xu, Wei

    2014-01-01

    In a genome-wide association study, association between disease trait and hundreds of thousands of genetic markers are tested. Several methods have been proposed to control the false discovery rate in such high-throughput data to adjust for multiple hypotheses testing. For Genetic Analysis Workshop 18, we applied the method of false discovery rate control with p value weighting on family-based association tests on quantitative trait to detect association between single-nucleotide polymorphisms (SNPs) and mean arterial pressure. This method can improve statistical power by incorporating independent but relevant information about the research objective. Using the real genetic and phenotype data of chromosome 3 from Genetic Analysis Workshop 18, 1 SNP from gene CACNA2D3 was found to have significant association with mean arterial pressure.

  9. 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.

  10. 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

  11. 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

  12. Murine candidate bleomycin induced pulmonary fibrosis susceptibility genes identified by gene expression and sequence analysis of linkage regions

    PubMed Central

    Haston, C; Tomko, T; Godin, N; Kerckhoff, L; Hallett, M

    2005-01-01

    Background: Pulmonary fibrosis is a complex disease for which the predisposing genetic variants remain unknown. In a prior study, susceptibility to bleomycin induced pulmonary fibrosis was mapped to loci Blmpf1 and Blmpf2 on chromosomes 17 and 11, respectively, in a C57BL/6J (B6, susceptible) and C3Hf/KAM (C3H, resistant) mouse cross. Methods: Herein, the genetic basis of bleomycin induced pulmonary fibrosis was investigated in an approach combining gene expression and sequencing data with previously mapped linkage intervals. Results: In this study, gene expression analysis with microarrays revealed 1892 genes or ESTs (expressed sequence tags) to be differentially expressed between bleomycin treated B6 and C3H mice and 67 of these genetic elements map to Blmpf1 or Blmpf2. This group included genes involved in an oxidative stress response, in apoptosis, and in immune regulation. A comparison of the B6 and C3H sequence, for Blmpf1 and Blmpf2, made using the NCBI database and available C3H sequence, revealed approximately 35% of the genes in these regions contain non-synonymous coding sequence changes. An assessment of genotype/phenotype correlation among other inbred strains revealed 36% of these B6/C3H sequence variations predict for the known bleomycin induced fibrosis susceptibility of the DBA (susceptible) and A/J (resistant) mouse strains. Conclusions: Combining genomics approaches of differential gene expression and sequence variation potentially identifies approximately 5% the linked genes as fibrosis susceptibility candidate genes in this mouse cross. PMID:15937080

  13. 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

  14. High-density polymorphisms analysis of 23 candidate genes for association with bone mineral density.

    PubMed

    Giroux, Sylvie; Elfassihi, Latifa; Clément, Valérie; Bussières, Johanne; Bureau, Alexandre; Cole, David E C; Rousseau, François

    2010-11-01

    Osteoporosis is a bone disease characterized by low bone mineral density (BMD), a highly heritable and polygenic trait. Women are more prone than men to develop osteoporosis due to a lower peak bone mass and accelerated bone loss at menopause. Peak bone mass has been convincingly shown to be due to genetic factors with heritability up to 80%. Menopausal bone loss has been shown to have around 38% to 49% heritability depending on the site studied. To have more statistical power to detect small genetic effects we focused on premenopausal women. We studied 23 candidate genes, some involved in calcium and vitamin-D regulation and others because estrogens strongly induced their gene expression in mice where it was correlated with humerus trabecular bone density. High-density polymorphisms were selected to cover the entire gene variability and 231 polymorphisms were genotyped in a first sample of 709 premenopausal women. Positive associations were retested in a second, independent, sample of 673 premenopausal women. Ten polymorphisms remained associated with BMD in the combined samples and one was further associated in a large sample of postmenopausal women (1401 women). This associated polymorphism was located in the gene CSF3R (granulocyte colony stimulating factor receptor) that had never been associated with BMD before. The results reported in this study suggest a role for CSF3R in the determination of bone density in women.

  15. Association analysis of GWAS and candidate gene loci in a Chinese population with coronary heart disease

    PubMed Central

    Gao, Min; Tang, Haiqin; Zheng, Xiaodong; Zhou, Fusheng; Lu, Wensheng

    2015-01-01

    Objective: Coronary heart disease (CHD), the most severe form of coronary artery disease (CAD), is a complex disease that involves a variety of genetic and environmental factors. Recently, multiple single nucleotide polymorphisms (SNPs) have been associated with CAD in Caucasians by genome-wide association (GWA) studies.However, the association of these SNPs with CHD in Asian populations has not yet been established. Here, we aim to investigate the genetic etiology of CHD in a Chinese population by genotyping SNPs previously been associated with CHD in other ethic origin in GWAS or candidate gene studies. Methods: Five SNPs, rs17114036, rs9369640, rs515135, rs579459 and rs8055236, from 5 different loci were genotyped using a sequenom Mass array system in 545CHD patients and 1008 unrelated controls from a Chinese population. Results: Our study showed that SNP rs515135 is strongly associated with CHD in a Chinese Han population (P-value=0.00333, OR=1.48). We also detected significant difference of SNP rs579459 in APOB gene in patients withsevere CAD compared to patients with mild CAD. Conclusion: SNP rs515135 is associated with the susceptibility of CHD in Chinese Han population. The location of rs515135 in the APOB gene supports its potential involvement in the pathogenesis of CAD. Our study data also support that SNP rs579459 may be associated with the severity of CHD. PMID:26221293

  16. Hereditary hemochromatosis: HFE mutation analysis in Greeks reveals genetic heterogeneity.

    PubMed

    Papanikolaou, G; Politou, M; Terpos, E; Fourlemadis, S; Sakellaropoulos, N; Loukopoulos, D

    2000-04-01

    Hereditary hemochromatosis (HH) is common among Caucasians; reported disease frequencies vary from 0.3 to 0.8%. Identification of a candidate HFE gene in 1996 was soon followed by the description of two ancestral mutations, i.e., c.845G-->A (C282Y) and c.187C-->G (H63D). To these was recently added the mutation S65C, which may represent a simple polymorphism. The incidence of HH in Greece is unknown but clinical cases are rare. Also unknown is the carrier frequency of the two mutant alleles. A first estimate of the latter is given in the present report. It is based on data from the genetic analysis of 10 unrelated patients of Greek origin who were referred to our center for genotyping and 158 unselected male blood donors. The allele frequencies for the C282Y and H63D mutations were 0.003 and 0.145, respectively. The C282Y allele was detected in 50% of HH patients. This is considerably lower than the frequencies reported for HH patients in the U.S.A. (82%) and France (91 %) and closer to that reported in Italy (64%). Five patients did not carry any known HFE mutation; three may represent cases of juvenile hemochromatosis, given their early onset with iron overload, hypogonadism, and heart disease. We suggest that genetic heterogeneity is more prominent in Southern Europe. It is also possible that the penetrance of the responsible genes is different across the Mediterranean.

  17. Quantitative genetic analysis of flowering time in tomato.

    PubMed

    Jiménez-Gómez, José M; Alonso-Blanco, Carlos; Borja, Alicia; Anastasio, Germán; Angosto, Trinidad; Lozano, Rafael; Martínez-Zapater, José M

    2007-03-01

    Artificial selection of cultivated tomato (Solanum lycopersicum L.) has resulted in the generation of early-flowering, day-length-insensitive cultivars, despite its close relationship to other Solanum species that need more time and specific photoperiods to flower. To investigate the genetic mechanisms controlling flowering time in tomato and related species, we performed a quantitative trait locus (QTL) analysis for flowering time in an F2 mapping population derived from S. lycopersicum and its late-flowering wild relative S. chmielewskii. Flowering time was scored as the number of days from sowing to the opening of the first flower (days to flowering), and as the number of leaves under the first inflorescence (leaf number). QTL analyses detected 2 QTLs affecting days to flowering, which explained 55.3% of the total phenotypic variance, and 6 QTLs for leaf number, accounting for 66.7% of the corresponding phenotypic variance. Four of the leaf number QTLs had not previously been detected for this trait in tomato. Colocation of some QTLs with flowering-time genes included in the genetic map suggests PHYB2, FALSIFLORA, and a tomato FLC-like sequence as candidate genes that might have been targets of selection during the domestication of tomato.

  18. 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

  19. 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.

  20. 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

  1. Role of Salivary and Candidal Proteins in Denture Stomatitis; an exploratory proteomic analysis

    PubMed Central

    Byrd, Warren C.; Schwartz-Baxter, Sarah; Carlson, Jim; Barros, Silvana; Offenbacher, Steven; Bencharit, Sompop

    2014-01-01

    Denture stomatitis, inflammation and redness beneath a denture, affects nearly half of all denture wearers. Candida organism, the presence of a denture, saliva, and host immunity are the key etiological factors for the condition. The role of salivary proteins in denture stomatitis is not clear. In this study 30 edentulous subjects wearing a maxillary complete denture were recruited. Unstimulated whole saliva from each subject was collected and pooled into two groups (n=15 each); healthy and stomatitis (Newton classification II and III). Label-free multidimensional liquid chromatography/tandem mass spectrometry (2D-LC-MS/MS) proteomics on two mass spectrometry platforms were used to determine peptide mass differences between control and stomatitis groups. Cluster analysis and principal component analysis were used to determine differential expression among the groups. The two proteomic platforms identified 97 and 176 proteins (ANOVA; p<0.01) differentially expressed among the healthy, type 2 and 3 stomatitis groups. Three proteins including carbonic anhydrase 6, cystatin C, and cystatin SN were found to be the same as previous study. Salivary proteomic profiles of patients with denture stomatitis were found to be uniquely different from controls. Analysis of protein components suggests that certain salivary proteins may predispose some patients to denture stomatitis while others are believed to be involved in the reaction to fungal infection. Analysis of candidal proteins suggest that multiple species of candidal organisms play a role in denture stomatitis. PMID:24947908

  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. Fine Mapping of a Dravet Syndrome Modifier Locus on Mouse Chromosome 5 and Candidate Gene Analysis by RNA-Seq

    PubMed Central

    Hawkins, Nicole A.; Zachwieja, Nicole J.; Miller, Alison R.; Anderson, Lyndsey L.; Kearney, Jennifer A.

    2016-01-01

    A substantial number of mutations have been identified in voltage-gated sodium channel genes that result in various forms of human epilepsy. SCN1A mutations result in a spectrum of severity ranging from mild febrile seizures to Dravet syndrome, an infant-onset epileptic encephalopathy. Dravet syndrome patients experience multiple seizures types that are often refractory to treatment, developmental delays, and elevated risk for SUDEP. The same sodium channel mutation can produce epilepsy phenotypes of varying clinical severity. This suggests that other factors, including genetic, modify the primary mutation and change disease severity. Mouse models provide a useful tool in studying the genetic basis of epilepsy. The mouse strain background can alter phenotype severity, supporting a contribution of genetic modifiers in epilepsy. The Scn1a+/- mouse model has a strain-dependent epilepsy phenotype. Scn1a+/- mice on the 129S6/SvEvTac (129) strain have a normal phenotype and lifespan, while [129xC57BL/6J]F1-Scn1a+/- mice experience spontaneous seizures, hyperthermia-induced seizures and high rates of premature death. We hypothesize the phenotypic differences are due to strain-specific genetic modifiers that influence expressivity of the Scn1a+/- phenotype. Low resolution mapping of Scn1a+/- identified several Dravet syndrome modifier (Dsm) loci responsible for the strain-dependent difference in survival. One locus of interest, Dsm1 located on chromosome 5, was fine mapped to a 9 Mb region using interval specific congenics. RNA-Seq was then utilized to identify candidate modifier genes within this narrowed region. Three genes with significant total gene expression differences between 129S6/SvEvTac and [129xC57BL/6J]F1 were identified, including the GABAA receptor subunit, Gabra2. Further analysis of Gabra2 demonstrated allele-specific expression. Pharmological manipulation by clobazam, a common anticonvulsant with preferential affinity for the GABRA2 receptor, revealed

  4. A Genetic Analysis of Mortality in Pigs

    PubMed Central

    Varona, Luis; Sorensen, Daniel

    2010-01-01

    An analysis of mortality is undertaken in two breeds of pigs: Danish Landrace and Yorkshire. Zero-inflated and standard versions of hierarchical Poisson, binomial, and negative binomial Bayesian models were fitted using Markov chain Monte Carlo (MCMC). The objectives of the study were to investigate whether there is support for genetic variation for mortality and to study the quality of fit and predictive properties of the various models. In both breeds, the model that provided the best fit to the data was the standard binomial hierarchical model. The model that performed best in terms of the ability to predict the distribution of stillbirths was the hierarchical zero-inflated negative binomial model. The best fit of the binomial hierarchical model and of the zero-inflated hierarchical negative binomial model was obtained when genetic variation was included as a parameter. For the hierarchical binomial model, the estimate of the posterior mean of the additive genetic variance (posterior standard deviation in brackets) at the level of the logit of the probability of a stillbirth was 0.173(0.039) in Landrace and 0.202(0.048) in Yorkshire. The implications of these results from a breeding perspective are briefly discussed. PMID:19901070

  5. 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

  6. Processability analysis of candidate waste forms. [For SRP high-level wastes

    SciTech Connect

    Gould, Jr, T H; Dunson, Jr, J B; Eisenberg, A M; Haight, Jr, H G; Mello, V E; Schuyler, III, R L

    1982-01-01

    A quantitative merit evaluation, or processability analysis, was performed to assess the relative difficulty of remote processing of Savannah River Plant high-level wastes for seven alternative waste form candidates. The reference borosilicate glass process was rated as the simplest, followed by FUETAP concrete, glass marbles in a lead matrix, high-silica glass, crystalline ceramics (SYNROC-D and tailored ceramics), and coated ceramic particles. Cost estimates for the borosilicate glass, high-silica glass, and ceramic waste form processing facilities are also reported.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Identification of Candidate Genes for Histiocytoid Cardiomyopathy (HC) Using Whole Genome Expression Analysis: Analyzing Material from the HC Registry

    PubMed Central

    Shehata, Bahig M.; Bouzyk, Mark; Tang, Weining; Steelman, Charlotte K.; Moreno, Carlos S.

    2012-01-01

    BACKGROUND Histiocytoid cardiomyopathy (HC) is a rare but distinctive arrhythmogenic disorder characterized by incessant ventricular tachycardia, cardiomegaly, and often sudden death by age 2 years. The underlying genetic mechanism of HC has eluded researchers for decades. To reveal the molecular-genetic basis of HC, molecular analyses of HC hearts and hearts of age-matched controls were performed. METHODS Total RNA and genomic DNA were prepared from formalin-fixed paraffin-embedded cardiac tissue from 12 cases of HC and 12 age-matched controls. To identify genes differentially expressed in HC, whole genome cDNA-mediated Annealing, Selection, extension and Ligation profiling was performed. TaqMan quantitative polymerase chain reaction confirmed changes in RNA expression. DNA copy number changes were measured by TaqMan copy number analysis. RESULTS Analysis of differential gene expression in HC cases identified two significantly down regulated gene sets aligned sequentially along the genome. The first gene cluster consisted of genes S100A8, S100A9, and S100A12 at 1q21.3c, and the second cluster consisted of genes IL1RL1 (ST2), IL18R1, and IL18RAP at 2q12.1a. Strong decreases in interleukin 33 expression were also observed. Decreases in copy number of the S100A genes were confirmed by TaqMan CNV assays. S100A genes are downstream of the p38-MAPK pathway that can be activated by interleukin 33 signaling. CONCLUSIONS These data suggest a model in which the interleukin 33-IL1RL1/p38-MAPK/S100A8-S100A9 axis is down regulated in HC cardiac tissue and provide several candidate genes on 1q21.3c and 2q12.1a for inherited mutations that may predispose individuals to HC. PMID:21585276

  12. Combination of a Stressor-Response Model with a Conditional Probability Analysis Approach for Developing Candidate Criteria from MBSS

    EPA Science Inventory

    I show that a conditional probability analysis using a stressor-response model based on a logistic regression provides a useful approach for developing candidate water quality criteria from empirical data, such as the Maryland Biological Streams Survey (MBSS) data.

  13. 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

  14. A 45-year followup study of breast and other cancers in kindred 107 and linkage analysis of candidate loci

    SciTech Connect

    Goldgar, D.E.; Neuhausen, S.L.; Ward, J.H.

    1994-09-01

    One of the earliest large kindreds with inherited susceptibility to breast cancer was reported by Gardner and Stephens in 1950. This family, denoted K107, was ascertained in 1947 by a genetics student with two great aunts who died of breast cancer in their 40`s. Subsequent clinical and genealogical follow-up identified 7 additional cases of early-onset breast cancer. The family was updated several times, most notably in 1980. For the present study K107 was recently reinvestigated and over 75 blood samples gathered for genotyping. The kindred now contains 38 cases of female breast cancer, 3 cases of male breast cancer, and 6 cases of ovarian cancer, 18 of which have been identified since the 1980 report. Examination of the obligate carriers demonstrates that that gene responsible for the breast and ovarian cancer in K107 is highly penetrant. Other cancers appear to be associated with expression of this gene, most notably prostate cancer, melanoma, and uterine cancer. Linkage to the BRCA1 region in K107 was excluded based upon the analysis of genotypings at four loci covering the BRCA1 gene on chromosome 17q has been excluded in this family, using four highly polymorphic markers in the BRCA1 region (multipoint LOD score -3.27). Eight other candidate breast cancer susceptibility genes and candidate regions, including p53 and ESR have also been tested for linkage and excluded. Studies to formally re-estimate penetrance and test for excesses of all cancer sites and a genomic search in this family are in progress.

  15. 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.

  16. 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.

  17. Transcriptome analysis reveals candidate genes involved in luciferin metabolism in Luciola aquatilis (Coleoptera: Lampyridae)

    PubMed Central

    Vongsangnak, Wanwipa; Chumnanpuen, Pramote

    2016-01-01

    Bioluminescence, which living organisms such as fireflies emit light, has been studied extensively for over half a century. This intriguing reaction, having its origins in nature where glowing insects can signal things such as attraction or defense, is now widely used in biotechnology with applications of bioluminescence and chemiluminescence. Luciferase, a key enzyme in this reaction, has been well characterized; however, the enzymes involved in the biosynthetic pathway of its substrate, luciferin, remains unsolved at present. To elucidate the luciferin metabolism, we performed a de novo transcriptome analysis using larvae of the firefly species, Luciola aquatilis. Here, a comparative analysis is performed with the model coleopteran insect Tribolium casteneum to elucidate the metabolic pathways in L. aquatilis. Based on a template luciferin biosynthetic pathway, combined with a range of protein and pathway databases, and various prediction tools for functional annotation, the candidate genes, enzymes, and biochemical reactions involved in luciferin metabolism are proposed for L. aquatilis. The candidate gene expression is validated in the adult L. aquatilis using reverse transcription PCR (RT-PCR). This study provides useful information on the bio-production of luciferin in the firefly and will benefit to future applications of the valuable firefly bioluminescence system. PMID:27761329

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. Limited potential for mosquito transmission of genetically engineered, live-attenuated western equine encephalitis virus vaccine candidates.

    PubMed

    Turell, Michael J; O'Guinn, Monica L; Parker, Michael D

    2003-02-01

    Specific mutations associated with attenuation of Venezuelan equine encephalitis (VEE) virus in rodent models were identified during efforts to develop an improved VEE vaccine. Analogous mutations were produced in full-length cDNA clones of the Cba 87 strain of western equine encephalitis (WEE) virus by site-directed mutagenesis in an attempt to develop an improved WEE vaccine. Isogenic viral strains with these mutations were recovered after transfection of baby hamster kidney cells with infectious RNA. We evaluated two of these strains (WE2102 and WE2130) for their ability to replicate in and be transmitted by Culex tarsalis, the principal natural vector of WEE virus in the United States. Each of the vaccine candidates contained a deletion of the PE2 furin cleavage site and a secondary mutation in the E1 or E2 glycoprotein. Both of these potential candidates replicated in mosquitoes significantly less efficiently than did either wild-type WEE (Cba 87) virus or the parental clone (WE2000). Likewise, after intrathoracic inoculation, mosquitoes transmitted the vaccine candidate strains significantly less efficiently than they transmitted either the wild-type or the parental clone. One-day-old chickens vaccinated with either of the two vaccine candidates did not become viremic when challenged with virulent WEE virus two weeks later. Mutations that result in less efficient replication in or transmission by mosquitoes should enhance vaccine safety and reduce the possibility of accidental introduction of the vaccine strain to unintentional hosts.

  3. Multiplexed Genetic Analysis Using an Expanded Genetic Alphabet

    PubMed Central

    Johnson, Scott C.; Marshall, David J.; Harms, Gerda; Miller, Christie M.; Sherrill, Christopher B.; Beaty, Edward L.; Lederer, Scott A.; Roesch, Eric B.; Madsen, Gary; Hoffman, Gary L.; Laessig, Ronald H.; Kopish, Greg J.; Baker, Mei Wang; Benner, Steven A.; Farrell, Philip M.; Prudent, James R.

    2006-01-01

    Background All states require some kind of testing for newborns, but the policies are far from standardized. In some states, newborn screening may include genetic tests for a wide range of targets, but the costs and complexities of the newer genetic tests inhibit expansion of newborn screening. We describe the development and technical evaluation of a multiplex platform that may foster increased newborn genetic screening. Methods MultiCode® PLx involves three major steps: PCR, target-specific extension, and liquid chip decoding. Each step is performed in the same reaction vessel, and the test is completed in ~3 h. For site-specific labeling and room-temperature decoding, we use an additional base pair constructed from isoguanosine and isocytidine. We used the method to test for mutations within the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The developed test was performed manually and by automated liquid handling. Initially, 225 samples with a range of genotypes were tested retrospectively with the method. A prospective study used samples from >400 newborns. Results In the retrospective study, 99.1% of samples were correctly genotyped with no incorrect calls made. In the perspective study, 95% of the samples were correctly genotyped for all targets, and there were no incorrect calls. Conclusions The unique genetic multiplexing platform was successfully able to test for 31 targets within the CFTR gene and provides accurate genotype assignments in a clinical setting. PMID:15319316

  4. 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.

  5. 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

  6. Gene expression profile analysis of testis and ovary of oriental river prawn, Macrobrachium nipponense, reveals candidate reproduction-related genes.

    PubMed

    Qiao, H; Xiong, Y W; Jiang, S F; Fu, H T; Sun, S M; Jin, S B; Gong, Y S; Zhang, W Y

    2015-01-01

    This study utilized high-throughput RNA sequencing technology to identify reproduction- and development-related genes of Macrobrachium nipponense by analyzing gene expression profiles of testis and ovary. More than 20 million 1 x 51-bp reads were obtained by Illumina sequencing, generating more than 7.7 and 11.7 million clean reads in the testis and ovary library, respectively. As a result, 10,018 unitags were supposed to be differentially expressed genes (DEGs) between ovary and testis. Compared to the ovary library, 4563 (45.5%) of these DEGs exhibited at least 6-fold upregulated expression, while 5455 (54.5%) DEGs exhibited at least 2-fold downregulated expression in the testis. The Gene Ontology (GO) enrichment analysis showed that 113 GO terms had potential molecular functions in reproduction. The Kyoto Encyclopedia of Genes and Genomes results revealed that the most important pathways may be relevant to reproduction and included 7 pathways. Forty-two genes were identified as reproduction-, development-, and sex-related genes based on GO classification and sequence comparison with other publications, including male reproductive-related LIM protein, spermatogenesis-associated protein, gametocyte-specific factor 1, VASA-like protein, vitellogenin, sex-determining protein fem-1, and other potential candidates. These results will advance research in the field of molecular genetics in M. nipponense and offer a valuable resource for further research related to reproduction in crustaceans. PMID:25867350

  7. Gene expression profile analysis of testis and ovary of oriental river prawn, Macrobrachium nipponense, reveals candidate reproduction-related genes.

    PubMed

    Qiao, H; Xiong, Y W; Jiang, S F; Fu, H T; Sun, S M; Jin, S B; Gong, Y S; Zhang, W Y

    2015-03-20

    This study utilized high-throughput RNA sequencing technology to identify reproduction- and development-related genes of Macrobrachium nipponense by analyzing gene expression profiles of testis and ovary. More than 20 million 1 x 51-bp reads were obtained by Illumina sequencing, generating more than 7.7 and 11.7 million clean reads in the testis and ovary library, respectively. As a result, 10,018 unitags were supposed to be differentially expressed genes (DEGs) between ovary and testis. Compared to the ovary library, 4563 (45.5%) of these DEGs exhibited at least 6-fold upregulated expression, while 5455 (54.5%) DEGs exhibited at least 2-fold downregulated expression in the testis. The Gene Ontology (GO) enrichment analysis showed that 113 GO terms had potential molecular functions in reproduction. The Kyoto Encyclopedia of Genes and Genomes results revealed that the most important pathways may be relevant to reproduction and included 7 pathways. Forty-two genes were identified as reproduction-, development-, and sex-related genes based on GO classification and sequence comparison with other publications, including male reproductive-related LIM protein, spermatogenesis-associated protein, gametocyte-specific factor 1, VASA-like protein, vitellogenin, sex-determining protein fem-1, and other potential candidates. These results will advance research in the field of molecular genetics in M. nipponense and offer a valuable resource for further research related to reproduction in crustaceans.

  8. 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…

  9. In silico analysis for identifying potential vaccine candidates against Staphylococcus aureus

    PubMed Central

    Sedighian, Hamid

    2015-01-01

    Purpose Staphylococcus aureus is one of the most important causes of nosocomial and community-acquired infections. The increasing incidence of multiple antibiotic-resistant S. aureus strains and the emergence of vancomycin resistant S. aureus strains have placed renewed interest on alternative means of prevention and control of infection. S. aureus produces a variety of virulence factors, so a multi-subunit vaccine will be more successful for preventing S. aureus infections than a mono-subunit vaccine. Materials and Methods We selected three important virulence factors of S. aureus, clumping factor A (ClfA), iron-regulated surface determinant (IsdB), and gamma hemolysin (Hlg) that are potential candidates for vaccine development. We designed synthetic genes encoding the clfA, isdB, and hlg and used bioinformatics tools to predict structure of the synthetic construct and its stabilities. VaxiJen analysis of the protein showed a high antigenicity. Linear and conformational B-cell epitopes were identified. Results The proteins encoded by these genes were useful as vaccine candidates against S. aureus infections. Conclusion In silico tools are highly suited to study, design, and evaluate vaccine strategies. PMID:25649548

  10. Analysis of the QTL for sleep homeostasis in mice: Homer1a is a likely candidate.

    PubMed

    Mackiewicz, M; Paigen, B; Naidoo, N; Pack, A I

    2008-03-14

    Electroencephalographic oscillations in the frequency range of 0.5-4 Hz, characteristic of slow-wave sleep (SWS), are often referred to as the delta oscillation or delta power. Delta power reflects sleep intensity and correlates with the homeostatic response to sleep loss. A published survey of inbred strains of mice demonstrated that the time course of accumulation of delta power varied among inbred strains, and the segregation of the rebound of delta power in BxD recombinant inbred strains identified a genomic region on chromosome 13 referred to as the delta power in SWS (or Dps1). The quantitative trait locus (QTL) contains genes that modify the accumulation of delta power after sleep deprivation. Here, we narrow the QTL using interval-specific haplotype analysis and present a comprehensive annotation of the remaining genes in the Dps1 region with sequence comparisons to identify polymorphisms within the coding and regulatory regions. We established the expression pattern of selected genes located in the Dps1 interval in sleep and wakefulness in B6 and D2 parental strains. Taken together, these steps reduced the number of potential candidate genes that may underlie the accumulation of delta power after sleep deprivation and explain the Dps1 QTL. The strongest candidate gene is Homer1a, which is supported by expression differences between sleep and wakefulness and the SNP polymorphism in the upstream regulatory regions.

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

    PubMed Central

    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

  12. 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.

  13. Identification of drug candidate for osteoporosis by computational bioinformatics analysis of gene expression profile

    PubMed Central

    2013-01-01

    Background Osteoporosis is a condition of bones that leads to an increased susceptibility to fracture and consequent painful morbidity. It has become a major issue of life quality worldwide. However, until now, the molecular mechanism of this disease is far from being clear. Methods In this study, we obtained the gene expression profile of osteoporosis and controls from Gene Expression Omnibus and identified differentially expressed genes (DEGs) using classical t-test method. Then, functional enrichment analyses were performed to identify the dysregulated Gene Ontology categories and dysfunctional pathways in osteoporosis patients compared to controls. Besides, the connectivity map was used to identify compounds that induced inverse gene changes to osteoporosis. Results A total of 5581 DEGs were identified. We found these DEGs were enriched in 9 pathways by pathway enrichment analysis, including focal adhesion and MAPK signaling pathway. Besides, sanguinarine was identified as a potential therapeutic drug candidate capable of targeting osteoporosis. Conclusion Although candidate agents identified by our approach may be premature for clinical trials, it is clearly a direction that warrants additional consideration. PMID:23448234

  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. Addictions Biology: Haplotype-Based Analysis for 130 Candidate Genes on a Single Array

    PubMed Central

    Hodgkinson, Colin A.; Yuan, Qiaoping; Xu, Ke; Shen, Pei-Hong; Heinz, Elizabeth; Lobos, Elizabeth A.; Binder, Elizabeth B.; Cubells, Joe; Ehlers, Cindy L.; Gelernter, Joel; Mann, John; Riley, Brien; Roy, Alec; Tabakoff, Boris; Todd, Richard D.; Zhou, Zhifeng; Goldman, David

    2008-01-01

    Aims: To develop a panel of markers able to extract full haplotype information for candidate genes in alcoholism, other addictions and disorders of mood and anxiety. Methods: A total of 130 genes were haplotype tagged and genotyped in 7 case/control populations and 51 reference populations using Illumina GoldenGate SNP genotyping technology, determining haplotype coverage. We also constructed and determined the efficacy of a panel of 186 ancestry informative markers. Results: An average of 1465 loci were genotyped at an average completion rate of 91.3%, with an average call rate of 98.3% and replication rate of 99.7%. Completion and call rates were lowered by the performance of two datasets, highlighting the importance of the DNA quality in high throughput assays. A comparison of haplotypes captured by the Addictions Array tagging SNPs and commercially available whole-genome arrays from Illumina and Affymetrix shows comparable performance of the tag SNPs to the best whole-genome array in all populations for which data are available. Conclusions: Arrays of haplotype-tagged candidate genes, such as this addictions-focused array, represent a cost-effective approach to generate high-quality SNP genotyping data useful for the haplotype-based analysis of panels of genes such as these 130 genes of interest to alcohol and addictions researchers. The inclusion of the 186 ancestry informative markers allows for the detection and correction for admixture and further enhances the utility of the array. PMID:18477577

  16. Identification of candidate susceptibility genes for colorectal cancer through eQTL analysis

    PubMed Central

    Closa, Adria; Cordero, David; Sanz-Pamplona, Rebeca; Solé, Xavier; Crous-Bou, Marta; Paré-Brunet, Laia; Berenguer, Antoni; Guino, Elisabet; Lopez-Doriga, Adriana; Guardiola, Jordi; Biondo, Sebastiano; Salazar, Ramon; Moreno, Victor

    2014-01-01

    In this study, we aim to identify the genes responsible for colorectal cancer risk behind the loci identified in genome-wide association studies (GWAS). These genes may be candidate targets for developing new strategies for prevention or therapy. We analyzed the association of genotypes for 26 GWAS single nucleotide polymorphisms (SNPs) with the expression of genes within a 2 Mb region (cis-eQTLs). Affymetrix Human Genome U219 expression arrays were used to assess gene expression in two series of samples, one of healthy colonic mucosa (n = 47) and other of normal mucosa adjacent to colon cancer (n = 97, total 144). Paired tumor tissues (n = 97) were also analyzed but did not provide additional findings. Partial Pearson correlation (r), adjusted for sample type, was used for the analysis. We have found Bonferroni-significant cis-eQTLs in three loci: rs3802842 in 11q23.1 associated to C11orf53, COLCA1 (C11orf92) and COLCA2 (C11orf93; r = 0.60); rs7136702 in 12q13.12 associated to DIP2B (r = 0.63) and rs5934683 in Xp22.3 associated to SHROOM2 and GPR143 (r = 0.47). For loci in chromosomes 11 and 12, we have found other SNPs in linkage disequilibrium that are more strongly associated with the expression of the identified genes and are better functional candidates: rs7130173 for 11q23.1 (r = 0.66) and rs61927768 for 12q13.12 (r = 0.86). These SNPs are located in DNA regions that may harbor enhancers or transcription factor binding sites. The analysis of trans-eQTLs has identified additional genes in these loci that may have common regulatory mechanisms as shown by the analysis of protein–protein interaction networks. PMID:24760461

  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. Expression analysis, single nucleotide polymorphisms and combined genotypes in candidate genes and their associations with growth and carcass traits in Qinchuan cattle.

    PubMed

    Wang, Li-jun; Liu, Xiao-lin; Wang, Hong-liang; He, Hua; Li, Zhi-xiong; Chen, Ling

    2013-03-01

    The apolipoprotein E (ApoE) gene is an important component of plasma lipoprotein, and Fas apoptosis inhibitory molecule (FAIM) is a novel anti-apoptotic gene. In this study, we researched and discussed seven genes in eight different tissues in Qinchuan cattle by quantitative Real-time PCR. The result of analysis showed that ApoE and FAIM 2 genes had a correlation with muscle and fat. PCR-RFLP was applied to analyze the genetic variations of the ApoE and FAIM 2 genes and verify the effect on growth and carcass traits in a total of 365 Qinchuan cattles. The result of haplotype analysis showed that nine different haplotypes were identified among the four SNPs in ApoE and FAIM 2 genes. The statistical analyses indicated that the four SNPs were significant association with growth and carcass traits (P < 0.05, N = 365); and the four SNPs were significant association between nine combined genotypes of candidate genes and growth and carcass traits. Taken together, our results provide the evidence that polymorphisms in candidate genes are associated with growth and carcass traits in Qinchuan cattle, and may be used as a possible candidate for marker-assisted selection and management in beef cattle breeding program.

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

    PubMed

    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

    2016-07-01

    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

  20. 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

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

    PubMed

    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

    2016-07-01

    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.

  2. 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.

  3. 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.

  4. 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.

  5. Systematic exploration of a class of hydrophobic unnatural base pairs yields multiple new candidates for the expansion of the genetic alphabet.

    PubMed

    Dhami, Kirandeep; Malyshev, Denis A; Ordoukhanian, Phillip; Kubelka, Tomáš; Hocek, Michal; Romesberg, Floyd E

    2014-01-01

    We have developed a family of unnatural base pairs (UBPs), which rely on hydrophobic and packing interactions for pairing and which are well replicated and transcribed. While the pair formed between d5SICS and dNaM (d5SICS-dNaM) has received the most attention, and has been used to expand the genetic alphabet of a living organism, recent efforts have identified dTPT3-dNaM, which is replicated with even higher fidelity. These efforts also resulted in more UBPs than could be independently analyzed, and thus we now report a PCR-based screen to identify the most promising. While we found that dTPT3-dNaM is generally the most promising UBP, we identified several others that are replicated nearly as well and significantly better than d5SICS-dNaM, and are thus viable candidates for the expansion of the genetic alphabet of a living organism. Moreover, the results suggest that continued optimization should be possible, and that the putatively essential hydrogen-bond acceptor at the position ortho to the glycosidic linkage may not be required. These results clearly demonstrate the generality of hydrophobic forces for the control of base pairing within DNA, provide a wealth of new structure-activity relationship data and importantly identify multiple new candidates for in vivo evaluation and further optimization.

  6. Systematic exploration of a class of hydrophobic unnatural base pairs yields multiple new candidates for the expansion of the genetic alphabet

    PubMed Central

    Dhami, Kirandeep; Malyshev, Denis A.; Ordoukhanian, Phillip; Kubelka, Tomáš; Hocek, Michal; Romesberg, Floyd E.

    2014-01-01

    We have developed a family of unnatural base pairs (UBPs), which rely on hydrophobic and packing interactions for pairing and which are well replicated and transcribed. While the pair formed between d5SICS and dNaM (d5SICS-dNaM) has received the most attention, and has been used to expand the genetic alphabet of a living organism, recent efforts have identified dTPT3-dNaM, which is replicated with even higher fidelity. These efforts also resulted in more UBPs than could be independently analyzed, and thus we now report a PCR-based screen to identify the most promising. While we found that dTPT3-dNaM is generally the most promising UBP, we identified several others that are replicated nearly as well and significantly better than d5SICS-dNaM, and are thus viable candidates for the expansion of the genetic alphabet of a living organism. Moreover, the results suggest that continued optimization should be possible, and that the putatively essential hydrogen-bond acceptor at the position ortho to the glycosidic linkage may not be required. These results clearly demonstrate the generality of hydrophobic forces for the control of base pairing within DNA, provide a wealth of new structure–activity relationship data and importantly identify multiple new candidates for in vivo evaluation and further optimization. PMID:25122747

  7. Analysis of functional abnormalities uncovered during preoperative evaluation of donor candidates for living-related liver transplantation.

    PubMed

    Morimoto, T; Awane, M; Tanaka, A; Ikai, I; Nakamura, Y; Yamamoto, Y; Takada, Y; Honda, K; Inamoto, T; Uemoto, S

    1995-02-01

    Functional abnormalities of the liver uncovered during preoperative routine evaluation were analyzed in 109 donor candidates for 100 cases of living-related liver transplantation (LRLT) performed during the period from June, 1990 to May, 1994 at the Second Department of Surgery, Kyoto University Hospital. High serum transaminase (GOT, GPT) levels were noted in 10 (9.2%) cases among 109 candidates, high alkaline phosphatase in 4 (3.7%), hyperbilirubinemia in 3 (2.8%), anemia in 3 and high choline esterase in 3 cases. Positive hepatitis C antibody (HCV) was also noted in 1 case. Fatty liver was detected in 10 (9.2%) cases, cholecystitis in 2 cases, 1 case each of cyst and calcification in the liver by diagnostic imaging (ultra sonograph and/or computed tomography). These abnormalities of the liver necessitated replacing the initial candidate with the other parent in 9 cases, including 1 case without any functional abnormality whose graft liver was too large to fit the recipient abdominal cavity. There were 14 cases of ABO blood type incompatible combination. Switching the initial candidate due to these abnormalities mentioned above resulted in incompatible combinations in 4 of these 14 cases. Although the advantages of the LRLT are the superior viability of the donor graft and the genetic histocompatibility between recipient and donor, to optimize the advantage of LRLT, all donor candidates should be strongly advised to make every effort preoperatively to improve their physical condition in preparation for the LRLT protocol, since many of these abnormalities are typically reversible.

  8. 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

  9. 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

  10. 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.

  11. Within-population genetic diversity of Plasmodium falciparum vaccine candidate antigens reveals geographic distance from a Central sub-Saharan African origin.

    PubMed

    Tanabe, Kazuyuki; Mita, Toshihiro; Palacpac, Nirianne M Q; Arisue, Nobuko; Tougan, Takahiro; Kawai, Satoru; Jombart, Thibaut; Kobayashi, Fumie; Horii, Toshihiro

    2013-02-18

    Populations of Plasmodium falciparum, the most virulent human malaria parasite, are diverse owing to wide levels of transmission and endemicity of infection. Genetic diversity of P. falciparum antigens, within and between parasite populations, remains a confounding factor in malaria pathogenesis as well as clinical trials of vaccine candidates. Variation of target antigens in parasite populations may arise from immune pressure depending on the levels of acquired immunity. Alternatively, similar to our study in housekeeping genes [Tanabe et al. Curr Biol 2010;70:1-7], within-population genetic diversity of vaccine candidate antigens may also be determined by geographical distance from a postulated origin in Central sub-Saharan Africa. To address this question, we obtained full-length sequences of P. falciparum genes, apical membrane antigen 1 (ama1) (n=459), circumsporozoite protein (csp) (n=472) and merozoite surface protein 1 (msp1) (n=389) from seven geographically diverse parasite populations in Africa, Southeast Asia and Oceania; and, together with previously determined sequences (n=13 and 15 for csp and msp1, respectively) analyzed within-population single nucleotide polymorphism (SNP) diversity. The three antigen genes showed SNP diversity that supports a model of isolation-by-distance. The standardized number of polymorphic sites per site, expressed as θ(S), indicates that 77-83% can be attributed by geographic distance from the African origin, suggesting that geographic distance plays a significant role in variation in target vaccine candidate antigens. Furthermore, we observed that a large proportion of SNPs in the antigen genes were shared between African and non-African parasite populations, demonstrating long term persistence of those SNPs. Our results provide important implications for developing effective malaria vaccines and better understanding of acquired immunity against falciparum malaria. PMID:23295064

  12. 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.

  13. Identification of novel candidate biomarkers of epithelial ovarian cancer by profiling the secretomes of three-dimensional genetic models of ovarian carcinogenesis.

    PubMed

    Lawrenson, Kate; Mhawech-Fauceglia, Paulette; Worthington, Jenny; Spindler, Tassja J; O'Brien, Darragh; Lee, Janet M; Spain, Georgia; Sharifian, Maryam; Wang, Guisong; Darcy, Kathleen M; Pejovic, Tanja; Sowter, Heidi; Timms, John F; Gayther, Simon A

    2015-10-15

    Epithelial ovarian cancer (EOC) is still considered the most lethal gynecological malignancy and improved early detection of ovarian cancer is crucial to improving patient prognoses. To address this need, we tested whether candidate EOC biomarkers can be identified using three-dimensional (3D) in vitro models. We quantified changes in the abundance of secreted proteins in a 3D genetic model of early-stage EOC, generated by expressing CMYC and KRAS(G) (12) (V) in TERT-immortalized normal ovarian epithelial cells. Cellular proteins were labeled in live cells using stable isotopic amino acid analogues, and secreted proteins identified and quantified using liquid chromatography-tandem mass spectrometry. Thirty-seven and 55 proteins were differentially expressed by CMYC and CMYC+KRAS(G) (12) (V) expressing cells respectively (p < 0.05; >2-fold). We evaluated expression of the top candidate biomarkers in ∼210 primary EOCs: CHI3L1 and FKBP4 are both expressed by >96% of primary EOCs, and FASN and API5 are expressed by 86 and 75% of cases. High expression of CHI3L1 and FKBP4 was associated with worse patient survival (p = 0.042 and p = 0.002, respectively). Expression of LGALS3BP was positively associated with recurrence (p = 0.0001) and suboptimal debulking (p = 0.018) suggesting that these proteins may be novel prognostic biomarkers. Furthermore, within early stage tumours (I/II), high expression of API5, CHI3L1 and FASN was associated with high tumour grade (p = 3 × 10(-4) , p = 0.016, p = 0.010, respectively). We show in vitro cell biology models of early-stage cancer development can be used to identify novel candidate biomarkers for disease, and report the identification of proteins that represent novel potential candidate diagnostic and prognostic biomarkers for this highly lethal disease.

  14. 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.

  15. Worldwide Genetic Analysis of the CFTR Region

    PubMed Central

    Mateu, Eva; Calafell, Francesc; Lao, Oscar; Bonné-Tamir, Batsheva; Kidd, Judith R.; Pakstis, Andrew; Kidd, Kenneth K.; Bertranpetit, Jaume

    2001-01-01

    Mutations at the cystic fibrosis transmembrane conductance regulator gene (CFTR) cause cystic fibrosis, the most prevalent severe genetic disorder in individuals of European descent. We have analyzed normal allele and haplotype variation at four short tandem repeat polymorphisms (STRPs) and two single-nucleotide polymorphisms (SNPs) in CFTR in 18 worldwide population samples, comprising a total of 1,944 chromosomes. The rooted phylogeny of the SNP haplotypes was established by typing ape samples. STRP variation within SNP haplotype backgrounds was highest in most ancestral haplotypes—although, when STRP allele sizes were taken into account, differences among haplotypes became smaller. Haplotype background determines STRP diversity to a greater extent than populations do, which indicates that haplotype backgrounds are older than populations. Heterogeneity among STRPs can be understood as the outcome of differences in mutation rate and pattern. STRP sites had higher heterozygosities in Africans, although, when whole haplotypes were considered, no significant differences remained. Linkage disequilibrium (LD) shows a complex pattern not easily related to physical distance. The analysis of the fraction of possible different haplotypes not found may circumvent some of the methodological difficulties of LD measure. LD analysis showed a positive correlation with locus polymorphism, which could partly explain the unusual pattern of similar LD between Africans and non-Africans. The low values found in non-Africans may imply that the size of the modern human population that emerged “Out of Africa” may be larger than what previous LD studies suggested. PMID:11104661

  16. Meta-Analysis of Candidate Gene Effects Using Bayesian Parametric and Non-Parametric Approaches

    PubMed Central

    Wu, Xiao-Lin; Gianola, Daniel; Rosa, Guilherme J. M.; Weigel, Kent A.

    2014-01-01

    Candidate gene (CG) approaches provide a strategy for identification and characterization of major genes underlying complex phenotypes such as production traits and susceptibility to diseases, but the conclusions tend to be inconsistent across individual studies. Meta-analysis approaches can deal with these situations, e.g., by pooling effect-size estimates or combining P values from multiple studies. In this paper, we evaluated the performance of two types of statistical models, parametric and non-parametric, for meta-analysis of CG effects using simulated data. Both models estimated a “central” effect size while taking into account heterogeneity over individual studies. The empirical distribution of study-specific CG effects was multi-modal. The parametric model assumed a normal distribution for the study-specific CG effects whereas the non-parametric model relaxed this assumption by posing a more general distribution with a Dirichlet process prior (DPP). Results indicated that the meta-analysis approaches could reduce false positive or false negative rates by pooling strengths from multiple studies, as compared to individual studies. In addition, the non-parametric, DPP model captured the variation of the “data” better than its parametric counterpart. PMID:25057320

  17. 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.

  18. Exome sequence analysis suggests genetic burden contributes to phenotypic variability and complex neuropathy

    PubMed Central

    Gonzaga-Jauregui, Claudia; Harel, Tamar; Gambin, Tomasz; Kousi, Maria; Griffin, Laurie B.; Francescatto, Ludmila; Ozes, Burcak; Karaca, Ender; Jhangiani, Shalini; Bainbridge, Matthew N.; Lawson, Kim S.; Pehlivan, Davut; Okamoto, Yuji; Withers, Marjorie; Mancias, Pedro; Slavotinek, Anne; Reitnauer, Pamela J; Goksungur, Meryem T.; Shy, Michael; Crawford, Thomas O.; Koenig, Michel; Willer, Jason; Flores, Brittany N.; Pediaditrakis, Igor; Us, Onder; Wiszniewski, Wojciech; Parman, Yesim; Antonellis, Anthony; Muzny, Donna M.; Katsanis, Nicholas; Battaloglu, Esra; Boerwinkle, Eric; Gibbs, Richard A.; Lupski, James R.

    2015-01-01

    Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ~45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy associated genes in subjects versus controls; confirmed in a second ethnically discrete neuropathy cohort, suggesting mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HMPVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity. PMID:26257172

  19. Premature ovarian failure (POF) syndrome: towards the molecular clinical analysis of its genetic complexity.

    PubMed

    Fassnacht, W; Mempel, A; Strowitzki, T; Vogt, P H

    2006-01-01

    The Premature Ovarian Failure (POF) syndrome is a very heterogeneous clinical disorder due probably to the complex genetic networks controlling human folliculogenesis. Clinical subgroups of POF patients whose aetiology of ovarian failure is based on the same genetic factors are therefore difficult to establish. Some experimental evidence suggests that these genes might be clustered on the female sex chromosome in the POF1 and POF2 loci. This review is aimed to present an overview of the actual structural changes of the X chromosome causing POF, and to present a number of X and autosomal female fertility genes which are probably key genes in human folliculogenesis and are therefore prominent POF candidate genes. Towards the molecular analysis of their functional contribution to the genetic aetiology of POF in the clinic, an interdisciplinary scheme for their diagnostic analysis is presented in a pilot study focussed on chromosome analyses and the expression analysis of some major POF candidate genes (DAZL, DBX, FOXL2, INHalpha, GDF9, USP9X) in the leukocytes of 101 POF patients. It starts with a comprehensive and significantly improved clinical diagnostic program for this large and heterogeneous patient group.

  20. 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 Central

    Brorsson, Caroline A.; Nielsen, Lotte B.; Andersen, Marie Louise; Kaur, Simranjeet; Bergholdt, Regine; Hansen, Lars; Mortensen, Henrik B.; Pociot, Flemming; Størling, Joachim; Hvidoere Study Group on Childhood Diabetes

    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

  1. 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.

  2. Genetic analysis of captive proboscis monkeys.

    PubMed

    Ogata, Mitsuaki; Seino, Satoru

    2015-01-01

    Information on the genetic relationships of captive founders is important for captive population management. In this study, we investigated DNA polymorphisms of four microsatellite loci and the mitochondrial control region sequence of five proboscis monkeys residing in a Japanese zoo as captive founders, to clarify their genetic relationship. We found that two of the five monkeys appeared to be genetically related. Furthermore, the haplotypes of the mitochondrial control region of the five monkeys were well differentiated from the haplotypes previously reported from wild populations from the northern area of Borneo, indicating a greater amount of genetic diversity in proboscis monkeys than previously reported. PMID:25266590

  3. Genetic analysis of captive proboscis monkeys.

    PubMed

    Ogata, Mitsuaki; Seino, Satoru

    2015-01-01

    Information on the genetic relationships of captive founders is important for captive population management. In this study, we investigated DNA polymorphisms of four microsatellite loci and the mitochondrial control region sequence of five proboscis monkeys residing in a Japanese zoo as captive founders, to clarify their genetic relationship. We found that two of the five monkeys appeared to be genetically related. Furthermore, the haplotypes of the mitochondrial control region of the five monkeys were well differentiated from the haplotypes previously reported from wild populations from the northern area of Borneo, indicating a greater amount of genetic diversity in proboscis monkeys than previously reported.

  4. Genes for human general transcription initiation factors TFIIIB, TFIIIB-associated proteins, TFIIIC2 and PTF/SNAPC: functional and positional candidates for tumour predisposition or inherited genetic diseases?

    PubMed

    Purrello, M; Di Pietro, C; Rapisarda, A; Amico, V; Giunta, V; Engel, H; Stevens, S; Hsieh, Y; Teichman, M; Wang, Z; Sichel, G; Roeder, R; Grzeschik, K H

    2001-08-01

    TFIIIB, TFIIIC2, and PTF/SNAPC are heteromultimeric general transcription factors (GTFs) needed for expression of genes encoding small cytoplasmic (scRNAs) and small nuclear RNAs (snRNAs). Their activity is stimulated by viral oncogenes, such as SV40 large T antigen and Adenovirus E1A, and is repressed by specific transcription factors (STFs) acting as anti-oncogenes, such as p53 and pRb. GTFs role as final targets of critical signal transduction pathways, that control cell proliferation and differentiation, and their involvement in gene expression regulation suggest that the genes encoding them are potential proto-oncogenes or anti-oncogenes or may be otherwise involved in the pathogenesis of inherited genetic diseases. To test our hypothesis through the positional candidate gene approach, we have determined the physical localization in the human genome of the 11 genes, encoding the subunits of these GTFs, and of three genes for proteins associated with TFIIIB (GTF3BAPs). Our data, obtained by chromosomal in situ hybridization, radiation hybrids and somatic cell hybrids analysis, demonstrate that these genes are present in the human genome as single copy sequences and that some cluster to the same cytogenetic band, alone or in combination with class II GTFs. Intriguingly, some of them are localized within chromosomal regions where recurrent, cytogenetically detectable mutations are seen in specific neoplasias, such as neuroblastoma, uterine leyomioma, mucoepidermoid carcinoma of the salivary glands and hemangiopericytoma, or where mutations causing inherited genetic diseases map, such as Peutz-Jeghers syndrome. Their molecular function and genomic position make these GTF genes interesting candidates for causal involvement in oncogenesis or in the pathogenesis of inherited genetic diseases.

  5. 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

  6. 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.

  7. 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.

  8. 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…

  9. 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.

  10. 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…

  11. 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…

  12. 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

  13. 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

  14. 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

    2016-07-07

    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.

  15. 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

  16. 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

  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. [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

  19. [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.

  20. Genetic analysis of patients with deep vein thrombosis during pregnancy and postpartum.

    PubMed

    Neki, Reiko; Fujita, Tomio; Kokame, Koichi; Nakanishi, Isao; Waguri, Masako; Imayoshi, Yuzo; Suehara, Noriyuki; Ikeda, Tomoaki; Miyata, Toshiyuki

    2011-08-01

    Deep vein thrombosis (DVT) is a serious pregnancy-related complication. Recent studies indicate that the genetic background for DVT differs with ethnicity. In our study, we enrolled 18 consecutive Japanese patients who had developed DVT during pregnancy and postpartum. We performed a genetic analysis of three candidate genes for DVT, protein S, protein C and antithrombin, in these patients. We found that four patients had missense mutations in the protein S gene, including the K196E mutation in two patients, the L446P mutation in one patient, and the D79Y and T630I mutations in one patient, as well as one patient with the C147Y mutation in the protein C gene. All five patients with genetic mutations had DVT in their first two trimesters. Nine of the patients without genetic mutations developed DVT in the first two trimesters, and four in the postpartum period. Thus, genetic mutations in the protein S gene were predominant in pregnant Japanese DVT women, and DVT in pregnant women with genetic mutations occurred more frequently at the early stage of pregnancy than postpartum. Considering the rapid decrease in protein S activity during pregnancy, we may need to assess thrombophilia in women before pregnancy.

  1. 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.

  2. 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.

  3. 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

  4. A spectroscopic study of southern (candidate) γ Doradus stars. II. Detailed abundance analysis and fundamental parameters

    NASA Astrophysics Data System (ADS)

    Bruntt, H.; De Cat, P.; Aerts, C.

    2008-02-01

    Context: The γ Doradus stars are a recent class of variable main sequence F-type stars located on the red edge of the Cepheid instability strip. They pulsate in gravity modes, and this makes them particularly interesting for detailed asteroseismic analysis, which can provide fundamental knowledge of properties near the convective cores of intermediate-mass main sequence stars. Aims: To improve current understanding of γ Dor stars through theoretical modelling, additional constraints are needed. Our aim is to estimate the fundamental atmospheric parameters and determine the chemical composition of these stars. Detailed analyses of single stars have previously suggested links to Am and λ Boo stars, so we wish to explore this interesting connection between chemical peculiarity and pulsation. Methods: We analysed a sample of γ Dor stars for the first time, including nine bona fide and three candidate members of the class. We determined the fundamental atmospheric parameters and compared the abundance pattern with other A-type stars. We used the semi-automatic software package VWA for the analysis. This code relies on the calculation of synthetic spectra and thus takes line-blending into account. This is important because of the fast rotation in some of the sample stars, and we made a thorough analysis of how VWA performs when increasing v sin i. We obtained good results in agreement with previously derived fundamental parameters and abundances in a few selected reference stars with properties similar to the γ Dor stars. Results: We find that the abundance pattern in the γ Dor stars is not distinct from the constant A- and F-type stars we analysed. Appendices A and B are only available in electronic form at http://www.aanda.org

  5. 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.

  6. 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

  7. Prioritizing disease candidate proteins in cardiomyopathy-specific protein-protein interaction networks based on "guilt by association" analysis.

    PubMed

    Li, Wan; Chen, Lina; He, Weiming; Li, Weiguo; Qu, Xiaoli; Liang, Binhua; Gao, Qianping; Feng, Chenchen; Jia, Xu; Lv, Yana; Zhang, Siya; Li, Xia

    2013-01-01

    The cardiomyopathies are a group of heart muscle diseases which can be inherited (familial). Identifying potential disease-related proteins is important to understand mechanisms of cardiomyopathies. Experimental identification of cardiomyophthies is costly and labour-intensive. In contrast, bioinformatics approach has a competitive advantage over experimental method. Based on "guilt by association" analysis, we prioritized candidate proteins involving in human cardiomyopathies. We first built weighted human cardiomyopathy-specific protein-protein interaction networks for three subtypes of cardiomyopathies using the known disease proteins from Online Mendelian Inheritance in Man as seeds. We then developed a method in prioritizing disease candidate proteins to rank candidate proteins in the network based on "guilt by association" analysis. It was found that most candidate proteins with high scores shared disease-related pathways with disease seed proteins. These top ranked candidate proteins were related with the corresponding disease subtypes, and were potential disease-related proteins. Cross-validation and comparison with other methods indicated that our approach could be used for the identification of potentially novel disease proteins, which may provide insights into cardiomyopathy-related mechanisms in a more comprehensive and integrated way.

  8. Analysis of protein interaction networks for the detection of candidate hepatitis B and C biomarkers.

    PubMed

    Simos, Thomas; Georgopoulou, Urania; Thyphronitis, George; Koskinas, John; Papaloukas, Costas

    2015-01-01

    Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are the major causes of chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). The resolution or chronicity of acute infection is dependent on a complex interplay between virus and innate/adaptive immunity. The mechanisms that lead a significant proportion of patients to more severe liver disease are not clearly defined and involve virus induced host gene/protein alterations. The utilization of protein interaction networks (PINs) is expected to identify novel aspects of the disease concerning the patients' immune response to virus as well as the main pathways that are involved in the development of fibrosis and HCC. In this study, we designed several PINs for HBV and HCV and employed topological, modular, and functional analysis techniques in order to determine significant network nodes that correspond to prominent candidate biomarkers. The networks were built using data from various interaction databases. When the overall PINs of HBV and HCV were compared, 48 nodes were found in common. The implementation of a statistical ranking procedure indicated that three of them are of higher importance. PMID:25099894

  9. Identification of candidate genes associated with porcine meat color traits by genome-wide transcriptome analysis

    PubMed Central

    Li, Bojiang; Dong, Chao; Li, Pinghua; Ren, Zhuqing; Wang, Han; Yu, Fengxiang; Ning, Caibo; Liu, Kaiqing; Wei, Wei; Huang, Ruihua; Chen, Jie; Wu, Wangjun; Liu, Honglin

    2016-01-01

    Meat color is considered to be the most important indicator of meat quality, however, the molecular mechanisms underlying traits related to meat color remain mostly unknown. In this study, to elucidate the molecular basis of meat color, we constructed six cDNA libraries from biceps femoris (Bf) and soleus (Sol), which exhibit obvious differences in meat color, and analyzed the whole-transcriptome differences between Bf (white muscle) and Sol (red muscle) using high-throughput sequencing technology. Using DEseq2 method, we identified 138 differentially expressed genes (DEGs) between Bf and Sol. Using DEGseq method, we identified 770, 810, and 476 DEGs in comparisons between Bf and Sol in three separate animals. Of these DEGs, 52 were overlapping DEGs. Using these data, we determined the enriched GO terms, metabolic pathways and candidate genes associated with meat color traits. Additionally, we mapped 114 non-redundant DEGs to the meat color QTLs via a comparative analysis with the porcine quantitative trait loci (QTL) database. Overall, our data serve as a valuable resource for identifying genes whose functions are critical for meat color traits and can accelerate studies of the molecular mechanisms of meat color formation. PMID:27748458

  10. 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.

  11. 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

  12. 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.

  13. 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

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

    PubMed Central

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

    2015-01-01

    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 (ĥ2 = 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

  15. 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…

  16. 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

  17. 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.

  18. 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

  19. 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

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

    PubMed Central

    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. DOI: http://dx.doi.org/10.7554/eLife.03582.001 PMID:25407681

  1. 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.

  2. Imputation-Based Population Genetics Analysis of Plasmodium falciparum Malaria Parasites

    PubMed Central

    Samad, Hanif; Coll, Francesc; Preston, Mark D.; Ocholla, Harold; Fairhurst, Rick M.; Clark, Taane G.

    2015-01-01

    Whole-genome sequencing technologies are being increasingly applied to Plasmodium falciparum clinical isolates to identify genetic determinants of malaria pathogenesis. However, genome-wide discovery methods, such as haplotype scans for signatures of natural selection, are hindered by missing genotypes in sequence data. Poor correlation between single nucleotide polymorphisms (SNPs) in the P. falciparum genome complicates efforts to apply established missing-genotype imputation methods that leverage off patterns of linkage disequilibrium (LD). The accuracy of state-of-the-art, LD-based imputation methods (IMPUTE, Beagle) was assessed by measuring allelic r2 for 459 P. falciparum samples from malaria patients in 4 countries: Thailand, Cambodia, Gambia, and Malawi. In restricting our analysis to 86k high-quality SNPs across the populations, we found that the complete-case analysis was restricted to 21k SNPs (24.5%), despite no single SNP having more than 10% missing genotypes. The accuracy of Beagle in filling in missing genotypes was consistently high across all populations (allelic r2, 0.87-0.96), but the performance of IMPUTE was mixed (allelic r2, 0.34-0.99) depending on reference haplotypes and population. Positive selection analysis using Beagle-imputed haplotypes identified loci involved in resistance to chloroquine (crt) in Thailand, Cambodia, and Gambia, sulfadoxine-pyrimethamine (dhfr, dhps) in Cambodia, and artemisinin (kelch13) in Cambodia. Tajima’s D-based analysis identified genes under balancing selection that encode well-characterized vaccine candidates: apical merozoite antigen 1 (ama1) and merozoite surface protein 1 (msp1). In contrast, the complete-case analysis failed to identify any well-validated drug resistance or candidate vaccine loci, except kelch13. In a setting of low LD and modest levels of missing genotypes, using Beagle to impute P. falciparum genotypes is a viable strategy for conducting accurate large-scale population genetics and

  3. Imputation-based population genetics analysis of Plasmodium falciparum malaria parasites.

    PubMed

    Samad, Hanif; Coll, Francesc; Preston, Mark D; Ocholla, Harold; Fairhurst, Rick M; Clark, Taane G

    2015-04-01

    Whole-genome sequencing technologies are being increasingly applied to Plasmodium falciparum clinical isolates to identify genetic determinants of malaria pathogenesis. However, genome-wide discovery methods, such as haplotype scans for signatures of natural selection, are hindered by missing genotypes in sequence data. Poor correlation between single nucleotide polymorphisms (SNPs) in the P. falciparum genome complicates efforts to apply established missing-genotype imputation methods that leverage off patterns of linkage disequilibrium (LD). The accuracy of state-of-the-art, LD-based imputation methods (IMPUTE, Beagle) was assessed by measuring allelic r2 for 459 P. falciparum samples from malaria patients in 4 countries: Thailand, Cambodia, Gambia, and Malawi. In restricting our analysis to 86 k high-quality SNPs across the populations, we found that the complete-case analysis was restricted to 21k SNPs (24.5%), despite no single SNP having more than 10% missing genotypes. The accuracy of Beagle in filling in missing genotypes was consistently high across all populations (allelic r2, 0.87-0.96), but the performance of IMPUTE was mixed (allelic r2, 0.34-0.99) depending on reference haplotypes and population. Positive selection analysis using Beagle-imputed haplotypes identified loci involved in resistance to chloroquine (crt) in Thailand, Cambodia, and Gambia, sulfadoxine-pyrimethamine (dhfr, dhps) in Cambodia, and artemisinin (kelch13) in Cambodia. Tajima's D-based analysis identified genes under balancing selection that encode well-characterized vaccine candidates: apical merozoite antigen 1 (ama1) and merozoite surface protein 1 (msp1). In contrast, the complete-case analysis failed to identify any well-validated drug resistance or candidate vaccine loci, except kelch13. In a setting of low LD and modest levels of missing genotypes, using Beagle to impute P. falciparum genotypes is a viable strategy for conducting accurate large-scale population genetics and

  4. Imputation-based population genetics analysis of Plasmodium falciparum malaria parasites.

    PubMed

    Samad, Hanif; Coll, Francesc; Preston, Mark D; Ocholla, Harold; Fairhurst, Rick M; Clark, Taane G

    2015-04-01

    Whole-genome sequencing technologies are being increasingly applied to Plasmodium falciparum clinical isolates to identify genetic determinants of malaria pathogenesis. However, genome-wide discovery methods, such as haplotype scans for signatures of natural selection, are hindered by missing genotypes in sequence data. Poor correlation between single nucleotide polymorphisms (SNPs) in the P. falciparum genome complicates efforts to apply established missing-genotype imputation methods that leverage off patterns of linkage disequilibrium (LD). The accuracy of state-of-the-art, LD-based imputation methods (IMPUTE, Beagle) was assessed by measuring allelic r2 for 459 P. falciparum samples from malaria patients in 4 countries: Thailand, Cambodia, Gambia, and Malawi. In restricting our analysis to 86 k high-quality SNPs across the populations, we found that the complete-case analysis was restricted to 21k SNPs (24.5%), despite no single SNP having more than 10% missing genotypes. The accuracy of Beagle in filling in missing genotypes was consistently high across all populations (allelic r2, 0.87-0.96), but the performance of IMPUTE was mixed (allelic r2, 0.34-0.99) depending on reference haplotypes and population. Positive selection analysis using Beagle-imputed haplotypes identified loci involved in resistance to chloroquine (crt) in Thailand, Cambodia, and Gambia, sulfadoxine-pyrimethamine (dhfr, dhps) in Cambodia, and artemisinin (kelch13) in Cambodia. Tajima's D-based analysis identified genes under balancing selection that encode well-characterized vaccine candidates: apical merozoite antigen 1 (ama1) and merozoite surface protein 1 (msp1). In contrast, the complete-case analysis failed to identify any well-validated drug resistance or candidate vaccine loci, except kelch13. In a setting of low LD and modest levels of missing genotypes, using Beagle to impute P. falciparum genotypes is a viable strategy for conducting accurate large-scale population genetics and

  5. Genetic and physical mapping of candidate genes for resistance to Fusarium oxysporum f.sp. tracheiphilum race 3 in cowpea [Vigna unguiculata (L.) Walp].

    PubMed

    Pottorff, Marti; Wanamaker, Steve; Ma, Yaqin Q; Ehlers, Jeffrey D; Roberts, Philip A; Close, Timothy J

    2012-01-01

    Fusarium oxysporum f.sp. tracheiphilum (Fot) is a soil-borne fungal pathogen that causes vascular wilt disease in cowpea. Fot race 3 is one of the major pathogens affecting cowpea production in California. Identification of Fot race 3 resistance determinants will expedite delivery of improved cultivars by replacing time-consuming phenotypic screening with selection based on perfect markers, thereby generating successful cultivars in a shorter time period. Resistance to Fot race 3 was studied in the RIL population California Blackeye 27 (resistant) x 24-125B-1 (susceptible). Biparental mapping identified a Fot race 3 resistance locus, Fot3-1, which spanned 3.56 cM on linkage group one of the CB27 x 24-125B-1 genetic map. A marker-trait association narrowed the resistance locus to a 1.2 cM region and identified SNP marker 1_1107 as co-segregating with Fot3-1 resistance. Macro and microsynteny was observed for the Fot3-1 locus region in Glycine max where six disease resistance genes were observed in the two syntenic regions of soybean chromosomes 9 and 15. Fot3-1 was identified on the cowpea physical map on BAC clone CH093L18, spanning approximately 208,868 bp on BAC contig250. The Fot3-1 locus was narrowed to 0.5 cM distance on the cowpea genetic map linkage group 6, flanked by SNP markers 1_0860 and 1_1107. BAC clone CH093L18 was sequenced and four cowpea sequences with similarity to leucine-rich repeat serine/threonine protein kinases were identified and are cowpea candidate genes for the Fot3-1 locus. This study has shown how readily candidate genes can be identified for simply inherited agronomic traits when appropriate genetic stocks and integrated genomic resources are available. High co-linearity between cowpea and soybean genomes illustrated that utilizing synteny can transfer knowledge from a reference legume to legumes with less complete genomic resources. Identification of Fot race 3 resistance genes will enable transfer into high yielding cowpea varieties

  6. Sub-Saharan genetic contribution in Morocco: microsatellite DNA analysis.

    PubMed

    Dios, S; Luis, J R; Carril, J C; Caeiro, B

    2001-10-01

    Northwest African populations occupy a strategic geographical area that has always been a zone of influence for diverse human groups from different regions. This article focuses on the analysis of the genetic contribution of sub-Saharan African populations by means of four short tandem repeat (STR) systems (HUMTPOX, HUMVWA31/A, HUMTHO1, and HUMF13B), which have proven informative in establishing genetic relationships between human populations. Genetic trees and multivariate analyses of European and Near Eastern populations show that the Moroccan population shares a common genetic substrate with all of them. However, the latter defines a specific lineage. Evolutionary factors inherent in the population's geographical isolation in early times, together with genetic flow from sub-Saharan populations (mainly as reflected by HUMF13B and HUMTPOX), appear to be particularly relevant in understanding the peculiarities of the genetic character of the present-day population.

  7. 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

  8. 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

  9. Fine genetic mapping using haplotype analysis and the missing data problem.

    PubMed

    Chiano, M N; Clayton, D G

    1998-01-01

    The genetic basis of many human diseases, especially those with substantial genetic determinants, has been identified. Notable amongst others are cystic fibrosis, Huntington's disease and some forms of cancer. However, the detection of genetic factors with more modest effects such as in bipolar disorders and a majority of the cancers, has been more complicated. Standard linkage analysis procedures may not only have little power to detect such genes but they do, at best, only narrow the location of the disease susceptibility gene to a rather large region. Association studies are therefore necessary to further unveil the aetiological relevance of these factors to disease. However, the number of tests required if such procedures were used in extended genome-wide screens, is prohibitive and as such association studies have seen limited application, except in the investigation of candidate genes. In this paper, we discuss a logistic regression approach as a generalization of this procedure so that it can accommodate clusters of linked markers or candidate genes. Furthermore, we introduce an expectation maximization (E-M) algorithm with which to estimate haplotype frequencies for multiple locus systems with incomplete information on phase.

  10. 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

  11. A Genome-Wide Association Analysis Reveals Epistatic Cancellation of Additive Genetic Variance for Root Length in Arabidopsis thaliana.

    PubMed

    Lachowiec, Jennifer; Shen, Xia; Queitsch, Christine; Carlborg, Örjan

    2015-01-01

    Efforts to identify loci underlying complex traits generally assume that most genetic variance is additive. Here, we examined the genetics of Arabidopsis thaliana root length and found that the genomic narrow-sense heritability for this trait in the examined population was statistically zero. The low amount of additive genetic variance that could be captured by the genome-wide genotypes likely explains why no associations to root length could be found using standard additive-model-based genome-wide association (GWA) approaches. However, as the broad-sense heritability for root length was significantly larger, and primarily due to epistasis, we also performed an epistatic GWA analysis to map loci contributing to the epistatic genetic variance. Four interacting pairs of loci were revealed, involving seven chromosomal loci that passed a standard multiple-testing corrected significance threshold. The genotype-phenotype maps for these pairs revealed epistasis that cancelled out the additive genetic variance, explaining why these loci were not detected in the additive GWA analysis. Small population sizes, such as in our experiment, increase the risk of identifying false epistatic interactions due to testing for associations with very large numbers of multi-marker genotypes in few phenotyped individuals. Therefore, we estimated the false-positive risk using a new statistical approach that suggested half of the associated pairs to be true positive associations. Our experimental evaluation of candidate genes within the seven associated loci suggests that this estimate is conservative; we identified functional candidate genes that affected root development in four loci that were part of three of the pairs. The statistical epistatic analyses were thus indispensable for confirming known, and identifying new, candidate genes for root length in this population of wild-collected A. thaliana accessions. We also illustrate how epistatic cancellation of the additive genetic variance

  12. A Genome-Wide Association Analysis Reveals Epistatic Cancellation of Additive Genetic Variance for Root Length in Arabidopsis thaliana

    PubMed Central

    Lachowiec, Jennifer; Shen, Xia; Queitsch, Christine; Carlborg, Örjan

    2015-01-01

    Efforts to identify loci underlying complex traits generally assume that most genetic variance is additive. Here, we examined the genetics of Arabidopsis thaliana root length and found that the genomic narrow-sense heritability for this trait in the examined population was statistically zero. The low amount of additive genetic variance that could be captured by the genome-wide genotypes likely explains why no associations to root length could be found using standard additive-model-based genome-wide association (GWA) approaches. However, as the broad-sense heritability for root length was significantly larger, and primarily due to epistasis, we also performed an epistatic GWA analysis to map loci contributing to the epistatic genetic variance. Four interacting pairs of loci were revealed, involving seven chromosomal loci that passed a standard multiple-testing corrected significance threshold. The genotype-phenotype maps for these pairs revealed epistasis that cancelled out the additive genetic variance, explaining why these loci were not detected in the additive GWA analysis. Small population sizes, such as in our experiment, increase the risk of identifying false epistatic interactions due to testing for associations with very large numbers of multi-marker genotypes in few phenotyped individuals. Therefore, we estimated the false-positive risk using a new statistical approach that suggested half of the associated pairs to be true positive associations. Our experimental evaluation of candidate genes within the seven associated loci suggests that this estimate is conservative; we identified functional candidate genes that affected root development in four loci that were part of three of the pairs. The statistical epistatic analyses were thus indispensable for confirming known, and identifying new, candidate genes for root length in this population of wild-collected A. thaliana accessions. We also illustrate how epistatic cancellation of the additive genetic variance

  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. 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.

  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. 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

  18. 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.

  19. 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

  20. Molecular genetic analysis of giant cell glioblastomas.

    PubMed Central

    Meyer-Puttlitz, B.; Hayashi, Y.; Waha, A.; Rollbrocker, B.; Boström, J.; Wiestler, O. D.; Louis, D. N.; Reifenberger, G.; von Deimling, A.

    1997-01-01

    Glioblastomas (GBMs) are a heterogeneous group of tumors. Recently, distinct molecular genetic alterations have been linked to subgroups of patients with GBM. Giant cell (gc)GBMs are a rare variant of GBM characterized by a marked preponderance of multinucleated giant cells. Several reports have associated this entity with a more favorable prognosis than the majority of GBMs. To evaluate whether gcGBM may also represent a genetically defined subgroup of GBM, we analyzed a series of 19 gcGBMs for mutations in the TP53 gene for amplification of the EGFR and CDK4 genes and for homozygous deletions in the CDKN2A (p16/MTS1) gene. Seventeen of nineteen gcGBMs carried TP53 mutations whereas EGFR and CDK4 gene amplification was seen in only one tumor each and homozygous deletion of CDKN2A was not observed at all. The strikingly high incidence of TP53 mutations and the relative absence of other genetic alterations groups gcGBM together with a previously recognized molecular genetic variant of GBM (type 1 GBM). It is tempting to speculate that the better prognosis of gcGBM patients may result from the low incidence of EGFR amplification and CDKN2A deletion, changes known for their growth-promoting potential. Images Figure 1 PMID:9284834

  1. 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

  2. DNA polymorphism analysis of candidate genes for type 2 diabetes mellitus in a Mexican ethnic group.

    PubMed

    Flores-Martínez, S E; Islas-Andrade, S; Machorro-Lazo, M V; Revilla, M C; Juárez, R E; Mújica-López, K I; Morán-Moguel, M C; López-Cardona, M G; Sánchez-Corona, J

    2004-01-01

    Type 2 diabetes mellitus is a complex metabolic disorder resulting from the action and interaction of many genetic and environmental factors. It has been reported that polymorphisms in genes involved in the metabolism of glucose are associated with the susceptibility to develop type 2 diabetes mellitus. Although the risk of developing type 2 diabetes mellitus increases with age, as well as with obesity and hypertension, its prevalence and incidence are different among geographical regions and ethnic groups. In Mexico, a higher prevalence and incidence has been described in the south of the country, and differences between urban and rural communities have been observed. We studied 73 individuals from Santiago Jamiltepec, a small indigenous community from Oaxaca State, Mexico. This population has shown a high prevalence of type 2 diabetes mellitus, and the aim of this study was to analyze the relationship between the Pst I (insulin gene), Nsi I (insulin receptor gene) and Gly972Arg (insulin receptor substrate 1 gene) polymorphisms and type 2 diabetes mellitus, obesity and hypertension in this population. Clinical evaluation consisted of BMI and blood pressure measurements, and biochemical assays consisted of determination of fasting plasma insulin and glucose levels. PCR and restriction enzyme digestion analysis were applied to genomic DNA to identify the three polymorphisms. From statistical analysis carried out here, individually, the Pst I, Nsi I and Gly972Arg polymorphisms were not associated with the type 2 diabetes, obese or hypertensive phenotypes in this population. Nevertheless, there was an association between the Nsi I and Pst I polymorphisms and increased serum insulin levels.

  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.

  4. 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.

  5. 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

  6. Genetic analysis of reproductive development in tomato.

    PubMed

    Lozano, Rafael; Giménez, Estela; Cara, Beatriz; Capel, Juan; Angosto, Trinidad

    2009-01-01

    Besides being an important commercial crop, tomato (Solanum lycopersicum L.) constitutes a model species for the study of plant developmental processes. Current research tends to combine classic disciplines such as physiology and genetics with modern approaches coming from molecular biology and genomics with a view to elucidating the biological mechanisms underlying plant architecture, floral transition and development of flowers and fruits. Comparative and functional analyses of tomato regulatory genes such as LATERAL SUPPRESSOR (LS), SELF PRUNING (SP), SINGLE FLOWER TRUSS (SFT) and FALSIFLORA (FA) have revealed mechanisms involved in shoot development and flowering time which are conserved among Arabidopsis, tomato and other plant species. Furthermore, several regulatory genes encoding transcription factors have been characterized as responsible for singular features of vegetative and reproductive development of tomato. Thus, the sympodial growth habit seems to require a specific control of the developmental fate followed by shoot meristems. In this process, novel genetic and molecular interactions involving SP, SFT and FA genes would be essential. Also this latter, but mainly ANANTHA (AN) and COMPOUND INFLORESCENCE (S) have recently been found to regulate the inflorescence architecture of the tomato. Concerning fruit development, genetic and molecular analyses of new genes such as fw2.2, FASCIATED, OVATE and SUN have proved their contribution to the domestication process and most importantly, their function as key regulators of fruit size and shape variation. Tomato ripening is also being elucidated thanks to the characterization of regulatory genes such as RIPENING INHIBITOR (RIN), NON-RIPENING (NOR), TDR4 and COLORLESS NON-RIPENING (CNR), which have been found to control early stages of fruit development and maturation. At the same time, much research is dedicated to isolating the targets of the ripening regulators, as well as the key genes promoting the

  7. 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…

  8. 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…

  9. 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…

  10. Microsatellite analysis of genetic variation in black bear populations.

    PubMed

    Paetkau, D; Strobeck, C

    1994-10-01

    Measuring levels of genetic variation is an important aspect of conservation genetics. The informativeness of such measurements is related to the variability of the genetic markers used; a particular concern in species, such as bears, which are characterized by low levels of genetic variation resulting from low population densities and small effective population sizes. We describe the development of microsatellite analysis in bears and its use in assessing interpopulation differences in genetic variation in black bears from three Canadian National Parks. These markers are highly variable and allowed identification of dramatic differences in both distribution and amount of variation between populations. Low levels of variation were observed in a population from the Island of Newfoundland. The significance of interpopulation differences in variability was tested using a likelihood ratio test of estimates of theta = 4Ne mu.

  11. 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

  12. 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

  13. Nucleotide sequence analysis of a candidate gene for ataxia-telangiectasia group D (ATDC)

    SciTech Connect

    Leonhardt, E.A.; Kapp, L.N.; Young, B.R.; Murnane, J.P. )

    1994-01-01

    A radioresistant cell clone (1B3) was previously isolated after transfection of an ataxia-telangiectasia (AT) group D cell line with a human cosmid library. A cosmid rescued from the integration site in 1B3 contained human DNA from chromosome position 11q23, the same region shown by both genetic linkage and chromosome transfer to contain the genes for AT complementation groups A/B, C, and D. A gene within the cosmid (ATDC) was found to produce mRNAs of different sizes. A cDNA for one of the most abundant mRNAs (3.0 kb) was isolated from a HeLa cell library. In the present study, the authors sequenced the 3.0-kb cDNA and the surrounding intron DNA in the cosmids. They used polymerase chain reaction, with primers in the introns, to confirm the number of exons and to analyze DNA from AT group D cells for mutations within this gene. Although no mutations were found, they do not rule out the possibility that mutations may be present within the regulatory sequences or coding sequences found in other mRNAs specific for this gene. From the sequence analysis, they found that the ATDC gene product is one of a group of proteins that share multiple zinc finger motifs and an adjacent leucine zipper motif. These proteins have been proposed to form homo- or hetero-dimers involved in nucleic acid binding, consistent with the fact that many of these proteins appear to be transcriptional regulatory factors involved in carcinogenesis and/or differentiation. The likelihood that the ATDC gene product is involved in transcriptional regulation could explain the pleiomorphic characteristics of AT, including abnormal cell cycle regulation. 36 refs., 5 figs., 2 tabs.

  14. 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

  15. 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

  16. 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

  17. 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.

  18. Rice artificial hybridization for genetic analysis.

    PubMed

    Sha, Xueyan

    2013-01-01

    Artificial hybridization has probably been practiced since ancient time; however, the science of genetics did not initiate until Gregor Mendel conducted a series of crosses between different pure lines of garden pea and made careful observations and systematical analyses of their offspring. Artificial hybridization or crossing between carefully chosen parents has been and still is the primary way to transfer genes from different germplasm for self-pollinated rice. Through gene recombination, novel genetic variation is created by different arrangements of genes existing in parental lines. Procedures of artificial hybridization involve the selection of appropriate panicles from representative plants of the female parents, the emasculation of female parents, and the pollination of emasculated panicles with abundant pollens of selected male parents. Of the numerous proposed methods, hot water and vacuum emasculation have proven to be the most robust and reliable ones. A successful and efficient hybridization program also relies on the knowledge of parental lines or germplasm, the reproductive biology and development of rice, the conditions needed to promote flowering and seed development, and the techniques to synchronize flowering of diverse parents.

  19. Pharmacogenetic analysis of clinically relevant genetic polymorphisms.

    PubMed

    McLeod, Howard L

    2005-11-15

    The ascertainment of the human genome sequence has generated great enthusiasm for the use of gene-based approaches to improve virtually all aspects of medical care. Particular interest has focused on the field of pharmacogenetics--for example, the use of an individual's genetic profile to optimize drug prescription. This approach takes advantage of the presence of single-nucleotide polymorphisms (SNPs) or other genetic variants in every gene in the human genome. There are currently > 9 million SNPs in the human SNP database dbSNP, with an estimated 11 million variants ultimately to be found in the human population. To date, the preponderance of interest in this field has centered on the potential of applying this approach to subacute or chronic illnesses, such as cancer, cardiovascular disease, human immunodeficiency virus infection, or rheumatologic disorders. In contrast, little attention has been devoted to the potential utility of implementing the pharmacogenomic methodology for guiding drug selection for acutely ill patients in the critical care environment. Although such an approach has theoretical appeal as a means of enhancing quality and improving outcomes in this setting, several obstacles currently exist and slow the progress toward clinical application. PMID:16237646

  20. Calculation of substructural analysis weights using a genetic algorithm.

    PubMed

    Holliday, John D; Sani, Nor; Willett, Peter

    2015-02-23

    This work describes a genetic algorithm for the calculation of substructural analysis for use in ligand-based virtual screening. The algorithm is simple in concept and effective in operation, with simulated virtual screening experiments using the MDDR and WOMBAT data sets showing it to be superior to substructural analysis weights based on a naive Bayesian classifier.

  1. Genetic risk score analysis indicates migraine with and without comorbid depression are genetically different disorders.

    PubMed

    Ligthart, Lannie; Hottenga, Jouke-Jan; Lewis, Cathryn M; Farmer, Anne E; Craig, Ian W; Breen, Gerome; Willemsen, Gonneke; Vink, Jacqueline M; Middeldorp, Christel M; Byrne, Enda M; Heath, Andrew C; Madden, Pamela A F; Pergadia, Michele L; Montgomery, Grant W; Martin, Nicholas G; Penninx, Brenda W J H; McGuffin, Peter; Boomsma, Dorret I; Nyholt, Dale R

    2014-02-01

    Migraine and major depressive disorder (MDD) are comorbid, moderately heritable and to some extent influenced by the same genes. In a previous paper, we suggested the possibility of causality (one trait causing the other) underlying this comorbidity. We present a new application of polygenic (genetic risk) score analysis to investigate the mechanisms underlying the genetic overlap of migraine and MDD. Genetic risk scores were constructed based on data from two discovery samples in which genome-wide association analyses (GWA) were performed for migraine and MDD, respectively. The Australian Twin Migraine GWA study (N = 6,350) included 2,825 migraine cases and 3,525 controls, 805 of whom met the diagnostic criteria for MDD. The RADIANT GWA study (N = 3,230) included 1,636 MDD cases and 1,594 controls. Genetic risk scores for migraine and for MDD were used to predict pure and comorbid forms of migraine and MDD in an independent Dutch target sample (NTR-NESDA, N = 2,966), which included 1,476 MDD cases and 1,058 migraine cases (723 of these individuals had both disorders concurrently). The observed patterns of prediction suggest that the 'pure' forms of migraine and MDD are genetically distinct disorders. The subgroup of individuals with comorbid MDD and migraine were genetically most similar to MDD patients. These results indicate that in at least a subset of migraine patients with MDD, migraine may be a symptom or consequence of MDD.

  2. 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.

  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. 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.

  5. 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

  6. 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

  7. 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.

  8. 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

  9. Heritability and Genetic Association Analysis of Neuroimaging Measures in the Diabetes Heart Study

    PubMed Central

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

    2014-01-01

    Patients with type 2 diabetes are at increased risk of age-related cognitive decline and dementia. Neuroimaging measures such as white matter lesion volume, brain volume, and fractional anisotropy may reflect the pathogenesis of these cognitive declines, and genetic factors may contribute to variability in these measures. This study examined multiple neuroimaging measures in 465 participants from 238 families with extensive genotype data in the type 2 diabetes enriched Diabetes Heart Study-Mind cohort. Heritability of these phenotypes and their association with candidate single nucleotide polymorphisms (SNPs) and SNP data from genome-and exome-wide arrays was explored. All neuroimaging measures analysed were significantly heritable (ĥ2 =0.55–0.99 in unadjusted models). Seventeen candidate SNPs (from 16 genes/regions) associated with neuroimaging phenotypes in prior studies showed no significant evidence of association. A missense variant (rs150706952, A432V) in PLEKHG4B from the exome-wide array was significantly associated with white matter mean diffusivity (p=3.66×10−7) and gray matter mean diffusivity (p=2.14×10−7). This analysis suggests genetic factors contribute to variation in neuroimaging measures in a population enriched for metabolic disease and other associated comorbidities. PMID:25523635

  10. Analysis of Variance Components for Genetic Markers with Unphased Genotypes.

    PubMed

    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.

  11. 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

  12. 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.

  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. Genetic Analysis of Biodegradation of Tetralin by a Sphingomonas Strain

    PubMed Central

    Hernáez, María José; Reineke, Walter; Santero, Eduardo

    1999-01-01

    A strain designated TFA which very efficiently utilizes tetralin has been isolated from the Rhine river. The strain has been identified as Sphingomonas macrogoltabidus, based on 16S rDNA sequence similarity. Genetic analysis of tetralin biodegradation has been performed by insertion mutagenesis and by physical analysis and analysis of complementation between the mutants. The genes involved in tetralin utilization are clustered in a region of 9 kb, comprising at least five genes grouped in two divergently transcribed operons. PMID:10103288

  15. Localization of the VHR phosphatase gene and its analysis as a candidate for BRCA1

    SciTech Connect

    Kamb, A.; Rosenthal, J.; Tran, T.

    1994-09-01

    The VH1-related human protein (VHR) gene was localized to human chromosome 17q21 in a region thought to contain the BCRA1 locus, a locus that confers susceptibility to breast and ovarian cancer. VHR encodes a phosphatase with dual specificity for tyrosine and serine residues. Thus it is a plausible candidate for a tumor suppressor gene such as BRCA1. To test this possibility, the VHR coding sequence was screened in individuals with familial breast cancer and in sporadic breast tumor and breast cancer cell lines. No mutations were detected, suggesting that the VHR gene is not BRCA1. 18 refs., 3 figs.

  16. 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

  17. 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.

  18. 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

  19. Genetic analysis of photosynthesis in Rhodospirillum centenum.

    PubMed Central

    Yildiz, F H; Gest, H; Bauer, C E

    1991-01-01

    A genetic system has been developed for studying bacterial photosynthesis in the recently described nonsulfur purple photosynthetic bacterium Rhodospirillum centenum. Nonphotosynthetic mutants of R. centenum were obtained by enrichment for spontaneous mutations, by ethyl methanesulfonate mutagenesis coupled to penicillin selection on solid medium, and by Tn5 transposition mutagenesis with an IncP plasmid vector containing a temperature-sensitive origin of replication. In vivo and in vitro characterization of individual strains demonstrated that 38 strains contained mutations that blocked bacteriochlorophyll a biosynthesis at defined steps of the biosynthetic pathway. Collectively, these mutations were shown to block seven of eight steps of the pathway leading from protoporphyrin IX to bacteriochlorophyll a. Three mutants were isolated in which carotenoid biosynthesis was blocked early in the biosynthetic pathway; the mutants also exhibited pleiotropic effects on stability or assembly of the photosynthetic apparatus. Five mutants failed to assemble a functional reaction center complex, and seven mutants contained defects in electron transport as shown by an alteration in cytochromes. In addition, several regulatory mutants were isolated that acquired enhanced repression of bacteriochlorophyll in response to the presence of molecular oxygen. The phenotypes of these mutants are discussed in relation to those of similar mutants of Rhodobacter and other Rhodospirillum species of purple photosynthetic bacteria. Images PMID:1648078

  20. Genetic analysis reveals promiscuity among female cheetahs.

    PubMed

    Gottelli, Dada; Wang, Jinliang; Bashir, Sultana; Durant, Sarah M

    2007-08-22

    Cheetahs (Acinonyx jubatus) have a combination of ranging patterns and social system that is unique in mammals, whereby male coalitions occupy small territories less than 10% of the home range of solitary females. This study uses non-invasive genetic sampling of a long-term study population of cheetah in the Serengeti National Park in Tanzania to infer the mating system. Individual cheetah genotypes at up to 13 microsatellite loci were obtained from 171 faecal samples. A statistical method was adapted to partition the cubs within each litter (n=47) into full-sibling clusters and to infer the father of each cluster using these loci. Our data showed a high rate of multiple paternity in the population; 43% of litters with more than one cub were fathered by more than one male. The results also demonstrated that female fidelity was low, and provided some evidence that females chose to mate with unrelated males within an oestrus cycle. The low rate of paternity assignments indicated that males living outside the study area contributed substantially to the reproduction of the cheetah population.

  1. Bayesian analysis of genetic differentiation between populations.

    PubMed Central

    Corander, Jukka; Waldmann, Patrik; Sillanpää, Mikko J

    2003-01-01

    We introduce a Bayesian method for estimating hidden population substructure using multilocus molecular markers and geographical information provided by the sampling design. The joint posterior distribution of the substructure and allele frequencies of the respective populations is available in an analytical form when the number of populations is small, whereas an approximation based on a Markov chain Monte Carlo simulation approach can be obtained for a moderate or large number of populations. Using the joint posterior distribution, posteriors can also be derived for any evolutionary population parameters, such as the traditional fixation indices. A major advantage compared to most earlier methods is that the number of populations is treated here as an unknown parameter. What is traditionally considered as two genetically distinct populations, either recently founded or connected by considerable gene flow, is here considered as one panmictic population with a certain probability based on marker data and prior information. Analyses of previously published data on the Moroccan argan tree (Argania spinosa) and of simulated data sets suggest that our method is capable of estimating a population substructure, while not artificially enforcing a substructure when it does not exist. The software (BAPS) used for the computations is freely available from http://www.rni.helsinki.fi/~mjs. PMID:12586722

  2. 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.

  3. 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 ...

  4. 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.

  5. 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.

  6. Genetic and physical mapping of the earliness per se locus Eps-A (m) 1 in Triticum monococcum identifies EARLY FLOWERING 3 (ELF3) as a candidate gene.

    PubMed

    Alvarez, M A; Tranquilli, G; Lewis, S; Kippes, N; Dubcovsky, J

    2016-07-01

    Wheat cultivars exposed to optimal photoperiod and vernalization treatments still exhibit differences in flowering time, referred to as earliness per se (Eps). We previously identified the Eps-A (m) 1 locus from Triticum monococcum and showed that the allele from cultivated accession DV92 significantly delays heading time and increases the number of spikelets per spike relative to the allele from wild accession G3116. Here, we expanded a high-density genetic and physical map of the Eps-A (m) 1 region and identified the wheat ortholog of circadian clock regulator EARLY FLOWERING 3 (ELF3) as a candidate gene. No differences in ELF3 transcript levels were found between near-isogenic lines carrying the DV92 and G3116 Eps-A (m) 1 alleles, but the encoded ELF3 proteins differed in four amino acids. These differences were associated with altered transcription profiles of PIF-like, PPD1, and FT1, which are known downstream targets of ELF3. Tetraploid wheat lines with combined truncation mutations in the A- and B-genome copies of ELF3 flowered earlier and had less spikelets per spike than the wild-type control under short- and long-day conditions. Both effects were stronger in a photoperiod-sensitive than in a reduced photoperiod-sensitive background, indicating a significant epistatic interaction between PPD1 and ELF3 (P < 0.0001). By contrast, the introgression of the T. monococcum chromosome segment carrying the Eps-A (m) 1 allele from DV92 into durum wheat delayed flowering and increased the number of spikelets per spike. Taken together, the above results support the hypothesis that ELF3 is Eps-A (m) 1. The ELF3 alleles identified here provide additional tools to modulate reproductive development in wheat.

  7. 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

  8. 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.

  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. 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.

  11. Whole-genome conditional two-locus analysis identifies novel candidate genes for late-onset Parkinson's disease.

    PubMed

    González-Pérez, A; Gayán, J; Marín, J; Galán, J J; Sáez, M E; Real, L M; Antúnez, C; Ruiz, A

    2009-07-01

    Whole-genome epistasis analysis may add a new layer of knowledge to whole-genome association studies, permitting the identification of new candidate genes which are completely transparent during conventional single-locus analysis. We present the first whole-genome conditional two-locus analysis in Parkinson's disease (PD). We scanned the entire genome and selected markers that interacted with a set of well-known loci previously associated to PD (SNCA, Parkin, LRRK2, UCHL1, DJ-1, PINK and MAPT). Our work describes several loci potentially related to PD risk which interact with SNCA, PARK1 and LRRK2 markers. We propose conditional whole-genome two-locus association analysis as a valuable method that might be helpful in re-analysing and re-interpreting data from whole-genome association studies.

  12. 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

  13. 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

  14. 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.

  15. Identification of candidate genes for Fusarium yellows resistance in Chinese cabbage by differential expression analysis.

    PubMed

    Shimizu, Motoki; Fujimoto, Ryo; Ying, Hua; Pu, Zi-jing; Ebe, Yusuke; Kawanabe, Takahiro; Saeki, Natsumi; Taylor, Jennifer M; Kaji, Makoto; Dennis, Elizabeth S; Okazaki, Keiichi

    2014-06-01

    Fusarium yellows caused by Fusarium oxysporum f. sp. conglutinans is an important disease of Brassica worldwide. To identify a resistance (R) gene against Fusarium yellows in Chinese cabbage (Brassica rapa var. pekinensis), we analyzed differential expression at the whole genome level between resistant and susceptible inbred lines using RNA sequencing. Four hundred and eighteen genes were significantly differentially expressed, and these were enriched for genes involved in response to stress or stimulus. Seven dominant DNA markers at putative R-genes were identified. Presence and absence of the sequence of the putative R-genes, Bra012688 and Bra012689, correlated with the resistance of six inbred lines and susceptibility of four inbred lines, respectively. In F(2) populations derived from crosses between resistant and susceptible inbred lines, presence of Bra012688 and Bra012689 cosegregated with resistance, suggesting that Bra012688 and Bra012689 are good candidates for fusarium yellows resistance in Chinese cabbage.

  16. Analysis of the coverage capacity of the StreptInCor candidate vaccine against Streptococcus pyogenes.

    PubMed

    De Amicis, Karine M; Freschi de Barros, Samar; Alencar, Raquel E; Postól, Edilberto; Martins, Carlo de Oliveira; Arcuri, Helen Andrade; Goulart, Cibelly; Kalil, Jorge; Guilherme, Luiza

    2014-07-01

    Streptococcus pyogenes is responsible for infections as pharyngitis, sepsis, necrotizing fasciitis and streptococcal toxic shock syndrome. The M protein is the major bacterial antigen and consists of both polymorphic N-terminal portion and a conserved region. In the present study, we analyzed the in vitro ability of StreptInCor a C-terminal candidate vaccine against S. pyogenes to induce antibodies to neutralize/opsonize the most common S. pyogenes strains in Sao Paulo by examining the recognition by sera from StreptInCor immunized mice. We also evaluated the presence of cross-reactive antibodies against human heart valve tissue. Anti-StreptInCor antibodies were able to neutralize/opsonize at least 5 strains, showing that immunization with StreptInCor is effective against several S. pyogenes strains and can prevent infection and subsequent sequelae without causing autoimmune reactions.

  17. 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.

  18. 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.

  19. 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

    2015-08-19

    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.

  20. 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

  1. [Global analysis strategies. Toward the genetic management of neoplasias].

    PubMed

    Hidalgo, A; Salcedo, M

    2001-01-01

    Biomedical research in oncological diseases, particularly focused on the study and understanding of the molecular mechanisms involved in cellular transformation, is opening new possibilities for the development of new and more efficient strategies for diagnosis and treatment. The generation and practical application of the results derived from molecular genetic studies in cancer, has evolved in parallel with the development of technological tools that allow us to get a global vision of diverse cellular processes, both in the normal and pathological states. This combination of basic research and technological application, has created methodologies that allow us to analyze the three principal levels of Molecular Genetics, the Genome (DNA, archive of the genetic information), the Transcriptome (RNA, expression of the genetic information), and finally, the Proteome (proteins, functional aspect of the genetic information). The vast amount of information obtained due to these advancements has begun to modify our fundamental vision about oncological diseases, and together with the traditional analytic tools, they hold the promise of changing the ways we classify, detect, diagnose and treat cancer. In this review, we present some of this methods for global genetic analysis, involving the three levels of genetic organization: the genome, with the Human Genome Project, comparative genomic hybridization and chromosome painting; the Transcriptome, with Serial analysis of Gene Expression and DNA microarrays; and the proteome, with bidimensional protein electrophoresis and antibody-microarrays. In each case, together with a brief description of the method, we also present the impact of every one of them on the study and management of neoplastic diseases.

  2. 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…

  3. 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.

  4. Castor bean organelle genome sequencing and worldwide genetic diversity analysis.

    PubMed

    Rivarola, Maximo; Foster, Jeffrey T; 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.

  5. 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

  6. 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.

  7. Genetic diversity analysis of fruit characteristics of hawthorn germplasm.

    PubMed

    Su, K; Guo, Y S; Wang, G; Zhao, Y H; Dong, W X

    2015-12-07

    One hundred and six accessions of hawthorn intraspecific resources, from the National Germplasm Repository at Shenyang, were subjected to genetic diversity and principal component analysis based on evaluation data of 15 fruit traits. Results showed that the genetic diversity of hawthorn fruit traits varied. Among the 15 traits, the fruit shape variable coefficient had the most obvious evaluation, followed by fruit surface state, dot color, taste, weight of single fruit, sepal posture, peduncle form, and metula traits. These are the primary traits by which hawthorn could be classified in the future. The principal component demonstrated that these traits are the most influential factors of hawthorn fruit characteristics.

  8. 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.

  9. 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

  10. [Quality of genetic services--analysis of medical genetic expert opinions solicited by private health insurance companies].

    PubMed

    Nippert, Reinhardt Peter; Schmidtke, Jörg

    2012-01-01

    Service quality for patients with genetic conditions can be assessed through the analysis of clinical genetic data sets, as was the case in this study. It represents a secondary analysis of a compilation of a single genetic expert's medical opinions covering the years 2000 to 2009, solicited by private health insurance companies with the intention of probing into medical necessity and adequacy of genetic testing ordered by physicians. Genetic testing has become an increasingly important part of clinical diagnostic services. Controlling these services does not only reduce costs but also saves patients from unwarranted over-utilisation. Therefore, the reasons given by doctors when ordering genetic tests are part of the quality of service delivery. The study revealed that more than 30% of the molecular genetic tests ordered lack sound medical reasoning and 30% of the cases studied show violation or neglect of guidelines and recommendations for diagnostic procedures with respect to genetic testing. In essence, the findings indicate a need for human genetic information among physicians. Their professional organisations are called upon to design and offer CME/CPD programmes in medical genetics to maintain and continually improve the quality of medical genetic care for patients with genetic conditions. PMID:22682419

  11. Comprehensive Primer Design for Analysis of Population Genetics in Non-Sequenced Organisms

    PubMed Central

    Tezuka, Ayumi; Matsushima, Noe; Nemoto, Yoriko; Akashi, Hiroshi D.; Kawata, Masakado; Makino, Takashi

    2012-01-01

    Nuclear sequence markers are useful tool for the study of the history of populations and adaptation. However, it is not easy to obtain multiple nuclear primers for organisms with poor or no genomic sequence information. Here we used the genomes of organisms that have been fully sequenced to design comprehensive sets of primers to amplify polymorphic genomic fragments of multiple nuclear genes in non-sequenced organisms. First, we identified a large number of candidate polymorphic regions that were flanked on each side by conserved regions in the reference genomes. We then designed primers based on these conserved sequences and examined whether the primers could be used to amplify sequences in target species, montane brown frog (Rana ornativentris), anole lizard (Anolis sagrei), guppy (Poecilia reticulata), and fruit fly (Drosophila melanogaster), for population genetic analysis. We successfully obtained polymorphic markers for all target species studied. In addition, we found that sequence identities of the regions between the primer sites in the reference genomes affected the experimental success of DNA amplification and identification of polymorphic loci in the target genomes, and that exonic primers had a higher success rate than intronic primers in amplifying readable sequences. We conclude that this comparative genomic approach is a time- and cost-effective way to obtain polymorphic markers for non-sequenced organisms, and that it will contribute to the further development of evolutionary ecology and population genetics for non-sequenced organisms, aiding in the understanding of the genetic basis of adaptation. PMID:22393396

  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. 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

  14. Genetic analysis of population differentiation and adaptation in Leuciscus waleckii.

    PubMed

    Chang, Yumei; Tang, Ran; Sun, Xiaowen; Liang, Liqun; Chen, Jinping; Huang, Jinfeng; Dou, Xinjie; Tao, Ran

    2013-12-01

    Demographic events and natural selection both influence animal phenotypic and genetic variation; exploring the effects of demography and selection on population divergence is of great significance in evolutionary biology. To uncover the causes behind the patterns of genetic differentiation and adaptation among six populations of Leuciscus waleckii from Dali Basin (two populations, alkaline vs. freshwater) and Amur Basin (four populations, freshwater rivers vs. alkaline lake), a set of 21 unlinked polymorphic microsatellite markers and two mitochondrial DNA sequences (Cytb and D-loop) were applied to examine whether populations from different environments or habitats have distinct genetic differentiation and whether alkalinity is the major factor that caused population divergence. Bayesian analysis and principal component analysis as well as haplotype network analysis showed that these populations are primarily divided into two groups, which are congruent with geographic separation but not inconsistent with the habitat environment (alkalinity). Using three different approaches, outlier detection indicated that one locus, HLJYL017, may be under directional selection and involved in local adaptation processes. Overall, this study suggested that demographic events and selection of local environmental conditions including of alkalinity are jointly responsible for population divergence. These findings constitute an important step towards the understanding of the genetic basis of differentiation and adaptation, as well as towards the conservation of L. waleckii.

  15. 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

  16. 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

  17. 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.

  18. 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

  19. [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.

  20. 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

  1. [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

  2. 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

  3. Genomic analysis reveals MATH gene(s) as candidate(s) for Plum pox virus (PPV) resistance in apricot (Prunus armeniaca L.).

    PubMed

    Zuriaga, Elena; Soriano, José Miguel; Zhebentyayeva, Tetyana; Romero, Carlos; Dardick, Chris; Cañizares, Joaquín; Badenes, Maria Luisa

    2013-09-01

    Sharka disease, caused by Plum pox virus (PPV), is the most important viral disease affecting Prunus species. A major PPV resistance locus (PPVres) has been mapped to the upper part of apricot (Prunus armeniaca) linkage group 1. In this study, a physical map of the PPVres locus in the PPV-resistant cultivar 'Goldrich' was constructed. Bacterial artificial chromosome (BAC) clones belonging to the resistant haplotype contig were sequenced using 454/GS-FLX Titanium technology. Concurrently, the whole genome of seven apricot varieties (three PPV-resistant and four PPV-susceptible) and two PPV-susceptible apricot relatives (P. sibirica var. davidiana and P. mume) were obtained using the Illumina-HiSeq2000 platform. Single nucleotide polymorphisms (SNPs) within the mapped interval, recorded from alignments against the peach genome, allowed us to narrow down the PPVres locus to a region of ∼196 kb. Searches for polymorphisms linked in coupling with the resistance led to the identification of 68 variants within 23 predicted transcripts according to peach genome annotation. Candidate resistance genes were ranked combining data from variant calling and predicted functions inferred from sequence homology. Together, the results suggest that members of a cluster of meprin and TRAF-C homology domain (MATHd)-containing proteins are the most likely candidate genes for PPV resistance in apricot. Interestingly, MATHd proteins are hypothesized to control long-distance movement (LDM) of potyviruses in Arabidopsis, and restriction for LDM is also a major component of PPV resistance in apricot. Although the PPV resistance gene(s) remains to be unambiguously identified, these results pave the way to the determination of the underlying mechanism and to the development of more accurate breeding strategies.

  4. 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.

  5. 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

  6. 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

  7. 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

  8. Genetic analysis of Streptococcus suis isolates from wild rabbits.

    PubMed

    Sánchez del Rey, V; Fernández-Garayzábal, J F; Briones, V; Iriso, A; Domínguez, L; Gottschalk, M; Vela, A I

    2013-08-30

    This work aims to investigate the presence of Streptococcus suis in wild rabbits. A total of 65 S. suis isolates were recovered from 33.3% of the wild rabbits examined. Most isolates (86.2%) belong to genotype cps9. These isolates were further characterized by pulsed field gel electrophoresis (PFGE), multilocus sequence typing (MLST) and virulence genotyping. Overall, S. suis exhibited a low genetic diversity. Only 5 genetic profiles were obtained by PFGE and most isolates (71.4%) were included in two pulsotypes that were also widely distributed among the wild rabbit population. MLST analysis assigned all cps9 isolates into three new singlestones (ST216, ST217 and ST284), which were not genetically related to the European ST87 and Spanish ST61 widespread swine clones, indicating a different genetic background for the S. suis isolates from wild rabbits and pigs. Wild rabbit isolates exhibited the genotype mrp-/epf-/sly-, different from those showed by most of the swine S. suis isolates of the ST87 and ST61 clones. None of the S. suis isolated from wild rabbits exhibited the genotype cps2/mrp+/epf+/sly+ associated with human infections. These results indicate that S. suis isolates from wild rabbits are not genetically related with prevalent clones usually associated with infections in pigs or humans in Europe and do not exhibit either their virulence genotypes. Therefore, although wild rabbits could represent an unknown reservoir of this pathogen, they could not represent a potential risk for pigs or humans.

  9. 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

  10. 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.

  11. 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

  12. 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

  13. 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.

  14. 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

  15. Analysis of expanded criteria to select candidates for active surveillance of low-risk prostate cancer

    PubMed Central

    Jo, Jung Ki; Lee, Han Sol; Lee, Young Ik; Lee, Sang Eun; Hong, Sung Kyu

    2015-01-01

    We aimed to analyze the value of each criterion for clinically insignificant prostate cancer (PCa) in the selection of men for active surveillance (AS) of low-risk PCa. We identified 532 men who were treated with radical prostatectomy from 2006 to 2013 who met 4 or all 5 of the criteria for clinically insignificant PCa (clinical stage ≤ T1, prostate specific antigen [PSA] density ≤ 0.15, biopsy Gleason score ≤ 6, number of positive biopsy cores ≤ 2, and no core with > 50% involvement) and analyzed their pathologic and biochemical outcomes. Patients who met all 5 criteria for clinically insignificant PCa were designated as group A (n = 172), and those who met 4 of 5 criteria were designated as group B (n = 360). The association of each criterion with adverse pathologic features was assessed via logistic regression analyses. Comparison of group A and B and also logistic regression analyses showed that PSA density > 0.15 ng ml−1 and high (≥7) biopsy Gleason score were associated with adverse pathologic features. Higher (> T1c) clinical stage was not associated with any adverse pathologic features. Although ≤ 3 positive cores were not associated with any adverse pathology, ≥4 positive cores were associated with higher risk of extracapsular extension. Among potential candidates for AS, PSA density > 0.15 ng ml−1 and biopsy Gleason score > 6 pose significantly higher risks of harboring more aggressive disease. The eligibility criteria for AS may be expanded to include men with clinical stage T2 tumor and 3 positive cores. PMID:25432498

  16. Analysis of expanded criteria to select candidates for active surveillance of low-risk prostate cancer.

    PubMed

    Jo, Jung Ki; Lee, Han Sol; Lee, Young Ik; Lee, Sang Eun; Hong, Sung Kyu

    2015-01-01

    We aimed to analyze the value of each criterion for clinically insignificant prostate cancer (PCa) in the selection of men for active surveillance (AS) of low-risk PCa. We identified 532 men who were treated with radical prostatectomy from 2006 to 2013 who met 4 or all 5 of the criteria for clinically insignificant PCa (clinical stage ≤ T1, prostate specific antigen [PSA] density ≤ 0.15, biopsy Gleason score ≤ 6, number of positive biopsy cores ≤ 2, and no core with > 50% involvement) and analyzed their pathologic and biochemical outcomes. Patients who met all 5 criteria for clinically insignificant PCa were designated as group A (n = 172), and those who met 4 of 5 criteria were designated as group B (n = 360). The association of each criterion with adverse pathologic features was assessed via logistic regression analyses. Comparison of group A and B and also logistic regression analyses showed that PSA density > 0.15 ng ml-1 and high (≥7) biopsy Gleason score were associated with adverse pathologic features. Higher (> T1c) clinical stage was not associated with any adverse pathologic features. Although ≤ 3 positive cores were not associated with any adverse pathology, ≥4 positive cores were associated with higher risk of extracapsular extension. Among potential candidates for AS, PSA density > 0.15 ng ml-1 and biopsy Gleason score > 6 pose significantly higher risks of harboring more aggressive disease. The eligibility criteria for AS may be expanded to include men with clinical stage T2 tumor and 3 positive cores.

  17. Genetic analysis of biodegradation of tetralin by a Sphingomonas strain

    SciTech Connect

    Hernaez, M.J.; Santero, E.; Reineke, W.

    1999-04-01

    Tetralin (1,2,3,4-tetrahydronaphthalene) is produced for industrial purposes from naphthalene by catalytic hydrogenation or from anthracene by cracking. A strain designated TFA which very efficiently utilizes tetralin has been isolated from the Rhine river. The strain has been identified as Sphingomonas macrogoltabidus, based on 16S rDNA sequence similarity. Genetic analysis of tetralin biodegradation has been performed by insertion mutagenesis and by physical analysis and analysis of complementation between the mutants. The genes involved in tetralin utilization are clustered in a region of 9 kb, comprising at least five genes grouped in two divergently transcribed operons.

  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.

  19. 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

  20. Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis

    PubMed Central

    Bagheri, Hani; Badduke, Chansonette; Qiao, Ying; Colnaghi, Rita; Abramowicz, Iga; Alcantara, Diana; Dunham, Christopher; Wen, Jiadi; Wildin, Robert S.; Nowaczyk, Malgorzata J.M.; Eichmeyer, Jennifer; Lehman, Anna; Maranda, Bruno; Martell, Sally; Shan, Xianghong; Lewis, Suzanne M.E.; O’Driscoll, Mark; Gregory-Evans, Cheryl Y.

    2016-01-01

    The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.1 microdeletion syndrome have been reported in the literature; however, the size of the deletions and their breakpoints vary, making it difficult to identify the candidate genes. Recent reports pointed to 4 genes (XPO1, USP34, BCL11A, and REL) that were included, alone or in combination, in the smallest deletions causing the syndrome. Here, we describe 8 new patients with the 2p15p16.1 deletion and review all published cases to date. We demonstrate functional deficits for the above 4 candidate genes using patients’ lymphoblast cell lines (LCLs) and knockdown of their orthologs in zebrafish. All genes were dosage sensitive on the basis of reduced protein expression in LCLs. In addition, deletion of XPO1, a nuclear exporter, cosegregated with nuclear accumulation of one of its cargo molecules (rpS5) in patients’ LCLs. Other pathways associated with these genes (e.g., NF-κB and Wnt signaling as well as the DNA damage response) were not impaired in patients’ LCLs. Knockdown of xpo1a, rel, bcl11aa, and bcl11ab resulted in abnormal zebrafish embryonic development including microcephaly, dysmorphic body, hindered growth, and small fins as well as structural brain abnormalities. Our multifaceted analysis strongly implicates XPO1, REL, and BCL11A as candidate genes for 2p15p16.1 microdeletion syndrome. PMID:27699255

  1. Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis

    PubMed Central

    Bagheri, Hani; Badduke, Chansonette; Qiao, Ying; Colnaghi, Rita; Abramowicz, Iga; Alcantara, Diana; Dunham, Christopher; Wen, Jiadi; Wildin, Robert S.; Nowaczyk, Malgorzata J.M.; Eichmeyer, Jennifer; Lehman, Anna; Maranda, Bruno; Martell, Sally; Shan, Xianghong; Lewis, Suzanne M.E.; O’Driscoll, Mark; Gregory-Evans, Cheryl Y.

    2016-01-01

    The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.1 microdeletion syndrome have been reported in the literature; however, the size of the deletions and their breakpoints vary, making it difficult to identify the candidate genes. Recent reports pointed to 4 genes (XPO1, USP34, BCL11A, and REL) that were included, alone or in combination, in the smallest deletions causing the syndrome. Here, we describe 8 new patients with the 2p15p16.1 deletion and review all published cases to date. We demonstrate functional deficits for the above 4 candidate genes using patients’ lymphoblast cell lines (LCLs) and knockdown of their orthologs in zebrafish. All genes were dosage sensitive on the basis of reduced protein expression in LCLs. In addition, deletion of XPO1, a nuclear exporter, cosegregated with nuclear accumulation of one of its cargo molecules (rpS5) in patients’ LCLs. Other pathways associated with these genes (e.g., NF-κB and Wnt signaling as well as the DNA damage response) were not impaired in patients’ LCLs. Knockdown of xpo1a, rel, bcl11aa, and bcl11ab resulted in abnormal zebrafish embryonic development including microcephaly, dysmorphic body, hindered growth, and small fins as well as structural brain abnormalities. Our multifaceted analysis strongly implicates XPO1, REL, and BCL11A as candidate genes for 2p15p16.1 microdeletion syndrome.

  2. 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

  3. Fine mapping and candidate gene analysis of the nuclear restorer gene Rfp for pol CMS in rapeseed (Brassica napus L.).

    PubMed

    Liu, Zhi; Liu, Pingwu; Long, Furong; Hong, Dengfeng; He, Qingbiao; Yang, Guangsheng

    2012-08-01

    The Polima (pol) system of cytoplasmic male sterility (CMS) in rapeseed is widely used in China for commercial hybrid seed production. Genetic studies have shown that its fertility restorer gene (Rfp) is monogenic dominant. For fine mapping of the Rfp gene, a near isogenic line comprising 3,662 individuals of BC(14)F(1) generation segregating for the Rfp gene was created. Based on the sequences of two SCAR markers, SCAP0612ST and SCAP0612EM2, developed by Zhao et al. (Genes Genom 30(3):191-196, 2008) and the synteny region of Brassica napus and other Brassica species, 13 markers strongly linked with the Rfp gene were identified. By integrating three of these markers to the published linkage map, the Rfp gene was mapped on linkage group N9 of B. napus. Using these markers, the Rfp locus was narrowed down to a 29.2-kb genomic region of Brassica rapa. Seven open reading frames (ORFs) were predicted in the target region, of these, ORF2, encoding a PPR protein, was the most likely candidate gene of Rfp. These results lay a solid foundation for map-based cloning of the Rfp gene and will be helpful for marker-assisted selection of elite CMS restorer lines.

  4. 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

  5. BRCA1: a new candidate gene for bovine mastitis and its association analysis between single nucleotide polymorphisms and milk somatic cell score.

    PubMed

    Yuan, Zhengrong; Chu, Guiyan; Dan, Yang; Li, Jiao; Zhang, Lupei; Gao, Xue; Gao, Huijiang; Li, Junya; Xu, Shangzhong; Liu, Zhihua

    2012-06-01

    Bovine mastitis is a very complex and common disease of dairy cattle and a major source of economic losses to the dairy industry worldwide. In this study, the bovine breast cancer 1, early onset gene (BRCA1) was taken as a candidate gene for mastitis resistance. The main object of this study was to investigate whether the BRCA1 gene was associated with mastitis in cattle. Through DNA sequencing, Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and Created Restriction Site PCR (CRS-PCR) methods, three SNPs (G22231T, T25025A, and C28300A) were detected and twenty-four combinations of these SNPs were observed. The single SNP and their genetic effects on somatic cell score (SCS) were evaluated and a significant association with SCS was found in C28300A. The mean of genotype EE was significantly lower than those of genotypes EF and FF. The results of combined genotypes analysis of three SNPs showed that BBDDFF genotype with the highest SCS were easily for the mastitis susceptibility, whereas AACCEE genotype with the lowest SCS were favorable for the mastitis resistance. The information provided in the present study will be very useful for improving mastitis resistance in dairy cattle by marker-assisted selection.

  6. Candidate gene expression analysis of toxin-induced dilated cardiomyopathy in the turkey (Meleagris gallopavo).

    PubMed

    Lin, K-C; Gyenai, K; Pyle, R L; Geng, T; Xu, J; Smith, E J

    2006-12-01

    Dilated cardiomyopathy (DCM), a heart disease, affects many vertebrates including humans and poultry. The disease can be either idiopathic (IDCM) or toxin-induced (TIDCM). Although genetic and other studies of IDCM are extensive, the specific etiology of TIDCM is still unknown. In this study, we compared mRNA levels of cardiac troponin T (cTnT) and phospholamban (PLN) in turkeys affected and unaffected by TIDCM. Cardiac TnT and PLN were chosen because their altered expression has been observed in IDCM-affected birds. A total of 72 birds, 44 affected and 28 unaffected with TIDCM, were used. Differences in the mRNA levels of cTnT and PLN between affected and unaffected turkeys were significant only for cTnT. The sequence of the turkey PLN showed significant similarity at the nucleotide level to the reference chicken sequence and to those of other species. In addition to implicating cTnT in TIDCM, the present work describes a partial turkey PLN coding sequence that could be useful for future studies.

  7. 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

  8. Molecular genetic analysis of hereditary non-polyposis colorectal cancer syndrome

    SciTech Connect

    Froggatt, N.J. |; Koch, D.J.; Barton, D.E.

    1994-09-01

    HNPCC is estimated to account for 5-10% of all cases of colorectal cancer. Recently genes for HNPCC have been mapped to chromosomes 2p and 3p and candidate genes (hMSH2 and hMLH1) have been identified. We have investigated the molecular pathology of HNPCC by linkage analysis and direct mutation analysis. 14 HNPCC families were investigated for linkage to hMSH2 and hMLH1 with microsatellite markers at D2S119, D2S123, D2S136, D2S391, D2S378 and D3S1007, D3S1029, D3S1076, D3S1298, D3S1611, respectively. Overall the only significant linkage was obtained with D2S123 (Zmax=3.77 at {theta}=0.0), but locus heterogeneity was confirmed: linkage to hMSH2 and hMLH1 was excluded in 6 and 5 families, respectively. 3 families were uniformative for linkage/exclusion to either candidate gene, but no evidence for a third HNPCC locus could be detected. There was no correlation between clinical phenotype (Lynch type I or II) and the results of linkage analysis. No individual family gave a lod score of >3 with any marker, and only a minority of our HNPCC families have been suitable for genetic linkage analysis. We therefore screened affected individuals from 37 unrelated kindreds for mutations in hMSH2 and exons 3 and 4 of the APC gene. Mutation screening was performed using exon specific primers and SSCP analysis. No abnormalities were found in the APC exons suggesting that mutations in these APC 5{prime} exons are not a common cause of HNPCC. hMSH2 screening is continuing, and one missense mutation in a highly conserved codon 322 in exon 6 has been identified.

  9. Identification and Expression Analysis of Candidate Genes Associated with Defense Responses to Phytophthora capsici in Pepper Line "PI 201234".

    PubMed

    Wang, Pingyong; Liu, Xiaodan; Guo, Jinju; Liu, Chen; Fu, Nan; Shen, Huolin

    2015-05-18

    Phytophthora capsici (Leonian), classified as an oomycete, seriously threatens the production of pepper (Capsicum annuum). Current understanding of the defense responses in pepper to P. capsici is limited. In this study, RNA-sequencing analysis was utilized to identify differentially expressed genes in the resistant line "PI 201234", with 1220 differentially expressed genes detected. Of those genes, 480 were up-regulated and 740 were down-regulated, with 211 candidate genes found to be involved in defense responses based on the gene annotations. Furthermore, the expression patterns of 12 candidate genes were further validated via quantitative real-time PCR (qPCR). These genes were found to be significantly up-regulated at different time points post-inoculation (6 hpi, 24 hpi, and 5 dpi) in the resistant line "PI 201234" and susceptible line "Qiemen". Seven genes were found to be involved in cell wall modification, phytoalexin biosynthesis, symptom development, and phytohormone signaling pathways, thus possibly playing important roles in combating exogenous pathogens. The genes identified herein will provide a basis for further gene cloning and functional verification studies and will aid in an understanding of the regulatory mechanism of pepper resistance to P. capsici.

  10. Types of disease and models for their genetic analysis.

    PubMed

    Elston, R C; Namboodiri, K K

    1980-01-01

    The authors compare schizophrenia with several other diseases and discuss how a few simple models that have already been successfully applied in other cases could be used in the genetic analysis of schizophrenia and MAO activity. Among the diseases discussed are Huntington's disease, xanthomatosis, and diabetes. The authors recommend undertaking multivariate studies of monoamine oxidase, dopamine beta-hydroxylase, and other traits associated with schizophrenia in single, large pedigrees ascertained through schizophrenic probands.

  11. The power of multiplexed functional analysis of genetic variants.

    PubMed

    Gasperini, Molly; Starita, Lea; Shendure, Jay

    2016-10-01

    New technologies have recently enabled saturation mutagenesis and functional analysis of nearly all possible variants of regulatory elements or proteins of interest in single experiments. Here we discuss the past, present, and future of such multiplexed (functional) assays for variant effects (MAVEs). MAVEs provide detailed insight into sequence-function relationships, and they may prove critical for the prospective clinical interpretation of genetic variants. PMID:27583640

  12. 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.

  13. 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

  14. 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.

  15. Automation of genetic linkage analysis using florescent microsatellite markers

    SciTech Connect

    Mansfield, D.C.; Brown, A.F.; Green, D.K.

    1994-11-15

    Automation of the typing of genetic markers offers advantages of speed, accuracy, and cost in the mapping of genetic traits and the construction of high-resolution linkage maps. The authors have developed an automated linkage analysis system by (i) using a robotic pipettor to set up polymerase chain reactions (PCR) to amplify microsatellites with incorporation of a single fluorescent label; (ii) using an automated sequencing apparatus for detection of the PCR products; (iii) sizing alleles automatically by the use of internal and external standards; (iv) iteratively filtering out nonallelic fragments and checking for Mendelian consistency; (v) calculating the probabilities of selected genotypes; and (vi) automatically formatting the results for input to linkage analysis programs. The method provides accurate sizing of alleles, minimizes the risk of error during manual reading and transcription of data, and increases the throughput of reliable data. It brings any consistencies or ambiguities in the data to the attention of the user and facilitates examination of the raw data. The ALF/ALP system, together with new, optimized microsatellite sets, particularly tetranucleotide repeats, is likely to be well-suited to fully automatic genetic linkage analysis. 32 refs., 2 figs., 2 tabs.

  16. 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

  17. 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