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Sample records for adhd candidate gene

  1. Functional Insight From Fruit Flies on Human ADHD Candidate Genes

    DEFF Research Database (Denmark)

    Rohde, Palle Duun; Demontis, Ditte; Arvidson, Sandra Marie Neumann

    2015-01-01

    for other mutants. Decreased activity level, when treated with dexamphetamine, is seen when using other ADHD animal models. Our findings suggest involvement of the proposed candidate genes Genes, Brain, and Behavior 2015 36 Talk Abstracts in hyperactivity in D. melanogaster, providing functional evidence...... of developing ADHD. We use Minos mutants, where target genes have been disrupted by the Minos transposable element, to test the effect on locomotor activity. By measuring the distance traveled, we find disparity in locomotor activity between control and Minos mutants. Impaired dopamine system underlies...

  2. The relationship between the presence of ADHD and certain candidate gene polymorphisms in a Turkish sample.

    Science.gov (United States)

    Pazvantoğlu, Ozan; Güneş, Sezgin; Karabekiroğlu, Koray; Yeğin, Zeynep; Erenkuş, Zehra; Akbaş, Seher; Sarısoy, Gökhan; Korkmaz, Işıl Zabun; Böke, Omer; Bağcı, Hasan; Sahin, Ahmet Rifat

    2013-10-10

    Due to the high heritability of attention-deficit hyperactivity disorder (ADHD), parents of children with ADHD appear to represent a good sample group for investigating the genetics of the disorder. The aim of this study was to investigate the association between ADHD and six polymorphisms in five candidate genes [5-HT2A (rs6311), NET1 (rs2242447), COMT (rs4818), NTF3 (rs6332), SNAP-25 (rs3746544) and (rs1051312)]. We included 228 parents of children diagnosed with ADHD and 109 healthy parents as the control group. The polymorphisms were genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) assays and analyzed using the chi-square test and the multinomial logit model. SNAP-25 (rs3746544) polymorphism was associated with loading for ADHD, while 5-HT2A (rs6311) and NET1 (rs2242447) polymorphisms were associated with ADHD. On the other hand, there was no significant association between the SNAP-25 (rs1051312), NTF3 (rs6332), or COMT (rs4818) gene polymorphisms and ADHD. In addition, we found that even if variation in the SNAP-25 gene alone does not affect the phenotype, it may nevertheless lead to the emergence of a clinical ADHD picture in the presence of other genetic factors. Our findings suggest that a combination of NET1 (rs2242447) and SNAP-25 (rs3746544) is a risk factor for ADHD. Problems associated with the noradrenergic and serotonergic systems and SNAP-25 may play a role, both alone and in interaction with one another, in the pathophysiological mechanisms of ADHD. © 2013 Elsevier B.V. All rights reserved.

  3. Overweight in Boys With ADHD Is Related to Candidate Genes and Not to Deficits in Cognitive Functions.

    Science.gov (United States)

    Hanć, Tomasz; Dmitrzak-Węglarz, Monika; Borkowska, Aneta; Wolańczyk, Tomasz; Pytlińska, Natalia; Rybakowski, Filip; Słopień, Radosław; Słopień, Agnieszka

    2016-11-03

    The aim of the study was to assess the relationship of overweight, the polymorphisms of selected candidate genes, and deficits in the executive functions among children with ADHD. We examined 109 boys with ADHD aged between 7 and 17 years. The study indicated variants of 14 polymorphisms in eight candidate genes. We applied seven neuropsychological tests to evaluate the executive functions. Overweight was diagnosed on the basis of the guidelines of the International Obesity Task Force. Analyses revealed significant association between DRD4 rs1800955, SNAP25 rs363039 and rs363043, 5HTR2A rs17288723, and overweight in boys with ADHD. There were no significant differences in the level of neuropsychological test results between patients with overweight and without overweight. Overweight in boys with ADHD is associated with polymorphisms in three candidate genes: DRD4, SNAP25, and 5HTR2A, but not through conditioning deficits in cognitive functions. © The Author(s) 2016.

  4. Attention déficit disorder (ADHD): socialdemographic description and study of candidates genes

    OpenAIRE

    Maria Aparecida da Silva Monteiro

    2005-01-01

    O Transtorno de déficit de atenção (TDAH) afeta entre 2% a 6% das crianças em idade escolar e os sintomas se caracterizam por desatenção, impulsividade e hiperatividade. Cerca de 2/3 persistem com sintomas na vida adulta que ocasionam desajustes em váriso setores da vida (afetivo, profissional, acadêmico).Em sua patofisiologia, há envolvimento dopaminérgico e estudos de associação observaram associação positiva com o gene para o transportador da dopamina (DAT1) e o gene para o receptor da dop...

  5. An Examination of the Behavioral and Neuropsychological Correlates of Three ADHD Candidate Gene Polymorphisms (DRD4 7+, DBH TaqI A2, and DAT1 40bp VNTR) in Hyperactive and Normal Children Followed to Adulthood

    Science.gov (United States)

    Barkley, Russell A.; Smith, Karen M.; Fischer, Mariellen; Navia, Bradford

    2008-01-01

    Several candidate gene polymorphisms have been implicated in attention deficit hyperactivity disorder (ADHD), including DAT1 40bp VNTR, DRD4 7+, and DBH TaqI A2 alleles. We used the Milwaukee longitudinal study of hyperactive (N=122) and normal (N=67) children to compare participants with and without these respective polymorphisms on ADHD-related behavioral ratings at childhood, 8 years later in adolescence, and 13+ years later into young adulthood. Neuropsychological tests were given at the adolescent and young adulthood follow-up. No differences were found between the DRD4-7+ and 7- repeat polymorphism. The DBH TaqI A2 allele, when homozygous, was associated with being more hyperactive in childhood, having more pervasive behavior problems at adolescence, and earning less money on a Card Playing Task in adulthood. At adolescence, poorer test scores were also found only in the hyperactive group with homozygous for this allele. The DAT1 40bp VNTR heterozygous 9/10 repeat, however, differed from the 10/10 repeat pair in many respects, having greater ADHD and externalizing symptoms at all three follow-ups, more cross-situational behavioral problems at both childhood and adolescence, poorer mother-teen relations at adolescence, and lower class rankings in high school. Participants with the 9/10 pair in the control group also had lower work performance, a lower grade point average in high school, greater teacher rated externalizing symptoms at adolescence, and greater omission errors on a continuous performance test in adulthood. The DAT1 40bp VNTR 9/10 polymorphism pairing appears to be reliably associated with greater symptoms of ADHD and externalizing behavior from childhood to adulthood, and with family, educational, and occupational impairments. We also present a contrary view on the appropriate endophenotypes for use in behavioral genetic research on ADHD. PMID:16741944

  6. Enlarged striatal volume in adults with ADHD carrying the 9-6 haplotype of the dopamine transporter gene DAT1.

    OpenAIRE

    Onnink, A.M.H; Franke, B.; Hulzen, K.J.E. van; M. P. Zwiers; J. C. Mostert; Schene, A.H.; Heslenfeld, D.J.; Oosterlaan, J.; Hoekstra, P.J.; Hartman, C. A.; Arias Vasquez, A.; Kan, C.C.; Buitelaar, J. K.; Hoogman, M.

    2016-01-01

    The dopamine transporter gene, DAT1 (SLC6A3), has been studied extensively as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). Different alleles of variable number of tandem repeats (VNTRs) in this gene have been associated with childhood ADHD (10/10 genotype and haplotype 10-6) and adult ADHD (haplotype 9-6). This suggests a differential association depending on age, and a role of DAT1 in modulating the ADHD phenotype over the lifespan. The DAT1 gene may mediate suscepti...

  7. The Dopamine Receptor D4 Gene ("DRD4") Moderates Family Environmental Effects on ADHD

    Science.gov (United States)

    Martel, Michelle M.; Nikolas, Molly; Jernigan, Katherine; Friderici, Karen; Waldman, Irwin; Nigg, Joel T.

    2011-01-01

    Attention-Deficit/Hyperactivity Disorder (ADHD) is a prime candidate for exploration of gene-by-environment interaction (i.e., G x E), particularly in relation to dopamine system genes, due to strong evidence that dopamine systems are dysregulated in the disorder. Using a G x E design, we examined whether the "DRD4" promoter 120-bp tandem repeat…

  8. ADHD

    Science.gov (United States)

    ... Situations Talking to Your Parents - or Other Adults ADHD KidsHealth > For Teens > ADHD Print A A A ... It Like for People With ADHD? What Is ADHD? Everyone has trouble at times with paying attention, ...

  9. Testing candidate genes for attention-deficit/hyperactivity disorder in fruit flies using a high throughput assay for complex behavior

    DEFF Research Database (Denmark)

    Rohde, Palle Duun; Madsen, Lisbeth Strøm; Arvidson, Sandra Marie Neumann

    2016-01-01

    Fruit flies are important model organisms for functional testing of candidate genes in multiple disciplines, including the study of human diseases. Here we use a high-throughput locomotor activity assay to test the response on activity behavior of gene disruption in Drosophila melanogaster. The aim...... was to investigate the impact of disruption of 14 candidate genes for human attention-deficit/hyperactivity disorder (ADHD) on fly behavior. By obtaining a range of correlated measures describing the space of variables for behavioral activity we show, that some mutants display similar phenotypic responses...... in fruit flies. Results provide additional support for the investigated genes being risk candidate genes for ADHD in humans....

  10. Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism.

    Science.gov (United States)

    Naaijen, J; Bralten, J; Poelmans, G; Glennon, J C; Franke, B; Buitelaar, J K

    2017-01-10

    Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample (n=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (P=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (P=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD.

  11. Evaluating historical candidate genes for schizophrenia

    DEFF Research Database (Denmark)

    Farrell, M S; Werge, T; Sklar, P

    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 (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of thes...

  12. Bioinformatics methods for identifying candidate disease genes

    Directory of Open Access Journals (Sweden)

    van Driel Marc A

    2006-06-01

    Full Text Available Abstract With the explosion in genomic and functional genomics information, methods for disease gene identification are rapidly evolving. Databases are now essential to the process of selecting candidate disease genes. Combining positional information with disease characteristics and functional information is the usual strategy by which candidate disease genes are selected. Enrichment for candidate disease genes, however, depends on the skills of the operating researcher. Over the past few years, a number of bioinformatics methods that enrich for the most likely candidate disease genes have been developed. Such in silico prioritisation methods may further improve by completion of datasets, by development of standardised ontologies across databases and species and, ultimately, by the integration of different strategies.

  13. Gene × environment interactions for ADHD: synergistic effect of 5HTTLPR genotype and youth appraisals of inter-parental conflict

    Directory of Open Access Journals (Sweden)

    Jernigan Katherine

    2010-04-01

    Full Text Available Abstract Background Serotonin genes have been hypothesized to play a role in the etiology of attention-deficit hyperactivity disorder (ADHD; prior work suggests that serotonin may interact with psychosocial stressors in ADHD, perhaps via mechanisms involved in emotional dysregulation. Because the development of behavioral and emotional regulation depends heavily both on the child's experience within the family context and the child's construals of that experience, children's appraisals of inter-parental conflict are a compelling candidate potentiator of the effects of variation within the serotonin transporter gene promoter polymorphism (5HTTLPR on liability for ADHD. Method 304 youth from the local community underwent a multi-informant diagnostic assessment procedure to identify ADHD cases and non-ADHD controls. Youth also completed the Children's Perception of Inter-Parental Conflict (CPIC scale to assess appraisals of self-blame in relation to their parents' marital disputes. The trialleic configuration of 5HTTLPR (long/short polymorphism with A> G substitution was genotyped and participants were assigned as having high (La/La N = 78, intermediate (La/Lg, La/short, N = 137, or low (Lg/Lg, Lg/short, short/short, N = 89 serotonin transporter activity genotypes. Teacher reported behavior problems were examined as the target outcome to avoid informant overlap for moderator and outcome measures. Results Hierarchical linear regression analyses indicated significant 5HTTLPR × self-blame interactions for ADHD symptoms. Examination of the interactions indicated positive relations between reports of self-blame and ADHD symptoms for those with the high and low serotonin activity genotypes. There was no relation between self-blame and ADHD for those with intermediate activity 5HTTLPR genotypes. Conclusion Both high and low serotonergic activity may exert risk for ADHD when coupled with psychosocial distress such as children's self-blame in relation to

  14. Gene x environment interactions for ADHD: synergistic effect of 5HTTLPR genotype and youth appraisals of inter-parental conflict.

    Science.gov (United States)

    Nikolas, Molly; Friderici, Karen; Waldman, Irwin; Jernigan, Katherine; Nigg, Joel T

    2010-04-16

    Serotonin genes have been hypothesized to play a role in the etiology of attention-deficit hyperactivity disorder (ADHD); prior work suggests that serotonin may interact with psychosocial stressors in ADHD, perhaps via mechanisms involved in emotional dysregulation. Because the development of behavioral and emotional regulation depends heavily both on the child's experience within the family context and the child's construals of that experience, children's appraisals of inter-parental conflict are a compelling candidate potentiator of the effects of variation within the serotonin transporter gene promoter polymorphism (5HTTLPR) on liability for ADHD. 304 youth from the local community underwent a multi-informant diagnostic assessment procedure to identify ADHD cases and non-ADHD controls. Youth also completed the Children's Perception of Inter-Parental Conflict (CPIC) scale to assess appraisals of self-blame in relation to their parents' marital disputes. The trialleic configuration of 5HTTLPR (long/short polymorphism with A> G substitution) was genotyped and participants were assigned as having high (La/La N = 78), intermediate (La/Lg, La/short, N = 137), or low (Lg/Lg, Lg/short, short/short, N = 89) serotonin transporter activity genotypes. Teacher reported behavior problems were examined as the target outcome to avoid informant overlap for moderator and outcome measures. Hierarchical linear regression analyses indicated significant 5HTTLPR x self-blame interactions for ADHD symptoms. Examination of the interactions indicated positive relations between reports of self-blame and ADHD symptoms for those with the high and low serotonin activity genotypes. There was no relation between self-blame and ADHD for those with intermediate activity 5HTTLPR genotypes. Both high and low serotonergic activity may exert risk for ADHD when coupled with psychosocial distress such as children's self-blame in relation to inter-parental conflict. Results are discussed in relation to

  15. Gene × environment interactions for ADHD: synergistic effect of 5HTTLPR genotype and youth appraisals of inter-parental conflict

    Science.gov (United States)

    2010-01-01

    Background Serotonin genes have been hypothesized to play a role in the etiology of attention-deficit hyperactivity disorder (ADHD); prior work suggests that serotonin may interact with psychosocial stressors in ADHD, perhaps via mechanisms involved in emotional dysregulation. Because the development of behavioral and emotional regulation depends heavily both on the child's experience within the family context and the child's construals of that experience, children's appraisals of inter-parental conflict are a compelling candidate potentiator of the effects of variation within the serotonin transporter gene promoter polymorphism (5HTTLPR) on liability for ADHD. Method 304 youth from the local community underwent a multi-informant diagnostic assessment procedure to identify ADHD cases and non-ADHD controls. Youth also completed the Children's Perception of Inter-Parental Conflict (CPIC) scale to assess appraisals of self-blame in relation to their parents' marital disputes. The trialleic configuration of 5HTTLPR (long/short polymorphism with A> G substitution) was genotyped and participants were assigned as having high (La/La N = 78), intermediate (La/Lg, La/short, N = 137), or low (Lg/Lg, Lg/short, short/short, N = 89) serotonin transporter activity genotypes. Teacher reported behavior problems were examined as the target outcome to avoid informant overlap for moderator and outcome measures. Results Hierarchical linear regression analyses indicated significant 5HTTLPR × self-blame interactions for ADHD symptoms. Examination of the interactions indicated positive relations between reports of self-blame and ADHD symptoms for those with the high and low serotonin activity genotypes. There was no relation between self-blame and ADHD for those with intermediate activity 5HTTLPR genotypes. Conclusion Both high and low serotonergic activity may exert risk for ADHD when coupled with psychosocial distress such as children's self-blame in relation to inter-parental conflict

  16. Candidate genes in panic disorder

    DEFF Research Database (Denmark)

    Howe, A. S.; Buttenschön, Henriette N; Bani-Fatemi, A.

    2016-01-01

    The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered...

  17. Is dopamine transporter gene effective on therapeutic response of methylphenidate in ADHD patients?

    Directory of Open Access Journals (Sweden)

    Fatemeh Moharrari

    2015-01-01

    Full Text Available Attention-deficit/hyperactivity disorder (ADHD is the most common neuropsychiatric illness, which affects about 5% of children worldwide. An 80% genetic background is responsible for ADHD due to its appearance in familial relationships. In addition, dopamine regulation in synaptic spaces, which have a central role in development of ADHD, is moderated by dopamine transporter neurotransmitter, which in turn is modulated by dopamine transporter gene named SLC6A3 or DAT1. Methylphenidate as the first line and most important prescribed medication for ADHD blocks dopamine transporter and increases the dopamine concentration in synaptic clefts. In theory, methylphenidate relay to dopamine transporter to play a role, and dopamine transporter synthesis is dependent on DAT1. This gene have 40 base pair in its 3`-untranslated region end that repeat from 3 to 11 times, with most frequent 9 and 10 repeats in human, forming several alleles in carriers including 9R and 10R and genotypes including 9R/9R, 10R/10R, 9R/10R. These genotypes, as the first suspected candidates, may explain why methylphenidate therapy is not sufficient some patients and how the side effects appear in some cases and not in all patients. Many studies have performed to investigate the association between responses to methylphenidate and genotypes and yet no consistency has occurred. This article has a rapid review on concerned literature.

  18. Psychiatric gene discoveries shape evidence on ADHD's biology.

    Science.gov (United States)

    Thapar, A; Martin, J; Mick, E; Arias Vásquez, A; Langley, K; Scherer, S W; Schachar, R; Crosbie, J; Williams, N; Franke, B; Elia, J; Glessner, J; Hakonarson, H; Owen, M J; Faraone, S V; O'Donovan, M C; Holmans, P

    2016-09-01

    A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10(-4)) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders.

  19. Psychiatric gene discoveries shape evidence on ADHD's biology

    NARCIS (Netherlands)

    Thapar, A.; Martin, J.; Mick, E.; Arias Vasquez, A.; Langley, K.; Scherer, S.W.; Schachar, R.; Crosbie, J.; Williams, N.; Franke, B.; Elia, J.; Glessner, J.; Hakonarson, H.; Owen, M.J.; Faraone, S.V; O'Donovan, M.C.; Holmans, P.

    2016-01-01

    A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its

  20. Cattle Candidate Genes for Meat Production Traits

    OpenAIRE

    Bláhová, Alice

    2013-01-01

    The objective of this study was to compile a summary of the most important candidate genes for meat production. The studied genes were: GH, GHR, MSTN, MyoD family, leptin, IGF, TG5, SCD, DGAT and STAT5A. Growth hormone (GH) is involved in physiological processes of growth and metabolism. Growth hormone receptor (GHR) has been proposed as a candidate gene for meat production in cattle. Myostatin is a significant marker. It affects the amount of muscle, reduces marbling and elevate meat tendern...

  1. Phenoscape: Identifying Candidate Genes for Evolutionary Phenotypes

    Science.gov (United States)

    Edmunds, Richard C.; Su, Baofeng; Balhoff, James P.; Eames, B. Frank; Dahdul, Wasila M.; Lapp, Hilmar; Lundberg, John G.; Vision, Todd J.; Dunham, Rex A.; Mabee, Paula M.; Westerfield, Monte

    2016-01-01

    Phenotypes resulting from mutations in genetic model organisms can help reveal candidate genes for evolutionarily important phenotypic changes in related taxa. Although testing candidate gene hypotheses experimentally in nonmodel organisms is typically difficult, ontology-driven information systems can help generate testable hypotheses about developmental processes in experimentally tractable organisms. Here, we tested candidate gene hypotheses suggested by expert use of the Phenoscape Knowledgebase, specifically looking for genes that are candidates responsible for evolutionarily interesting phenotypes in the ostariophysan fishes that bear resemblance to mutant phenotypes in zebrafish. For this, we searched ZFIN for genetic perturbations that result in either loss of basihyal element or loss of scales phenotypes, because these are the ancestral phenotypes observed in catfishes (Siluriformes). We tested the identified candidate genes by examining their endogenous expression patterns in the channel catfish, Ictalurus punctatus. The experimental results were consistent with the hypotheses that these features evolved through disruption in developmental pathways at, or upstream of, brpf1 and eda/edar for the ancestral losses of basihyal element and scales, respectively. These results demonstrate that ontological annotations of the phenotypic effects of genetic alterations in model organisms, when aggregated within a knowledgebase, can be used effectively to generate testable, and useful, hypotheses about evolutionary changes in morphology. PMID:26500251

  2. Association of the dopamine transporter gene and ADHD symptoms in a Canadian population-based sample of same-age twins.

    Science.gov (United States)

    Ouellet-Morin, Isabelle; Wigg, Karen G; Feng, Yu; Dionne, Ginette; Robaey, Philippe; Brendgen, Mara; Vitaro, Frank; Simard, Louise; Schachar, Russell; Tremblay, Richard E; Pérusse, Daniel; Boivin, Michel; Barr, Cathy L

    2008-12-05

    Attention deficit hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder emerging during childhood. Psychostimulant medications (e.g., methylphenidate) noticeably reduce ADHD symptoms in most children. Since methylphenidate inhibits dopamine transporter activity, the dopamine transporter gene (DAT1) was considered to be the prime candidate risk gene in ADHD. Several studies found evidence for an association between the 10-repeat allele of the variable number of tandem repeat (VNTR) located in the 3' untranslated region and ADHD and/or ADHD symptoms in clinical and population-based samples. However, this finding was not replicated in all samples. In this study, we investigated the association between the DAT1 gene and ADHD symptoms in a population-based twin sample from Québec (Canada). We used two polymorphisms, the VNTR and rs27072, the last providing the most significant results in a clinical sample from Toronto (Ontario, Canada). No association was noted between the VNTR and ADHD symptoms in children at 6 and 7 years of age, as reported by teachers. However, a significant association was found for the rs27072 polymorphism and symptoms of inattention and hyperactivity/impulsivity. These findings indicate that the DAT1 gene contributes to ADHD symptoms in this sample and further suggest that the VNTR may not be the optimal polymorphism for study in all populations. Copyright 2007 Wiley-Liss, Inc.

  3. Candidate genetic pathways for attention-deficit/hyperactivity disorder (ADHD) show association to hyperactive/impulsive symptoms in children with ADHD.

    Science.gov (United States)

    Bralten, Janita; Franke, Barbara; Waldman, Irwin; Rommelse, Nanda; Hartman, Catharina; Asherson, Philip; Banaschewski, Tobias; Ebstein, Richard P; Gill, Michael; Miranda, Ana; Oades, Robert D; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph A; Oosterlaan, Jaap; Sonuga-Barke, Edmund; Steinhausen, Hans-Christoph; Faraone, Stephen V; Buitelaar, Jan K; Arias-Vásquez, Alejandro

    2013-11-01

    Because multiple genes with small effect sizes are assumed to play a role in attention-deficit/hyperactivity disorder (ADHD) etiology, considering multiple variants within the same analysis likely increases the total explained phenotypic variance, thereby boosting the power of genetic studies. This study investigated whether pathway-based analysis could bring scientists closer to unraveling the biology of ADHD. The pathway was described as a predefined gene selection based on a well-established database or literature data. Common genetic variants in pathways involved in dopamine/norepinephrine and serotonin neurotransmission and genes involved in neuritic outgrowth were investigated in cases from the International Multicentre ADHD Genetics (IMAGE) study. Multivariable analysis was performed to combine the effects of single genetic variants within the pathway genes. Phenotypes were DSM-IV symptom counts for inattention and hyperactivity/impulsivity (n = 871) and symptom severity measured with the Conners Parent (n = 930) and Teacher (n = 916) Rating Scales. Summing genetic effects of common genetic variants within the pathways showed a significant association with hyperactive/impulsive symptoms ((p)empirical = .007) but not with inattentive symptoms ((p)empirical = .73). Analysis of parent-rated Conners hyperactive/impulsive symptom scores validated this result ((p)empirical = .0018). Teacher-rated Conners scores were not associated. Post hoc analyses showed a significant contribution of all pathways to the hyperactive/impulsive symptom domain (dopamine/norepinephrine, (p)empirical = .0004; serotonin, (p)empirical = .0149; neuritic outgrowth, (p)empirical = .0452). The present analysis shows an association between common variants in 3 genetic pathways and the hyperactive/impulsive component of ADHD. This study demonstrates that pathway-based association analyses, using quantitative measurements of ADHD symptom domains, can increase the power of genetic analyses to

  4. ADHD

    Science.gov (United States)

    ... If you or your doctor has concerns about ADHD, you can take your child to a specialist such as a child psychologist or developmental pediatrician, or you can contact your local early intervention agency (for children under 3) or public school ( ...

  5. DAZLA: an important candidate gene in male subfertility?

    NARCIS (Netherlands)

    Golde, R.J.T. van; Tuerlings, J.H.A.M.; Kremer, J.A.M.; Braat, D.D.M.; Schoute, F.; Hoefsloot, L.H.

    2001-01-01

    PURPOSE: To study the role of the autosomal candidate gene DAZLA (Deleted in AZoospermia Like Autosome) in male subfertility. METHODS: We reviewed clinical data of subfertile men with oligozoospermia or azoospermia, mostly candidates for intracytoplasmic sperm injection (ICSI). Mutation detection

  6. Evaluation of common variants in 16 genes involved in the regulation of neurotransmitter release in ADHD.

    Science.gov (United States)

    Sánchez-Mora, Cristina; Cormand, Bru; Ramos-Quiroga, Josep Antoni; Hervás, Amaia; Bosch, Rosa; Palomar, Glòria; Nogueira, Mariana; Gómez-Barros, Núria; Richarte, Vanesa; Corrales, Montse; Garcia-Martinez, Iris; Corominas, Roser; Guijarro, Silvina; Bigorra, Aitana; Bayés, Mònica; Casas, Miguel; Ribasés, Marta

    2013-06-01

    Attention-deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by inappropriate difficulties to sustain attention, control impulses and modulate activity level. Although ADHD is one of the most prevalent childhood psychiatric disorders, it also persists into adulthood in around 30-50% of the cases. Based on the effect of psychostimulants used in the pharmacological treatment of ADHD, dysfunctions in neuroplasticity mechanisms and synapses have been postulated to be involved in the pathophysiology of ADHD. With this background, we evaluated, both in childhood and adulthood ADHD, the role of several genes involved in the control of neurotransmitter release through synaptic vesicle docking, fusion and recycling processes by means of a population-based association study. We analyzed single nucleotide polymorphisms across 16 genes in a clinical sample of 950 ADHD patients (506 adults and 444 children) and 905 controls. Single and multiple-marker analyses identified several significant associations after correcting for multiple testing with a false discovery rate (FDR) of 15%: (i) the SYT2 gene was strongly associated with both adulthood and childhood ADHD (p=0.001, OR=1.49 (1.18-1.89) and p=0.007, OR=1.37 (1.09-1.72), respectively) and (ii) STX1A was found associated with ADHD only in adults (p=0.0041; OR=1.28 (1.08-1.51)). These data provide preliminary evidence for the involvement of genes that participate in the control of neurotransmitter release in the genetic predisposition to ADHD through a gene-system association study. Further follow-up studies in larger cohorts and deep-sequencing of the associated genomic regions are required to identify sequence variants directly involved in ADHD. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

  7. Folate metabolism gene 5,10-methylenetetrahydrofolate reductase (MTHFR is associated with ADHD in myelomeningocele patients.

    Directory of Open Access Journals (Sweden)

    Catherine J Spellicy

    Full Text Available The objective of this study was to examine the relation between the 5, 10-methylenetetrahydrofolate reductase (MTHFR gene and behaviors related to attention- deficit/hyperactivity disorder (ADHD in individuals with myelomeningocele. The rationale for the study was twofold: folate metabolizing genes, (e.g. MTHFR, are important not only in the etiology of neural tube defects but are also critical to cognitive function; and individuals with myelomeningocele have an elevated incidence of ADHD. Here, we tested 478 individuals with myelomeningocele for attention-deficit hyperactivity disorder behavior using the Swanson Nolan Achenbach Pelham-IV ADHD rating scale. Myelomeningocele participants in this group for whom DNAs were available were genotyped for seven single nucleotide polymorphisms (SNPs in the MTHFR gene. The SNPs were evaluated for an association with manifestation of the ADHD phenotype in children with myelomeningocele. The data show that 28.7% of myelomeningocele participants exhibit rating scale elevations consistent with ADHD; of these 70.1% had scores consistent with the predominantly inattentive subtype. In addition, we also show a positive association between the SNP rs4846049 in the 3'-untranslated region of the MTHFR gene and the attention-deficit hyperactivity disorder phenotype in myelomeningocele participants. These results lend further support to the finding that behavior related to ADHD is more prevalent in patients with myelomeningocele than in the general population. These data also indicate the potential importance of the MTHFR gene in the etiology of the ADHD phenotype.

  8. Folate metabolism gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with ADHD in myelomeningocele patients.

    Science.gov (United States)

    Spellicy, Catherine J; Northrup, Hope; Fletcher, Jack M; Cirino, Paul T; Dennis, Maureen; Morrison, Alanna C; Martinez, Carla A; Au, Kit Sing

    2012-01-01

    The objective of this study was to examine the relation between the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and behaviors related to attention- deficit/hyperactivity disorder (ADHD) in individuals with myelomeningocele. The rationale for the study was twofold: folate metabolizing genes, (e.g. MTHFR), are important not only in the etiology of neural tube defects but are also critical to cognitive function; and individuals with myelomeningocele have an elevated incidence of ADHD. Here, we tested 478 individuals with myelomeningocele for attention-deficit hyperactivity disorder behavior using the Swanson Nolan Achenbach Pelham-IV ADHD rating scale. Myelomeningocele participants in this group for whom DNAs were available were genotyped for seven single nucleotide polymorphisms (SNPs) in the MTHFR gene. The SNPs were evaluated for an association with manifestation of the ADHD phenotype in children with myelomeningocele. The data show that 28.7% of myelomeningocele participants exhibit rating scale elevations consistent with ADHD; of these 70.1% had scores consistent with the predominantly inattentive subtype. In addition, we also show a positive association between the SNP rs4846049 in the 3'-untranslated region of the MTHFR gene and the attention-deficit hyperactivity disorder phenotype in myelomeningocele participants. These results lend further support to the finding that behavior related to ADHD is more prevalent in patients with myelomeningocele than in the general population. These data also indicate the potential importance of the MTHFR gene in the etiology of the ADHD phenotype.

  9. Candidate Gene Identification of Flowering Time Genes in Cotton

    Directory of Open Access Journals (Sweden)

    Corrinne E. Grover

    2015-07-01

    Full Text Available Flowering time control is critically important to all sexually reproducing angiosperms in both natural ecological and agronomic settings. Accordingly, there is much interest in defining the genes involved in the complex flowering-time network and how these respond to natural and artificial selection, the latter often entailing transitions in day-length responses. Here we describe a candidate gene analysis in the cotton genus , which uses homologs from the well-described flowering network to bioinformatically and phylogenetically identify orthologs in the published genome sequence from Ulbr., one of the two model diploid progenitors of the commercially important allopolyploid cottons, L. and L. Presence and patterns of expression were evaluated from 13 aboveground tissues related to flowering for each of the candidate genes using allopolyploid as a model. Furthermore, we use a comparative context to determine copy number variability of each key gene family across 10 published angiosperm genomes. Data suggest a pattern of repeated loss of duplicates following ancient whole-genome doubling events in diverse lineages. The data presented here provide a foundation for understanding both the parallel evolution of day-length neutrality in domesticated cottons and the flowering-time network, in general, in this important crop plant.

  10. The ATXN1 and TRIM31 genes are related to intelligence in an ADHD background: Evidence from a large collaborative study totaling 4,963 Subjects

    Science.gov (United States)

    Rizzi, Thais S; Arias-Vasquez, Alejandro; Rommelse, Nanda; Kuntsi, Jonna; Anney, Richard; Asherson, Philip; Buitelaar, Jan; Banaschewski, Tobias; Ebstein, Richard; Ruano, Dina; Van der Sluis, Sophie; Markunas, Christina A; Garrett, Melanie E; Ashley-Koch, Allison E; Kollins, Scott H; Anastopoulos, Arthur D; Hansell, Narelle K; Wright, Margaret J; Montgomery, Grant W; Martin, Nicholas G; Harris, Sarah E; Davies, Gail; Tenesa, Albert; Porteous, David J; Starr, John M; Deary, Ian J; St. Pourcain, Beate; Smith, George Davey; Timpson, Nicholas J; Evans, David M; Gill, Michael; Miranda, Ana; Mulas, Fernando; Oades, Robert D; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph; Sonuga-Barke, Edmund; Steinhausen, Hans Christoph; Taylor, Eric; Faraone, Stephen V; Franke, Barbara; Posthuma, Danielle

    2011-01-01

    Intelligence is a highly heritable trait for which it has proven difficult to identify the actual genes. In the past decade, five whole-genome linkage scans have suggested genomic regions important to human intelligence; however, so far none of the responsible genes or variants in those regions have been identified. Apart from these regions, a handful of candidate genes have been identified, although most of these are in need of replication. The recent growth in publicly available data sets that contain both whole genome association data and a wealth of phenotypic data, serves as an excellent resource for fine mapping and candidate gene replication. We used the publicly available data of 947 families participating in the International Multi-Centre ADHD Genetics (IMAGE) study to conduct an in silico fine mapping study of previously associated genomic locations, and to attempt replication of previously reported candidate genes for intelligence. Although this sample was ascertained for attention deficit/hyperactivity disorder (ADHD), intelligence quotient (IQ) scores were distributed normally. We tested 667 single nucleotide polymorphisms (SNPs) within 15 previously reported candidate genes for intelligence and 29451 SNPs in five genomic loci previously identified through whole genome linkage and association analyses. Significant SNPs were tested in four independent samples (4,357 subjects), one ascertained for ADHD, and three population-based samples. Associations between intelligence and SNPs in the ATXN1 and TRIM31 genes and in three genomic locations showed replicated association, but only in the samples ascertained for ADHD, suggesting that these genetic variants become particularly relevant to IQ on the background of a psychiatric disorder. © 2010 Wiley-Liss, Inc. PMID:21302343

  11. Disease candidate gene identification and prioritization using protein interaction networks

    Directory of Open Access Journals (Sweden)

    Aronow Bruce J

    2009-02-01

    Full Text Available Abstract Background Although most of the current disease candidate gene identification and prioritization methods depend on functional annotations, the coverage of the gene functional annotations is a limiting factor. In the current study, we describe a candidate gene prioritization method that is entirely based on protein-protein interaction network (PPIN analyses. Results For the first time, extended versions of the PageRank and HITS algorithms, and the K-Step Markov method are applied to prioritize disease candidate genes in a training-test schema. Using a list of known disease-related genes from our earlier study as a training set ("seeds", and the rest of the known genes as a test list, we perform large-scale cross validation to rank the candidate genes and also evaluate and compare the performance of our approach. Under appropriate settings – for example, a back probability of 0.3 for PageRank with Priors and HITS with Priors, and step size 6 for K-Step Markov method – the three methods achieved a comparable AUC value, suggesting a similar performance. Conclusion Even though network-based methods are generally not as effective as integrated functional annotation-based methods for disease candidate gene prioritization, in a one-to-one comparison, PPIN-based candidate gene prioritization performs better than all other gene features or annotations. Additionally, we demonstrate that methods used for studying both social and Web networks can be successfully used for disease candidate gene prioritization.

  12. Candidate gene polymorphisms among North Indians and their ...

    Indian Academy of Sciences (India)

    Knowledge of candidate gene polymorphisms in a population is useful for a variety of gene–disease association studies, particularly for some complex traits. A number of candidate genes, a majority of them from the monoaminergic pathway in the brain, have been very popular in association studies with schizophrenia, ...

  13. Generating Genome-Scale Candidate Gene Lists for Pharmacogenomics

    DEFF Research Database (Denmark)

    Hansen, Niclas Tue; Brunak, Søren; Altman, R. B.

    2009-01-01

    A critical task in pharmacogenomics is identifying genes that may be important modulators of drug response. High-throughput experimental methods are often plagued by false positives and do not take advantage of existing knowledge. Candidate gene lists can usefully summarize existing knowledge, bu...... method achieves an overall area under the curve of 0.82. To showcase our method, we found novel gene candidates for warfarin, gefitinib, carboplatin, and gemcitabine, and we provide the molecular hypotheses for these predictions....

  14. Identification of putative candidate gene markers for grain zinc ...

    African Journals Online (AJOL)

    Identification of putative candidate gene markers for grain zinc content using recombinant inbred lines (RIL) population of IRRI38 X Jeerigesanna. Naveen Kumar Gande, Pavan J Kundur, Rakhi Soman, Rajeswari Ambati, R Ashwathanarayana, Berhanu Dagnaw Bekele, HE Shashidhar ...

  15. Assessment of ADHD Documentation from Candidates Requesting Americans with Disabilities Act (ADA) Accommodations for the National Board of Osteopathic Medical Examiners COMLEX Exam

    Science.gov (United States)

    Joy, Javed A.; Julius, Rose J.; Akter, Rashida; Baron, David A.

    2010-01-01

    Purpose: Every year increasing numbers of candidates request special accommodations for high-stakes medical licensing examinations, due to ADHD, on the basis of the Americans with Disabilities Act (ADA). This poses significant challenges for both the applicant and the medical boards and has significant financial, legal, and ethical implications.…

  16. Novel candidate genes associated with hippocampal oscillations.

    NARCIS (Netherlands)

    Jansen, R.; Timmerman, J.; Loos, M.; Spijker, S.; van Ooyen, A.; Brussaard, A.B.; Mansvelder, H.D.; Smit, A.B.; de Gunst, M.; Linkenkaer-Hansen, K.

    2011-01-01

    The hippocampus is critical for a wide range of emotional and cognitive behaviors. Here, we performed the first genome-wide search for genes influencing hippocampal oscillations. We measured local field potentials (LFPs) using 64-channel multi-electrode arrays in acute hippocampal slices of 29 BXD

  17. Whole genome homology-based identification of candidate genes ...

    African Journals Online (AJOL)

    ... and might play some important roles in drought tolerance in sesame. Our results provided genomic resources for further functional analysis and genetic engineering towards drought tolerance improvement in sesame. Keywords: Sesamum indicum, candidate genes, drought tolerance, orthologous gene, whole genome ...

  18. Candidate genes for idiopathic epilepsy in four dog breeds

    Directory of Open Access Journals (Sweden)

    Mickelson James R

    2011-04-01

    Full Text Available Abstract Background Idiopathic epilepsy (IE is a naturally occurring and significant seizure disorder affecting all dog breeds. Because dog breeds are genetically isolated populations, it is possible that IE is attributable to common founders and is genetically homogenous within breeds. In humans, a number of mutations, the majority of which are genes encoding ion channels, neurotransmitters, or their regulatory subunits, have been discovered to cause rare, specific types of IE. It was hypothesized that there are simple genetic bases for IE in some purebred dog breeds, specifically in Vizslas, English Springer Spaniels (ESS, Greater Swiss Mountain Dogs (GSMD, and Beagles, and that the gene(s responsible may, in some cases, be the same as those already discovered in humans. Results Candidate genes known to be involved in human epilepsy, along with selected additional genes in the same gene families that are involved in murine epilepsy or are expressed in neural tissue, were examined in populations of affected and unaffected dogs. Microsatellite markers in close proximity to each candidate gene were genotyped and subjected to two-point linkage in Vizslas, and association analysis in ESS, GSMD and Beagles. Conclusions Most of these candidate genes were not significantly associated with IE in these four dog breeds, while a few genes remained inconclusive. Other genes not included in this study may still be causing monogenic IE in these breeds or, like many cases of human IE, the disease in dogs may be likewise polygenic.

  19. Candidate genes for idiopathic epilepsy in four dog breeds.

    Science.gov (United States)

    Ekenstedt, Kari J; Patterson, Edward E; Minor, Katie M; Mickelson, James R

    2011-04-25

    Idiopathic epilepsy (IE) is a naturally occurring and significant seizure disorder affecting all dog breeds. Because dog breeds are genetically isolated populations, it is possible that IE is attributable to common founders and is genetically homogenous within breeds. In humans, a number of mutations, the majority of which are genes encoding ion channels, neurotransmitters, or their regulatory subunits, have been discovered to cause rare, specific types of IE. It was hypothesized that there are simple genetic bases for IE in some purebred dog breeds, specifically in Vizslas, English Springer Spaniels (ESS), Greater Swiss Mountain Dogs (GSMD), and Beagles, and that the gene(s) responsible may, in some cases, be the same as those already discovered in humans. Candidate genes known to be involved in human epilepsy, along with selected additional genes in the same gene families that are involved in murine epilepsy or are expressed in neural tissue, were examined in populations of affected and unaffected dogs. Microsatellite markers in close proximity to each candidate gene were genotyped and subjected to two-point linkage in Vizslas, and association analysis in ESS, GSMD and Beagles. Most of these candidate genes were not significantly associated with IE in these four dog breeds, while a few genes remained inconclusive. Other genes not included in this study may still be causing monogenic IE in these breeds or, like many cases of human IE, the disease in dogs may be likewise polygenic.

  20. Screening of three Usher syndrome type II candidate genes

    Energy Technology Data Exchange (ETDEWEB)

    Bloemker, B.K. [Boys Town National Research hospital, Omaha, NE (United States); Swaroop, A. [Univ. of Michigan, Ann Arbor, MI (United States); Kimberling, W.J. [Yale medical School, New Haven, CT (United States)

    1994-09-01

    Usher syndrome type II (US2) is an autosomal recessive disorder that results in blindness due to retinitis pigmentosa and congenital hearing loss. The disease affects approximately 1 in 20,000 individuals in the general population and is responsible for over 50% of all cases of deafness with blindness. The underlying US2 defect is unknown. The US2 gene has been localized to the 1q41 region of chromosome 1 by linkage studies. Three genes previously localized to 1q were analyzed to assess their candidacy as the US2 gene. These were evaluated by PCR assays using DNA from a YAC contig spanning the US2 region on chromosome 1. The first gene evaluated was the human choroideremia-like gene (hCHML), which had been mapped to chromosome 1q. The sequence on 1q is a homologue of the human choroideremia gene on chromosome X. Choroideremia is a degenerative disorder causing ocular pathology similar to that observed in US2 patients. Therefore, hCHML is a candidate for the US2 gene. Two cDNAs (A and B) from an enriched human retinal pigment epithelium library have been mapped to 1q41 by in situ hybridization. Both cDNAs are considered good candidates. The hCHML and cDNA A were ruled out as candidates for the US2 gene based on negative results from PCR assays performed on YACs spanning the US2 region. cDNA B could not be ruled out as a candidate for the US2 gene by these assays. Answers to many clinical questions regarding US2 will only be resolved after the gene is identified and characterized. Eventually, understanding the function and expression of the US2 gene will provide a basis for the development of therapy.

  1. Gene network analysis of candidate loci for human anorectal malformations.

    Directory of Open Access Journals (Sweden)

    Emily H M Wong

    Full Text Available Anorectal malformations (ARMs are birth defects that require surgery and carry significant chronic morbidity. Our earlier genome-wide copy number variation (CNV study had provided a wealth of candidate loci. To find out whether these candidate loci are related to important developmental pathways, we have performed an extensive literature search coupled with the currently available bioinformatics tools. This has allowed us to assign both genic and non-genic CNVs to interrelated pathways known to govern the development of the anorectal region. We have linked 11 candidate genes to the WNT signalling pathway and 17 genes to the cytoskeletal network. Interestingly, candidate genes with similar functions are disrupted by the same type of CNV. The gene network we discovered provides evidence that rare mutations in different interrelated genes may lead to similar phenotypes, accounting for genetic heterogeneity in ARMs. Classification of patients according to the affected pathway and lesion type should eventually improve the diagnosis and the identification of common genes/molecules as therapeutic targets.

  2. Population differences in the International Multi-Centre ADHD Gene Project

    NARCIS (Netherlands)

    Neale, B.; Sham, P.; Purcell, S.; Banaschewski, T.; Buitelaar, J.; Franke, B.; Sonuga-Barke, E.J.S.; Ebstein, R.; Eisenberg, J.; Mulligan, A.; Gill, M.; Manor, I.; Miranda, A.; Mulas, F.; Oades, R.D.; Roeyers, H.; Rothenberger, A.; Sergeant, J.A.; Steinhausen, H.C.; Taylor, E.; Thompson, M.; Chen, W.; Zhou, K.; Asherson, P.; Faraone, S.V.

    2008-01-01

    The International Multi-Centre ADHD Gene sample consists of 674 families from eight countries (Belgium, England, Germany, Holland, Ireland, Israel, Spain, and Switzerland) ascertained from clinics for combined-type attention definity hyperactivity disorder in an offspring. 863 SNPs were successfully

  3. Population differences in the International Multi-Centre ADHD Gene Project.

    NARCIS (Netherlands)

    Neale, B.; Sham, P.C.; Purcell, S.; Banaschewski, T.; Buitelaar, J.K.; Franke, B.; Sonuga-Barke, E.J.S.; Ebstein, R.P.; Eisenberg, J.; Mulligan, A.; Gill, M.; Manor, I.; Miranda, A.; Mulas, F.; Oades, R.D.; Roeyers, H.; Rothenberger, A.; Sergeant, J.A.; Steinhausen, H.C.; Taylor, E.; Thompson, M.; Chen, W.; Zhou, K.; Asherson, P.; Faraone, S.V.

    2008-01-01

    The International Multi-Centre ADHD Gene sample consists of 674 families from eight countries (Belgium, England, Germany, Holland, Ireland, Israel, Spain, and Switzerland) ascertained from clinics for combined-type attention definity hyperactivity disorder in an offspring. 863 SNPs were successfully

  4. Dopamine Transporter Gene Moderates Response to Behavioral Parent Training in Children With ADHD : A Pilot Study

    NARCIS (Netherlands)

    van den Hoofdakker, Barbara J.; Dijck-Brouwer, D. A. Janneke; Nauta, Maaike H.; van der Veen-Mulders, Lianne; Sytema, Sjoerd; Emmelkamp, Paul M. G.; Minderaa, Ruud B.; Hoekstra, Pieter J.

    There is great variability in the degree to which children with attention deficit/hyperactivity disorder (ADHD) improve through behavioral treatments. This study investigates the influence of the dopamine transporter gene (SCL6A3/DAT1) on outcome of behavioral parent training (BPT). Study subjects

  5. The role of age in association analyses of ADHD and related neurocognitive functioning: A proof of concept for dopaminergic and serotonergic genes.

    NARCIS (Netherlands)

    Thissen, A.J.A.M.; Bralten, J.; Rommelse, N.N.J.; Arias Vazquez, A.; Greven, C.U.; Heslenfeld, D.J.; Luman, M.; Oosterlaan, J.; Hoekstra, P.J.; Hartman, C.A.; Franke, B.; Buitelaar, J.K.

    2015-01-01

    Elucidating genetic mechanisms involved in Attention-Deficit/Hyperactivity Disorder (ADHD) has been challenging. Relatively unexplored is the fact that genetic mechanisms can differ with age. The current study explored the association between dopaminergic and serotonergic genes, ADHD symptoms, and

  6. The role of age in association analyses of ADHD and related neurocognitive functioning : A proof of concept for dopaminergic and serotonergic genes

    NARCIS (Netherlands)

    Thissen, Andrieke J. A. M.; Bralten, Janita; Rommelse, Nanda N. J.; Arias-Vasquez, Alejandro; Greven, Corina U.; Heslenfeld, Dirk; Luman, Marjolein; Oosterlaan, Jaap; Hoekstra, Pieter J.; Hartman, Catharina; Franke, Barbara; Buitelaar, Jan K.

    Elucidating genetic mechanisms involved in Attention-Deficit/Hyperactivity Disorder (ADHD) has been challenging. Relatively unexplored is the fact that genetic mechanisms can differ with age. The current study explored the association between dopaminergic and serotonergic genes, ADHD symptoms, and

  7. 'Omics' approaches in tomato aimed at identifying candidate genes ...

    African Journals Online (AJOL)

    In this review, we will focus on the role of the different high-throughput technologies in enhancing tomato breeding particularly for fruit quality traits. We also describe how two 'omics' approaches could be combined in order to identify candidate genes for the genetic control of ascorbic acid accumulation in tomato fruit.

  8. Whole genome homology-based identification of candidate genes ...

    African Journals Online (AJOL)

    Josephine Erhiakporeh

    2016-07-06

    Jul 6, 2016 ... 1,075 from potato and 270 from tomato, comparative analysis against sesame genome led to the identification of a set of 75 candidate genes (42, 22 and 11 from Arabidopsis, potato and tomato, respectively). Mapping results .... applying drought stress by withholding water for 5 days. At this stage, all plants ...

  9. Candidate genes for individual recognition in Polistes fuscatus paper wasps.

    Science.gov (United States)

    Berens, A J; Tibbetts, E A; Toth, A L

    2016-02-01

    Few animals are known to individually recognize conspecifics, i.e. learn and recall unique individuals during subsequent encounters, and nearly all are social vertebrates. Remarkably, the social paper wasp Polistes fuscatus has recently been discovered to possess this ability, which is useful for remembering identities during competitive social interactions. We analyzed brain gene expression in staged encounters between pairs of individuals to explore potential mechanisms underlying wasps' ability to recall familiar individuals using real-time qRT-PCR. We identified four candidate genes (IP3K, IP3R, Nckx30C and Su(var)2-10) that were down-regulated in the presence of familiar individuals compared to single wasps and pairs of wasps meeting for the first time. These candidate genes are related to calcium signaling, therefore, we treated wasps with lithium chloride, a pharmacological agent that inhibits calcium signaling in neurons. This treatment decreased aggression in paper wasps, but did not affect expression of genes related to calcium signaling. The results suggest calcium signaling differences may be related to individual memory recall in wasps, and we present four promising candidate genes for future study. These data suggest genes associated with dominance behavior may be co-opted for individual recognition, but further work is needed to establish a causal association with the behavior.

  10. Ranking candidate genes in rat models of type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Ståhl Fredrik

    2009-07-01

    Full Text Available Abstract Background Rat models are frequently used to find genomic regions that contribute to complex diseases, so called quantitative trait loci (QTLs. In general, the genomic regions found to be associated with a quantitative trait are rather large, covering hundreds of genes. To help selecting appropriate candidate genes from QTLs associated with type 2 diabetes models in rat, we have developed a web tool called Candidate Gene Capture (CGC, specifically adopted for this disorder. Methods CGC combines diabetes-related genomic regions in rat with rat/human homology data, textual descriptions of gene effects and an array of 789 keywords. Each keyword is assigned values that reflect its co-occurrence with 24 different reference terms describing sub-phenotypes of type 2 diabetes (for example "insulin resistance". The genes are then ranked based on the occurrences of keywords in the describing texts. Results CGC includes QTLs from type 2 diabetes models in rat. When comparing gene rankings from CGC based on one sub-phenotype, with manual gene ratings for four QTLs, very similar results were obtained. In total, 24 different sub-phenotypes are available as reference terms in the application and based on differences in gene ranking, they fall into separate clusters. Conclusion The very good agreement between the CGC gene ranking and the manual rating confirms that CGC is as a reliable tool for interpreting textual information. This, together with the possibility to select many different sub-phenotypes, makes CGC a versatile tool for finding candidate genes. CGC is publicly available at http://ratmap.org/CGC.

  11. Candidate genes for COPD: current evidence and research

    Directory of Open Access Journals (Sweden)

    Kim WJ

    2015-10-01

    Full Text Available Woo Jin Kim,1 Sang Do Lee2 1Department of Internal Medicine and Environmental Health Center, Kangwon National University, Chuncheon, 2Department of Pulmonary and Critical Care Medicine, Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea Abstract: COPD is a common complex disease characterized by progressive airflow limitation. Several genome-wide association studies (GWASs have discovered genes that are associated with COPD. Recently, candidate genes for COPD identified by GWASs include CHRNA3/5 (cholinergic nicotine receptor alpha 3/5, IREB2 (iron regulatory binding protein 2, HHIP (hedgehog-interacting protein, FAM13A (family with sequence similarity 13, member A, and AGER (advanced glycosylation end product–specific receptor. Their association with COPD susceptibility has been replicated in multiple populations. Since these candidate genes have not been considered in COPD, their pathological roles are still largely unknown. Herein, we review some evidences that they can be effective drug targets or serve as biomarkers for diagnosis or subtyping. However, more study is required to understand the functional roles of these candidate genes. Future research is needed to characterize the effect of genetic variants, validate gene function in humans and model systems, and elucidate the genes’ transcriptional and posttranscriptional regulatory mechanisms. Keywords: chronic obstructive pulmonary disease, genetics, genome-wide association study

  12. Identification of candidate genes for dyslexia susceptibility on chromosome 18.

    Directory of Open Access Journals (Sweden)

    Thomas S Scerri

    2010-10-01

    Full Text Available Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s conferring susceptibility by a two stage strategy of linkage and association analysis.Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R, dymeclin (DYM and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L.Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.

  13. Are TMEM genes potential candidate genes for panic disorder?

    DEFF Research Database (Denmark)

    NO, Gregersen; Buttenschøn, Henriette Nørmølle; Hedemand, Anne

    2014-01-01

    We analysed single nucleotide polymorphisms in two transmembrane genes (TMEM98 and TMEM132E) in panic disorder (PD) patients and control individuals from the Faroe Islands, Denmark and Germany. The genes encode single-pass membrane proteins and are located within chromosome 17q11.2-q12, a previou......We analysed single nucleotide polymorphisms in two transmembrane genes (TMEM98 and TMEM132E) in panic disorder (PD) patients and control individuals from the Faroe Islands, Denmark and Germany. The genes encode single-pass membrane proteins and are located within chromosome 17q11.2-q12...

  14. CANDIDATE GENE ANALYSIS IN ISRAELI SOLDIERS WITH STRESS FRACTURES

    Directory of Open Access Journals (Sweden)

    Ran Yanovich

    2012-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Pereira Fernando CN

    2008-10-01

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

  16. The genetics of reading disabilities: from phenotypes to candidate genes.

    Science.gov (United States)

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

    2012-01-01

    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.

  17. The KCNE genes in hypertrophic cardiomyopathy: a candidate gene study

    DEFF Research Database (Denmark)

    Hedley, Paula L; Haundrup, Ole; Andersen, Paal S

    2011-01-01

    as well as the T-tubules of the sarcolemma. It has been suggested that minK forms part of an "electro-mechanical feed-back" which links cardiomyocyte stretching to changes in ion channel function. We examined whether mutations in KCNE genes were associated with hypertrophic cardiomyopathy (HCM), a genetic...... disease associated with an improper hypertrophic response....

  18. Expression studies of the obesity candidate gene FTO in pig

    DEFF Research Database (Denmark)

    Madsen, Majbritt Busk; Birck, Malene Muusfeldt; Fredholm, Merete

    2010-01-01

    Obesity is an increasing problem worldwide and research on candidate genes in good animal models is highly needed. The pig is an excellent model as its metabolism, organ size, and eating habits resemble that of humans. The present study is focused on the characterization of the fat mass and obesity...... associated gene (FTO) in pig. This gene has recently been associated with increased body mass index in several human populations. To establish information on the expression profile of FTO in the pig we performed quantitative PCR in a panel of adult pig tissues and in tissues sampled at different...... and cerebellum). Additionally, in order to see the involvement of the FTO gene in obesity, the changes in expression level were investigated in a nutritional study in brain of Gottingen minipigs under a high cholesterol diet. Significantly higher (P

  19. Candidate driver genes in microsatellite-unstable colorectal cancer

    DEFF Research Database (Denmark)

    Alhopuro, Pia; Sammalkorpi, Heli; Niittymäki, Iina

    2012-01-01

    . Here, we evaluated somatic mutations in microsatellite repeats of 790 genes chosen based on reduced expression in MSI CRC and existence of a coding mononucleotide repeat of 6–10 bp in length. All the repeats were initially sequenced in 30 primary MSI CRC samples and whenever frameshift mutations were...... types (A/T and C/G, 6–10 bp). Along with several know target genes, including TGFBR2, ACVR2, and MSH3, six novel candidate driver genes emerged that harbored significantly more mutations than identical control repeats. The mutation frequencies in 100 MSI CRC samples were 51% in G8 of GLYR1, 47% in T9...... genes that when mutated are likely to contribute to MSI CRC development....

  20. Machine Learning-Based Gene Prioritization Identifies Novel Candidate Risk Genes for Inflammatory Bowel Disease.

    Science.gov (United States)

    Isakov, Ofer; Dotan, Iris; Ben-Shachar, Shay

    2017-09-01

    The inflammatory bowel diseases (IBDs) are chronic inflammatory disorders, associated with genetic, immunologic, and environmental factors. Although hundreds of genes are implicated in IBD etiology, it is likely that additional genes play a role in the disease process. We developed a machine learning-based gene prioritization method to identify novel IBD-risk genes. Known IBD genes were collected from genome-wide association studies and annotated with expression and pathway information. Using these genes, a model was trained to identify IBD-risk genes. A comprehensive list of 16,390 genes was then scored and classified. Immune and inflammatory responses, as well as pathways such as cell adhesion, cytokine-cytokine receptor interaction, and sulfur metabolism were identified to be related to IBD. Scores predicted for IBD genes were significantly higher than those for non-IBD genes (P genes had a high prediction score (>0.8). A literature review of the genes, excluding those used to train the model, identified 67 genes without any publication concerning IBD. These genes represent novel candidate IBD-risk genes, which can be targeted in future studies. Our method successfully differentiated IBD-risk genes from non-IBD genes by using information from expression data and a multitude of gene annotations. Crucial features were defined, and we were able to detect novel candidate risk genes for IBD. These findings may help detect new IBD-risk genes and improve the understanding of IBD pathogenesis.

  1. Characterizations of 9p21 candidate genes in familial melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Walker, G.J.; Flores, J.F.; Glendening, J.M. [Univ. of California, Los Angeles, CA (United States)] [and others

    1994-09-01

    We have previously collected and characterized 16 melanoma families for the inheritance of a familial melanoma predisposition gene on 9p21. Clear evidence for genetic linkage has been detected in 8 of these families with the 9p21 markers D9S126 and 1FNA, while linkage of the remaining families to this region is less certain. A candidate for the 9p21 familial melanoma gene, the cyclin kinase inhibitor gene p16 (also known as the multiple tumor suppressor 1 (MTS1) gene), has been recently indentified. Notably, a nonsense mutation within the p16 gene has been detected in the lymphoblastoid cell line DNA from a dysplastic nevus syndrome (DNS), or familial melanoma, patient. The p16 gene is also known to be frequently deleted or mutated in a variety of tumor cell lines (including melanoma) and resides within a region that has been defined as harboring the 9p21 melanoma predisposition locus. This region is delineated on the distal side by the marker D9S736 (which resides just distal to the p16 gene) and extends in a proximal direction to the marker D9S171. Overall, the entire distance between these two loci is estimated at 3-5Mb. Preliminary analysis of our two largest 9p21-linked melanoma kindreds (by direct sequencing of PCR products) has not yet revealed mutations within the coding region of the p16 gene. Others have reported that 8/11 unrelated 9p21-linked melanoma families do not appear to carry p16 mutations; thus the possibility exists that p16 is not a melanoma susceptibility gene per se, although it appears to play some role in melanoma tumor progression. Our melanoma kindred DNAs are currently being analyzed by SSCP using primers that amplify exons of other candidate genes from the 9p21 region implicated in familial melanoma. These novel genes reside within a distinct critical region of homozygous loss in melanoma which is located >2 Mb from the p16 gene on 9p21.

  2. Association study of 182 candidate genes in anorexia nervosa.

    Science.gov (United States)

    Pinheiro, Andrea Poyastro; Bulik, Cynthia M; Thornton, Laura M; Sullivan, Patrick F; Root, Tammy L; Bloss, Cinnamon S; Berrettini, Wade H; Schork, Nicholas J; Kaye, Walter H; Bergen, Andrew W; Magistretti, Pierre; Brandt, Harry; Crawford, Steve; Crow, Scott; Fichter, Manfred M; Goldman, David; Halmi, Katherine A; Johnson, Craig; Kaplan, Allan S; Keel, Pamela K; Klump, Kelly L; La Via, Maria; Mitchell, James E; Strober, Michael; Rotondo, Alessandro; Treasure, Janet; Woodside, D Blake

    2010-07-01

    We performed association studies with 5,151 SNPs that were judged as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN) based on location under reported linkage peaks, previous results in the literature (182 candidate genes), brain expression, biological plausibility, and estrogen responsivity. We employed a case-control design that tested each SNP individually as well as haplotypes derived from these SNPs in 1,085 case individuals with AN diagnoses and 677 control individuals. We also performed separate association analyses using three increasingly restrictive case definitions for AN: all individuals with any subtype of AN (All AN: n = 1,085); individuals with AN with no binge eating behavior (AN with No Binge Eating: n = 687); and individuals with the restricting subtype of AN (Restricting AN: n = 421). After accounting for multiple comparisons, there were no statistically significant associations for any individual SNP or haplotype block with any definition of illness. These results underscore the importance of large samples to yield appropriate power to detect genotypic differences in individuals with AN and also motivate complementary approaches involving Genome-Wide Association (GWA) studies, Copy Number Variation (CNV) analyses, sequencing-based rare variant discovery assays, and pathway-based analysis in order to make up for deficiencies in traditional candidate gene approaches to AN. (c) 2010 Wiley-Liss, Inc.

  3. Identifying candidate driver genes by integrative ovarian cancer genomics data

    Science.gov (United States)

    Lu, Xinguo; Lu, Jibo

    2017-08-01

    Integrative analysis of molecular mechanics underlying cancer can distinguish interactions that cannot be revealed based on one kind of data for the appropriate diagnosis and treatment of cancer patients. Tumor samples exhibit heterogeneity in omics data, such as somatic mutations, Copy Number Variations CNVs), gene expression profiles and so on. In this paper we combined gene co-expression modules and mutation modulators separately in tumor patients to obtain the candidate driver genes for resistant and sensitive tumor from the heterogeneous data. The final list of modulators identified are well known in biological processes associated with ovarian cancer, such as CCL17, CACTIN, CCL16, CCL22, APOB, KDF1, CCL11, HNF1B, LRG1, MED1 and so on, which can help to facilitate the discovery of biomarkers, molecular diagnostics, and drug discovery.

  4. Adaptations to climate in candidate genes for common metabolic disorders.

    Directory of Open Access Journals (Sweden)

    Angela M Hancock

    2008-02-01

    Full Text Available Evolutionary pressures due to variation in climate play an important role in shaping phenotypic variation among and within species and have been shown to influence variation in phenotypes such as body shape and size among humans. Genes involved in energy metabolism are likely to be central to heat and cold tolerance. To test the hypothesis that climate shaped variation in metabolism genes in humans, we used a bioinformatics approach based on network theory to select 82 candidate genes for common metabolic disorders. We genotyped 873 tag SNPs in these genes in 54 worldwide populations (including the 52 in the Human Genome Diversity Project panel and found correlations with climate variables using rank correlation analysis and a newly developed method termed Bayesian geographic analysis. In addition, we genotyped 210 carefully matched control SNPs to provide an empirical null distribution for spatial patterns of allele frequency due to population history alone. For nearly all climate variables, we found an excess of genic SNPs in the tail of the distributions of the test statistics compared to the control SNPs, implying that metabolic genes as a group show signals of spatially varying selection. Among our strongest signals were several SNPs (e.g., LEPR R109K, FABP2 A54T that had previously been associated with phenotypes directly related to cold tolerance. Since variation in climate may be correlated with other aspects of environmental variation, it is possible that some of the signals that we detected reflect selective pressures other than climate. Nevertheless, our results are consistent with the idea that climate has been an important selective pressure acting on candidate genes for common metabolic disorders.

  5. Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing.

    Science.gov (United States)

    Hoebel, A K; Drichel, D; van de Vorst, M; Böhmer, A C; Sivalingam, S; Ishorst, N; Klamt, J; Gölz, L; Alblas, M; Maaser, A; Keppler, K; Zink, A M; Dixon, M J; Dixon, J; Hemprich, A; Kruse, T; Graf, I; Dunsche, A; Schmidt, G; Daratsianos, N; Nowak, S; Aldhorae, K A; Nöthen, M M; Knapp, M; Thiele, H; Gilissen, C; Reutter, H; Hoischen, A; Mangold, E; Ludwig, K U

    2017-10-01

    Nonsyndromic cleft palate only (nsCPO) is a facial malformation that has a livebirth prevalence of 1 in 2,500. Research suggests that the etiology of nsCPO is multifactorial, with a clear genetic component. To date, genome-wide association studies have identified only 1 conclusive common variant for nsCPO, that is, a missense variant in the gene grainyhead-like-3 ( GRHL3). Thus, the underlying genetic causes of nsCPO remain largely unknown. The present study aimed at identifying rare variants that might contribute to nsCPO risk, via whole-exome sequencing (WES), in multiply affected Central European nsCPO pedigrees. WES was performed in 2 affected first-degree relatives from each family. Variants shared between both individuals were analyzed for their potential deleterious nature and a low frequency in the general population. Genes carrying promising variants were annotated for 1) reported associations with facial development, 2) multiple occurrence of variants, and 3) expression in mouse embryonic palatal shelves. This strategy resulted in the identification of a set of 26 candidate genes that were resequenced in 132 independent nsCPO cases and 623 independent controls of 2 different ethnicities, using molecular inversion probes. No rare loss-of-function mutation was identified in either WES or resequencing step. However, we identified 2 or more missense variants predicted to be deleterious in each of 3 genes ( ACACB, PTPRS, MIB1) in individuals from independent families. In addition, the analyses identified a novel variant in GRHL3 in 1 patient and a variant in CREBBP in 2 siblings. Both genes underlie different syndromic forms of CPO. A plausible hypothesis is that the apparently nonsyndromic clefts in these 3 patients might represent hypomorphic forms of the respective syndromes. In summary, the present study identified rare variants that might contribute to nsCPO risk and suggests candidate genes for further investigation.

  6. Identification of candidate genes for phenolics accumulation in tomato fruit.

    Science.gov (United States)

    Di Matteo, Antonio; Ruggieri, Valentino; Sacco, Adriana; Rigano, Maria Manuela; Carriero, Filomena; Bolger, Anthony; Fernie, Alisdair R; Frusciante, Luigi; Barone, Amalia

    2013-05-01

    Phenolics are antioxidants present in tomato fruit that confer healthy benefits and exhibit crucial roles for plant metabolism and response to environmental stimuli. An approach based on two genomics platforms was undertaken to identify candidate genes associated to higher phenolics content in tomato fruit. A comparative transcriptomic analysis between the S. pennellii Introgression Line 7-3, which produced an average higher level of fruit phenolics, and the cultivated variety M82, revealed that their differences are attributed to genes involved in phenolics accumulation into the vacuole. The up-regulation of genes coding for one MATE-transporter, one vacuolar sorting protein and three GSTs supported this hypothesis. The observed balancing effect between two ethylene responsive factors (ERF1 and ERF4) was also hypothesized to drive the transcriptional regulation of these transport genes. In order to confirm such model a TILLING platform was explored. A mutant was isolated harbouring a point mutation in the ERF1 cds that affects the protein sequence and its expected function. Fruits of the mutant exhibited a significant reduced level of phenolics than the control variety. Changes in the expression of genes involved in sequestration of phenolics in vacuole also supported the hypothesized key-role of ERF1 in orchestrating these genes. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  7. Gene by environment interactions influencing reading disability (RD) and the inattentive symptom dimension of attention deficit/hyperactivity disorder (ADHD)

    Science.gov (United States)

    Rosenberg, Jenni; Pennington, Bruce F.; Willcutt, Erik G.; Olson, Richard K.

    2011-01-01

    Background RD and ADHD are comorbid and genetically correlated, especially the inattentive dimension of ADHD (ADHD-I). However, previous research indicates that RD and ADHD enter into opposite gene by environment (GxE) interactions. Methods This study used behavioral genetic methods to replicate these opposite GxE interactions in a sample of same-sex MZ and DZ twin pairs from the Colorado Learning Disabilities Research Center (CLDRC; DeFries et al., 1997) and to test a genetic hypothesis for why these opposite interactions occur. Results We replicated opposite GxE interactions for RD (bioecological) and ADHD-I (diathesis-stress) with parental education in the same sample of participants. The genetic hypothesis for this opposite pattern of interactions is that only genes specific to each disorder enter into these opposite interactions, not the shared genes underlying their comorbidity. To test this hypothesis, we used single models with an exploratory three-way interaction, in which the GxE interactions for each disorder were moderated by comorbidity. Neither three-way interaction was significant. The heritability of RD did not vary as a function of parental education and ADHD-I. Similarly, the heritability of ADHD-I did not vary as a function of parental education and RD. Conclusions We documented opposite GxE interactions in RD and ADHD-I in the same overall twin sample, but the explanation for this apparent paradox remains unclear. Examining specific genes and more specific environmental factors may help resolve the paradox. PMID:21884522

  8. Shared Genetic Influences on ADHD Symptoms and Very Low-Frequency EEG Activity: A Twin Study

    Science.gov (United States)

    Tye, Charlotte; Rijsdijk, Fruhling; Greven, Corina U.; Kuntsi, Jonna; Asherson, Philip; McLoughlin, Grainne

    2012-01-01

    Background: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex aetiology. The identification of candidate intermediate phenotypes that are both heritable and genetically linked to ADHD may facilitate the detection of susceptibility genes and elucidate aetiological pathways.…

  9. Candidate genes for performance in horses, including monocarboxylate transporters

    Directory of Open Access Journals (Sweden)

    Inaê Cristina Regatieri

    Full Text Available ABSTRACT: Some horse breeds are highly selected for athletic activities. The athletic potential of each animal can be measured by its performance in sports. High athletic performance depends on the animal capacity to produce energy through aerobic and anaerobic metabolic pathways, among other factors. Transmembrane proteins called monocarboxylate transporters, mainly the isoform 1 (MCT1 and its ancillary protein CD147, can help the organism to adapt to physiological stress caused by physical exercise, transporting lactate and H+ ions. Horse breeds are selected for different purposes so we might expect differences in the amount of those proteins and in the genotypic frequencies for genes that play a significant role in the performance of the animals. The study of MCT1 and CD147 gene polymorphisms, which can affect the formation of the proteins and transport of lactate and H+, can provide enough information to be used for selection of athletic horses increasingly resistant to intense exercise. Two other candidate genes, the PDK4 and DMRT3, have been associated with athletic potential and indicated as possible markers for performance in horses. The oxidation of fatty acids is highly effective in generating ATP and is controlled by the expression of PDK4 (pyruvate dehydrogenase kinase, isozyme 4 in skeletal muscle during and after exercise. The doublesex and mab-3 related transcription factor 3 (DMRT3 gene encodes an important transcription factor in the setting of spinal cord circuits controlling movement in vertebrates and may be associated with gait performance in horses. This review describes how the monocarboxylate transporters work during physical exercise in athletic horses and the influence of polymorphisms in candidate genes for athletic performance in horses.

  10. Association of Dopamine Transporter Gene Variants with Childhood ADHD Features in Bipolar Disorder

    Science.gov (United States)

    Greenwood, Tiffany A.; Joo, Eun-Jeong; Shektman, Tatyana; Sadovnick, A. Dessa; Remick, Ronald A.; Keck, Paul E.; McElroy, Susan L.; Kelsoe, John R.

    2014-01-01

    Bipolar Disorder (BD) and Attention Deficit Hyperactivity Disorder (ADHD) exhibit remarkably high rates of comorbidity, as well as patterns of familial co-segregation. Epidemiological data suggests that these disorders either share a common genetic architecture or that ADHD features in BD may represent an etiologically distinct subtype. We previously used the Wender Utah Rating Scale (WURS) to assess ADHD features in BD families and identified three heritable factors relating to impulsivity, mood instability, and inattention. Linkage analysis revealed a LOD score of 1.33 for the inattention factor on 5p15.3 near the dopamine transporter gene (DAT1), which has been associated with both BD and ADHD. Pharmacological evidence also suggests a role for DAT in both disorders. We have now evaluated the association of ten DAT1 variants for the WURS total score and factors in an overlapping sample of 87 BD families. Significant associations for three SNPs were observed across the WURS measures, notably for a SNP in intron 8 with the WURS total score (p=0.007) and for variants in introns 9 and 13 with mood instability (p=0.009 and 0.004, respectively). Analysis of an independent sample of 52 BD cases and 46 healthy controls further supported association of the intron 8 variant with mood instability (p=0.005), and a combined analysis confirmed the associations of this SNP with WURS total score. Impulsivity, and mood instability (p= 0.002, 0.007, and 8×10−4, respectively). These data suggest that variants within DAT1 may predispose to a subtype of BD characterized by early prodromal features that include attentional deficits. PMID:23255304

  11. ADHD Medications

    Science.gov (United States)

    ... Situations Talking to Your Parents - or Other Adults ADHD Medicines KidsHealth > For Teens > ADHD Medicines Print A ... para el tratamiento del TDAH (ADHD) What Is ADHD Medicine? After someone has been diagnosed with ADHD , ...

  12. Computational selection and prioritization of candidate genes for Fetal Alcohol Syndrome

    Directory of Open Access Journals (Sweden)

    Hide Winston

    2007-10-01

    Full Text Available Abstract Background Fetal alcohol syndrome (FAS is a serious global health problem and is observed at high frequencies in certain South African communities. Although in utero alcohol exposure is the primary trigger, there is evidence for genetic- and other susceptibility factors in FAS development. No genome-wide association or linkage studies have been performed for FAS, making computational selection and -prioritization of candidate disease genes an attractive approach. Results 10174 Candidate genes were initially selected from the whole genome using a previously described method, which selects candidate genes according to their expression in disease-affected tissues. Hereafter candidates were prioritized for experimental investigation by investigating criteria pertinent to FAS and binary filtering. 29 Criteria were assessed by mining various database sources to populate criteria-specific gene lists. Candidate genes were then prioritized for experimental investigation using a binary system that assessed the criteria gene lists against the candidate list, and candidate genes were scored accordingly. A group of 87 genes was prioritized as candidates and for future experimental validation. The validity of the binary prioritization method was assessed by investigating the protein-protein interactions, functional enrichment and common promoter element binding sites of the top-ranked genes. Conclusion This analysis highlighted a list of strong candidate genes from the TGF-β, MAPK and Hedgehog signalling pathways, which are all integral to fetal development and potential targets for alcohol's teratogenic effect. We conclude that this novel bioinformatics approach effectively prioritizes credible candidate genes for further experimental analysis.

  13. Walking on multiple disease-gene networks to prioritize candidate genes.

    Science.gov (United States)

    Jiang, Rui

    2015-06-01

    Uncovering causal genes for human inherited diseases, as the primary step toward understanding the pathogenesis of these diseases, requires a combined analysis of genetic and genomic data. Although bioinformatics methods have been designed to prioritize candidate genes resulting from genetic linkage analysis or association studies, the coverage of both diseases and genes in existing methods is quite limited, thereby preventing the scan of causal genes for a significant proportion of diseases at the whole-genome level. To overcome this limitation, we propose a method named pgWalk to prioritize candidate genes by integrating multiple phenomic and genomic data. We derive three types of phenotype similarities among 7719 diseases and nine types of functional similarities among 20327 genes. Based on a pair of phenotype and gene similarities, we construct a disease-gene network and then simulate the process that a random walker wanders on such a heterogeneous network to quantify the strength of association between a candidate gene and a query disease. A weighted version of the Fisher's method with dependent correction is adopted to integrate 27 scores obtained in this way, and a final q-value is calibrated for prioritizing candidate genes. A series of validation experiments are conducted to demonstrate the superior performance of this approach. We further show the effectiveness of this method in exome sequencing studies of autism and epileptic encephalopathies. An online service and the standalone software of pgWalk can be found at http://bioinfo.au.tsinghua.edu.cn/jianglab/pgwalk. © The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

  14. Candidate driver genes in microsatellite-unstable colorectal cancer.

    Science.gov (United States)

    Alhopuro, Pia; Sammalkorpi, Heli; Niittymäki, Iina; Biström, Mia; Raitila, Anniina; Saharinen, Juha; Nousiainen, Kari; Lehtonen, Heli J; Heliövaara, Elina; Puhakka, Jani; Tuupanen, Sari; Sousa, Sónia; Seruca, Raquel; Ferreira, Ana M; Hofstra, Robert M W; Mecklin, Jukka-Pekka; Järvinen, Heikki; Ristimäki, Ari; Orntoft, Torben F; Hautaniemi, Sampsa; Arango, Diego; Karhu, Auli; Aaltonen, Lauri A

    2012-04-01

    Defects in the mismatch repair system lead to microsatellite instability (MSI), a feature observed in ∼ 15% of all colorectal cancers (CRCs). Microsatellite mutations that drive tumourigenesis, typically inactivation of tumour suppressors, are selected for and are frequently detected in MSI cancers. Here, we evaluated somatic mutations in microsatellite repeats of 790 genes chosen based on reduced expression in MSI CRC and existence of a coding mononucleotide repeat of 6-10 bp in length. All the repeats were initially sequenced in 30 primary MSI CRC samples and whenever frameshift mutations were identified in >20%, additional 70 samples were sequenced. To distinguish driver mutations from passengers, we similarly analyzed the occurrence of frameshift mutations in 121 intronic control repeats and utilized a statistical regression model to determine cut-off mutation frequencies for repeats of all types (A/T and C/G, 6-10 bp). Along with several know target genes, including TGFBR2, ACVR2, and MSH3, six novel candidate driver genes emerged that harbored significantly more mutations than identical control repeats. The mutation frequencies in 100 MSI CRC samples were 51% in G8 of GLYR1, 47% in T9 of ABCC5, 43% in G8 of WDTC1, 33% in A8 of ROCK1, 30% in T8 of OR51E2, and 28% in A8 of TCEB3. Immunohistochemical staining of GLYR1 revealed defective protein expression in tumors carrying biallelic mutations, supporting a loss of function hypothesis. This is a large scale, unbiased effort to identify genes that when mutated are likely to contribute to MSI CRC development. Copyright © 2011 UICC.

  15. Functional Gene-Set Analysis Does Not Support a Major Role for Synaptic Function in Attention Deficit/Hyperactivity Disorder (ADHD

    Directory of Open Access Journals (Sweden)

    Anke R. Hammerschlag

    2014-07-01

    Full Text Available Attention Deficit/Hyperactivity Disorder (ADHD is one of the most common childhood-onset neuropsychiatric disorders. Despite high heritability estimates, genome-wide association studies (GWAS have failed to find significant genetic associations, likely due to the polygenic character of ADHD. Nevertheless, genetic studies suggested the involvement of several processes important for synaptic function. Therefore, we applied a functional gene-set analysis to formally test whether synaptic functions are associated with ADHD. Gene-set analysis tests the joint effect of multiple genetic variants in groups of functionally related genes. This method provides increased statistical power compared to conventional GWAS. We used data from the Psychiatric Genomics Consortium including 896 ADHD cases and 2455 controls, and 2064 parent-affected offspring trios, providing sufficient statistical power to detect gene sets representing a genotype relative risk of at least 1.17. Although all synaptic genes together showed a significant association with ADHD, this association was not stronger than that of randomly generated gene sets matched for same number of genes. Further analyses showed no association of specific synaptic function categories with ADHD after correction for multiple testing. Given current sample size and gene sets based on current knowledge of genes related to synaptic function, our results do not support a major role for common genetic variants in synaptic genes in the etiology of ADHD.

  16. Assessment of PALB2 as a candidate melanoma susceptibility gene.

    Directory of Open Access Journals (Sweden)

    Lauren G Aoude

    Full Text Available Partner and localizer of BRCA2 (PALB2 interacts with BRCA2 to enable double strand break repair through homologous recombination. Similar to BRCA2, germline mutations in PALB2 have been shown to predispose to Fanconi anaemia as well as pancreatic and breast cancer. The PALB2/BRCA2 protein interaction, as well as the increased melanoma risk observed in families harbouring BRCA2 mutations, makes PALB2 a candidate for melanoma susceptibility. In order to assess PALB2 as a melanoma predisposition gene, we sequenced the entire protein-coding sequence of PALB2 in probands from 182 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, and BAP1. In addition, we interrogated whole-genome and exome data from another 19 kindreds with a strong family history of melanoma for deleterious mutations in PALB2. Here we report a rare known deleterious PALB2 mutation (rs118203998 causing a premature truncation of the protein (p.Y1183X in an individual who had developed four different cancer types, including melanoma. Three other family members affected with melanoma did not carry the variant. Overall our data do not support a case for PALB2 being associated with melanoma predisposition.

  17. Association of candidate genes with drought tolerance traits in diverse perennial ryegrass accessions

    Science.gov (United States)

    Xiaoqing Yu; Guihua Bai; Shuwei Liu; Na Luo; Ying Wang; Douglas S. Richmond; Paula M. Pijut; Scott A. Jackson; Jianming Yu; Yiwei. Jiang

    2013-01-01

    Drought is a major environmental stress limiting growth of perennial grasses in temperate regions. Plant drought tolerance is a complex trait that is controlled by multiple genes. Candidate gene association mapping provides a powerful tool for dissection of complex traits. Candidate gene association mapping of drought tolerance traits was conducted in 192 diverse...

  18. Association of twelve candidate gene polymorphisms and response to challenge with Salmonella enteritidis in poultry

    NARCIS (Netherlands)

    Kramer, J.; Malek, M.; Lamont, S.J.

    2003-01-01

    Breeding for disease resistance to Salmonella enteritidis (SE) could be an effective approach to control Salmonella in poultry. The candidate gene approach is a useful method to investigate genes that are involved in genetic resistance. In this study, 12 candidate genes that are involved in the

  19. Linkage and candidate gene studies of autism spectrum disorders in European populations

    NARCIS (Netherlands)

    Holt, Richard; Barnby, Gabrielle; Maestrini, Elena; Bacchelli, Elena; Brocklebank, Denise; Sousa, Ines; Mulder, Erik J.; Kantojarvi, Katri; Jarvela, Irma; Klauck, Sabine M.; Poustka, Fritz; Bailey, Anthony J.; Monaco, Anthony P.

    2010-01-01

    Over the past decade, research on the genetic variants underlying susceptibility to autism and autism spectrum disorders (ASDs) has focused on linkage and candidate gene studies. This research has implicated various chromosomal loci and genes. Candidate gene studies have proven to be particularly

  20. Candidate genes detected in transcriptome studies are strongly dependent on genetic background.

    Directory of Open Access Journals (Sweden)

    Pernille Sarup

    Full Text Available Whole genome transcriptomic studies can point to potential candidate genes for organismal traits. However, the importance of potential candidates is rarely followed up through functional studies and/or by comparing results across independent studies. We have analysed the overlap of candidate genes identified from studies of gene expression in Drosophila melanogaster using similar technical platforms. We found little overlap across studies between putative candidate genes for the same traits in the same sex. Instead there was a high degree of overlap between different traits and sexes within the same genetic backgrounds. Putative candidates found using transcriptomics therefore appear very sensitive to genetic background and this can mask or override effects of treatments. The functional importance of putative candidate genes emerging from transcriptome studies needs to be validated through additional experiments and in future studies we suggest a focus on the genes, networks and pathways affecting traits in a consistent manner across backgrounds.

  1. Inferring Gene Regulatory Networks Using Conditional Regulation Pattern to Guide Candidate Genes.

    Science.gov (United States)

    Xiao, Fei; Gao, Lin; Ye, Yusen; Hu, Yuxuan; He, Ruijie

    2016-01-01

    Combining path consistency (PC) algorithms with conditional mutual information (CMI) are widely used in reconstruction of gene regulatory networks. CMI has many advantages over Pearson correlation coefficient in measuring non-linear dependence to infer gene regulatory networks. It can also discriminate the direct regulations from indirect ones. However, it is still a challenge to select the conditional genes in an optimal way, which affects the performance and computation complexity of the PC algorithm. In this study, we develop a novel conditional mutual information-based algorithm, namely RPNI (Regulation Pattern based Network Inference), to infer gene regulatory networks. For conditional gene selection, we define the co-regulation pattern, indirect-regulation pattern and mixture-regulation pattern as three candidate patterns to guide the selection of candidate genes. To demonstrate the potential of our algorithm, we apply it to gene expression data from DREAM challenge. Experimental results show that RPNI outperforms existing conditional mutual information-based methods in both accuracy and time complexity for different sizes of gene samples. Furthermore, the robustness of our algorithm is demonstrated by noisy interference analysis using different types of noise.

  2. Association of a Monoamine Oxidase-A Gene Promoter Polymorphism with ADHD and Anxiety in Boys with Autism Spectrum Disorder

    Science.gov (United States)

    Roohi, Jasmin; DeVincent, Carla J.; Hatchwell, Eli; Gadow, Kenneth D.

    2009-01-01

    The aim of the present study was to examine the association between a variable number tandem repeat (VNTR) functional polymorphism in the promoter region of the MAO-A gene and severity of ADHD and anxiety in boys with ASD. Parents and teachers completed a DSM-IV-referenced rating scale for 5- to 14-year-old boys with ASD (n = 43). Planned…

  3. Absence of linkage of apparently single gene mediated ADHD with the human syntenic region of the mouse mutant coloboma

    Energy Technology Data Exchange (ETDEWEB)

    Hess, E.J.; Rogan, P.K.; Domoto, M. [Pennsylvania State Univ. College of Medicine, Hershey, PA (United States)] [and others

    1995-12-18

    Attention deficit disorder (ADHD) is a complex biobehavioral phenotype which affects up to 8% of the general population and often impairs social, academic, and job performance. Its origins are heterogeneous, but a significant genetic component is suggested by family and twin studies. The murine strain, coloboma, displays a spontaneously hyperactive phenotype that is responsive to dextroamphetamine and has been proposed as a genetic model for ADHD. Coloboma is a semi-dominant mutation that is caused by a hemizygous deletion of the SNAP-25 and other genes on mouse chromosome 2q. To test the possibility that the human homolog of the mouse coloboma gene(s) could be responsible for ADHD, we have carried out linkage studies with polymorphic markers in the region syntenic to coloboma (20p11-p12). Five families in which the pattern of inheritance of ADHD appears to be autosomal dominant were studied. Segregation analysis of the traits studied suggested that the best fitting model was a sex-influenced, single gene, Mendelian pattern. Several genetic models were evaluated based on estimates of penetrance, phenocopy rate, and allele frequency derived from our patient population and those of other investigators. No significant linkage was detected between the disease locus and markers spanning this chromosome 20 interval. 39 refs., 2 figs., 1 tab.

  4. COMT Val[superscript 108/158] Met Gene Variant, Birth Weight, and Conduct Disorder in Children with ADHD

    Science.gov (United States)

    Sengupta, Sarojini M.; Grizenko, Natalie; Schmitz, Norbert; Schwartz, George; Amor, Leila Ben; Bellingham, Johanne; de Guzman, Rosherrie; Polotskaia, Anna; Stepanian, Marina Ter; Thakur, Geeta; Joober, Ridha

    2006-01-01

    Objective: In a recent study, Thapar and colleagues reported that COMT "gene variant and birth weight predict early-onset antisocial behavior in children" with attention-deficit/hyperactivity disorder. We have attempted to replicate these findings in a group of ADHD children using a similar research design. Method: Children (n = 191)…

  5. Epigenetic characteristics in inflammatory candidate genes in aggressive periodontitis.

    Science.gov (United States)

    Schulz, Susanne; Immel, Uta Dorothee; Just, Louise; Schaller, Hans-Günter; Gläser, Christiane; Reichert, Stefan

    2016-01-01

    Periodontitis is a chronic inflammatory disease triggered by the host immune response. Epigenetic modifications also affect the immune response. We assessed CpG methylation in 22 inflammatory candidate genes (ATF2, CCL25, CXCL14, CXCL3, CXCL5, CXCL6, FADD, GATA3, IL10RA, IL12A, IL12B, IL13, IL13RA1, IL15, IL17C, IL17RA, IL4R, IL6R, IL6ST, IL7, INHA, and TYK2) with respect to the occurrence of aggressive periodontitis (AgP). In this study 15 AgP patients (53.3% males, 41.4±10.5 years) and 10 controls (40.0% males, 36.9±17.5 years) were included. The methylation patterns of gingival biopsies were quantified using EpiTect® Methyl Signature PCR Array Human Inflammatory Response. In gingival biopsies taken from patients with AgP, CpG methylation of CCL25 (1.73% vs. 2.59%, p=0.015) and IL17C (6.89% vs. 19.27%, p=0.002) was significantly reduced as compared with periodontally healthy tissues. We showed for the first time a differential methylation pattern for CCL25 and IL17C in periodontitis. CCL25 plays an important role in T-cell development, whereas IL17C regulates innate epithelial immune responses. The decrease in CpG methylation is presumably accompanied by an increase in gene expression. This could lead to a greater availability of CCL25 and interleukin 17C and support periodontal loss of attachment. Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  6. Novel Candidate Genes Underlying Extreme Trophic Specialization in Caribbean Pupfishes.

    Science.gov (United States)

    McGirr, Joseph A; Martin, Christopher H

    2017-04-01

    The genetic changes responsible for evolutionary transitions from generalist to specialist phenotypes are poorly understood. Here we examine the genetic basis of craniofacial traits enabling novel trophic specialization in a sympatric radiation of Cyprinodon pupfishes endemic to San Salvador Island, Bahamas. This recent radiation consists of a generalist species and two novel specialists: a small-jawed "snail-eater" and a large-jawed "scale-eater." We genotyped 12 million single nucleotide polymorphisms (SNPs) by whole-genome resequencing of 37 individuals of all three species from nine populations and integrated genome-wide divergence scans with association mapping to identify divergent regions containing putatively causal SNPs affecting jaw size-the most rapidly diversifying trait in this radiation. A mere 22 fixed variants accompanied extreme ecological divergence between generalist and scale-eater species. We identified 31 regions (20 kb) containing variants fixed between specialists that were significantly associated with variation in jaw size which contained 11 genes annotated for skeletal system effects and 18 novel candidate genes never previously associated with craniofacial phenotypes. Six of these 31 regions showed robust signs of hard selective sweeps after accounting for demographic history. Our data are consistent with predictions based on quantitative genetic models of adaptation, suggesting that the effect sizes of regions influencing jaw phenotypes are positively correlated with distance between fitness peaks on a complex adaptive landscape. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  7. Network Candidate Genes in Breeding for Drought Tolerant Crops.

    Science.gov (United States)

    Krannich, Christoph Tim; Maletzki, Lisa; Kurowsky, Christina; Horn, Renate

    2015-07-17

    Climate change leading to increased periods of low water availability as well as increasing demands for food in the coming years makes breeding for drought tolerant crops a high priority. Plants have developed diverse strategies and mechanisms to survive drought stress. However, most of these represent drought escape or avoidance strategies like early flowering or low stomatal conductance that are not applicable in breeding for crops with high yields under drought conditions. Even though a great deal of research is ongoing, especially in cereals, in this regard, not all mechanisms involved in drought tolerance are yet understood. The identification of candidate genes for drought tolerance that have a high potential to be used for breeding drought tolerant crops represents a challenge. Breeding for drought tolerant crops has to focus on acceptable yields under water-limited conditions and not on survival. However, as more and more knowledge about the complex networks and the cross talk during drought is available, more options are revealed. In addition, it has to be considered that conditioning a crop for drought tolerance might require the production of metabolites and might cost the plants energy and resources that cannot be used in terms of yield. Recent research indicates that yield penalty exists and efficient breeding for drought tolerant crops with acceptable yields under well-watered and drought conditions might require uncoupling yield penalty from drought tolerance.

  8. Lack of Association between a 3'UTR VNTR Polymorphism of Dopamine Transporter Gene (SLC6A3) and ADHD in a Brazilian Sample of Adult Patients

    Science.gov (United States)

    Aperecida da Silva, Maria; Cordeiro, Quirino; Louza, Mario; Vallada, Homero

    2011-01-01

    Objective: To investigate a possible association between a 3'UTR VNTR polymorphism of the dopamine transporter gene (SLC6A3) and ADHD in a Brazilian sample of adult patients. Method: Study Case-control with 102 ADHD adult outpatients ("DSM-IV" criteria) and 479 healthy controls. The primers' sequence used were: 3'UTR-Forward: 5' TGT GGT…

  9. The Dopamine Receptor D4 7-Repeat Allele and Prenatal Smoking in ADHD-Affected Children and Their Unaffected Siblings: No Gene-Environment Interaction

    Science.gov (United States)

    Altink, Marieke E.; Arias-Vasquez, Alejandro; Franke, Barbara; Slaats-Willemse, Dorine I. E.; Buschgens, Cathelijne J. M.; Rommelse, Nanda N. J.; Fliers, Ellen A.; Anney, Richard; Brookes, Keeley-Joanne; Chen, Wai; Gill, Michael; Mulligan, Aisling; Sonuga-Barke, Edmund; Thompson, Margaret; Sergeant, Joseph A.; Faraone, Stephen V.; Asherson, Philip; Buitelaar, Jan K.

    2008-01-01

    Background: The dopamine receptor D4 ("DRD4") 7-repeat allele and maternal smoking during pregnancy are both considered as risk factors in the aetiology of attention deficit hyperactivity disorder (ADHD), but few studies have been conducted on their interactive effects in causing ADHD. The purpose of this study is to examine the gene by…

  10. Integration of text- and data-mining using ontologies successfully selects disease gene candidates.

    Science.gov (United States)

    Tiffin, Nicki; Kelso, Janet F; Powell, Alan R; Pan, Hong; Bajic, Vladimir B; Hide, Winston A

    2005-01-01

    Genome-wide techniques such as microarray analysis, Serial Analysis of Gene Expression (SAGE), Massively Parallel Signature Sequencing (MPSS), linkage analysis and association studies are used extensively in the search for genes that cause diseases, and often identify many hundreds of candidate disease genes. Selection of the most probable of these candidate disease genes for further empirical analysis is a significant challenge. Additionally, identifying the genes that cause complex diseases is problematic due to low penetrance of multiple contributing genes. Here, we describe a novel bioinformatic approach that selects candidate disease genes according to their expression profiles. We use the eVOC anatomical ontology to integrate text-mining of biomedical literature and data-mining of available human gene expression data. To demonstrate that our method is successful and widely applicable, we apply it to a database of 417 candidate genes containing 17 known disease genes. We successfully select the known disease gene for 15 out of 17 diseases and reduce the candidate gene set to 63.3% (+/-18.8%) of its original size. This approach facilitates direct association between genomic data describing gene expression and information from biomedical texts describing disease phenotype, and successfully prioritizes candidate genes according to their expression in disease-affected tissues.

  11. Candidate gene investigation of spinal degenerative osteoarthritis in Greek population.

    Science.gov (United States)

    Liva, Eleni; Panagiotou, Irene; Palikyras, Spyros; Parpa, Efi; Tsilika, Eleni; Paschou, Peristera; Mystakidou, Kyriaki

    2017-12-01

    Few data exist concerning the natural history of degenerative osteoarthritis (OA) of the spine and its associated gene investigation. Degenerative spinal OA demonstrates an international prevalence of 15% in the general population. The aim of this Greek case-control study is to examine gene polymorphisms that have been previously shown or hypothesized to be correlated to degenerative OA. Gene polymorphisms, especially for OA, have never been previously studied in the Greek population. The study was conducted from May 2009 to December 2012. Eligible subjects who agreed to take part in the study were Greek adults from all of Greece, referred for consultation to the Palliative Care and Pain Relief Unit of Aretaieion University Hospital, in Athens, Greece. A total of 601 matched pairs (cases and controls) participated in the study, 258 patients (188 women and 70 men) with clinically and radiologically confirmed degenerative OA and 243 control subjects (138 women and 105 men). All patients presented with chronic pain at the spine (cervical, thoracic or lumbar) caused by sympomatic osteophytes or disc narrowing, whereas clinical diagnosis of OA was based on the presence of both joint symptoms and evidence of structural changes seen on plain conventional X-rays. We investigated genetic variation across candidate OA gene GDF5, CDMP1, CDMP2, Asporin, SMAD3, and chromosomal region 7q22, in a sample of 258 patients with clinically and radiologically confirmed degenerative OA, and 243 control subjects from the Greek population. All subjects (patients and controls) were subsequently matched for the epidemiologic, demographic, and clinical risk factors, to prevent selection biases. A tagging single nucleotide polymorphism (SNP) approach was pursued to cover variation across all targeted loci. Single marker tests as well as haplotypic tests of association were performed. There is no conflict of interest, and also, there are no study funding sources. We found significant

  12. Tag SNP selection for candidate gene association studies using HapMap and gene resequencing data.

    Science.gov (United States)

    Xu, Zongli; Kaplan, Norman L; Taylor, Jack A

    2007-10-01

    HapMap provides linkage disequilibrium (LD) information on a sample of 3.7 million SNPs that can be used for tag SNP selection in whole-genome association studies. HapMap can also be used for tag SNP selection in candidate genes, although its performance has yet to be evaluated against gene resequencing data, where there is near-complete SNP ascertainment. The Environmental Genome Project (EGP) is the largest gene resequencing effort to date with over 500 resequenced genes. We used HapMap data to select tag SNPs and calculated the proportions of common SNPs (MAF>or=0.05) tagged (rho2>or=0.8) for each of 127 EGP Panel 2 genes where individual ethnic information was available. Median gene-tagging proportions are 50, 80 and 74% for African, Asian, and European groups, respectively. These low gene-tagging proportions may be problematic for some candidate gene studies. In addition, although HapMap targeted nonsynonymous SNPs (nsSNPs), we estimate only approximately 30% of nonsynonymous SNPs in EGP are in high LD with any HapMap SNP. We show that gene-tagging proportions can be improved by adding a relatively small number of tag SNPs that were selected based on resequencing data. We also demonstrate that ethnic-mixed data can be used to improve HapMap gene-tagging proportions, but are not as efficient as ethnic-specific data. Finally, we generalized the greedy algorithm proposed by Carlson et al (2004) to select tag SNPs for multiple populations and implemented the algorithm into a freely available software package mPopTag.

  13. Study on candidate gene for fecundity traits in Xingjiang Cele black ...

    African Journals Online (AJOL)

    The aim of the present study is to find a potential candidate gene for high fecundity in Cele black sheep. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technology was used to detect single nuclear polymorphism (SNP) of four candidate genes (BMPR-IB, BMP15, GDF9, and ESRα) in Cele ...

  14. Candidate Gene Analyses of Skeletal Variation in Malocclusion

    Science.gov (United States)

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

    2015-01-01

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

  15. DRD4 and DAT1 in ADHD: Functional neurobiology to pharmacogenetics

    Directory of Open Access Journals (Sweden)

    Darko Turic

    2010-05-01

    Full Text Available Darko Turic1, James Swanson2, Edmund Sonuga-Barke1,31Institute for Disorders of Impulse and Attention, School of Psychology, University of Southampton, UK; 2Child Development Center, University of California, Irvine, California, US; 3Department of Experimental, Clinical and Health Psychology, Ghent University, BelgiumAbstract: Attention deficit/hyperactivity disorder (ADHD is a common and potentially very impairing neuropsychiatric disorder of childhood. Statistical genetic studies of twins have shown ADHD to be highly heritable, with the combination of genes and gene by environment interactions accounting for around 80% of phenotypic variance. The initial molecular genetic studies where candidates were selected because of the efficacy of dopaminergic compounds in the treatment of ADHD were remarkably successful and provided strong evidence for the role of DRD4 and DAT1 variants in the pathogenesis of ADHD. However, the recent application of noncandidate gene strategies (eg, genome-wide association scans has failed to identify additional genes with substantial genetic main effects, and the effects for DRD4 and DAT1 have not been replicated. This is the usual pattern observed for most other physical and mental disorders evaluated with current state-of-the-art methods. In this paper we discuss future strategies for genetic studies in ADHD, highlighting both the pitfalls and possible solutions relating to candidate gene studies, genome-wide studies, defining the phenotype, and statistical approaches.Keywords: dopamine, ADHD, pharmacogenetics, candidate gene

  16. Candidate genes and molecular markers associated with heat tolerance in colonial Bentgrass.

    Directory of Open Access Journals (Sweden)

    David Jespersen

    Full Text Available Elevated temperature is a major abiotic stress limiting the growth of cool-season grasses during the summer months. The objectives of this study were to determine the genetic variation in the expression patterns of selected genes involved in several major metabolic pathways regulating heat tolerance for two genotypes contrasting in heat tolerance to confirm their status as potential candidate genes, and to identify PCR-based markers associated with candidate genes related to heat tolerance in a colonial (Agrostis capillaris L. x creeping bentgrass (Agrostis stolonifera L. hybrid backcross population. Plants were subjected to heat stress in controlled-environmental growth chambers for phenotypic evaluation and determination of genetic variation in candidate gene expression. Molecular markers were developed for genes involved in protein degradation (cysteine protease, antioxidant defense (catalase and glutathione-S-transferase, energy metabolism (glyceraldehyde-3-phosphate dehydrogenase, cell expansion (expansin, and stress protection (heat shock proteins HSP26, HSP70, and HSP101. Kruskal-Wallis analysis, a commonly used non-parametric test used to compare population individuals with or without the gene marker, found the physiological traits of chlorophyll content, electrolyte leakage, normalized difference vegetative index, and turf quality were associated with all candidate gene markers with the exception of HSP101. Differential gene expression was frequently found for the tested candidate genes. The development of candidate gene markers for important heat tolerance genes may allow for the development of new cultivars with increased abiotic stress tolerance using marker-assisted selection.

  17. Sequencing of sporadic Attention-Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder.

    Science.gov (United States)

    Kim, Daniel Seung; Burt, Amber A; Ranchalis, Jane E; Wilmot, Beth; Smith, Joshua D; Patterson, Karynne E; Coe, Bradley P; Li, Yatong K; Bamshad, Michael J; Nikolas, Molly; Eichler, Evan E; Swanson, James M; Nigg, Joel T; Nickerson, Deborah A; Jarvik, Gail P

    2017-06-01

    Attention-Deficit Hyperactivity Disorder (ADHD) has high heritability; however, studies of common variation account for ADHD variance. Using data from affected participants without a family history of ADHD, we sought to identify de novo variants that could account for sporadic ADHD. Considering a total of 128 families, two analyses were conducted in parallel: first, in 11 unaffected parent/affected proband trios (or quads with the addition of an unaffected sibling) we completed exome sequencing. Six de novo missense variants at highly conserved bases were identified and validated from four of the 11 families: the brain-expressed genes TBC1D9, DAGLA, QARS, CSMD2, TRPM2, and WDR83. Separately, in 117 unrelated probands with sporadic ADHD, we sequenced a panel of 26 genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD) to evaluate whether variation in ASD/ID-associated genes were also present in participants with ADHD. Only one putative deleterious variant (Gln600STOP) in CHD1L was identified; this was found in a single proband. Notably, no other nonsense, splice, frameshift, or highly conserved missense variants in the 26 gene panel were identified and validated. These data suggest that de novo variant analysis in families with independently adjudicated sporadic ADHD diagnosis can identify novel genes implicated in ADHD pathogenesis. Moreover, that only one of the 128 cases (0.8%, 11 exome, and 117 MIP sequenced participants) had putative deleterious variants within our data in 26 genes related to ID and ASD suggests significant independence in the genetic pathogenesis of ADHD as compared to ASD and ID phenotypes. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  18. Candidate genes for migration do not distinguish migratory and non-migratory birds.

    Science.gov (United States)

    Lugo Ramos, Juan S; Delmore, Kira E; Liedvogel, Miriam

    2017-07-01

    Migratory traits in birds have been shown to have a strong heritable component and several candidate genes have been suggested to control these migratory traits. To investigate if the genetic makeup of one or a set of these candidate genes can be used to identify a general pattern between migratory and non-migratory birds, we extracted genomic sequence data for 25 hypothesised candidate genes for migration from 70 available genomes across all orders of Aves and characterised sequence divergence between migratory and non-migratory phenotypes. When examining each gene separately across all species, we did not identify any genetic variants in candidate genes that distinguished migrants from non-migrants; any resulting pattern was driven by the phylogenetic signal. This was true for each gene analysed independently, but also for concatenated sequence alignments of all candidate genes combined. We also attempted to distinguish between migrant and non-migrants using structural features at four candidate genes that have previously been reported to show associated with migratory behaviour but did not pick up a signal for migratory phenotype here either. Finally, a screen for dN/dS ratio across all focal candidate genes to probe for putative features of selection did not uncover a pattern, though this might not be expected given the broad phylogenetic scale used here. Our study demonstrates the potential of public genomic data to test for general patterns of migratory gene candidates in a cross-species comparative context, and raise questions on the applicability of candidate gene approaches in a macro-evolutionary context to understand the genetic architecture of migratory behaviour.

  19. Exclusion of the PAX2 gene as a candidate gene for Crouzon craniofacial dysostosis

    Energy Technology Data Exchange (ETDEWEB)

    Preston, R.A.; Gorry, M.C. [Univ. of Pittsburgh, PA (United States); Warman, M. [Harvard Univ., Boston, MA (United States)] [and others

    1994-09-01

    Crouzon craniofacial dysostosis (CFD, MIM 123500) is an abnormality of craniofacial development characterized by premature craniosynostosis, maxillary hypoplasia, and shallow orbits. We have mapped the CFD gene locus using a candidate gene approach to a 7 centiMorgan region on chromosome 10q in three CFD families. A maximal multipoint LOD score of 12.33 was achieved for a locus 2 cM distal to the microsatellite marker D10S209. A comparison of several physical, cytogenetic, and linkage maps revealed that the cytogenetic bands, 10q25-q26, most likely contain this CFD locus. The PAX2 gene, which has been mapped near another marker which in turn has been mapped to 10q25, was analyzed as a candidate gene. PAX2 was chosen for analysis because mutations in other members of the PAX gene family have been identified with human craniofacial abnormalities (e.g. Waardenburg syndrome). A YAC contig, consisting of 5 overlapping groups and composed of 11 YACs that spans the entire 7 cM region, was assembled for PAX2 analyses. None of these YACs supported PAX2-specific amplification using primer sets for both the second and third PAX2 exons. Control amplifications for YAC vector sequences produced robust amplifications in all cases. In addition, SSCP analyses of amplification products generated from the second and third PAX2 exons and the 3{prime} untranslated region of the PAX2 gene from both affected and unaffected family members in two of the kindreds failed to reveal any polymorphisms. Although it remains theoretically possible, due to artifacts in the YAC contigs, it is unlikely that PAX2 is the CFD gene.

  20. Genes associated with genotype-specific DNA methylation in squamous cell carcinoma as candidate drug targets

    Science.gov (United States)

    2014-01-01

    Background Aberrant DNA methylation is often associated with cancers. Thus, screening genes with cancer-associated aberrant DNA methylation is a useful method to identify candidate cancer-causing genes. Aberrant DNA methylation is also genotype dependent. Thus, the selection of genes with genotype-specific aberrant DNA methylation in cancers is potentially important for tailor-made medicine. The selected genes are important candidate drug targets. Results The recently proposed principal component analysis based selection of genes with aberrant DNA methylation was applied to genotype and DNA methylation patterns in squamous cell carcinoma measured using single nucleotide polymorphism (SNP) arrays. SNPs that are frequently found in cancers are usually highly methylated, and the genes that were selected using this method were reported previously to be related to cancers. Thus, genes with genotype-specific DNA methylation patterns will be good therapeutic candidates. The tertiary structures of the proteins encoded by the selected genes were successfully inferred using two profile-based protein structure servers, FAMS and Phyre2. Candidate drugs for three of these proteins, tyrosine kinase receptor (ALK), EGLN3 protein, and NUAK family SNF1-like kinase 1 (NUAK1), were identified by ChooseLD. Conclusions We detected genes with genotype-specific DNA methylation in squamous cell carcinoma that are candidate drug targets. Using in silico drug discovery, we successfully identified several candidate drugs for the ALK, EGLN3 and NUAK1 genes that displayed genotype-specific DNA methylation. PMID:24565165

  1. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis.

    Science.gov (United States)

    Burney, Richard O; Talbi, Said; Hamilton, Amy E; Vo, Kim Chi; Nyegaard, Mette; Nezhat, Camran R; Lessey, Bruce A; Giudice, Linda C

    2007-08-01

    The identification of molecular differences in the endometrium of women with endometriosis is an important step toward understanding the pathogenesis of this condition and toward developing novel strategies for the treatment of associated infertility and pain. In this study, we conducted global gene expression analysis of endometrium from women with and without moderate/severe stage endometriosis and compared the gene expression signatures across various phases of the menstrual cycle. The transcriptome analysis revealed molecular dysregulation of the proliferative-to-secretory transition in endometrium of women with endometriosis. Paralleled gene expression analysis of endometrial specimens obtained during the early secretory phase demonstrated a signature of enhanced cellular survival and persistent expression of genes involved in DNA synthesis and cellular mitosis in the setting of endometriosis. Comparative gene expression analysis of progesterone-regulated genes in secretory phase endometrium confirmed the observation of attenuated progesterone response. Additionally, interesting candidate susceptibility genes were identified that may be associated with this disorder, including FOXO1A, MIG6, and CYP26A1. Collectively these findings provide a framework for further investigations on causality and mechanisms underlying attenuated progesterone response in endometrium of women with endometriosis.

  2. Physical mapping and candidate gene prediction of fertility restorer gene of cytoplasmic male sterility in cotton.

    Science.gov (United States)

    Zhao, Cunpeng; Zhao, Guiyuan; Geng, Zhao; Wang, Zhaoxiao; Wang, Kaihui; Liu, Suen; Zhang, Hanshuang; Guo, Baosheng; Geng, Junyi

    2018-01-02

    Cytoplasmic male sterility (CMS) is a maternally inherited trait failing to produce functional pollen. It plays a pivotal role in the exploitation of crop heterosis. The specific locus amplified fragment sequencing (SLAF-seq) as a high-resolution strategy for the identification of new SNPs on a large-scale is gradually applied for functional gene mining. The current study combined the bulked segregant analysis (BSA) with SLAF-seq to identify the candidate genes associated with fertility restorer gene (Rf) in CMS cotton. Illumina sequencing systematically investigated the parents. A segregating population comprising of 30 + 30 F2 individuals was developed using 3096A (female parent) as sterile and 866R (male parent) as a restorer. The original data obtained by dual-index sequencing were analyzed to obtain the reads of each sample that were compared to the reference genome in order to identify the SLAF tag with a polymorphism in parent lines and the SNP with read-associated coverage. Based on SLAF tags, SNP-index analysis, Euclidean distance (ED) correlation analysis, and whole genome resequencing, the hot regions were annotated. A total of 165,007 high-quality SLAF tags, with an average depth of 47.90× in the parents and 50.78× in F2 individuals, were sequenced. In addition, a total of 137,741 SNPs were detected: 113,311 and 98,861 SNPs in the male and female parent, respectively. A correlation analysis by SNP-index and ED initially located the candidate gene on 1.35 Mb of chrD05, and 20 candidate genes were identified. These genes were involved in genetic variations, single base mutations, insertions, and deletions. Moreover, 42 InDel markers of the whole genome resequencing were also detected. In this study, associated markers identified by super-BSA could accelerate the study of CMS in cotton, and as well as in other crops. Some of the 20 genes' preliminary characteristics provided useful information for further studies on CMS crops.

  3. Dopamine D4 Receptor Gene Polymorphism in a Sample of Egyptian Children With Attention-Deficit Hyperactivity Disorder (ADHD).

    Science.gov (United States)

    ElBaz Mohamed, Farida; Kamal, Tarek Mostafa; Zahra, Sally Soliman; Khfagy, Mona Abdel Hakiem; Youssef, Azza Mohamed

    2017-02-01

    This study aimed to detect DRD4 receptor gene polymorphisms in attention-deficit hyperactivity disorder (ADHD) children and to correlate their phenotype-genotype. Fifty children with ADHD were diagnosed by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria and were subjected to Conners Parent Rating Scale. All cases and controls were subjected to history taking, physical examination, IQ assessment, and dopamine receptor D4 (DRD4) exon 3 genotyping. The 7-repeat allele was present only in controls, whereas 2-repeat allele was present in the ADHD children (heterozygous 2-repeat allele in 16% and homozygous in 26% of cases). Eight percent of cases had homozygous 4-repeat allele vs 28% of controls, whereas 10% of cases had heterozygous 4-repeat allele vs 6% of controls, with its predominance in controls. The 2-repeat and 4-repeat alleles have been associated with more inattention, hyperactivity, and impulsivity phenotypes. In conclusion, children with ADHD had a significant presence of the 2-repeat allele and absence of the 7-repeat allele.

  4. Localization of a new autosomal dominant retinitis pigmentosa gene on chromosome 17p screeningof candidate genes

    Energy Technology Data Exchange (ETDEWEB)

    Greenberg, J.; Goliath, R.; Shugart, Y.Y. [Univ. of Cape Town Medical School, Cape Town (South Africa)] [and others

    1994-09-01

    A new gene locus for autosomal dominant retinitis pigmentosa (ADRP) on 17p has been identified in a large South African (SA) family consisting of 28 living affected individuals in 4 successive generations. This is the first ADRP gene to be reported from SA. The human recoverin (RCVN) gene, which codes for a retinal-specific protein important in recovery to the dark state after visual excitation, has been mapped to 17p13.1 and was considered as a prime candidate gene for the disorder in this family. Mutation screening (using 8 different electrophoretic conditions to resolve heteroduplexes and SSCPs) did not produce any evidence of RCVN being involved in the pathogenesis of ADRP in this SA family. In addition, a mobility shift detected within exon 1 of the RCVN gene did not track with the ADRP phenotype. RP patients from 77 SA families and 30 normal individuals are being examined to establish the frequency of this polymorphism in the SA population. Highly polymorphic markers from 17p13 are now being sought in order to establish the minimum region containing this novel ADRP-SA gene. Two additional recently described retinal-expressed cDNAs, guanylyl cyclase and pigment epithelium-derived factor, which map to 17p13.1, will be tested for tight linkage to ADRP-SA.

  5. Identification of candidate B-lymphoma genes by cross-species gene expression profiling.

    Directory of Open Access Journals (Sweden)

    Van S Tompkins

    Full Text Available Comparative genome-wide expression profiling of malignant tumor counterparts across the human-mouse species barrier has a successful track record as a gene discovery tool in liver, breast, lung, prostate and other cancers, but has been largely neglected in studies on neoplasms of mature B-lymphocytes such as diffuse large B cell lymphoma (DLBCL and Burkitt lymphoma (BL. We used global gene expression profiles of DLBCL-like tumors that arose spontaneously in Myc-transgenic C57BL/6 mice as a phylogenetically conserved filter for analyzing the human DLBCL transcriptome. The human and mouse lymphomas were found to have 60 concordantly deregulated genes in common, including 8 genes that Cox hazard regression analysis associated with overall survival in a published landmark dataset of DLBCL. Genetic network analysis of the 60 genes followed by biological validation studies indicate FOXM1 as a candidate DLBCL and BL gene, supporting a number of studies contending that FOXM1 is a therapeutic target in mature B cell tumors. Our findings demonstrate the value of the "mouse filter" for genomic studies of human B-lineage neoplasms for which a vast knowledge base already exists.

  6. Population differences in the International Multi-Centre ADHD Gene Project.

    Science.gov (United States)

    Neale, Benjamin M; Sham, Pak C; Purcell, Shaun; Banaschewski, Tobias; Buitelaar, Jan; Franke, Barbara; Sonuga-Barke, Edmund; Ebstein, Richard; Eisenberg, Jacques; Mulligan, Aisling; Gill, Michael; Manor, Iris; Miranda, Ana; Mulas, Fernando; Oades, Robert D; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph; Steinhausen, Hans-Christoph; Taylor, Eric; Thompson, Margaret; Chen, Wai; Zhou, Kaixin; Asherson, Philip; Faraone, Stephen V

    2008-02-01

    The International Multi-Centre ADHD Gene sample consists of 674 families from eight countries (Belgium, England, Germany, Holland, Ireland, Israel, Spain, and Switzerland) ascertained from clinics for combined-type attention definity hyperactivity disorder in an offspring. 863 SNPs were successfully genotyped across 47 autosomal genes implicated in psychiatric disorders yielding a single nucleotide polymorphism (SNP) density of approximately one SNP per 2.5 kb. A global test of heterogeneity showed 269 SNPs nominally significant (expected 43). Inclusion of the Israeli population accounted for approximately 70% of these nominally significant tests. Hardy-Weinberg equilibrium tests suggest that combining all these populations would induce stratification, but that the Northern European populations (Belgium, England, Germany, Holland, and Ireland) could be appropriate. Tag SNPs were generated using pair-wise and aggressive tagging from Carlson et al. [2004] and de Bakker et al. [2005], respectively, in each population and applied to the other populations. Cross-population performance across Northern Europe was consistent with within population comparisons. Smaller sample size for each population tended to yield more problems for the generation of aggressive tags and the application of pair-wise tags. Any case-control sample employing an Israeli sample with Northern Europeans must consider stratification. A Northern European tag set, however, appears to be appropriate for capturing the variation across populations.

  7. Polymorphisms of candidate genes associated with meat quality and ...

    African Journals Online (AJOL)

    No mutation was found in the RFLP-fragment of the FUT1 gene of four indigenous pig breeds by sequencing, while in the BPI gene two mutations were detected in the Tap Na breed. The resistant alleles of the FUT1 and BPI genes in the exotic breeds were significantly higher than those of indigenous pig breeds. Among the ...

  8. Isolation of candidate disease resistance genes from enrichment ...

    African Journals Online (AJOL)

    Full sequencing of a clone revealed a gene similar to a putative brassinosteroid LRR receptor kinase in japonica rice; the protein structure analysis suggested that it may be a disease resistance gene or functionally involved in a signal transduction pathway. These results indicate these clones may include new R genes and ...

  9. RARβ gene methylation is a candidate for primary glioblastoma ...

    African Journals Online (AJOL)

    genetic mechanisms. It is the oldest and most widely used epigenetic mechanism used to identify expressions of the cancer specific genes. Many genes in glioblasto- mas have epigenetic characteristics that include hyper- methylation of the MGMT, RASSF1A, p16/INK4A and p15/INK4. These hypermethylated genes have.

  10. Degrees of separation as a statistical tool for evaluating candidate genes.

    Science.gov (United States)

    Nelson, Ronald M; Pettersson, Mats E

    2014-12-01

    Selection of candidate genes is an important step in the exploration of complex genetic architecture. The number of gene networks available is increasing and these can provide information to help with candidate gene selection. It is currently common to use the degree of connectedness in gene networks as validation in Genome Wide Association (GWA) and Quantitative Trait Locus (QTL) mapping studies. However, it can cause misleading results if not validated properly. Here we present a method and tool for validating the gene pairs from GWA studies given the context of the network they co-occur in. It ensures that proposed interactions and gene associations are not statistical artefacts inherent to the specific gene network architecture. The CandidateBacon package provides an easy and efficient method to calculate the average degree of separation (DoS) between pairs of genes to currently available gene networks. We show how these empirical estimates of average connectedness are used to validate candidate gene pairs. Validation of interacting genes by comparing their connectedness with the average connectedness in the gene network will provide support for said interactions by utilising the growing amount of gene network information available. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Candidate genes and single nucleotide polymorphisms associated with variation in residual feed intake in beef cattle.

    Science.gov (United States)

    Karisa, B K; Thomson, J; Wang, Z; Stothard, P; Moore, S S; Plastow, G S

    2013-08-01

    The candidate gene approach was used to identify genes associated with residual feed intake (RFI) in beef steers. The approach uses prior knowledge of gene functions to predict their biological role in the variation observed in a trait. It is suited to identify genes associated with complex traits where each gene has a relatively small effect. First, positional candidate genes were identified within the genomic positions of previously reported QTL associated with component traits related to RFI such as dry matter intake (DMI), growth, feed conversion ratio (FCR), average daily gain (ADG), and energy balance. Secondly, the positional candidate genes were prioritized into functional candidate genes according to their biological functions and their relationship with the biological processes associated with RFI including carbohydrate, fat and protein metabolism, thermoregulation, immunity and muscle activity. Single nucleotide polymorphisms (SNPs) located within the functional candidate genes were identified using mRNA sequences and prioritized into functional classes such as non-synonymous (nsSNP), synonymous (sSNP) or intronic SNP. A total of 117 nsSNP were considered as functional SNP and genotyped in steers at the University of Alberta ranch in Kinsella. Multiple marker association analysis in ASReml was performed using RFI data obtained from 531 beef steers. Twenty-five SNP were significantly associated with RFI (P energy metabolism, electron transport and membrane signaling. The genes in this study, if validated in other beef cattle populations, may be useful for marker assisted selection for feed efficiency.

  12. Expression of the dyslexia candidate gene kiaa0319-like in insect cells

    NARCIS (Netherlands)

    Holster, Savanne; Oers, van Monique M.; Roode, Els C.; Tsang, Otto W.H.; Yeung, Venus S.Y.; Vlak, Just M.; Waye, Mary M.Y.

    2015-01-01

    The human kiaa0319-like gene is one of the candidate genes for developmental dyslexia, but the exact function of the encoded KIAA0319L (KL) protein is not known. To allow functional analysis a purified, biologically active KL protein is required. The kiaa0319-like gene was expressed in insect

  13. Epidermal growth factor gene is a newly identified candidate gene for gout

    Science.gov (United States)

    Han, Lin; Cao, Chunwei; Jia, Zhaotong; Liu, Shiguo; Liu, Zhen; Xin, Ruosai; Wang, Can; Li, Xinde; Ren, Wei; Wang, Xuefeng; Li, Changgui

    2016-01-01

    Chromosome 4q25 has been identified as a genomic region associated with gout. However, the associations of gout with the genes in this region have not yet been confirmed. Here, we performed two-stage analysis to determine whether variations in candidate genes in the 4q25 region are associated with gout in a male Chinese Han population. We first evaluated 96 tag single nucleotide polymorphisms (SNPs) in eight inflammatory/immune pathway- or glucose/lipid metabolism-related genes in the 4q25 region in 480 male gout patients and 480 controls. The SNP rs12504538, located in the elongation of very-long-chain-fatty-acid-like family member 6 gene (Elovl6), was found to be associated with gout susceptibility (Padjusted = 0.00595). In the second stage of analysis, we performed fine mapping analysis of 93 tag SNPs in Elovl6 and in the epidermal growth factor gene (EGF) and its flanking regions in 1017 male patients gout and 1897 healthy male controls. We observed a significant association between the T allele of EGF rs2298999 and gout (odds ratio = 0.77, 95% confidence interval = 0.67–0.88, Padjusted = 6.42 × 10−3). These results provide the first evidence for an association between the EGF rs2298999 C/T polymorphism and gout. Our findings should be validated in additional populations. PMID:27506295

  14. Poor replication of candidate genes for major depressive disorder using genome-wide association data

    NARCIS (Netherlands)

    Bosker, F. J.; Hartman, C. A.; Nolte, I. M.; Prins, B. P.; Terpstra, P.; Posthuma, D.; van Veen, T.; Willemsen, G.; DeRijk, R. H.; de Geus, E. J.; Hoogendijk, W. J.; Sullivan, P. F.; Penninx, B. W.; Boomsma, D. I.; Snieder, H.; Nolen, W. A.

    Data from the Genetic Association Information Network ( GAIN) genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and single-nucleotide polymorphism (SNP) associations in MDD. A systematic literature search of candidate

  15. Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis

    DEFF Research Database (Denmark)

    Grauers, Anna; Wang, Jingwen; Einarsdottir, Elisabet

    2015-01-01

    BACKGROUND CONTEXT: Idiopathic scoliosis is a spinal deformity affecting approximately 3% of otherwise healthy children or adolescents. The etiology is still largely unknown but has an important genetic component. Genome-wide association studies have identified a number of common genetic variants...... that are significantly associated with idiopathic scoliosis in Asian and Caucasian populations, rs11190870 close to the LBX1 gene being the most replicated finding. PURPOSE: The aim of the present study was to investigate the genetics of idiopathic scoliosis in a Scandinavian cohort by performing a candidate gene study...... of four variants previously shown to be associated with idiopathic scoliosis and exome sequencing of idiopathic scoliosis patients with a severe phenotype to identify possible novel scoliosis risk variants. STUDY DESIGN: This was a case control study. PATIENT SAMPLE: A total of 1,739 patients...

  16. Mining for novel candidate clock genes in the circadian regulatory network.

    Science.gov (United States)

    Bhargava, Anuprabha; Herzel, Hanspeter; Ananthasubramaniam, Bharath

    2015-11-14

    Most physiological processes in mammals are temporally regulated by means of a master circadian clock in the brain and peripheral oscillators in most other tissues. A transcriptional-translation feedback network of clock genes produces near 24 h oscillations in clock gene and protein expression. Here, we aim to identify novel additions to the clock network using a meta-analysis of public chromatin immunoprecipitation sequencing (ChIP-seq), proteomics and protein-protein interaction data starting from a published list of 1000 genes with robust transcriptional rhythms and circadian phenotypes of knockdowns. We identified 20 candidate genes including nine known clock genes that received significantly high scores and were also robust to the relative weights assigned to different data types. Our scoring was consistent with the original ranking of the 1000 genes, but also provided novel complementary insights. Candidate genes were enriched for genes expressed in a circadian manner in multiple tissues with regulation driven mainly by transcription factors BMAL1 and REV-ERB α,β. Moreover, peak transcription of candidate genes was remarkably consistent across tissues. While peaks of the 1000 genes were distributed uniformly throughout the day, candidate gene peaks were strongly concentrated around dusk. Finally, we showed that binding of specific transcription factors to a gene promoter was predictive of peak transcription at a certain time of day and discuss combinatorial phase regulation. Combining complementary publicly-available data targeting different levels of regulation within the circadian network, we filtered the original list and found 11 novel robust candidate clock genes. Using the criteria of circadian proteomic expression, circadian expression in multiple tissues and independent gene knockdown data, we propose six genes (Por, Mtss1, Dgat2, Pim3, Ppp1r3b, Upp2) involved in metabolism and cancer for further experimental investigation. The availability of

  17. Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies

    NARCIS (Netherlands)

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

    2014-01-01

    textabstractObjective 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

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Erin M Siegel

    Full Text Available 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.

  20. Defining the Human Macula Transcriptome and Candidate Retinal Disease Genes UsingEyeSAGE

    Science.gov (United States)

    Rickman, Catherine Bowes; Ebright, Jessica N.; Zavodni, Zachary J.; Yu, Ling; Wang, Tianyuan; Daiger, Stephen P.; Wistow, Graeme; Boon, Kathy; Hauser, Michael A.

    2009-01-01

    Purpose To develop large-scale, high-throughput annotation of the human macula transcriptome and to identify and prioritize candidate genes for inherited retinal dystrophies, based on ocular-expression profiles using serial analysis of gene expression (SAGE). Methods Two human retina and two retinal pigment epithelium (RPE)/choroid SAGE libraries made from matched macula or midperipheral retina and adjacent RPE/choroid of morphologically normal 28- to 66-year-old donors and a human central retina longSAGE library made from 41- to 66-year-old donors were generated. Their transcription profiles were entered into a relational database, EyeSAGE, including microarray expression profiles of retina and publicly available normal human tissue SAGE libraries. EyeSAGE was used to identify retina- and RPE-specific and -associated genes, and candidate genes for retina and RPE disease loci. Differential and/or cell-type specific expression was validated by quantitative and single-cell RT-PCR. Results Cone photoreceptor-associated gene expression was elevated in the macula transcription profiles. Analysis of the longSAGE retina tags enhanced tag-to-gene mapping and revealed alternatively spliced genes. Analysis of candidate gene expression tables for the identified Bardet-Biedl syndrome disease gene (BBS5) in the BBS5 disease region table yielded BBS5 as the top candidate. Compelling candidates for inherited retina diseases were identified. Conclusions The EyeSAGE database, combining three different gene-profiling platforms including the authors’ multidonor-derived retina/RPE SAGE libraries and existing single-donor retina/RPE libraries, is a powerful resource for definition of the retina and RPE transcriptomes. It can be used to identify retina-specific genes, including alternatively spliced transcripts and to prioritize candidate genes within mapped retinal disease regions. PMID:16723438

  1. Prioritization of candidate disease genes by topological similarity between disease and protein diffusion profiles.

    Science.gov (United States)

    Zhu, Jie; Qin, Yufang; Liu, Taigang; Wang, Jun; Zheng, Xiaoqi

    2013-01-01

    Identification of gene-phenotype relationships is a fundamental challenge in human health clinic. Based on the observation that genes causing the same or similar phenotypes tend to correlate with each other in the protein-protein interaction network, a lot of network-based approaches were proposed based on different underlying models. A recent comparative study showed that diffusion-based methods achieve the state-of-the-art predictive performance. In this paper, a new diffusion-based method was proposed to prioritize candidate disease genes. Diffusion profile of a disease was defined as the stationary distribution of candidate genes given a random walk with restart where similarities between phenotypes are incorporated. Then, candidate disease genes are prioritized by comparing their diffusion profiles with that of the disease. Finally, the effectiveness of our method was demonstrated through the leave-one-out cross-validation against control genes from artificial linkage intervals and randomly chosen genes. Comparative study showed that our method achieves improved performance compared to some classical diffusion-based methods. To further illustrate our method, we used our algorithm to predict new causing genes of 16 multifactorial diseases including Prostate cancer and Alzheimer's disease, and the top predictions were in good consistent with literature reports. Our study indicates that integration of multiple information sources, especially the phenotype similarity profile data, and introduction of global similarity measure between disease and gene diffusion profiles are helpful for prioritizing candidate disease genes. Programs and data are available upon request.

  2. Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis.

    Science.gov (United States)

    Grauers, Anna; Wang, Jingwen; Einarsdottir, Elisabet; Simony, Ane; Danielsson, Aina; Åkesson, Kristina; Ohlin, Acke; Halldin, Klas; Grabowski, Pawel; Tenne, Max; Laivuori, Hannele; Dahlman, Ingrid; Andersen, Mikkel; Christensen, Steen Bach; Karlsson, Magnus K; Jiao, Hong; Kere, Juha; Gerdhem, Paul

    2015-10-01

    Idiopathic scoliosis is a spinal deformity affecting approximately 3% of otherwise healthy children or adolescents. The etiology is still largely unknown but has an important genetic component. Genome-wide association studies have identified a number of common genetic variants that are significantly associated with idiopathic scoliosis in Asian and Caucasian populations, rs11190870 close to the LBX1 gene being the most replicated finding. The aim of the present study was to investigate the genetics of idiopathic scoliosis in a Scandinavian cohort by performing a candidate gene study of four variants previously shown to be associated with idiopathic scoliosis and exome sequencing of idiopathic scoliosis patients with a severe phenotype to identify possible novel scoliosis risk variants. This was a case control study. A total of 1,739 patients with idiopathic scoliosis and 1,812 controls were included. The outcome measure was idiopathic scoliosis. The variants rs10510181, rs11190870, rs12946942, and rs6570507 were genotyped in 1,739 patients with idiopathic scoliosis and 1,812 controls. Exome sequencing was performed on pooled samples from 100 surgically treated idiopathic scoliosis patients. Novel or rare missense, nonsense, or splice site variants were selected for individual genotyping in the 1,739 cases and 1,812 controls. In addition, the 5'UTR, noncoding exon and promoter regions of LBX1, not covered by exome sequencing, were Sanger sequenced in the 100 pooled samples. Of the four candidate genes, an intergenic variant, rs11190870, downstream of the LBX1 gene, showed a highly significant association to idiopathic scoliosis in 1,739 cases and 1,812 controls (p=7.0×10(-18)). We identified 20 novel variants by exome sequencing after filtration and an initial genotyping validation. However, we could not verify any association to idiopathic scoliosis in the large cohort of 1,739 cases and 1,812 controls. We did not find any variants in the 5'UTR, noncoding exon and

  3. Potential Candidate Genes for Improving Rice Disease Resistance

    National Research Council Canada - National Science Library

    Delteil, Amandine; Zhang, Jie; Lessard, Philippe; Morel, Jean-Benoit

    2010-01-01

    .... oryzae are responsible for considerable yield loss. Up to now, in rice, the modification of the expression of more than 60 genes from diverse origins has shown beneficial effects with respect to disease resistance...

  4. Exome Analyses of Long QT Syndrome Reveal Candidate Pathogenic Mutations in Calmodulin-Interacting Genes

    Science.gov (United States)

    Nakagawa, Hidewaki; Ozaki, Kouichi; Miya, Fuyuki; Satake, Wataru; Toda, Tatsushi; Miyamoto, Yoshihiro; Fujimoto, Akihiro; Suzuki, Yutaka; Kubo, Michiaki; Tsunoda, Tatsuhiko; Shimizu, Wataru; Tanaka, Toshihiro

    2015-01-01

    Long QT syndrome (LQTS) is an arrhythmogenic disorder that can lead to sudden death. To date, mutations in 15 LQTS-susceptibility genes have been implicated. However, the genetic cause for approximately 20% of LQTS patients remains elusive. Here, we performed whole-exome sequencing analyses on 59 LQTS and 61 unaffected individuals in 35 families and 138 unrelated LQTS cases, after genetic screening of known LQTS genes. Our systematic analysis of familial cases and subsequent verification by Sanger sequencing identified 92 candidate mutations in 88 genes for 23 of the 35 families (65.7%): these included eleven de novo, five recessive (two homozygous and three compound heterozygous) and seventy-three dominant mutations. Although no novel commonly mutated gene was identified other than known LQTS genes, protein-protein interaction (PPI) network analyses revealed ten new pathogenic candidates that directly or indirectly interact with proteins encoded by known LQTS genes. Furthermore, candidate gene based association studies using an independent set of 138 unrelated LQTS cases and 587 controls identified an additional novel candidate. Together, mutations in these new candidates and known genes explained 37.1% of the LQTS families (13 in 35). Moreover, half of the newly identified candidates directly interact with calmodulin (5 in 11; comparison with all genes; p=0.042). Subsequent variant analysis in the independent set of 138 cases identified 16 variants in the 11 genes, of which 14 were in calmodulin-interacting genes (87.5%). These results suggest an important role of calmodulin and its interacting proteins in the pathogenesis of LQTS. PMID:26132555

  5. Candidate gene linkage analysis indicates genetic heterogeneity in Marfan syndrome.

    Science.gov (United States)

    Teixeira, L V S; Lezirovitz, K; Mandelbaum, K L; Pereira, L V; Perez, A B A

    2011-08-01

    Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue that affects the ocular, skeletal and cardiovascular systems, with a wide clinical variability. Although mutations in the FBN1 gene have been recognized as the cause of the disease, more recently other loci have been associated with MFS, indicating the genetic heterogeneity of this disease. We addressed the issue of genetic heterogeneity in MFS by performing linkage analysis of the FBN1 and TGFBR2 genes in 34 families (345 subjects) who met the clinical diagnostic criteria for the disease according to Ghent. Using a total of six microsatellite markers, we found that linkage with the FBN1 gene was observed or not excluded in 70.6% (24/34) of the families, and in 1 family the MFS phenotype segregated with the TGFBR2 gene. Moreover, in 4 families linkage with the FBN1 and TGFBR2 genes was excluded, and no mutations were identified in the coding region of TGFBR1, indicating the existence of other genes involved in MFS. Our results suggest that the genetic heterogeneity of MFS may be greater that previously reported.

  6. Candidate gene linkage analysis indicates genetic heterogeneity in Marfan syndrome

    Directory of Open Access Journals (Sweden)

    L.V.S. Teixeira

    2011-08-01

    Full Text Available Marfan syndrome (MFS is an autosomal dominant disease of the connective tissue that affects the ocular, skeletal and cardiovascular systems, with a wide clinical variability. Although mutations in the FBN1 gene have been recognized as the cause of the disease, more recently other loci have been associated with MFS, indicating the genetic heterogeneity of this disease. We addressed the issue of genetic heterogeneity in MFS by performing linkage analysis of the FBN1 and TGFBR2 genes in 34 families (345 subjects who met the clinical diagnostic criteria for the disease according to Ghent. Using a total of six microsatellite markers, we found that linkage with the FBN1 gene was observed or not excluded in 70.6% (24/34 of the families, and in 1 family the MFS phenotype segregated with the TGFBR2 gene. Moreover, in 4 families linkage with the FBN1 and TGFBR2 genes was excluded, and no mutations were identified in the coding region of TGFBR1, indicating the existence of other genes involved in MFS. Our results suggest that the genetic heterogeneity of MFS may be greater that previously reported.

  7. Mutation burden of rare variants in schizophrenia candidate genes.

    Science.gov (United States)

    Girard, Simon L; Dion, Patrick A; Bourassa, Cynthia V; Geoffroy, Steve; Lachance-Touchette, Pamela; Barhdadi, Amina; Langlois, Mathieu; Joober, Ridha; Krebs, Marie-Odile; Dubé, Marie-Pierre; Rouleau, Guy A

    2015-01-01

    Schizophrenia (SCZ) is a very heterogeneous disease that affects approximately 1% of the general population. Recently, the genetic complexity thought to underlie this condition was further supported by three independent studies that identified an increased number of damaging de novo mutations DNM in different SCZ probands. While these three reports support the implication of DNM in the pathogenesis of SCZ, the absence of overlap in the genes identified suggests that the number of genes involved in SCZ is likely to be very large; a notion that has been supported by the moderate success of Genome-Wide Association Studies (GWAS). To further examine the genetic heterogeneity of this disease, we resequenced 62 genes that were found to have a DNM in SCZ patients, and 40 genes that encode for proteins known to interact with the products of the genes with DNM, in a cohort of 235 SCZ cases and 233 controls. We found an enrichment of private nonsense mutations amongst schizophrenia patients. Using a kernel association method, we were able to assess for association for different sets. Although our power of detection was limited, we observed an increased mutation burden in the genes that have DNM.

  8. Characterisation of five candidate genes within the ETEC F4ab/ac candidate region in pigs

    DEFF Research Database (Denmark)

    Jacobsen, Mette Juul; Cirera Salicio, Susanna; Joller, David

    2011-01-01

    /ac resistant and ETEC F4ab/ac susceptible animals in any of the tested tissues. CONCLUSIONS: None of the identified polymorphisms are obvious causative mutations for ETEC F4ab/ac susceptibility, as they have no impact on the level of the overall mRNA expression nor predicted to influence the composition...... of the amino acids composition. However, we cannot exclude that the five tested genes are bona fide candidate genes for susceptibility to ETEC F4ab/ac infection since the identified polymorphism might affect the translational apparatus, alternative splice forms may exist and post translational mechanisms might...... dominant Mendelian trait. Indentifying the genetics behind this trait will greatly benefit pig welfare as well as the pig breeding industry by providing an opportunity to select against genetically susceptible animals, thereby reducing the number of diarrhoea outbreaks. The trait has recently been mapped...

  9. Developing integrated crop knowledge networks to advance candidate gene discovery.

    Science.gov (United States)

    Hassani-Pak, Keywan; Castellote, Martin; Esch, Maria; Hindle, Matthew; Lysenko, Artem; Taubert, Jan; Rawlings, Christopher

    2016-12-01

    The chances of raising crop productivity to enhance global food security would be greatly improved if we had a complete understanding of all the biological mechanisms that underpinned traits such as crop yield, disease resistance or nutrient and water use efficiency. With more crop genomes emerging all the time, we are nearer having the basic information, at the gene-level, to begin assembling crop gene catalogues and using data from other plant species to understand how the genes function and how their interactions govern crop development and physiology. Unfortunately, the task of creating such a complete knowledge base of gene functions, interaction networks and trait biology is technically challenging because the relevant data are dispersed in myriad databases in a variety of data formats with variable quality and coverage. In this paper we present a general approach for building genome-scale knowledge networks that provide a unified representation of heterogeneous but interconnected datasets to enable effective knowledge mining and gene discovery. We describe the datasets and outline the methods, workflows and tools that we have developed for creating and visualising these networks for the major crop species, wheat and barley. We present the global characteristics of such knowledge networks and with an example linking a seed size phenotype to a barley WRKY transcription factor orthologous to TTG2 from Arabidopsis, we illustrate the value of integrated data in biological knowledge discovery. The software we have developed (www.ondex.org) and the knowledge resources (http://knetminer.rothamsted.ac.uk) we have created are all open-source and provide a first step towards systematic and evidence-based gene discovery in order to facilitate crop improvement.

  10. Congenital diaphragmatic hernia candidate genes derived from embryonic transcriptomes

    DEFF Research Database (Denmark)

    Russell, Meaghan K; Longoni, Mauro; Wells, Julie

    2012-01-01

    expression profiling of developing embryonic diaphragms would help identify genes likely to be associated with diaphragm defects. We generated a time series of whole-transcriptome expression profiles from laser captured embryonic mouse diaphragms at embryonic day (E)11.5 and E12.5 when experimental...

  11. Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study

    NARCIS (Netherlands)

    Lee, A.W.; Tyrer, J.P.; Doherty, J.A.; Stram, D.A.; Kupryjanczyk, J.; Dansonka-Mieszkowska, A.; Plisiecka-Halasa, J.; Spiewankiewicz, B.; Myers, E.J.; Study, G.; Chenevix-Trench, G.; Fasching, P.A.; Beckmann, M.W.; Ekici, A.B.; Hein, A.; Vergote, I.; Nieuwenhuysen, E. Van; Lambrechts, D.; Wicklund, K.G.; Eilber, U.; Wang-Gohrke, S.; Chang-Claude, J.; Rudolph, A.; Sucheston-Campbell, L.; Odunsi, K.; Moysich, K.B.; Shvetsov, Y.B.; Thompson, P.J.; Goodman, M.T.; Wilkens, L.R.; Dork, T.; Hillemanns, P.; Durst, M.; Runnebaum, I.B.; Bogdanova, N.; Pelttari, L.M.; Nevanlinna, H.; Leminen, A.; Edwards, R.P.; Kelley, J.L.; Harter, P.; Schwaab, I.; Heitz, F.; Bois, A. du; Orsulic, S.; Lester, J.; Walsh, C.; Karlan, B.Y.; Hogdall, E.; Kjaer, S.K.; Jensen, A.; Vierkant, R.A.; Cunningham, J.M.; Goode, E.L.; Fridley, B.L.; Southey, M.C.; Giles, G.G.; Bruinsma, F.; Wu, X.; Hildebrandt, M.A.T.; Lu, K.; Liang, D.; Bisogna, M.; Levine, D.A.; Weber, R.P.; Schildkraut, J.M.; Iversen, E.S.; Berchuck, A.; Terry, K.L.; Cramer, D.W; Tworoger, S.S.; Poole, E.M.; Olson, S.H.; Orlow, I.; Bandera, E.V.; Bjorge, L.; Tangen, I.L.; Salvesen, H.B.; Krakstad, C.; Massuger, L.F.A.G.; Kiemeney, L.A.L.M.; Aben, K.K.H.; Altena, A.M. van; Bean, Y.; Pejovic, T.; Kellar, M.; Le, N.D.; Cook, L.S.; Kelemen, L.E.; Brooks-Wilson, A.; Lubinski, J.; Gronwald, J.; Cybulski, C.; Jakubowska, A.; Wentzensen, N.; Brinton, L.A.; Lissowska, J.; Yang, H.; Nedergaard, L.

    2015-01-01

    OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of

  12. Genomic dissection and prioritizing of candidate genes of QTL for ...

    Indian Academy of Sciences (India)

    IL-1RN levels are elevated in the blood of patients with a variety of infectious, immune, and traumatic conditions. Balb/c mice deficient in IL-1ra (mouse gene of IL-1RN) develop spontaneous autoimmune arthritis while DBA/1 mice deficient in IL-1ra do not. Previously, we identified a major QTL that regulates the susceptibility ...

  13. Isolation and characterization of a candidate gene for resistance to ...

    African Journals Online (AJOL)

    The deduced peptide sequence consisted of 920 amino acid residues and shared 97.83% amino acid identity with Cre3. The sequence harbored a signal peptide domain, a nucleotide-binding ARC (NB-ARC) domain, and a leucine-rich repeat (LRR) domain, all of which are typical characteristics of resistance genes.

  14. SREBP pathway genes as candidate markers in country ham production

    Directory of Open Access Journals (Sweden)

    Max F. Rothschild

    2010-02-01

    Full Text Available Country hams are dry-cured products from the Southeastern region of the USA. This high value product initially requires quality fresh meat to avoid later processing problems. The marker SREBF1, is a transcription factor involved in the regulation of fatty acid synthesis and anti-oxidative enzyme transcription. The SREBF1 gene and its regulating genes, SCAP and MBTPS1, were investigated for associations with several meat quality traits in country hams. After single nucleotide polymorphism (SNP identification, PCR-RFLP tests were designed for one polymorphism in each of the three investigated genes. Meat quality and physical traits were collected on 299 fresh hams. Significant associations were found with ham yield (MBTPS1, P<0.05 and SREBF1xMBTPS1, P<0.05 and ham circumference (MBTPS1, P<0.05 and SREBF1x MBTPS1, P<0.01, Hunter A colour score on fresh meat (SREBF1, P<0.05, Hunter B colour score on cured meat (MBTPS1, P<0.05 and SREBF1xMBTPS1, P<0.01, moisture (SCAPxMBTPS1, P<0.05 and salt percentage (SREBF1xSCAP, P<0.05. Our findings provide initial evidence that SNPs in SREBF1, SCAP and MBTPS1 are associated with some country ham quality traits. Breeders could use these gene tests to improve their animals, which would in turn improve country ham processing and other desired production goals.

  15. Identification of Novel Congenital Heart Disease Candidate Genes Using Chromosome Microarray.

    Science.gov (United States)

    Shanshen, Enas; Rosenberg, Janine; Van Bergen, Andrew H

    2017-10-09

    While the majority of patients have isolated heart disease, congenital heart disease (CHD) may be associated with other congenital anomalies or syndromes. Our institution utilizes chromosomal microarray (CMA) to identify chromosomal abnormalities, specifically copy number variations (CNVs). While CNVs have been associated with CHD, their direct impact on cardiac development remains unclear. This study sought to identify potential novel CHD candidate genes by comparing CNVs present in our institution's CHD population with those already recognized in the literature. A list of candidate genes was compiled from recent medical literature that utilized CMA. Records from neonatal cases at our institution over 10 years were reviewed. Genes identified from CMAs were compared with those reported in the literature and cross-referenced with the Online Mendelian Inheritance in Man catalog. We identified 375 CNVs reported in patients with CHD. At our institution between 2005 and 2015, 307 neonates with CHD had CMA. Of these, 77 patients (25%) had CNVs containing 832 unique candidate genes. 49 patients (16%) had isolated CHD with 353 candidate genes expressed within the CNVs, many of which were previously reported. However, there were 16 unique candidate genes identified that have been expressed with heart structure of the mouse knock-out models. Our findings demonstrate a high incidence of abnormal genes identified by CMA in CHD patients, including many CNVs of "unknown clinical significance". We conclude that a portion of these CNVs (including 16 genes expressed in the heart of the mouse knock-out models) could be candidate genes involved in CHD pathogenesis.

  16. Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility.

    Science.gov (United States)

    Bruse, Shannon; Moreau, Michael; Bromberg, Yana; Jang, Jun-Ho; Wang, Nan; Ha, Hongseok; Picchi, Maria; Lin, Yong; Langley, Raymond J; Qualls, Clifford; Klensney-Tait, Julia; Zabner, Joseph; Leng, Shuguang; Mao, Jenny; Belinsky, Steven A; Xing, Jinchuan; Nyunoya, Toru

    2016-01-07

    Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible airflow limitation in response to inhalation of noxious stimuli, such as cigarette smoke. However, only 15-20 % smokers manifest COPD, suggesting a role for genetic predisposition. Although genome-wide association studies have identified common genetic variants that are associated with susceptibility to COPD, effect sizes of the identified variants are modest, as is the total heritability accounted for by these variants. In this study, an extreme phenotype exome sequencing study was combined with in vitro modeling to identify COPD candidate genes. We performed whole exome sequencing of 62 highly susceptible smokers and 30 exceptionally resistant smokers to identify rare variants that may contribute to disease risk or resistance to COPD. This was a cross-sectional case-control study without therapeutic intervention or longitudinal follow-up information. We identified candidate genes based on rare variant analyses and evaluated exonic variants to pinpoint individual genes whose function was computationally established to be significantly different between susceptible and resistant smokers. Top scoring candidate genes from these analyses were further filtered by requiring that each gene be expressed in human bronchial epithelial cells (HBECs). A total of 81 candidate genes were thus selected for in vitro functional testing in cigarette smoke extract (CSE)-exposed HBECs. Using small interfering RNA (siRNA)-mediated gene silencing experiments, we showed that silencing of several candidate genes augmented CSE-induced cytotoxicity in vitro. Our integrative analysis through both genetic and functional approaches identified two candidate genes (TACC2 and MYO1E) that augment cigarette smoke (CS)-induced cytotoxicity and, potentially, COPD susceptibility.

  17. Mapping of Candidate Genes Involved in Bud Dormancy and Flowering Time in Sweet Cherry (Prunus avium.

    Directory of Open Access Journals (Sweden)

    Sophie Castède

    Full Text Available The timing of flowering in perennial plants is crucial for their survival in temperate climates and is regulated by the duration of bud dormancy. Bud dormancy release and bud break depend on the perception of cumulative chilling during endodormancy and heat during the bud development. The objectives of this work were to identify candidate genes involved in dormancy and flowering processes in sweet cherry, their mapping in two mapping progenies 'Regina' × 'Garnet' and 'Regina' × 'Lapins', and to select those candidate genes which co-localized with quantitative trait loci (QTLs associated with temperature requirements for bud dormancy release and flowering. Based on available data on flowering processes in various species, a list of 79 candidate genes was established. The peach and sweet cherry orthologs were identified and primers were designed to amplify sweet cherry candidate gene fragments. Based on the amplified sequences of the three parents of the mapping progenies, SNPs segregations in the progenies were identified. Thirty five candidate genes were genetically mapped in at least one of the two progenies and all were in silico mapped. Co-localization between candidate genes and QTLs associated with temperature requirements and flowering date were identified for the first time in sweet cherry. The allelic composition of the candidate genes located in the major QTL for heat requirements and flowering date located on linkage group 4 have a significant effect on these two traits indicating their potential use for breeding programs in sweet cherry to select new varieties adapted to putative future climatic conditions.

  18. Characterization of Gene Candidates for Vacuolar Sodium Transport from Hordeum Vulgare

    KAUST Repository

    Scheu, Arne Hagen August

    2017-05-01

    Soil salinity is a major abiotic stress for land plants, and multiple mechanisms of salt tolerance have evolved. Tissue tolerance is one of these mechanisms, which involves the sequestration of sodium into the vacuole to retain low cytosolic sodium concentrations. This enables the plant to maintain cellular functions, and ultimately maintain growth and yield. However, the molecular components involved in tissue tolerance remain elusive. Several candidate genes for vacuolar sodium sequestration have recently been identified by proteome analysis of vacuolar membranes purified from the salt-tolerant cereal Hordeum vulgare (barley). In this study, I aimed to characterize these candidates in more detail. I successfully cloned coding sequences for the majority of candidate genes with primers designed based on the barley reference genome sequence. During the course of this study a newer genome sequence with improved annotations was published, to which I also compared my observations. To study the candidate genes, I used the heterologous expression system Saccharomyces cerevisiae (yeast). I used several salt sensitive yeast strains (deficient in intrinsic sodium transporters) to test whether the candidate genes would affect their salt tolerance by mediating the sequestration of sodium into the yeast vacuole. I observed a reduction in growth upon expression for several of the gene candidate under salt-stress conditions. However, confocal microscopy suggests that most gene products are subject to degradation, and did not localize to the vacuolar membrane (tonoplast). Therefore, growth effects cannot be linked to protein function without further evidence. Various potential causes are discussed, including inaccuracies in the genome resource used as reference for primer design and issues inherent to the model system. Finally, I make suggestions on how to proceed to further characterize the candidate genes and hopefully identify novel sodium transporters from barley.

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

    Energy Technology Data Exchange (ETDEWEB)

    Shaid, D.J.; Sommer, S.S. (Mayo Clinic/Foundation, Rochester, MN (United States))

    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.

  20. Positional RNA-Seq identifies candidate genes for phenotypic engineering of sexual traits

    NARCIS (Netherlands)

    Arbore, Roberto; Sekii, Kiyono; Beisel, Christian; Ladurner, Peter; Berezikov, Eugene; Schaerer, Lukas

    2015-01-01

    Introduction: RNA interference (RNAi) of trait-specific genes permits the manipulation of specific phenotypic traits ("phenotypic engineering") and thus represents a powerful tool to test trait function in evolutionary studies. The identification of suitable candidate genes, however, often relies on

  1. Test for positional candidate genes for body composition on pig chromosome 6

    Directory of Open Access Journals (Sweden)

    Pérez-Enciso Miguel

    2002-07-01

    Full Text Available Abstract One QTL affecting backfat thickness (BF, intramuscular fat content (IMF and eye muscle area (MA was previously localized on porcine chromosome 6 in an F2 cross between Iberian and Landrace pigs. This work was done to study the effect of two positional candidate genes on these traits: H-FABP and LEPR genes. The QTL mapping analysis was repeated with a regression method using genotypes for seven microsatellites and two PCR-RFLPs in the H-FABP and LEPR genes. H-FABP and LEPR genes were located at 85.4 and 107 cM respectively, by linkage analysis. The effects of the candidate gene polymorphisms were analyzed in two ways. When an animal model was fitted, both genes showed significant effects on fatness traits, the H-FABP polymorphism showed significant effects on IMF and MA, and the LEPR polymorphism on BF and IMF. But when the candidate gene effect was included in a QTL regression analysis these associations were not observed, suggesting that they must not be the causal mutations responsible for the effects found. Differences in the results of both analyses showed the inadequacy of the animal model approach for the evaluation of positional candidate genes in populations with linkage disequilibrium, when the probabilities of the parental origin of the QTL alleles are not included in the model.

  2. Haplotype sharing analysis with SNPs in candidate genes : The genetic analysis workshop 12 example

    NARCIS (Netherlands)

    Fischer, C; Beckmann, L; Majoram, P; Meerman, GT; Chang-Claude, J

    Haplotype sharing analysis was used to investigate the association of affection status with single nucleotide polymorphism (SNP) haplotypes within candidate gene 1 in one sample each from the isolated and the general population of Genetic Analysis Workshop (GAW) 12 simulated data. Gene 1 has direct

  3. Candidates in Astroviruses, Seadornaviruses, Cytorhabdoviruses and Coronaviruses for +1 frame overlapping genes accessed by leaky scanning

    Directory of Open Access Journals (Sweden)

    Atkins John F

    2010-01-01

    Full Text Available Abstract Background Overlapping genes are common in RNA viruses where they serve as a mechanism to optimize the coding potential of compact genomes. However, annotation of overlapping genes can be difficult using conventional gene-finding software. Recently we have been using a number of complementary approaches to systematically identify previously undetected overlapping genes in RNA virus genomes. In this article we gather together a number of promising candidate new overlapping genes that may be of interest to the community. Results Overlapping gene predictions are presented for the astroviruses, seadornaviruses, cytorhabdoviruses and coronaviruses (families Astroviridae, Reoviridae, Rhabdoviridae and Coronaviridae, respectively.

  4. Candidate genes expressed in human islets and their role in the pathogenesis of type 1 diabetes

    DEFF Research Database (Denmark)

    Storling, Joachim; Brorsson, Caroline Anna

    2013-01-01

    , but more than 40 additional loci are known to significantly affect T1D risk. Since most of the currently known genetic candidates have annotated immune cell functions, it is generally considered that most of the genetic susceptibility in T1D is caused by variation in genes affecting immune cell function...... exposure to proinflammatory cytokines highlighting that these genes may be involved in the response of β cells to immune attack. In this review, the compiling evidence that many of the candidate genes are expressed in islets and β cells will be presented. Further, we perform the first systematic human...

  5. Candidate genes for cross-resistance against DNA-damaging drugs

    DEFF Research Database (Denmark)

    Wittig, Rainer; Nessling, Michelle; Will, Rainer D

    2002-01-01

    Drug resistance of tumor cells leads to major drawbacks in the treatment of cancer. To identify candidate genes for drug resistance, we compared the expression patterns of the drug-sensitive human malignant melanoma cell line MeWo and three derived sublines with acquired resistance to the DNA...... as several apoptosis-related genes, in particular STK17A and CRYAB. As MPP1 and CRYAB are also among the 14 genes differentially expressed in all three of the drug-resistant sublines, they represent the strongest candidates for resistance against DNA-damaging drugs....

  6. Candidate genes for idiopathic epilepsy in four dog breeds

    OpenAIRE

    Mickelson James R; Minor Katie M; Patterson Edward E; Ekenstedt Kari J

    2011-01-01

    Abstract Background Idiopathic epilepsy (IE) is a naturally occurring and significant seizure disorder affecting all dog breeds. Because dog breeds are genetically isolated populations, it is possible that IE is attributable to common founders and is genetically homogenous within breeds. In humans, a number of mutations, the majority of which are genes encoding ion channels, neurotransmitters, or their regulatory subunits, have been discovered to cause rare, specific types of IE. It was hypot...

  7. Study of candidate genes for obesity in children and adolescents.

    OpenAIRE

    Dušátková, Lenka

    2010-01-01

    Obesity is one of the most common metabolic diseases in the whole world that increases risk of many other health problems. Origin of this multifactorial disease is influenced by many factors, including genetic ones. This work was realized within the project COPAT (Childhood Obesity Prevalence And Treatment). The main goal was to study two single nucleotide polymorphisms (SNPs) (rs9939609, rs1421085) in FTO (fat mass and obesity associated) gene and their possible impact on anthropometric trai...

  8. A candidate gene for choanal atresia in alpaca.

    Science.gov (United States)

    Reed, Kent M; Bauer, Miranda M; Mendoza, Kristelle M; Armién, Aníbal G

    2010-03-01

    Choanal atresia (CA) is a common nasal craniofacial malformation in New World domestic camelids (alpaca and llama). CA results from abnormal development of the nasal passages and is especially debilitating to newborn crias. CA in camelids shares many of the clinical manifestations of a similar condition in humans (CHARGE syndrome). Herein we report on the regulatory gene CHD7 of alpaca, whose homologue in humans is most frequently associated with CHARGE. Sequence of the CHD7 coding region was obtained from a non-affected cria. The complete coding region was 9003 bp, corresponding to a translated amino acid sequence of 3000 aa. Additional genomic sequences corresponding to a significant portion of the CHD7 gene were identified and assembled from the 2x alpaca whole genome sequence, providing confirmatory sequence for much of the CHD7 coding region. The alpaca CHD7 mRNA sequence was 97.9% similar to the human sequence, with the greatest sequence difference being an insertion in exon 38 that results in a polyalanine repeat (A12). Polymorphism in this repeat was tested for association with CA in alpaca by cloning and sequencing the repeat from both affected and non-affected individuals. Variation in length of the poly-A repeat was not associated with CA. Complete sequencing of the CHD7 gene will be necessary to determine whether other mutations in CHD7 are the cause of CA in camelids.

  9. Nucleotide diversity and linkage disequilibrium in 11 expressed resistance candidate genes in Lolium perenne

    Directory of Open Access Journals (Sweden)

    Asp Torben

    2007-08-01

    Full Text Available Abstract Background Association analysis is an alternative way for QTL mapping in ryegrass. So far, knowledge on nucleotide diversity and linkage disequilibrium in ryegrass is lacking, which is essential for the efficiency of association analyses. Results 11 expressed disease resistance candidate (R genes including 6 nucleotide binding site and leucine rich repeat (NBS-LRR like genes and 5 non-NBS-LRR genes were analyzed for nucleotide diversity. For each of the genes about 1 kb genomic fragments were isolated from 20 heterozygous genotypes in ryegrass. The number of haplotypes per gene ranged from 9 to 27. On average, one single nucleotide polymorphism (SNP was present per 33 bp between two randomly sampled sequences for the 11 genes. NBS-LRR like gene fragments showed a high degree of nucleotide diversity, with one SNP every 22 bp between two randomly sampled sequences. NBS-LRR like gene fragments showed very high non-synonymous mutation rates, leading to altered amino acid sequences. Particularly LRR regions showed very high diversity with on average one SNP every 10 bp between two sequences. In contrast, non-NBS LRR resistance candidate genes showed a lower degree of nucleotide diversity, with one SNP every 112 bp. 78% of haplotypes occurred at low frequency ( Conclusion Substantial LD decay was found within a distance of 500 bp for most resistance candidate genes in this study. Hence, LD based association analysis is feasible and promising for QTL fine mapping of resistance traits in ryegrass.

  10. Positional RNA-Seq identifies candidate genes for phenotypic engineering of sexual traits.

    Science.gov (United States)

    Arbore, Roberto; Sekii, Kiyono; Beisel, Christian; Ladurner, Peter; Berezikov, Eugene; Schärer, Lukas

    2015-01-01

    RNA interference (RNAi) of trait-specific genes permits the manipulation of specific phenotypic traits ("phenotypic engineering") and thus represents a powerful tool to test trait function in evolutionary studies. The identification of suitable candidate genes, however, often relies on existing functional gene annotation, which is usually limited in emerging model organisms, especially when they are only distantly related to traditional genetic model organisms. A case in point is the free-living flatworm Macrostomum lignano (Lophotrochozoa: Platyhelminthes: Rhabditophora), an increasingly powerful model organism for evolutionary studies of sex in simultaneous hermaphrodites. To overcome the limitation of sparse functional annotation, we have performed a positional RNA-Seq analysis on different body fragments in order to identify organ-specific candidate transcripts. We then performed gene expression (in situ hybridization) and gene function (RNAi) analyses on 23 candidate transcripts, both to evaluate the predictive potential of this approach and to obtain preliminary functional characterizations of these candidate genes. We identified over 4000 transcripts that could be expected to show specific expression in different reproductive organs (including testis, ovary and the male and female genital systems). The predictive potential of the method could then be verified by confirming organ-specific expression for several candidate transcripts, some of which yielded interesting trait-specific knock-down phenotypes that can now be followed up in future phenotypic engineering studies. Our positional RNA-Seq analysis represents a highly useful resource for the identification of candidate transcripts for functional and phenotypic engineering studies in M. lignano, and it has already been used successfully in several studies. Moreover, this approach can overcome some inherent limitations of homology-based candidate selection and thus should be applicable to a broad range of

  11. Using microarrays to identify positional candidate genes for QTL: the case study of ACTH response in pigs

    DEFF Research Database (Denmark)

    Jouffe, Vincent; Rowe, Suzanne; Liaubet, Laurence

    2009-01-01

    Background: Microarray studies can supplement QTL studies by suggesting potential candidate. Microarray studies can supplement QTL studies by suggesting potential candidate genes in the QTL regions, which by themselves are too large to provide a limited selection of candidate genes. Here we provi...

  12. Identifying Novel Candidate Genes Related to Apoptosis from a Protein-Protein Interaction Network

    Directory of Open Access Journals (Sweden)

    Baoman Wang

    2015-01-01

    Full Text Available Apoptosis is the process of programmed cell death (PCD that occurs in multicellular organisms. This process of normal cell death is required to maintain the balance of homeostasis. In addition, some diseases, such as obesity, cancer, and neurodegenerative diseases, can be cured through apoptosis, which produces few side effects. An effective comprehension of the mechanisms underlying apoptosis will be helpful to prevent and treat some diseases. The identification of genes related to apoptosis is essential to uncover its underlying mechanisms. In this study, a computational method was proposed to identify novel candidate genes related to apoptosis. First, protein-protein interaction information was used to construct a weighted graph. Second, a shortest path algorithm was applied to the graph to search for new candidate genes. Finally, the obtained genes were filtered by a permutation test. As a result, 26 genes were obtained, and we discuss their likelihood of being novel apoptosis-related genes by collecting evidence from published literature.

  13. A potato skin SSH library yields new candidate genes for suberin biosynthesis and periderm formation.

    Science.gov (United States)

    Soler, Marçal; Serra, Olga; Fluch, Silvia; Molinas, Marisa; Figueras, Mercè

    2011-05-01

    Potato (Solanum tuberosum) tubers are underground storage organs covered by the skin or periderm, a suberized layer that protects inner flesh from dehydration and pathogens. Understanding the molecular processes associated with periderm formation is of great importance for a better knowledge of this protective tissue and for improving the storage life of tubers. Here, to isolate new candidate genes for potato periderm, a suppression subtractive hybridization library from potato skin was performed. This library yielded a comprehensive list of 108 candidate genes that were manually sorted in functional categories according to the main cellular and metabolic processes in periderm. As expected, the list contains Suberin and wax genes, including some genes with a demonstrated role in the biosynthesis of these cell wall aliphatic compounds. Moreover, Regulation and Stress and defence genes are highly abundant in the library in general agreement with previous potato skin proteomic studies. The putative function of the genes in periderm is discussed.

  14. Candidate genes and cerebral palsy: a population-based study.

    Science.gov (United States)

    Gibson, Catherine S; Maclennan, Alastair H; Dekker, Gustaaf A; Goldwater, Paul N; Sullivan, Thomas R; Munroe, David J; Tsang, Shirley; Stewart, Claudia; Nelson, Karin B

    2008-11-01

    The objective of this study was to examine whether selected genetic polymorphisms in the infant are associated with later-diagnosed cerebral palsy. A population-based case-control study was conducted of 28 single-nucleotide polymorphisms measured in newborn screening blood spots. A total of 413 children with later-diagnosed cerebral palsy were born to white women in South Australia in 1986-1999, and there were 856 control children. Distributions of genotypic frequencies were examined in total cerebral palsy, in gestational age groups, and by types of cerebral palsy and gender. Genotyping was performed by using a TaqMan assay. For inducible nitric-oxide synthase, possession of the T allele was more common in all children with cerebral palsy and for heterozygotes who were born at term. For lymphotoxin alpha, homozygous variant status was associated with risk for cerebral palsy and with spastic hemiplegic or quadriplegic cerebral palsy. Among term infants, heterozygosity for the endothelial protein C receptor single-nucleotide polymorphism was more frequent in children with cerebral palsy. In preterm infants, the variant A allele of interleukin 8 and heterozygosity for the beta-2 adrenergic receptor were associated with cerebral palsy risk. Interleukin 8 heterozygote status was associated with spastic diplegia. Variants of several genes were associated with cerebral palsy in girls but not in boys. Two of the 28 single-nucleotide polymorphisms examined were associated with all types of spastic cerebral palsy in both gestational age groups and others with cerebral palsy in gestational age or cerebral palsy subgroups. Some of these associations support previous findings. There may be a genetic contribution to cerebral palsy risk, and additional investigation is warranted of genes and gene-environment interactions in cerebral palsy.

  15. Microsatellite Scan Identifies New Candidate Genes for Susceptibility to Alcoholic Chronic Pancreatitis in Japanese Patients

    Directory of Open Access Journals (Sweden)

    Kei Kitahara

    2008-01-01

    Full Text Available Alcohol abuse is one of the most common risk factor for chronic pancreatitis, but the underlying pathophysiological mechanisms remain unclear. The aim of this study was to identify genes that contribute to susceptibility or resistance for alcoholic chronic pancreatitis by screening the whole genome. Sixty-five patients with alcoholic chronic pancreatitis (63 men and 2 women, mean age 55.2 years and 99 healthy Japanese controls were enrolled in this study. This was an association study using 400 polymorphic microsatellite markers with an average spacing of 10.8 cM distributed throughout the whole genome. This search revealed 10 candidate susceptibility regions and 5 candidate resistant regions throughout the genome. No specific microsatellite markers were detected in association with previously reported susceptibility genes for chronic pancreatitis, such as PRSS1, PRSS2, CTRC, SPINK1, CFTR, ALDH2, and CYP2E1. Among the statistically significant markers, D15S1007 on chromosome 15q14 showed strong evidence for disease susceptibility (70.8% vs. 35.1%, Pc = 0.0001. Within 500 kb of D15S1007, several genes were candidate genes for susceptibility, including FMN1, DKFZP686C2281, LOC440268, RYR3, and AVEN, This study identified 10 candidate susceptibility and 5 candidate resistant regions that may contain genes involved in ACP pathogenesis.

  16. Microsatellite Scan Identifies New Candidate Genes for Susceptibility to Alcoholic Chronic Pancreatitis in Japanese Patients

    Science.gov (United States)

    Kitahara, Kei; Kawa, Shigeyuki; Katsuyama, Yoshihiko; Umemura, Takeji; Ozaki, Yayoi; Takayama, Mari; Arakura, Norikazu; Ota, Masao

    2008-01-01

    Alcohol abuse is one of the most common risk factor for chronic pancreatitis, but the underlying pathophysiological mechanisms remain unclear. The aim of this study was to identify genes that contribute to susceptibility or resistance for alcoholic chronic pancreatitis by screening the whole genome. Sixty-five patients with alcoholic chronic pancreatitis (63 men and 2 women, mean age 55.2 years) and 99 healthy Japanese controls were enrolled in this study. This was an association study using 400 polymorphic microsatellite markers with an average spacing of 10.8 cM distributed throughout the whole genome. This search revealed 10 candidate susceptibility regions and 5 candidate resistant regions throughout the genome. No specific microsatellite markers were detected in association with previously reported susceptibility genes for chronic pancreatitis, such as PRSS1, PRSS2, CTRC, SPINK1, CFTR, ALDH2, and CYP2E1. Among the statistically significant markers, D15S1007 on chromosome 15q14 showed strong evidence for disease susceptibility (70.8% vs. 35.1%, Pc = 0.0001). Within 500 kb of D15S1007, several genes were candidate genes for susceptibility, including FMN1, DKFZP686C2281, LOC440268, RYR3, and AVEN, This study identified 10 candidate susceptibility and 5 candidate resistant regions that may contain genes involved in ACP pathogenesis. PMID:19096130

  17. An extensive candidate gene approach to speciation: diversity, divergence and linkage disequilibrium in candidate pigmentation genes across the European crow hybrid zone.

    Science.gov (United States)

    Poelstra, J W; Ellegren, H; Wolf, J B W

    2013-12-01

    Colouration patterns have an important role in adaptation and speciation. The European crow system, in which all-black carrion crows and grey-coated hooded crows meet in a narrow hybrid zone, is a prominent example. The marked phenotypic difference is maintained by assortative mating in the absence of neutral genetic divergence, suggesting the presence of few pigmentation genes of major effect. We made use of the rich phenotypic and genetic resources in mammals and identified a comprehensive panel of 95 candidate pigmentation genes for birds. Based on functional annotation, we chose a subset of the most promising 37 candidates, for which we developed a marker system that demonstrably works across the avian phylogeny. In total, we sequenced 107 amplicons (∼3 loci per gene, totalling 60 kb) in population samples of crows (n=23 for each taxon). Tajima's D, Fu's FS, DHEW and HKA (Hudson-Kreitman-Aguade) statistics revealed several amplicons that deviated from neutrality; however, none of these showed significantly elevated differentiation between the two taxa. Hence, colour divergence in this system may be mediated by uncharacterized pigmentation genes or regulatory regions outside genes. Alternatively, the observed high population recombination rate (4Ner∼0.03), with overall linkage disequilibrium dropping rapidly within the order of few 100 bp, may compromise the power to detect causal loci with nearby markers. Our results add to the debate as to the utility of candidate gene approaches in relation to genomic features and the genetic architecture of the phenotypic trait in question.

  18. Prioritizing chronic obstructive pulmonary disease (COPD) candidate genes in COPD-related networks

    OpenAIRE

    Zhang, Yihua; Li, Wan; Feng, Yuyan; Guo, Shanshan; Zhao, Xilei; Wang, Yahui; He, Yuehan; He, Weiming; Chen, Lina

    2017-01-01

    Chronic obstructive pulmonary disease (COPD) is a multi-factor disease, which could be caused by many factors, including disturbances of metabolism and protein-protein interactions (PPIs). In this paper, a weighted COPD-related metabolic network and a weighted COPD-related PPI network were constructed base on COPD disease genes and functional information. Candidate genes in these weighted COPD-related networks were prioritized by making use of a gene prioritization method, respectively. Liter...

  19. Candidate Genes Detected in Transcriptome Studies are Strongly Dependent on Genetic Background

    DEFF Research Database (Denmark)

    Sarup, Pernille Merete; Sørensen, Jesper Givskov; Kristensen, Torsten Nygård

    2011-01-01

    identified from studies of gene expression in Drosophila melanogaster using similar technical platforms. We found little overlap across studies between putative candidate genes for the same traits in the same sex. Instead there was a high degree of overlap between different traits and sexes within the same...... experiments and in future studies we suggest a focus on the genes, networks and pathways affecting traits in a consistent manner across backgrounds....

  20. Gene Duplication and Gene Expression Changes Play a Role in the Evolution of Candidate Pollen Feeding Genes in Heliconius Butterflies.

    Science.gov (United States)

    Smith, Gilbert; Macias-Muñoz, Aide; Briscoe, Adriana D

    2016-09-02

    Heliconius possess a unique ability among butterflies to feed on pollen. Pollen feeding significantly extends their lifespan, and is thought to have been important to the diversification of the genus. We used RNA sequencing to examine feeding-related gene expression in the mouthparts of four species of Heliconius and one nonpollen feeding species, Eueides isabella We hypothesized that genes involved in morphology and protein metabolism might be upregulated in Heliconius because they have longer proboscides than Eueides, and because pollen contains more protein than nectar. Using de novo transcriptome assemblies, we tested these hypotheses by comparing gene expression in mouthparts against antennae and legs. We first looked for genes upregulated in mouthparts across all five species and discovered several hundred genes, many of which had functional annotations involving metabolism of proteins (cocoonase), lipids, and carbohydrates. We then looked specifically within Heliconius where we found eleven common upregulated genes with roles in morphology (CPR cuticle proteins), behavior (takeout-like), and metabolism (luciferase-like). Closer examination of these candidates revealed that cocoonase underwent several duplications along the lineage leading to heliconiine butterflies, including two Heliconius-specific duplications. Luciferase-like genes also underwent duplication within lepidopterans, and upregulation in Heliconius mouthparts. Reverse-transcription PCR confirmed that three cocoonases, a peptidase, and one luciferase-like gene are expressed in the proboscis with little to no expression in labial palps and salivary glands. Our results suggest pollen feeding, like other dietary specializations, was likely facilitated by adaptive expansions of preexisting genes-and that the butterfly proboscis is involved in digestive enzyme production. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  1. Replication of type 2 diabetes candidate genes variations in three geographically unrelated Indian population groups.

    Science.gov (United States)

    Ali, Shafat; Chopra, Rupali; Manvati, Siddharth; Singh, Yoginder Pal; Kaul, Nabodita; Behura, Anita; Mahajan, Ankit; Sehajpal, Prabodh; Gupta, Subash; Dhar, Manoj K; Chainy, Gagan B N; Bhanwer, Amarjit S; Sharma, Swarkar; Bamezai, Rameshwar N K

    2013-01-01

    Type 2 diabetes (T2D) is a syndrome of multiple metabolic disorders and is genetically heterogeneous. India comprises one of the largest global populations with highest number of reported type 2 diabetes cases. However, limited information about T2D associated loci is available for Indian populations. It is, therefore, pertinent to evaluate the previously associated candidates as well as identify novel genetic variations in Indian populations to understand the extent of genetic heterogeneity. We chose to do a cost effective high-throughput mass-array genotyping and studied the candidate gene variations associated with T2D in literature. In this case-control candidate genes association study, 91 SNPs from 55 candidate genes have been analyzed in three geographically independent population groups from India. We report the genetic variants in five candidate genes: TCF7L2, HHEX, ENPP1, IDE and FTO, are significantly associated (after Bonferroni correction, ppopulation. Interestingly, SNP rs7903146 of the TCF7L2 gene passed the genome wide significance threshold (combined P value = 2.05E-08) in the studied populations. We also observed the association of rs7903146 with blood glucose (fasting and postprandial) levels, supporting the role of TCF7L2 gene in blood glucose homeostasis. Further, we noted that the moderate risk provided by the independently associated loci in combined population with Odds Ratio (OR)<1.38 increased to OR = 2.44, (95%CI = 1.67-3.59) when the risk providing genotypes of TCF7L2, HHEX, ENPP1 and FTO genes were combined, suggesting the importance of gene-gene interactions evaluation in complex disorders like T2D.

  2. Replication of type 2 diabetes candidate genes variations in three geographically unrelated Indian population groups.

    Directory of Open Access Journals (Sweden)

    Shafat Ali

    Full Text Available Type 2 diabetes (T2D is a syndrome of multiple metabolic disorders and is genetically heterogeneous. India comprises one of the largest global populations with highest number of reported type 2 diabetes cases. However, limited information about T2D associated loci is available for Indian populations. It is, therefore, pertinent to evaluate the previously associated candidates as well as identify novel genetic variations in Indian populations to understand the extent of genetic heterogeneity. We chose to do a cost effective high-throughput mass-array genotyping and studied the candidate gene variations associated with T2D in literature. In this case-control candidate genes association study, 91 SNPs from 55 candidate genes have been analyzed in three geographically independent population groups from India. We report the genetic variants in five candidate genes: TCF7L2, HHEX, ENPP1, IDE and FTO, are significantly associated (after Bonferroni correction, p<5.5E-04 with T2D susceptibility in combined population. Interestingly, SNP rs7903146 of the TCF7L2 gene passed the genome wide significance threshold (combined P value = 2.05E-08 in the studied populations. We also observed the association of rs7903146 with blood glucose (fasting and postprandial levels, supporting the role of TCF7L2 gene in blood glucose homeostasis. Further, we noted that the moderate risk provided by the independently associated loci in combined population with Odds Ratio (OR<1.38 increased to OR = 2.44, (95%CI = 1.67-3.59 when the risk providing genotypes of TCF7L2, HHEX, ENPP1 and FTO genes were combined, suggesting the importance of gene-gene interactions evaluation in complex disorders like T2D.

  3. Excess of Rare Variants in Non-GWAS Candidate Genes in Patients with Hypertriglyceridemia

    Science.gov (United States)

    Johansen, Christopher T.; Wang, Jian; McIntyre, Adam D.; Martins, Rebecca A.; Ban, Matthew R.; Lanktree, Matthew B.; Huff, Murray W.; Péterfy, Miklós; Mehrabian, Margarete; Lusis, Aldons J.; Kathiresan, Sekar; Anand, Sonia S.; Yusuf, Salim; Lee, Ann-Hwee; Glimcher, Laurie H.; Cao, Henian; Hegele, Robert A.

    2012-01-01

    Background Rare variant accumulation studies can implicate genes in disease susceptibility when a significant burden is observed in patients versus controls. Such analyses might be particularly useful for candidate genes that are selected based on experiments other than genome-wide association studies (GWAS). We sought to determine whether rare variants in non-GWAS candidate genes identified from mouse models and human Mendelian syndromes of hypertriglyceridemia (HTG) accumulate in patients with polygenic adult-onset HTG. Methods and Results We resequenced protein coding regions of 3 genes with established roles (APOC2, GPIHBP1, LMF1) and 2 genes recently implicated (CREB3L3 and ZHX3) in TG metabolism. We identified 41 distinct heterozygous rare variants, including 29 singleton variants, in the combined sample; in total, we observed 47 rare variants in 413 HTG patients versus 16 in 324 controls (OR=2.3; P=0.0050). Post hoc assessment of genetic burden in individual genes using three different tests suggested that the genetic burden was most prominent in the established genes LMF1 and APOC2, and also in the recently identified CREB3L3 gene. Conclusions These extensive resequencing studies show a significant accumulation of rare genetic variants in non-GWAS candidate genes among patients with polygenic HTG, and indicate the importance of testing specific hypotheses in large-scale resequencing studies. PMID:22135386

  4. SORBS1 gene, a new candidate for diabetic nephropathy

    DEFF Research Database (Denmark)

    Germain, Marine; Pezzolesi, Marcus G; Sandholm, Niina

    2015-01-01

    cases with proteinuria and with or without renal failure with control patients who have had diabetes for more than 15 years and no evidence of renal disease. RESULTS: None of the single nucleotide polymorphisms (SNPs) tested in a discovery cohort composed of 683 cases and 779 controls reached genome......-wide statistical significance. The 46 top hits (p Diabetes US (US-GoKinD) study, an independent population of 820 cases and 885 controls. Two SNPs in strong linkage disequilibrium with each other and located in the SORBS1 gene were...... consistently and significantly (p diabetic nephropathy. The minor rs1326934-C allele was less frequent in cases than in controls (0.34 vs 0.43) and was associated with a decreased risk for diabetic nephropathy (OR 0.70; 95% CI 0.60, 0.82). However, this association was not observed...

  5. Similarity of molecular phenotype between known epilepsy gene LGI1 and disease candidate gene LGI2

    Directory of Open Access Journals (Sweden)

    Eisenhaber Frank

    2010-09-01

    Full Text Available Abstract Background The LGI2 (leucine-rich, glioma inactivated 2 gene, a prime candidate for partial epilepsy with pericentral spikes, belongs to a family encoding secreted, beta-propeller domain proteins with EPTP/EAR epilepsy-associated repeats. In another family member, LGI1 (leucine-rich, glioma inactivated 1 mutations are responsible for autosomal dominant lateral temporal epilepsy (ADLTE. Because a few LGI1 disease mutations described in the literature cause secretion failure, we experimentally analyzed the secretion efficiency and subcellular localization of several LGI1 and LGI2 mutant proteins corresponding to observed non-synonymous single nucleotide polymorphisms (nsSNPs affecting the signal peptide, the leucine-rich repeats and the EAR propeller. Results Mapping of disease-causing mutations in the EAR domain region onto a 3D-structure model shows that many of these mutations co-localize at an evolutionary conserved surface region of the propeller. We find that wild-type LGI2 is secreted to the extracellular medium in glycosylated form similarly to LGI1, whereas several mutant proteins tested in this study are secretion-deficient and accumulate in the endoplasmic reticulum. Interestingly, mutations at structurally homologous positions in the EAR domain have the same effect on secretion in LGI1 and LGI2. Conclusions This similarity of experimental mislocalization phenotypes for mutations at homologous positions of LGI2 and the established epilepsy gene LGI1 suggests that both genes share a potentially common molecular pathogenesis mechanism that might be the reason for genotypically distinct but phenotypically related forms of epilepsy.

  6. Development of New Candidate Gene and EST-Based Molecular Markers for Gossypium Species.

    Science.gov (United States)

    Buyyarapu, Ramesh; Kantety, Ramesh V; Yu, John Z; Saha, Sukumar; Sharma, Govind C

    2011-01-01

    New source of molecular markers accelerate the efforts in improving cotton fiber traits and aid in developing high-density integrated genetic maps. We developed new markers based on candidate genes and G. arboreum EST sequences that were used for polymorphism detection followed by genetic and physical mapping. Nineteen gene-based markers were surveyed for polymorphism detection in 26 Gossypium species. Cluster analysis generated a phylogenetic tree with four major sub-clusters for 23 species while three species branched out individually. CAP method enhanced the rate of polymorphism of candidate gene-based markers between G. hirsutum and G. barbadense. Two hundred A-genome based SSR markers were designed after datamining of G. arboreum EST sequences (Mississippi Gossypium arboreum  EST-SSR: MGAES). Over 70% of MGAES markers successfully produced amplicons while 65 of them demonstrated polymorphism between the parents of G. hirsutum and G. barbadense RIL population and formed 14 linkage groups. Chromosomal localization of both candidate gene-based and MGAES markers was assisted by euploid and hypoaneuploid CS-B analysis. Gene-based and MGAES markers were highly informative as they were designed from candidate genes and fiber transcriptome with a potential to be integrated into the existing cotton genetic and physical maps.

  7. Epstein-Barr virus candidate genes and multiple sclerosis.

    Science.gov (United States)

    Claire Simon, Kelly; Schmidt, Hollie; Loud, Sara; Ascherio, Alberto

    2015-01-01

    Previous infection with Epstein-Barr virus (EBV) and a history of infectious mononucleosis (IM) have been previously associated with an increased risk of multiple sclerosis (MS). Whether there are common genetic factors that may partially explain these associations has not been thoroughly explored. To investigate whether select polymorphisms in genes associated with IM susceptibility are related to MS risk-a self-reported history of IM or antibody titer against Epstein-Barr virus nuclear antigen 1 (anti-EBNA1). A case-control study including 1213 MS cases and 454 controls enrolled in the Accelerated Cure Project for MS (ACP) Repository. Select polymorphisms in HLA-A, SH2D1A and IL15RA and anti-EBNA1 Ab titers were measured using stored blood samples provided by participants. Generalized linear models were used to assess the associations between select polymorphisms and odds of MS, odds of IM or anti-EBNA1 Ab titers. No significant associations were observed between the selected polymorphisms and odds of MS, odds of IM or anti-EBNA1 Ab titer. It is unlikely that any of the studied polymorphisms contribute to the explaining the association between anti-EBNA1 Ab titer or history of IM and MS. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. CELSR2 is a candidate susceptibility gene in idiopathic scoliosis.

    Science.gov (United States)

    Einarsdottir, Elisabet; Grauers, Anna; Wang, Jingwen; Jiao, Hong; Escher, Stefan A; Danielsson, Aina; Simony, Ane; Andersen, Mikkel; Christensen, Steen Bach; Åkesson, Kristina; Kou, Ikuyo; Khanshour, Anas M; Ohlin, Acke; Wise, Carol; Ikegawa, Shiro; Kere, Juha; Gerdhem, Paul

    2017-01-01

    A Swedish pedigree with an autosomal dominant inheritance of idiopathic scoliosis was initially studied by genetic linkage analysis, prioritising genomic regions for further analysis. This revealed a locus on chromosome 1 with a putative risk haplotype shared by all affected individuals. Two affected individuals were subsequently exome-sequenced, identifying a rare, non-synonymous variant in the CELSR2 gene. This variant is rs141489111, a c.G6859A change in exon 21 (NM_001408), leading to a predicted p.V2287I (NP_001399.1) change. This variant was found in all affected members of the pedigree, but showed reduced penetrance. Analysis of tagging variants in CELSR1-3 in a set of 1739 Swedish-Danish scoliosis cases and 1812 controls revealed significant association (p = 0.0001) to rs2281894, a common synonymous variant in CELSR2. This association was not replicated in case-control cohorts from Japan and the US. No association was found to variants in CELSR1 or CELSR3. Our findings suggest a rare variant in CELSR2 as causative for idiopathic scoliosis in a family with dominant segregation and further highlight common variation in CELSR2 in general susceptibility to idiopathic scoliosis in the Swedish-Danish population. Both variants are located in the highly conserved GAIN protein domain, which is necessary for the auto-proteolysis of CELSR2, suggesting its functional importance.

  9. Elevated transcription factor specificity protein 1 in autistic brains alters the expression of autism candidate genes.

    Science.gov (United States)

    Thanseem, Ismail; Anitha, Ayyappan; Nakamura, Kazuhiko; Suda, Shiro; Iwata, Keiko; Matsuzaki, Hideo; Ohtsubo, Masafumi; Ueki, Takatoshi; Katayama, Taiichi; Iwata, Yasuhide; Suzuki, Katsuaki; Minoshima, Shinsei; Mori, Norio

    2012-03-01

    Profound changes in gene expression can result from abnormalities in the concentrations of sequence-specific transcription factors like specificity protein 1 (Sp1). Specificity protein 1 binding sites have been reported in the promoter regions of several genes implicated in autism. We hypothesize that dysfunction of Sp1 could affect the expression of multiple autism candidate genes, contributing to the heterogeneity of autism. We assessed any alterations in the expression of Sp1 and that of autism candidate genes in the postmortem brain (anterior cingulate gyrus [ACG], motor cortex, and thalamus) of autism patients (n = 8) compared with healthy control subjects (n = 13). Alterations in the expression of candidate genes upon Sp1/DNA binding inhibition with mithramycin and Sp1 silencing by RNAi were studied in SK-N-SH neuronal cells. We observed elevated expression of Sp1 in ACG of autism patients (p = .010). We also observed altered expression of several autism candidate genes. GABRB3, RELN, and HTR2A showed reduced expression, whereas CD38, ITGB3, MAOA, MECP2, OXTR, and PTEN showed elevated expression in autism. In SK-N-SH cells, OXTR, PTEN, and RELN showed reduced expression upon Sp1/DNA binding inhibition and Sp1 silencing. The RNA integrity number was not available for any of the samples. Transcription factor Sp1 is dysfunctional in the ACG of autistic brain. Consequently, the expression of potential autism candidate genes regulated by Sp1, especially OXTR and PTEN, could be affected. The diverse downstream pathways mediated by the Sp1-regulated genes, along with the environmental and intracellular signal-related regulation of Sp1, could explain the complex phenotypes associated with autism.

  10. Candidate gene analysis using imputed genotypes: cell cycle single-nucleotide polymorphisms and ovarian cancer risk

    DEFF Research Database (Denmark)

    Goode, Ellen L; Fridley, Brooke L; Vierkant, Robert A

    2009-01-01

    Polymorphisms in genes critical to cell cycle control are outstanding candidates for association with ovarian cancer risk; numerous genes have been interrogated by multiple research groups using differing tagging single-nucleotide polymorphism (SNP) sets. To maximize information gleaned from...... existing genotype data, we conducted a combined analysis of five independent studies of invasive epithelial ovarian cancer. Up to 2,120 cases and 3,382 controls were genotyped in the course of two collaborations at a variety of SNPs in 11 cell cycle genes (CDKN2C, CDKN1A, CCND3, CCND1, CCND2, CDKN1B, CDK2......, and rs3212891; CDK2 rs2069391, rs2069414, and rs17528736; and CCNE1 rs3218036. These results exemplify the utility of imputation in candidate gene studies and lend evidence to a role of cell cycle genes in ovarian cancer etiology, suggest a reduced set of SNPs to target in additional cases and controls....

  11. Identification and Validation of Candidate Genes Associated with Domesticated and Improved Traits in Soybean

    Directory of Open Access Journals (Sweden)

    Ling Zhou

    2016-07-01

    Full Text Available Soybean, an important source of vegetable oils and proteins for humans, has undergone significant phenotypic changes during domestication and improvement. However, there is limited knowledge about genes related to these domesticated and improved traits, such as flowering time, seed development, alkaline-salt tolerance, and seed oil content (SOC. In this study, more than 106,000 single nucleotide polymorphisms (SNPs were identified by restriction site associated DNA sequencing of 14 wild, 153 landrace, and 119 bred soybean accessions, and 198 candidate domestication regions (CDRs were identified via multiple genetic diversity analyses. Of the 1489 candidate domestication genes (CDGs within these CDRs, a total of 330 CDGs were related to the above four traits in the domestication, gene ontology (GO enrichment, gene expression, and pathway analyses. Eighteen, 60, 66, and 10 of the 330 CDGs were significantly associated with the above four traits, respectively. Of 134 trait-associated CDGs, 29 overlapped with previous CDGs, 11 were consistent with candidate genes in previous trait association studies, and 66 were covered by the domesticated and improved quantitative trait loci or their adjacent regions, having six common CDGs, such as one functionally characterized gene (. Of the 68 seed size (SS and SOC CDGs, 37 were further confirmed by gene expression analysis. In addition, eight genes were found to be related to artificial selection during modern breeding. Therefore, this study provides an integrated method for efficiently identifying CDGs and valuable information for domestication and genetic research.

  12. The landscape of candidate driver genes differs between male and female breast cancer.

    Directory of Open Access Journals (Sweden)

    Ida Johansson

    Full Text Available The rapidly growing collection of diverse genome-scale data from multiple tumor types sheds light on various aspects of the underlying tumor biology. With the objective to identify genes of importance for breast tumorigenesis in men and to enable comparisons with genes important for breast cancer development in women, we applied the computational framework COpy Number and EXpression In Cancer (CONEXIC to detect candidate driver genes among all altered passenger genes. Unique to this approach is that each driver gene is associated with several gene modules that are believed to be altered by the driver. Thirty candidate drivers were found in the male breast cancers and 67 in the female breast cancers. We identified many known drivers of breast cancer and other types of cancer, in the female dataset (e.g. GATA3, CCNE1, GRB7, CDK4. In contrast, only three known cancer genes were found among male breast cancers; MAP2K4, LHP, and ZNF217. Many of the candidate drivers identified are known to be involved in processes associated with tumorigenesis, including proliferation, invasion and differentiation. One of the modules identified in male breast cancer was regulated by THY1, a gene involved in invasion and related to epithelial-mesenchymal transition. Furthermore, men with THY1 positive breast cancers had significantly inferior survival. THY1 may thus be a promising novel prognostic marker for male breast cancer. Another module identified among male breast cancers, regulated by SPAG5, was closely associated with proliferation. Our data indicate that male and female breast cancers display highly different landscapes of candidate driver genes, as only a few genes were found in common between the two. Consequently, the pathobiology of male breast cancer may differ from that of female breast cancer and can be associated with differences in prognosis; men diagnosed with breast cancer may consequently require different management and treatment strategies than

  13. Social cognitive role of schizophrenia candidate gene GABRB2.

    Directory of Open Access Journals (Sweden)

    Shui Ying Tsang

    Full Text Available The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis to psychological (altruism spectrum of social cognition suggesting GABRB2 involvement in human cognition.

  14. Bioinformatics-Driven Identification and Examination of Candidate Genes for Non-Alcoholic Fatty Liver Disease

    DEFF Research Database (Denmark)

    Banasik, Karina; Justesen, Johanne M.; Hornbak, Malene

    2011-01-01

    Objective: Candidate genes for non-alcoholic fatty liver disease (NAFLD) identified by a bioinformatics approach were examined for variant associations to quantitative traits of NAFLD-related phenotypes. Research Design and Methods: By integrating public database text mining, trans-organism protein......, central obesity, and MetS, respectively. Bonferroni adjustments for multiple testing negated all associations. Conclusions: Using a bioinformatics approach we identified five candidate genes for NAFLD. However, we failed to provide evidence of associations with major effects between SNPs in these five...

  15. Candidate gene study of HOXB1 in autism spectrum disorder

    Directory of Open Access Journals (Sweden)

    Muscarella Lucia A

    2010-05-01

    Full Text Available Abstract Background HOXB1 plays a major role in brainstem morphogenesis and could partly determine the cranial circumference in conjunction with HOXA1. In our sample, HOXA1 alleles significantly influence head growth rates both in autistic patients and in population controls. An initial report, suggesting that HOXB1 could confer autism vulnerability in interaction with HOXA1, was not confirmed by five small association studies. Methods Our sample includes 269 autistic individuals, belonging to 219 simplex and 28 multiplex families. A mutational analysis of the two exons and flanking intronic sequences of the HOXB1 gene was carried out in 84 autistic patients by denaturing high performance liquid chromatography, followed by DNA sequencing. Identified rare variants were then searched by a restriction analysis in 236 autistic patients and 325-345 controls. Case-control and family-based association studies were performed on two common variants in 169 Italian patients versus 184 Italian controls and in 247 trios. Results We identified three common polymorphisms, rs72338773 [c.82insACAGCGCCC (INS/nINS], rs12939811 [c.309A>T (Q103H], and rs7207109 [c.450G>A (A150A] and three rare variants, namely IVS1+63G>A, rs35115415 [c.702G>A (V234V] and c.872_873delinsAA (S291N. SNPs rs72338773 and rs12939811 were not associated with autism, using either a case-control (alleles, exact P = 0.13 or a family-based design [transmission/disequilibrium test (TDTχ2 = 1.774, P = 0.183]. The rare variants, all inherited from one of the parents, were present in two Italian and in two Caucasian-American families. Autistic probands in two families surprisingly inherited a distinct rare variant from each parent. The IVS1+63A allele was present in 3/690 control chromosomes, whereas rare alleles at rs35115415 and c.872_873delinsAA (S291N were not found in 662 and 650 control chromosomes, respectively. The INS-T309 allele influenced head size, but its effect appears more modest

  16. Biological processes, properties and molecular wiring diagrams of candidate low-penetrance breast cancer susceptibility genes

    Directory of Open Access Journals (Sweden)

    Moreno Víctor

    2008-12-01

    Full Text Available Abstract Background Recent advances in whole-genome association studies (WGASs for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined. Methods We applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence. Results First, examination of the distribution of Gene Ontology terms in ordered WGAS results identified asymmetrical distribution of Cell Communication and Cell Death processes linked to risk. Second, analysis of 11 different types of molecular or functional relationships in genomic and proteomic data sets defined the "omic" properties of candidate genes: i/ differential expression in tumors relative to normal tissue; ii/ somatic genomic copy number changes correlating with gene expression levels; iii/ differentially expressed across age at diagnosis; and iv/ expression changes after BRCA1 perturbation. Finally, network modeling of the effects of variants on germline gene expression showed higher connectivity than expected by chance between novel candidates and with known susceptibility genes, which supports functional relationships and provides mechanistic hypotheses of risk. Conclusion This study proposes that cell communication and cell death are major biological processes perturbed in risk of breast cancer conferred by low-penetrance variants, and defines the common

  17. Biological processes, properties and molecular wiring diagrams of candidate low-penetrance breast cancer susceptibility genes.

    Science.gov (United States)

    Bonifaci, Núria; Berenguer, Antoni; Díez, Javier; Reina, Oscar; Medina, Ignacio; Dopazo, Joaquín; Moreno, Víctor; Pujana, Miguel Angel

    2008-12-18

    Recent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined. We applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence. First, examination of the distribution of Gene Ontology terms in ordered WGAS results identified asymmetrical distribution of Cell Communication and Cell Death processes linked to risk. Second, analysis of 11 different types of molecular or functional relationships in genomic and proteomic data sets defined the "omic" properties of candidate genes: i/ differential expression in tumors relative to normal tissue; ii/ somatic genomic copy number changes correlating with gene expression levels; iii/ differentially expressed across age at diagnosis; and iv/ expression changes after BRCA1 perturbation. Finally, network modeling of the effects of variants on germline gene expression showed higher connectivity than expected by chance between novel candidates and with known susceptibility genes, which supports functional relationships and provides mechanistic hypotheses of risk. This study proposes that cell communication and cell death are major biological processes perturbed in risk of breast cancer conferred by low-penetrance variants, and defines the common omic properties, molecular interactions and possible functional

  18. Fitting the pieces together: current research on the genetic basis of attention-deficit/hyperactivity disorder (ADHD

    Directory of Open Access Journals (Sweden)

    Evangelia Stergiakouli

    2010-08-01

    Full Text Available Evangelia Stergiakouli, Anita ThaparDepartment of Psychological Medicine and Neurology, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, United KingdomAbstract: Attention-deficit/hyperactivity disorder (ADHD is a highly disruptive childhood-onset disorder that often persists into adolescence and adulthood. Comorbidity with other problems, such as autism, dyslexia and conduct disorder (CD is very common. Although little is known about the pathophysiology of ADHD, family, twin and adoption studies have shown that it is highly heritable. Whole genome linkage studies suggest there are no common susceptibility genes of moderate effect size. Most published research has been based on functional candidate gene studies. The most consistent evidence for association with ADHD relates to a dopamine D4 receptor (DRD4 gene variable number tandem repeat (VNTR, a dopamine D5 receptor (DRD5 gene microsatellite and a dopamine transporter (DAT1 gene VNTR. In addition, the catechol-O-methyltransferase (COMT val158/108 met variant has been shown to increase risk for associated antisocial behavior. The first genome-wide association studies (GWAS of ADHD have been completed and although larger studies are still required to detect common risk variants, novel risk pathways are being suggested for ADHD. Further research on the contribution of rare variants, larger genome-wide association and sequencing studies and ADHD phenotype refinement is now needed.Keywords: attention-deficit/hyperactivity disorder (ADHD, genetics, molecular genetics, genome-wide association study (GWAS, gene-environment interplay

  19. Exclusion of BBC1 and CMAR as candidate breast tumour-suppressor genes.

    OpenAIRE

    Moerland, E.; Breuning, M H; Cornelisse, C J; Cleton-Jansen, A M

    1997-01-01

    Loss of heterozygosity (LOH) on chromosome arm 16q occurs in 48-65% of breast tumours. One small region of overlap is located at 16q24.3. Two genes located in this region, the cellular adhesion regulatory molecule (CMAR) and the breast basic conserved gene (BBC1), are plausible candidate tumour-suppressor genes. Mutational analysis of the retained copy of these genes has been performed by direct sequencing in a selected set of breast tumours that show LOH at 16q24.3 but not at other regions o...

  20. Multiple sclerosis genetics: Results from meta-analyses of candidate-gene association studies.

    Science.gov (United States)

    Tizaoui, Kalthoum

    2017-11-02

    As a complex disease, multiple sclerosis (MS) susceptibility implicates many genetic and environmental factors. Usually, individual genetic association studies have several limitations, and results are specific to the population of study. The Meta-analysis approach has been proposed to resolve these limitations and to increase the power of statistical analyses. In this review, we summarize results from meta-analyses of candidate genes of MS. Using the keywords: multiple sclerosis, genetic polymorphism and meta-analysis, we searched electronic databases (PubMed, Embase and Web of Sciences) for published meta-analyses until May 2017. Meta-analyses confirmed the association of polymorphisms in fifteen candidate genes with MS disease. However, polymorphisms in fourteen genes showed none significant association. Results outlined the importance of confirmed genes to understand signaling pathways in MS disease and shed light on their utility to develop new drugs targets. Copyright © 2017. Published by Elsevier Ltd.

  1. Pharmacological Validation of Candidate Causal Sleep Genes Identified in an N2 Cross

    OpenAIRE

    Brunner, Joseph I; Gotter, Anthony L.; Millstein, Joshua; Garson, Susan; Binns, Jacquelyn; Fox, Steven V.; Savitz, Alan T.; Yang, He S.; Fitzpatrick, Karrie; Zhou, Lili; Owens, Joseph R.; Webber, Andrea L.; Vitaterna, Martha H.; Kasarskis, Andrew; Uebele, Victor N.

    2011-01-01

    Despite the substantial impact of sleep disturbances on human health and the many years of study dedicated to understanding sleep pathologies, the underlying genetic mechanisms that govern sleep and wake largely remain unknown. Recently, we completed large scale genetic and gene expression analyses in a segregating inbred mouse cross and identified candidate causal genes that regulate the mammalian sleep-wake cycle, across multiple traits including total sleep time, amounts of REM, non-REM, s...

  2. The role of age in association analyses of ADHD and related neurocognitive functioning: A proof of concept for dopaminergic and serotonergic genes.

    Science.gov (United States)

    Thissen, Andrieke J A M; Bralten, Janita; Rommelse, Nanda N J; Arias-Vasquez, Alejandro; Greven, Corina U; Heslenfeld, Dirk; Luman, Marjolein; Oosterlaan, Jaap; Hoekstra, Pieter J; Hartman, Catharina; Franke, Barbara; Buitelaar, Jan K

    2015-09-01

    Elucidating genetic mechanisms involved in Attention-Deficit/Hyperactivity Disorder (ADHD) has been challenging. Relatively unexplored is the fact that genetic mechanisms can differ with age. The current study explored the association between dopaminergic and serotonergic genes, ADHD symptoms, and neurocognitive functioning in relation to age. Associations of three genetic ADHD risk factors, DAT1, DRD4, and 5-HTT with symptoms and six neurocognitive measures were explored in two samples of the NeuroIMAGE study: 756 children, adolescents, and young adults with ADHD, their siblings, and controls (M age 17 years, SD 3.2), and 393 parents with and without ADHD (M age 48 years, SD 4.8). Association analyses were performed in both samples, and effects were compared to address dichotomous age effects. Gene*age interactions were examined to address continuous age effects. Moderating effects of age were found for DRD4-7R carriership and ADHD symptoms in the adult group only; in the adolescents the 5-HTT LL genotype was differentially associated with inhibition and with motor timing at different ages, and to inhibition in adults; DAT1 10-6 haplotype carriership showed differential working memory performance depending on age. None of our effects survived correction for multiple comparisons. Our results are preliminary, but may point to differential genotype-phenotype associations at different ages. This can be seen as a proof of concept for the importance of age in dopaminergic and serotonergic genetic association analyses. Our findings are consistent with the idea that genetic and neurocognitive mechanisms underlying ADHD may change throughout life. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  3. Development of new candidate gene and EST-based molecular markers for Gossypium species

    Science.gov (United States)

    New source of molecular markers accelerates the efforts in improving cotton fiber traits and aid in developing high-density integrated genetic maps. We developed new markers based on candidate genes and G. arboreum expressed sequence tag (EST) sequences, and validated them through amplification, ge...

  4. Mining the secretome of the root-knot nematode Meloidogyne chitwoodi for candidate parasitism genes

    NARCIS (Netherlands)

    Roze, E.H.A.; Hanse, B.; Mitreva, M.; Vanholme, B.; Bakker, J.; Smant, G.

    2008-01-01

    Parasite proteins secreted at the interface of nematode and host are believed to play an essential role in parasitism. Here, we present an efficient pipeline of bio-informatic algorithms and laboratory experiments to identify candidate parasitism genes within nematode secretomes, i.e. the repertoire

  5. Single nucleotide polymorphisms in candidate genes related to daughter pregnancy rate in Holstein cows

    Science.gov (United States)

    ABSTRACT: Previously, a candidate gene approach identified 40 SNPs associated with daughter pregnancy rate (DPR) in dairy bulls. We evaluated 39 of these SNPs for relationship to DPR in a separate population of Holstein cows grouped on their predicted transmitting ability for DPR: <= -1 (n=1266) a...

  6. Identification of novel candidate genes associated with cleft lip and palate using array comparative genomic hybridisation.

    NARCIS (Netherlands)

    Osoegawa, K.; Vessere, G.M.; Utami, K.H.; Mansilla, M.A.; Johnson, M.K.; Riley, B.M.; L'Heureux, J.; Pfundt, R.P.; Staaf, J.; Vliet, W.A. van der; Lidral, A.C.; Schoenmakers, E.F.P.M.; Borg, A.; Schutte, B.C.; Lammer, E.J.; Murray, J.C.; Jong, PJ de

    2008-01-01

    AIM AND METHOD: We analysed DNA samples isolated from individuals born with cleft lip and cleft palate to identify deletions and duplications of candidate gene loci using array comparative genomic hybridisation (array-CGH). RESULTS: Of 83 syndromic cases analysed we identified one subject with a

  7. A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy

    DEFF Research Database (Denmark)

    Bruhn, Sören; Fang, Yu; Barrenäs, Fredrik

    2014-01-01

    identified a T helper 2 (TH2) cell module by small interfering RNA–mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells...

  8. Identification of candidate driver genes in common focal chromosomal aberrations of microsatellite stable colorectal cancer.

    Directory of Open Access Journals (Sweden)

    George J Burghel

    Full Text Available Colorectal cancer (CRC is a leading cause of cancer deaths worldwide. Chromosomal instability (CIN is a major driving force of microsatellite stable (MSS sporadic CRC. CIN tumours are characterised by a large number of somatic chromosomal copy number aberrations (SCNA that frequently affect oncogenes and tumour suppressor genes. The main aim of this work was to identify novel candidate CRC driver genes affected by recurrent and focal SCNA. High resolution genome-wide comparative genome hybridisation (CGH arrays were used to compare tumour and normal DNA for 53 sporadic CRC cases. Context corrected common aberration (COCA analysis and custom algorithms identified 64 deletions and 32 gains of focal minimal common regions (FMCR at high frequency (>10%. Comparison of these FMCR with published genomic profiles from CRC revealed common overlap (42.2% of deletions and 34.4% of copy gains. Pathway analysis showed that apoptosis and p53 signalling pathways were commonly affected by deleted FMCR, and MAPK and potassium channel pathways by gains of FMCR. Candidate tumour suppressor genes in deleted FMCR included RASSF3, IFNAR1, IFNAR2 and NFKBIA and candidate oncogenes in gained FMCR included PRDM16, TNS1, RPA3 and KCNMA1. In conclusion, this study confirms some previously identified aberrations in MSS CRC and provides in silico evidence for some novel candidate driver genes.

  9. Identification of candidate driver genes in common focal chromosomal aberrations of microsatellite stable colorectal cancer.

    Science.gov (United States)

    Burghel, George J; Lin, Wei-Yu; Whitehouse, Helen; Brock, Ian; Hammond, David; Bury, Jonathan; Stephenson, Yvonne; George, Rina; Cox, Angela

    2013-01-01

    Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Chromosomal instability (CIN) is a major driving force of microsatellite stable (MSS) sporadic CRC. CIN tumours are characterised by a large number of somatic chromosomal copy number aberrations (SCNA) that frequently affect oncogenes and tumour suppressor genes. The main aim of this work was to identify novel candidate CRC driver genes affected by recurrent and focal SCNA. High resolution genome-wide comparative genome hybridisation (CGH) arrays were used to compare tumour and normal DNA for 53 sporadic CRC cases. Context corrected common aberration (COCA) analysis and custom algorithms identified 64 deletions and 32 gains of focal minimal common regions (FMCR) at high frequency (>10%). Comparison of these FMCR with published genomic profiles from CRC revealed common overlap (42.2% of deletions and 34.4% of copy gains). Pathway analysis showed that apoptosis and p53 signalling pathways were commonly affected by deleted FMCR, and MAPK and potassium channel pathways by gains of FMCR. Candidate tumour suppressor genes in deleted FMCR included RASSF3, IFNAR1, IFNAR2 and NFKBIA and candidate oncogenes in gained FMCR included PRDM16, TNS1, RPA3 and KCNMA1. In conclusion, this study confirms some previously identified aberrations in MSS CRC and provides in silico evidence for some novel candidate driver genes.

  10. ReCGiP, a database of reproduction candidate genes in pigs based on bibliomics.

    Science.gov (United States)

    Yang, Lun; Zhang, Xiangzhe; Chen, Jian; Wang, Qishan; Wang, Lishan; Jiang, Yue; Pan, Yuchun

    2010-08-14

    Reproduction in pigs is one of the most economically important traits. To improve the reproductive performances, numerous studies have focused on the identification of candidate genes. However, it is hard for one to read all literatures thoroughly to get information. So we have developed a database providing candidate genes for reproductive researches in pig by mining and processing existing biological literatures in human and pigs, named as ReCGiP. Based on text-mining and comparative genomics, ReCGiP presents diverse information of reproduction-relevant genes in human and pig. The genes were sorted by the degree of relevance with the reproduction topics and were visualized in a gene's co-occurrence network where two genes were connected if they were co-cited in a PubMed abstract. The 'hub' genes which had more 'neighbors' were thought to be have more important functions and could be identified by the user in their web browser. In addition, ReCGiP provided integrated GO annotation, OMIM and biological pathway information collected from the Internet. Both pig and human gene information can be found in the database, which is now available. ReCGiP is a unique database providing information on reproduction related genes for pig. It can be used in the area of the molecular genetics, the genetic linkage map, and the breeding of the pig and other livestock. Moreover, it can be used as a reference for human reproduction research.

  11. ReCGiP, a database of reproduction candidate genes in pigs based on bibliomics

    Directory of Open Access Journals (Sweden)

    Yang Lun

    2010-08-01

    Full Text Available Abstract Background Reproduction in pigs is one of the most economically important traits. To improve the reproductive performances, numerous studies have focused on the identification of candidate genes. However, it is hard for one to read all literatures thoroughly to get information. So we have developed a database providing candidate genes for reproductive researches in pig by mining and processing existing biological literatures in human and pigs, named as ReCGiP. Description Based on text-mining and comparative genomics, ReCGiP presents diverse information of reproduction-relevant genes in human and pig. The genes were sorted by the degree of relevance with the reproduction topics and were visualized in a gene's co-occurrence network where two genes were connected if they were co-cited in a PubMed abstract. The 'hub' genes which had more 'neighbors' were thought to be have more important functions and could be identified by the user in their web browser. In addition, ReCGiP provided integrated GO annotation, OMIM and biological pathway information collected from the Internet. Both pig and human gene information can be found in the database, which is now available. Conclusions ReCGiP is a unique database providing information on reproduction related genes for pig. It can be used in the area of the molecular genetics, the genetic linkage map, and the breeding of the pig and other livestock. Moreover, it can be used as a reference for human reproduction research.

  12. Molecular evolution of candidate genes for crop-related traits in sunflower (Helianthus annuus L.).

    Science.gov (United States)

    Mandel, Jennifer R; McAssey, Edward V; Nambeesan, Savithri; Garcia-Navarro, Elena; Burke, John M

    2014-01-01

    Evolutionary analyses aimed at detecting the molecular signature of selection during crop domestication and/or improvement can be used to identify genes or genomic regions of likely agronomic importance. Here, we describe the DNA sequence-based characterization of a pool of candidate genes for crop-related traits in sunflower. These genes, which were identified based on homology to genes of known effect in other study systems, were initially sequenced from a panel of improved lines. All genes that exhibited a paucity of sequence diversity, consistent with the possible effects of selection during the evolution of cultivated sunflower, were then sequenced from a panel of wild sunflower accessions an outgroup. These data enabled formal tests for the effects of selection in shaping sequence diversity at these loci. When selection was detected, we further sequenced these genes from a panel of primitive landraces, thereby allowing us to investigate the likely timing of selection (i.e., domestication vs. improvement). We ultimately identified seven genes that exhibited the signature of positive selection during either domestication or improvement. Genetic mapping of a subset of these genes revealed co-localization between candidates for genes involved in the determination of flowering time, seed germination, plant growth/development, and branching and QTL that were previously identified for these traits in cultivated × wild sunflower mapping populations.

  13. Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability.

    Science.gov (United States)

    Riazuddin, S; Hussain, M; Razzaq, A; Iqbal, Z; Shahzad, M; Polla, D L; Song, Y; van Beusekom, E; Khan, A A; Tomas-Roca, L; Rashid, M; Zahoor, M Y; Wissink-Lindhout, W M; Basra, M A R; Ansar, M; Agha, Z; van Heeswijk, K; Rasheed, F; Van de Vorst, M; Veltman, J A; Gilissen, C; Akram, J; Kleefstra, T; Assir, M Z; Grozeva, D; Carss, K; Raymond, F L; O'Connor, T D; Riazuddin, S A; Khan, S N; Ahmed, Z M; de Brouwer, A P M; van Bokhoven, H; Riazuddin, S

    2016-07-26

    Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (Pnovel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (Pgenes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID.Molecular Psychiatry advance online publication, 26 July 2016; doi:10.1038/mp.2016.109.

  14. Nicotinic acetylcholine receptor β2 subunit gene implicated in a systems-based candidate gene study of smoking cessation

    OpenAIRE

    Conti, DV; Lee, W.; D. Li; Liu, J.; Van Den Berg, D.; Thomas, PD; Bergen, AW; Swan, GE; Tyndale, RF; Benowitz, NL; Lerman, C

    2008-01-01

    Although the efficacy of pharmacotherapy for tobacco dependence has been previously demonstrated, there is substantial variability among individuals in treatment response. We performed a systems-based candidate gene study of 1295 single nucleotide polymorphisms (SNPs) in 58 genes within the neuronal nicotinic receptor and dopamine systems to investigate their role in smoking cessation in a bupropion placebo-controlled randomized clinical trial. Putative functional variants were supplemented w...

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

    Directory of Open Access Journals (Sweden)

    David G Ashbrook

    2015-07-01

    Full Text Available 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.

  16. SNP detection using RNA-sequences of candidate genes associated with puberty in cattle.

    Science.gov (United States)

    Dias, M M; Cánovas, A; Mantilla-Rojas, C; Riley, D G; Luna-Nevarez, P; Coleman, S J; Speidel, S E; Enns, R M; Islas-Trejo, A; Medrano, J F; Moore, S S; Fortes, M R S; Nguyen, L T; Venus, B; Diaz, I S D P; Souza, F R P; Fonseca, L F S; Baldi, F; Albuquerque, L G; Thomas, M G; Oliveira, H N

    2017-03-22

    Fertility traits, such as heifer pregnancy, are economically important in cattle production systems, and are therefore, used in genetic selection programs. The aim of this study was to identify single nucleotide polymorphisms (SNPs) using RNA-sequencing (RNA-Seq) data from ovary, uterus, endometrium, pituitary gland, hypothalamus, liver, longissimus dorsi muscle, and adipose tissue in 62 candidate genes associated with heifer puberty in cattle. RNA-Seq reads were assembled to the bovine reference genome (UMD 3.1.1) and analyzed in five cattle breeds; Brangus, Brahman, Nellore, Angus, and Holstein. Two approaches used the Brangus data for SNP discovery 1) pooling all samples, and 2) within each individual sample. These approaches revealed 1157 SNPs. These were compared with those identified in the pooled samples of the other breeds. Overall, 172 SNPs within 13 genes (CPNE5, FAM19A4, FOXN4, KLF1, LOC777593, MGC157266, NEBL, NRXN3, PEPT-1, PPP3CA, SCG5, TSG101, and TSHR) were concordant in the five breeds. Using Ensembl's Variant Effector Predictor, we determined that 12% of SNPs were in exons (71% synonymous, 29% nonsynonymous), 1% were in untranslated regions (UTRs), 86% were in introns, and 1% were in intergenic regions. Since these SNPs were discovered in RNA, the variants were predicted to be within exons or UTRs. Overall, 160 novel transcripts in 42 candidate genes and five novel genes overlapping five candidate genes were observed. In conclusion, 1157 SNPs were identified in 62 candidate genes associated with puberty in Brangus cattle, of which, 172 were concordant in the five cattle breeds. Novel transcripts and genes were also identified.

  17. Identification of novel candidate genes for follicle selection in the broiler breeder ovary

    Science.gov (United States)

    2012-01-01

    Background Broiler breeders fed ad libitum are characterised by multiple ovulation, which leads to poor shell quality and egg production. Multiple ovulation is controlled by food restriction in commercial flocks. However, the level of food restriction raises welfare concerns, including that of severe hunger. Reducing the rate of multiple ovulation by genetic selection would facilitate progress towards developing a growth profile for optimum animal welfare. Results The study utilised 3 models of ovarian follicle development; laying hens fed ad libitum (experiment 2) and broiler breeders fed ad libitum or a restricted diet (experiments 1 & 3). This allowed us to investigate gene candidates for follicular development by comparing normal, abnormal and “controlled” follicle hierarchies at different stages of development. Several candidate genes for multiple ovulation were identified by combining microarray analysis of restricted vs. ad libitum feeding, literature searches and QPCR expression profiling throughout follicle development. Three candidate genes were confirmed by QPCR as showing significant differential expression between restricted and ad libitum feeding: FSHR, GDF9 and PDGFRL. PDGFRL, a candidate for steroidogenesis, showed significantly up-regulated expression in 6–8 mm follicles of ad libitum fed broiler breeders (P = 0.016), the period at which follicle recruitment occurs. Conclusions Gene candidates have been identified and evidence provided to support a possible role in regulation of ovarian function and follicle number. Further characterisation of these genes will be required to assess their potential for inclusion into breeding programmes to improve the regulation of follicle selection and reduce the need for feed restriction. PMID:22992265

  18. Changes in gene expression linked with adult reproductive diapause in a northern malt fly species: a candidate gene microarray study

    Directory of Open Access Journals (Sweden)

    Hoikkala Anneli

    2010-02-01

    Full Text Available Abstract Background Insect diapause is an important biological process which involves many life-history parameters important for survival and reproductive fitness at both individual and population level. Drosophila montana, a species of D. virilis group, has a profound photoperiodic reproductive diapause that enables the adult flies to survive through the harsh winter conditions of high latitudes and altitudes. We created a custom-made microarray for D. montana with 101 genes known to affect traits important in diapause, photoperiodism, reproductive behaviour, circadian clock and stress tolerance in model Drosophila species. This array gave us a chance to filter out genes showing expression changes during photoperiodic reproductive diapause in a species adapted to live in northern latitudes with high seasonal changes in environmental conditions. Results Comparisons among diapausing, reproducing and young D. montana females revealed expression changes in 24 genes on microarray; for example in comparison between diapausing and reproducing females one gene (Drosophila cold acclimation gene, Dca showed up-regulation and 15 genes showed down-regulation in diapausing females. Down-regulation of seven of these genes was specific to diapause state while in five genes the expression changes were linked with the age of the females rather than with their reproductive status. Also, qRT-PCR experiments confirmed couch potato (cpo gene to be involved in diapause of D. montana. Conclusions A candidate gene microarray proved to offer a practical and cost-effective way to trace genes that are likely to play an important role in photoperiodic reproductive diapause and further in adaptation to seasonally varying environmental conditions. The present study revealed two genes, Dca and cpo, whose role in photoperiodic diapause in D. montana is worth of studying in more details. Also, further studies using the candidate gene microarray with more specific experimental

  19. Investigation of the molecular relationship between breast cancer and obesity by candidate gene prioritization methods

    Directory of Open Access Journals (Sweden)

    Saba Garshasbi

    2015-10-01

    Full Text Available Background: Cancer and obesity are two major public health concerns. More than 12 million cases of cancer are reported annually. Many reports confirmed obesity as a risk factor for cancer. The molecular relationship between obesity and breast cancer has not been clear yet. The purpose of this study was to investigate priorities of effective genes in the molecular relationship between obesity and breast cancer. Methods: In this study, computer simulation method was used for prioritizing the genes that involved in the molecular links between obesity and breast cancer in laboratory of systems biology and bioinformatics (LBB, Tehran University, Tehran, Iran, from March to July 2014. In this study, ENDEAVOUR software was used for prioritizing the genes and integrating multiple data sources was used for data analysis. Training genes were selected from effective genes in obesity and/or breast cancer. Two groups of candidate genes were selected. The first group was included the existential genes in 5 common region chromosomes (between obesity and breast cancer and the second group was included the results of genes microarray data analysis of research Creighton, et al (In 2012 on patients with breast cancer. The microarray data were analyzed with GER2 software (R online software on GEO website. Finally, both training and candidate genes were entered in ENDEAVOUR software package. Results: The candidate genes were prioritized to four style and five genes in ten of the first priorities were repeated twice. In other word, the outcome of prioritizing of 72 genes (Product of microarray data analysis and genes of 5 common chromosome regions (Between obesity and breast cancer showed, 5 genes (TNFRSF10B, F2, IGFALS, NTRK3 and HSP90B1 were the priorities in the molecular connection between obesity and breast cancer. Conclusion: There are some common genes between breast cancer and obesity. So, molecular relationship is confirmed. In this study the possible effect

  20. Polymorphisms in swine candidate genes for meat quality detected by PCR-SSCP

    Directory of Open Access Journals (Sweden)

    Stefania Chessa

    2010-01-01

    Full Text Available In order to identify SNPs in seven candidate genes for meat quality, PCR-SSCP experiments were carried out. Statistical analyses in a population of 240 individuals identified the animals constituting the extreme tails of the Gaussian distribution for three selected phenotypes: muscle compactness, fat thickness, and the principal component 1. Twenty-two of these animals were chosen for the molecular analyses. Several fragments in the candidate genes were tested by PCR-SSCP and many different patterns were found, indicating the presence of polymorphisms. The polymorphic fragments were sequenced and analyzed. CRADD was the most interesting gene, because many PCR-SSCP patterns were found in the samples. The results will be tested in another Italian Large White population to verify the segregation and the association of SNPs with phenotypes that influence meat quality.

  1. Identification of microdeletions in candidate genes for cleft lip and/or palate

    DEFF Research Database (Denmark)

    Shi, Min; Mostowska, Adrianna; Jugessur, Astanand

    2009-01-01

    BACKGROUND: Genome-wide association studies are now used routinely to identify genes implicated in complex traits. The panels used for such analyses can detect single nucleotide polymorphisms and copy number variants, both of which may help to identify small deleted regions of the genome that may...... contribute to a particular disease. METHODS: We performed a candidate gene analysis involving 1,221 SNPs in 333 candidate genes for orofacial clefting, using 2,823 samples from 725 two- and three-generation families with a proband having cleft lip with or without cleft palate. We used SNP genotyping, DNA...... for deletion detection. Apparent Mendelian inconsistencies between parents and children suggested deletion events in 15 individuals in 11 genomic regions. We confirmed deletions involving CYP1B1, FGF10, SP8, SUMO1, TBX1, TFAP2A, and UGT7A1, including both de novo and familial cases. Deletions of SUMO1, TBX1...

  2. Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice

    Energy Technology Data Exchange (ETDEWEB)

    Moyer, J.H.; Lee-Tischler, M.J.; Kwon, H.Y.; Schrick, J.J. (Univ. of Tennessee Graduate School of Biomedical Sciences, Oak Ridge, TN (United States)); Avner, E.D.; Sweeney, W.E. (Univ. of Washington, Seattle, WA (United States)); Godfrey, V.L.; Cacheiro, N.L.A.; Woychik, R.P. (Oak Ridge National Lab., TN (United States)); Wilkinson, J.E. (Univ. of Tennessee, Knoxville, TN (United States))

    1994-05-27

    A line of transgenic mice was generated that contains an insertional mutation causing a phenotype similar to human autosomal recessive polycystic kidney disease. Homozygotes displayed a complex phenotype that included bilateral polycystic kidneys and an unusual liver lesion. The mutant locus was cloned and characterized through use of the transgene as a molecular marker. Additionally, a candidate polycystic kidney disease (PKD) gene was identified whose structure and expression are directly associated with the mutant locus. A complementary DNA derived from this gene predicted a peptide containing a motif that was originally identified in several genes involved in cell cycle control.

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

    Science.gov (United States)

    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. © 2013 BSPP AND JOHN WILEY & SONS LTD.

  4. A Cross-Disorder Method to Identify Novel Candidate Genes for Developmental Brain Disorders.

    Science.gov (United States)

    Gonzalez-Mantilla, Andrea J; Moreno-De-Luca, Andres; Ledbetter, David H; Martin, Christa Lese

    2016-03-01

    Developmental brain disorders are a group of clinically and genetically heterogeneous disorders characterized by high heritability. Specific highly penetrant genetic causes can often be shared by a subset of individuals with different phenotypic features, and recent advances in genome sequencing have allowed the rapid and cost-effective identification of many of these pathogenic variants. To identify novel candidate genes for developmental brain disorders and provide additional evidence of previously implicated genes. The PubMed database was searched for studies published from March 28, 2003, through May 7, 2015, with large cohorts of individuals with developmental brain disorders. A tiered, multilevel data-integration approach was used, which intersects (1) whole-genome data from structural and sequence pathogenic loss-of-function (pLOF) variants, (2) phenotype data from 6 apparently distinct disorders (intellectual disability, autism, attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorder, and epilepsy), and (3) additional data from large-scale studies, smaller cohorts, and case reports focusing on specific candidate genes. All candidate genes were ranked into 4 tiers based on the strength of evidence as follows: tier 1, genes with 3 or more de novo pathogenic loss-of-function variants; tier 2, genes with 2 de novo pathogenic loss-of-function variants; tier 3, genes with 1 de novo pathogenic loss-of-function variant; and tier 4, genes with only inherited (or unknown inheritance) pathogenic loss-of-function variants. Development of a comprehensive knowledge base of candidate genes related to developmental brain disorders. Genes were prioritized based on the inheritance pattern and total number of pathogenic loss-of-function variants identified amongst unrelated individuals with any one of six developmental brain disorders. A combination of phenotype-based and genotype-based literature review yielded 384 studies that used whole-genome or exome

  5. KIAA1462, a coronary artery disease associated gene, is a candidate gene for late onset Alzheimer disease in APOE carriers.

    Directory of Open Access Journals (Sweden)

    Deborah G Murdock

    Full Text Available Alzheimer disease (AD is a devastating neurodegenerative disease affecting more than five million Americans. In this study, we have used updated genetic linkage data from chromosome 10 in combination with expression data from serial analysis of gene expression to choose a new set of thirteen candidate genes for genetic analysis in late onset Alzheimer disease (LOAD. Results in this study identify the KIAA1462 locus as a candidate locus for LOAD in APOE4 carriers. Two genes exist at this locus, KIAA1462, a gene associated with coronary artery disease, and "rokimi", encoding an untranslated spliced RNA The genetic architecture at this locus suggests that the gene product important in this association is either "rokimi", or a different isoform of KIAA1462 than the isoform that is important in cardiovascular disease. Expression data suggests that isoform f of KIAA1462 is a more attractive candidate for association with LOAD in APOE4 carriers than "rokimi" which had no detectable expression in brain.

  6. Defining the Sequence Elements and Candidate Genes for the Coloboma Mutation.

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    Elizabeth A. Robb

    Full Text Available The chicken coloboma mutation exhibits features similar to human congenital developmental malformations such as ocular coloboma, cleft-palate, dwarfism, and polydactyly. The coloboma-associated region and encoded genes were investigated using advanced genomic, genetic, and gene expression technologies. Initially, the mutation was linked to a 990 kb region encoding 11 genes; the application of the genetic and genomic tools led to a reduction of the linked region to 176 kb and the elimination of 7 genes. Furthermore, bioinformatics analyses of capture array-next generation sequence data identified genetic elements including SNPs, insertions, deletions, gaps, chromosomal rearrangements, and miRNA binding sites within the introgressed causative region relative to the reference genome sequence. Coloboma-specific variants within exons, UTRs, and splice sites were studied for their contribution to the mutant phenotype. Our compiled results suggest three genes for future studies. The three candidate genes, SLC30A5 (a zinc transporter, CENPH (a centromere protein, and CDK7 (a cyclin-dependent kinase, are differentially expressed (compared to normal embryos at stages and in tissues affected by the coloboma mutation. Of these genes, two (SLC30A5 and CENPH are considered high-priority candidate based upon studies in other vertebrate model systems.

  7. Network Based Integrated Analysis of Phenotype-Genotype Data for Prioritization of Candidate Symptom Genes

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    Xing Li

    2014-01-01

    Full Text Available Background. Symptoms and signs (symptoms in brief are the essential clinical manifestations for individualized diagnosis and treatment in traditional Chinese medicine (TCM. To gain insights into the molecular mechanism of symptoms, we develop a computational approach to identify the candidate genes of symptoms. Methods. This paper presents a network-based approach for the integrated analysis of multiple phenotype-genotype data sources and the prediction of the prioritizing genes for the associated symptoms. The method first calculates the similarities between symptoms and diseases based on the symptom-disease relationships retrieved from the PubMed bibliographic database. Then the disease-gene associations and protein-protein interactions are utilized to construct a phenotype-genotype network. The PRINCE algorithm is finally used to rank the potential genes for the associated symptoms. Results. The proposed method gets reliable gene rank list with AUC (area under curve 0.616 in classification. Some novel genes like CALCA, ESR1, and MTHFR were predicted to be associated with headache symptoms, which are not recorded in the benchmark data set, but have been reported in recent published literatures. Conclusions. Our study demonstrated that by integrating phenotype-genotype relationships into a complex network framework it provides an effective approach to identify candidate genes of symptoms.

  8. Evolutionary conservation of candidate osmoregulation genes in plant phloem sap-feeding insects.

    Science.gov (United States)

    Jing, X; White, T A; Luan, J; Jiao, C; Fei, Z; Douglas, A E

    2016-06-01

    The high osmotic pressure generated by sugars in plant phloem sap is reduced in phloem-feeding aphids by sugar transformations and facilitated water flux in the gut. The genes mediating these osmoregulatory functions have been identified and validated empirically in the pea aphid Acyrthosiphon pisum: sucrase 1 (SUC1), a sucrase in glycoside hydrolase family 13 (GH13), and aquaporin 1 (AQP1), a member of the Drosophila integral protein (DRIP) family of aquaporins. Here, we describe molecular analysis of GH13 and AQP genes in phloem-feeding representatives of the four phloem-feeding groups: aphids (Myzus persicae), coccids (Planococcus citri), psyllids (Diaphorina citri, Bactericera cockerelli) and whiteflies (Bemisia tabaci MEAM1 and MED). A single candidate GH13-SUC gene and DRIP-AQP gene were identified in the genome/transcriptome of most insects tested by the criteria of sequence motif and gene expression in the gut. Exceptionally, the psyllid Ba. cockerelli transcriptome included a gut-expressed Pyrocoelia rufa integral protein (PRIP)-AQP, but has no DRIP-AQP transcripts, suggesting that PRIP-AQP is recruited for osmoregulatory function in this insect. This study indicates that phylogenetically related SUC and AQP genes may generally mediate osmoregulatory functions in these diverse phloem-feeding insects, and provides candidate genes for empirical validation and development as targets for osmotic disruption of pest species. © 2016 The Authors. Insect Molecular Biology published by John Wiley & Sons Ltd on behalf of The Royal Entomological Society.

  9. Bioinformatics-driven identification and examination of candidate genes for non-alcoholic fatty liver disease.

    Directory of Open Access Journals (Sweden)

    Karina Banasik

    2011-01-01

    Full Text Available Candidate genes for non-alcoholic fatty liver disease (NAFLD identified by a bioinformatics approach were examined for variant associations to quantitative traits of NAFLD-related phenotypes.By integrating public database text mining, trans-organism protein-protein interaction transferal, and information on liver protein expression a protein-protein interaction network was constructed and from this a smaller isolated interactome was identified. Five genes from this interactome were selected for genetic analysis. Twenty-one tag single-nucleotide polymorphisms (SNPs which captured all common variation in these genes were genotyped in 10,196 Danes, and analyzed for association with NAFLD-related quantitative traits, type 2 diabetes (T2D, central obesity, and WHO-defined metabolic syndrome (MetS.273 genes were included in the protein-protein interaction analysis and EHHADH, ECHS1, HADHA, HADHB, and ACADL were selected for further examination. A total of 10 nominal statistical significant associations (P<0.05 to quantitative metabolic traits were identified. Also, the case-control study showed associations between variation in the five genes and T2D, central obesity, and MetS, respectively. Bonferroni adjustments for multiple testing negated all associations.Using a bioinformatics approach we identified five candidate genes for NAFLD. However, we failed to provide evidence of associations with major effects between SNPs in these five genes and NAFLD-related quantitative traits, T2D, central obesity, and MetS.

  10. Candidate genes for the progression of malignant gliomas identified by microarray analysis.

    Science.gov (United States)

    Bozinov, Oliver; Köhler, Sylvia; Samans, Birgit; Benes, Ludwig; Miller, Dorothea; Ritter, Markus; Sure, Ulrich; Bertalanffy, Helmut

    2008-01-01

    Malignant astrocytomas of World Health Organization (WHO) grade III or IV have a reduced median survival time, and possible pathways have been described for the progression of anaplastic astrocytomas and glioblastomas, but the molecular basis of malignant astrocytoma progression is still poorly understood. Microarray analysis provides the chance to accelerate studies by comparison of the expression of thousands of genes in these tumours and consequently identify targeting genes. We compared the transcriptional profile of 4,608 genes in tumours of 15 patients including 6 anaplastic astrocytomas (WHO grade III) and 9 glioblastomas (WHO grade IV) using microarray analysis. The microarray data were corroborated by real-time reverse transcription-polymerase chain reaction analysis of two selected genes. We identified 166 gene alterations with a fold change of 2 and higher whose mRNA levels differed (absolute value of the t statistic of 1.96) between the two malignant glioma groups. Further analyses confirmed same transcription directions for Olig2 and IL-13Ralpha2 in anaplastic astrocytomas as compared to glioblastomas. Microarray analyses with a close binary question reveal numerous interesting candidate genes, which need further histochemical testing after selection for confirmation. IL-13Ralpha2 and Olig2 have been identified and confirmed to be interesting candidate genes whose differential expression likely plays a role in malignant progression of astrocytomas.

  11. Prioritization of candidate genes for cattle reproductive traits, based on protein-protein interactions, gene expression, and text-mining

    DEFF Research Database (Denmark)

    Hulsegge, Ina; Woelders, Henri; Smits, Mari

    2013-01-01

    and processes in brain areas and pituitary involved in reproductive traits in cattle using information derived from three different data sources: gene expression, protein-protein interactions, and literature. We identified 59, 89, 53, 23, and 71 genes in bovine amygdala, dorsal hypothalamus, hippocampus......, pituitary, and ventral hypothalamus, respectively, potentially involved in processes underlying estrus and estrous behavior. Functional annotation of the candidate genes points to a number of tissue-specific processes of which the "neurotransmitter/ion channel/synapse" process in the amygdala, "steroid...

  12. Industrial melanism in the peppered moth is not associated with genetic variation in canonical melanisation gene candidates.

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    Arjen E van't Hof

    Full Text Available Industrial melanism in the peppered moth (Biston betularia is an iconic case study of ecological genetics but the molecular identity of the gene determining the difference between the typical and melanic (carbonaria morphs is entirely unknown. We applied the candidate gene approach to look for associations between genetic polymorphisms within sixteen a priori melanisation gene candidates and the carbonaria morph. The genes were isolated and sequence characterised in B. betularia using degenerate PCR and from whole-transcriptome sequence. The list of candidates contains all the genes previously implicated in melanisation pattern differences in other insects, including aaNAT, DOPA-decarboxylase, ebony, tan, tyrosine hydroxylase, yellow and yellow2 (yellow-fa. Co-segregation of candidate gene alleles and carbonaria morph was tested in 73 offspring of a carbonaria male-typical female backcross. Surprisingly, none of the sixteen candidate genes was in close linkage with the locus controlling the carbonaria-typical polymorphism. Our study demonstrates that the 'carbonaria gene' is not a structural variant of a canonical melanisation pathway gene, neither is it a cis-regulatory element of these enzyme-coding genes. The implication is either that we have failed to characterize an unknown enzyme-coding gene in the melanisation pathway, or more likely, that the 'carbonaria gene' is a higher level trans-acting factor which regulates the spatial expression of one or more of the melanisation candidates in this study to alter the pattern of melanin production.

  13. Genome-wide association study identifies candidate genes for starch content regulation in maize kernels

    Directory of Open Access Journals (Sweden)

    Na Liu

    2016-07-01

    Full Text Available Kernel starch content is an important trait in maize (Zea mays L. as it accounts for 65% to 75% of the dry kernel weight and positively correlates with seed yield. A number of starch synthesis-related genes have been identified in maize in recent years. However, many loci underlying variation in starch content among maize inbred lines still remain to be identified. The current study is a genome-wide association study that used a set of 263 maize inbred lines. In this panel, the average kernel starch content was 66.99%, ranging from 60.60% to 71.58% over the three study years. These inbred lines were genotyped with the SNP50 BeadChip maize array, which is comprised of 56,110 evenly spaced, random SNPs. Population structure was controlled by a mixed linear model (MLM as implemented in the software package TASSEL. After the statistical analyses, four SNPs were identified as significantly associated with starch content (P ≤ 0.0001, among which one each are located on chromosomes 1 and 5 and two are on chromosome 2. Furthermore, 77 candidate genes associated with starch synthesis were found within the 100-kb intervals containing these four QTLs, and four highly associated genes were within 20-kb intervals of the associated SNPs. Among the four genes, Glucose-1-phosphate adenylyltransferase (APS1; Gene ID GRMZM2G163437 is known as an important regulator of kernel starch content. The identified SNPs, QTLs, and candidate genes may not only be readily used for germplasm improvement by marker-assisted selection in breeding, but can also elucidate the genetic basis of starch content. Further studies on these identified candidate genes may help determine the molecular mechanisms regulating kernel starch content in maize and other important cereal crops.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Prioritizing chronic obstructive pulmonary disease (COPD) candidate genes in COPD-related networks.

    Science.gov (United States)

    Zhang, Yihua; Li, Wan; Feng, Yuyan; Guo, Shanshan; Zhao, Xilei; Wang, Yahui; He, Yuehan; He, Weiming; Chen, Lina

    2017-11-28

    Chronic obstructive pulmonary disease (COPD) is a multi-factor disease, which could be caused by many factors, including disturbances of metabolism and protein-protein interactions (PPIs). In this paper, a weighted COPD-related metabolic network and a weighted COPD-related PPI network were constructed base on COPD disease genes and functional information. Candidate genes in these weighted COPD-related networks were prioritized by making use of a gene prioritization method, respectively. Literature review and functional enrichment analysis of the top 100 genes in these two networks suggested the correlation of COPD and these genes. The performance of our gene prioritization method was superior to that of ToppGene and ToppNet for genes from the COPD-related metabolic network or the COPD-related PPI network after assessing using leave-one-out cross-validation, literature validation and functional enrichment analysis. The top-ranked genes prioritized from COPD-related metabolic and PPI networks could promote the better understanding about the molecular mechanism of this disease from different perspectives. The top 100 genes in COPD-related metabolic network or COPD-related PPI network might be potential markers for the diagnosis and treatment of COPD.

  17. High-throughput testing of terpenoid biosynthesis candidate genes using transient expression in Nicotiana benthamiana.

    Science.gov (United States)

    Bach, Søren Spanner; Bassard, Jean-Étienne; Andersen-Ranberg, Johan; Møldrup, Morten Emil; Simonsen, Henrik Toft; Hamberger, Björn

    2014-01-01

    To respond to the rapidly growing number of genes putatively involved in terpenoid metabolism, a robust high-throughput platform for functional testing is needed. An in planta expression system offers several advantages such as the capacity to produce correctly folded and active enzymes localized to the native compartments, unlike microbial or prokaryotic expression systems. Two inherent drawbacks of plant-based expression systems, time-consuming generation of transgenic plant lines and challenging gene-stacking, can be circumvented by transient expression in Nicotiana benthamiana. In this chapter we describe an expression platform for rapid testing of candidate terpenoid biosynthetic genes based on Agrobacterium mediated gene expression in N. benthamiana leaves. Simultaneous expression of multiple genes is facilitated by co-infiltration of leaves with several engineered Agrobacterium strains, possibly making this the fastest and most convenient system for the assembly of plant terpenoid biosynthetic routes. Tools for cloning of expression plasmids, N. benthamiana culturing, Agrobacterium preparation, leaf infiltration, metabolite extraction, and automated GC-MS data mining are provided. With all steps optimized for high throughput, this in planta expression platform is particularly suited for testing large panels of candidate genes in all possible permutations.

  18. Identification of novel candidate disease genes from de novo exonic copy number variants.

    Science.gov (United States)

    Gambin, Tomasz; Yuan, Bo; Bi, Weimin; Liu, Pengfei; Rosenfeld, Jill A; Coban-Akdemir, Zeynep; Pursley, Amber N; Nagamani, Sandesh C S; Marom, Ronit; Golla, Sailaja; Dengle, Lauren; Petrie, Heather G; Matalon, Reuben; Emrick, Lisa; Proud, Monica B; Treadwell-Deering, Diane; Chao, Hsiao-Tuan; Koillinen, Hannele; Brown, Chester; Urraca, Nora; Mostafavi, Roya; Bernes, Saunder; Roeder, Elizabeth R; Nugent, Kimberly M; Bader, Patricia I; Bellus, Gary; Cummings, Michael; Northrup, Hope; Ashfaq, Myla; Westman, Rachel; Wildin, Robert; Beck, Anita E; Immken, LaDonna; Elton, Lindsay; Varghese, Shaun; Buchanan, Edward; Faivre, Laurence; Lefebvre, Mathilde; Schaaf, Christian P; Walkiewicz, Magdalena; Yang, Yaping; Kang, Sung-Hae L; Lalani, Seema R; Bacino, Carlos A; Beaudet, Arthur L; Breman, Amy M; Smith, Janice L; Cheung, Sau Wai; Lupski, James R; Patel, Ankita; Shaw, Chad A; Stankiewicz, Paweł

    2017-09-21

    Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery. We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association. In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation

  19. Rare variants in known and novel candidate genes predisposing to statin-associated myopathy.

    Science.gov (United States)

    Neřoldová, Magdaléna; Stránecký, Viktor; Hodaňová, Kateřina; Hartmannová, Hana; Piherová, Lenka; Přistoupilová, Anna; Mrázová, Lenka; Vrablík, Michal; Adámková, Věra; Hubáček, Jaroslav A; Jirsa, Milan; Kmoch, Stanislav

    2016-08-01

    Genetic variants affecting statin uptake, metabolism or predisposing to muscular diseases may confer susceptibility to statin-induced myopathy. Besides the SLCO1B1 rs4149056 genotype, common genetic variants do not seem to determine statin-associated myopathy. Here we aimed to address the potential role of rare variants. We performed whole exome sequencing in 88 individuals suffering from statin-associated myopathy and assessed the burden of rare variants using candidate-gene and exome-wide association analysis. In the novel candidate gene CLCN1, we identified a heterozygote truncating mutation p.R894* in four patients. In addition, we detected predictably pathogenic case-specific variants in MYOT, CYP3A5, SH3TC2, FBXO32 and RBM20. These findings support the role of rare variants and nominate loci for follow-up studies.

  20. Targeted resequencing of candidate genes reveals novel variants associated with severe Beh?et's uveitis

    OpenAIRE

    Kim, Sang Jin; Lee, Seungbok; Park, Changho; Seo, Jeong-Sun; Kim, Jong-Il; Yu, Hyeong Gon

    2013-01-01

    Beh?et's disease (BD) is a chronic systemic inflammatory disorder characterized by four major manifestations: recurrent uveitis, oral and genital ulcers and skin lesions. To identify some pathogenic variants associated with severe Beh?et's uveitis, we used targeted and massively parallel sequencing methods to explore the genetic diversity of target regions. A solution-based target enrichment kit was designed to capture whole-exonic regions of 132 candidate genes. Using a multiplexing strategy...

  1. Associations between SNPs in candidate immune-relevant genes and rubella antibody levels: a multigenic assessment

    Directory of Open Access Journals (Sweden)

    Ovsyannikova Inna G

    2010-10-01

    Full Text Available Abstract Background The mechanisms of immune response are structured within a highly complex regulatory system. Genetic associations with variation in the immune response to rubella vaccine have typically been assessed one locus at a time. We simultaneously assessed the associations between 726 SNPs tagging 84 candidate immune response genes and rubella-specific antibody levels. Blood samples were obtained from 714 school-aged children who had received two doses of MMR vaccine. Associations between rubella-specific antibody levels and 726 candidate tagSNPs were assessed both one SNP at a time and in a variety of multigenic analyses. Results Single-SNP assessments identified 4 SNPs that appeared to be univariately associated with rubella antibody levels: rs2844482 (p = 0.0002 and rs2857708 (p = 0.001 in the 5'UTR of the LTA gene, rs7801617 in the 5'UTR of the IL6 gene (p = 0.0005, and rs4787947 in the 5'UTR of the IL4R gene (p = 0.002. While there was not significant evidence in favor of epistatic genetic associations among the candidate SNPs, multigenic analyses identified 29 SNPs significantly associated with rubella antibody levels when selected as a group (p = 0.017. This collection of SNPs included not only those that were significant univariately, but others that would not have been identified if only considered in isolation from the other SNPs. Conclusions For the first time, multigenic assessment of associations between candidate SNPs and rubella antibody levels identified a broad number of genetic associations that would not have been deemed important univariately. It is important to consider approaches like those applied here in order to better understand the full genetic complexity of response to vaccination.

  2. RNA-Seq analysis reveals candidate genes for ontogenic resistance in Malus-Venturia pathosystem.

    Science.gov (United States)

    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

  3. RNA-Seq analysis reveals candidate genes for ontogenic resistance in Malus-Venturia pathosystem.

    Directory of Open Access Journals (Sweden)

    Michele Gusberti

    Full Text Available 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

  4. SNP discovery in candidate adaptive genes using exon capture in a free-ranging alpine ungulate

    Science.gov (United States)

    Roffler, Gretchen H.; Amish, Stephen J.; Smith, Seth; Cosart, Ted F.; Kardos, Marty; Schwartz, Michael K.; Luikart, Gordon

    2016-01-01

    Identification of genes underlying genomic signatures of natural selection is key to understanding adaptation to local conditions. We used targeted resequencing to identify SNP markers in 5321 candidate adaptive genes associated with known immunological, metabolic and growth functions in ovids and other ungulates. We selectively targeted 8161 exons in protein-coding and nearby 5′ and 3′ untranslated regions of chosen candidate genes. Targeted sequences were taken from bighorn sheep (Ovis canadensis) exon capture data and directly from the domestic sheep genome (Ovis aries v. 3; oviAri3). The bighorn sheep sequences used in the Dall's sheep (Ovis dalli dalli) exon capture aligned to 2350 genes on the oviAri3 genome with an average of 2 exons each. We developed a microfluidic qPCR-based SNP chip to genotype 476 Dall's sheep from locations across their range and test for patterns of selection. Using multiple corroborating approaches (lositan and bayescan), we detected 28 SNP loci potentially under selection. We additionally identified candidate loci significantly associated with latitude, longitude, precipitation and temperature, suggesting local environmental adaptation. The three methods demonstrated consistent support for natural selection on nine genes with immune and disease-regulating functions (e.g. Ovar-DRA, APC, BATF2, MAGEB18), cell regulation signalling pathways (e.g. KRIT1, PI3K, ORRC3), and respiratory health (CYSLTR1). Characterizing adaptive allele distributions from novel genetic techniques will facilitate investigation of the influence of environmental variation on local adaptation of a northern alpine ungulate throughout its range. This research demonstrated the utility of exon capture for gene-targeted SNP discovery and subsequent SNP chip genotyping using low-quality samples in a nonmodel species.

  5. Transcriptome and proteome data reveal candidate genes for pollinator attraction in sexually deceptive orchids.

    Science.gov (United States)

    Sedeek, Khalid E M; Qi, Weihong; Schauer, Monica A; Gupta, Alok K; Poveda, Lucy; Xu, Shuqing; Liu, Zhong-Jian; Grossniklaus, Ueli; Schiestl, Florian P; Schlüter, Philipp M

    2013-01-01

    Sexually deceptive orchids of the genus Ophrys mimic the mating signals of their pollinator females to attract males as pollinators. This mode of pollination is highly specific and leads to strong reproductive isolation between species. This study aims to identify candidate genes responsible for pollinator attraction and reproductive isolation between three closely related species, O. exaltata, O. sphegodes and O. garganica. Floral traits such as odour, colour and morphology are necessary for successful pollinator attraction. In particular, different odour hydrocarbon profiles have been linked to differences in specific pollinator attraction among these species. Therefore, the identification of genes involved in these traits is important for understanding the molecular basis of pollinator attraction by sexually deceptive orchids. We have created floral reference transcriptomes and proteomes for these three Ophrys species using a combination of next-generation sequencing (454 and Solexa), Sanger sequencing, and shotgun proteomics (tandem mass spectrometry). In total, 121 917 unique transcripts and 3531 proteins were identified. This represents the first orchid proteome and transcriptome from the orchid subfamily Orchidoideae. Proteome data revealed proteins corresponding to 2644 transcripts and 887 proteins not observed in the transcriptome. Candidate genes for hydrocarbon and anthocyanin biosynthesis were represented by 156 and 61 unique transcripts in 20 and 7 genes classes, respectively. Moreover, transcription factors putatively involved in the regulation of flower odour, colour and morphology were annotated, including Myb, MADS and TCP factors. Our comprehensive data set generated by combining transcriptome and proteome technologies allowed identification of candidate genes for pollinator attraction and reproductive isolation among sexually deceptive orchids. This includes genes for hydrocarbon and anthocyanin biosynthesis and regulation, and the development of

  6. Clinically relevant known and candidate genes for obesity and their overlap with human infertility and reproduction.

    Science.gov (United States)

    Butler, Merlin G; McGuire, Austen; Manzardo, Ann M

    2015-04-01

    Obesity is a growing public health concern now reaching epidemic status worldwide for children and adults due to multiple problems impacting on energy intake and expenditure with influences on human reproduction and infertility. A positive family history and genetic factors are known to play a role in obesity by influencing eating behavior, weight and level of physical activity and also contributing to human reproduction and infertility. Recent advances in genetic technology have led to discoveries of new susceptibility genes for obesity and causation of infertility. The goal of our study was to provide an update of clinically relevant candidate and known genes for obesity and infertility using high resolution chromosome ideograms with gene symbols and tabular form. We used computer-based internet websites including PubMed to search for combinations of key words such as obesity, body mass index, infertility, reproduction, azoospermia, endometriosis, diminished ovarian reserve, estrogen along with genetics, gene mutations or variants to identify evidence for development of a master list of recognized obesity genes in humans and those involved with infertility and reproduction. Gene symbols for known and candidate genes for obesity were plotted on high resolution chromosome ideograms at the 850 band level. Both infertility and obesity genes were listed separately in alphabetical order in tabular form and those highlighted when involved with both conditions. By searching the medical literature and computer generated websites for key words, we found documented evidence for 370 genes playing a role in obesity and 153 genes for human reproduction or infertility. The obesity genes primarily affected common pathways in lipid metabolism, deposition or transport, eating behavior and food selection, physical activity or energy expenditure. Twenty-one of the obesity genes were also associated with human infertility and reproduction. Gene symbols were plotted on high resolution

  7. Discovery of new candidate genes related to brain development using protein interaction information.

    Science.gov (United States)

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

    2015-01-01

    Human brain development is a dramatic process composed of a series of complex and fine-tuned spatiotemporal gene expressions. A good comprehension of this process can assist us in developing the potential of our brain. However, we have only limited knowledge about the genes and gene functions that are involved in this biological process. Therefore, a substantial demand remains to discover new brain development-related genes and identify their biological functions. In this study, we aimed to discover new brain-development related genes by building a computational method. We referred to a series of computational methods used to discover new disease-related genes and developed a similar method. In this method, the shortest path algorithm was executed on a weighted graph that was constructed using protein-protein interactions. New candidate genes fell on at least one of the shortest paths connecting two known genes that are related to brain development. A randomization test was then adopted to filter positive discoveries. Of the final identified genes, several have been reported to be associated with brain development, indicating the effectiveness of the method, whereas several of the others may have potential roles in brain development.

  8. Rrp1b, a new candidate susceptibility gene for breast cancer progression and metastasis.

    Directory of Open Access Journals (Sweden)

    Nigel P S Crawford

    2007-11-01

    Full Text Available A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b, was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis.

  9. A candidate gene association study of bone mineral density in an Iranian population.

    Directory of Open Access Journals (Sweden)

    Seyed Alireza Dastgheib

    2016-10-01

    Full Text Available The genetic epidemiology of variation in bone mineral density (BMD and osteoporosis is not well studied in Iranian populations and needs more research. We report a candidate gene association study of BMD variation in a healthy cross sectional study of 501 males and females sampled from the IMOS study Shiraz, Iran. We selected to study the association with 21 SNPs located in the 7 candidate genes LRP5, RANK, RANKL, OPG, P2RX7, VDR and ESR1. BMD was measured at the three sites L2-L4, neck of femur and total hip. Association between BMD and each SNP was assessed using multiple linear regression assuming an allele dose (additive effect on BMD (adjusted for age and sex. Statistically significant (at the unadjusted 5% level associations were seen with 7 SNPs in 5 of the candidate genes. Two SNPs showed statistically significant association with more than one BMD site. Significant association was seen between BMD at all three sites with the VDR SNP rs731246 (L2-L4 p=0.038; neck of femur p=0.001 and total hip p<0.001. The T allele was consistently associated with lower BMD than the C allele. Significant association was also seen for the P2RX7 SNP rs3751143 where the G allele was consistently associated with lower BMD than the T allele, (L2-L4 p=0.069; neck of femur p=0.024, total hip p=0.045.

  10. Candidate gene association studies in syndromic and non-syndromic cleft lip and palate

    Energy Technology Data Exchange (ETDEWEB)

    Daack-Hirsch, S.; Basart, A.; Frischmeyer, P. [Univ. of Iowa, IA (United States)] [and others

    1994-09-01

    Using ongoing case ascertainment through a birth defects registry, we have collected 219 nuclear families with non-syndromic cleft lip and/or palate and 111 families with a collection of syndromic forms. Syndromic cases include 24 with recognized forms and 72 with unrecognized syndromes. Candidate gene studies as well as genome-wide searches for evidence of microdeletions and isodisomy are currently being carried out. Candidate gene association studies, to date, have made use of PCR-based polymorphisms for TGFA, MSX1, CLPG13 (a CA repeat associated with a human homologue of a locus that results in craniofacial dysmorphogenesis in the mouse) and an STRP found in a Van der Woude syndrome microdeletion. Control tetranucleotide repeats, which insure that population-based differences are not responsible for any observed associations, are also tested. Studies of the syndromic cases have included the same list of candidate genes searching for evidence of microdeletions and a genome-wide search using tri- and tetranucleotide polymorphic markers to search for isodisomy or structural rearrangements. Significant associations have previously been identified for TGFA, and, in this report, identified for MSX1 and nonsyndromic cleft palate only (p = 0.04, uncorrected). Preliminary results of the genome-wide scan for isodisomy has returned no true positives and there has been no evidence for microdeletion cases.

  11. Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease.

    Science.gov (United States)

    Meddens, Claartje A; Harakalova, Magdalena; van den Dungen, Noortje A M; Foroughi Asl, Hassan; Hijma, Hemme J; Cuppen, Edwin P J G; Björkegren, Johan L M; Asselbergs, Folkert W; Nieuwenhuis, Edward E S; Mokry, Michal

    2016-11-30

    Genome-wide association studies (GWAS) have revealed many susceptibility loci for complex genetic diseases. For most loci, the causal genes have not been identified. Currently, the identification of candidate genes is predominantly based on genes that localize close to or within identified loci. We have recently shown that 92 of the 163 inflammatory bowel disease (IBD)-loci co-localize with non-coding DNA regulatory elements (DREs). Mutations in DREs can contribute to IBD pathogenesis through dysregulation of gene expression. Consequently, genes that are regulated by these 92 DREs are to be considered as candidate genes. This study uses circular chromosome conformation capture-sequencing (4C-seq) to systematically analyze chromatin-interactions at IBD susceptibility loci that localize to regulatory DNA. Using 4C-seq, we identify genomic regions that physically interact with the 92 DRE that were found at IBD susceptibility loci. Since the activity of regulatory elements is cell-type specific, 4C-seq was performed in monocytes, lymphocytes, and intestinal epithelial cells. Altogether, we identified 902 novel IBD candidate genes. These include genes specific for IBD-subtypes and many noteworthy genes including ATG9A and IL10RA. We show that expression of many novel candidate genes is genotype-dependent and that these genes are upregulated during intestinal inflammation in IBD. Furthermore, we identify HNF4α as a potential key upstream regulator of IBD candidate genes. We reveal many novel and relevant IBD candidate genes, pathways, and regulators. Our approach complements classical candidate gene identification, links novel genes to IBD and can be applied to any existing GWAS data.

  12. Addictions biology: haplotype-based analysis for 130 candidate genes on a single array.

    Science.gov (United States)

    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

    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. 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. 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. 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.

  13. Exome sequencing of a large family identifies potential candidate genes contributing risk to bipolar disorder.

    Science.gov (United States)

    Zhang, Tianxiao; Hou, Liping; Chen, David T; McMahon, Francis J; Wang, Jen-Chyong; Rice, John P

    2018-03-01

    Bipolar disorder is a mental illness with lifetime prevalence of about 1%. Previous genetic studies have identified multiple chromosomal linkage regions and candidate genes that might be associated with bipolar disorder. The present study aimed to identify potential susceptibility variants for bipolar disorder using 6 related case samples from a four-generation family. A combination of exome sequencing and linkage analysis was performed to identify potential susceptibility variants for bipolar disorder. Our study identified a list of five potential candidate genes for bipolar disorder. Among these five genes, GRID1(Glutamate Receptor Delta-1 Subunit), which was previously reported to be associated with several psychiatric disorders and brain related traits, is particularly interesting. Variants with functional significance in this gene were identified from two cousins in our bipolar disorder pedigree. Our findings suggest a potential role for these genes and the related rare variants in the onset and development of bipolar disorder in this one family. Additional research is needed to replicate these findings and evaluate their patho-biological significance. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Cadherin-13 gene is associated with hyperactive/impulsive symptoms in attention/deficit hyperactivity disorder.

    Science.gov (United States)

    Salatino-Oliveira, Angélica; Genro, Julia Pasqualini; Polanczyk, Guilherme; Zeni, Cristian; Schmitz, Marcelo; Kieling, Christian; Anselmi, Luciana; Menezes, Ana Maria Baptista; Barros, Fernando Cde; Polina, Evelise Regina; Mota, Nina R; Grevet, Eugênio Horácio; Bau, Claiton Henrique Dotto; Rohde, Luis Augusto; Hutz, Mara Helena

    2015-04-01

    Several efforts have been made to find new genetic risk variants which explain the high heritability of ADHD. At the genome level, genes involved in neurodevelopmental pathways were pointed as candidates. CDH13 and CTNNA2 genes are within GWAS top hits in ADHD and there are emerging notions about their contribution to ADHD pathophysiology. The main goal of this study is to test the association between SNPs in CDH13 and CTNNA2 genes and ADHD across the life cycle in subjects with ADHD. This study included 1,136 unrelated ADHD cases and 946 individuals without ADHD. No significant association between CDH13 and CTNNA2 was observed between cases and controls across different samples (P ≥ 0.096 for all comparisons). No allele was significantly more transmitted than expected from parents to ADHD probands. The CDH13 rs11150556 CC genotype was associated with more hyperactive/impulsive symptoms in youths with ADHD (children/adolescents clinical sample: F = 7.666, P = 0.006, FDR P-value = 0.032; Pelotas Birth Cohort sample: F = 6.711, P = 0.011, FDR P-value = 0.032). Although there are many open questions regarding the role of neurodevelopmental genes in ADHD symptoms, the present study suggests that CDH13 is associated with hyperactive/impulsive symptoms in youths with ADHD. © 2015 Wiley Periodicals, Inc.

  15. Analysis of breast cancer metastasis candidate genes from next generation-sequencing via systematic functional genomics

    DEFF Research Database (Denmark)

    Blomstrøm, Monica Marie

    2016-01-01

    ) and non-CSCs. The main goal of this project was to functionally characterize a set of candidate genes recovered from next-generation sequencing analysis for their role in breast cancer metastasis formation. The starting gene set comprised 104 gene variants; i.e. 57 wildtype and 47 mutated variants. During...... the project, the aim was to generate a panel of genetically identical (“isogenic”) MCF7 breast cancer cell lines with inducible overexpression of the gene variants, and to analyze these for effects on breast cancer growth and invasion in vitro under standardized conditions. Moreover, it was aimed at acquiring......Metastatic breast cancer remains an incurable disease accounting for the vast majority of deaths from breast cancer. Understanding the molecular mechanisms for metastatic spread is important to improve diagnosis and for generating starting points for novel treatment strategies. Inhibition...

  16. Quantitative transcription dynamic analysis reveals candidate genes and key regulators for ethanol tolerance in Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    Ma Menggen

    2010-06-01

    Full Text Available Abstract Background Derived from our lignocellulosic conversion inhibitor-tolerant yeast, we generated an ethanol-tolerant strain Saccharomyces cerevisiae NRRL Y-50316 by enforced evolutionary adaptation. Using a newly developed robust mRNA reference and a master equation unifying gene expression data analyses, we investigated comparative quantitative transcription dynamics of 175 genes selected from previous studies for an ethanol-tolerant yeast and its closely related parental strain. Results A highly fitted master equation was established and applied for quantitative gene expression analyses using pathway-based qRT-PCR array assays. The ethanol-tolerant Y-50316 displayed significantly enriched background of mRNA abundance for at least 35 genes without ethanol challenge compared with its parental strain Y-50049. Under the ethanol challenge, the tolerant Y-50316 responded in consistent expressions over time for numerous genes belonging to groups of heat shock proteins, trehalose metabolism, glycolysis, pentose phosphate pathway, fatty acid metabolism, amino acid biosynthesis, pleiotropic drug resistance gene family and transcription factors. The parental strain showed repressed expressions for many genes and was unable to withstand the ethanol stress and establish a viable culture and fermentation. The distinct expression dynamics between the two strains and their close association with cell growth, viability and ethanol fermentation profiles distinguished the tolerance-response from the stress-response in yeast under the ethanol challenge. At least 82 genes were identified as candidate and key genes for ethanol-tolerance and subsequent fermentation under the stress. Among which, 36 genes were newly recognized by the present study. Most of the ethanol-tolerance candidate genes were found to share protein binding motifs of transcription factors Msn4p/Msn2p, Yap1p, Hsf1p and Pdr1p/Pdr3p. Conclusion Enriched background of transcription abundance

  17. From QTL to candidate gene: Genetical genomics of simple and complex traits in potato using a pooling strategy

    Directory of Open Access Journals (Sweden)

    de Vos Ric

    2010-03-01

    Full Text Available Abstract Background Utilization of the natural genetic variation in traditional breeding programs remains a major challenge in crop plants. The identification of candidate genes underlying, or associated with, phenotypic trait QTLs is desired for effective marker assisted breeding. With the advent of high throughput -omics technologies, screening of entire populations for association of gene expression with targeted traits is becoming feasible but remains costly. Here we present the identification of novel candidate genes for different potato tuber quality traits by employing a pooling approach reducing the number of hybridizations needed. Extreme genotypes for a quantitative trait are collected and the RNA from contrasting bulks is then profiled with the aim of finding differentially expressed genes. Results We have successfully implemented the pooling strategy for potato quality traits and identified candidate genes associated with potato tuber flesh color and tuber cooking type. Elevated expression level of a dominant allele of the β-carotene hydroxylase (bch gene was associated with yellow flesh color through mapping of the gene under a major QTL for flesh color on chromosome 3. For a second trait, a candidate gene with homology to a tyrosine-lysine rich protein (TLRP was identified based on allele specificity of the probe on the microarray. TLRP was mapped on chromosome 9 in close proximity to a QTL for potato cooking type strengthening its significance as a candidate gene. Furthermore, we have performed a profiling experiment targeting a polygenic trait, by pooling individual genotypes based both on phenotypic and marker data, allowing the identification of candidate genes associated with the two different linkage groups. Conclusions A pooling approach for RNA-profiling with the aim of identifying novel candidate genes associated with tuber quality traits was successfully implemented. The identified candidate genes for tuber flesh color

  18. Whole exome sequencing identification of novel candidate genes in patients with proliferative diabetic retinopathy.

    Science.gov (United States)

    Ung, Cindy; Sanchez, Angie V; Shen, Lishuang; Davoudi, Samaneh; Ahmadi, Tina; Navarro-Gomez, Daniel; Chen, Ching J; Hancock, Heather; Penman, Alan; Hoadley, Suzanne; Consugar, Mark; Restrepo, Carlos; Shah, Vinay A; Arboleda-Velasquez, Joseph F; Sobrin, Lucia; Gai, Xiaowu; Kim, Leo A

    2017-05-09

    Rare or novel gene variants in patients with proliferative diabetic retinopathy may contribute to disease development. We performed whole exome sequencing (WES) on patients at the phenotypic extremes of diabetic retinal complications: 57 patients diagnosed with proliferative diabetic retinopathy (PDR) as cases and 13 patients with no diabetic retinopathy despite at least 10years of type 2 diabetes as controls. Thirty-one out of the 57 cases and all 13 controls were from the African American Proliferative Diabetic Retinopathy Study (AA). The rest of the cases were of mixed ethnicities (ME). WES identified 721 candidate genes with rare or novel non-synonymous variants found in at least one case with PDR and not present in any controls. After filtering for genes with null alleles in greater than two cases, 28 candidate genes were identified in our ME cases and 16 genes were identified in our AA cases. Our analysis showed rare and novel variants within these genes that could contribute to the development of PDR, including rare non-synonymous variants in FAM132A, SLC5A9, ZNF600, and TMEM217. We also found previously unidentified variants in VEGFB and APOB. We found that VEGFB, VPS13B, PHF21A, NAT1, ZNF600, PKHD1L1 expression was reduced in human retinal endothelial cells (HRECs) cultured under high glucose conditions. In an exome sequence analysis of patients with PDR, we identified variants in genes that could contribute to pathogenesis. Six of these genes were further validated and found to have reduced expression in HRECs under high glucose conditions, suggestive of an important role in the development of PDR. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Gene-level integrated metric of negative selection (GIMS prioritizes candidate genes for nephrotic syndrome.

    Directory of Open Access Journals (Sweden)

    Matthew G Sampson

    Full Text Available Nephrotic syndrome (NS gene discovery efforts are now occurring in small kindreds and cohorts of sporadic cases. Power to identify causal variants in these groups beyond a statistical significance threshold is challenging due to small sample size and/or lack of family information. There is a need to develop novel methods to identify NS-associated variants. One way to determine putative functional relevance of a gene is to measure its strength of negative selection, as variants in genes under strong negative selection are more likely to be deleterious. We created a gene-level, integrated metric of negative selection (GIMS score for 20,079 genes by combining multiple comparative genomics and population genetics measures. To understand the utility of GIMS for NS gene discovery, we examined this score in a diverse set of NS-relevant gene sets. These included genes known to cause monogenic forms of NS in humans as well as genes expressed in the cells of the glomerulus and, particularly, the podocyte. We found strong negative selection in the following NS-relevant gene sets: (1 autosomal-dominant Mendelian focal segmental glomerulosclerosis (FSGS genes (p = 0.03 compared to reference, (2 glomerular expressed genes (p = 4×10(-23, and (3 predicted podocyte genes (p = 3×10(-9. Eight genes causing autosomal dominant forms of FSGS had a stronger combined score of negative selection and podocyte enrichment as compared to all other genes (p = 1 x 10(-3. As a whole, recessive FSGS genes were not enriched for negative selection. Thus, we also created a transcript-level, integrated metric of negative selection (TIMS to quantify negative selection on an isoform level. These revealed transcripts of known autosomal recessive disease-causing genes that were nonetheless under strong selection. We suggest that a filtering strategy that includes measuring negative selection on a gene or isoform level could aid in identifying NS-related genes. Our GIMS and TIMS

  20. Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.

    Science.gov (United States)

    Reuter, Miriam S; Tawamie, Hasan; Buchert, Rebecca; Hosny Gebril, Ola; Froukh, Tawfiq; Thiel, Christian; Uebe, Steffen; Ekici, Arif B; Krumbiegel, Mandy; Zweier, Christiane; Hoyer, Juliane; Eberlein, Karolin; Bauer, Judith; Scheller, Ute; Strom, Tim M; Hoffjan, Sabine; Abdelraouf, Ehab R; Meguid, Nagwa A; Abboud, Ahmad; Al Khateeb, Mohammed Ayman; Fakher, Mahmoud; Hamdan, Saber; Ismael, Amina; Muhammad, Safia; Abdallah, Ebtessam; Sticht, Heinrich; Wieczorek, Dagmar; Reis, André; Abou Jamra, Rami

    2017-03-01

    Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown. To promote the identification of disease genes through confirmation of previously described genes and presentation of novel candidates and provide an overview of the diagnostic yield of exome sequencing in consanguineous families. Autozygosity mapping in families and exome sequencing of index patients were performed in 152 consanguineous families (the parents descended from a same ancestor) with at least 1 offspring with intellectual disability (ID). The study was conducted from July 1, 2008, to June 30, 2015, and data analysis was conducted from July 1, 2015, to August 31, 2016. Of the 152 consanguineous families enrolled, 1 child (in 45 families [29.6%]) or multiple children (107 families [70.4%]) had ID; additional features were present in 140 of the families (92.1%). The mean (SD) age of the children was 10.3 (9.0) years, and 171 of 297 (57.6%) were male. In 109 families (71.7%), potentially protein-disrupting and clinically relevant variants were identified. Of these, a clear clinical genetic diagnosis was made in 56 families (36.8%) owing to 57 (likely) pathogenic variants in 50 genes already established in neurodevelopmental disorders (46 autosomal recessive, 2 X-linked, and 2 de novo) or in 7 previously proposed recessive candidates. In 5 of these families, potentially treatable disorders were diagnosed (mutations in PAH, CBS, MTHFR, CYP27A1, and HIBCH), and in 1 family, 2 disease-causing homozygous variants in different genes were identified. In another 48 families (31.6%), 52 convincing recessive variants in candidate genes that were not previously reported in regard to neurodevelopmental disorders were identified. Of these, 14 were homozygous and truncating in GRM7, STX1A, CCAR2, EEF1D, GALNT2, SLC44A1, LRRIQ3, AMZ2, CLMN, SEC23IP, INIP, NARG2, FAM234B, and TRAP1. The diagnostic yield was higher in

  1. Medical Sequencing of Candidate Genes for Nonsyndromic Cleft Lip and Palate.

    Directory of Open Access Journals (Sweden)

    2005-12-01

    Full Text Available Nonsyndromic or isolated cleft lip with or without cleft palate (CL/P occurs in wide geographic distribution with an average birth prevalence of 1/700. We used direct sequencing as an approach to study candidate genes for CL/P. We report here the results of sequencing on 20 candidate genes for clefts in 184 cases with CL/P selected with an emphasis on severity and positive family history. Genes were selected based on expression patterns, animal models, and/or role in known human clefting syndromes. For seven genes with identified coding mutations that are potentially etiologic, we performed linkage disequilibrium studies as well in 501 family triads (affected child/mother/father. The recently reported MSX1 P147Q mutation was also studied in an additional 1,098 cleft cases. Selected missense mutations were screened in 1,064 controls from unrelated individuals on the Centre d'Etude du Polymorphisme Humain (CEPH diversity cell line panel. Our aggregate data suggest that point mutations in these candidate genes are likely to contribute to 6% of isolated clefts, particularly those with more severe phenotypes (bilateral cleft of the lip with cleft palate. Additional cases, possibly due to microdeletions or isodisomy, were also detected and may contribute to clefts as well. Sequence analysis alone suggests that point mutations in FOXE1, GLI2, JAG2, LHX8, MSX1, MSX2, SATB2, SKI, SPRY2, and TBX10 may be rare causes of isolated cleft lip with or without cleft palate, and the linkage disequilibrium data support a larger, as yet unspecified, role for variants in or near MSX2, JAG2, and SKI. This study also illustrates the need to test large numbers of controls to distinguish rare polymorphic variants and prioritize functional studies for rare point mutations.

  2. Cholesterol synthesis in the lactating cow: Induced expression of candidate genes.

    Science.gov (United States)

    Viturro, Enrique; Koenning, Matthias; Kroemer, Angelika; Schlamberger, Gregor; Wiedemann, Steffi; Kaske, Martin; Meyer, Heinrich H D

    2009-05-01

    Despite the extensive knowledge for other species, cholesterol metabolism in ruminants is nowadays still not clear. Huge differences in milk cholesterol concentration are observed between breeds, managing strategies, individuals and moment of the lactating cycle, but the genetic actors working in the process of cholesterol secretion into milk have not been identified. As ruminant diet contains no cholesterol, understanding the mechanisms and regulation of synthesis, transport and secretion into milk is crucial when trying to reduce the amount of this metabolite in dairy products. The present work aims to study the expression of candidate genes for these processes in the liver of Bos taurus during the lactating cycle. Liver biopsies were obtained from 16 adult brown Swiss cows at different time points (2 weeks pre-partum and 0, 2, 4 and 8 weeks post-partum). After RNA extraction and reverse transcription, gene expression of candidate genes was studied using quantitative RT-PCR. Key enzymes of the cholesterol synthesis (3-hydroxy-methyglutaryl-coenzyme-A (HMG-CoA) synthase, HMG-CoA reductase and farnesyldiphosphat-farnesyltransferase (FDFT)) and gene expression feed-back regulators involved in lipid metabolism (sterol regulatory element binding proteins (SREBP1and 2) SREBP-cleavage activating protein (Scap) were selected as candidate genes. HMG-CoA-reductase and FDFT showed a huge expression increase until week 2 post-partum (pmilk and blood cholesterol levels in B. taurus after parturition might be the result of a coordinated induction in the expression of key liver enzymes and their regulating factors.

  3. Influence of SNPs in nutrient-sensitive candidate genes and gene-diet interactions on blood lipids

    DEFF Research Database (Denmark)

    Brahe, Lena Kirchner; Angquist, Lars; Larsen, Lesli Hingstrup

    2013-01-01

    Blood lipid response to a given dietary intervention could be determined by the effect of diet, gene variants or gene-diet interactions. The objective of the present study was to investigate whether variants in presumed nutrient-sensitive genes involved in lipid metabolism modified lipid profile...... (LPIN1) rs4315495, with a decrease in TAG of - 0·26 mmol/l per A-allele/protein unit (95 % CI - 0·38, - 0·14, P= 0·000043). In conclusion, we investigated SNP-diet interactions for blood lipid profiles for 240 SNPs in twenty-four candidate genes, selected for their involvement in lipid metabolism...

  4. Digital gene expression tag profiling of bat digits provides robust candidates contributing to wing formation

    Directory of Open Access Journals (Sweden)

    Young Rebecca L

    2010-11-01

    Full Text Available Abstract Background As the only truly flying mammals, bats use their unique wing - consisting of four elongated digits (digits II-V connected by membranes - to power their flight. In addition to the elongated digits II-V, the forelimb contains one shorter digit (digit I that is morphologically similar to the hindlimb digits. Here, we capitalized on the morphological variation among the bat forelimb digits to investigate the molecular mechanisms underlying digit elongation and wing formation. Using next generation sequencing technology, we performed digital gene expression tag profiling (DGE-tag profiling of developing digits in a pooled sample of two Myotis ricketti and validated our sequencing results using real-time quantitative PCR (RT-qPCR of gene expression in the developing digits of two Hipposideros armiger. Results Among hundreds of genes exhibiting significant differences in expression between the short and long digits, we highlight 14 genes most related to digit elongation. These genes include two Tbx genes (Tbx3 and Tbx15, five BMP pathway genes (Bmp3, RGMB, Smad1, Smad4 and Nog, four Homeobox genes (Hoxd8, Hoxd9, Hoxa1 and Satb1, and three other genes (Twist1, Tmeff2 and Enpp2 related to digit malformations or cell proliferation. In addition, our results suggest that Tbx4 and Pitx2 contribute to the morphological similarity and five genes (Acta1, Tnnc2, Atp2a1, Hrc and Myoz1 contribute to the functional similarity between the thumb and hindlimb digits. Conclusions Results of this study not only implicate many developmental genes as robust candidates underlying digit elongation and wing formation in bats, but also provide a better understanding of the genes involved in autopodial development in general.

  5. Identification of Candidate Genes Associated with Beef Marbling Using QTL and Pathway Analysis in Hanwoo (Korean Cattle

    Directory of Open Access Journals (Sweden)

    Hyesun Park

    2012-05-01

    Full Text Available Marbling from intramuscular fat is an important trait of meat quality and has an economic benefit for the beef industry. Quantitative trait loci (QTL fine mapping was performed to identify the marbling trait in 266 Hanwoo steers using a 10K single nucleotide polymorphism panel with the combined linkage and linkage disequilibrium method. As a result, we found nine putative QTL regions for marbling: three on BTA6, two on BTA17, two on BTA22, and two on BTA29. We detected candidate genes for marbling within 1 cM of either side of the putative QTL regions. Additionally, to understand the functions of these candidate genes at the molecular level, we conducted a functional categorization using gene ontology and pathway analyses for those genes involved in lipid metabolism or fat deposition. In these putative QTL regions, we found 95 candidate genes for marbling. Using these candidate genes, we found five genes that had a direct interaction with the candidate genes. We also found SCARB1 as a putative candidate gene for marbling that involves fat deposition related to cholesterol transport.

  6. Meta-Analysis Approach identifies Candidate Genes and associated Molecular Networks for Type-2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Herwig Ralf

    2008-06-01

    Full Text Available Abstract Background Multiple functional genomics data for complex human diseases have been published and made available by researchers worldwide. The main goal of these studies is the detailed analysis of a particular aspect of the disease. Complementary, meta-analysis approaches try to extract supersets of disease genes and interaction networks by integrating and combining these individual studies using statistical approaches. Results Here we report on a meta-analysis approach that integrates data of heterogeneous origin in the domain of type-2 diabetes mellitus (T2DM. Different data sources such as DNA microarrays and, complementing, qualitative data covering several human and mouse tissues are integrated and analyzed with a Bootstrap scoring approach in order to extract disease relevance of the genes. The purpose of the meta-analysis is two-fold: on the one hand it identifies a group of genes with overall disease relevance indicating common, tissue-independent processes related to the disease; on the other hand it identifies genes showing specific alterations with respect to a single study. Using a random sampling approach we computed a core set of 213 T2DM genes across multiple tissues in human and mouse, including well-known genes such as Pdk4, Adipoq, Scd, Pik3r1, Socs2 that monitor important hallmarks of T2DM, for example the strong relationship between obesity and insulin resistance, as well as a large fraction (128 of yet barely characterized novel candidate genes. Furthermore, we explored functional information and identified cellular networks associated with this core set of genes such as pathway information, protein-protein interactions and gene regulatory networks. Additionally, we set up a web interface in order to allow users to screen T2DM relevance for any – yet non-associated – gene. Conclusion In our paper we have identified a core set of 213 T2DM candidate genes by a meta-analysis of existing data sources. We have

  7. The systematic functional characterisation of Xq28 genes prioritises candidate disease genes

    Directory of Open Access Journals (Sweden)

    Wiemann Stefan

    2006-02-01

    Full Text Available Abstract Background Well known for its gene density and the large number of mapped diseases, the human sub-chromosomal region Xq28 has long been a focus of genome research. Over 40 of approximately 300 X-linked diseases map to this region, and systematic mapping, transcript identification, and mutation analysis has led to the identification of causative genes for 26 of these diseases, leaving another 17 diseases mapped to Xq28, where the causative gene is still unknown. To expedite disease gene identification, we have initiated the functional characterisation of all known Xq28 genes. Results By using a systematic approach, we describe the Xq28 genes by RNA in situ hybridisation and Northern blotting of the mouse orthologs, as well as subcellular localisation and data mining of the human genes. We have developed a relational web-accessible database with comprehensive query options integrating all experimental data. Using this database, we matched gene expression patterns with affected tissues for 16 of the 17 remaining Xq28 linked diseases, where the causative gene is unknown. Conclusion By using this systematic approach, we have prioritised genes in linkage regions of Xq28-mapped diseases to an amenable number for mutational screens. Our database can be queried by any researcher performing highly specified searches including diseases not listed in OMIM or diseases that might be linked to Xq28 in the future.

  8. Selection in the dopamine receptor 2 gene: a candidate SNP study

    Directory of Open Access Journals (Sweden)

    Tobias Göllner

    2015-08-01

    Full Text Available Dopamine is a major neurotransmitter in the human brain and is associated with various diseases. Schizophrenia, for example, is treated by blocking the dopamine receptors type 2. Shaner, Miller & Mintz (2004 stated that schizophrenia was the low fitness variant of a highly variable mental trait. We therefore explore whether the dopamine receptor 2 gene (DRD2 underwent any selection processes. We acquired genotype data of the 1,000 Genomes project (phase I, which contains 1,093 individuals from 14 populations. We included single nucleotide polymorphisms (SNPs with two minor allele frequencies (MAFs in the analysis: MAF over 0.05 and over 0.01. This is equivalent to 151 SNPs (MAF > 0.05 and 246 SNPs (MAF > 0.01 for DRD2. We used two different approaches (an outlier approach and a Bayesian approach to detect loci under selection. The combined results of both approaches yielded nine (MAF > 0.05 and two candidate SNPs (MAF > 0.01, under balancing selection. We also found weak signs for directional selection on DRD2, but in our opinion these were too weak to draw any final conclusions on directional selection in DRD2. All candidates for balancing selection are in the intronic region of the gene and only one (rs12574471 has been mentioned in the literature. Two of our candidate SNPs are located in specific regions of the gene: rs80215768 lies within a promoter flanking region and rs74751335 lies within a transcription factor binding site. We strongly encourage research on our candidate SNPs and their possible effects.

  9. Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors.

    Science.gov (United States)

    Usset, Joseph L; Raghavan, Rama; Tyrer, Jonathan P; McGuire, Valerie; Sieh, Weiva; Webb, Penelope; Chang-Claude, Jenny; Rudolph, Anja; Anton-Culver, Hoda; Berchuck, Andrew; Brinton, Louise; Cunningham, Julie M; DeFazio, Anna; Doherty, Jennifer A; Edwards, Robert P; Gayther, Simon A; Gentry-Maharaj, Aleksandra; Goodman, Marc T; Høgdall, Estrid; Jensen, Allan; Johnatty, Sharon E; Kiemeney, Lambertus A; Kjaer, Susanne K; Larson, Melissa C; Lurie, Galina; Massuger, Leon; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Ness, Roberta B; Pike, Malcolm C; Ramus, Susan J; Rossing, Mary Anne; Rothstein, Joseph; Song, Honglin; Thompson, Pamela J; van den Berg, David J; Vierkant, Robert A; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S; Wilkens, Lynne R; Wu, Anna H; Yang, Hannah; Pearce, Celeste Leigh; Schildkraut, Joellen M; Pharoah, Paul; Goode, Ellen L; Fridley, Brooke L

    2016-05-01

    Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese and non-obese women. We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case-control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed. SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10(-6)) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10(-5)). The most notable obesity-gene-hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10(-6)). We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2 Future work is needed to develop powerful statistical methods able to detect these complex interactions. Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780-90. ©2016 AACR. ©2016 American Association for Cancer Research.

  10. The point mutation and polymorphism in keratoconus candidate gene TGFBI in Chinese population.

    Science.gov (United States)

    Guan, Tao; Liu, Chibo; Ma, Zhangwei; Ding, Shiping

    2012-07-15

    To understand the region point mutations and single nucleotide polymorphisms characteristic of keratoconus candidate gene in Chinese population, the TGFBI. Polymerase chain reaction-single strand conformation polymorphism and DNA direct sequencing were performed on blood samples from 30 cases of keratoconus patients and 30 normal controls. 17 exons from the coding region of TGFBI gene were examined for point mutations and single nucleotide polymorphisms. Two types of base mutation were found in exon 12, which were both heterozygous. In 1 patient the site 535 showed GGA→TGA substitution, which was the change from glycine to stop codon (G535X). This was not found in all control cases. In 2 patients and 1 control case the site 540 showed TTT→TTC substitutions without changing of the coding for phenylalanine (F540F), suggesting for the polymorphism. The candidate keratoconus gene TGFB1 showed genetic variation and mutation in keratoconus population. The gene might play a role in the development of keratoconus in Chinese population. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. Cold sweetening in diploid potato: mapping quantitative trait loci and candidate genes.

    Science.gov (United States)

    Menéndez, Cristina M; Ritter, Enrique; Schäfer-Pregl, Ralf; Walkemeier, Birgit; Kalde, Alexandra; Salamini, Francesco; Gebhardt, Christiane

    2002-01-01

    A candidate gene approach has been used as a first step to identify the molecular basis of quantitative trait variation in potato. Sugar content of tubers upon cold storage was the model trait chosen because the metabolic pathways involved in starch and sugar metabolism are well known and many of the genes have been cloned. Tubers of two F(1) populations of diploid potato grown in six environments were evaluated for sugar content after cold storage. The populations were genotyped with RFLP, AFLP, and candidate gene markers. QTL analysis revealed that QTL for glucose, fructose, and sucrose content were located on all potato chromosomes. Most QTL for glucose content mapped to the same positions as QTL for fructose content. QTL explaining >10% of the variability for reducing sugars were located on linkage groups I, III, VII, VIII, IX, and XI. QTL consistent across populations and/or environments were identified. QTL were linked to genes encoding invertase, sucrose synthase 3, sucrose phosphate synthase, ADP-glucose pyrophosphorylase, sucrose transporter 1, and a putative sucrose sensor. The results suggest that allelic variants of enzymes operating in carbohydrate metabolic pathways contribute to the genetic variation in cold sweetening. PMID:12454085

  12. Targeted resequencing of candidate genes reveals novel variants associated with severe Behçet's uveitis.

    Science.gov (United States)

    Kim, Sang Jin; Lee, Seungbok; Park, Changho; Seo, Jeong-Sun; Kim, Jong-Il; Yu, Hyeong Gon

    2013-10-18

    Behçet's disease (BD) is a chronic systemic inflammatory disorder characterized by four major manifestations: recurrent uveitis, oral and genital ulcers and skin lesions. To identify some pathogenic variants associated with severe Behçet's uveitis, we used targeted and massively parallel sequencing methods to explore the genetic diversity of target regions. A solution-based target enrichment kit was designed to capture whole-exonic regions of 132 candidate genes. Using a multiplexing strategy, 32 samples from patients with a severe type of Behçet's uveitis were sequenced with a Genome Analyzer IIx. We compared the frequency of each variant with that of 59 normal Korean controls, and selected five rare and eight common single-nucleotide variants as the candidates for a replication study. The selected variants were genotyped in 61 cases and 320 controls and, as a result, two rare and seven common variants showed significant associations with severe Behçet's uveitis (PMTFHR and MICA also replicated the previous reports at the gene level. The KIR3DL3 and KIR2DL4 genes are novel susceptibility genes that have not been reported in association with BD. In conclusion, this study showed that target enrichment and next-generation sequencing technologies can provide valuable information on the genetic predisposition for Behçet's uveitis.

  13. Identification of quantitative trait loci and candidate genes for cadmium tolerance in Populus

    Energy Technology Data Exchange (ETDEWEB)

    Induri, Brahma R [West Virginia University; Ellis, Danielle R [West Virginia University; Slavov, Goncho T. [West Virginia University; Yin, Tongming [ORNL; Zhang, Xinye [ORNL; Tuskan, Gerald A [ORNL; DiFazio, Steven P [West Virginia University

    2012-01-01

    Understanding genetic variation for the response of Populus to heavy metals like cadmium (Cd) is an important step in elucidating the underlying mechanisms of tolerance. In this study, a pseudo-backcross pedigree of Populus trichocarpa Torr. & Gray and Populus deltoides Bart. was characterized for growth and performance traits after Cd exposure. A total of 16 quantitative trait loci (QTL) at logarithm of odds (LOD) ratio 2.5 were detected for total dry weight, its components and root volume. Major QTL for Cd responses were mapped to two different linkage groups and the relative allelic effects were in opposing directions on the two chromosomes, suggesting differential mechanisms at these two loci. The phenotypic variance explained by Cd QTL ranged from 5.9 to 11.6% and averaged 8.2% across all QTL. A whole-genome microarray study led to the identification of nine Cd-responsive genes from these QTL. Promising candidates for Cd tolerance include an NHL repeat membrane-spanning protein, a metal transporter and a putative transcription factor. Additional candidates in the QTL intervals include a putative homolog of a glutamate cysteine ligase, and a glutathione-S-transferase. Functional characterization of these candidate genes should enhance our understanding of Cd metabolism and transport and phytoremediation capabilities of Populus.

  14. Transcriptomic Comparison Reveals Candidate Genes for Triterpenoid Biosynthesis in Two Closely RelatedIlexSpecies.

    Science.gov (United States)

    Wen, Lingling; Yun, Xiaoyun; Zheng, Xiasheng; Xu, Hui; Zhan, Ruoting; Chen, Weiwen; Xu, Yaping; Chen, Ye; Zhang, Jie

    2017-01-01

    Native to Southern China, Ilex pubescens and Ilex asprella are frequently used in traditional Chinese medicine. Both of them produce a large variety of ursane-type triterpenoid saponins, which have been demonstrated to have different pharmacological effects. However, little is known about their biosynthesis. In this study, transcriptomic analysis of I. pubescens and comparison with its closely related specie I. asprella were carried out to identify potential genes involved in triterpenoid saponin biosynthesis. Through RNA sequencing (RNA-seq) and de novo transcriptome assembly of I. pubescens , a total of 68,688 UniGene clusters are obtained, of which 32,184 (46.86%) are successfully annotated by comparison with the sequences in major public databases (NCBI, Swiss-Prot, and KEGG). It includes 128 UniGenes related to triterpenoid backbone biosynthesis, 11 OSCs (oxidosqualene cyclases), 233 CYPs (cytochrome P450), and 269 UGTs (UDP-glycosyltransferases). By homology-based blast and phylogenetic analysis with well-characterized genes involved in triterpenoid saponin biosynthesis, 5 OSC s, 14 CYP s, and 1 UGT are further proposed as the most promising candidate genes. Transcriptomic comparison between two Ilex species using blastp and OrthoMCL method reveals high sequence similarity. All OSC s and UGT s as well as most CYP s are classified as orthologous genes, while only 5 CYP s in I. pubescens and 3 CYP s in I. asprella are species-specific. One of OSC candidates, named as IpAS 1, was successfully cloned and expressed in Saccharomyces cerevisiae INV Sc 1. Analysis of the yeast extract by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) shows IpAS 1 is a mixed amyrin synthase, producing α-amyrin and β-amyrin at ratio of 5:1, which is similar to its ortholog IaAS 1 from I. asprella . This study is the first exploration to profile the transcriptome of I. pubescens , the generated data and gene models will facilitate further molecular studies on

  15. Reconstruction of a functional human gene network, with an application for prioritizing positional candidate genes.

    NARCIS (Netherlands)

    Franke, L.; Bakel, H. van; Fokkens, L.; Jong, E.D. de; Egmont-Peterson, M.; Wijmenga, C.

    2006-01-01

    Most common genetic disorders have a complex inheritance and may result from variants in many genes, each contributing only weak effects to the disease. Pinpointing these disease genes within the myriad of susceptibility loci identified in linkage studies is difficult because these loci may contain

  16. The norepinephrine transporter gene is a candidate gene for panic disorder

    DEFF Research Database (Denmark)

    Buttenschøn, Henriette Nørmølle; Kristensen, A S; Buch, H N

    2011-01-01

    of PD. The SLC6A2 gene is located on chromosome 16q12.2 and encodes the norepinephrine transporter (NET), responsible for the reuptake of norepinephrine into presynaptic nerve terminals. The aim of the present study was to analyze genetic variants located within the NET gene for association with PD...

  17. Validation of candidate reference genes in Bifidobacterium adolescentis for gene expression normalization.

    Science.gov (United States)

    Stenico, Verena; Baffoni, Loredana; Gaggìa, Francesca; Biavati, Bruno

    2014-06-01

    Normalization is an essential prerequisite for producing accurate real-time PCR expression analyses. The objective of this study is the selection of a set of optimal reference genes in Bifidobacterium adolescentis gene expression studies under bile exposure. B adolescentis is a particularly abundant species in the human adults gut microbiota, exerting relevant probiotic activities. In the gastrointestinal tract, bile represents a hard challenge for bacterial survival, because of its toxic effect. The natural exposure to bile in the colonic environment induces cells adaptation and tolerance mechanisms in bifidobacteria, which determines changes in gene expression profile, influencing the expression levels of housekeeping genes. In this context, the stability of 9 putative reference genes (cysS, purB, recA, rpoB-L, GADPH-R, 16S rRNA, glnA1, gyrA2, sdhA) was examined in B. adolescentis exposed to bile extract, using two different software (BestKeeper and NormFinder). Both algorithms identified gyrA2 and sdhA as the most stable genes under our experimental conditions, while 16S rRNA is the least reliable HKGs. To our best knowledge, this is the first attempt to validate reference genes in Bifidobacterium spp. and the results offer an appropriate set of reference genes suitable for qRT-PCR studies on B. adolescentis strains under bile stress. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Pharmacological Validation of Candidate Causal Sleep Genes Identified in an N2 Cross

    Science.gov (United States)

    Brunner, Joseph I.; Gotter, Anthony L.; Millstein, Joshua; Garson, Susan; Binns, Jacquelyn; Fox, Steven V.; Savitz, Alan T.; Yang, He S.; Fitzpatrick, Karrie; Zhou, Lili; Owens, Joseph R.; Webber, Andrea L.; Vitaterna, Martha H.; Kasarskis, Andrew; Uebele, Victor N.; Turek, Fred; Renger, John J.; Winrow, Christopher J.

    2013-01-01

    Despite the substantial impact of sleep disturbances on human health and the many years of study dedicated to understanding sleep pathologies, the underlying genetic mechanisms that govern sleep and wake largely remain unknown. Recently, we completed large scale genetic and gene expression analyses in a segregating inbred mouse cross and identified candidate causal genes that regulate the mammalian sleep-wake cycle, across multiple traits including total sleep time, amounts of REM, non-REM, sleep bout duration and sleep fragmentation. Here we describe a novel approach toward validating candidate causal genes, while also identifying potential targets for sleep-related indications. Select small molecule antagonists and agonists were used to interrogate candidate causal gene function in rodent sleep polysomnography assays to determine impact on overall sleep architecture and to evaluate alignment with associated sleep-wake traits. Significant effects on sleep architecture were observed in validation studies using compounds targeting the muscarinic acetylcholine receptor M3 subunit (Chrm3)(wake promotion), nicotinic acetylcholine receptor alpha4 subunit (Chrna4)(wake promotion), dopamine receptor D5 subunit (Drd5)(sleep induction), serotonin 1D receptor (Htr1d)(altered REM fragmentation), glucagon-like peptide-1 receptor (Glp1r)(light sleep promotion and reduction of deep sleep), and Calcium channel, voltage-dependent, T type, alpha 1I subunit (Cacna1i)(increased bout duration slow wave sleep). Taken together, these results show the complexity of genetic components that regulate sleep-wake traits and highlight the importance of evaluating this complex behavior at a systems level. Pharmacological validation of genetically identified putative targets provides a rapid alternative to generating knock out or transgenic animal models, and may ultimately lead towards new therapeutic opportunities. PMID:22091728

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

    Directory of Open Access Journals (Sweden)

    Patricia M Guimaraes

    Full Text Available 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.

  20. Pharmacological validation of candidate causal sleep genes identified in an N2 cross.

    Science.gov (United States)

    Brunner, Joseph I; Gotter, Anthony L; Millstein, Joshua; Garson, Susan; Binns, Jacquelyn; Fox, Steven V; Savitz, Alan T; Yang, He S; Fitzpatrick, Karrie; Zhou, Lili; Owens, Joseph R; Webber, Andrea L; Vitaterna, Martha H; Kasarskis, Andrew; Uebele, Victor N; Turek, Fred; Renger, John J; Winrow, Christopher J

    2011-12-01

    Despite the substantial impact of sleep disturbances on human health and the many years of study dedicated to understanding sleep pathologies, the underlying genetic mechanisms that govern sleep and wake largely remain unknown. Recently, the authors completed large-scale genetic and gene expression analyses in a segregating inbred mouse cross and identified candidate causal genes that regulate the mammalian sleep-wake cycle, across multiple traits including total sleep time, amounts of rapid eye movement (REM), non-REM, sleep bout duration, and sleep fragmentation. Here the authors describe a novel approach toward validating candidate causal genes, while also identifying potential targets for sleep-related indications. Select small-molecule antagonists and agonists were used to interrogate candidate causal gene function in rodent sleep polysomnography assays to determine impact on overall sleep architecture and to evaluate alignment with associated sleep-wake traits. Significant effects on sleep architecture were observed in validation studies using compounds targeting the muscarinic acetylcholine receptor M3 subunit (Chrm3) (wake promotion), nicotinic acetylcholine receptor alpha4 subunit (Chrna4) (wake promotion), dopamine receptor D5 subunit (Drd5) (sleep induction), serotonin 1D receptor (Htr1d) (altered REM fragmentation), glucagon-like peptide-1 receptor (Glp1r) (light sleep promotion and reduction of deep sleep), and calcium channel, voltage-dependent, T type, alpha 1I subunit (Cacna1i) (increased bout duration of slow wave sleep). Taken together, these results show the complexity of genetic components that regulate sleep-wake traits and highlight the importance of evaluating this complex behavior at a systems level. Pharmacological validation of genetically identified putative targets provides a rapid alternative to generating knock out or transgenic animal models, and may ultimately lead towards new therapeutic opportunities.

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

    Science.gov (United States)

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

    2016-08-01

    Genetic studies have identified several genes and genomic regions contributing to the control of host susceptibility to leprosy. Here, we test variants of the positional and functional candidate gene SOD2 for association with leprosy in 2 independent population samples. Family-based analysis revealed an association between leprosy and allele G of marker rs295340 (P = .042) and borderline evidence of an association between leprosy and alleles C and A of markers rs4880 (P = .077) and rs5746136 (P = .071), respectively. Findings were validated in an independent case-control sample for markers rs295340 (P = .049) and rs4880 (P = .038). These results suggest SOD2 as a newly identified gene conferring susceptibility to leprosy. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  2. Analysis of SSH library of rice variety Aganni reveals candidate gall midge resistance genes.

    Science.gov (United States)

    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.

  3. Candidate genes associated with bud dormancy release in blackcurrant (Ribes nigrum L.).

    Science.gov (United States)

    Hedley, Peter E; Russell, Joanne R; Jorgensen, Linzi; Gordon, Sandra; Morris, Jenny A; Hackett, Christine A; Cardle, Linda; Brennan, Rex

    2010-09-14

    The detrimental effects of mild winter temperatures on the consistency of cropping of blackcurrant (Ribes nigrum L.) in parts of Europe have led to increasing interest in the genetic control of dormancy release in this species. This study examined patterns of gene expression in leaf buds of blackcurrant to identify key differential changes in these profiles around the time of budbreak. Using leaf bud tissue of blackcurrant, a cDNA library was generated as a source of blackcurrant ESTs for construction of a custom microarray, which was used to identify differential gene expression during dormancy release. Gene activity was lowest in early stages of dormancy, increasing to reach a maximum around the time of budbreak. Genes with significantly changing expression profiles were clustered and evidence is provided for the transient activity of genes previously associated with dormancy processes in other species. Expression profiling identified candidate genes which were mapped onto a blackcurrant genetic linkage map containing budbreak-related QTL. Three genes, which putatively encode calmodulin-binding protein, beta tubulin and acetyl CoA carboxylase respectively, were found to co-localise with budbreak QTL. This study provides insight into the genetic control of dormancy transition in blackcurrant, identifying key changes in gene expression around budbreak. Genetic mapping of ESTs enabled the identification of genes which co-localise with previously-characterised blackcurrant QTL, and it is concluded that these genes have probable roles in release of dormancy and can therefore provide a basis for the development of genetic markers for future breeding deployment.

  4. Candidate genes associated with bud dormancy release in blackcurrant (Ribes nigrum L.

    Directory of Open Access Journals (Sweden)

    Hedley Peter E

    2010-09-01

    Full Text Available Abstract Background The detrimental effects of mild winter temperatures on the consistency of cropping of blackcurrant (Ribes nigrum L. in parts of Europe have led to increasing interest in the genetic control of dormancy release in this species. This study examined patterns of gene expression in leaf buds of blackcurrant to identify key differential changes in these profiles around the time of budbreak. Results Using leaf bud tissue of blackcurrant, a cDNA library was generated as a source of blackcurrant ESTs for construction of a custom microarray, which was used to identify differential gene expression during dormancy release. Gene activity was lowest in early stages of dormancy, increasing to reach a maximum around the time of budbreak. Genes with significantly changing expression profiles were clustered and evidence is provided for the transient activity of genes previously associated with dormancy processes in other species. Expression profiling identified candidate genes which were mapped onto a blackcurrant genetic linkage map containing budbreak-related QTL. Three genes, which putatively encode calmodulin-binding protein, beta tubulin and acetyl CoA carboxylase respectively, were found to co-localise with budbreak QTL. Conclusions This study provides insight into the genetic control of dormancy transition in blackcurrant, identifying key changes in gene expression around budbreak. Genetic mapping of ESTs enabled the identification of genes which co-localise with previously-characterised blackcurrant QTL, and it is concluded that these genes have probable roles in release of dormancy and can therefore provide a basis for the development of genetic markers for future breeding deployment.

  5. Sequence-Based Introgression Mapping Identifies Candidate White Mold Tolerance Genes in Common Bean

    Directory of Open Access Journals (Sweden)

    Sujan Mamidi

    2016-07-01

    Full Text Available White mold, caused by the necrotrophic fungus (Lib. de Bary, is a major disease of common bean ( L.. WM7.1 and WM8.3 are two quantitative trait loci (QTL with major effects on tolerance to the pathogen. Advanced backcross populations segregating individually for either of the two QTL, and a recombinant inbred (RI population segregating for both QTL were used to fine map and confirm the genetic location of the QTL. The QTL intervals were physically mapped using the reference common bean genome sequence, and the physical intervals for each QTL were further confirmed by sequence-based introgression mapping. Using whole-genome sequence data from susceptible and tolerant DNA pools, introgressed regions were identified as those with significantly higher numbers of single-nucleotide polymorphisms (SNPs relative to the whole genome. By combining the QTL and SNP data, WM7.1 was located to a 660-kb region that contained 41 gene models on the proximal end of chromosome Pv07, while the WM8.3 introgression was narrowed to a 1.36-Mb region containing 70 gene models. The most polymorphic candidate gene in the WM7.1 region encodes a BEACH-domain protein associated with apoptosis. Within the WM8.3 interval, a receptor-like protein with the potential to recognize pathogen effectors was the most polymorphic gene. The use of gene and sequence-based mapping identified two candidate genes whose putative functions are consistent with the current model of pathogenicity.

  6. A physical map of the heterozygous grapevine 'Cabernet Sauvignon' allows mapping candidate genes for disease resistance

    Directory of Open Access Journals (Sweden)

    Scalabrin Simone

    2008-06-01

    Full Text Available Abstract Background Whole-genome physical maps facilitate genome sequencing, sequence assembly, mapping of candidate genes, and the design of targeted genetic markers. An automated protocol was used to construct a Vitis vinifera 'Cabernet Sauvignon' physical map. The quality of the result was addressed with regard to the effect of high heterozygosity on the accuracy of contig assembly. Its usefulness for the genome-wide mapping of genes for disease resistance, which is an important trait for grapevine, was then assessed. Results The physical map included 29,727 BAC clones assembled into 1,770 contigs, spanning 715,684 kbp, and corresponding to 1.5-fold the genome size. Map inflation was due to high heterozygosity, which caused either the separation of allelic BACs in two different contigs, or local mis-assembly in contigs containing BACs from the two haplotypes. Genetic markers anchored 395 contigs or 255,476 kbp to chromosomes. The fully automated assembly and anchorage procedures were validated by BAC-by-BAC blast of the end sequences against the grape genome sequence, unveiling 7.3% of chimerical contigs. The distribution across the physical map of candidate genes for non-host and host resistance, and for defence signalling pathways was then studied. NBS-LRR and RLK genes for host resistance were found in 424 contigs, 133 of them (32% were assigned to chromosomes, on which they are mostly organised in clusters. Non-host and defence signalling genes were found in 99 contigs dispersed without a discernable pattern across the genome. Conclusion Despite some limitations that interfere with the correct assembly of heterozygous clones into contigs, the 'Cabernet Sauvignon' physical map is a useful and reliable intermediary step between a genetic map and the genome sequence. This tool was successfully exploited for a quick mapping of complex families of genes, and it strengthened previous clues of co-localisation of major NBS-LRR clusters and

  7. Selection on plant male function genes identifies candidates for reproductive isolation of yellow monkeyflowers.

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    Jan E Aagaard

    Full Text Available Understanding the genetic basis of reproductive isolation promises insight into speciation and the origins of biological diversity. While progress has been made in identifying genes underlying barriers to reproduction that function after fertilization (post-zygotic isolation, we know much less about earlier acting pre-zygotic barriers. Of particular interest are barriers involved in mating and fertilization that can evolve extremely rapidly under sexual selection, suggesting they may play a prominent role in the initial stages of reproductive isolation. A significant challenge to the field of speciation genetics is developing new approaches for identification of candidate genes underlying these barriers, particularly among non-traditional model systems. We employ powerful proteomic and genomic strategies to study the genetic basis of conspecific pollen precedence, an important component of pre-zygotic reproductive isolation among yellow monkeyflowers (Mimulus spp. resulting from male pollen competition. We use isotopic labeling in combination with shotgun proteomics to identify more than 2,000 male function (pollen tube proteins within maternal reproductive structures (styles of M. guttatus flowers where pollen competition occurs. We then sequence array-captured pollen tube exomes from a large outcrossing population of M. guttatus, and identify those genes with evidence of selective sweeps or balancing selection consistent with their role in pollen competition. We also test for evidence of positive selection on these genes more broadly across yellow monkeyflowers, because a signal of adaptive divergence is a common feature of genes causing reproductive isolation. Together the molecular evolution studies identify 159 pollen tube proteins that are candidate genes for conspecific pollen precedence. Our work demonstrates how powerful proteomic and genomic tools can be readily adapted to non-traditional model systems, allowing for genome-wide screens

  8. Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects

    LENUS (Irish Health Repository)

    Pangilinan, Faith

    2012-08-02

    AbstractBackgroundNeural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate\\/B12 pathway genes contribute to NTD risk.MethodsA tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate\\/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects.ResultsNearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003–0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing.ConclusionsTo our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the

  9. Candidate Genes Within Tissue Culture Regeneration QTL Revisited with a Linkage Map Based on Transcript Derived Markers

    Science.gov (United States)

    Green plant regeneration from tissue culture is under the genetic control of multiple genes. Candidate genes for regeneration have been identified in multiple species using QTL and microarray analyses, and some of these genes have been verified as improving regeneration through transformation. Multi...

  10. Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease

    NARCIS (Netherlands)

    Meddens, Claartje A; Harakalova, Magdalena; van den Dungen, Noortje A M; Foroughi Asl, Hassan; Hijma, Hemme J; Cuppen, Edwin P J G; Björkegren, Johan L M; Asselbergs, Folkert W; Nieuwenhuis, Edward E S; Mokry, Michal

    2016-01-01

    BACKGROUND: Genome-wide association studies (GWAS) have revealed many susceptibility loci for complex genetic diseases. For most loci, the causal genes have not been identified. Currently, the identification of candidate genes is predominantly based on genes that localize close to or within

  11. Computational analysis of candidate disease genes and variants for Salt-sensitive hypertension in indigenous Southern Africans

    KAUST Repository

    Tiffin, Nicki

    2010-09-27

    Multiple factors underlie susceptibility to essential hypertension, including a significant genetic and ethnic component, and environmental effects. Blood pressure response of hypertensive individuals to salt is heterogeneous, but salt sensitivity appears more prevalent in people of indigenous African origin. The underlying genetics of salt-sensitive hypertension, however, are poorly understood. In this study, computational methods including text- and data-mining have been used to select and prioritize candidate aetiological genes for salt-sensitive hypertension. Additionally, we have compared allele frequencies and copy number variation for single nucleotide polymorphisms in candidate genes between indigenous Southern African and Caucasian populations, with the aim of identifying candidate genes with significant variability between the population groups: identifying genetic variability between population groups can exploit ethnic differences in disease prevalence to aid with prioritisation of good candidate genes. Our top-ranking candidate genes include parathyroid hormone precursor (PTH) and type-1angiotensin II receptor (AGTR1). We propose that the candidate genes identified in this study warrant further investigation as potential aetiological genes for salt-sensitive hypertension. © 2010 Tiffin et al.

  12. Candidate gene approach for parasite resistance in sheep--variation in immune pathway genes and association with fecal egg count.

    Directory of Open Access Journals (Sweden)

    Kathiravan Periasamy

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

  13. Hypomorphic mutations identified in the candidate Leber congenital amaurosis gene CLUAP1.

    Science.gov (United States)

    Soens, Zachry T; Li, Yuanyuan; Zhao, Li; Eblimit, Aiden; Dharmat, Rachayata; Li, Yumei; Chen, Yiyun; Naqeeb, Mohammed; Fajardo, Norma; Lopez, Irma; Sun, Zhaoxia; Koenekoop, Robert K; Chen, Rui

    2016-10-01

    Leber congenital amaurosis (LCA) is an early-onset form of retinal degeneration. Six of the 22 known LCA genes encode photoreceptor ciliary proteins. Despite the identification of 22 LCA genes, the genetic basis of ~30% of LCA patients remains unknown. We sought to investigate the cause of disease in the remaining 30% by examining cilia-associated genes. Whole-exome sequencing was performed on an LCA cohort of 212 unsolved probands previously screened for mutations in known retinal-disease genes. Immunohistochemistry using mouse retinas was used to confirm protein localization and zebrafish were used to perform rescue experiments. A homozygous nonsynonymous mutation was found in a single proband in CLUAP1, a gene required for ciliogenesis and cilia maintenance. Cluap1 knockout zebrafish exhibit photoreceptor cell death as early as 5 days after fertilization, and rescue experiments revealed that our proband's mutation is significantly hypomorphic. Consistent with the knowledge that CLUAP1 plays an important role in cilia function and that cilia are critical to photoreceptor function, our results indicate that hypomorphic mutations in CLUAP1 can result in dysfunctional photoreceptors without systemic abnormalities. This is the first report linking mutations in CLUAP1 to human disease and establishes CLUAP1 as a candidate LCA gene.Genet Med 18 10, 1044-1051.

  14. Assessing the Validity of Asthma Associations for Eight Candidate Genes and Age at Diagnosis Effects

    Science.gov (United States)

    Pino-Yanes, María; Corrales, Almudena; Cumplido, José; Poza, Paloma; Sánchez-Machín, Inmaculada; Sánchez-Palacios, Anselmo; Figueroa, Javier; Acosta-Fernández, Orlando; Buset, Nisa; García-Robaina, José Carlos; Hernández, Mariano; Villar, Jesús; Carrillo, Teresa; Flores, Carlos

    2013-01-01

    Background Before the advent of genome-wide association studies (GWAS), ADAM33, ADRB2, CD14, MS4A2 (alias FCER1B), IL13, IL4, IL4R, and TNF constituted the most replicated non-HLA candidate genes with asthma and related traits. However, except for the IL13-IL4 region, none of these genes have been found in close proximity of genome-wide significant hits among GWAS for asthma or related traits. Here we aimed to assess the reproducibility of these asthma associations and to test if associations were more evident considering the effect of age at diagnosis. Methodology/Principal Findings We systematically evaluated 286 common single nucleotide polymorphisms (SNPs) of these 8 genes in a sample of 1,865 unrelated Spanish individuals (606 asthmatics and 1,259 controls). We found that variants at MS4A2, IL4R and ADAM33 genes demonstrated varying association effects with the age at diagnosis of asthma, with 10 SNPs showing study-wise significance after the multiple comparison adjustment. In addition, in silico replication with GWAS data supported the association of IL4R. Conclusions/Significance Our results support the important role of MS4A2, IL4R and ADAM33 genes in asthma and/or atopy susceptibility. However, additional studies in larger samples sets are needed to firmly implicate these genes in asthma susceptibility, and also to identify the causal variation underlying the associations found. PMID:24039878

  15. Expression profiling of autism candidate genes during human brain development implicates central immune signaling pathways.

    Directory of Open Access Journals (Sweden)

    Mark N Ziats

    Full Text Available The Autism Spectrum Disorders (ASD represent a clinically heterogeneous set of conditions with strong hereditary components. Despite substantial efforts to uncover the genetic basis of ASD, the genomic etiology appears complex and a clear understanding of the molecular mechanisms underlying Autism remains elusive. We hypothesized that focusing gene interaction networks on ASD-implicated genes that are highly expressed in the developing brain may reveal core mechanisms that are otherwise obscured by the genomic heterogeneity of the disorder. Here we report an in silico study of the gene expression profile from ASD-implicated genes in the unaffected developing human brain. By implementing a biologically relevant approach, we identified a subset of highly expressed ASD-candidate genes from which interactome networks were derived. Strikingly, immune signaling through NFκB, Tnf, and Jnk was central to ASD networks at multiple levels of our analysis, and cell-type specific expression suggested glia--in addition to neurons--deserve consideration. This work provides integrated genomic evidence that ASD-implicated genes may converge on central cytokine signaling pathways.

  16. Expression profiling of autism candidate genes during human brain development implicates central immune signaling pathways.

    Science.gov (United States)

    Ziats, Mark N; Rennert, Owen M

    2011-01-01

    The Autism Spectrum Disorders (ASD) represent a clinically heterogeneous set of conditions with strong hereditary components. Despite substantial efforts to uncover the genetic basis of ASD, the genomic etiology appears complex and a clear understanding of the molecular mechanisms underlying Autism remains elusive. We hypothesized that focusing gene interaction networks on ASD-implicated genes that are highly expressed in the developing brain may reveal core mechanisms that are otherwise obscured by the genomic heterogeneity of the disorder. Here we report an in silico study of the gene expression profile from ASD-implicated genes in the unaffected developing human brain. By implementing a biologically relevant approach, we identified a subset of highly expressed ASD-candidate genes from which interactome networks were derived. Strikingly, immune signaling through NFκB, Tnf, and Jnk was central to ASD networks at multiple levels of our analysis, and cell-type specific expression suggested glia--in addition to neurons--deserve consideration. This work provides integrated genomic evidence that ASD-implicated genes may converge on central cytokine signaling pathways.

  17. Back to the sea twice: identifying candidate plant genes for molecular evolution to marine life

    Directory of Open Access Journals (Sweden)

    Reusch Thorsten BH

    2011-01-01

    Full Text Available Abstract Background Seagrasses are a polyphyletic group of monocotyledonous angiosperms that have adapted to a completely submerged lifestyle in marine waters. Here, we exploit two collections of expressed sequence tags (ESTs of two wide-spread and ecologically important seagrass species, the Mediterranean seagrass Posidonia oceanica (L. Delile and the eelgrass Zostera marina L., which have independently evolved from aquatic ancestors. This replicated, yet independent evolutionary history facilitates the identification of traits that may have evolved in parallel and are possible instrumental candidates for adaptation to a marine habitat. Results In our study, we provide the first quantitative perspective on molecular adaptations in two seagrass species. By constructing orthologous gene clusters shared between two seagrasses (Z. marina and P. oceanica and eight distantly related terrestrial angiosperm species, 51 genes could be identified with detection of positive selection along the seagrass branches of the phylogenetic tree. Characterization of these positively selected genes using KEGG pathways and the Gene Ontology uncovered that these genes are mostly involved in translation, metabolism, and photosynthesis. Conclusions These results provide first insights into which seagrass genes have diverged from their terrestrial counterparts via an initial aquatic stage characteristic of the order and to the derived fully-marine stage characteristic of seagrasses. We discuss how adaptive changes in these processes may have contributed to the evolution towards an aquatic and marine existence.

  18. The WRKY Transcription Factor Family in Citrus: Valuable and Useful Candidate Genes for Citrus Breeding.

    Science.gov (United States)

    Ayadi, M; Hanana, M; Kharrat, N; Merchaoui, H; Marzoug, R Ben; Lauvergeat, V; Rebaï, A; Mzid, R

    2016-10-01

    WRKY transcription factors belong to a large family of plant transcriptional regulators whose members have been reported to be involved in a wide range of biological roles including plant development, adaptation to environmental constraints and response to several diseases. However, little or poor information is available about WRKY's in Citrus. The recent release of completely assembled genomes sequences of Citrus sinensis and Citrus clementina and the availability of ESTs sequences from other citrus species allowed us to perform a genome survey for Citrus WRKY proteins. In the present study, we identified 100 WRKY members from C. sinensis (51), C. clementina (48) and Citrus unshiu (1), and analyzed their chromosomal distribution, gene structure, gene duplication, syntenic relation and phylogenetic analysis. A phylogenetic tree of 100 Citrus WRKY sequences with their orthologs from Arabidopsis has distinguished seven groups. The CsWRKY genes were distributed across all ten sweet orange chromosomes. A comprehensive approach and an integrative analysis of Citrus WRKY gene expression revealed variable profiles of expression within tissues and stress conditions indicating functional diversification. Thus, candidate Citrus WRKY genes have been proposed as potentially involved in fruit acidification, essential oil biosynthesis and abiotic/biotic stress tolerance. Our results provided essential prerequisites for further WRKY genes cloning and functional analysis with an aim of citrus crop improvement.

  19. Back to the sea twice: identifying candidate plant genes for molecular evolution to marine life.

    Science.gov (United States)

    Wissler, Lothar; Codoñer, Francisco M; Gu, Jenny; Reusch, Thorsten B H; Olsen, Jeanine L; Procaccini, Gabriele; Bornberg-Bauer, Erich

    2011-01-12

    Seagrasses are a polyphyletic group of monocotyledonous angiosperms that have adapted to a completely submerged lifestyle in marine waters. Here, we exploit two collections of expressed sequence tags (ESTs) of two wide-spread and ecologically important seagrass species, the Mediterranean seagrass Posidonia oceanica (L.) Delile and the eelgrass Zostera marina L., which have independently evolved from aquatic ancestors. This replicated, yet independent evolutionary history facilitates the identification of traits that may have evolved in parallel and are possible instrumental candidates for adaptation to a marine habitat. In our study, we provide the first quantitative perspective on molecular adaptations in two seagrass species. By constructing orthologous gene clusters shared between two seagrasses (Z. marina and P. oceanica) and eight distantly related terrestrial angiosperm species, 51 genes could be identified with detection of positive selection along the seagrass branches of the phylogenetic tree. Characterization of these positively selected genes using KEGG pathways and the Gene Ontology uncovered that these genes are mostly involved in translation, metabolism, and photosynthesis. These results provide first insights into which seagrass genes have diverged from their terrestrial counterparts via an initial aquatic stage characteristic of the order and to the derived fully-marine stage characteristic of seagrasses. We discuss how adaptive changes in these processes may have contributed to the evolution towards an aquatic and marine existence.

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

    Science.gov (United States)

    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.

  1. Systems genetics: a paradigm to improve discovery of candidate genes and mechanisms underlying complex traits.

    Science.gov (United States)

    Feltus, F Alex

    2014-06-01

    Understanding the control of any trait optimally requires the detection of causal genes, gene interaction, and mechanism of action to discover and model the biochemical pathways underlying the expressed phenotype. Functional genomics techniques, including RNA expression profiling via microarray and high-throughput DNA sequencing, allow for the precise genome localization of biological information. Powerful genetic approaches, including quantitative trait locus (QTL) and genome-wide association study mapping, link phenotype with genome positions, yet genetics is less precise in localizing the relevant mechanistic information encoded in DNA. The coupling of salient functional genomic signals with genetically mapped positions is an appealing approach to discover meaningful gene-phenotype relationships. Techniques used to define this genetic-genomic convergence comprise the field of systems genetics. This short review will address an application of systems genetics where RNA profiles are associated with genetically mapped genome positions of individual genes (eQTL mapping) or as gene sets (co-expression network modules). Both approaches can be applied for knowledge independent selection of candidate genes (and possible control mechanisms) underlying complex traits where multiple, likely unlinked, genomic regions might control specific complex traits. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  2. Assessing the validity of asthma associations for eight candidate genes and age at diagnosis effects.

    Science.gov (United States)

    Pino-Yanes, María; Corrales, Almudena; Cumplido, José; Poza, Paloma; Sánchez-Machín, Inmaculada; Sánchez-Palacios, Anselmo; Figueroa, Javier; Acosta-Fernández, Orlando; Buset, Nisa; García-Robaina, José Carlos; Hernández, Mariano; Villar, Jesús; Carrillo, Teresa; Flores, Carlos

    2013-01-01

    Before the advent of genome-wide association studies (GWAS), ADAM33, ADRB2, CD14, MS4A2 (alias FCER1B), IL13, IL4, IL4R, and TNF constituted the most replicated non-HLA candidate genes with asthma and related traits. However, except for the IL13-IL4 region, none of these genes have been found in close proximity of genome-wide significant hits among GWAS for asthma or related traits. Here we aimed to assess the reproducibility of these asthma associations and to test if associations were more evident considering the effect of age at diagnosis. We systematically evaluated 286 common single nucleotide polymorphisms (SNPs) of these 8 genes in a sample of 1,865 unrelated Spanish individuals (606 asthmatics and 1,259 controls). We found that variants at MS4A2, IL4R and ADAM33 genes demonstrated varying association effects with the age at diagnosis of asthma, with 10 SNPs showing study-wise significance after the multiple comparison adjustment. In addition, in silico replication with GWAS data supported the association of IL4R. Our results support the important role of MS4A2, IL4R and ADAM33 genes in asthma and/or atopy susceptibility. However, additional studies in larger samples sets are needed to firmly implicate these genes in asthma susceptibility, and also to identify the causal variation underlying the associations found.

  3. Assessing the validity of asthma associations for eight candidate genes and age at diagnosis effects.

    Directory of Open Access Journals (Sweden)

    María Pino-Yanes

    Full Text Available BACKGROUND: Before the advent of genome-wide association studies (GWAS, ADAM33, ADRB2, CD14, MS4A2 (alias FCER1B, IL13, IL4, IL4R, and TNF constituted the most replicated non-HLA candidate genes with asthma and related traits. However, except for the IL13-IL4 region, none of these genes have been found in close proximity of genome-wide significant hits among GWAS for asthma or related traits. Here we aimed to assess the reproducibility of these asthma associations and to test if associations were more evident considering the effect of age at diagnosis. METHODOLOGY/PRINCIPAL FINDINGS: We systematically evaluated 286 common single nucleotide polymorphisms (SNPs of these 8 genes in a sample of 1,865 unrelated Spanish individuals (606 asthmatics and 1,259 controls. We found that variants at MS4A2, IL4R and ADAM33 genes demonstrated varying association effects with the age at diagnosis of asthma, with 10 SNPs showing study-wise significance after the multiple comparison adjustment. In addition, in silico replication with GWAS data supported the association of IL4R. CONCLUSIONS/SIGNIFICANCE: Our results support the important role of MS4A2, IL4R and ADAM33 genes in asthma and/or atopy susceptibility. However, additional studies in larger samples sets are needed to firmly implicate these genes in asthma susceptibility, and also to identify the causal variation underlying the associations found.

  4. Identification of putative candidate genes for water stress tolerance in canola (Brassica napus

    Directory of Open Access Journals (Sweden)

    Jing eZhang

    2015-11-01

    Full Text Available Drought stress can directly inhibit seedling establishment in canola (Brassica napus, resulting in lower plant densities and reduced yields. To dissect this complex trait, 140 B. napus accessions were phenotyped under normal (0.0 MPa, S0 and water-stressed conditions simulated by polyethylene glycol (PEG 6000 (–0.5 MPa, S5 in a hydroponic system. Phenotypic variation and heritability indicated that the root to shoot length ratio was a reliable indicator for water stress tolerance. Thereafter, 66 accessions (16 water stress tolerant, 34 moderate and 16 sensitive lines were genotyped using 25,495 Brassica single nucleotide polymorphisms. Genome-wide association studies identified 16 loci significantly associated with water stress response. Two B. napus accessions were used for RNA-seq, with differentially-expressed genes under normal and water-stressed conditions examined. By combining differentially-expressed genes detected by RNA-seq with significantly associated loci from genome-wide association studies, 79 candidate genes were identified, of which eight were putatively associated with drought tolerance based on gene ontology of Arabidopsis. Functional validation of these genes may confirm key drought-related genes for selection and breeding in B. napus. Our results provide insight into the genetic basis of water stress tolerance in canola.

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

    Directory of Open Access Journals (Sweden)

    Ubadah Sabbagh

    2016-01-01

    Full Text Available 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.

  6. Genomic analysis of differentiation between soil types reveals candidate genes for local adaptation in Arabidopsis lyrata.

    Directory of Open Access Journals (Sweden)

    Thomas L Turner

    2008-09-01

    Full Text Available 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 CaratioMg ratio in A. lyrata.

  7. Distilling a Visual Network of Retinitis Pigmentosa Gene-Protein Interactions to Uncover New Disease Candidates.

    Directory of Open Access Journals (Sweden)

    Daniel Boloc

    Full Text Available Retinitis pigmentosa (RP is a highly heterogeneous genetic visual disorder with more than 70 known causative genes, some of them shared with other non-syndromic retinal dystrophies (e.g. Leber congenital amaurosis, LCA. The identification of RP genes has increased steadily during the last decade, and the 30% of the cases that still remain unassigned will soon decrease after the advent of exome/genome sequencing. A considerable amount of genetic and functional data on single RD genes and mutations has been gathered, but a comprehensive view of the RP genes and their interacting partners is still very fragmentary. This is the main gap that needs to be filled in order to understand how mutations relate to progressive blinding disorders and devise effective therapies.We have built an RP-specific network (RPGeNet by merging data from different sources: high-throughput data from BioGRID and STRING databases, manually curated data for interactions retrieved from iHOP, as well as interactions filtered out by syntactical parsing from up-to-date abstracts and full-text papers related to the RP research field. The paths emerging when known RP genes were used as baits over the whole interactome have been analysed, and the minimal number of connections among the RP genes and their close neighbors were distilled in order to simplify the search space.In contrast to the analysis of single isolated genes, finding the networks linking disease genes renders powerful etiopathological insights. We here provide an interactive interface, RPGeNet, for the molecular biologist to explore the network centered on the non-syndromic and syndromic RP and LCA causative genes. By integrating tissue-specific expression levels and phenotypic data on top of that network, a more comprehensive biological view will highlight key molecular players of retinal degeneration and unveil new RP disease candidates.

  8. Genetic and molecular functional characterization of variants within TNFSF13B, a positional candidate preeclampsia susceptibility gene on 13q

    National Research Council Canada - National Science Library

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

    2010-01-01

    .... The current study aimed to identify potential functional and structural variants in the positional candidate gene TNFSF13B under the 13q linkage peak and assess their association status with maternal...

  9. Comparative Analysis of Fruit Metabolites and Pungency Candidate Genes Expression between Bhut Jolokia and Other Capsicum Species

    National Research Council Canada - National Science Library

    M, Sarpras; Gaur, Rashmi; Sharma, Vineet; Chhapekar, Sushil Satish; Das, Jharna; Kumar, Ajay; Yadava, Satish Kumar; Nitin, Mukesh; Brahma, Vijaya; Abraham, Suresh K; Ramchiary, Nirala

    2016-01-01

    .... Although few studies have reported variation in pungency content of this particular species, no study till date has reported detailed expression analysis of candidate genes involved in capsaicinoids (pungency...

  10. Harvesting candidate genes responsible for serious adverse drug reactions from a chemical-protein interactome.

    Directory of Open Access Journals (Sweden)

    Lun Yang

    2009-07-01

    Full Text Available Identifying genetic factors responsible for serious adverse drug reaction (SADR is of critical importance to personalized medicine. However, genome-wide association studies are hampered due to the lack of case-control samples, and the selection of candidate genes is limited by the lack of understanding of the underlying mechanisms of SADRs. We hypothesize that drugs causing the same type of SADR might share a common mechanism by targeting unexpectedly the same SADR-mediating protein. Hence we propose an approach of identifying the common SADR-targets through constructing and mining an in silico chemical-protein interactome (CPI, a matrix of binding strengths among 162 drug molecules known to cause at least one type of SADR and 845 proteins. Drugs sharing the same SADR outcome were also found to possess similarities in their CPI profiles towards this 845 protein set. This methodology identified the candidate gene of sulfonamide-induced toxic epidermal necrolysis (TEN: all nine sulfonamides that cause TEN were found to bind strongly to MHC I (Cw*4, whereas none of the 17 control drugs that do not cause TEN were found to bind to it. Through an insight into the CPI, we found the Y116S substitution of MHC I (B*5703 enhances the unexpected binding of abacavir to its antigen presentation groove, which explains why B*5701, not B*5703, is the risk allele of abacavir-induced hypersensitivity. In conclusion, SADR targets and the patient-specific off-targets could be identified through a systematic investigation of the CPI, generating important hypotheses for prospective experimental validation of the candidate genes.

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

    Science.gov (United States)

    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

    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. 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. 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.

  12. Candidate genes involved in the biosynthesis of triterpenoid saponins in Platycodon grandiflorum identified by transcriptome analysis

    Directory of Open Access Journals (Sweden)

    Chunhua eMa

    2016-05-01

    Full Text Available 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.

  13. An improved Bayesian network method for reconstructing gene regulatory network based on candidate auto selection.

    Science.gov (United States)

    Xing, Linlin; Guo, Maozu; Liu, Xiaoyan; Wang, Chunyu; Wang, Lei; Zhang, Yin

    2017-11-17

    The reconstruction of gene regulatory network (GRN) from gene expression data can discover regulatory relationships among genes and gain deep insights into the complicated regulation mechanism of life. However, it is still a great challenge in systems biology and bioinformatics. During the past years, numerous computational approaches have been developed for this goal, and Bayesian network (BN) methods draw most of attention among these methods because of its inherent probability characteristics. However, Bayesian network methods are time consuming and cannot handle large-scale networks due to their high computational complexity, while the mutual information-based methods are highly effective but directionless and have a high false-positive rate. To solve these problems, we propose a Candidate Auto Selection algorithm (CAS) based on mutual information and breakpoint detection to restrict the search space in order to accelerate the learning process of Bayesian network. First, the proposed CAS algorithm automatically selects the neighbor candidates of each node before searching the best structure of GRN. Then based on CAS algorithm, we propose a globally optimal greedy search method (CAS + G), which focuses on finding the highest rated network structure, and a local learning method (CAS + L), which focuses on faster learning the structure with little loss of quality. Results show that the proposed CAS algorithm can effectively reduce the search space of Bayesian networks through identifying the neighbor candidates of each node. In our experiments, the CAS + G method outperforms the state-of-the-art method on simulation data for inferring GRNs, and the CAS + L method is significantly faster than the state-of-the-art method with little loss of accuracy. Hence, the CAS based methods effectively decrease the computational complexity of Bayesian network and are more suitable for GRN inference.

  14. Transcriptome sequencing of Mycosphaerella fijiensis during association with Musa acuminata reveals candidate pathogenicity genes.

    Science.gov (United States)

    Noar, Roslyn D; Daub, Margaret E

    2016-08-30

    Mycosphaerella fijiensis, causative agent of the black Sigatoka disease of banana, is considered the most economically damaging banana disease. Despite its importance, the genetics of pathogenicity are poorly understood. Previous studies have characterized polyketide pathways with possible roles in pathogenicity. To identify additional candidate pathogenicity genes, we compared the transcriptome of this fungus during the necrotrophic phase of infection with that during saprophytic growth in medium. Transcriptome analysis was conducted, and the functions of differentially expressed genes were predicted by identifying conserved domains, Gene Ontology (GO) annotation and GO enrichment analysis, Carbohydrate-Active EnZymes (CAZy) annotation, and identification of genes encoding effector-like proteins. The analysis showed that genes commonly involved in secondary metabolism have higher expression in infected leaf tissue, including genes encoding cytochrome P450s, short-chain dehydrogenases, and oxidoreductases in the 2-oxoglutarate and Fe(II)-dependent oxygenase superfamily. Other pathogenicity-related genes with higher expression in infected leaf tissue include genes encoding salicylate hydroxylase-like proteins, hydrophobic surface binding proteins, CFEM domain-containing proteins, and genes encoding secreted cysteine-rich proteins characteristic of effectors. More genes encoding amino acid transporters, oligopeptide transporters, peptidases, proteases, proteinases, sugar transporters, and proteins containing Domain of Unknown Function (DUF) 3328 had higher expression in infected leaf tissue, while more genes encoding inhibitors of peptidases and proteinases had higher expression in medium. Sixteen gene clusters with higher expression in leaf tissue were identified including clusters for the synthesis of a non-ribosomal peptide. A cluster encoding a novel fusicoccane was also identified. Two putative dispensable scaffolds were identified with a large proportion of

  15. Dynamic QTL analysis and candidate gene mapping for waterlogging tolerance at maize seedling stage.

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    Khalid A Osman

    Full Text Available 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.

  16. Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects

    Directory of Open Access Journals (Sweden)

    Pangilinan Faith

    2012-08-01

    Full Text Available Abstract Background Neural tube defects (NTDs are common birth defects (~1 in 1000 pregnancies in the US and Europe that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T and MTHFD1 rs2236225 (R653Q have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk. Methods A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents, including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects. Results Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury and included the known NTD risk factor MTHFD1 R653Q (rs2236225. The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele. Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing. Conclusions To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive

  17. Canine candidate genes for dilated cardiomyopathy: annotation of and polymorphic markers for 14 genes

    Directory of Open Access Journals (Sweden)

    van Oost Bernard A

    2007-10-01

    Full Text Available Abstract Background Dilated cardiomyopathy is a myocardial disease occurring in humans and domestic animals and is characterized by dilatation of the left ventricle, reduced systolic function and increased sphericity of the left ventricle. Dilated cardiomyopathy has been observed in several, mostly large and giant, dog breeds, such as the Dobermann and the Great Dane. A number of genes have been identified, which are associated with dilated cardiomyopathy in the human, mouse and hamster. These genes mainly encode structural proteins of the cardiac myocyte. Results We present the annotation of, and marker development for, 14 of these genes of the dog genome, i.e. α-cardiac actin, caveolin 1, cysteine-rich protein 3, desmin, lamin A/C, LIM-domain binding factor 3, myosin heavy polypeptide 7, phospholamban, sarcoglycan δ, titin cap, α-tropomyosin, troponin I, troponin T and vinculin. A total of 33 Single Nucleotide Polymorphisms were identified for these canine genes and 11 polymorphic microsatellite repeats were developed. Conclusion The presented polymorphisms provide a tool to investigate the role of the corresponding genes in canine Dilated Cardiomyopathy by linkage analysis or association studies.

  18. The imprinted gene DIO3 is a candidate gene for litter size in pigs.

    Directory of Open Access Journals (Sweden)

    Albart Coster

    Full Text Available Genomic imprinting is an important epigenetic phenomenon, which on the phenotypic level can be detected by the difference between the two heterozygote classes of a gene. Imprinted genes are important in both the development of the placenta and the embryo, and we hypothesized that imprinted genes might be involved in female fertility traits. We therefore performed an association study for imprinted genes related to female fertility traits in two commercial pig populations. For this purpose, 309 SNPs in fifteen evolutionary conserved imprinted regions were genotyped on 689 and 1050 pigs from the two pig populations. A single SNP association study was used to detect additive, dominant and imprinting effects related to four reproduction traits; total number of piglets born, the number of piglets born alive, the total weight of the piglets born and the total weight of the piglets born alive. Several SNPs showed significant (q-value 0.10, but had a similar effect as in the first population. The results of this study indicate a possible association between the imprinted gene DIO3 and female fertility traits in pigs.

  19. ABCG5/G8 gene is associated with hypercholesterolemias without mutation in candidate genes and noncholesterol sterols.

    Science.gov (United States)

    Lamiquiz-Moneo, Itziar; Baila-Rueda, Lucía; Bea, Ana M; Mateo-Gallego, Rocío; Pérez-Calahorra, Sofía; Marco-Benedí, Victoria; Martín-Navarro, Antonio; Ros, Emilio; Cofán, Montserrat; Rodríguez-Rey, José Carlos; Pocovi, Miguel; Cenarro, Ana; Civeira, Fernando

    Approximately 20% to 40% of clinically defined familial hypercholesterolemia (FH) cases do not show a causative mutation in candidate genes (mutation-negative FH), and some of them may have a polygenic origin. The aim of this work was to study the prevalence of ABCG5/G8 genetic variants in mutation-negative FH, as defects in these genes relate to intestinal hyperabsorption of cholesterol and thus ABCG5/G8 variants could explain in part the mechanism of hypercholesterolemia. We sequenced the ABCG5/G8 genes in 214 mutation-negative FH and 97 controls. Surrogate markers of cholesterol absorption (5α-cholestanol, β-sitosterol, campesterol, stigmasterol, and sitostanol) were quantified by high-performance liquid chromatography-tandem mass spectrometry in both studied groups. We found 8 mutation-negative FH patients (3.73%) with a pathogenic mutation in ABCG5/G8 genes. We observed significantly higher concentration of surrogate markers of cholesterol absorption in mutation-negative FH than in controls. In addition, we found significantly higher concentrations of cholesterol absorption markers in mutation-negative FH with ABCG5/G8 defects than in mutation-negative, ABCG5/G8-negative FH. A gene score reflecting the number of common single nucleotide variants associated with hypercholesterolemia was significantly higher in cases than in controls (P = .032). Subjects with a gene score above the mean had significantly higher 5α-cholestanol and stigmasterol than those with a lower gene score. Mutation-negative FH subjects accumulate an excess of rare and common gene variations in ABCG5/G8 genes. This variation is associated with increased intestinal absorption of cholesterol, as determined by surrogate makers, suggesting that these loci contribute to hypercholesterolemia by enhancing intestinal cholesterol absorption. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  20. A candidate gene approach to searching for low-penetrance breast and prostate cancer genes.

    Science.gov (United States)

    Hunter, D J; Riboli, E; Haiman, C A; Albanes, D; Altshuler, D; Chanock, S J; Haynes, R B; Henderson, B E; Kaaks, R; Stram, D O; Thomas, G; Thun, M J; Blanché, H; Buring, J E; Burtt, N P; Calle, E E; Cann, H; Canzian, F; Chen, Y C; Colditz, G A; Cox, D G; Dunning, A M; Feigelson, H S; Freedman, M L; Gaziano, J M; Giovannucci, E; Hankinson, S E; Hirschhorn, J N; Hoover, R N; Key, T; Kolonel, L N; Kraft, P; Le Marchand, L; Liu, S; Ma, J; Melnick, S; Pharaoh, P; Pike, M C; Rodriguez, C; Setiawan, V W; Stampfer, M J; Trapido, E; Travis, R; Virtamo, J; Wacholder, S; Willett, W C

    2005-12-01

    Most cases of breast and prostate cancer are not associated with mutations in known high-penetrance genes, indicating the involvement of multiple low-penetrance risk alleles. Studies that have attempted to identify these genes have met with limited success. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium--a pooled analysis of multiple large cohort studies with a total of more than 5,000 cases of breast cancer and 8,000 cases of prostate cancer--was therefore initiated. The goal of this consortium is to characterize variations in approximately 50 genes that mediate two pathways that are associated with these cancers--the steroid-hormone metabolism pathway and the insulin-like growth factor signalling pathway--and to associate these variations with cancer risk.

  1. Investigation of candidate genes for osteoarthritis based on gene expression profiles.

    Science.gov (United States)

    Dong, Shuanghai; Xia, Tian; Wang, Lei; Zhao, Qinghua; Tian, Jiwei

    2016-12-01

    To explore the mechanism of osteoarthritis (OA) and provide valid biological information for further investigation. Gene expression profile of GSE46750 was downloaded from Gene Expression Omnibus database. The Linear Models for Microarray Data (limma) package (Bioconductor project, http://www.bioconductor.org/packages/release/bioc/html/limma.html) was used to identify differentially expressed genes (DEGs) in inflamed OA samples. Gene Ontology function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis of DEGs were performed based on Database for Annotation, Visualization and Integrated Discovery data, and protein-protein interaction (PPI) network was constructed based on the Search Tool for the Retrieval of Interacting Genes/Proteins database. Regulatory network was screened based on Encyclopedia of DNA Elements. Molecular Complex Detection was used for sub-network screening. Two sub-networks with highest node degree were integrated with transcriptional regulatory network and KEGG functional enrichment analysis was processed for 2 modules. In total, 401 up- and 196 down-regulated DEGs were obtained. Up-regulated DEGs were involved in inflammatory response, while down-regulated DEGs were involved in cell cycle. PPI network with 2392 protein interactions was constructed. Moreover, 10 genes including Interleukin 6 (IL6) and Aurora B kinase (AURKB) were found to be outstanding in PPI network. There are 214 up- and 8 down-regulated transcription factor (TF)-target pairs in the TF regulatory network. Module 1 had TFs including SPI1, PRDM1, and FOS, while module 2 contained FOSL1. The nodes in module 1 were enriched in chemokine signaling pathway, while the nodes in module 2 were mainly enriched in cell cycle. The screened DEGs including IL6, AGT, and AURKB might be potential biomarkers for gene therapy for OA by being regulated by TFs such as FOS and SPI1, and participating in the cell cycle and cytokine-cytokine receptor

  2. Identification of candidate susceptibility and resistance genes of mice infected with Streptococcus suis type 2.

    Directory of Open Access Journals (Sweden)

    Jie Rong

    infection. This study identified candidate genes that may influence susceptibility or resistance to SS2 infection in A/J and B6 mice, providing further validation of these models and contributing to understanding of S. suis pathogenic mechanisms.

  3. Novel single nucleotide polymorphisms in candidate genes for growth in tilapia ( Oreochromis niloticus

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    Breidy Lizeth Cuevas-Rodríguez

    2016-06-01

    Full Text Available ABSTRACT The objective of the present work was to identify and validate single nucleotide variations located in candidate genes to growth traits in tilapia (Oreochromis niloticus. Two transitions were identified in the promoter region of the growth hormone gene (GH; eight nucleotide changes were identified in introns and promoter region of the IGF-I gene; and a transition (T/C was identified in the Myogenin gene (MyoG. The highest genotypic frequency (0.8 for GHpA1 and MyoG was found in the GG and TT homozygous individuals, while the highest frequency (0.9 for GHpB1 was observed in the CT heterozygous fish. There was no genotypic frequency in the CC homozygous tilapia for the GHpB1 and MyoG markers. Based on their allelic frequencies, validation as novel single nucleotide polymorphisms (SNP of those variations located at O. niloticus GH and MyoG genes was possible. These new markers will allow their association with growth traits in tilapia to be exploited in order to determine their potential use as assisted-selection markers.

  4. Co-localization of growth QTL with differentially expressed candidate genes in rainbow trout.

    Science.gov (United States)

    Kocmarek, Andrea L; Ferguson, Moira M; Danzmann, Roy G

    2015-09-01

    We tested whether genes differentially expressed between large and small rainbow trout co-localized with familial QTL regions for body size. Eleven chromosomes, known from previous work to house QTL for weight and length in rainbow trout, were examined for QTL in half-sibling families produced in September (1 XY male and 1 XX neomale) and December (1 XY male). In previous studies, we identified 108 candidate genes for growth expressed in the liver and white muscle in a subset of the fish used in this study. These gene sequences were BLASTN aligned against the rainbow trout and stickleback genomes to determine their location (rainbow trout) and inferred location based on synteny with the stickleback genome. Across the progeny of all three males used in the study, 63.9% of the genes with differential expression appear to co-localize with the QTL regions on 6 of the 11 chromosomes tested in these males. Genes that co-localized with QTL in the mixed-sex offspring of the two XY males primarily showed up-regulation in the muscle of large fish and were related to muscle growth, metabolism, and the stress response.

  5. Exclusion of candidate genes for coat colour phenotypes of the American mink (Neovison vison).

    Science.gov (United States)

    Anistoroaei, R; Markakis, M N; Vissenberg, K; Christensen, K

    2012-12-01

    In a previous project, we screened the American mink Bacterial Artificial Chromosome library, CHORI-231, for genes potentially involved in various coat colour phenotypes in the American mink. Subsequently, we 454 sequenced the inserts containing these genes and developed microsatellite markers for each of these genes. Here, we describe a lack of association between three different 'roan-type' phenotypes represented by Cross, Stardust and Cinnamon in American mink and six different genes that we considered to be potentially linked to these phenotypes. Thus, c-KIT (HUGO-approved symbol KIT), ATOH-1 (HUGO-approved symbol ATOH1) and POMC were excluded as potential candidates for these three phenotypes. In addition, MITF and SLC24A5 were excluded for Cross and Cinnamon, and KITL (HUGO-approved symbol KITLG) for Cross and Stardust. Although most of these genes have been implicated as the cause of similar phenotypes in other mammals, including horses, pigs, cows, dogs, cats, mice and humans, they do not appear to be responsible for comparable phenotypes found in American mink. © 2012 The Authors, Animal Genetics © 2012 Stichting International Foundation for Animal Genetics.

  6. HLA genes and other candidate genes involved in susceptibility for (pre)neoplastic cervical disease

    NARCIS (Netherlands)

    Zoodsma, M; Nolte, IM; Meerman, GJT; De Vries, EGE; Van Der Zee, AGJ

    This review focuses on common and genetic risk factors such as HLA and other genes that may be involved in susceptibility for (pre)neoplastic cervical disease. The goal of this review is the evaluation of polymorphisms that are either associated with cervical intraepithelial neoplasia (CIN) and/or

  7. The ACACA gene is a potential candidate gene for fat content in sheep milk.

    Science.gov (United States)

    Moioli, B; Scatà, M C; De Matteis, G; Annicchiarico, G; Catillo, G; Napolitano, F

    2013-08-01

    No major gene has yet been reported in sheep that explains the variation of milk fat content. The coding region of the acetyl-CoA carboxylase alpha (ACACA) gene, which plays an important role in de novo fatty acid synthesis, had been investigated, but no non-synonymous mutations have been reported. In this study, the genomic regions encoding the three promoters of the ACACA gene were directly sequenced in 264 sheep of three different breeds, and 10 SNPs were identified. Allele frequencies of most SNPs significantly differed (P = 0.05-0.0001) between breeds. The SNPs that potentially altered either gene regulatory elements or putative binding sites of transcription factors were made evident through in silico analysis. The association analysis with milk traits, performed for one SNP of PIII (GenBank AJ292286, g.1330G>T), showed a significant allelic substitution effect (+0.33%, P sheep milk. © 2013 The Authors, Animal Genetics © 2013 Stichting International Foundation for Animal Genetics.

  8. TargetMine, an integrated data warehouse for candidate gene prioritisation and target discovery.

    Directory of Open Access Journals (Sweden)

    Yi-An Chen

    Full Text Available Prioritising candidate genes for further experimental characterisation is a non-trivial challenge in drug discovery and biomedical research in general. An integrated approach that combines results from multiple data types is best suited for optimal target selection. We developed TargetMine, a data warehouse for efficient target prioritisation. TargetMine utilises the InterMine framework, with new data models such as protein-DNA interactions integrated in a novel way. It enables complicated searches that are difficult to perform with existing tools and it also offers integration of custom annotations and in-house experimental data. We proposed an objective protocol for target prioritisation using TargetMine and set up a benchmarking procedure to evaluate its performance. The results show that the protocol can identify known disease-associated genes with high precision and coverage. A demonstration version of TargetMine is available at http://targetmine.nibio.go.jp/.

  9. Analysis of ten candidate genes in autism by association and linkage.

    Science.gov (United States)

    Philippe, Anne; Guilloud-Bataille, Michel; Martinez, Maria; Gillberg, Christopher; Råstam, Maria; Sponheim, Eili; Coleman, Mary; Zappella, Michele; Aschauer, Harald; Penet, Christiane; Feingold, Josué; Brice, Alexis; Leboyer, Marion

    2002-03-08

    We studied the possible involvement of ten candidate genes in autism: proenkephalin, prodynorphin, and proprotein convertase subtilisin/kexin type 2 (opioid metabolism); tyrosine hydroxylase, dopamine receptors D2 and D5, monoamine oxidases A and B (monoaminergic system); brain-derived neurotrophic factor, and neural cell adhesion molecule (involved in neurodevelopment). Thirty-eight families with two affected siblings and one family with two affected half-siblings, recruited by the Paris Autism Research International Sibpair Study (PARIS), were tested using the transmission disequilibrium test and two-point affected sib-pair linkage analysis. We found no evidence for association or linkage with intragenic or linked markers. Our family sample has good power for detecting a linkage disequilibrium of 0.80. Thus, these genes are unlikely to play a major role in the families studied, but further studies in a much larger sample would be needed to highlight weaker genetic effects. Copyright 2002 Wiley-Liss, Inc.

  10. Resolving candidate genes of mouse skeletal muscle QTL via RNA-Seq and expression network analyses

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    Lionikas Arimantas

    2012-11-01

    Full Text Available Abstract Background We have recently identified a number of Quantitative Trait Loci (QTL contributing to the 2-fold muscle weight difference between the LG/J and SM/J mouse strains and refined their confidence intervals. To facilitate nomination of the candidate genes responsible for these differences we examined the transcriptome of the tibialis anterior (TA muscle of each strain by RNA-Seq. Results 13,726 genes were expressed in mouse skeletal muscle. Intersection of a set of 1061 differentially expressed transcripts with a mouse muscle Bayesian Network identified a coherent set of differentially expressed genes that we term the LG/J and SM/J Regulatory Network (LSRN. The integration of the QTL, transcriptome and the network analyses identified eight key drivers of the LSRN (Kdr, Plbd1, Mgp, Fah, Prss23, 2310014F06Rik, Grtp1, Stk10 residing within five QTL regions, which were either polymorphic or differentially expressed between the two strains and are strong candidates for quantitative trait genes (QTGs underlying muscle mass. The insight gained from network analysis including the ability to make testable predictions is illustrated by annotating the LSRN with knowledge-based signatures and showing that the SM/J state of the network corresponds to a more oxidative state. We validated this prediction by NADH tetrazolium reductase staining in the TA muscle revealing higher oxidative potential of the SM/J compared to the LG/J strain (p Conclusion Thus, integration of fine resolution QTL mapping, RNA-Seq transcriptome information and mouse muscle Bayesian Network analysis provides a novel and unbiased strategy for nomination of muscle QTGs.

  11. Comparative genomics identifies candidate genes for infectious salmon anemia (ISA) resistance in Atlantic salmon (Salmo salar).

    Science.gov (United States)

    Li, Jieying; Boroevich, Keith A; Koop, Ben F; Davidson, William S

    2011-04-01

    Infectious salmon anemia (ISA) has been described as the hoof and mouth disease of salmon farming. ISA is caused by a lethal and highly communicable virus, which can have a major impact on salmon aquaculture, as demonstrated by an outbreak in Chile in 2007. A quantitative trait locus (QTL) for ISA resistance has been mapped to three microsatellite markers on linkage group (LG) 8 (Chr 15) on the Atlantic salmon genetic map. We identified bacterial artificial chromosome (BAC) clones and three fingerprint contigs from the Atlantic salmon physical map that contains these markers. We made use of the extensive BAC end sequence database to extend these contigs by chromosome walking and identified additional two markers in this region. The BAC end sequences were used to search for conserved synteny between this segment of LG8 and the fish genomes that have been sequenced. An examination of the genes in the syntenic segments of the tetraodon and medaka genomes identified candidates for association with ISA resistance in Atlantic salmon based on differential expression profiles from ISA challenges or on the putative biological functions of the proteins they encode. One gene in particular, HIV-EP2/MBP-2, caught our attention as it may influence the expression of several genes that have been implicated in the response to infection by infectious salmon anemia virus (ISAV). Therefore, we suggest that HIV-EP2/MBP-2 is a very strong candidate for the gene associated with the ISAV resistance QTL in Atlantic salmon and is worthy of further study.

  12. Serotonin and Dopamine Candidate Gene Variants and Alcohol- and Non-Alcohol-Related Aggression.

    Science.gov (United States)

    Preuss, Ulrich W; Koller, Gabriele; Samochowiec, Agnieszka; Zill, Peter; Samochowiec, Jerzy; Kucharska-Mazur, Jolanta; Wong, Jessica; Soyka, Michael

    2015-11-01

    Aggressive and criminal traits have a complex genetic background which interacts with environmental factors. Alcohol intoxication has been related to lower thresholds of aggressive behaviors. In this association study of two independent samples, a number of candidate gene variants (5HT2A T102C, 5-HTTLPR, DRD Ins-141Del, DAT1 VNTR) were related to violent criminal behavior and alcohol-related aggressive traits. Treatment-seeking alcohol-dependent individuals (293 patients and 499 controls from Germany, 180 patients and 402 controls from Poland) underwent a Semi-Structured Assessment for the Genetics of Alcoholism interview which gathered information on alcohol-related violence and criminal behaviors, beside alcohol dependence characteristics. Patients with a history of violent or non-violent crime were more often male, had an earlier onset of alcoholism, more withdrawal seizures and delirium tremens, and were more likely to have a history of suicide attempts. No significant association between candidate gene variants and criminal behavior was detected. 5HTTLPR variant was related to one characteristic of alcohol-related violence. With findings from genome-wide association studies linking aggression-related traits to second messenger systems, further studies are needed to determine the genetic underpinnings of non-alcohol and alcohol-related aggression. © The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.

  13. A multilocus candidate approach identifies ACE and HIF1A as susceptibility genes for cellulite.

    Science.gov (United States)

    Emanuele, E; Bertona, M; Geroldi, D

    2010-08-01

    Cellulite is a common complex cosmetic problem for many post-adolescent women characterised by relief alterations of the skin surface, which give the skin an orange-peel appearance. Although genetic factors have been suggested to play a role in the development of cellulite, the genetic background of this condition remains unclear. We therefore conducted a multi-locus genetic study examining the potential associations of candidate gene variants in oestrogen receptors, endothelial function/adipose tissue hypoxia, lipid metabolism, extracellular matrix homeostasis, inflammation and adipose tissue biology, with the risk of cellulite. Using a case-control study of 200 lean women with cellulite and 200 age- and BMI-matched controls (grade 0 according to Nurnberger-Muller scale), we examined the association of cellulite with 25 polymorphisms in 15 candidate genes. Two of the 25 polymorphisms were significantly associated with cellulite at the P cellulite were 1.19 (95% CI: 1.10-1.51; P cellulite, may provide novel information on the pathophysiology of this common cosmetic problem, and offer a topic for research for novel beautification interventions.

  14. Association study of candidate gene polymorphisms with amnestic mild cognitive impairment in a Chinese population.

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    Xiaoyan Liu

    Full Text Available To investigate the relationship between amnestic mild cognitive impairment (aMCI and candidate gene polymorphisms in a Chinese population, 116 aMCI patients and 93 normal controls were recruited. Multi-dimensional neuropsychological tests were used to extensively assess the cognitive functions of the subjects. MassARRAY and iPLEX systems were used to measure candidate single nucleotide polymorohisms (SNPs and analyse allelic, genotypic or haplotypic distributions. The scores of the neuropsychological tests were significantly lower for the aMCI patients than for the normal controls. The distributions of SNPs relating to the amyloid cascade hypothesis (TOMM40 rs157581 G and TOMM40 rs2075650 G, to the cholesterol metabolism hypothesis (ApoE rs429358 C, LDLR rs11668477 G and CH25H rs7091822 T and PLAU rs2227564 CT and to the tau hypothesis (MAPT/STH rs242562 GG in aMCI were significantly different than those in normal controls. Interactions were also found in aMCI amongst SNPs in LDLR rs11668477, PLAU rs2227564, and TOMM40 rs157581, between SNPs in TOMM40 rs157580 and BACE2 rs9975138. The study suggests that aMCI is characterised by memory impairment and associated with SNPs in three systems relating to the pathogenesis of AD--those of the amyloid cascade, tau and cholesterol metabolism pathways. Interactions were also observed between genes in the amyloid pathway and between the amyloid and cholesterol pathways.

  15. Fine Mapping and Transcriptome Analysis Reveal Candidate Genes Associated with Hybrid Lethality in Cabbage (Brassica Oleracea).

    Science.gov (United States)

    Xiao, Zhiliang; Hu, Yang; Zhang, Xiaoli; Xue, Yuqian; Fang, Zhiyuan; Yang, Limei; Zhang, Yangyong; Liu, Yumei; Li, Zhansheng; Liu, Xing; Liu, Zezhou; Lv, Honghao; Zhuang, Mu

    2017-06-05

    Hybrid lethality is a deleterious phenotype that is vital to species evolution. We previously reported hybrid lethality in cabbage (Brassica oleracea) and performed preliminary mapping of related genes. In the present study, the fine mapping of hybrid lethal genes revealed that BoHL1 was located on chromosome C1 between BoHLTO124 and BoHLTO130, with an interval of 101 kb. BoHL2 was confirmed to be between insertion-deletion (InDels) markers HL234 and HL235 on C4, with a marker interval of 70 kb. Twenty-eight and nine annotated genes were found within the two intervals of BoHL1 and BoHL2, respectively. We also applied RNA-Seq to analyze hybrid lethality in cabbage. In the region of BoHL1, seven differentially expressed genes (DEGs) and five resistance (R)-related genes (two in common, i.e., Bo1g153320 and Bo1g153380) were found, whereas in the region of BoHL2, two DEGs and four R-related genes (two in common, i.e., Bo4g173780 and Bo4g173810) were found. Along with studies in which R genes were frequently involved in hybrid lethality in other plants, these interesting R-DEGs may be good candidates associated with hybrid lethality. We also used SNP/InDel analyses and quantitative real-time PCR to confirm the results. This work provides new insight into the mechanisms of hybrid lethality in cabbage.

  16. A candidate-gene association study for berry colour and anthocyanin content in Vitis vinifera L.

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    Silvana Cardoso

    Full Text Available Anthocyanin content is a trait of major interest in Vitis vinifera L. These compounds affect grape and wine quality, and have beneficial effects on human health. A candidate-gene approach was used to identify genetic variants associated with anthocyanin content in grape berries. A total of 445 polymorphisms were identified in 5 genes encoding transcription factors and 10 genes involved in either the biosynthetic pathway or transport of anthocyanins. A total of 124 SNPs were selected to examine association with a wide range of phenotypes based on RP-HPLC analysis and visual characterization. The phenotypes were total skin anthocyanin (TSA concentration but also specific types of anthocyanins and relative abundance. The visual assessment was based on OIV (Organisation Internationale de la Vigne et du Vin descriptors for berry and skin colour. The genes encoding the transcription factors MYB11, MYBCC and MYC(B were significantly associated with TSA concentration. UFGT and MRP were associated with several different types of anthocyanins. Skin and pulp colour were associated with nine genes (MYB11, MYBCC, MYC(B, UFGT, MRP, DFR, LDOX, CHI and GST. Pulp colour was associated with a similar group of 11 genes (MYB11, MYBCC, MYC(B, MYC(A, UFGT, MRP, GST, DFR, LDOX, CHI and CHS(A. Statistical interactions were observed between SNPs within the transcription factors MYB11, MYBCC and MYC(B. SNPs within LDOX interacted with MYB11 and MYC(B, while SNPs within CHI interacted with MYB11 only. Together, these findings suggest the involvement of these genes in anthocyanin content and on the regulation of anthocyanin biosynthesis. This work forms a benchmark for replication and functional studies.

  17. Transcriptomic Analysis Reveals Candidate Genes for Female Sterility in Pomegranate Flowers

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    Lina Chen

    2017-08-01

    Full Text Available Pomegranate has two types of flowers on the same plant: functional male flowers (FMF and bisexual flowers (BF. BF are female-fertile flowers that can set fruits. FMF are female-sterile flowers that fail to set fruit and that eventually drop. The putative cause of pomegranate FMF female sterility is abnormal ovule development. However, the key stage at which the FMF pomegranate ovules become abnormal and the mechanism of regulation of pomegranate female sterility remain unknown. Here, we studied ovule development in FMF and BF, using scanning electron microscopy to explore the key stage at which ovule development was terminated and then analyzed genes differentially expressed (differentially expressed genes – DEGs between FMF and BF to investigate the mechanism responsible for pomegranate female sterility. Ovule development in FMF ceased following the formation of the inner integument primordium. The key stage for the termination of FMF ovule development was when the bud vertical diameter was 5.0–13.0 mm. Candidate genes influencing ovule development may be crucial factors in pomegranate female sterility. INNER OUTER (INO/YABBY4 (Gglean016270 and AINTEGUMENTA (ANT homolog genes (Gglean003340 and Gglean011480, which regulate the development of the integument, showed down-regulation in FMF at the key stage of ovule development cessation (ATNSII. Their upstream regulator genes, such as AGAMOUS-like (AG-like (Gglean028014, Gglean026618, and Gglean028632 and SPOROCYTELESS (SPL homolog genes (Gglean005812, also showed differential expression pattern between BF and FMF at this key stage. The differential expression of the ethylene response signal genes, ETR (ethylene-resistant (Gglean022853 and ERF1/2 (ethylene-responsive factor (Gglean022880, between FMF and BF indicated that ethylene signaling may also be an important factor in the development of pomegranate female sterility. The increase in BF observed after spraying with ethephon supported this

  18. Comparative gene expression analysis of avian embryonic facial structures reveals new candidates for human craniofacial disorders.

    Science.gov (United States)

    Brugmann, S A; Powder, K E; Young, N M; Goodnough, L H; Hahn, S M; James, A W; Helms, J A; Lovett, M

    2010-03-01

    Mammals and birds have common embryological facial structures, and appear to employ the same molecular genetic developmental toolkit. We utilized natural variation found in bird beaks to investigate what genes drive vertebrate facial morphogenesis. We employed cross-species microarrays to describe the molecular genetic signatures, developmental signaling pathways and the spectrum of transcription factor (TF) gene expression changes that differ between cranial neural crest cells in the developing beaks of ducks, quails and chickens. Surprisingly, we observed that the neural crest cells established a species-specific TF gene expression profile that predates morphological differences between the species. A total of 232 genes were differentially expressed between the three species. Twenty-two of these genes, including Fgfr2, Jagged2, Msx2, Satb2 and Tgfb3, have been previously implicated in a variety of mammalian craniofacial defects. Seventy-two of the differentially expressed genes overlap with un-cloned loci for human craniofacial disorders, suggesting that our data will provide a valuable candidate gene resource for human craniofacial genetics. The most dramatic changes between species were in the Wnt signaling pathway, including a 20-fold up-regulation of Dkk2, Fzd1 and Wnt1 in the duck compared with the other two species. We functionally validated these changes by demonstrating that spatial domains of Wnt activity differ in avian beaks, and that Wnt signals regulate Bmp pathway activity and promote regional growth in facial prominences. This study is the first of its kind, extending on previous work in Darwin's finches and provides the first large-scale insights into cross-species facial morphogenesis.

  19. Genetic determinants of the ankle-brachial index : A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium

    NARCIS (Netherlands)

    Wassel, Christina L.; Lamina, Claudia; Nambi, Vijay; Coassin, Stefan; Mukamal, Kenneth J.; Ganesh, Santhi K.; Jacobs, David R.; Franceschini, Nora; Papanicolaou, George J.; Gibson, Quince; Yanek, Lisa R.; van der Harst, Pim; Ferguson, Jane F.; Crawford, Dana C.; Waite, Lindsay L.; Allison, Matthew A.; Criqui, Michael H.; McDermott, Mary M.; Mehra, Reena; Cupples, L. Adrienne; Hwang, Shih-Jen; Redline, Susan; Kaplan, Robert C.; Heiss, Gerardo; Rotter, Jerome I.; Boerwinkle, Eric; Taylor, Herman A.; Eraso, Luis H.; Haun, Margot; Li, Mingyao; Meisinger, Christa; O'Connell, Jeffrey R.; Shuldineri, Alan R.; Tybjaerg-Hansen, Anne; Frikke-Schmidt, Ruth; Kollerits, Barbara; Rantner, Barbara; Dieplinger, Benjamin; Stadler, Marietta; Mueller, Thomas; Haltmayer, Meinhard; Klein-Weigel, Peter; Summerer, Monika; Wichmann, H. -Erich; Asselbergs, Folkert W.; Navis, Gerjan; Mateo Leach, Irene; Brown-Gentry, Kristin; Goodloe, Robert; Assimes, Themistocles L.; Becker, Diane M.; Cooke, John P.; Absher, Devin M.; Olin, Jeffrey W.; Mitchell, Braxton D.; Reilly, Muredach P.; Mohler, Emile R.; North, Kari E.; Reiner, Alexander P.; Kronenberg, Florian; Murabito, Joanne M.

    Background: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of similar to 50,000 SNPs across similar to

  20. Identification of candidate genes associated with leaf senescence in cultivated sunflower (Helianthus annuus L.).

    Science.gov (United States)

    Moschen, Sebastian; Bengoa Luoni, Sofia; Paniego, Norma B; Hopp, H Esteban; Dosio, Guillermo A A; Fernandez, Paula; Heinz, Ruth A

    2014-01-01

    Cultivated sunflower (Helianthus annuus L.), an important source of edible vegetable oil, shows rapid onset of senescence, which limits production by reducing photosynthetic capacity under specific growing conditions. Carbon for grain filling depends strongly on light interception by green leaf area, which diminishes during grain filling due to leaf senescence. Transcription factors (TFs) regulate the progression of leaf senescence in plants and have been well explored in model systems, but information for many agronomic crops remains limited. Here, we characterize the expression profiles of a set of putative senescence associated genes (SAGs) identified by a candidate gene approach and sunflower microarray expression studies. We examined a time course of sunflower leaves undergoing natural senescence and used quantitative PCR (qPCR) to measure the expression of 11 candidate genes representing the NAC, WRKY, MYB and NF-Y TF families. In addition, we measured physiological parameters such as chlorophyll, total soluble sugars and nitrogen content. The expression of Ha-NAC01, Ha-NAC03, Ha-NAC04, Ha-NAC05 and Ha-MYB01 TFs increased before the remobilization rate increased and therefore, before the appearance of the first physiological symptoms of senescence, whereas Ha-NAC02 expression decreased. In addition, we also examined the trifurcate feed-forward pathway (involving ORE1, miR164, and ethylene insensitive 2) previously reported for Arabidopsis. We measured transcription of Ha-NAC01 (the sunflower homolog of ORE1) and Ha-EIN2, along with the levels of miR164, in two leaves from different stem positions, and identified differences in transcription between basal and upper leaves. Interestingly, Ha-NAC01 and Ha-EIN2 transcription profiles showed an earlier up-regulation in upper leaves of plants close to maturity, compared with basal leaves of plants at pre-anthesis stages. These results suggest that the H. annuus TFs characterized in this work could play important

  1. Identification of candidate genes associated with leaf senescence in cultivated sunflower (Helianthus annuus L..

    Directory of Open Access Journals (Sweden)

    Sebastian Moschen

    Full Text Available Cultivated sunflower (Helianthus annuus L., an important source of edible vegetable oil, shows rapid onset of senescence, which limits production by reducing photosynthetic capacity under specific growing conditions. Carbon for grain filling depends strongly on light interception by green leaf area, which diminishes during grain filling due to leaf senescence. Transcription factors (TFs regulate the progression of leaf senescence in plants and have been well explored in model systems, but information for many agronomic crops remains limited. Here, we characterize the expression profiles of a set of putative senescence associated genes (SAGs identified by a candidate gene approach and sunflower microarray expression studies. We examined a time course of sunflower leaves undergoing natural senescence and used quantitative PCR (qPCR to measure the expression of 11 candidate genes representing the NAC, WRKY, MYB and NF-Y TF families. In addition, we measured physiological parameters such as chlorophyll, total soluble sugars and nitrogen content. The expression of Ha-NAC01, Ha-NAC03, Ha-NAC04, Ha-NAC05 and Ha-MYB01 TFs increased before the remobilization rate increased and therefore, before the appearance of the first physiological symptoms of senescence, whereas Ha-NAC02 expression decreased. In addition, we also examined the trifurcate feed-forward pathway (involving ORE1, miR164, and ethylene insensitive 2 previously reported for Arabidopsis. We measured transcription of Ha-NAC01 (the sunflower homolog of ORE1 and Ha-EIN2, along with the levels of miR164, in two leaves from different stem positions, and identified differences in transcription between basal and upper leaves. Interestingly, Ha-NAC01 and Ha-EIN2 transcription profiles showed an earlier up-regulation in upper leaves of plants close to maturity, compared with basal leaves of plants at pre-anthesis stages. These results suggest that the H. annuus TFs characterized in this work could

  2. Molecular basis of albinism in India: evaluation of seven potential candidate genes and some new findings.

    Science.gov (United States)

    Mondal, M; Sengupta, M; Samanta, S; Sil, A; Ray, K

    2012-12-15

    Albinism represents a group of genetic disorders with a broad spectrum of hypopigmentary phenotypes dependent on the genetic background of the patients. Oculocutaneous albinism (OCA) patients have little or no pigment in their eyes, skin and hair, whereas ocular albinism (OA) primarily presents the ocular symptoms, and the skin and hair color may vary from near normal to very fair. Mutations in genes directly or indirectly regulating melanin production are responsible for different forms of albinism with overlapping clinical features. In this study, 27 albinistic individuals from 24 families were screened for causal variants by a PCR-sequencing based approach. TYR, OCA2, TYRP1, SLC45A2, SLC24A5, TYRP2 and SILV were selected as candidate genes. We identified 5 TYR and 3 OCA2 mutations, majority in homozygous state, in 8 unrelated patients including a case of autosomal recessive ocular albinism (AROA). A homozygous 4-nucleotide novel insertion in SLC24A5 was detected in a person showing with extreme cutaneous hypopigmentation. A potential causal variant was identified in the TYRP2 gene in a single patient. Haplotype analyses in the patients carrying homozygous mutations in the classical OCA genes suggested founder effect. This is the first report of an Indian AROA patient harboring a mutation in OCA2. Our results also reveal for the first time that mutations in SLC24A5 could contribute to extreme hypopigmentation in humans. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Identification and expression pattern of candidate olfactory genes in Chrysoperla sinica by antennal transcriptome analysis.

    Science.gov (United States)

    Li, Zhao-Qun; Zhang, Shuai; Luo, Jun-Yu; Wang, Si-Bao; Wang, Chun-Yi; Lv, Li-Min; Dong, Shuang-Lin; Cui, Jin-Jie

    2015-09-01

    Chrysoperla sinica is one of the most prominent natural enemies of many agricultural pests. Host seeking in insects is strongly mediated by olfaction. Understanding the sophisticated olfactory system of insect antennae is crucial for studying the physiological bases of olfaction and could also help enhance the effectiveness of C. sinica in biological control. Obtaining olfactory genes is a research priority for investigating the olfactory system in this species. However, no olfaction sequence information is available for C. sinica. Consequently, we sequenced female- and male-antennae transcriptome of C. sinica. Many candidate chemosensory genes were identified, including 12 odorant-binding proteins (OBPs), 19 chemosensory proteins (CSPs), 37 odorant receptors (ORs), and 64 ionotropic receptors from C. sinica. The expression patterns of 12 OBPs, 19 CSPs and 37 ORs were determined by RT-PCR, and demonstrated antennae-dominantly expression of most OBP and OR genes. Our finding provided large scale genes for further investigation on the olfactory system of C. sinica at the molecular level. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. The candidate tumor suppressor gene ECRG4 inhibits cancer cells migration and invasion in esophageal carcinoma

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    Lu ShihHsin

    2010-10-01

    Full Text Available Abstract Background The esophageal cancer related gene 4 (ECRG4 was initially identified and cloned in our laboratory from human normal esophageal epithelium (GenBank accession no.AF325503. ECRG4 was a new tumor suppressor gene in esophageal squamous cell carcinoma (ESCC associated with prognosis. In this study, we investigated the novel tumor-suppressing function of ECRG4 in cancer cell migration, invasion, adhesion and cell cycle regulation in ESCC. Methods Transwell and Boyden chamber experiments were utilized to examined the effects of ECRG4 expression on ESCC cells migration, invasion and adhesion. And flow cytometric analysis was used to observe the impact of ECRG4 expression on cell cycle regulation. Finally, the expression levels of cell cycle regulating proteins p53 and p21 in human ESCC cells transfected with ECRG4 gene were evaluated by Western blotting. Results The restoration of ECRG4 expression in ESCC cells inhibited cancer cells migration and invasion (P P > 0.05. Furthermore, ECRG4 could cause cell cycle G1 phase arrest in ESCC (P Conclusion ECRG4 is a candidate tumor suppressor gene which suppressed tumor cells migration and invasion without affecting cell adhesion ability in ESCC. Furthermore, ECRG4 might cause cell cycle G1 phase block possibly through inducing the increased expression of p53 and p21 proteins in ESCC.

  5. NECC1, a candidate choriocarcinoma suppressor gene that encodes a homeodomain consensus motif.

    Science.gov (United States)

    Asanoma, Kazuo; Matsuda, Takao; Kondo, Haruhiko; Kato, Kiyoko; Kishino, Tatsuya; Niikawa, Norio; Wake, Norio; Kato, Hidenori

    2003-01-01

    We isolated a candidate choriocarcinoma suppressor gene from a PCR-based subtracted fragmentary cDNA library between normal placental villi and the choriocarcinoma cell line CC1. This gene comprises an open reading frame of 219 nt encoding 73 amino acids and contains a homeodomain as a consensus motif. This gene, designated NECC1 (not expressed in choriocarcinoma clone 1), is located on human chromosome 4q11-q12. NECC1 expression is ubiquitous in the brain, placenta, lung, smooth muscle, uterus, bladder, kidney, and spleen. Normal placental villi expressed NECC1, but all choriocarcinoma cell lines examined and most of the surgically removed choriocarcinoma tissue samples failed to express it. We transfected this gene into choriocarcinoma cell lines and observed remarkable alterations in cell morphology and suppression of in vivo tumorigenesis. Induction of CSH1 (chorionic somatomammotropin hormone 1) by NECC1 expression suggested differentiation of choriocarcinoma cells to syncytiotrophoblasts. Our results suggest that loss of NECC1 expression is involved in malignant conversion of placental trophoblasts.

  6. Identification of Candidate Genes Potentially Relevant to Chamber-Specific Remodeling in Postnatal Ventricular Myocardium

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    Mario Torrado

    2010-01-01

    Full Text Available Molecular predisposition of postnatal ventricular myocardium to chamber-dependent (concentric or eccentric remodeling remains largely elusive. To this end, we compared gene expression in the left (LV versus right ventricle (RV in newborn piglets, using a differential display reverse transcription-PCR (DDRT-PCR technique. Out of more than 5600 DDRT-PCR bands, a total of 153 bands were identified as being differentially displayed. Of these, 96 bands were enriched in the LV, whereas the remaining 57 bands were predominant in the RV. The transcripts, displaying over twofold LV-RV expression differences, were sequenced and identified by BLAST comparison to known mRNA sequences. Among the genes, whose expression was not previously recognized as being chamber-dependent, we identified a small cohort of key regulators of muscle cell growth/proliferation (MAP3K7IP2, MSTN, PHB2, APOBEC3F and gene expression (PTPLAD1, JMJD1C, CEP290, which may be relevant to the chamber-dependent predisposition of ventricular myocardium to respond differentially to pressure (LV and volume (RV overloads after birth. In addition, our data demonstrate chamber-dependent alterations in expression of as yet uncharacterized novel genes, which may also be suitable candidates for association studies in animal models of LV/RV hypertrophy.

  7. Fine mapping and candidate gene analysis of the virescent gene v1in Upland cotton (Gossypium hirsutum).

    Science.gov (United States)

    Mao, Guangzhi; Ma, Qiang; Wei, Hengling; Su, Junji; Wang, Hantao; Ma, Qifeng; Fan, Shuli; Song, Meizhen; Zhang, Xianlong; Yu, Shuxun

    2018-02-01

    The young leaves of virescent mutants are yellowish and gradually turn green as the plants reach maturity. Understanding the genetic basis of virescent mutants can aid research of the regulatory mechanisms underlying chloroplast development and chlorophyll biosynthesis, as well as contribute to the application of virescent traits in crop breeding. In this study, fine mapping was employed, and a recessive gene (v 1 ) from a virescent mutant of Upland cotton was narrowed to an 84.1-Kb region containing ten candidate genes. The GhChlI gene encodes the cotton Mg-chelatase I subunit (CHLI) and was identified as the candidate gene for the virescent mutation using gene annotation. BLAST analysis showed that the GhChlI gene has two copies, Gh_A10G0282 and Gh_D10G0283. Sequence analysis indicated that the coding region (CDS) of GhChlI is 1269 bp in length, with three predicted exons and one non-synonymous nucleotide mutation (G1082A) in the third exon of Gh_D10G0283, with an amino acid (AA) substitution of arginine (R) to lysine (K). GhChlI-silenced TM-1 plants exhibited a lower GhChlI expression level, a lower chlorophyll content, and the virescent phenotype. Analysis of upstream regulatory elements and expression levels of GhChlI showed that the expression quantity of GhChlI may be normal, and with the development of the true leaf, the increase in the Gh_A10G0282 dosage may partially make up for the deficiency of Gh_D10G0283 in the v 1 mutant. Phylogenetic analysis and sequence alignment revealed that the protein sequence encoded by the third exon of GhChlI is highly conserved across diverse plant species, in which AA substitutions among the completely conserved residues frequently result in changes in leaf color in various species. These results suggest that the mutation (G1082A) within the GhChlI gene may cause a functional defect of the GhCHLI subunit and thus the virescent phenotype in the v 1 mutant. The GhChlI mutation not only provides a tool for understanding the

  8. Learning Disabilities and ADHD

    Science.gov (United States)

    ... disabilities Learning disabilities and ADHD Learning disabilities and ADHD Learning disabilities affect how you understand, remember, and ... learning skills, including memory tips from LD Online. Attention deficit hyperactivity disorder (ADHD) top ADHD is a medical condition that ...

  9. Getting Treatment for ADHD

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    Full Text Available ... grow, learn, and feel better about themselves. The goal of any type of ADHD treatment is to ... children with ADHD benefit from taking medication. Medications do not cure ADHD. Medications can control ADHD symptoms ...

  10. Analysis of human sarcospan as a candidate gene for CFEOM1

    Directory of Open Access Journals (Sweden)

    Engle Elizabeth C

    2001-02-01

    Full Text Available Abstract Background Congenital fibrosis of the extraocular muscles type 1 (CFEOM1 is an autosomal dominant eye movement disorder linked to the pericentromere of chromosome 12 (12p11.2 - q12. Sarcospan is a member of the dystrophin associated protein complex in skeletal and extraocular muscle and maps to human chromosome 12p11.2. Mutations in the genes encoding each of the other components of the skeletal muscle sarcospan-sarcoglycan complex (α - δ sarcoglycan have been shown to cause limb girdle muscular dystrophy (LGMD2C-F. To determine whether mutations in the sarcospan gene are responsible for CFEOM1 we: (1 attempted to map sarcospan to the CFEOM1 critical region; (2 developed a genomic primer set to directly sequence the sarcospan gene in CFEOM1 patients; and (3 generated an anti-sarcospan antibody to examine extraocular muscle biopsies from CFEOM1 patients. Results When tested by polymerase chain reaction, sarcospan sequence was not detected on yeast or bacterial artificial chromosomes from the CFEOM1 critical region. Sequencing of the sarcospan gene in CFEOM1 patients from 6 families revealed no mutations. Immunohistochemical studies of CFEOM1 extraocular muscles showed normal levels of sarcospan at the membrane. Finally, sarcospan was electronically mapped to bacterial artificial chromosomes that are considered to be outside of the CFEOM1 critical region. Conclusions In this report we evaluate sarcospan as a candidate gene for CFEOM1. We have found that it is highly unlikely that sarcospan is involved in the pathogenesis of this disease. As of yet no sarcospan gene mutations have been found to cause muscular abnormalities.

  11. A candidate gene for X-linked Ocular Albinism (OA1)

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    Bassi, M.T.; Schiaffino, V.; Rugarli, E. [Baylor College of Medicine, Houston, TX (United States)

    1994-09-01

    Ocular Albinism of the Nettleship-Fall type 1 (OA1) is the most common form of ocular albinism. It is transmitted as an X-linked recessive trait with affected males showing severe reduction of visual acuity, nystagmus, strabismus, photophobia. Ophthalmologic examination reveals foveal hypoplasia, hypopigmentation of the retina and iris translucency. Microscopic examination of melanocytes suggests that the underlying defect in OA1 is an abnormality in melanosome formation. Recently we assembled a 350 kb cosmid contig spanning the entire critical region on Xp22.3, which measures approximately 110 kb. A minimum set of cosmids was used to identify transcribed sequences using both cDNA selection and exon amplification. Two putative exons recovered by exon amplification strategy were found to be highly conserved throughout evolution and, therefore, they were used as probes for the screening of fetal and adult retina cDNA libraries. This led to the isolation of clones spanning a full-length cDNA which measures 7.6 kb. Sequence analysis revealed that the predicted protein product shows homology with syntrophines and a Xenopus laevis apical protein. The gene covers approximately 170 kb of DNA and spans the entire critical region for OA1, being deleted in two patients with contiguous gene deletion including OA1 and in one patient with isolated OA1. Therefore, this new gene represents a very strong candidate for involvement in OA1 (an alternative, but unlikely possibility to be considered is that the true OA1 gene lies within an intron of the former). Northern analysis revealed very high level of expression in retina and melanoma. Unlike most Xp22.3 genes, this gene is conserved in the mouse. We are currently performing SSCP analysis and direct sequencing of exons on DNAs from approximately 60 unrelated patients with OA1 for mutation detection.

  12. Identification of Arabidopsis candidate genes in response to biotic and abiotic stresses using comparative microarrays.

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    Arjun Sham

    Full Text Available Plants have evolved with intricate mechanisms to cope with multiple environmental stresses. To adapt with biotic and abiotic stresses, plant responses involve changes at the cellular and molecular levels. The current study was designed to investigate the effects of combinations of different environmental stresses on the transcriptome level of Arabidopsis genome using public microarray databases. We investigated the role of cyclopentenones in mediating plant responses to environmental stress through TGA (TGACG motif-binding factor transcription factor, independently from jasmonic acid. Candidate genes were identified by comparing plants inoculated with Botrytis cinerea or treated with heat, salt or osmotic stress with non-inoculated or non-treated tissues. About 2.5% heat-, 19% salinity- and 41% osmotic stress-induced genes were commonly upregulated by B. cinerea-treatment; and 7.6%, 19% and 48% of genes were commonly downregulated by B. cinerea-treatment, respectively. Our results indicate that plant responses to biotic and abiotic stresses are mediated by several common regulatory genes. Comparisons between transcriptome data from Arabidopsis stressed-plants support our hypothesis that some molecular and biological processes involved in biotic and abiotic stress response are conserved. Thirteen of the common regulated genes to abiotic and biotic stresses were studied in detail to determine their role in plant resistance to B. cinerea. Moreover, a T-DNA insertion mutant of the Responsive to Dehydration gene (rd20, encoding for a member of the caleosin (lipid surface protein family, showed an enhanced sensitivity to B. cinerea infection and drought. Overall, the overlapping of plant responses to abiotic and biotic stresses, coupled with the sensitivity of the rd20 mutant, may provide new interesting programs for increased plant resistance to multiple environmental stresses, and ultimately increases its chances to survive. Future research

  13. Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer.

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    Sofie Claerhout

    Full Text Available Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future.Using microarray technology, we generated a gene expression profile of human gastric cancer-specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern.We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment.

  14. Copy number variants in candidate genes are genetic modifiers of Hirschsprung disease.

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    Qian Jiang

    Full Text Available Hirschsprung disease (HSCR is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract. The HSCR phenotype is highly variable with respect to gender, length of aganglionosis, familiality and the presence of additional anomalies. By molecular genetic analysis, a minimum of 11 neuro-developmental genes (RET, GDNF, NRTN, SOX10, EDNRB, EDN3, ECE1, ZFHX1B, PHOX2B, KIAA1279, TCF4 are known to harbor rare, high-penetrance mutations that confer a large risk to the bearer. In addition, two other genes (RET, NRG1 harbor common, low-penetrance polymorphisms that contribute only partially to risk and can act as genetic modifiers. To broaden this search, we examined whether a set of 67 proven and candidate HSCR genes harbored additional modifier alleles. In this pilot study, we utilized a custom-designed array CGH with ∼33,000 test probes at an average resolution of ∼185 bp to detect gene-sized or smaller copy number variants (CNVs within these 67 genes in 18 heterogeneous HSCR patients. Using stringent criteria, we identified CNVs at three loci (MAPK10, ZFHX1B, SOX2 that are novel, involve regulatory and coding sequences of neuro-developmental genes, and show association with HSCR in combination with other congenital anomalies. Additional CNVs are observed under relaxed criteria. Our research suggests a role for CNVs in HSCR and, importantly, emphasizes the role of variation in regulatory sequences. A much larger study will be necessary both for replication and for identifying the full spectrum of small CNV effects.

  15. Copy Number Variants in Candidate Genes Are Genetic Modifiers of Hirschsprung Disease

    Science.gov (United States)

    Jiang, Qian; Ho, Yen-Yi; Hao, Li; Nichols Berrios, Courtney; Chakravarti, Aravinda

    2011-01-01

    Hirschsprung disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract. The HSCR phenotype is highly variable with respect to gender, length of aganglionosis, familiality and the presence of additional anomalies. By molecular genetic analysis, a minimum of 11 neuro-developmental genes (RET, GDNF, NRTN, SOX10, EDNRB, EDN3, ECE1, ZFHX1B, PHOX2B, KIAA1279, TCF4) are known to harbor rare, high-penetrance mutations that confer a large risk to the bearer. In addition, two other genes (RET, NRG1) harbor common, low-penetrance polymorphisms that contribute only partially to risk and can act as genetic modifiers. To broaden this search, we examined whether a set of 67 proven and candidate HSCR genes harbored additional modifier alleles. In this pilot study, we utilized a custom-designed array CGH with ∼33,000 test probes at an average resolution of ∼185 bp to detect gene-sized or smaller copy number variants (CNVs) within these 67 genes in 18 heterogeneous HSCR patients. Using stringent criteria, we identified CNVs at three loci (MAPK10, ZFHX1B, SOX2) that are novel, involve regulatory and coding sequences of neuro-developmental genes, and show association with HSCR in combination with other congenital anomalies. Additional CNVs are observed under relaxed criteria. Our research suggests a role for CNVs in HSCR and, importantly, emphasizes the role of variation in regulatory sequences. A much larger study will be necessary both for replication and for identifying the full spectrum of small CNV effects. PMID:21712996

  16. The Axon Guidance Receptor Gene ROBO1 Is a Candidate Gene for Developmental Dyslexia.

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    2005-10-01

    Full Text Available Dyslexia, or specific reading disability, is the most common learning disorder with a complex, partially genetic basis, but its biochemical mechanisms remain poorly understood. A locus on Chromosome 3, DYX5, has been linked to dyslexia in one large family and speech-sound disorder in a subset of small families. We found that the axon guidance receptor gene ROBO1, orthologous to the Drosophila roundabout gene, is disrupted by a chromosome translocation in a dyslexic individual. In a large pedigree with 21 dyslexic individuals genetically linked to a specific haplotype of ROBO1 (not found in any other chromosomes in our samples, the expression of ROBO1 from this haplotype was absent or attenuated in affected individuals. Sequencing of ROBO1 in apes revealed multiple coding differences, and the selection pressure was significantly different between the human, chimpanzee, and gorilla branch as compared to orangutan. We also identified novel exons and splice variants of ROBO1 that may explain the apparent phenotypic differences between human and mouse in heterozygous loss of ROBO1. We conclude that dyslexia may be caused by partial haplo-insufficiency for ROBO1 in rare families. Thus, our data suggest that a slight disturbance in neuronal axon crossing across the midline between brain hemispheres, dendrite guidance, or another function of ROBO1 may manifest as a specific reading disability in humans.

  17. The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia.

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    Katariina Hannula-Jouppi

    2005-10-01

    Full Text Available Dyslexia, or specific reading disability, is the most common learning disorder with a complex, partially genetic basis, but its biochemical mechanisms remain poorly understood. A locus on Chromosome 3, DYX5, has been linked to dyslexia in one large family and speech-sound disorder in a subset of small families. We found that the axon guidance receptor gene ROBO1, orthologous to the Drosophila roundabout gene, is disrupted by a chromosome translocation in a dyslexic individual. In a large pedigree with 21 dyslexic individuals genetically linked to a specific haplotype of ROBO1 (not found in any other chromosomes in our samples, the expression of ROBO1 from this haplotype was absent or attenuated in affected individuals. Sequencing of ROBO1 in apes revealed multiple coding differences, and the selection pressure was significantly different between the human, chimpanzee, and gorilla branch as compared to orangutan. We also identified novel exons and splice variants of ROBO1 that may explain the apparent phenotypic differences between human and mouse in heterozygous loss of ROBO1. We conclude that dyslexia may be caused by partial haplo-insufficiency for ROBO1 in rare families. Thus, our data suggest that a slight disturbance in neuronal axon crossing across the midline between brain hemispheres, dendrite guidance, or another function of ROBO1 may manifest as a specific reading disability in humans.

  18. Variation in umami perception and in candidate genes for the umami receptor in mice and humans.

    Science.gov (United States)

    Shigemura, Noriatsu; Shirosaki, Shinya; Ohkuri, Tadahiro; Sanematsu, Keisuke; Islam, A A Shahidul; Ogiwara, Yoko; Kawai, Misako; Yoshida, Ryusuke; Ninomiya, Yuzo

    2009-09-01

    The unique taste induced by monosodium glutamate is referred to as umami taste. The umami taste is also elicited by the purine nucleotides inosine 5'-monophosphate and guanosine 5'-monophosphate. There is evidence that a heterodimeric G protein-coupled receptor, which consists of the T1R1 (taste receptor type 1, member 1, Tas1r1) and the T1R3 (taste receptor type 1, member 3, Tas1r3) proteins, functions as an umami taste receptor for rodents and humans. Splice variants of metabotropic glutamate receptors, mGluR(1) (glutamate receptor, metabotropic 1, Grm1) and mGluR(4) (glutamate receptor, metabotropic 4, Grm4), also have been proposed as taste receptors for glutamate. The taste sensitivity to umami substances varies in inbred mouse strains and in individual humans. However, little is known about the relation of umami taste sensitivity to variations in candidate umami receptor genes in rodents or in humans. In this article, we summarize current knowledge of the diversity of umami perception in mice and humans. Furthermore, we combine previously published data and new information from the single nucleotide polymorphism databases regarding variation in the mouse and human candidate umami receptor genes: mouse Tas1r1 (TAS1R1 for human), mouse Tas1r3 (TAS1R3 for human), mouse Grm1 (GRM1 for human), and mouse Grm4 (GRM4 for human). Finally, we discuss prospective associations between variation of these genes and umami taste perception in both species.

  19. Regional Association Analysis of MetaQTLs Delineates Candidate Grain Size Genes in Rice

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    Anurag V. Daware

    2017-05-01

    Full Text Available Molecular mapping studies which aim to identify genetic basis of diverse agronomic traits are vital for marker-assisted crop improvement. Numerous Quantitative Trait Loci (QTLs mapped in rice span long genomic intervals with hundreds to thousands of genes, which limits their utilization for marker-assisted genetic enhancement of rice. Although potent, fine mapping of QTLs is challenging task as it requires screening of large number of segregants to identify suitable recombination events. Association mapping offers much higher resolution as compared to QTL mapping, but detects considerable number of spurious QTLs. Therefore, combined use of QTL and association mapping strategies can provide advantages associated with both these methods. In the current study, we utilized meta-analysis approach to identify metaQTLs associated with grain size/weight in diverse Indian indica and aromatic rice accessions. Subsequently, attempt has been made to narrow-down identified grain size/weight metaQTLs through individual SNP- as well as haplotype-based regional association analysis. The study identified six different metaQTL regions, three of which were successfully revalidated, and substantially scaled-down along with GS3 QTL interval (positive control by regional association analysis. Consequently, two potential candidate genes within two reduced metaQTLs were identified based on their differential expression profiles in different tissues/stages of rice accessions during seed development. The developed strategy has broader practical utility for rapid delineation of candidate genes and natural alleles underlying QTLs associated with complex agronomic traits in rice as well as major crop plants enriched with useful genetic and genomic information.

  20. Identification of Novel Candidate Genes for Early-Onset Colorectal Cancer Susceptibility.

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    Richarda M de Voer

    2016-02-01

    Full Text Available Approximately 25-30% of colorectal cancer (CRC cases are expected to result from a genetic predisposition, but in only 5-10% of these cases highly penetrant germline mutations are found. The remaining CRC heritability is still unexplained, and may be caused by a hitherto-undefined set of rare variants with a moderately penetrant risk. Here we aimed to identify novel risk factors for early-onset CRC using whole-exome sequencing, which was performed on a cohort of CRC individuals (n = 55 with a disease onset before 45 years of age. We searched for genes that were recurrently affected by rare variants (minor allele frequency ≤ 0.001 with potentially damaging effects and, subsequently, re-sequenced the candidate genes in a replication cohort of 174 early-onset or familial CRC individuals. Two functionally relevant genes with low frequency variants with potentially damaging effects, PTPN12 and LRP6, were found in at least three individuals. The protein tyrosine phosphatase PTP-PEST, encoded by PTPN12, is a regulator of cell motility and LRP6 is a component of the WNT-FZD-LRP5-LRP6 complex that triggers WNT signaling. All variants in LRP6 were identified in individuals with an extremely early-onset of the disease (≤30 years of age, and two of the three variants showed increased WNT signaling activity in vitro. In conclusion, we present PTPN12 and LRP6 as novel candidates contributing to the heterogeneous susceptibility to CRC.

  1. Identification of Quantitative Trait Loci (QTL) and Candidate Genes for Cadmium Tolerance in Populus

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    Induri, Brahma R [West Virginia University; Ellis, Danielle R [West Virginia University; Slavov, Gancho [West Virginia University; Yin, Tongming [ORNL; Muchero, Wellington [ORNL; Tuskan, Gerald A [ORNL; DiFazio, Stephen P [West Virginia University

    2012-01-01

    Knowledge of genetic variation in response of Populus to heavy metals like cadmium (Cd) is an important step in understanding the underlying mechanisms of tolerance. In this study, a pseudo-backcross pedigree of Populus trichocarpa and Populus deltoides was characterized for Cd exposure. The pedigree showed significant variation for Cd tolerance thus enabling the identification of relatively tolerant and susceptible genotypes for intensive characterization. A total of 16 QTLs at logarithm of odds (LOD) ratio > 2.5, were found to be associated with total dry weight, its components, and root volume. Four major QTLs for total dry weight were mapped to different linkage groups in control (LG III) and Cd conditions (LG XVI) and had opposite allelic effects on Cd tolerance, suggesting that these genomic regions were differentially controlled. The phenotypic variation explained by Cd QTL for all traits under study varied from 5.9% to 11.6% and averaged 8.2% across all QTL. Leaf Cd contents also showed significant variation suggesting the phytoextraction potential of Populus genotypes, though heritability of this trait was low (0.22). A whole-genome microarray study was conducted by using two genotypes with extreme responses for Cd tolerance in the above study and differentially expressed genes were identified. Candidate genes including CAD2 (CADMIUM SENSITIVE 2), HMA5 (HEAVY METAL ATPase5), ATGTST1 (Arabidopsis thaliana Glutathione S-Transferase1), ATGPX6 (Glutathione peroxidase 6), and ATMRP 14 (Arabidopsis thaliana Multidrug Resistance associated Protein 14) were identified from QTL intervals and microarray study. Functional characterization of these candidate genes could enhance phytoremediation capabilities of Populus.

  2. Leveraging Online Resources to Prioritize Candidate Genes for Functional Analyses: Using the Fetal Testis as a Test Case.

    Science.gov (United States)

    McClelland, Kathryn S; Yao, Humphrey H-C

    2017-01-01

    With each new microarray or RNA-seq experiment, massive quantities of transcriptomic information are generated with the purpose to produce a list of candidate genes for functional analyses. Yet an effective strategy remains elusive to prioritize the genes on these candidate lists. In this review, we outline a prioritizing strategy by taking a step back from the bench and leveraging the rich range of public databases. This in silico approach provides an economical, less biased, and more effective solution. We discuss the publicly available online resources that can be used to answer a range of questions about a gene. Is the gene of interest expressed in the system of interest (using expression databases)? Where else is this gene expressed (using added-value transcriptomic resources)? What pathways and processes is the gene involved in (using enriched gene pathway analysis and mouse knockout databases)? Is this gene correlated with human diseases (using human disease variant databases)? Using mouse fetal testis as an example, our strategies identified 298 genes annotated as expressed in the fetal testis. We cross-referenced these genes to existing microarray data and narrowed the list down to cell-type-specific candidates (35 for Sertoli cells, 11 for Leydig cells, and 25 for germ cells). Our strategies can be customized so that they allow researchers to effectively and confidently prioritize genes for functional analysis. © 2017 S. Karger AG, Basel.

  3. Novel candidate genes for 46,XY gonadal dysgenesis identified by a customized 1 M array-CGH platform.

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    Norling, Ameli; Lindén Hirschberg, Angelica; Iwarsson, Erik; Persson, Bengt; Wedell, Anna; Barbaro, Michela

    2013-12-01

    Half of all patients with a disorder of sex development (DSD) do not receive a specific molecular diagnosis. Comparative genomic hybridization (CGH) can detect copy number changes causing gene haploinsufficiency or over-expression that can lead to impaired gonadal development and gonadal DSD. The purpose of this study was to identify novel candidate genes for 46,XY gonadal dysgenesis (GD) using a customized 1 M array-CGH platform with whole-genome coverage and probe enrichment targeting 78 genes involved in sex development. Fourteen patients with 46,XY gonadal DSD were enrolled in the study. Nine individuals were analyzed by array CGH. All patients were included in a follow up sequencing study of candidate genes. Three novel candidate regions for 46,XY GD were identified in two patients. An interstitial duplication of the SUPT3H gene and a deletion of C2ORF80 were detected in a pair of affected siblings. Sequence analysis of these genes in all patients revealed no additional mutations. A large duplication highlighting PIP5K1B, PRKACG and FAM189A2 as candidates for 46,XY GD, were also detected. All five genes are expressed in testicular tissues, and one is shown to cause gonadal DSD in mice. However detailed functional information is lacking for these genes. Copyright © 2013 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

  4. Interactions Between Early Trauma and Catechol-O-Methyltransferase Genes on Inhibitory Deficits in Children With ADHD.

    Science.gov (United States)

    Park, Subin; Kim, Bung-Nyun; Kim, Jae-Won; Shin, Min-Sup; Yoo, Hee Jeong; Cho, Soo-Churl

    2017-02-01

    To investigate the interaction between childhood trauma exposure with the catechol-O-methyltransferase (COMT) and dopamine receptor D4 (DRD4) polymorphisms in relation to neuropsychological measures in children with ADHD. A cross-sectional examination of early traumatic experiences and the continuous performance test (CPT) were performed in 55 children with ADHD. Participants were also genotyped for the DRD4 exon III 48-bp variable number of tandem repeats (VNTR) polymorphism and the COMT Val158-Met (rs4680) polymorphism. There was significant interaction between the effects of the COMT genotype and trauma in commission errors. In participants with ADHD carrying the COMT Val/Val genotype, the group exposed to trauma showed significantly higher commission errors than the non-traumatized group. However, for the participants with other genotypes, no significant differences were found. This study suggests that there exists a genetic influence on the association between childhood trauma and the severity of inhibitory deficits in children with ADHD.

  5. Candidate Gene Identification with SNP Marker-Based Fine Mapping of Anthracnose Resistance Gene Co-4 in Common Bean

    Science.gov (United States)

    Burt, Andrew J.; William, H. Manilal; Perry, Gregory; Khanal, Raja; Pauls, K. Peter; Kelly, James D.; Navabi, Alireza

    2015-01-01

    Anthracnose, caused by Colletotrichum lindemuthianum, is an important fungal disease of common bean (Phaseolus vulgaris). Alleles at the Co–4 locus confer resistance to a number of races of C. lindemuthianum. A population of 94 F4:5 recombinant inbred lines of a cross between resistant black bean genotype B09197 and susceptible navy bean cultivar Nautica was used to identify markers associated with resistance in bean chromosome 8 (Pv08) where Co–4 is localized. Three SCAR markers with known linkage to Co–4 and a panel of single nucleotide markers were used for genotyping. A refined physical region on Pv08 with significant association with anthracnose resistance identified by markers was used in BLAST searches with the genomic sequence of common bean accession G19833. Thirty two unique annotated candidate genes were identified that spanned a physical region of 936.46 kb. A majority of the annotated genes identified had functional similarity to leucine rich repeats/receptor like kinase domains. Three annotated genes had similarity to 1, 3-β-glucanase domains. There were sequence similarities between some of the annotated genes found in the study and the genes associated with phosphoinositide-specific phosphilipases C associated with Co-x and the COK–4 loci found in previous studies. It is possible that the Co–4 locus is structured as a group of genes with functional domains dominated by protein tyrosine kinase along with leucine rich repeats/nucleotide binding site, phosphilipases C as well as β-glucanases. PMID:26431031

  6. Identification of candidate genes in Populus cell wall biosynthesis using text-mining, co-expression network and comparative genomics

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    Yang, Xiaohan [ORNL; Ye, Chuyu [ORNL; Bisaria, Anjali [ORNL; Tuskan, Gerald A [ORNL; Kalluri, Udaya C [ORNL

    2011-01-01

    Populus is an important bioenergy crop for bioethanol production. A greater understanding of cell wall biosynthesis processes is critical in reducing biomass recalcitrance, a major hindrance in efficient generation of ethanol from lignocellulosic biomass. Here, we report the identification of candidate cell wall biosynthesis genes through the development and application of a novel bioinformatics pipeline. As a first step, via text-mining of PubMed publications, we obtained 121 Arabidopsis genes that had the experimental evidences supporting their involvement in cell wall biosynthesis or remodeling. The 121 genes were then used as bait genes to query an Arabidopsis co-expression database and additional genes were identified as neighbors of the bait genes in the network, increasing the number of genes to 548. The 548 Arabidopsis genes were then used to re-query the Arabidopsis co-expression database and re-construct a network that captured additional network neighbors, expanding to a total of 694 genes. The 694 Arabidopsis genes were computationally divided into 22 clusters. Queries of the Populus genome using the Arabidopsis genes revealed 817 Populus orthologs. Functional analysis of gene ontology and tissue-specific gene expression indicated that these Arabidopsis and Populus genes are high likelihood candidates for functional genomics in relation to cell wall biosynthesis.

  7. Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk.

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    Montserrat García-Closas

    2007-02-01

    Full Text Available Common genetic variation could alter the risk for developing bladder cancer. We conducted a large-scale evaluation of single nucleotide polymorphisms (SNPs in candidate genes for cancer to identify common variants that influence bladder cancer risk. An Illumina GoldenGate assay was used to genotype 1,433 SNPs within or near 386 genes in 1,086 cases and 1,033 controls in Spain. The most significant finding was in the 5' UTR of VEGF (rs25648, p for likelihood ratio test, 2 degrees of freedom = 1 x 10(-5. To further investigate the region, we analyzed 29 additional SNPs in VEGF, selected to saturate the promoter and 5' UTR and to tag common genetic variation in this gene. Three additional SNPs in the promoter region (rs833052, rs1109324, and rs1547651 were associated with increased risk for bladder cancer: odds ratio (95% confidence interval: 2.52 (1.06-5.97, 2.74 (1.26-5.98, and 3.02 (1.36-6.63, respectively; and a polymorphism in intron 2 (rs3024994 was associated with reduced risk: 0.65 (0.46-0.91. Two of the promoter SNPs and the intron 2 SNP showed linkage disequilibrium with rs25648. Haplotype analyses revealed three blocks of linkage disequilibrium with significant associations for two blocks including the promoter and 5' UTR (global p = 0.02 and 0.009, respectively. These findings are biologically plausible since VEGF is critical in angiogenesis, which is important for tumor growth, its elevated expression in bladder tumors correlates with tumor progression, and specific 5' UTR haplotypes have been shown to influence promoter activity. Associations between bladder cancer risk and other genes in this report were not robust based on false discovery rate calculations. In conclusion, this large-scale evaluation of candidate cancer genes has identified common genetic variants in the regulatory regions of VEGF that could be associated with bladder cancer risk.

  8. Association analysis of nine candidate gene polymorphisms in Indian patients with type 2 diabetic retinopathy

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    Govindarajan Gowthaman

    2010-11-01

    Full Text Available Abstract Background Diabetic retinopathy (DR is classically defined as a microvasculopathy that primarily affects the small blood vessels of the inner retina as a complication of diabetes mellitus (DM.It is a multifactorial disease with a strong genetic component. The aim of this study is to investigate the association of a set of nine candidate genes with the development of diabetic retinopathy in a South Indian cohort who have type 2 diabetes mellitus (T2DM. Methods Seven candidate genes (RAGE, PEDF, AKR1B1, EPO, HTRA1, ICAM and HFE were chosen based on reported association with DR in the literature. Two more, CFH and ARMS2, were chosen based on their roles in biological pathways previously implicated in DR. Fourteen single nucleotide polymorphisms (SNPs and one dinucleotide repeat polymorphism, previously reported to show association with DR or other related diseases, were genotyped in 345 DR and 356 diabetic patients without retinopathy (DNR. The genes which showed positive association in this screening set were tested further in additional sets of 100 DR and 90 DNR additional patients from the Aravind Eye Hospital. Those which showed association in the secondary screen were subjected to a combined analysis with the 100 DR and 100 DNR subjects previously recruited and genotyped through the Sankara Nethralaya Hospital, India. Genotypes were evaluated using a combination of direct sequencing, TaqMan SNP genotyping, RFLP analysis, and SNaPshot PCR assays. Chi-square and Fisher exact tests were used to analyze the genotype and allele frequencies. Results Among the nine loci (15 polymorphisms screened, SNP rs2070600 (G82S in the RAGE gene, showed significant association with DR (allelic P = 0.016, dominant model P = 0.012, compared to DNR. SNP rs2070600 further showed significant association with DR in the confirmation cohort (P = 0.035, dominant model P = 0.032. Combining the two cohorts gave an allelic P HTRA1, rs11200638 (G>A, showed marginal

  9. A stratified transcriptomics analysis of polygenic fat and lean mouse adipose tissues identifies novel candidate obesity genes.

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    Nicholas M Morton

    Full Text Available 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.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.A focussed candidate gene enrichment strategy in the unique F and L model has identified novel adipose tissue-enriched genes contributing to obesity.

  10. Hardy-Weinberg equilibrium analysis of the 48 bp VNTR in the III exon of the DRD4 gene in a sample of parents of ADHD cases.

    Science.gov (United States)

    Trejo, Salvador; Toscano-Flores, José J; Matute, Esmeralda; Ramírez-Dueñas, María de Lourdes

    2015-01-01

    The aim of this study was to obtain the genotype and gene frequency from parents of children with attention-deficit/hyperactivity disorder (ADHD) and then assess the Hardy-Weinberg equilibrium of genotype frequency of the variable number tandem repeat (VNTR) III exon of the dopamine receptor D4 (DRD4) gene. The genotypes of the III exon of 48 bp VNTR repeats of the DRD4 gene were determined by polymerase chain reaction in a sample of 30 parents of ADHD cases. In the 60 chromosomes analyzed, the following frequencies of DRD4 gene polymorphisms were observed: six chromosomes (c) with two repeat alleles (r) (10%); 1c with 3r (1.5%); 36c with 4r (60%); 1c with 5r (1.5%); and 16c with 7r (27%). The genotypic distribution of the 30 parents was two parents (p) with 2r/2r (6.67%); 1p with 2r/4r (3.33%); 1p with 2r/5r (3.33%); 1p with 3r/4r (3.33%); 15p with 4r/4r (50%); 4p with 4r/7r (13.33); and 6p with 7r/7r (20%). A Hardy-Weinberg disequilibrium (χ (2)=13.03, P<0.01) was found due to an over-representation of the 7r/7r genotype. These results suggest that the 7r polymorphism of the DRD4 gene is associated with the ADHD condition in a Mexican population.

  11. Candidate Gene Discovery Procedure after Follow-Up Confirmatory Analyses of Candidate Regions of Interests for Alzheimer’s Disease in the NIMH Sibling Dataset

    Directory of Open Access Journals (Sweden)

    Tesfaye M. Baye

    2008-01-01

    Full Text Available The objective of this research was to develop a procedure to identify candidate genes under linkage peaks confirmed in a follow-up of candidate regions of interests (CRIs identified in our original genome scan in the NIMH Alzheimer’s diseases (AD Initiative families (Blacker et al. [1]. There were six CRIs identified that met the threshold of multipoint lod score (MLS of ≥ 2.0 from the original scan. The most significant peak (MLS = 7.7 was at 19q13, which was attributed to APOE. The remaining CRIs with ‘suggestive’ evidence for linkage were identified at 9q22, 6q27, 14q22, 11q25, and 3p26. We have followed up and narrowed the 9q22 CRI signal using simple tandem repeat (STR markers (Perry et al. [2]. In this confirmatory project, we have followed up the 6q27, 14q22, 11q25, and 3p26 CRIs with a total of 24 additional flanking STRs, reducing the mean interval marker distance (MID in each CRI, and substantially increase in the information content (IC. The linkage signals at 6q27, 14q22 and 11q25 remain ‘suggestive’, indicating that these CRIs are promising and worthy of detailed fine mapping and assessment of candidate genes associated with AD.

  12. Genetic susceptibility to chronic otitis media with effusion: candidate gene single nucleotide polymorphisms.

    Science.gov (United States)

    MacArthur, Carol J; Wilmot, Beth; Wang, Linda; Schuller, Michael; Lighthall, Jessyka; Trune, Dennis

    2014-05-01

    The genetic factors leading to a predisposition to otitis media are not well understood. The objective of the current study was to develop a tag-single nucleotide polymorphism (SNP) panel to determine if there is an association between candidate gene polymorphisms and the development of chronic otitis media with effusion. A 1:1 case/control design of 100 cases and 100 controls was used. The study was limited to the chronic otitis media with effusion phenotype to increase the population homogeneity. A panel of 192 tag-SNPs was selected. Saliva for DNA extraction was collected from 100 chronic otitis media with effusion cases and 100 controls. After quality control, 100 case and 79 control samples were available for hybridization. Genomic DNA from each subject was hybridized to the SNP probes, and genotypes were generated. Quality control across all samples and SNPs reduced the final SNPs used for analysis to 170. Each SNP was then analyzed for statistical association with chronic otitis media with effusion. Eight SNPs from four genes had an unadjusted P value of otitis media with effusion phenotype (TLR4, MUC5B, SMAD2, SMAD4); five of these polymorphisms were in the TLR4 gene. Even though these results need to be replicated in a novel population, the presence of five SNPs in the TLR4 gene having association with chronic otitis media with effusion in our study population lends evidence for the possible role of this gene in the susceptibility to otitis media. © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

  13. Prediction potential of candidate biomarker sets identified and validated on gene expression data from multiple datasets

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    Karacali Bilge

    2007-10-01

    Full Text Available Abstract Background Independently derived expression profiles of the same biological condition often have few genes in common. In this study, we created populations of expression profiles from publicly available microarray datasets of cancer (breast, lymphoma and renal samples linked to clinical information with an iterative machine learning algorithm. ROC curves were used to assess the prediction error of each profile for classification. We compared the prediction error of profiles correlated with molecular phenotype against profiles correlated with relapse-free status. Prediction error of profiles identified with supervised univariate feature selection algorithms were compared to profiles selected randomly from a all genes on the microarray platform and b a list of known disease-related genes (a priori selection. We also determined the relevance of expression profiles on test arrays from independent datasets, measured on either the same or different microarray platforms. Results Highly discriminative expression profiles were produced on both simulated gene expression data and expression data from breast cancer and lymphoma datasets on the basis of ER and BCL-6 expression, respectively. Use of relapse-free status to identify profiles for prognosis prediction resulted in poorly discriminative decision rules. Supervised feature selection resulted in more accurate classifications than random or a priori selection, however, the difference in prediction error decreased as the number of features increased. These results held when decision rules were applied across-datasets to samples profiled on the same microarray platform. Conclusion Our results show that many gene sets predict molecular phenotypes accurately. Given this, expression profiles identified using different training datasets should be expected to show little agreement. In addition, we demonstrate the difficulty in predicting relapse directly from microarray data using supervised machine

  14. MRPL53, a New Candidate Gene for Orofacial Clefting, Identified Using an eQTL Approach.

    Science.gov (United States)

    Masotti, C; Brito, L A; Nica, A C; Ludwig, K U; Nunes, K; Savastano, C P; Malcher, C; Ferreira, S G; Kobayashi, G S; Bueno, D F; Alonso, N; Franco, D; Rojas-Martinez, A; Dos Santos, S E; Galante, P A; Meyer, D; Hünemeier, T; Mangold, E; Dermitzakis, E T; Passos-Bueno, M R

    2018-01-01

    A valuable approach to understand how individual and population genetic differences can predispose to disease is to assess the impact of genetic variants on cellular functions (e.g., gene expression) of cell and tissue types related to pathological states. To understand the genetic basis of nonsyndromic cleft lip with or without cleft palate (NSCL/P) susceptibility, a complex and highly prevalent congenital malformation, we searched for genetic variants with a regulatory role in a disease-related tissue, the lip muscle (orbicularis oris muscle [OOM]), of affected individuals. From 46 OOM samples, which are frequently discarded during routine corrective surgeries on patients with orofacial clefts, we derived mesenchymal stem cells and correlated the individual genetic variants with gene expression from these cultured cells. Through this strategy, we detected significant cis-eQTLs (i.e., DNA variants affecting gene expression) and selected a few candidates to conduct an association study in a large Brazilian cohort (624 patients and 668 controls). This resulted in the discovery of a novel susceptibility locus for NSCL/P, rs1063588, the best eQTL for the MRPL53 gene, where evidence for association was mostly driven by the Native American ancestry component of our Brazilian sample. MRPL53 (2p13.1) encodes a 39S protein subunit of mitochondrial ribosomes and interacts with MYC, a transcription factor required for normal facial morphogenesis. Our study illustrates not only the importance of sampling admixed populations but also the relevance of measuring the functional effects of genetic variants over gene expression to dissect the complexity of disease phenotypes.

  15. Candidate Genes for Testicular Cancer Evaluated by In Situ Protein Expression Analyses on Tissue Microarrays1

    Science.gov (United States)

    Skotheim, Rolf I; Abeler, Vera M; Nesland, Jahn M; Fosså, Sophie D; Holm, Ruth; Wagner, Urs; Flørenes, Vivi Ann; Aass, Nina; Kallioniemi, Olli P; Lothe, Ragnhild A

    2003-01-01

    Abstract By the use of high-throughput molecular technologies, the number of genes and proteins potentially relevant to testicular germ cell tumor (TGCT) and other diseases will increase rapidly. In a recent transcriptional profiling, we demonstrated the overexpression of GRB7 and JUP in TGCTs, and confirmed the reported overexpression of CCND2. We also have recent evidences for frequent genetic alterations of FHIT and epigenetic alterations of MGMT. To evaluate whether the expression of these genes is related to any clinicopathological variables, we constructed a tissue microarray with 510 testicular tissue cores from 279 patients diagnosed with TGCT, covering various histological subgroups and clinical stages. By immunohistochemistry, we found that JUP, GRB7, and CCND2 proteins were rarely present in normal testis, but frequently expressed at high levels in TGCT. Additionally, all premalignant intratubular germ cell neoplasias were JUP-immunopositive. MGMT and FHIT were expressed by normal testicular tissues, but at significantly lower frequencies in TGCT. Except for CCND2, the expressions of all markers were significantly associated with various TGCT subtypes. In summary, we have developed a high-throughput tool for the evaluation of TGCT markers, and utilized this to validate five candidate genes whose protein expressions were indeed deregulated in TGCT. PMID:14670177

  16. Transcriptome Analysis Reveals Candidate Genes involved in Blister Blight defense in Tea (Camellia sinensis (L) Kuntze)

    Science.gov (United States)

    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.

  17. Candidate gene mutation analysis in idiopathic acquired sideroblastic anemia (refractory anemia with ringed sideroblasts).

    Science.gov (United States)

    Steensma, David P; Hecksel, Kathleen A; Porcher, Julie C; Lasho, Terra L

    2007-05-01

    For most cases of idiopathic acquired sideroblastic anemia (IASA), the molecular pathogenesis is unknown, despite the consistent morphological signature of abundant pathological ringed sideroblasts with their characteristic iron-engorged mitochondria. Moderately elevated free erythrocyte protoporphyrin (FEP) levels have been described in IASA, suggesting that the activity of ferrochelatase, the enzyme that catalyzes the final step in heme biosynthesis (incorporation of ferrous iron into protoporphyrin), might be diminished in erythroid progenitor cells from IASA patients. We confirmed FEP elevation in IASA, then pursued a candidate gene approach that included screening the gene encoding ferrochelatase, FECH, for promoter and coding region mutations and mRNA expression changes in bone marrow from 37 patients with IASA. The analytical techniques employed detected mutations in a test cohort of previously undiagnosed patients with biochemical evidence for erythropoietic protoporphyria, a condition resulting from germline mutations in FECH, but somatic missense mutations of FECH and its promoter were not observed in IASA patients. FECH was modestly overexpressed in progenitor cells from patients with IASA, compared with MDS patients without sideroblasts and healthy controls. In addition, we analyzed ABCB7 and PUS1, genes implicated in congenital sideroblastic anemia syndromes, but again found no coding mutations in acquired cases. We conclude that acquired mutations in the factors currently known to cause inherited sideroblastic anemias are uncommon in IASA.

  18. Candidate Genes for Testicular Cancer Evaluated by In Situ Protein Expression Analyses on Tissue Microarrays

    Directory of Open Access Journals (Sweden)

    Rolf I. Skotheim

    2003-09-01

    Full Text Available By the use of high-throughput molecular technologies, the number of genes and proteins potentially relevant to testicular germ cell tumor (TGCT and other diseases will increase rapidly. In a recent transcriptional profiling, we demonstrated the overexpression of GRB7 and JUP in TGCTs, confirmed the reported overexpression of CCND2. We also have recent evidences for frequent genetic alterations of FHIT and epigenetic alterations of MGMT. To evaluate whether the expression of these genes is related to any clinicopathological variables, we constructed a tissue microarray with 510 testicular tissue cores from 279 patients diagnosed with TGCT, covering various histological subgroups and clinical stages. By immunohistochemistry, we found that JUP, GRB7, CCND2 proteins were rarely present in normal testis, but frequently expressed at high levels in TGCT. Additionally, all premalignant intratubular germ cell neoplasias were JUP-immunopositive. MGMT and FHIT were expressed by normal testicular tissues, but at significantly lower frequencies in TGCT. Except for CCND2, the expressions of all markers were significantly associated with various TGCT subtypes. In summary, we have developed a high-throughput tool for the evaluation of TGCT markers, utilized this to validate five candidate genes whose protein expressions were indeed deregulated in TGCT.

  19. Transcription of candidate virulence genes of Haemophilus ducreyi during infection of human volunteers.

    Science.gov (United States)

    Throm, R E; Spinola, S M

    2001-03-01

    Haemophilus ducreyi expresses several putative virulence factors in vitro. Isogenic mutant-to-parent comparisons have been performed in a human model of experimental infection to examine whether specific gene products are involved in pathogenesis. Several mutants (momp, ftpA, losB, lst, cdtC, and hhdB) were as virulent as the parent in the human model, suggesting that their gene products did not play a major role in pustule formation. However, we could not exclude the possibility that the gene of interest was not expressed during the initial stages of infection. Biopsies of pustules obtained from volunteers infected with H. ducreyi were subjected to reverse transcription-PCR. Transcripts corresponding to momp, ftpA, losB, lst, cdtB, and hhdA were expressed in vivo. In addition, transcripts for other putative virulence determinants such as ompA2, tdhA, lspA1, and lspA2 were detected in the biopsies. These results indicate that although several candidate virulence determinants are expressed during experimental infection, they do not have a major role in the initial stages of pathogenesis.

  20. Exome sequencing in 53 sporadic cases of schizophrenia identifies 18 putative candidate genes.

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    Michel Guipponi

    Full Text Available Schizophrenia (SCZ is a severe, debilitating mental illness which has a significant genetic component. The identification of genetic factors related to SCZ has been challenging and these factors remain largely unknown. To evaluate the contribution of de novo variants (DNVs to SCZ, we sequenced the exomes of 53 individuals with sporadic SCZ and of their non-affected parents. We identified 49 DNVs, 18 of which were predicted to alter gene function, including 13 damaging missense mutations, 2 conserved splice site mutations, 2 nonsense mutations, and 1 frameshift deletion. The average number of exonic DNV per proband was 0.88, which corresponds to an exonic point mutation rate of 1.7×10(-8 per nucleotide per generation. The non-synonymous-to-synonymous mutation ratio of 2.06 did not differ from neutral expectations. Overall, this study provides a list of 18 putative candidate genes for sporadic SCZ, and when combined with the results of similar reports, identifies a second proband carrying a non-synonymous DNV in the RGS12 gene.

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

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    Rajani Rai

    2015-11-01

    Full Text Available 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.

  2. Congenital keratoconjunctivitis sicca and ichthyosiform dermatosis in Cavalier King Charles spaniel dogs. Part II: candidate gene study.

    Science.gov (United States)

    Hartley, Claudia; Barnett, Keith C; Pettitt, Louise; Forman, Oliver P; Blott, Sarah; Mellersh, Cathryn S

    2012-09-01

    To identify causative mutation(s) for congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID) in Cavalier King Charles spaniel (CKCS) dogs using a candidate gene approach. DNA samples from 21 cases/parents were collected. Canine candidate genes (CCGs) for similar inherited human diseases were chosen. Twenty-eight candidate genes were identified by searching the Pubmed OMIM database (http://www.ncbi.nlm.nih.gov/omim). Canine orthologues of human candidate genes were identified using the Ensembl orthologue prediction facility (http://www.ensembl.org/index.html). Two microsatellites flanking each candidate gene were selected, and primers to amplify each microsatellite were designed using the Whitehead Institute primer design website (http://frodo.wi.mit.edu/primer3/). The microsatellites associated with all 28 CCGs were genotyped on a panel of 21 DNA samples from CKCS dogs (13 affected and eight carriers). Genotyping data was analyzed to identify markers homozygous in affected dogs and heterozygous in carriers (homozygosity mapping). None of the microsatellites associated with 25 of the CCGs displayed an association with CKCSID in the 21 DNA samples tested. Three CCGs associated microsatellites were monomorphic across all samples tested. Twenty-five CCGs were excluded as cause of CKCSID. Three CCGs could not be excluded from involvement in the inheritance of CKCSID. © 2012 American College of Veterinary Ophthalmologists.

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

    Science.gov (United States)

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

    2015-04-30

    Despite large-scale cancer genomics studies, key somatic mutations driving cancer, and their functional roles, remain elusive. Here, we propose that analysis of comorbidities of Mendelian diseases with cancers provides a novel, systematic way to discover new cancer genes. If germline genetic variation in Mendelian loci predisposes bearers to common cancers, the same loci may harbour cancer-associated somatic variation. Compilations of clinical records spanning over 100 million patients provide an unprecedented opportunity to assess clinical associations between Mendelian diseases and cancers. We systematically compare these comorbidities against recurrent somatic mutations from more than 5,000 patients across many cancers. Using multiple measures of genetic similarity, we show that a Mendelian disease and comorbid cancer indeed have genetic alterations of significant functional similarity. This result provides a basis to identify candidate drivers in cancers including melanoma and glioblastoma. Some Mendelian diseases demonstrate 'pan-cancer' comorbidity and shared genetics across cancers.

  4. Conserving marine biodiversity: insights from life-history trait candidate genes in Atlantic cod (Gadus morhua)

    DEFF Research Database (Denmark)

    Hansen, Jakob Hemmer; Therkildsen, Nina Overgaard; Meldrup, Dorte

    2014-01-01

    Recent technological developments have facilitated an increased focus on identifying genomic regions underlying adaptive trait variation in natural populations, and it has been advocated that this information should be important for designating population units for conservation. In marine fishes......, phenotypic studies have suggested adaptation through divergence of life-history traits among natural populations, but the distribution of adaptive genetic variation in these species is still relatively poorly known. In this study, we extract information about the geographical distribution of genetic...... variation for 33 single nucleotide polymorphisms (SNPs) associated with life-history trait candidate genes, and compare this to variation in 70 putatively neutral SNPs in Atlantic cod (Gadus morhua). We analyse samples covering the major population complexes in the eastern Atlantic and find strong evidence...

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

    Directory of Open Access Journals (Sweden)

    Cindy F Verdu

    Full Text Available 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.

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

    Science.gov (United States)

    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.

  7. Candidate gene approach identifies multiple genes and signaling pathways downstream of Tbx4 in the developing allantois.

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    Ripla Arora

    Full Text Available Loss of Tbx4 results in absence of chorio-allantoic fusion and failure of formation of the primary vascular plexus of the allantois leading to embryonic death at E10.5. We reviewed the literature for genes implicated in chorio-allantoic fusion, cavitation and vascular plexus formation, processes affected in Tbx4 mutant allantoises. Using this candidate gene approach, we identified a number of genes downstream of Tbx4 in the allantois including extracellular matrix molecules Vcan, Has2, and Itgα5, transcription factors Snai1 and Twist, and signaling molecules Bmp2, Bmp7, Notch2, Jag1 and Wnt2. In addition, we show that the canonical Wnt signaling pathway contributes to the vessel-forming potential of the allantois. Ex vivo, the Tbx4 mutant phenotype can be rescued using agonists of the Wnt signaling pathway and, in wildtype allantoises, an inhibitor of the canonical Wnt signaling pathway disrupts vascular plexus formation. In vivo, Tbx4 and Wnt2 double heterozygous placentas show decreased vasculature suggesting interactions between Tbx4 and the canonical Wnt signaling pathway in the process of allantois-derived blood vessel formation.

  8. Identifying candidate genes affecting developmental time in Drosophila melanogaster: pervasive pleiotropy and gene-by-environment interaction

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    Hasson Esteban

    2008-08-01

    Full Text Available Abstract Background Understanding the genetic architecture of ecologically relevant adaptive traits requires the contribution of developmental and evolutionary biology. The time to reach the age of reproduction is a complex life history trait commonly known as developmental time. In particular, in holometabolous insects that occupy ephemeral habitats, like fruit flies, the impact of developmental time on fitness is further exaggerated. The present work is one of the first systematic studies of the genetic basis of developmental time, in which we also evaluate the impact of environmental variation on the expression of the trait. Results We analyzed 179 co-isogenic single P[GT1]-element insertion lines of Drosophila melanogaster to identify novel genes affecting developmental time in flies reared at 25°C. Sixty percent of the lines showed a heterochronic phenotype, suggesting that a large number of genes affect this trait. Mutant lines for the genes Merlin and Karl showed the most extreme phenotypes exhibiting a developmental time reduction and increase, respectively, of over 2 days and 4 days relative to the control (a co-isogenic P-element insertion free line. In addition, a subset of 42 lines selected at random from the initial set of 179 lines was screened at 17°C. Interestingly, the gene-by-environment interaction accounted for 52% of total phenotypic variance. Plastic reaction norms were found for a large number of developmental time candidate genes. Conclusion We identified components of several integrated time-dependent pathways affecting egg-to-adult developmental time in Drosophila. At the same time, we also show that many heterochronic phenotypes may arise from changes in genes involved in several developmental mechanisms that do not explicitly control the timing of specific events. We also demonstrate that many developmental time genes have pleiotropic effects on several adult traits and that the action of most of them is sensitive

  9. Candidate cytochrome P450 genes for ethoxyresorufin O-deethylase activity in oyster Crassostrea gigas.

    Science.gov (United States)

    Siebert, Marília Nardelli; Mattos, Jacó Joaquim; Toledo-Silva, Guilherme; Razzera, Guilherme; Bainy, Afonso Celso Dias

    2017-08-01

    Vertebrate cytochrome P450 1 (CYP1) enzymes metabolize endogenous and xenobiotic compounds and usually demonstrate a substrate-inducible response. Ethoxyresorufin O-deethylase activity (EROD) is a common method to quantify CYP1 enzymes activity in these organisms. Despite the absence of this gene family in protostomes, CYP1-like genes were identified in several species, even though no evolutionary relationship has been established with the vertebrate CYP1 family. In the present study, EROD activity was evaluated in microsomal fraction of gills, digestive gland and mantle of Crassostrea gigas. Enzyme activity was quantified in gills, although no activity was detected in digestive gland and mantle. EROD kinetic characterization in gills using typical Michaelis-Menten equation demonstrated an apparent Km of 1.15μM and Vmax of 229.2 fmol.min-1mg.protein -1. EROD activity was analyzed in the presence of CYP1 inhibitors, ellipticine (ELP), furafylline (FRF), clotrimazole (CTZ), α-naphthoflavone (ANF), and the non-ionic surfactant Triton X-100. CTZ inhibited EROD activity in all tested concentrations while Triton X-100 (0.5mM) caused 16% inhibition. Transcript levels of four CYP1-like genes were determined in gills, digestive gland and mantle. In general, CYP1-like genes showed higher transcript levels in gills compared to other tissues. The transcript levels of CYP1-like 1 and 2, analyzed together, positively correlated with EROD activity observed in gills, suggesting the possible involvement of these two gene products in EROD activity in this tissue. Homology models of translated CYP1-like 1 and 2 were generated based on human CYP1A1 structure and were similar to the general canonical cytochrome P450 fold. Molecular docking analysis showed that the two putative oyster CYP1-like structures have the potential to metabolize 7-ethoxyresorufin (7-ER), although the contribution of other CYP1-like genes needs to be investigated. Proteins encoded by CYP1-like 1 and 2 genes

  10. Dynamic compression of chondrocyte-agarose constructs reveals new candidate mechanosensitive genes.

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    Carole Bougault

    Full Text Available Articular cartilage is physiologically exposed to repeated loads. The mechanical properties of cartilage are due to its extracellular matrix, and homeostasis is maintained by the sole cell type found in cartilage, the chondrocyte. Although mechanical forces clearly control the functions of articular chondrocytes, the biochemical pathways that mediate cellular responses to mechanical stress have not been fully characterised. The aim of our study was to examine early molecular events triggered by dynamic compression in chondrocytes. We used an experimental system consisting of primary mouse chondrocytes embedded within an agarose hydrogel; embedded cells were pre-cultured for one week and subjected to short-term compression experiments. Using Western blots, we demonstrated that chondrocytes maintain a differentiated phenotype in this model system and reproduce typical chondrocyte-cartilage matrix interactions. We investigated the impact of dynamic compression on the phosphorylation state of signalling molecules and genome-wide gene expression. After 15 min of dynamic compression, we observed transient activation of ERK1/2 and p38 (members of the mitogen-activated protein kinase (MAPK pathways and Smad2/3 (members of the canonical transforming growth factor (TGF-β pathways. A microarray analysis performed on chondrocytes compressed for 30 min revealed that only 20 transcripts were modulated more than 2-fold. A less conservative list of 325 modulated genes included genes related to the MAPK and TGF-β pathways and/or known to be mechanosensitive in other biological contexts. Of these candidate mechanosensitive genes, 85% were down-regulated. Down-regulation may therefore represent a general control mechanism for a rapid response to dynamic compression. Furthermore, modulation of transcripts corresponding to different aspects of cellular physiology was observed, such as non-coding RNAs or primary cilium. This study provides new insight into how

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

    Science.gov (United States)

    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. © 2015 John Wiley & Sons Ltd.

  12. A candidate gene-based association study of tocopherol content and composition in rapeseed (Brassica napus

    Directory of Open Access Journals (Sweden)

    Steffi eFritsche

    2012-06-01

    Full Text Available Rapeseed (Brassica napus L. is the most important oil crop of temperate climates. Rapeseed oil contains tocopherols, also known as vitamin E, which is an indispensable nutrient for humans and animals due to its antioxidant and radical scavenging abilities. Moreover, tocopherols are also important for the oxidative stability of vegetable oils. Therefore, seed oil with increased tocopherol content or altered tocopherol composition is a target for breeding. We investigated the role of nucleotide variations within candidate genes from the tocopherol biosynthesis pathway. Field trials were carried out with 229 accessions from a worldwide B. napus collection which was divided into two panels of 96 and 133 accessions. Seed tocopherol content and composition were measured by HPLC. High heritabilities were found for both traits, ranging from 0.62 to 0.94. We identified polymorphisms by sequencing selected regions of the tocopherol genes from the 96 accession panel. Subsequently, we determined the population structure (Q and relative kinship (K as detected by genotyping with genome-wide distributed SSR markers. Association studies were performed using two models, the structure-based GLM+Q and the PK mixed model. Between 26 and 12 polymorphisms within two genes (BnaX.VTE3.a, BnaA.PDS1.c were significantly associated with tocopherol traits. The SNPs explained up to 16.93 % of the genetic variance for tocopherol composition and up to 10.48 % for total tocopherol content. Based on the sequence information we designed CAPS markers for genotyping the 133 accessions from the 2nd panel. Significant associations with various tocopherol traits confirmed the results from the first experiment. We demonstrate that the polymorphisms within the tocopherol genes clearly impact tocopherol content and composition in B. napus seeds. We suggest that these nucleotide variations may be used as selectable markers for breeding rapeseed with enhanced tocopherol quality.

  13. PSPHL as a candidate gene influencing racial disparities in endometrial cancer incidence and survival

    Directory of Open Access Journals (Sweden)

    Jay eAllard

    2012-07-01

    Full Text Available Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States and is characterized by a well recognized racial disparity in both incidence and survival. Specifically Caucasians are about two times more likely to develop endometrial cancer than are African Americans. However, African American women are more likely to die from this disease than are Caucasians. The basis for this disparity remains unknown. Previous studies have identified differences in the types and frequencies of gene mutations among endometrial cancers from Caucasians and African Americans suggesting. We performed a gene expression microarray study in an effort to further examine differences between African American and Caucasian women’s endometrial cancers. This expression screen identified a list of potential biomarkers differentially expressed between these two groups of cancers. Of these we identified a poorly characterized transcript with a region of homology to phospho serine phospatase (PSPH and designated phospho serine phospatase like (PSPHL as the most differentially over-expressed gene in cancers from African Americans. We clarified the nature of expressed transcripts. Northern blot analysis confirmed PSPHL messages under 1 KB. Sequence analysis of transcripts confirmed two alternate open reading frame (ORF isoforms due to alternative splicing events. Splice specific primer sets confirmed both isoforms were differentially expressed in tissues from Caucasians and African Americans. We further examined the expression in other tissues from women to include normal endometrium, normal and malignant ovary. In all cases PSPHL expression was more often present in tissues from African-Americans than Caucasians. Our data confirm the African-American based expression of the PSPHL transcript several tissue types. PSPHL represents a candidate gene that might influence the observed racial disparity in endometrial and other cancers.

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

    Science.gov (United States)

    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. © The American Genetic Association. 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Expression QTL-based analyses reveal candidate causal genes and loci across five tumor types

    Science.gov (United States)

    Li, Qiyuan; Stram, Alexander; Chen, Constance; Kar, Siddhartha; Gayther, Simon; Pharoah, Paul; Haiman, Christopher; Stranger, Barbara; Kraft, Peter; Freedman, Matthew L.

    2014-01-01

    The majority of trait-associated loci discovered through genome-wide association studies are located outside of known protein coding regions. Consequently, it is difficult to ascertain the mechanism underlying these variants and to pinpoint the causal alleles. Expression quantitative trait loci (eQTLs) provide an organizing principle to address both of these issues. eQTLs are genetic loci that correlate with RNA transcript levels. Large-scale data sets such as the Cancer Genome Atlas (TCGA) provide an ideal opportunity to systematically evaluate eQTLs as they have generated multiple data types on hundreds of samples. We evaluated the determinants of gene expression (germline variants and somatic copy number and methylation) and performed cis-eQTL analyses for mRNA expression and miRNA expression in five tumor types (breast, colon, kidney, lung and prostate). We next tested 149 known cancer risk loci for eQTL effects, and observed that 42 (28.2%) were significantly associated with at least one transcript. Lastly, we described a fine-mapping strategy for these 42 eQTL target–gene associations based on an integrated strategy that combines the eQTL level of significance and the regulatory potential as measured by DNaseI hypersensitivity. For each of the risk loci, our analyses suggested 1 to 81 candidate causal variants that may be prioritized for downstream functional analysis. In summary, our study provided a comprehensive landscape of the genetic determinants of gene expression in different tumor types and ranked the genes and loci for further functional assessment of known cancer risk loci. PMID:24907074

  16. Association mapping in Salix viminalis L. (Salicaceae) - identification of candidate genes associated with growth and phenology.

    Science.gov (United States)

    Hallingbäck, Henrik R; Fogelqvist, Johan; Powers, Stephen J; Turrion-Gomez, Juan; Rossiter, Rachel; Amey, Joanna; Martin, Tom; Weih, Martin; Gyllenstrand, Niclas; Karp, Angela; Lagercrantz, Ulf; Hanley, Steven J; Berlin, Sofia; Rönnberg-Wästljung, Ann-Christin

    2016-05-01

    Willow species (Salix) are important as short-rotation biomass crops for bioenergy, which creates a demand for faster genetic improvement and breeding through deployment of molecular marker-assisted selection (MAS). To find markers associated with important adaptive traits, such as growth and phenology, for use in MAS, we genetically dissected the trait variation of a Salix viminalis (L.) population of 323 accessions. The accessions were sampled throughout northern Europe and were established at two field sites in Pustnäs, Sweden, and at Woburn, UK, offering the opportunity to assess the impact of genotype-by-environment interactions (G × E) on trait-marker associations. Field measurements were recorded for growth and phenology traits. The accessions were genotyped using 1536 SNP markers developed from phenology candidate genes and from genes previously observed to be differentially expressed in contrasting environments. Association mapping between 1233 of these SNPs and the measured traits was performed taking into account population structure and threshold selection bias. At a false discovery rate (FDR) of 0.2, 29 SNPs were associated with bud burst, leaf senescence, number of shoots or shoot diameter. The percentage of accession variation (Radj2) explained by these associations ranged from 0.3% to 4.4%, suggesting that the studied traits are controlled by many loci of limited individual impact. Despite this, a SNP in the EARLY FLOWERING 3 gene was repeatedly associated (FDR < 0.2) with bud burst. The rare homozygous genotype exhibited 0.4-1.0 lower bud burst scores than the other genotype classes on a five-grade scale. Consequently, this marker could be promising for use in MAS and the gene deserves further study. Otherwise, associations were less consistent across sites, likely due to their small Radj2 estimates and to considerable G × E interactions indicated by multivariate association analyses and modest trait accession correlations across sites (0.32-0.61).

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

    Directory of Open Access Journals (Sweden)

    Tisdale Michele

    2009-09-01

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

  18. Association study of candidate genes for susceptibility to schizophrenia and bipolar disorder on chromosome 22Q13

    DEFF Research Database (Denmark)

    Severinsen, Jacob; Binderup, Helle; Mors, Ole

    Chromosome 22q is suspected to harbor risk genes for schizophrenia as well as bipolar affective disorder. This is evidenced through genetic mapping studies, investigations of cytogenetic abnormalities, and direct examination of candidate genes. In a recent study of distantly related patients from...... the Faroe Islands we have obtained evidence suggesting two regions on chromosome 22q13 to potentially harbor susceptibility genes for both schizophrenia and bipolar affective disorder. We have selected a number of candidate genes from these two regions for further analysis, including the neuro-gene WKL1...... and unrelated controls, and in a Scottish case-control sample comprising 200 schizophrenics, 200 bipolar patients and 200 controls. None of the investigated SNPs have so far showed strong evidence of association to either bipolar disorder or schizophrenia....

  19. Could the gene coding for human uteroglobin (clara cell 10 kDa protein) be a candidate gene for atopy?

    Energy Technology Data Exchange (ETDEWEB)

    Mukherjee, A.B.; Peri, A.; Miele, L. [SDG, Bethesda, MD (United States)] [and others

    1994-09-01

    It has been proposed that human immune response to allergens is genetically determined. Most of these allergic responses are directed to environmental proteins and are mediated by immunoglobulin E (IgE). These allergic disorders (eg. allergic asthma) are commonly known as atopy. IgE activates phospholipase A{sub 2} (PLA{sub 2}) which hydrolyzes cell membrane phospholipids generating free fatty acids, such as arachidonic acid (AA). AA is utilized as the substrate for the generation of pro-inflammatory eicosanoids and platelet activating factor (PAF). These agents can cause inflammation as well as bronchoconstriction, hallmarks of asthma. IgE-induced mast cell degranulation and accumulation of basophils and eosinophils in the lung are also characteristic immunological processes commonly found in atopic asthma. Recent investigations suggest that a group I PLA{sub 2} may be associated with the secretory granules of these cells. An inverse relationship between the levels of eicosanoids and hUG has been found in the nasopharyngeal lavage fluid of children with viral infections of the upper respiratory tract, often a precipitating factor in asthma. Results of genetic linkage studies mapped a putative atopy gene in human chromosome 11q{sup 13}, the same region in which we localized the hUG gene. Moreover, a genetic linkage between atopic IgE responses and chromosome 11q{sup 13} has been reported. In addition, hUG is: (i) a potent inhibitor of PLA{sub 2} activity, (ii) a potent antiinflammatory/immunomodulatory and antichemotactic protein and has a hitherto undetermined receptor-mediated activity. Taken together, these findings suggest that a mutation either in the hUG or its receptor genes may manifest symptoms characteristic of atopy. Hence, we raise the question whether hUG is a candidate gene for this disease.

  20. Association analysis of single nucleotide polymorphisms in candidate genes with root traits in maize (Zea mays L.) seedlings.

    Science.gov (United States)

    Kumar, Bharath; Abdel-Ghani, Adel H; Pace, Jordon; Reyes-Matamoros, Jenaro; Hochholdinger, Frank; Lübberstedt, Thomas

    2014-07-01

    Several genes involved in maize root development have been isolated. Identification of SNPs associated with root traits would enable the selection of maize lines with better root architecture that might help to improve N uptake, and consequently plant growth particularly under N deficient conditions. In the present study, an association study (AS) panel consisting of 74 maize inbred lines was screened for seedling root traits in 6, 10, and 14-day-old seedlings. Allele re-sequencing of candidate root genes Rtcl, Rth3, Rum1, and Rul1 was also carried out in the same AS panel lines. All four candidate genes displayed different levels of nucleotide diversity, haplotype diversity and linkage disequilibrium. Gene based association analyses were carried out between individual polymorphisms in candidate genes, and root traits measured in 6, 10, and 14-day-old maize seedlings. Association analyses revealed several polymorphisms within the Rtcl, Rth3, Rum1, and Rul1 genes associated with seedling root traits. Several nucleotide polymorphisms in Rtcl, Rth3, Rum1, and Rul1 were significantly (P<0.05) associated with seedling root traits in maize suggesting that all four tested genes are involved in the maize root development. Thus considerable allelic variation present in these root genes can be exploited for improving maize root characteristics. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  1. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder

    Science.gov (United States)

    Yuen, Ryan KC; Merico, Daniele; Bookman, Matt; Howe, Jennifer L; Thiruvahindrapuram, Bhooma; Patel, Rohan V; Whitney, Joe; Deflaux, Nicole; Bingham, Jonathan; Wang, Zhuozhi; Pellecchia, Giovanna; Buchanan, Janet A; Walker, Susan; Marshall, Christian R; Uddin, Mohammed; Zarrei, Mehdi; Deneault, Eric; D’Abate, Lia; Chan, Ada JS; Koyanagi, Stephanie; Paton, Tara; Pereira, Sergio L; Hoang, Ny; Engchuan, Worrawat; Higginbotham, Edward J; Ho, Karen; Lamoureux, Sylvia; Li, Weili; MacDonald, Jeffrey R; Nalpathamkalam, Thomas; Sung, Wilson WL; Tsoi, Fiona J; Wei, John; Xu, Lizhen; Tasse, Anne-Marie; Kirby, Emily; Van Etten, William; Twigger, Simon; Roberts, Wendy; Drmic, Irene; Jilderda, Sanne; Modi, Bonnie MacKinnon; Kellam, Barbara; Szego, Michael; Cytrynbaum, Cheryl; Weksberg, Rosanna; Zwaigenbaum, Lonnie; Woodbury-Smith, Marc; Brian, Jessica; Senman, Lili; Iaboni, Alana; Doyle-Thomas, Krissy; Thompson, Ann; Chrysler, Christina; Leef, Jonathan; Savion-Lemieux, Tal; Smith, Isabel M; Liu, Xudong; Nicolson, Rob; Seifer, Vicki; Fedele, Angie; Cook, Edwin H; Dager, Stephen; Estes, Annette; Gallagher, Louise; Malow, Beth A; Parr, Jeremy R; Spence, Sarah J; Vorstman, Jacob; Frey, Brendan J; Robinson, James T; Strug, Lisa J; Fernandez, Bridget A; Elsabbagh, Mayada; Carter, Melissa T; Hallmayer, Joachim; Knoppers, Bartha M; Anagnostou, Evdokia; Szatmari, Peter; Ring, Robert H; Glazer, David; Pletcher, Mathew T; Scherer, Stephen W

    2017-01-01

    We are performing whole genome sequencing (WGS) of families with Autism Spectrum Disorder (ASD) to build a resource, named MSSNG, to enable the sub-categorization of phenotypes and underlying genetic factors involved. Here, we report WGS of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible in a cloud platform, and through an internet portal with controlled access. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertion/deletions (indels) or copy number variations (CNVs) per ASD subject. We identified 18 new candidate ASD-risk genes such as MED13 and PHF3, and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (p=6×10−4). In 294/2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried CNV/chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD. PMID:28263302

  2. Identification of Candidate Genes for Generalized Tonic-Clonic Seizures in Noda Epileptic Rat.

    Science.gov (United States)

    Kuramoto, Takashi; Voigt, Birger; Nakanishi, Satoshi; Kitada, Kazuhiro; Nakamura, Tadashi; Wakamatsu, Kaori; Yoshihara, Minako; Suyama, Mikita; Uemura, Risa; Tanaka, Miyuu; Kuwamura, Mitsuru; Shimizu, Saki; Ohno, Yukihiro; Sasa, Masashi; Serikawa, Tadao

    2017-11-01

    The Noda epileptic rat (NER) exhibits generalized tonic-clonic seizures (GTCS). A genetic linkage analysis identified two GTCS-associated loci, Ner1 on Chr 1 and Ner3 on Chr 5. The wild-type Ner1 and Ner3 alleles suppressed GTCS when combined in double-locus congenic lines, but not when present in single-locus congenic lines. Global expression analysis revealed that cholecystokinin B receptor (Cckbr) and suppressor of tumorigenicity 5 (St5), which map within Ner1, and PHD finger protein 24 (Phf24), which maps within Ner3, were significantly downregulated in NER. De novo BAC sequencing detected an insertion of an endogenous retrovirus sequence in intron 2 of the Phf24 gene in the NER genome, and PHF24 protein was almost absent in the NER brain. Phf24 encodes a Gαi-interacting protein involved in GABAB receptor signaling pathway. Based on these findings, we conclude that Cckbr, St5, and Phf24 are strong candidate genes for GTCS in NER.

  3. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.

    Science.gov (United States)

    C Yuen, Ryan K; Merico, Daniele; Bookman, Matt; L Howe, Jennifer; Thiruvahindrapuram, Bhooma; Patel, Rohan V; Whitney, Joe; Deflaux, Nicole; Bingham, Jonathan; Wang, Zhuozhi; Pellecchia, Giovanna; Buchanan, Janet A; Walker, Susan; Marshall, Christian R; Uddin, Mohammed; Zarrei, Mehdi; Deneault, Eric; D'Abate, Lia; Chan, Ada J S; Koyanagi, Stephanie; Paton, Tara; Pereira, Sergio L; Hoang, Ny; Engchuan, Worrawat; Higginbotham, Edward J; Ho, Karen; Lamoureux, Sylvia; Li, Weili; MacDonald, Jeffrey R; Nalpathamkalam, Thomas; Sung, Wilson W L; Tsoi, Fiona J; Wei, John; Xu, Lizhen; Tasse, Anne-Marie; Kirby, Emily; Van Etten, William; Twigger, Simon; Roberts, Wendy; Drmic, Irene; Jilderda, Sanne; Modi, Bonnie MacKinnon; Kellam, Barbara; Szego, Michael; Cytrynbaum, Cheryl; Weksberg, Rosanna; Zwaigenbaum, Lonnie; Woodbury-Smith, Marc; Brian, Jessica; Senman, Lili; Iaboni, Alana; Doyle-Thomas, Krissy; Thompson, Ann; Chrysler, Christina; Leef, Jonathan; Savion-Lemieux, Tal; Smith, Isabel M; Liu, Xudong; Nicolson, Rob; Seifer, Vicki; Fedele, Angie; Cook, Edwin H; Dager, Stephen; Estes, Annette; Gallagher, Louise; Malow, Beth A; Parr, Jeremy R; Spence, Sarah J; Vorstman, Jacob; Frey, Brendan J; Robinson, James T; Strug, Lisa J; Fernandez, Bridget A; Elsabbagh, Mayada; Carter, Melissa T; Hallmayer, Joachim; Knoppers, Bartha M; Anagnostou, Evdokia; Szatmari, Peter; Ring, Robert H; Glazer, David; Pletcher, Mathew T; Scherer, Stephen W

    2017-04-01

    We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10(-4)). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.

  4. Meta-analysis of candidate gene effects using bayesian parametric and non-parametric approaches.

    Science.gov (United States)

    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.

  5. Malaria Host Candidate Genes Validated by Association With Current, Recent, and Historical Measures of Transmission Intensity.

    Science.gov (United States)

    Sepúlveda, Nuno; Manjurano, Alphaxard; Campino, Susana G; Lemnge, Martha; Lusingu, John; Olomi, Raimos; Rockett, Kirk A; Hubbart, Christina; Jeffreys, Anna; Rowlands, Kate; Clark, Taane G; Riley, Eleanor M; Drakeley, Chris J

    2017-07-01

    Human malaria susceptibility is determined by multiple genetic factors. It is unclear, however, which genetic variants remain important over time. Genetic associations of 175 high-quality polymorphisms within several malaria candidate genes were examined in a sample of 8096 individuals from northeast Tanzania using altitude, seroconversion rates, and parasite rates as proxies of historical, recent, and current malaria transmission intensity. A principal component analysis was used to derive 2 alternative measures of overall malaria propensity of a location across different time scales. Common red blood cell polymorphisms (ie, hemoglobin S, glucose-6-phosphate dehydrogenase, and α-thalassemia) were the only ones to be associated with all 3 measures of transmission intensity and the first principal component. Moderate associations were found between some immune response genes (ie, IL3 and IL13) and parasite rates, but these could not be reproduced using the alternative measures of malaria propensity. We have demonstrated the potential of using altitude and seroconversion rate as measures of malaria transmission capturing medium- to long-term time scales to detect genetic associations that are likely to persist over time. These measures also have the advantage of minimizing the deleterious effects of random factors affecting parasite rates on the respective association signals.

  6. Candidate genes and QTLs for fruit ripening and softening in melon.

    Science.gov (United States)

    Moreno, Eduard; Obando, Javier M; Dos-Santos, Noelia; Fernández-Trujillo, J Pablo; Monforte, Antonio J; Garcia-Mas, Jordi

    2008-02-01

    Different factors affect the quality of melon fruit and among them long shelf life is critical from the consumer's point of view. In melon, cultivars showing both climacteric and non-climacteric ripening types are found. In this study we have investigated climacteric ripening and fruit softening using a collection of near-isogenic lines (NILs) derived from the non-climacteric melon parental lines PI 161375 (SC) and "Piel de Sapo" (PS). Surprisingly, we found that QTL eth3.5 in NIL SC3-5b induced a climacteric-ripening phenotype with increased respiration and ethylene levels. Data suggest that the non-climacteric phenotypes from PI 161375 and "Piel de Sapo" may be the result of mutations in different genes. Several QTLs for fruit flesh firmness were also detected. Candidate genes putatively involved in ethylene regulation, biosynthesis and perception and cell wall degradation were mapped and some colocations with QTLs were observed. These results may provide additional data towards understanding of non-climacteric ripening in melon.

  7. Identification of novel type 1 diabetes candidate genes by integrating genome-wide association data, protein-protein interactions, and human pancreatic islet gene expression

    DEFF Research Database (Denmark)

    Bergholdt, Regine; Brorsson, Caroline; Palleja, Albert

    2012-01-01

    genes (CD83, IFNGR1, IL17RD, TRAF3IP2, IL27RA, PLCG2, MYO1B, and CXCR7) in these networks also harbored single nucleotide polymorphisms nominally associated with type 1 diabetes. Finally, the expression and cytokine regulation of these new candidate genes were confirmed in insulin-secreting INS-1 ß...

  8. Identification of Novel Susceptibility Genes for Breast Cancer – Genome-Wide Association Studies or Evaluation of Candidate Genes?

    Science.gov (United States)

    Meindl, Alfons

    2009-01-01

    Summary To determine the genetic components that constitute polygenic traits in familial or sporadic breast cancer, low-risk variants on the one hand and mutations conferring moderate penetrance on the other hand have to be identified. While members of the latter group were found by comprehensive screening of candidate genes which are, like the 2 highly penetrant genes BRCA1/BRCA2, located in the DNA repair pathway, the development of novel techniques was urgently needed to identify low-risk variants. The hybridization of chips which contain several hundred thousand single nucleotide polymorphisms (SNPs) with several thousand DNAs from either sporadic breast cancer cases or healthy controls (genome-wide association study, GWAS) has already led to the detection of at least 8 low-risk variants, conferring odds ratios of 1.06–1.64. As they are common in the population, it is likely that extended GWAS will develop a genetic pattern that is able to discriminate women suitable or not for population screening programs. PMID:21049069

  9. Identification of Novel Susceptibility Genes for Breast Cancer - Genome-Wide Association Studies or Evaluation of Candidate Genes?

    Science.gov (United States)

    Meindl, Alfons

    2009-01-01

    To determine the genetic components that constitute polygenic traits in familial or sporadic breast cancer, low-risk variants on the one hand and mutations conferring moderate penetrance on the other hand have to be identified. While members of the latter group were found by comprehensive screening of candidate genes which are, like the 2 highly penetrant genes BRCA1/BRCA2, located in the DNA repair pathway, the development of novel techniques was urgently needed to identify low-risk variants. The hybridization of chips which contain several hundred thousand single nucleotide polymorphisms (SNPs) with several thousand DNAs from either sporadic breast cancer cases or healthy controls (genome-wide association study, GWAS) has already led to the detection of at least 8 low-risk variants, conferring odds ratios of 1.06-1.64. As they are common in the population, it is likely that extended GWAS will develop a genetic pattern that is able to discriminate women suitable or not for population screening programs.

  10. Obstructive heart defects associated with candidate genes, maternal obesity, and folic acid supplementation.

    Science.gov (United States)

    Tang, Xinyu; Cleves, Mario A; Nick, Todd G; Li, Ming; MacLeod, Stewart L; Erickson, Stephen W; Li, Jingyun; Shaw, Gary M; Mosley, Bridget S; Hobbs, Charlotte A

    2015-06-01

    Right-sided and left-sided obstructive heart defects (OHDs) are subtypes of congenital heart defects, in which the heart valves, arteries, or veins are abnormally narrow or blocked. Previous studies have suggested that the development of OHDs involved a complex interplay between genetic variants and maternal factors. Using the data from 569 OHD case families and 1,644 control families enrolled in the National Birth Defects Prevention Study (NBDPS) between 1997 and 2008, we conducted an analysis to investigate the genetic effects of 877 single nucleotide polymorphisms (SNPs) in 60 candidate genes for association with the risk of OHDs, and their interactions with maternal use of folic acid supplements, and pre-pregnancy obesity. Applying log-linear models based on the hybrid design, we identified a SNP in methylenetetrahydrofolate reductase (MTHFR) gene (C677T polymorphism) with a main genetic effect on the occurrence of OHDs. In addition, multiple SNPs in betaine-homocysteine methyltransferase (BHMT and BHMT2) were also identified to be associated with the occurrence of OHDs through significant main infant genetic effects and interaction effects with maternal use of folic acid supplements. We also identified multiple SNPs in glutamate-cysteine ligase, catalytic subunit (GCLC) and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) that were associated with elevated risk of OHDs among obese women. Our findings suggested that the risk of OHDs was closely related to a combined effect of variations in genes in the folate, homocysteine, or glutathione/transsulfuration pathways, maternal use of folic acid supplements and pre-pregnancy obesity. © 2015 Wiley Periodicals, Inc.

  11. Porcine Is a Positional Candidate Gene Associated with Growth and Fat Deposition

    Directory of Open Access Journals (Sweden)

    Bong Hwan Choi

    2012-12-01

    Full Text Available Crosses between Korean and Landrace pigs have revealed a large quantitative trait loci (QTL region for fat deposition in a region (89 cM of porcine chromosome 4 (SSC4. To more finely map this QTL region and identify candidate genes for this trait, comparative mapping of pig and human chromosomes was performed in the present study. A region in the human genome that corresponds to the porcine QTL region was identified in HSA1q21. Furthermore, the LMNA gene, which is tightly associated with fat augmentation in humans, was localized to this region. Radiation hybrid (RH mapping using a Sus scrofa RH panel localized LMNA to a region of 90.3 cM in the porcine genome, distinct from microsatellite marker S0214 (87.3 cM. Two-point analysis showed that LMNA was linked to S0214, SW1996, and S0073 on SSC4 with logarithm (base 10 of odds scores of 20.98, 17.78, and 16.73, respectively. To clone the porcine LMNA gene and to delineate the genomic structure and sequences, including the 3′untranslated region (UTR, rapid amplification of cDNA ends was performed. The coding sequence of porcine LMNA consisted of 1,719 bp, flanked by a 5’UTR and a 3’UTR. Two synonymous single nucleotide polymorphisms (SNPs were identified in exons 3 and 7. Association tests showed that the SNP located in exon 3 (A193A was significantly associated with weight at 30 wks (p<0.01 and crude fat content (p<0.05. This association suggests that SNPs located in LMNA could be used for marker-assisted selection in pigs.

  12. Centrosomal localization of the psoriasis candidate gene product, CCHCR1, supports a role in cytoskeletal organization.

    Directory of Open Access Journals (Sweden)

    Mari H Tervaniemi

    Full Text Available CCHCR1 (Coiled-Coil α-Helical Rod protein 1, within the major psoriasis susceptibility locus PSORS1, is a plausible candidate gene with the psoriasis associated risk allele CCHCR1*WWCC. Although its expression pattern in psoriatic skin differs from healthy skin and its overexpression influences cell proliferation in transgenic mice, its role as a psoriasis effector gene has remained unsettled. The 5'-region of the gene contains a SNP (rs3130453 that controls a 5'-extended open reading frame and thus the translation of alternative isoforms. We have now compared the function of two CCHCR1 isoforms: the novel longer isoform 1 and the previously studied isoform 3. In samples of Finnish and Swedish families, the allele generating only isoform 3 shows association with psoriasis (P<10(-7. Both isoforms localize at the centrosome, a cell organelle playing a role in cell division. In stably transfected cells the isoform 3 affects cell proliferation and with the CCHCR1*WWCC allele, also apoptosis. Furthermore, cells overexpressing CCHCR1 show isoform- and haplotype-specific influences in the cell size and shape and alterations in the organization and expression of the cytoskeletal proteins actin, vimentin, and cytokeratins. The isoform 1 with the non-risk allele induces the expression of keratin 17, a hallmark for psoriasis; the silencing of CCHCR1 reduces its expression in HEK293 cells. CCHCR1 also regulates EGF-induced STAT3 activation in an isoform-specific manner: the tyrosine phosphorylation of STAT3 is disturbed in isoform 3-transfected cells. The centrosomal localization of CCHCR1 provides a connection to the abnormal cell proliferation and offers a link to possible cellular pathways altered in psoriasis.

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

    Directory of Open Access Journals (Sweden)

    Julia Welzenbach

    2016-08-01

    Full Text Available 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.

  14. Genome-wide association links candidate genes to resistance to Plum Pox Virus in apricot (Prunus armeniaca).

    Science.gov (United States)

    Mariette, Stéphanie; Wong Jun Tai, Fabienne; Roch, Guillaume; Barre, Aurélien; Chague, Aurélie; Decroocq, Stéphane; Groppi, Alexis; Laizet, Yec'han; Lambert, Patrick; Tricon, David; Nikolski, Macha; Audergon, Jean-Marc; Abbott, Albert G; Decroocq, Véronique

    2016-01-01

    In fruit tree species, many important traits have been characterized genetically by using single-family descent mapping in progenies segregating for the traits. However, most mapped loci have not been sufficiently resolved to the individual genes due to insufficient progeny sizes for high resolution mapping and the previous lack of whole-genome sequence resources of the study species. To address this problem for Plum Pox Virus (PPV) candidate resistance gene identification in Prunus species, we implemented a genome-wide association (GWA) approach in apricot. This study exploited the broad genetic diversity of the apricot (Prunus armeniaca) germplasm containing resistance to PPV, next-generation sequence-based genotyping, and the high-quality peach (Prunus persica) genome reference sequence for single nucleotide polymorphism (SNP) identification. The results of this GWA study validated previously reported PPV resistance quantitative trait loci (QTL) intervals, highlighted other potential resistance loci, and resolved each to a limited set of candidate genes for further study. This work substantiates the association genetics approach for resolution of QTL to candidate genes in apricot and suggests that this approach could simplify identification of other candidate genes for other marked trait intervals in this germplasm. © 2015 INRA, UMR 1332 BFP New Phytologist © 2015 New Phytologist Trust.

  15. Transcriptome assembly and candidate genes involved in nutritional programming in the swordtail fish Xiphophorus multilineatus.

    Science.gov (United States)

    Lu, Yuan; Klimovich, Charlotte M; Robeson, Kalen Z; Boswell, William; Ríos-Cardenas, Oscar; Walter, Ronald B; Morris, Molly R

    2017-01-01

    reared in a low quality juvenile environment to males from the same size class reared in high quality juvenile environment, 131 genes were differentially expressed, including metabolism and appetite master regulator agrp gene. Our study provides evidence for nutritional programming in X. multilineatus, with variation across size classes of males in how juvenile environment and adult diet influences behaviors involved in energy homeostasis. In addition, we provide the first transcriptome of X. multilineatus, and identify a group of candidate genes involved in nutritional programming.

  16. Integration of gene chip and topological network techniques to screen a candidate biomarker gene (CBG) for predication of the source water carcinogenesis risks on mouse Mus musculus.

    Science.gov (United States)

    Sun, Jie; Cheng, Shupei; Li, Aimin; Zhang, Rui; Wu, Bing; Zhang, Yan; Zhang, Xuxiang

    2011-07-01

    Screening of a candidate biomarker gene (CBG) to predicate the carcinogenesis risks in the Yangtze River source of drinking water in Nanjing area (YZR-SDW-NJ) on mouse (Mus musculus) was conducted in this research. The effects of YZR-SDW-NJ on the genomic transcriptional expression levels were measured by the GeneChip(®) Mouse Genome and data treated by the GO database analysis. The 298 genes discovered as the differently expressed genes (DEGs) were down-regulated and their values were ≤-1.5-fold. Of the 298 DEGs, 25 were cancer-related genes selected as the seed genes to build a topological network map with Genes2Networks software, only 7 of them occurred at the constructed map. Smad2 gene was at the constructed map center and could be identified as a candidate biomarker gene (CBG) primarily which involves the genesis and development of colorectal, leukemia, lung and prostate cancers directly. Analysis of the gene signal pathway further approved that smad2 gene had the relationships closely to other 16 cancer-related genes and could be used as a CBG to indicate the carcinogenic risks in YZR-SDW-NJ. The data suggest that integration of gene chip and network techniques may be a way effectively to screen a CBG. And the parameter values for further judgment of the CBG through signal pathway relationship analysis also will be discussed.

  17. QTL mapping and candidate genes for resistance to Fusarium ear rot and fumonisin contamination in maize.

    Science.gov (United States)

    Maschietto, Valentina; Colombi, Cinzia; Pirona, Raul; Pea, Giorgio; Strozzi, Francesco; Marocco, Adriano; Rossini, Laura; Lanubile, Alessandra

    2017-01-21

    Fusarium verticillioides is a common maize pathogen causing ear rot (FER) and contamination of the grains with the fumonisin B1 (FB1) mycotoxin. Resistance to FER and FB1 contamination are quantitative traits, affected by environmental conditions, and completely resistant maize genotypes to the pathogen are so far unknown. In order to uncover genomic regions associated to reduced FER and FB1 contamination and identify molecular markers for assisted selection, an F2:3 population of 188 progenies was developed crossing CO441 (resistant) and CO354 (susceptible) genotypes. FER severity and FB1 contamination content were evaluated over 2 years and sowing dates (early and late) in ears artificially inoculated with F. verticillioides by the use of either side-needle or toothpick inoculation techniques. Weather conditions significantly changed in the two phenotyping seasons and FER and FB1 content distribution significantly differed in the F3 progenies according to the year and the sowing time. Significant positive correlations (P contamination, ranging from 0.72 to 0.81. A low positive correlation was determined between FB1 contamination and silking time (DTS). A genetic map was generated for the cross, based on 41 microsatellite markers and 342 single nucleotide polymorphisms (SNPs) derived from Genotyping-by-Sequencing (GBS). QTL analyses revealed 15 QTLs for FER, 17 QTLs for FB1 contamination and nine QTLs for DTS. Eight QTLs located on linkage group (LG) 1, 2, 3, 6, 7 and 9 were in common between FER and FB1, making possible the selection of genotypes with both low disease severity and low fumonisin contamination. Moreover, five QTLs on LGs 1, 2, 4, 5 and 9 located close to previously reported QTLs for resistance to other mycotoxigenic fungi. Finally, 24 candidate genes for resistance to F. verticillioides are proposed combining previous transcriptomic data with QTL mapping. This study identified a set of QTLs and candidate genes that could accelerate breeding for

  18. Analysis of genetic structure in Slovak Pinzgau cattle using five candidate genes related to milk production traits

    Directory of Open Access Journals (Sweden)

    Miluchova Martina

    2014-01-01

    Full Text Available The goal of the paper was to identify genetic structure of five candidate genes for milk production in Slovak Pinzgau breed. A total of 86 mothers of bulls of Slovak Pinzgau cattle were use in this study. To genotype of cows for candidate genes we used PCR methods (PCR-RFLP, ARMS-PCR, multiplex PCR-RFLP. On the basis of PCR analyses we established genotype structure of cattle population and calculated allelic frequencies. Effectiveness of allele incidence and genetic diversity was evaluated with following parameters: theoretical heterozygosity (He exp, experimental heterozygosity (He obs, polymorphism information content (PIC, expected homozygosity (E, effective number of alleles (ENA, level of possible variability realization (V%. Slovak Pinzgau cattle exhibit the high values of heterozygosity, polymorphism information content, effective number of alleles and level of possible variability realization for genes CSN2, CSN3 and LALBA. In opposite, for genes CSN1S1 and LGB show high values of homozygosity.

  19. Molecular characterization and exclusion of porcine GUSB as a candidate gene for congenital hernia inguinalis/scrotalis

    OpenAIRE

    Beck, Julia; Bornemann-Kolatzki, Kirsten; Knorr, Christoph; Taeubert, Helge; Brenig, Bertram

    2006-01-01

    Background Inguinal hernias are usually caused by a congenital defect, which occurs as a weakness of the inguinal canal. Porcine β-glucuronidase gene (GUSB) was chosen as functional candidate gene because of its involvement in degradation of hyaluronan within gubernacular tissue during descent of testes. Since a genome-wide linkage analysis approach has shown evidence that two regions on porcine chromosome 3 (SSC 3) are involved in the inheritance of hernia inguinalis/scrotalis in German pig ...

  20. Novel candidate genes for 46,XY gonadal dysgenesis identified by a customized 1 M array-CGH platform

    OpenAIRE

    Norling, Ameli; Lindén Hirschberg, Angelica; Iwarsson, Erik; Persson, Bengt; Wedell, Anna; Barbaro, Michela

    2013-01-01

    Half of all patients with a disorder of sex development (DSD) do not receive a specific molecular diagnosis. Comparative genomic hybridization (CGH) can detect copy number changes causing gene haploinsufficiency or over-expression that can lead to impaired gonadal development and gonadal DSD. The purpose of this study was to identify novel candidate genes for 46,XY gonadal dysgenesis (GD) using a customized 1 M array-CGH platform with whole-genome coverage and probe enrichment targeting 78 ge...

  1. What Is ADHD?

    Science.gov (United States)

    ... Late for the Flu Vaccine? Eating Disorders Arrhythmias ADHD KidsHealth > For Parents > ADHD Print A A A ... ADHD? en español Qué es TDAH? What Is ADHD? ADHD stands for attention deficit hyperactivity disorder. It ...

  2. Coaching for ADHD

    Science.gov (United States)

    Murphy, Kevin; Ratey, Nancy; Maynard, Sandy; Sussman, Susan; Wright, Sarah D.

    2010-01-01

    Despite limited scientific study on ADHD coaching as an intervention for adults with ADHD, the field of ADHD coaching has grown significantly and gained popularity in recent years. ADHD coaching is becoming a bona fide profession where one must advance through a rigorous training process, in order to be certified as a professional ADHD coach.…

  3. Resequencing three candidate genes for major depressive disorder in a Dutch cohort.

    Directory of Open Access Journals (Sweden)

    Eva C Verbeek

    Full Text Available Major depressive disorder (MDD is a psychiatric disorder, characterized by periods of low mood of more than two weeks, loss of interest in normally enjoyable activities and behavioral changes. MDD is a complex disorder and does not have a single genetic cause. In 2009 a genome wide association study (GWAS was performed on the Dutch GAIN-MDD cohort. Many of the top signals of this GWAS mapped to a region spanning the gene PCLO, and the non-synonymous coding single nucleotide polymorphism (SNP rs2522833 in the PCLO gene became genome wide significant after post-hoc analysis. We performed resequencing of PCLO, GRM7, and SLC6A4 in 50 control samples from the GAIN-MDD cohort, to detect new genomic variants. Subsequently, we genotyped these variants in the entire GAIN-MDD cohort and performed association analysis to investigate if rs2522833 is the causal variant or simply in linkage disequilibrium with a more associated variant. GRM7 and SLC6A4 are both candidate genes for MDD from literature. We aimed to gather more evidence that rs2522833 is indeed the causal variant in the GAIN-MDD cohort or to find a previously undetected common variant in either PCLO, GRM7, or SLC6A4 with a higher association in this cohort. After next generation sequencing and association analysis we excluded the possibility of an undetected common variant to be more associated. For neither PCLO nor GRM7 we found a more associated variant. For SLC6A4, we found a new SNP that showed a lower P-value (P = 0.07 than in the GAIN-MDD GWAS (P = 0.09. However, no evidence for genome-wide significance was found. Although we did not take into account rare variants, we conclude that our results provide further support for the hypothesis that the non-synonymous coding SNP rs2522833 in the PCLO gene is indeed likely to be the causal variant in the GAIN-MDD cohort.

  4. Linkage study of 14 candidate genes and loci in four large Dutch families with vesico-ureteral reflux

    NARCIS (Netherlands)

    Eerde, A.M. van; Koeleman, B.P.C.; Kamp, J.M. van de; Jong, T.P.V.M. de; Wijmenga, C.; Giltay, J.C.

    2007-01-01

    Vesico-ureteral reflux (VUR) is a major contributing factor to end-stage renal disease in paediatric patients. Primary VUR is a familial disorder, but little is known about its genetic causes. To investigate the involvement of 12 functional candidate genes and two reported loci in VUR, we

  5. Linkage study of 14 candidate genes and loci in four large Dutch families with vesico-ureteral reflux

    NARCIS (Netherlands)

    van Eerde, Albertien M.; Koeleman, Bobby P. C.; van de Kamp, Jiddeke M.; de Jong, Tom P. V. M.; Wijmenga, Cisca; Giltay, Jacques C.

    2007-01-01

    Vesico-ureteral reflux (VUR) is a major contributing factor to end-stage renal disease in paediatric patients. Primary VUR is a familial disorder, but little is known about its genetic causes. To investigate the involvement of 12 functional candidate genes and two reported loci in VUR, we performed

  6. Quantitative trait locus mapping and candidate gene analysis for plant architecture traits using whole genome re-sequencing in rice.

    Science.gov (United States)

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

    2014-02-01

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

  7. Candidate disease gene prediction using Gentrepid: application to a genome-wide association study on coronary artery disease

    NARCIS (Netherlands)

    Ballouz, S.; Liu, J.Y.; Oti, M.O.; Gaeta, B.; Fatkin, D.; Bahlo, M.; Wouters, M.A.

    2014-01-01

    Current single-locus-based analyses and candidate disease gene prediction methodologies used in genome-wide association studies (GWAS) do not capitalize on the wealth of the underlying genetic data, nor functional data available from molecular biology. Here, we analyzed GWAS data from the Wellcome

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

    Directory of Open Access Journals (Sweden)

    Cristiana Paina

    Full Text Available 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.

  9. Candidate genes for colour and vision exhibit signals of selection across the pied flycatcher (Ficedula hypoleuca) breeding range

    NARCIS (Netherlands)

    Lehtonen, P. K.; Laaksonen, T.; Artemyev, A. V.; Belskii, E.; Berg, P. R.; Both, C.; Buggiotti, L.; Bures, S.; Burgess, M. D.; Bushuev, A. V.; Krams, I.; Moreno, Juan; Maegi, M.; Nord, A.; Potti, J.; Ravussin, P-A; Sirkia, P. M.; Saetre, G-P; Winkel, W.; Primmer, C. R.; Bureš, S.; Mägi, M.; Sirkiä, P.M.

    The role of natural selection in shaping adaptive trait differentiation in natural populations has long been recognized. Determining its molecular basis, however, remains a challenge. Here, we search for signals of selection in candidate genes for colour and its perception in a passerine bird. Pied

  10. Linkage study of nonsyndromic cleft lip with or without cleft palate using candidate genes and mapped polymorphic markers

    Energy Technology Data Exchange (ETDEWEB)

    Stein, J.D.; Nelson, L.D.; Conner, B.J. [Univ. of Texas, Houston (United States)] [and others

    1994-09-01

    Nonsyndromic cleft lip with or without cleft palate (CL(P)) involves fusion or growth failure of facial primordia during development. Complex segregation analysis of clefting populations suggest that an autosomal dominant gene may play a role in this common craniofacial disorder. We have ascertained 16 multigenerational families with CL(P) and tested linkage to 29 candidate genes and 139 mapped short tandem repeat markers. The candidate genes were selected based on their expression in craniofacial development or were identified through murine models. These include: TGF{alpha}, TGF{beta}1, TGF{beta}2, TGF{beta}3, EGF, EGFR, GRAS, cMyc, FGFR, Jun, JunB, PDFG{alpha}, PDGF{beta}, IGF2R, GCR Hox7, Hox8, Hox2B, twirler, 5 collagen and 3 extracellular matrix genes. Linkage was tested assuming an autosomal dominant model with sex-specific decreased penetrance. Linkage to all of the candidate loci was excluded in 11 families. RARA was tested and was not informative. However, haplotype analysis of markers flanking RARA on 17q allowed exclusion of this candidate locus. We have previously excluded linkage to 61 STR markers in 11 families. Seventy-eight mapped short tandem repeat markers have recently been tested in 16 families and 30 have been excluded. The remaining are being analyzed and an exclusion map is being developed based on the entire study results.

  11. Dopaminergic, Serotonergic, and Oxytonergic Candidate Genes Associated with Infant Attachment Security and Disorganization? In Search of Main and Interaction Effects

    Science.gov (United States)

    Luijk, Maartje P. C. M.; Roisman, Glenn I.; Haltigan, John D.; Tiemeier, Henning; Booth-LaForce, Cathryn; van IJzendoorn, Marinus H.; Belsky, Jay; Uitterlinden, Andre G.; Jaddoe, Vincent W. V.; Hofman, Albert; Verhulst, Frank C.; Tharner, Anne; Bakermans-Kranenburg, Marian J.

    2011-01-01

    Background and methods: In two birth cohort studies with genetic, sensitive parenting, and attachment data of more than 1,000 infants in total, we tested main and interaction effects of candidate genes involved in the dopamine, serotonin, and oxytocin systems ("DRD4", "DRD2", "COMT", "5-HTT", "OXTR") on attachment security and disorganization.…

  12. No Association between Variation in Longevity Candidate Genes and Aging-related Phenotypes in Oldest-old Danes

    DEFF Research Database (Denmark)

    Sørensen, Mette; Nygaard, Marianne; Debrabant, Birgit

    2016-01-01

    additional genes repeatedly considered as candidates for human longevity: APOE, APOA4, APOC3, ACE, CETP, HFE, IL6, IL6R, MTHFR, TGFB1, SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. Altogether, 1,049 single nucleotide polymorphisms (SNPs) were genotyped in 1,088 oldest-old (age 92-93 years) Danes and analysed...

  13. Using gene expression databases for classical trait QTL candidate gene discovery in the BXD recombinant inbred genetic reference population: Mouse forebrain weight

    Directory of Open Access Journals (Sweden)

    Zhou Jianhua

    2008-09-01

    Full Text Available Abstract Background Successful strategies for QTL gene identification benefit from combined experimental and bioinformatic approaches. Unique design aspects of the BXD recombinant inbred line mapping panel allow use of archived gene microarray expression data to filter likely from unlikely candidates. This prompted us to propose a simple five-filter protocol for candidate nomination. To filter more likely from less likely candidates, we required candidate genes near to the QTL to have mRNA abundance that correlated with the phenotype among the BXD lines as well as differed between the parental lines C57BL/6J and DBA/2J. We also required verification of mRNA abundance by an independent method, and finally we required either differences in protein levels or confirmed DNA sequence differences. Results QTL mapping of mouse forebrain weight in 34 BXD RI lines found significant association on chromosomes 1 and 11, with each C57BL/6J allele increasing weight by more than half a standard deviation. The intersection of gene lists that were within ± 10 Mb of the strongest associated location, that had forebrain mRNA abundance correlated with forebrain weight among the BXD, and that had forebrain mRNA abundance differing between C57BL/6J and DBA/2J, produced two candidates, Tnni1 (troponin 1 and Asb3 (ankyrin repeat and SOCS box-containing protein 3. Quantitative RT-PCR confirmed the direction of an increased expression in C57BL/6J genotype over the DBA/2J genotype for both genes, a difference that translated to a 2-fold difference in Asb3 protein. Although Tnni1 protein differences could not be confirmed, a 273 bp indel polymorphism was discovered 1 Kb upstream of the transcription start site. Conclusion Delivery of well supported candidate genes following a single quantitative trait locus mapping experiment is difficult. However, by combining available gene expression data with QTL mapping, we illustrated a five-filter protocol that nominated Asb3 and

  14. QTL and candidate gene mapping for polyphenolic composition in apple fruit

    Science.gov (United States)

    2012-01-01

    Background The polyphenolic products of the phenylpropanoid pathway, including proanthocyanidins, anthocyanins and flavonols, possess antioxidant properties that may provide health benefits. To investigate the genetic architecture of control of their biosynthesis in apple fruit, various polyphenolic compounds were quantified in progeny from a 'Royal Gala' × 'Braeburn' apple population segregating for antioxidant content, using ultra high performance liquid chromatography of extracts derived from fruit cortex and skin. Results Construction of genetic maps for 'Royal Gala' and 'Braeburn' enabled detection of 79 quantitative trait loci (QTL) for content of 17 fruit polyphenolic compounds. Seven QTL clusters were stable across two years of harvest and included QTLs for content of flavanols, flavonols, anthocyanins and hydroxycinnamic acids. Alignment of the parental genetic maps with the apple whole genome sequence in silico enabled screening for co-segregation with the QTLs of a range of candidate genes coding for enzymes in the polyphenolic biosynthetic pathway. This co-location was confirmed by genetic mapping of markers derived from the gene sequences. Leucoanthocyanidin reductase (LAR1) co-located with a QTL cluster for the fruit flavanols catechin, epicatechin, procyanidin dimer and five unknown procyanidin oligomers identified near the top of linkage group (LG) 16, while hydroxy cinnamate/quinate transferase (HCT/HQT) co-located with a QTL for chlorogenic acid concentration mapping near the bottom of LG 17. Conclusion We conclude that LAR1 and HCT/HQT are likely to influence the concentration of these compounds in apple fruit and provide useful allele-specific markers for marker assisted selection of trees bearing fruit with healthy attributes. PMID:22269060

  15. QTL and candidate gene mapping for polyphenolic composition in apple fruit

    Directory of Open Access Journals (Sweden)

    Chagné David

    2012-01-01

    Full Text Available Abstract Background The polyphenolic products of the phenylpropanoid pathway, including proanthocyanidins, anthocyanins and flavonols, possess antioxidant properties that may provide health benefits. To investigate the genetic architecture of control of their biosynthesis in apple fruit, various polyphenolic compounds were quantified in progeny from a 'Royal Gala' × 'Braeburn' apple population segregating for antioxidant content, using ultra high performance liquid chromatography of extracts derived from fruit cortex and skin. Results Construction of genetic maps for 'Royal Gala' and 'Braeburn' enabled detection of 79 quantitative trait loci (QTL for content of 17 fruit polyphenolic compounds. Seven QTL clusters were stable across two years of harvest and included QTLs for content of flavanols, flavonols, anthocyanins and hydroxycinnamic acids. Alignment of the parental genetic maps with the apple whole genome sequence in silico enabled screening for co-segregation with the QTLs of a range of candidate genes coding for enzymes in the polyphenolic biosynthetic pathway. This co-location was confirmed by genetic mapping of markers derived from the gene sequences. Leucoanthocyanidin reductase (LAR1 co-located with a QTL cluster for the fruit flavanols catechin, epicatechin, procyanidin dimer and five unknown procyanidin oligomers identified near the top of linkage group (LG 16, while hydroxy cinnamate/quinate transferase (HCT/HQT co-located with a QTL for chlorogenic acid concentration mapping near the bottom of LG 17. Conclusion We conclude that LAR1 and HCT/HQT are likely to influence the concentration of these compounds in apple fruit and provide useful allele-specific markers for marker assisted selection of trees bearing fruit with healthy attributes.

  16. Variation in the autism candidate gene GABRB3 modulates tactile sensitivity in typically developing children

    Directory of Open Access Journals (Sweden)

    Tavassoli Teresa

    2012-07-01

    Full Text Available Abstract Background Autism spectrum conditions have a strong genetic component. Atypical sensory sensitivities are one of the core but neglected features of autism spectrum conditions. GABRB3 is a well-characterised candidate gene for autism spectrum conditions. In mice, heterozygous Gabrb3 deletion is associated with increased tactile sensitivity. However, no study has examined if tactile sensitivity is associated with GABRB3 genetic variation in humans. To test this, we conducted two pilot genetic association studies in the general population, analysing two phenotypic measures of tactile sensitivity (a parent-report and a behavioural measure for association with 43 SNPs in GABRB3. Findings Across both tactile sensitivity measures, three SNPs (rs11636966, rs8023959 and rs2162241 were nominally associated with both phenotypes, providing a measure of internal validation. Parent-report scores were nominally associated with six SNPs (P Conclusions This is the first human study to show an association between GABRB3 variation and tactile sensitivity. This provides support for the evidence from animal models implicating the role of GABRB3 variation in the atypical sensory sensitivity in autism spectrum conditions. Future research is underway to directly test this association in cases of autism spectrum conditions.

  17. ASSOCIATION OF SINGLE NUCLEOTIDE POLYMORPHISMS IN THE LEPR CANDIDATE GENE WITH CARCASS TRAITS OF PIGS

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    Anton Kováčik

    2013-02-01

    Full Text Available Leptin and leptin receptor genetic variants are associated with obese phenotypes in humans and mice and are expected to influence fat deposition in pigs. This study aimed to investigate the associations of LEPR polymorphism with carcass traits (half carcass weight, lean meat percentage, back-fat thickness, MLT area - musculus longisimus thoracis and evaluation of genotypic values, additive values and dominance deviations. To identify the genotypes of LEPR candidate genes, we used biological material obtained from sows (55 and boars (51 of hybrid combination Large White x Landrace after reaching the slaughter weight. We identified three genotypes using restriction endonuclease HpaII in a group of 106 pigs. The AA genotype was the dominant one (42.45%, AB heterozygotes constituted 39.62%, while the BB genotype was the lowest (17.93%. Analyzing the half carcass weight the highest value detected was the highest in the dominant AA homozygotes together with the highest genotypic value (GAA = 0.3649. The pork genotype AA presented the highest back-fat thickness, A high correlation between the additive genetic effect of the A allele and back-fat thickness (0.8183 has been observed while the effect of the allelic dominance was relatively low (0.1907. Based on our results we may conclude that there is an inverse and antagonistic relationship between the quality of the half carcass weight together with the back-fat thickness and the lean meat marker.

  18. Identification of candidate genes of QTLs for seed weight in Brassica napus through comparative mapping among Arabidopsis and Brassica species

    Science.gov (United States)

    2012-01-01

    Background Map-based cloning of quantitative trait loci (QTLs) in polyploidy crop species remains a challenge due to the complexity of their genome structures. QTLs for seed weight in B. napus have been identified, but information on candidate genes for identified QTLs of this important trait is still rare. Results In this study, a whole genome genetic linkage map for B. napus was constructed using simple sequence repeat (SSR) markers that covered a genetic distance of 2,126.4 cM with an average distance of 5.36 cM between markers. A procedure was developed to establish colinearity of SSR loci on B. napus with its two progenitor diploid species B. rapa and B. oleracea through extensive bioinformatics analysis. With the aid of B. rapa and B. oleracea genome sequences, the 421 homologous colinear loci deduced from the SSR loci of B. napus were shown to correspond to 398 homologous loci in Arabidopsis thaliana. Through comparative mapping of Arabidopsis and the three Brassica species, 227 homologous genes for seed size/weight were mapped on the B. napus genetic map, establishing the genetic bases for the important agronomic trait in this amphidiploid species. Furthermore, 12 candidate genes underlying 8 QTLs for seed weight were identified, and a gene-specific marker for BnAP2 was developed through molecular cloning using the seed weight/size gene distribution map in B. napus. Conclusions Our study showed that it is feasible to identify candidate genes of QTLs using a SSR-based B. napus genetic map through comparative mapping among Arabidopsis and B. napus and its two progenitor species B. rapa and B. oleracea. Identification of candidate genes for seed weight in amphidiploid B. napus will accelerate the process of isolating the mapped QTLs for this important trait, and this approach may be useful for QTL identification of other traits of agronomic significance. PMID:23216693

  19. Candidate genes and adaptive radiation: insights from transcriptional adaptation to the limnetic niche among coregonine fishes (Coregonus spp., Salmonidae).

    Science.gov (United States)

    Jeukens, Julie; Bittner, David; Knudsen, Rune; Bernatchez, Louis

    2009-01-01

    In the past 40 years, there has been increasing acceptance that variation in levels of gene expression represents a major source of evolutionary novelty. Gene expression divergence is therefore likely to be involved in the emergence of incipient species, namely, in a context of adaptive radiation. In the lake whitefish species complex (Coregonus clupeaformis), previous microarray experiments have led to the identification of candidate genes potentially implicated in the parallel evolution of the limnetic dwarf lake whitefish, which is highly distinct from the benthic normal lake whitefish in life history, morphology, metabolism, and behavior, and yet diverged from it only approximately 15,000 years before present. The aim of the present study was to address transcriptional divergence for six candidate genes among lake whitefish and European whitefish (Coregonus lavaretus) species pairs, as well as lake cisco (Coregonus artedi) and vendace (Coregonus albula). The main goal was to test the hypothesis that parallel phenotypic adaptation toward the use of the limnetic niche in coregonine fishes is accompanied by parallelism in candidate gene transcription as measured by quantitative real-time polymerase chain reaction. Results obtained for three candidate genes, whereby parallelism in expression was observed across all whitefish species pairs, provide strong support for the hypothesis that divergent natural selection plays an important role in the adaptive radiation of whitefish species. However, this parallelism in expression did not extend to cisco and vendace, thereby infirming transcriptional convergence between limnetic whitefish species and their limnetic congeners for these genes. As recently proposed (Lynch 2007a. The evolution of genetic networks by non-adaptive processes. Nat Rev Genet. 8:803-813), these results may suggest that convergent phenotypic evolution can result from nonadaptive shaping of genome architecture in independently evolved coregonine

  20. A meta-analysis based method for prioritizing candidate genes involved in a pre-specific function

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    Jingjing Zhai

    2016-12-01

    Full Text Available The identification of genes associated with a given biological function in plants remains a challenge, although network-based gene prioritization algorithms have been developed for Arabidopsis thaliana and many non-model plant species. Nevertheless, these network-based gene prioritization algorithms have encountered several problems; one in particular is that of unsatisfactory prediction accuracy due to limited network coverage, varying link quality, and/or uncertain network connectivity. Thus a model that integrates complementary biological data may be expected to increase the prediction accuracy of gene prioritization. Towards this goal, we developed a novel gene prioritization method named RafSee, to rank candidate genes using a random forest algorithm that integrates sequence, evolutionary, and epigenetic features of plants. Subsequently, we proposed an integrative approach named RAP (Rank Aggregation-based data fusion for gene Prioritization, in which an order statistics-based meta-analysis was used to aggregate the rank of the network-based gene prioritization method and RafSee, for accurately prioritizing candidate genes involved in a pre-specific biological function. Finally, we showcased the utility of RAP by prioritizing 380 flowering-time genes in Arabidopsis. The ‘leave-one-out’ cross-validation experiment showed that RafSee could work as a complement to a current state-of-art network-based gene prioritization system (AraNet v2. Moreover, RAP ranked 53.68% (204/380 flowering-time genes higher than AraNet v2, resulting in an 39.46% improvement in term of the first quartile rank. Further evaluations also showed that RAP was effective in prioritizing genes-related to different abiotic stresses. To enhance the usability of RAP for Arabidopsis and non-model plant species, an R package implementing the method is freely available at http://bioinfo.nwafu.edu.cn/software.

  1. Fine Mapping and Characterization of Candidate Genes that Control Resistance to Cercospora sojina K. Hara in Two Soybean Germplasm Accessions.

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    Anh-Tung Pham

    Full Text Available Frogeye leaf spot (FLS, caused by the fungus Cercospora sojina K. Hara, may cause a significant yield loss to soybean growers in regions with a warm and humid climate. Two soybean accessions, PI 594891 and PI 594774, were identified to carry a high level of resistance similar to that conditioned by the Rcs3 gene in 'Davis'. Previously, we reported that the resistance to FLS in these two plant introductions (PIs was controlled by a novel gene (s on chromosome 13 that is different from Rcs3. To fine-map the novel FLS resistance gene(s in these two PIs, F2: 3 seeds from the crosses between PI 594891 and PI 594774, and the FLS susceptible genotype 'Blackhawk' were genotyped with SNP markers that were designed based on the SoySNP50k iSelect BeadChip data to identify recombinant events and locate candidate genes. Analysis of lines possessing key recombination events helped narrow down the FLS-resistance genomic region in PI 594891 from 3.3 Mb to a 72.6 kb region with five annotated genes. The resistance gene in PI 594774 was fine-mapped into a 540 kb region that encompasses the 72.6 kb region found in PI 594891. Sequencing five candidate genes in PI 594891 identified three genes that have several mutations in the promoter, intron, 5', and 3' UTR regions. qPCR analysis showed a difference in expression levels of these genes in both lines compared to Blackhawk in the presence of C. sojina. Based on phenotype, genotype and haplotype analysis results, these two soybean accessions might carry different resistance alleles of the same gene or two different gene(s. The identified SNPs were used to develop Kompetitive Allele Specific PCR (KASP assays to detect the resistance alleles on chromosome 13 from the two PIs for marker-assisted selection.

  2. Epidemiological survey of idiopathic scoliosis and sequence alignment analysis of multiple candidate genes.

    Science.gov (United States)

    Yang, Tao; Jia, Quanzhang; Guo, Hong; Xu, Jianzhong; Bai, Yun; Yang, Kai; Luo, Fei; Zhang, Zehua; Hou, Tianyong

    2012-06-01

    To investigate the effects of genetic factors on idiopathic scoliosis (IS) and genetic modes through genetic epidemiological survey on IS in Chongqing City, China, and to determine whether SH3GL1, GADD45B, and FGF22 in the chromosome 19p13.3 are the pathogenic genes of IS through genetic sequence analysis. 214 nuclear families were investigated to analyse the age incidence, familial aggregation, and heritability. SH3GL1, GADD45B, and FGF22 were chosen as candidate genes for mutation screening in 56 IS patients of 214 families. The sequence alignment analysis was performed to determine mutations and predict the protein structure. The average age of onset of 10.8 years suggests that IS is a early onset disease. Incidences of IS in first-, second-, third-degree relatives and the overall incidence in families (5.68%) were also significantly higher than that of the general population (1.04%). The U test indicated a significant difference, suggesting that IS has a familial aggregation. The heritability of first-degree relatives (77.68 ±10.39%), second-degree relatives (69.89 ±3.14%), and third-degree relatives (62.14 ±11.92%) illustrated that genetic factors play an important role in IS pathogenesis. The incidence of first-degree relatives (10.01%), second-degree relatives (2.55%) and third-degree relatives (1.76%) illustrated that IS is not in simple accord with monogenic Mendel's law but manifests as traits of multifactorial hereditary diseases. Sequence alignment of exons of SH3GL1, GADD45B, and FGF22 showed 17 base mutations, of which 16 mutations do not induce open reading frame (ORF) shift or amino acid changes whereas one mutation (C→T)occurred in SH3GL1 results in formation of the termination codon, which induces variation of protein reading frame. Prediction analysis of protein sequence showed that the SH3GL1 mutant encoded a truncated protein, thus affecting the protein structure. IS is a multifactorial genetic disease and SH3GL1 may be one of the

  3. Lack of direct evidence for natural selection at the candidate thrifty gene locus, PPARGC1A.

    Science.gov (United States)

    Cadzow, Murray; Merriman, Tony R; Boocock, James; Dalbeth, Nicola; Stamp, Lisa K; Black, Michael A; Visscher, Peter M; Wilcox, Phillip L

    2016-11-15

    The gene PPARGC1A, in particular the Gly482Ser variant (rs8192678), had been proposed to be subject to natural selection, particularly in recent progenitors of extant Polynesian populations. Reasons include high levels of population differentiation and increased frequencies of the derived type 2 diabetes (T2D) risk 482Ser allele, and association with body mass index (BMI) in a small Tongan population. However, no direct statistical tests for selection have been applied. Using a range of Polynesian populations (Tongan, Māori, Samoan) we re-examined evidence for association between Gly482Ser with T2D and BMI as well as gout. Using also Asian, European, and African 1000 Genome Project samples a range of statistical tests for selection (F ST , integrated haplotype score (iHS), cross population extended haplotype homozygosity (XP-EHH), Tajima's D and Fay and Wu's H) were conducted on the PPARGC1A locus. No statistically significant evidence for association between Gly482Ser and any of BMI, T2D or gout was found. Population differentiation (F ST ) was smallest between Asian and Pacific populations (New Zealand Māori ≤ 0.35, Samoan ≤ 0.20). When compared to European (New Zealand Māori ≤ 0.40, Samoan ≤ 0.25) or African populations (New Zealand Māori ≤ 0.80, Samoan ≤ 0.66) this differentiation was larger. We did not find any strong evidence for departure from neutral evolution at this locus when applying any of the other statistical tests for selection. However, using the same analytical methods, we found evidence for selection in specific populations at previously identified loci, indicating that lack of selection was the most likely explanation for the lack of evidence of selection in PPARGC1A. We conclude that there is no compelling evidence for selection at this locus, and that this gene should not be considered a candidate thrifty gene locus in Pacific populations. High levels of population differentiation at this locus and the

  4. Association between SNPs within candidate genes and compounds related to boar taint and reproduction

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    Meuwissen Theo HE

    2009-07-01

    Full Text Available Abstract Background Boar taint is an unpleasant odour and flavour of the meat from some uncastrated male pigs primarily caused by elevated levels of androstenone and skatole in adipose tissue. Androstenone is produced in the same biochemical pathway as testosterone and estrogens, which represents a particular challenge when selecting against high levels of androstenone in the breeding programme, without simultaneously decreasing levels of other steroids. Detection of single nucleotide polymorphisms (SNPs associated with compounds affecting boar taint is important both for gaining a better understanding of the complex regulation of the trait and for the purpose of identifying markers that can be used to improve the gain of breeding. The beneficial SNPs to be used in breeding would have the combinational effects of reducing levels of boar taint without affecting fertility of the animals. The aim of this study was to detect SNPs in boar taint candidate genes and to perform association studies for both single SNPs and haplotypes with levels of boar taint compounds and phenotypes related to reproduction. Results An association study involving 275 SNPs in 121 genes and compounds related to boar taint and reproduction were carried out in Duroc and Norwegian Landrace boars. Phenotypes investigated were levels of androstenone, skatole and indole in adipose tissue, levels of androstenone, testosterone, estrone sulphate and 17β-estradiol in plasma, and length of bulbo urethralis gland. The SNPs were genotyped in more than 2800 individuals and several SNPs were found to be significantly (LRT > 5.4 associated with the different phenotypes. Genes with significant SNPs in either of the traits investigated include cytochrome P450 members CYP2E1, CYP21, CYP2D6 and CYP2C49, steroid 5α-reductase SRD5A2, nuclear receptor NGFIB, catenin CTNND1, BRCA1 associated protein BAP1 and hyaluronoglucosaminidase HYAL2. Haplotype analysis provided additional evidence for an

  5. GAD2 on chromosome 10p12 is a candidate gene for human obesity.

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    Philippe Boutin

    2003-12-01

    Full Text Available The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65 is a positional candidate gene for obesity on Chromosome 10p11-12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of gamma-aminobutyric acid (GABA, which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681-0.972], p = 0.0049 and an at-risk SNP (-243 A>G for morbid obesity (OR = 1.3, 95% CI [1.053-1.585], p = 0.014. Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (chi(2 = 7.637, p = 0.02. In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times GAD2 promoter activity (p G SNP was associated with higher hunger scores (p = 0.007 and disinhibition scores (p = 0.028, as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic beta cells, we analyzed GAD65 antibody level as a marker of beta-cell activity and of insulin secretion. In the control group, -243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively. SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of beta-cell function (p = 0.009 and 0.01, respectively. These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.

  6. Resequencing three candidate genes discovers seven potentially deleterious variants susceptibility to major depressive disorder and suicide attempts in Chinese.

    Science.gov (United States)

    Rao, Shitao; Leung, Cherry She Ting; Lam, Macro Hb; Wing, Yun Kwok; Waye, Mary Miu Yee; Tsui, Stephen Kwok Wing

    2017-03-01

    To date almost 200 genes were found to be associated with major depressive disorder (MDD) or suicide attempts (SA), but very few genes were reported for their molecular mechanisms. This study aimed to find out whether there were common or rare variants in three candidate genes altering the risk for MDD and SA in Chinese. Three candidate genes (HOMER1, SLC6A4 and TEF) were chosen for resequencing analysis and association studies as they were reported to be involved in the etiology of MDD and SA. Following that, bioinformatics analyses were applied on those variants of interest. After resequencing analysis and alignment for the amplicons, a total of 34 common or rare variants were found in the randomly selected 36 Hong Kong Chinese patients with both MDD and SA. Among those, seven variants show potentially deleterious features. Rs60029191 and a rare variant located in regulatory region of the HOMER1 gene may affect the promoter activities through interacting with predicted transcription factors. Two missense mutations existed in the SLC6A4 coding regions were firstly reported in Hong Kong Chinese MDD and SA patients, and both of them could affect the transport efficiency of SLC6A4 to serotonin. Moreover, a common variant rs6354 located in the untranslated region of this gene may affect the expression level or exonic splicing of serotonin transporter. In addition, both of a most studied polymorphism rs738499 and a low-frequency variant in the promoter region of the TEF gene were found to be located in potential transcription factor binding sites, which may let the two variants be able to influence the promoter activities of the gene. This study elucidated the potentially molecular mechanisms of the three candidate genes altering the risk for MDD and SA. These findings implied that not only common variants but rare variants could make contributions to the genetic susceptibility to MDD and SA in Chinese. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. My ADHD and me

    DEFF Research Database (Denmark)

    Nielsen, Mikka

    2017-01-01

    In this article, I illustrate how individuals diagnosed with ADHD relate to, engage with, and interpret both ADHD and explanations of the diagnosis. Based on my research on adults’ experiences of ADHD, I describe how my informants 1) identify with ADHD as a specific way of being human as well as 2......) distance themselves from ADHD by separating themselves from and disclaiming behavior connected to ADHD. Notions of ADHD as a brain disorder, I argue, form the basis of both ways of relating to ADHD. Lastly, I discuss how neurobiological explanations of ADHD produce specific choices about and hopes...... for treatment. The analysis is based on interviews with 13 adults diagnosed with ADHD in adulthood; on observations made at conferences and seminars about ADHD for professionals, patients and relatives; and lastly on observations from online blogs and forums about ADHD as part of a two-year anthropological...

  8. Getting Treatment for ADHD

    Medline Plus

    Full Text Available ... to research and develop new drugs for ADHD. It is important to confer with your child’s doctor ... medication for ADHD will continue to benefit from it as teenagers. In fact, many adults with ADHD ...

  9. Getting Treatment for ADHD

    Medline Plus

    Full Text Available ... for your child. Medications Most children with ADHD benefit from taking medication. Medications do not cure ADHD. ... for side effects. A majority of children who benefit from medication for ADHD will continue to benefit ...

  10. College Students with ADHD

    Science.gov (United States)

    ... Guide Facts for Families - Vietnamese College Students with ADHD No. 111; Updated December 2013 Many students with Attention Deficit Hyperactivity Disorder (ADHD) attend college. College students with ADHD face ...

  11. Getting Treatment for ADHD

    Medline Plus

    Full Text Available ... behind in school and continue having trouble with friendships. Family life may also suffer. Untreated ADHD can ... for your child. Medications Most children with ADHD benefit from taking medication. Medications do not cure ADHD. ...

  12. A whole genome SNP genotyping by DNA microarray and candidate gene association study for kidney stone disease

    Science.gov (United States)

    2014-01-01

    Background Kidney stone disease (KSD) is a complex disorder with unknown etiology in majority of the patients. Genetic and environmental factors may cause the disease. In the present study, we used DNA microarray to genotype single nucleotide polymorphisms (SNP) and performed candidate gene association analysis to determine genetic variations associated with the disease. Methods A whole genome SNP genotyping by DNA microarray was initially conducted in 101 patients and 105 control subjects. A set of 104 candidate genes reported to be involved in KSD, gathered from public databases and candidate gene association study databases, were evaluated for their variations associated with KSD. Results Altogether 82 SNPs distributed within 22 candidate gene regions showed significant differences in SNP allele frequencies between the patient and control groups (P AHSG, CD44, and HAO1, encoding osteocalcin, fetuin-A, CD44-molecule and glycolate oxidase 1, respectively, were further assessed for their associations with the disease because they carried high proportion of SNPs with statistical differences of allele frequencies between the patient and control groups within the gene. The total of 26 SNPs showed significant differences of allele frequencies between the patient and control groups and haplotypes associated with disease risk were identified. The SNP rs759330 located 144 bp downstream of BGLAP where it is a predicted microRNA binding site at 3′UTR of PAQR6 – a gene encoding progestin and adipoQ receptor family member VI, was genotyped in 216 patients and 216 control subjects and found to have significant differences in its genotype and allele frequencies (P = 0.0007, OR 2.02 and P = 0.0001, OR 2.02, respectively). Conclusions Our results suggest that these candidate genes are associated with KSD and PAQR6 comes into our view as the most potent candidate since associated SNP rs759330 is located in the miRNA binding site and may affect mRNA expression level

  13. The Development of Comorbid Conduct Problems in Children With ADHD: An Example of an Integrative Developmental Psychopathology Perspective.

    Science.gov (United States)

    Danforth, Jeffrey S; Connor, Daniel F; Doerfler, Leonard A

    2016-03-01

    We describe interactions among factors that contribute to the development of conduct problems among children with ADHD. An integrative developmental psychopathology analysis combines various approaches and posits one model of how diverse risk factors operate together to contribute to the development of conduct problems among children with ADHD. Substantial genetic risk increases covariation between ADHD and conduct problems. Candidate genes are associated with CNS monoaminergic neurotransmission. Subsequent neurodevelopmental impairment interferes with executive function, with impaired verbal working memory playing an important role. Parent/child bi-directional influences exacerbate the risk for conduct problems when ADHD symptoms increase the likelihood of a coercive parenting style. Parent stress in reaction to child comorbid ADHD and conduct problems, and parent attribution for the child's conduct problem behavior, add to the potential for coercion and reduce constructive parent-child interaction that might otherwise enhance the development of verbal working memory. In an integrated manner, these variables increase the risk that a child with ADHD will subsequently develop conduct problems. © The Author(s) 2014.

  14. RNA deep sequencing reveals novel candidate genes and polymorphisms in boar testis and liver tissues with divergent androstenone levels.

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    Asep Gunawan

    Full Text Available Boar taint is an unpleasant smell and taste of pork meat derived from some entire male pigs. The main causes of boar taint are the two compounds androstenone (5α-androst-16-en-3-one and skatole (3-methylindole. It is crucial to understand the genetic mechanism of boar taint to select pigs for lower androstenone levels and thus reduce boar taint. The aim of the present study was to investigate transcriptome differences in boar testis and liver tissues with divergent androstenone levels using RNA deep sequencing (RNA-Seq. The total number of reads produced for each testis and liver sample ranged from 13,221,550 to 33,206,723 and 12,755,487 to 46,050,468, respectively. In testis samples 46 genes were differentially regulated whereas 25 genes showed differential expression in the liver. The fold change values ranged from -4.68 to 2.90 in testis samples and -2.86 to 3.89 in liver samples. Differentially regulated genes in high androstenone testis and liver samples were enriched in metabolic processes such as lipid metabolism, small molecule biochemistry and molecular transport. This study provides evidence for transcriptome profile and gene polymorphisms of boars with divergent androstenone level using RNA-Seq technology. Digital gene expression analysis identified candidate genes in flavin monooxygenease family, cytochrome P450 family and hydroxysteroid dehydrogenase family. Moreover, polymorphism and association analysis revealed mutation in IRG6, MX1, IFIT2, CYP7A1, FMO5 and KRT18 genes could be potential candidate markers for androstenone levels in boars. Further studies are required for proving the role of candidate genes to be used in genomic selection against boar taint in pig breeding programs.

  15. Variation in serotonin neurotransmission genes affects neural activation during response inhibition in adolescents and young adults with ADHD and healthy controls

    NARCIS (Netherlands)

    Van Rooij, Daan; Hartman, Catharina A.; Van Donkelaar, Marjolein M. J.; Bralten, Janita; Von Rhein, Daniel; Hakobjan, Marina; Franke, Barbara; Heslenfeld, Dirk J.; Oosterlaan, Jaap; Rommelse, Nanda; Buitelaar, Jan K.; Hoekstra, Pieter J.

    2015-01-01

    Objectives. Deficits in response inhibition have been associated with attention-deficit/hyperactivity disorder (ADHD). Given the role of serotonin in ADHD and impulsivity, we postulated that genetic variants within the serotonin pathway might influence response inhibition. Methods. We measured

  16. Evaluation of 6 candidate genes on chromosome 11q23 for coeliac disease susceptibility: a case control study

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    Close Eimear

    2010-05-01

    Full Text Available Abstract Background Recent whole genome analysis and follow-up studies have identified many new risk variants for coeliac disease (CD, gluten intolerance. The majority of newly associated regions encode candidate genes with a clear functional role in T-cell regulation. Furthermore, the newly discovered risk loci, together with the well established HLA locus, account for less than 50% of the heritability of CD, suggesting that numerous additional loci remain undiscovered. Linkage studies have identified some well-replicated risk regions, most notably chromosome 5q31 and 11q23. Methods We have evaluated six candidate genes in one of these regions (11q23, namely CD3E, CD3D, CD3G, IL10RA, THY1 and IL18, as risk factors for CD using a 2-phase candidate gene approach directed at chromosome 11q. 377 CD cases and 349 ethnically matched controls were used in the initial screening, followed by an extended sample of 171 additional coeliac cases and 536 additional controls. Results Promotor SNPs (-607, -137 in the IL18 gene, which has shown association with several autoimmune diseases, initially suggested association with CD (P IL18-137/-607 also supported this effect, primarily due to one relatively rare haplotype IL18-607C/-137C (P Conclusion Haplotypes of the IL18 promotor region may contribute to CD risk, consistent with this cytokine's role in maintaining inflammation in active CD.

  17. Rapid Identification of Candidate Genes for Seed Weight Using the SLAF-Seq Method in Brassica napus.

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    Xinxin Geng

    Full Text Available Seed weight is a critical and direct trait for oilseed crop seed yield. Understanding its genetic mechanism is of great importance for yield improvement in Brassica napus breeding. Two hundred and fifty doubled haploid lines derived by microspore culture were developed from a cross between a large-seed line G-42 and a small-seed line 7-9. According to the 1000-seed weight (TSW data, the individual DNA of the heaviest 46 lines and the lightest 47 lines were respectively selected to establish two bulked DNA pools. A new high-throughput sequencing technology, Specific Locus Amplified Fragment Sequencing (SLAF-seq, was used to identify candidate genes of TSW in association analysis combined with bulked segregant analysis (BSA. A total of 1,933 high quality polymorphic SLAF markers were developed and 4 associated markers of TSW were procured. A hot region of ~0.58 Mb at nucleotides 25,401,885-25,985,931 on ChrA09 containing 91 candidate genes was identified as tightly associated with the TSW trait. From annotation information, four genes (GSBRNA2T00037136001, GSBRNA2T00037157001, GSBRNA2T00037129001 and GSBRNA2T00069389001 might be interesting candidate genes that are highly related to seed weight.

  18. Drawing networks of rejection - a systems biological approach to the identification of candidate genes in heart transplantation.

    Science.gov (United States)

    Cadeiras, Martin; von Bayern, Manuel; Sinha, Anshu; Shahzad, Khurram; Latif, Farhana; Lim, Wei Keat; Grenett, Hernan; Tabak, Esteban; Klingler, Tod; Califano, Andrea; Deng, Mario C

    2011-04-01

    Technological development led to an increased interest in systems biological approaches to characterize disease mechanisms and candidate genes relevant to specific diseases. We suggested that the human peripheral blood mononuclear cells (PBMC) network can be delineated by cellular reconstruction to guide identification of candidate genes. Based on 285 microarrays (7370 genes) from 98 heart transplant patients enrolled in the Cardiac Allograft Rejection Gene Expression Observational study, we used an information-theoretic, reverse-engineering algorithm called ARACNe (algorithm for the reconstruction of accurate cellular networks) and chromatin immunoprecipitation assay to reconstruct and validate a putative gene PBMC interaction network. We focused our analysis on transcription factor (TF) genes and developed a priority score to incorporate aspects of network dynamics and information from published literature to supervise gene discovery. ARACNe generated a cellular network and predicted interactions for each TF during rejection and quiescence. Genes ranked highest by priority score included those related to apoptosis, humoural and cellular immune response such as GA binding protein transcription factor (GABP), nuclear factor of κ light polypeptide gene enhancer in B-cells (NFκB), Fas (TNFRSF6)-associated via death domain (FADD) and c-AMP response element binding protein. We used the TF CREB to validate our network. ARACNe predicted 29 putative first-neighbour genes of CREB. Eleven of these (37%) were previously reported. Out of the 18 unknown predicted interactions, 14 primers were identified and 11 could be immunoprecipitated (78.6%). Overall, 75% (n= 22) inferred CREB targets were validated, a significantly higher fraction than randomly expected (P biological approaches to identify possible molecular targets and biomarkers. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing

  19. Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes.

    Science.gov (United States)

    Rasmussen, Malene B; Nielsen, Jakob V; Lourenço, Charles M; Melo, Joana B; Halgren, Christina; Geraldi, Camila V L; Marques, Wilson; Rodrigues, Guilherme R; Thomassen, Mads; Bak, Mads; Hansen, Claus; Ferreira, Susana I; Venâncio, Margarida; Henriksen, Karen F; Lind-Thomsen, Allan; Carreira, Isabel M; Jensen, Niels A; Tommerup, Niels

    2014-09-01

    Recently, a number of patients have been described with structural rearrangements at 3q13.31, delineating a novel microdeletion syndrome with common clinical features including developmental delay and other neurodevelopmental disorders (NDD). A smallest region of overlapping deletions (SRO) involved five RefSeq genes, including the transcription factor gene ZBTB20 and the dopamine receptor gene DRD3, considered as candidate genes for the syndrome. We used array comparative genomic hybridization and next-generation mate-pair sequencing to identify key structural rearrangements involving ZBTB20 in two patients with NDD. In a patient with developmental delay, attention-deficit hyperactivity disorder, psychosis, Tourette's syndrome and autistic traits, a de novo balanced t(3;18) translocation truncated ZBTB20. The other breakpoint did not disrupt any gene. In a second patient with developmental delay and autism, we detected the first microdeletion at 3q13.31, which truncated ZBTB20 but did not involve DRD3 or the other genes within the previously defined SRO. Zbtb20 directly represses 346 genes in the developing murine brain. Of the 342 human orthologous ZBTB20 candidate target genes, we found 68 associated with NDD. Using chromatin immunoprecipitation and quantitative PCR, we validated the in vivo binding of Zbtb20 in evolutionary conserved regions in six of these genes (Cntn4, Gad1, Nrxn1, Nrxn3, Scn2a, Snap25). Our study links dosage imbalance of ZBTB20 to a range of neurodevelopmental, cognitive and psychiatric disorders, likely mediated by dysregulation of multiple ZBTB20 target genes, and provides new knowledge on the genetic background of the NDD seen in the 3q13.31 microdeletion syndrome. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  20. VennPainter: A Tool for the Comparison and Identification of Candidate Genes Based on Venn Diagrams.

    Directory of Open Access Journals (Sweden)

    Guoliang Lin

    Full Text Available VennPainter is a program for depicting unique and shared sets of genes lists and generating Venn diagrams, by using the Qt C++ framework. The software produces Classic Venn, Edwards' Venn and Nested Venn diagrams and allows for eight sets in a graph mode and 31 sets in data processing mode only. In comparison, previous programs produce Classic Venn and Edwards' Venn diagrams and allow for a maximum of six sets. The software incorporates user-friendly features and works in Windows, Linux and Mac OS. Its graphical interface does not require a user to have programing skills. Users can modify diagram content for up to eight datasets because of the Scalable Vector Graphics output. VennPainter can provide output results in vertical, horizontal and matrix formats, which facilitates sharing datasets as required for further identification of candidate genes. Users can obtain gene lists from shared sets by clicking the numbers on the diagram. Thus, VennPainter is an easy-to-use, highly efficient, cross-platform and powerful program that provides a more comprehensive tool for identifying candidate genes and visualizing the relationships among genes or gene families in comparative analysis.

  1. Genetic heterogeneity according to age at onset in bipolar disorder: a combined positional cloning and candidate gene approach.

    Science.gov (United States)

    Dizier, Marie-Hélène; Etain, Bruno; Lajnef, Mohamed; Lathrop, Mark; Grozeva, Detelina; Craddock, Nick; Henry, Chantal; Gard, Sébastien; Jamain, Stéphane; Leboyer, Marion; Bellivier, Frank; Mathieu, Flavie

    2012-09-01

    This study is the first that formally tests for genetic heterogeneity of bipolar disorder (BD) according to age at onset (AAO) sub-groups by combining positional cloning and candidate gene approaches. Our previous genome-wide linkage-scan identified five genomic regions linked to early-onset form of BD. The present study uses association analysis to test genetic heterogeneity of candidate genes located in these five regions in a sample of 443 unrelated bipolar patients and 1,731 controls. The study involved the following steps: (1) test of heterogeneity by comparing early-onset BD patients versus later-onset BD patients; and (2) for significant results in step 1, comparison of early-onset BD patients and later-onset BD patients separately to controls. Two types of analyses were used: the single SNP test and the gene-based association test. We provide evidence for genetic heterogeneity within the ADRB2 (beta-2adrenoreceptor) gene region that is specifically associated with the early onset form of BD with an OR of 1.8. Unfortunately, the genotyping coverage of ADRB2 in the Wellcome Trust Case Control Consortium sample meant undermined our efforts to undertake a replication. However, as the ADRB2 gene product directly interacts with the CACNA1C gene product, and is known to be implicated in BD susceptibility, we conclude that further exploration of the relationships between ADRB2 and BD needs to be undertaken. Copyright © 2012 Wiley Periodicals, Inc.

  2. Identification of novel candidate target genes in amplicons of Glioblastoma multiforme tumors detected by expression and CGH microarray profiling.

    Science.gov (United States)

    Ruano, Yolanda; Mollejo, Manuela; Ribalta, Teresa; Fiaño, Concepción; Camacho, Francisca I; Gómez, Elena; de Lope, Angel Rodríguez; Hernández-Moneo, Jose-Luis; Martínez, Pedro; Meléndez, Bárbara

    2006-09-26

    Conventional cytogenetic and comparative genomic hybridization (CGH) studies in brain malignancies have shown that glioblastoma multiforme (GBM) is characterized by complex structural and numerical alterations. However, the limited resolution of these techniques has precluded the precise identification of detailed specific gene copy number alterations. We performed a genome-wide survey of gene copy number changes in 20 primary GBMs by CGH on cDNA microarrays. A novel amplicon at 4p15, and previously uncharacterized amplicons at 13q32-34 and 1q32 were detected and are analyzed here. These amplicons contained amplified genes not previously reported. Other amplified regions containing well-known oncogenes in GBMs were also detected at 7p12 (EGFR), 7q21 (CDK6), 4q12 (PDGFRA), and 12q13-15 (MDM2 and CDK4). In order to identify the putative target genes of the amplifications, and to determine the changes in gene expression levels associated with copy number change events, we carried out parallel gene expression profiling analyses using the same cDNA microarrays. We detected overexpression of the novel amplified genes SLA/LP and STIM2 (4p15), and TNFSF13B and COL4A2 (13q32-34). Some of the candidate target genes of amplification (EGFR, CDK6, MDM2, CDK4, and TNFSF13B) were tested in an independent set of 111 primary GBMs by using FISH and immunohistological assays. The novel candidate 13q-amplification target TNFSF13B was amplified in 8% of the tumors, and showed protein expression in 20% of the GBMs. This high-resolution analysis allowed us to propose novel candidate target genes such as STIM2 at 4p15, and TNFSF13B or COL4A2 at 13q32-34 that could potentially contribute to the pathogenesis of these tumors and which would require futher investigations. We showed that overexpression of the amplified genes could be attributable to gene dosage and speculate that deregulation of those genes could be important in the development and progression of GBM. Our findings highlight

  3. Identification of novel candidate target genes in amplicons of Glioblastoma multiforme tumors detected by expression and CGH microarray profiling

    Directory of Open Access Journals (Sweden)

    Hernández-Moneo Jose-Luis

    2006-09-01

    Full Text Available Abstract Background Conventional cytogenetic and comparative genomic hybridization (CGH studies in brain malignancies have shown that glioblastoma multiforme (GBM is characterized by complex structural and numerical alterations. However, the limited resolution of these techniques has precluded the precise identification of detailed specific gene copy number alterations. Results We performed a genome-wide survey of gene copy number changes in 20 primary GBMs by CGH on cDNA microarrays. A novel amplicon at 4p15, and previously uncharacterized amplicons at 13q32-34 and 1q32 were detected and are analyzed here. These amplicons contained amplified genes not previously reported. Other amplified regions containg well-known oncogenes in GBMs were also detected at 7p12 (EGFR, 7q21 (CDK6, 4q12 (PDGFRA, and 12q13-15 (MDM2 and CDK4. In order to identify the putative target genes of the amplifications, and to determine the changes in gene expression levels associated with copy number change events, we carried out parallel gene expression profiling analyses using the same cDNA microarrays. We detected overexpression of the novel amplified genes SLA/LP and STIM2 (4p15, and TNFSF13B and COL4A2 (13q32-34. Some of the candidate target genes of amplification (EGFR, CDK6, MDM2, CDK4, and TNFSF13B were tested in an independent set of 111 primary GBMs by using FISH and immunohistological assays. The novel candidate 13q-amplification target TNFSF13B was amplified in 8% of the tumors, and showed protein expression in 20% of the GBMs. Conclusion This high-resolution analysis allowed us to propose novel candidate target genes such as STIM2 at 4p15, and TNFSF13B or COL4A2 at 13q32-34 that could potentially contribute to the pathogenesis of these tumors and which would require futher investigations. We showed that overexpression of the amplified genes could be attributable to gene dosage and speculate that deregulation of those genes could be important in the development

  4. Selection and validation of reference genes for qRT-PCR expression analysis of candidate genes involved in olfactory communication in the butterfly Bicyclus anynana.

    Science.gov (United States)

    Arun, Alok; Baumlé, Véronique; Amelot, Gaël; Nieberding, Caroline M

    2015-01-01

    Real-time quantitative reverse transcription PCR (qRT-PCR) is a technique widely used to quantify the transcriptional expression level of candidate genes. qRT-PCR requires the selection of one or several suitable reference genes, whose expression profiles remain stable across conditions, to normalize the qRT-PCR expression profiles of candidate genes. Although several butterfly species (Lepidoptera) have become important models in molecular evolutionary ecology, so far no study aimed at identifying reference genes for accurate data normalization for any butterfly is available. The African bush brown butterfly Bicyclus anynana has drawn considerable attention owing to its suitability as a model for evolutionary ecology, and we here provide a maiden extensive study to identify suitable reference gene in this species. We monitored the expression profile of twelve reference genes: eEF-1α, FK506, UBQL40, RpS8, RpS18, HSP, GAPDH, VATPase, ACT3, TBP, eIF2 and G6PD. We tested the stability of their expression profiles in three different tissues (wings, brains, antennae), two developmental stages (pupal and adult) and two sexes (male and female), all of which were subjected to two food treatments (food stress and control feeding ad libitum). The expression stability and ranking of twelve reference genes was assessed using two algorithm-based methods, NormFinder and geNorm. Both methods identified RpS8 as the best suitable reference gene for expression data normalization. We also showed that the use of two reference genes is sufficient to effectively normalize the qRT-PCR data under varying tissues and experimental conditions that we used in B. anynana. Finally, we tested the effect of choosing reference genes with different stability on the normalization of the transcript abundance of a candidate gene involved in olfactory communication in B. anynana, the Fatty Acyl Reductase 2, and we confirmed that using an unstable reference gene can drastically alter the expression

  5. Selection and validation of reference