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Sample records for modified intracellular-associated phenotypes

  1. The renal microenvironment modifies dendritic cell phenotype.

    PubMed

    Chessa, Federica; Mathow, Daniel; Wang, Shijun; Hielscher, Thomas; Atzberger, Ann; Porubsky, Stefan; Gretz, Norbert; Burgdorf, Sven; Gröne, Hermann-Josef; Popovic, Zoran V

    2016-01-01

    Renal dendritic cells are a major component of the renal mononuclear phagocytic system. In the renal interstitium, these cells are exposed to an osmotic gradient, mainly sodium, whose concentration progressively increases towards inner medulla. Renal allograft rejection affects predominantly the cortex, suggesting a protective role of the renal medullary micromilieu. Whether osmolar variations can modulate the function of renal dendritic cells is currently undefined. Considering the central role of dendritic cells in promoting allorejection, we tested whether the biophysical micromilieu, particularly the interstitial osmotic gradient, influences their alloreactivity. There was a progressive depletion of leukocytes towards the medulla of homeostatic kidney. Only macrophages opposed this tendency. Flow cytometry of homeostatic and post-transplant medullary dendritic cells revealed a switch towards a macrophage-like phenotype. Similarly, bone marrow-derived dendritic cells developed ex vivo in sodium chloride-enriched medium acquired a M2-like signature. Microarray analysis of allotransplant dendritic cells posed a medullary downregulation of genes mainly involved in alloantigen recognition. Gene expression profiles of both medullary dendritic cells and bone marrow-derived dendritic cells matured in hyperosmolar medium had an overlap with the macrophage M2 signature. Thus, the medullary environment inhibits an alloimmune response by modulating the phenotype and function of dendritic cells.

  2. Genetic and Molecular Characterization of Drosophia Brakeless: A Novel Modifier of Merlin Phenotypes

    DTIC Science & Technology

    2005-07-01

    transcription. From genetic epistasis , we know that Merlin functions upstream of scribbler and Cyclin E. We are currently in the process of determining...modifier of sbb gain-of-function and CycE Merlin acts as a dominant modifier of sbb gain-of-function phenotypes. Heterozygosity for a recessive null...hypomorphic allele of Cyclin E that expresses a small eye and small wing phenotype (Secombe et al., 1998; Fig. 2C, D). Heterozygosity for recessive mutant

  3. A Novel Lung Disease Phenotype Adjusted for Mortality Attrition for Cystic Fibrosis Genetic Modifier Studies

    PubMed Central

    Taylor, Chelsea; Commander, Clayton W.; Collaco, Joseph M.; Strug, Lisa J.; Li, Weili; Wright, Fred A.; Webel, Aaron D.; Pace, Rhonda G.; Stonebraker, Jaclyn R.; Naughton, Kathleen; Dorfman, Ruslan; Sandford, Andrew; Blackman, Scott M.; Berthiaume, Yves; Paré, Peter; Drumm, Mitchell L.; Zielenski, Julian; Durie, Peter; Cutting, Garry R.; Knowles, Michael R.; Corey, Mary

    2011-01-01

    SUMMARY Genetic studies of lung disease in Cystic Fibrosis are hampered by the lack of a severity measure that accounts for chronic disease progression and mortality attrition. Further, combining analyses across studies requires common phenotypes that are robust to study design and patient ascertainment. Using data from the North American Cystic Fibrosis Modifier Consortium (Canadian Consortium for CF Genetic Studies, Johns Hopkins University CF Twin and Sibling Study, and University of North Carolina/Case Western Reserve University Gene Modifier Study), the authors calculated age-specific CF percentile values of FEV1 which were adjusted for CF age-specific mortality data. The phenotype was computed for 2061 patients representing the Canadian CF population, 1137 extreme phenotype patients in the UNC/Case Western study, and 1323 patients from multiple CF sib families in the CF Twin and Sibling Study. Despite differences in ascertainment and median age, our phenotype score was distributed in all three samples in a manner consistent with ascertainment differences, reflecting the lung disease severity of each individual in the underlying population. The new phenotype score was highly correlated with the previously recommended complex phenotype, but the new phenotype is more robust for shorter follow-up and for extreme ages. A disease progression and mortality adjusted phenotype reduces the need for stratification or additional covariates, increasing statistical power and avoiding possible distortions. This approach will facilitate large scale genetic and environmental epidemiological studies which will provide targeted therapeutic pathways for the clinical benefit of patients with CF. PMID:21462361

  4. Induction of phenotype modifying cytokines by FERMT1 mutations.

    PubMed

    Heinemann, Anja; He, Yinghong; Zimina, Elena; Boerries, Melanie; Busch, Hauke; Chmel, Nadja; Kurz, Thorsten; Bruckner-Tuderman, Leena; Has, Cristina

    2011-04-01

    Kindler syndrome (KS) is a progressive skin disorder caused by FERMT1 mutations. Early in life, KS manifests as a mechanobullous disease reflecting diminished cell adhesion, but the mechanisms of its later phenotypic features, progressive poikiloderma, and mucocutaneous fibrosis, remain elusive. The FERMT1 gene product and KS protein, kindlin-1, is an epithelial-specific phosphoprotein involved in integrin beta-1 activation, without an obvious link to dermal connective tissue. Here we show how lack of intracellular kindlin-1 in epidermal keratinocytes leads to profound changes in another skin compartment, the dermis. Kindlin-1-deficient keratinocytes respond to cell stress by upregulating the expression of cytokines such as IL-20, IL-24, TGF-β2, IL1F5, PDGFB, and CTGF. These launch-via paracrine communication-an inflammatory response in the dermis, accompanied by the presence of TGF-β, IL-6, and CTGF, activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins. These data are concordant with a model wherein repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie mucocutaneous fibrosis in KS. © 2011 Wiley-Liss, Inc.

  5. Explaining variation in familial adenomatous polyposis: relationship between genotype and phenotype and evidence for modifier genes

    PubMed Central

    Crabtree, M D; Tomlinson, I P M; Hodgson, S V; Neale, K; Phillips, R K S; Houlston, R S

    2002-01-01

    Background: Familial adenomatous polyposis (FAP) is characterised by variable phenotypic expression. Part of this is attributable to a relationship between APC genotype and phenotype but there remains significant intrafamilial variation. In the Min mouse model of FAP, differences in the severity of gastrointestinal polyposis result from the action of modifier genes. Aims: To determine whether phenotypic variation in human FAP has an inherited component consistent with the action of modifier genes. Method: We systematically examined polyp numbers in colectomy specimens from patients with classical FAP. Variation both between and within families was analysed. Formal modelling of the segregation of disease severity in families was performed Results: There was strong evidence for a relationship between site of mutation and the number of colorectal polyps, with germline mutations in the “cluster region” causing the most severe disease and those with mutations between codons 1020 and 1169 having the mildest disease. In addition to this genotype-phenotype relationship, we found evidence for non-APC linked genetic modifiers of disease expression. First degree relatives had more similar polyp counts than more distant relatives. Formal modelling of the segregation of disease severity in families revealed further evidence for the action of modifier genes, with a best fit to a mixed model of inheritance. Conclusion: Our data provide good evidence to support the hypothesis that modifier genes influence the severity of FAP in humans. PMID:12171967

  6. Modifiers of the Genotype–Phenotype Map: Hsp90 and Beyond

    PubMed Central

    Ehrenreich, Ian M.

    2016-01-01

    Disruption of certain genes alters the heritable phenotypic variation among individuals. Research on the chaperone Hsp90 has played a central role in determining the genetic basis of this phenomenon, which may be important to evolution and disease. Key studies have shown that Hsp90 perturbation modifies the effects of many genetic variants throughout the genome. These modifications collectively transform the genotype–phenotype map, often resulting in a net increase or decrease in heritable phenotypic variation. Here, we summarize some of the foundational work on Hsp90 that led to these insights, discuss a framework for interpreting this research that is centered upon the standard genetics concept of epistasis, and propose major questions that future studies in this area should address. PMID:27832066

  7. Approaches for the Identification of Genetic Modifiers of Nutrient Dependent Phenotypes: Examples from Folate

    PubMed Central

    Zinck, John W. R.; MacFarlane, Amanda J.

    2014-01-01

    By combining the sciences of nutrition, bioinformatics, genomics, population genetics, and epidemiology, nutrigenomics is improving our understanding of how diet and nutrient intake can interact with or modify gene expression and disease risk. In this review, we explore various approaches to examine gene–nutrient interactions and the modifying role of nutrient consumption, as they relate to nutrient status and disease risk in human populations. Two common approaches include the use of SNPs in candidate genes to identify their association with nutritional status or disease outcomes, or genome-wide association studies to identify genetic polymorphisms associated with a given phenotype. Here, we examine the results of various gene–nutrient interaction studies, the association of genetic polymorphisms with disease expression, and the identification of nutritional factors that modify gene-dependent disease phenotypes. We have focused on specific examples from investigations of the interactions of folate, B-vitamin consumption, and polymorphisms in the genes of B-vitamin dependent enzymes and their association with disease risk, followed by an examination of the strengths and limitations of the methods employed. We also present suggestions for future studies, including an approach from an on-going large scale study, to examine the interaction of nutrient intake and genotypic variation and their impact on nutritional status. PMID:25988111

  8. Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans

    PubMed Central

    Buonocore, Federica; Kühnen, Peter; Suntharalingham, Jenifer P.; Del Valle, Ignacio; Digweed, Martin; Khajavi, Noushafarin; Didi, Mohammed; Brady, Angela F.; Procter, Annie M.; Dimitri, Paul; Wales, Jerry K.H.; Ghirri, Paolo; Knöbl, Dieter; Strahm, Brigitte; Erlacher, Miriam; Wlodarski, Marcin W.; Chen, Wei; Kokai, George K.; Anderson, Glenn; Morrogh, Deborah; Moulding, Dale A.; McKee, Shane A.; Niemeyer, Charlotte M.; Grüters, Annette; Achermann, John C.

    2017-01-01

    It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain–containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (–7), deletions of 7q (7q–), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with –7 and 7q– developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized. PMID:28346228

  9. Evaluation of Potential Modifiers of the Palatal Phenotype in the 22q11.2 Deletion Syndrome

    PubMed Central

    Driscoll, Deborah A.; Boland, Torrey; Emanuel, Beverly S.; Kirschner, Richard E.; LaRossa, Don; Manson, Jeanne; McDonald-McGinn, Donna; Randall, Peter; Solot, Cynthia; Zackai, Elaine; Mitchell, Laura E.

    2010-01-01

    Objective To evaluate potential modifiers of the palatal phenotype in individuals with the 22q11.2 deletion syndrome. Design Data from 356 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the palatal phenotype. Specifically, subjects with and without velopharyngeal inadequacy and/or structural malformations of the palate were compared with respect to gender, race, and genotype for variants of seven genes that may influence palatal development. Methods The chi-square test or Fisher exact test was used to evaluate the association between palatal phenotype and each potential modifier. Odds ratios and their associated 95% confidence intervals were used to measure the magnitude of the association between palatal phenotype, subject gender and race, and each of the bi-allelic variants. Results The palatal phenotype observed in individuals with the 22q11.2 deletion syndrome was significantly associated with both gender and race. In addition, there was tentative evidence that the palatal phenotype may be influenced by variation within the gene that encodes methionine synthase. Conclusions Variation in the palatal phenotype observed between individuals with the 22q11.2 deletion syndrome may be related to personal characteristics such as gender and race as well as variation within genes that reside outside of the 22q11.2 region. PMID:16854201

  10. A model of band-pass phenotypic resistance in a modified Beverton-Holt framework.

    PubMed

    Nemzer, Louis R

    2014-06-01

    A new mathematical model of phenotypic bacterial resistance to a periodically applied antibiotic is presented. Using a modified Beverton-Holt framework, and without appealing to any explicit internal timescale or heritable mutations, we map the parameter-space regions corresponding to bacterial colony survival or extinction. It is demonstrated that band-pass behavior, in which colony survival occurs at intermediate - but not short or long - antibiotic application periods, is a possible regime for some initial population values if the bactericidal activity is sufficient. However, below this threshold value of antibiotic efficacy, a "fixed-point catastrophe" occurs, and colony extinction does not occur when the bacteria are challenged with long application periods. These results suggest that the dosing schedule of antibiotics within a clinical setting merits additional scrutiny, since even seemingly unimportant modifications to the frequency of administration may lead to widely diverging patient outcomes. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Clinical and biological phenotypes of frontotemporal dementia: Perspectives for disease modifying therapies.

    PubMed

    Gazzina, S; Manes, M A; Padovani, A; Borroni, B

    2017-06-01

    Frontotemporal Dementia (FTD) is a progressive neurodegenerative condition which encompasses a group of clinically, neuropathologically and genetically heterogeneous disorders characterized by selective involvement of the frontal and temporal lobes. FTD is characterized by changes in behaviour and personality, frontal executive deficits and language dysfunction. Different phenotypes have been defined on the basis of presenting clinical symptoms, behavioural variants of FTD (bvFTD) and primary progressive aphasia (PPA), which includes nonfluent/agrammatic variant PPA (avPPA) and semantic variant PPA (svPPA). These presentations can overlap with atypical parkinsonian disorders (i.e., corticobasal syndrome, progressive supranuclear palsy) and amyotrophic lateral sclerosis. Each syndrome can be associated with one or more neuropathological hallmark, and in some cases it may be due to autosomal inherited disorder caused by mutations in a number of genes. Currently, there is no specific treatment available to prevent disease progression. FTD treatment is based on symptomatic management, and most therapies lack quality evidence from randomized, placebo-controlled clinical trials. Recent advances in the understanding of FTD pathophysiology and genetics have led to the development of potentially disease-modifying therapies. In this review, we discussed current knowledge and recommendations with regards to symptomatic and disease-modifying therapies. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Does the SLC40A1 gene modify HFE-related haemochromatosis phenotypes?

    PubMed

    Altès, Albert; Bach, Vanessa; Ruiz, Angels; Esteve, Anna; Remacha, Angel F; Sardà, M Pilar; Felez, Jordi; Baiget, Montserrat

    2009-04-01

    Most hereditary haemochromatosis patients are homozygous for the C282Y mutation of the HFE gene. However, the phenotypic expression and clinical aggressiveness of the disease differs considerably from patient to patient. The main objective of this work was to study the role of variants in the SLC40A1 gene in the severity of iron overload and his clinical consequences in 100 Spanish probands homozygous for the C282Y mutation of the HFE gene. We performed automated sequencing of the coding regions, including intron-exon junctions of the SLC40A1 gene. We studied the association between polymorphisms in the SLC40A1 gene and median values of iron removed, taking into account statistical corrections for multiple comparisons. No pathogenic mutations in the SLC40A1 were detected. Five known single nucleotide polymorphisms (SNPs) were identified, and two of them were associated with phenotypic characteristics. IVS1-24 C>G was associated with the amount of iron removed and presence of liver disease: Of the 83 patients finally studied for this SNP, the amount of iron removed was above the median in 36 of 56 (64.3%) for C/C, in nine of 23(39.1%) for C/G and in zero of four (0%) for G/G patients (P=0.01). Liver damage was observed in 34 of 56 patients (60.7%) for C/C, in eight of 23 (34.8%) for C/G and in zero of four (0%) for G/G (P=0.01). Both associations remained significant at multivariate analysis (P=0.011 and P=0.023, respectively). IVS1-24 C>G on the ferroportin gene seems to be a genetic modifier for clinical aggressiveness of HFE1 haemochromatosis.

  13. Polysaccharide storage myopathy phenotype in quarter horse-related breeds is modified by the presence of an RYR1 mutation.

    PubMed

    McCue, M E; Valberg, S J; Jackson, M; Borgia, L; Lucio, M; Mickelson, J R

    2009-01-01

    In this study we examined a family of Quarter Horses with Polysaccharide Storage Myopathy (PSSM) with a dominant mutation in the skeletal muscle glycogen synthase (GYS1) gene. A subset of horses within this family had a more severe and occasionally fatal PSSM phenotype. The purpose of this study was to identify a modifying gene(s) for the severe clinical phenotype. A genetic association analysis was used to identify RYR1 as a candidate modifying gene. A rare, known equine RYR1 mutation, associated with malignant hyperthermia (MH), was found to segregate in this GYS1 PSSM family. Retrospective analysis of patient records (n=179) demonstrated that horses with both the GYS1 and RYR1 mutations had a more severe clinical phenotype than horses with the GYS1 mutation alone. A treadmill trial (n=8) showed that serum creatine kinase activity was higher and exercise intolerance greater in horses with both mutations compared to the GYS1 mutation alone.

  14. Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework.

    PubMed

    Fanous, A H; Kendler, K S

    2005-01-01

    Schizophrenia has long been thought to be clinically heterogeneous. A range of studies suggests that this is due to genetic heterogeneity. Some clinical features, such as negative symptoms, are associated with a greater risk of illness in relatives. Affected sibling pairs are correlated for clinical and course features as well as subforms of illness, and twin studies suggest that this is due to genetic factors. This is further supported by findings that subjects from families linked to some chromosomal regions may differ clinically from those from unlinked families. Moreover, some genes may affect clinical features without altering susceptibility (ie are modifier genes). High-risk genotypes may have quantitative, rather than categorical effects, and may influence milder or subclinical phenotypes. Another recent finding is that nonpsychotic relatives may have personality features that resemble those of their affected relatives. These findings taken together suggest that there may be several classes of gene action in schizophrenia: some genes may influence susceptibility only, others may influence clinical features only, and still others may have a mixed effect. Furthermore, subsets of these classes may affect personality and other traits in nonpsychotic relatives. Understanding these classes of gene action may help guide the design of linkage and association studies that have increased power. We describe five classes of genes and their predictions of the outcomes of family, twin, and several types of linkage studies. We go on to explore how these predictions can in turn be used to aid in the design of linkage studies.

  15. The modifier effect of the BDNF gene in the phenotype of the WAGRO syndrome.

    PubMed

    Rodríguez-López, Raquel; Pérez, José M Carbonell; Balsera, Aránzazu Margallo; Rodríguez, Guillermo Gervasini; Moreno, Trinidad Herrera; García de Cáceres, Mayte; Serrano, Marta González-Carpio; Freijo, Felipe Casanueva; Ruiz, Juan Ramón González; Angueira, Francisco Barros; Pérez, Pilar Méndez; Estévez, Manuela Núñez; Gómez, Enrique Galán

    2013-03-10

    Individuals who are carriers of deletions of various sizes that cause haploinsufficiency in the contiguous WT1 and PAX6 genes, located on chromosome 11p13 approximately 4 Mb centromeric to the BDNF gene, are susceptible to Wilms tumor, aniridia, mental retardation, genitourinary anomalies and obesity (WAGRO syndrome). The molecular characterization of the wide deletion 11p15.1p12 arr (18676926-36576388) x1 dn in a child with 3 years and 4 months of age only affected by aniridia, predicts not only other serious associated diseases, but also allows us to hypothesize a specific phenotype of mental impairment, conduct alterations and childhood obesity, possibly added to the onset of metabolic alterations. The variable appearance and/or description of haploinsufficiency for obesity susceptibility in the WAGR syndrome mainly depends on the critical region located within 80 kb of exon 1 of BDNF. The relationship between genetic variation based on the genotype combinations of the 4 gene SNPs tagging the BDNF gene and the body mass index (BMI) was studied. The polymorphic variability was similarly distributed in 218 children suffering a severe and non-syndromic obesity from families at high risk for obesity, as compared with 198 controls. The corroborated role of the BDNF gene as highly susceptible to severe syndromic obesity has not already been evidenced in the molecular basis of overweight attributed to the common polygenic principles. Its potential role as risk modifier variant to provoke more severe phenotype has not yet been demonstrated. Some genetic variants of brain-derived neurotrophic factor (BDNF) have resulted in important disorders of energy balance, but it is essential to know exactly their deleterious human capacity because they play a fundamental role in the development and plasticity of the central nervous system in regulating food intake. The existence of polymorphic amino acid changes of unknown functional significance in patients carrying the

  16. A Modified Approach to Inducing Bone Marrow Stromal Cells to Differentiate into Cells with Mature Schwann Cell Phenotypes.

    PubMed

    Liu, Yutian; Chen, Jianghai; Liu, Wei; Lu, Xiaocheng; Liu, Zhenyu; Zhao, Xiaobo; Li, Gongchi; Chen, Zhenbing

    2016-02-15

    Marrow stromal cells (MSCs) can be induced to differentiate into Schwann-like cells under classical induction conditions. However, cells derived from this method are unstable, exhibiting a low neurotrophin expression level after the induction conditions are removed. In Schwann cell (SC) culture, progesterone (PROG) enhances neurotrophic synthesis and myelination, specifically regulating the expression of the myelin protein zero (P0)- and peripheral myelin protein 22 (PMP22)-encoding genes by acting in concert or in synergy with insulin and glucocorticoids (GLUCs). In the present study, we investigated whether combined PROG, GLUC, and insulin therapy induced MSCs to differentiate into modified SC-like cells with phenotypes similar to those of mature SCs. After being cultured for 2 weeks in modified differentiation medium, the modified SC-like cells showed increased expression of P0 and PMP22. In addition, morphological and phenotypic characterizations were conducted over a period of over 2 weeks, and functional characteristics persisted for more than 3 weeks after the induction reagents were withdrawn. The transplantation of green fluorescent protein-labeled, modified SC-like cells into transected sciatic nerves with a 10-mm gap significantly increased the proliferation of the original SCs and improved axon regeneration and myelination compared with original BM-SCs. Immunostaining for P0 revealed that more of the transplanted modified SC-like cells retained the phenotypic characteristics of SCs. Taken together, these results reveal that the combined application of PROG, GLUC, and insulin induces MSCs to differentiate into cells with phenotypic, molecular, and functional properties of mature SCs.

  17. ENU Mutagenesis Screen to Establish Motor Phenotypes in Wild-Type Mice and Modifiers of a Pre-Existing Motor Phenotype in Tau Mutant Mice

    PubMed Central

    Liu, Xin; Dobbie, Michael; Tunningley, Rob; Whittle, Belinda; Zhang, Yafei; Ittner, Lars M.; Götz, Jürgen

    2011-01-01

    Modifier screening is a powerful genetic tool. While not widely used in the vertebrate system, we applied these tools to transgenic mouse strains that recapitulate key aspects of Alzheimer's disease (AD), such as tau-expressing mice. These are characterized by a robust pathology including both motor and memory impairment. The phenotype can be modulated by ENU mutagenesis, which results in novel mutant mouse strains and allows identifying the underlying gene/mutation. Here we discuss this strategy in detail. We firstly obtained pedigrees that modify the tau-related motor phenotype, with mapping ongoing. We further obtained transgene-independent motor pedigrees: (i) hyperactive, circling ENU 37 mice with a causal mutation in the Tbx1 gene—the complete knock-out of Tbx1 models DiGeorge Syndrome; (ii) ENU12/301 mice that show sudden jerky movements and tremor constantly; they have a causal mutation in the Kcnq1 gene, modelling aspects of the Romano-Ward and Jervell and Lange-Nielsen syndromes; and (iii) ENU16/069 mice with tremor and hypermetric gait that have a causal mutation in the Mpz (Myelin Protein Zero) gene, modelling Charcot-Marie-Tooth disease type 1 (CMT1B). Together, we provide evidence for a real potential of an ENU mutagenesis to dissect motor functions in wild-type and tau mutant mice. PMID:22219655

  18. Evaluation of Potential Modifiers of the Cardiac Phenotype in the 22q11.2 Deletion Syndrome

    PubMed Central

    Goldmuntz, Elizabeth; Driscoll, Deborah A.; Emanuel, Beverly S.; McDonald-McGinn, Donna; Mei, Minghua; Zackai, Elaine; Mitchell, Laura E.

    2010-01-01

    BACKGROUND The phenotype associated with deletion of the 22q11.2 chromosomal region is highly variable, yet little is known about the source of this variability. Cardiovascular anomalies, including tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, perimembranous ventricular septal defects, and aortic arch anomalies, occur in approximately 75% of individuals with a 22q11.2 deletion. METHODS Data from 343 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the cardiac phenotype in this disorder. Subjects with and without cardiac malformations, and subjects with and without aortic arch anomalies were compared with respect to sex and race. In addition, in the subset of subjects from whom a DNA sample was available, genotypes for variants of four genes that are involved in the folate-homocysteine metabolic pathway and that have been implicated as risk factors for other birth defects were compared. Five variants in four genes were genotyped by heteroduplex or restriction digest assays. The chi-square or Fisher’s exact test was used to evaluate the association between the cardiac phenotype and each potential modifier. RESULTS The cardiac phenotype observed in individuals with a 22q11.2 deletion was not significantly associated with either sex or race. The genetic variants that were evaluated also did not appear to be associated with the cardiovascular phenotype. CONCLUSIONS Variation in the cardiac phenotype observed between individuals with a 22q11.2 deletion does not appear to be related to sex, race, or five sequence variants in four folate-related genes that are located outside of the 22q11.2 region. PMID:18770859

  19. A genetic screen for modifiers of a kinase suppressor of Ras-dependent rough eye phenotype in Drosophila.

    PubMed Central

    Therrien, M; Morrison, D K; Wong, A M; Rubin, G M

    2000-01-01

    kinase suppressor of Ras (ksr) encodes a putative protein kinase that by genetic criteria appears to function downstream of RAS in multiple receptor tyrosine kinase (RTK) pathways. While biochemical evidence suggests that the role of KSR is closely linked to the signal transduction mechanism of the MAPK cascade, the precise molecular function of KSR remains unresolved. To further elucidate the role of KSR and to identify proteins that may be required for KSR function, we conducted a dominant modifier screen in Drosophila based on a KSR-dependent phenotype. Overexpression of the KSR kinase domain in a subset of cells during Drosophila eye development blocks photoreceptor cell differentiation and results in the external roughening of the adult eye. Therefore, mutations in genes functioning with KSR might modify the KSR-dependent phenotype. We screened approximately 185,000 mutagenized progeny for dominant modifiers of the KSR-dependent rough eye phenotype. A total of 15 complementation groups of Enhancers and four complementation groups of Suppressors were derived. Ten of these complementation groups correspond to mutations in known components of the Ras1 pathway, demonstrating the ability of the screen to specifically identify loci critical for Ras1 signaling and further confirming a role for KSR in Ras1 signaling. In addition, we have identified 4 additional complementation groups. One of them corresponds to the kismet locus, which encodes a putative chromatin remodeling factor. The relevance of these loci with respect to the function of KSR and the Ras1 pathway in general is discussed. PMID:11063697

  20. Genetic modifiers of sickle cell anemia in the BABY HUG cohort: influence on laboratory and clinical phenotypes.

    PubMed

    Sheehan, Vivien A; Luo, Zhaoyu; Flanagan, Jonathan M; Howard, Thad A; Thompson, Bruce W; Wang, Winfred C; Kutlar, Abdullah; Ware, Russell E

    2013-07-01

    The recently completed BABY HUG trial investigated the safety and efficacy of hydroxyurea in infants with sickle cell anemia (SCA). To investigate the effects of known genetic modifiers, genomic DNA on 190 randomized subjects were analyzed for alpha thalassemia, beta-globin haplotype, polymorphisms affecting endogenous fetal hemoglobin (HbF) levels (XmnI, BCL11A, and HBS1L-MYB), UGT1A1 promoter polymorphisms, and the common G6PD A(-) mutation. At study entry, infants with alpha thalassemia trait had significantly lower mean corpuscular volume, total bilirubin, and absolute reticulocyte count. Beta-globin haplotypes associated with milder disease had significantly higher hemoglobin and %HbF. BCL11A and XmnI polymorphisms had significant effects on baseline HbF, while UGT1A1 promoter polymorphisms significantly influenced baseline serum bilirubin. At study exit, subjects randomized to placebo still exhibited laboratory effects of alpha thalassemia and other modifiers, while those assigned hydroxyurea had treatment effects that exceeded most genetic influences. The pain phenotype was influenced by HbF modifiers in both treatment groups. These data document that genetic polymorphisms do modify laboratory and clinical phenotypes even in very young patients with SCA. The hydroxyurea effects are more potent, however, indicating that treatment criteria should not be limited to certain genetic subsets, and supporting the use of hydroxyurea for all young patients with SCA.

  1. Asthma phenotypes modify the impact of environmetnal factors on lung function

    EPA Science Inventory

    Previous studies have examined the role of childhood asthma phenotypes based on clinical history on asthma severity and symptom aggravation by environmental risk factors. The current study focuses on the associations between lung function in childhood and environmental factors an...

  2. Asthma phenotypes modify the impact of environmetnal factors on lung function

    EPA Science Inventory

    Previous studies have examined the role of childhood asthma phenotypes based on clinical history on asthma severity and symptom aggravation by environmental risk factors. The current study focuses on the associations between lung function in childhood and environmental factors an...

  3. Modifying effects of phenotypic plasticity on interactions among natural selection, adaptation and gene flow.

    PubMed

    Crispo, E

    2008-11-01

    Divergent natural selection, adaptive divergence and gene flow may interact in a number of ways. Recent studies have focused on the balance between selection and gene flow in natural populations, and empirical work has shown that gene flow can constrain adaptive divergence, and that divergent selection can constrain gene flow. A caveat is that phenotypic diversification may be under the direct influence of environmental factors (i.e. it may be due to phenotypic plasticity), in addition to partial genetic influence. In this case, phenotypic divergence may occur between populations despite high gene flow that imposes a constraint on genetic divergence. Plasticity may dampen the effects of natural selection by allowing individuals to rapidly adapt phenotypically to new conditions, thus slowing adaptive genetic divergence. On the other hand, plasticity may promote future adaptive divergence by allowing populations to persist in novel environments. Plasticity may promote gene flow between selective regimes by allowing dispersers to adapt to alternate conditions, or high gene flow may result in the selection for increased plasticity. Here I expand frameworks for understanding relationships among selection, adaptation and gene flow to include the effects of phenotypic plasticity in natural populations, and highlight its importance in evolutionary diversification.

  4. The effect of chemically modified alginates on macrophage phenotype and biomolecule transport.

    PubMed

    Bygd, Hannah C; Bratlie, Kaitlin M

    2016-07-01

    Macrophage (MΦ) reprogramming has received significant attention in applications such as cancer therapeutics and tissue engineering where the host immune response to biomaterials is crucial in determining the success or failure of an implanted device. Polymeric systems can potentially be used to redirect infiltrating M1 MΦs toward a proangiogenic phenotype. This work exploits the concept of MΦ reprogramming in the engineering of materials for improving the longevity of tissue engineering scaffolds. We have investigated the effect of 13 different chemical modifications of alginate on MΦ phenotype. Markers of the M1 response-tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase-and the M2 response-arginase-were measured and used to determine the ability of the materials to alter MΦ phenotype. It was found that some modifications were able to reduce the pro-inflammatory response of M1 MΦs, others appeared to amplify the M2 phenotype, and the results for two materials suggested they were able to reprogram a MΦ population from M1 to M2. These findings were supplemented by studies done to examine the permselectivity of the materials. Diffusion of TNF-α was completely prevented through some of these materials, while up to 84% was found to diffuse through others. The diffusion of insulin through the materials was statistically consistent. These results suggest that the modification of these materials might alter mass transport in beneficial ways. The ability to control polarization of MΦ phenotypes with immunoprotective materials has the potential to augment the success of tissue engineering scaffolds. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1707-1719, 2016.

  5. Manufacture of gene-modified human T-cells with a memory stem/central memory phenotype.

    PubMed

    Gomez-Eerland, Raquel; Nuijen, Bastiaan; Heemskerk, Bianca; van Rooij, Nienke; van den Berg, Joost H; Beijnen, Jos H; Uckert, Wolfgang; Kvistborg, Pia; Schumacher, Ton N; Haanen, John B A G; Jorritsma, Annelies

    2014-10-01

    Advances in genetic engineering have made it possible to generate human T-cell products that carry desired functionalities, such as the ability to recognize cancer cells. The currently used strategies for the generation of gene-modified T-cell products lead to highly differentiated cells within the infusion product, and on the basis of data obtained in preclinical models, this is likely to impact the efficacy of these products. We set out to develop a good manufacturing practice (GMP) protocol that yields T-cell receptor (TCR) gene-modified T-cells with more favorable properties for clinical application. Here, we show the robust clinical-scale production of human peripheral blood T-cells with an early memory phenotype that express a MART-1-specific TCR. By combining selection and stimulation using anti-CD3/CD28 beads for retroviral transduction, followed by expansion in the presence of IL-7 and IL-15, production of a well-defined clinical-scale TCR gene-modified T-cell product could be achieved. A major fraction of the T-cells generated in this fashion were shown to coexpress CD62L and CD45RA, and express CD27 and CD28, indicating a central memory or memory stemlike phenotype. Furthermore, these cells produced IFNγ, TNFα, and IL-2 and displayed cytolytic activity against target cells expressing the relevant antigen. The T-cell products manufactured by this robust and validated GMP production process are now undergoing testing in a phase I/IIa clinical trial in HLA-A*02:01 MART-1-positive advanced stage melanoma patients. To our knowledge, this is the first clinical trial protocol in which the combination of IL-7 and IL-15 has been applied for the generation of gene-modified T-cell products.

  6. Manufacture of Gene-Modified Human T-Cells with a Memory Stem/Central Memory Phenotype

    PubMed Central

    Gomez-Eerland, Raquel; Nuijen, Bastiaan; Heemskerk, Bianca; van Rooij, Nienke; van den Berg, Joost H.; Beijnen, Jos H.; Uckert, Wolfgang; Kvistborg, Pia; Schumacher, Ton N.; Jorritsma, Annelies

    2014-01-01

    Abstract Advances in genetic engineering have made it possible to generate human T-cell products that carry desired functionalities, such as the ability to recognize cancer cells. The currently used strategies for the generation of gene-modified T-cell products lead to highly differentiated cells within the infusion product, and on the basis of data obtained in preclinical models, this is likely to impact the efficacy of these products. We set out to develop a good manufacturing practice (GMP) protocol that yields T-cell receptor (TCR) gene-modified T-cells with more favorable properties for clinical application. Here, we show the robust clinical-scale production of human peripheral blood T-cells with an early memory phenotype that express a MART-1-specific TCR. By combining selection and stimulation using anti-CD3/CD28 beads for retroviral transduction, followed by expansion in the presence of IL-7 and IL-15, production of a well-defined clinical-scale TCR gene-modified T-cell product could be achieved. A major fraction of the T-cells generated in this fashion were shown to coexpress CD62L and CD45RA, and express CD27 and CD28, indicating a central memory or memory stemlike phenotype. Furthermore, these cells produced IFNγ, TNFα, and IL-2 and displayed cytolytic activity against target cells expressing the relevant antigen. The T-cell products manufactured by this robust and validated GMP production process are now undergoing testing in a phase I/IIa clinical trial in HLA-A*02:01 MART-1-positive advanced stage melanoma patients. To our knowledge, this is the first clinical trial protocol in which the combination of IL-7 and IL-15 has been applied for the generation of gene-modified T-cell products. PMID:25143008

  7. A modified protocol to maximize differentiation of human preadipocytes and improve metabolic phenotypes

    PubMed Central

    Lee, Mi-Jeong; Wu, Yuanyuan; Fried, Susan K.

    2012-01-01

    Adipose stromal cells proliferate and differentiate into adipocytes, providing a valuable model system for studies of adipocyte biology. We compared differentiation protocols for human preadipocytes and report on their metabolic phenotypes. By simply prolonging the adipogenic induction period from the first 3 days to 7 days, the proportion of cells (passage 5–6) acquiring adipocyte morphology increased from 30–70% to over 80% in human subcutaneous preadipocytes. These morphological changes were accompanied by increases in the adipogenic marker expression and improved adipocyte metabolic phenotypes: enhanced responses to beta-adrenergically-stimulated lipolysis and to insulin-stimulated glucose metabolism into triglyceride. Confirming previous studies, FBS dose-dependently inhibited adipogenesis. However, in subcutaneous preadipocytes that differentiate well (donor-dependant high capacity and subcultured fewer than 2 times), the use of 7d-induction protocols in both 3% FBS and serum-free conditions allowed >80% differentiation. Responsiveness to β-adrenergically stimulated lipolysis was lower in 3% FBS. Rates of insulin-stimulated glucose uptake were higher in adipocytes differentiated with 3% FBS, while the sensitivity to insulin was almost identical between the two groups. In summary, extending the length of the induction period in adipogenic cocktail improves the degree of differentiation and responses to key metabolic hormones. This protocol permits functional analysis of metabolic phenotypes in valuable primary human adipocyte cultures through multiple passages. PMID:22627913

  8. Strain Background Modifies Phenotypes in the ATP8B1-Deficient Mouse

    PubMed Central

    Vargas, Julie C.; Xu, Hongmei; Groen, Annamiek; Paulusma, Coen C.; Grenert, James P.; Pawlikowska, Ludmila; Sen, Saunak; Elferink, Ronald P. J. Oude; Bull, Laura N.

    2010-01-01

    Background Mutations in ATP8B1 (FIC1) underlie cases of cholestatic disease, ranging from chronic and progressive (progressive familial intrahepatic cholestasis) to intermittent (benign recurrent intrahepatic cholestasis). The ATP8B1-deficient mouse serves as an animal model of human ATP8B1 deficiency. Methodology/Principal Findings We investigated the effect of genetic background on phenotypes of ATP8B1-deficient and wild-type mice, using C57Bl/6 (B6), 129, and (B6-129) F1 strain backgrounds. B6 background resulted in greater abnormalities in ATP8B1-deficient mice than did 129 and/or F1 background. ATP8B1-deficient pups of B6 background gained less weight. In adult ATP8B1-deficient mice at baseline, those of B6 background had lower serum cholesterol levels, higher serum alkaline phosphatase levels, and larger livers. After challenge with cholate-supplemented diet, these mice exhibited higher serum alkaline phosphatase and bilirubin levels, greater weight loss and larger livers. ATP8B1-deficient phenotypes in mice of F1 and 129 backgrounds are usually similar, suggesting that susceptibility to manifestations of ATP8B1 deficiency may be recessive. We also detected differences in hepatobiliary phenotypes between wild-type mice of differing strains. Conclusions/Significance Our results indicate that the ATP8B1-deficient mouse in a B6 background may be a better model of human ATP8B1 deficiency and highlight the importance of informed background strain selection for mouse models of liver disease. PMID:20126555

  9. Evaluation of Cronobacter Growth and Phenotypic Variation Under Modified Culture Conditions.

    PubMed

    Segars, Katharine; Simpson, Steven; Kerdahi, Khalil; Sulaiman, Irshad M

    2016-02-01

    Cronobacter sakazakii is an opportunistic pathogen known to cause acute meningitis and necrotizing enterocolitis in neonates and immunocompromised individuals. It has been isolated from a wide range of food and environmental samples, and has been linked to outbreaks associated with powdered infant formula. This study was carried out to assess variations in growth conditions (temperature, pH, and sugar supplement) and to establish how these changes impact phenotypic characteristics for successful recovery and identification of Cronobacter, particularly for routine surveillance purposes. A total of six Cronobacter isolates were tested to evaluate the above growth conditions, including three ATCC Cronobacter reference and three environmental isolates obtained from regulatory sample screening. Although only slight changes in colony-forming units were observed across the pH range and the sugars tested, the morphology was significantly impacted by changes in these growth factors. Incubation between 30 and 50 °C resulted in growth after 24 h, and the growth was slower at ambient temperature and colony formation was most robust at 30 °C. Results of this study suggest that 30 °C may be suitable for recovery of some Cronobacter strains, and minor variations in growth conditions can alter colony morphology and appearance. Expression of unique biological characteristics based on phenotypic observations may be beneficial for differentiating various Cronobacter strains.

  10. The therapeutic potential of skeletal muscle plasticity in Duchenne muscular dystrophy: phenotypic modifiers as pharmacologic targets.

    PubMed

    Ljubicic, Vladimir; Burt, Matthew; Jasmin, Bernard J

    2014-02-01

    Duchenne muscular dystrophy (DMD) is a life-limiting, neuromuscular disorder that causes progressive, severe muscle wasting in boys and young men. Although there is no cure, scientists and clinicians can leverage the fact that slower, more oxidative skeletal muscle fibers possess an enhanced degree of resistance to the dystrophic pathology relative to their faster, more glycolytic counterparts, and can thus use this knowledge when investigating novel therapeutic avenues. Several factors have been identified as powerful regulators of muscle plasticity. Some proteins, such as calcineurin, peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α), PPARβ/δ, and AMP-activated protein kinase (AMPK), when chronically stimulated in animal models, remodel skeletal muscle toward the slow, oxidative myogenic program, whereas others, such as receptor-interacting protein 140 (RIP140) and E2F transcription factor 1 (E2F1), repress this phenotype. Recent studies demonstrating that pharmacologic and physiological activation of targets that shift dystrophic muscle toward the slow, oxidative myogenic program provide appreciable molecular and functional benefits. This review surveys the rationale behind, and evidence for, the study of skeletal muscle plasticity in preclinical models of DMD and highlights the potential therapeutic opportunities in advancing a strategy focused on remodeling skeletal muscle in patients with DMD toward the slow, oxidative phenotype.

  11. Genotyping and phenotyping of an epigenetic modifier Unstable factor for orange1 (Ufo1) in maize

    NASA Astrophysics Data System (ADS)

    Bowersox, Karisa; Chopra, Surinder

    2012-02-01

    Pericarp color 1 is a model system for the study of epigenetic gene regulation. It has more than 100 alleles that contribute to the color of the pericarp and cob glume of maize. Unstable factor for orange 1 (Ufo1) is a spontaneous dominant mutation that leads to a gain in pigmentation due to a decrease in methylation in p1 genes. This decrease in methylation of cytosine in the DNA leads to changes in chromatin structure. Finding the mechanism for this spontaneous mutation can lead to way of preventing the mutation increasing production colorless maize for food production. Through genotyping and phenotyping fine gene mapping, gene expression and whole genome profiling can be accomplished for plants with the Ufo1 mutation present.

  12. Histone Modifier Genes Alter Conotruncal Heart Phenotypes in 22q11.2 Deletion Syndrome.

    PubMed

    Guo, Tingwei; Chung, Jonathan H; Wang, Tao; McDonald-McGinn, Donna M; Kates, Wendy R; Hawuła, Wanda; Coleman, Karlene; Zackai, Elaine; Emanuel, Beverly S; Morrow, Bernice E

    2015-12-03

    We performed whole exome sequence (WES) to identify genetic modifiers on 184 individuals with 22q11.2 deletion syndrome (22q11DS), of whom 89 case subjects had severe congenital heart disease (CHD) and 95 control subjects had normal hearts. Three genes including JMJD1C (jumonji domain containing 1C), RREB1 (Ras responsive element binding protein 1), and SEC24C (SEC24 family member C) had rare (MAF < 0.001) predicted deleterious single-nucleotide variations (rdSNVs) in seven case subjects and no control subjects (p = 0.005; Fisher exact and permutation tests). Because JMJD1C and RREB1 are involved in chromatin modification, we investigated other histone modification genes. Eighteen case subjects (20%) had rdSNVs in four genes (JMJD1C, RREB1, MINA, KDM7A) all involved in demethylation of histones (H3K9, H3K27). Overall, rdSNVs were enriched in histone modifier genes that activate transcription (Fisher exact p = 0.0004, permutations, p = 0.0003, OR = 5.16); however, rdSNVs in control subjects were not enriched. This implicates histone modification genes as influencing risk for CHD in presence of the deletion.

  13. Consistent and reproducible positioning in longitudinal imaging for phenotyping genetically modified swine

    NASA Astrophysics Data System (ADS)

    Hammond, Emily; Dilger, Samantha K. N.; Stoyles, Nicholas; Judisch, Alexandra; Morgan, John; Sieren, Jessica C.

    2015-03-01

    Recent growth of genetic disease models in swine has presented the opportunity to advance translation of developed imaging protocols, while characterizing the genotype to phenotype relationship. Repeated imaging with multiple clinical modalities provides non-invasive detection, diagnosis, and monitoring of disease to accomplish these goals; however, longitudinal scanning requires repeatable and reproducible positioning of the animals. A modular positioning unit was designed to provide a fixed, stable base for the anesthetized animal through transit and imaging. Post ventilation and sedation, animals were placed supine in the unit and monitored for consistent vitals. Comprehensive imaging was performed with a computed tomography (CT) chest-abdomen-pelvis scan at each screening time point. Longitudinal images were rigidly registered, accounting for rotation, translation, and anisotropic scaling, and the skeleton was isolated using a basic thresholding algorithm. Assessment of alignment was quantified via eleven pairs of corresponding points on the skeleton with the first time point as the reference. Results were obtained with five animals over five screening time points. The developed unit aided in skeletal alignment within an average of 13.13 +/- 6.7 mm for all five subjects providing a strong foundation for developing qualitative and quantitative methods of disease tracking.

  14. Renin-angiotensin system gene polymorphisms as potential modifiers of hypertrophic and dilated cardiomyopathy phenotypes.

    PubMed

    Rani, Bindu; Kumar, Amit; Bahl, Ajay; Sharma, Rajni; Prasad, Rishikesh; Khullar, Madhu

    2017-03-01

    The renin-angiotensin (RAS) pathway has an important role in the etiology of heart failure and given the importance of RAS as a therapeutic target in various cardiomyopathies, genetic polymorphisms in the RAS genes may modulate the risk and severity of disease in cardiomyopathy patients. In the present study, we examined the association of RAS pathway gene polymorphisms, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin receptor type 1 (AGTR1) with risk and disease severity in Asian Indian idiopathic cardiomyopathy patients. The case-control study was conducted in 400 cardiomyopathy patients diagnosed with HCM, DCM, or restrictive cardiomyopathy (RCM) and 235 healthy controls. Genotyping of patients and controls was done by PCR-RFLP assays. Left ventricular wall thickness and left ventricular ejection fraction were measured by means of M-mode echocardiography. We observed significantly higher prevalence of ACE DD and AGTR1 1166CC genotypes in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) patients. Also, 235TT genotype of AGT (M235T) was significantly associated with enhanced risk of the disease phenotype in HCM, DCM, and RCM.

  15. SCN4A mutation as modifying factor of myotonic dystrophy type 2 phenotype.

    PubMed

    Bugiardini, E; Rivolta, I; Binda, A; Soriano Caminero, A; Cirillo, F; Cinti, A; Giovannoni, R; Botta, A; Cardani, R; Wicklund, M P; Meola, G

    2015-04-01

    In myotonic dystrophy type 2 (DM2), an association has been reported between early and severe myotonia and recessive chloride channel (CLCN1) mutations. No DM2 cases have been described with sodium channel gene (SCN4A) mutations. The aim is to describe a DM2 patient with severe and early onset myotonia and co-occurrence of a novel missense mutation in SNC4A. A 26-year-old patient complaining of hand cramps and difficulty relaxing her hands after activity was evaluated at our department. Neurophysiology and genetic analysis for DM1, DM2, CLCN1 and SCN4A mutations were performed. Genetic testing was positive for DM2 (2650 CCTG repeat) and for a variant c.215C>T (p.Pro72Leu) in the SCN4A gene. The variation affects the cytoplasmic N terminus domain of Nav1.4, where mutations have never been reported. The biophysical properties of the mutant Nav1.4 channels were evaluated by whole-cell voltage-clamp analysis of heterologously expressed mutant channel in tsA201 cells. Electrophysiological studies of the P72L variant showed a hyperpolarizing shift (-5 mV) of the voltage dependence of activation that may increase cell excitability. This case suggests that SCN4A mutations may enhance the myotonic phenotype of DM2 patients and should be screened for atypical cases with severe myotonia.

  16. Experimental and husbandry procedures as potential modifiers of the results of phenotyping tests

    PubMed Central

    Gerdin, Anna-Karin; Igosheva, Natalia; Roberson, Laura-Anne; Ismail, Ozama; Karp, Natasha; Sanderson, Mark; Cambridge, Emma; Shannon, Carl; Sunter, David; Ramirez-Solis, Ramiro; Bussell, James; White, Jacqueline K.

    2012-01-01

    To maximize the sensitivity of detecting affects of genetic variants in mice, variables have been minimized through the use of inbred mouse lines, by eliminating infectious organisms and controlling environmental variables. However, the impact of standard animal husbandry and experimental procedures on the validity of experimental data is under appreciated. In this study we monitored the impact of these procedures by using parameters that reflect stress and physiological responses to it. Short-term measures included telemetered heart rate and systolic arterial pressure, core body temperature and blood glucose, while longer-term parameters were assessed such as body weight. Male and female C57BL6/NTac mice were subjected to a range of stressors with different perceived severities ranging from repeated blood glucose and core temperature measurement procedures, intra-peritoneal injection and overnight fasting to cage transport and cage changing. Our studies reveal that common husbandry and experimental procedures significantly influence mouse physiology and behaviour. Systolic arterial pressure, heart rate, locomotor activity, core temperature and blood glucose were elevated in response to a range of experimental procedures. Differences between sexes were evident, female mice displayed more sustained cardiovascular responses and locomotor activity than male mice. These results have important implications for the design and implementation of multiple component experiments where the lasting effects of stress from previous tests may modify the outcomes of subsequent ones. PMID:22713295

  17. Staphylococcal Phenotypes Induced by Naturally Occurring and Synthetic Membrane-Interactive Polyphenolic β-Lactam Resistance Modifiers

    PubMed Central

    Palacios, Lucia; Rosado, Helena; Micol, Vicente; Rosato, Adriana E.; Bernal, Patricia; Arroyo, Raquel; Grounds, Helen; Anderson, James C.; Stabler, Richard A.; Taylor, Peter W.

    2014-01-01

    Galloyl catechins, in particular (-)-epicatechin gallate (ECg), have the capacity to abrogate β-lactam resistance in methicillin-resistant strains of Staphylococcus aureus (MRSA); they also prevent biofilm formation, reduce the secretion of a large proportion of the exoproteome and induce profound changes to cell morphology. Current evidence suggests that these reversible phenotypic traits result from their intercalation into the bacterial cytoplasmic membrane. We have endeavoured to potentiate the capacity of ECg to modify the MRSA phenotype by stepwise removal of hydroxyl groups from the B-ring pharmacophore and the A:C fused ring system of the naturally occurring molecule. ECg binds rapidly to the membrane, inducing up-regulation of genes responsible for protection against cell wall stress and maintenance of membrane integrity and function. Studies with artificial membranes modelled on the lipid composition of the staphylococcal bilayer indicated that ECg adopts a position deep within the lipid palisade, eliciting major alterations in the thermotropic behaviour of the bilayer. The non-galloylated homolog (-)-epicatechin enhanced ECg-mediated effects by facilitating entry of ECg molecules into the membrane. ECg analogs with unnatural B-ring hydroxylation patterns induced higher levels of gene expression and more profound changes to MRSA membrane fluidity than ECg but adopted a more superficial location within the bilayer. ECg possessed a high affinity for the positively charged staphylococcal membrane and induced changes to the biophysical properties of the bilayer that are likely to account for its capacity to disperse the cell wall biosynthetic machinery responsible for β-lactam resistance. The ability to enhance these properties by chemical modification of ECg raises the possibility that more potent analogs could be developed for clinical evaluation. PMID:24699700

  18. F12-46C/T polymorphism as modifier of the clinical phenotype of hereditary angioedema.

    PubMed

    Speletas, M; Szilágyi, Á; Csuka, D; Koutsostathis, N; Psarros, F; Moldovan, D; Magerl, M; Kompoti, M; Varga, L; Maurer, M; Farkas, H; Germenis, A E

    2015-12-01

    The factors influencing the heterogeneous clinical manifestation of hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) represent one of the oldest unsolved problems of the disease. Considering that factor XII (FXII) levels may affect bradykinin production, we investigated the contribution of the functional promoter polymorphism F12-46C/T in disease phenotype. We studied 258 C1-INH-HAE patients from 113 European families, and we explored possible associations of F12-46C/T with clinical features and the SERPING1 mutational status. Given that our cohort consisted of related subjects, we implemented generalized estimating equations (GEEs), an extension of the generalized linear model accounting for the within-subject correlation. F12-46C/T carriers exhibited a significantly delayed disease onset (P < 0.001) and did not need long-term treatment (P = 0.02). In a GEE linear regression model, the presence of F12-46C/T was significantly associated with a 7-year delay in disease onset (P < 0.0001) regardless of SERPING1 mutational status. It is concluded that F12-46C/T carriage acts as an independent modifier of C1-INH-HAE severity.

  19. Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene

    PubMed Central

    Hilgert, Nele; Huentelman, Matthew J; Thorburn, Ashley Q; Fransen, Erik; Dieltjens, Nele; Mueller-Malesinska, Malgorzata; Pollak, Agnieszka; Skorka, Agata; Waligora, Jaroslaw; Ploski, Rafal; Castorina, Pierangela; Primignani, Paola; Ambrosetti, Umberto; Murgia, Alessandra; Orzan, Eva; Pandya, Arti; Arnos, Kathleen; Norris, Virginia; Seeman, Pavel; Janousek, Petr; Feldmann, Delphine; Marlin, Sandrine; Denoyelle, Françoise; Nishimura, Carla J; Janecke, Andreas; Nekahm-Heis, Doris; Martini, Alessandro; Mennucci, Elena; Tóth, Timea; Sziklai, Istvan; del Castillo, Ignacio; Moreno, Felipe; Petersen, Michael B; Iliadou, Vasiliki; Tekin, Mustafa; Incesulu, Armagan; Nowakowska, Ewa; Bal, Jerzy; Van de Heyning, Paul; Roux, Anne-Françoise; Blanchet, Catherine; Goizet, Cyril; Lancelot, Guenaëlle; Fialho, Graça; Caria, Helena; Liu, Xue Zhong; Xiaomei, Ouyang; Govaerts, Paul; Grønskov, Karen; Hostmark, Karianne; Frei, Klemens; Dhooge, Ingeborg; Vlaeminck, Stephen; Kunstmann, Erdmute; Van Laer, Lut; Smith, Richard JH; Van Camp, Guy

    2009-01-01

    Hereditary hearing loss (HL) is a very heterogeneous trait, with 46 gene identifications for non-syndromic HL. Mutations in GJB2 cause up to half of all cases of severe-to-profound congenital autosomal recessive non-syndromic HL, with 35delG being the most frequent mutation in Caucasians. Although a genotype–phenotype correlation has been established for most GJB2 genotypes, the HL of 35delG homozygous patients is mild to profound. We hypothesise that this phenotypic variability is at least partly caused by the influence of modifier genes. By performing a whole-genome association (WGA) study on 35delG homozygotes, we sought to identify modifier genes. The association study was performed by comparing the genotypes of mild/moderate cases and profound cases. The first analysis included a pooling-based WGA study of a first set of 255 samples by using both the Illumina 550K and Affymetrix 500K chips. This analysis resulted in a ranking of all analysed single-nucleotide polymorphisms (SNPs) according to their P-values. The top 250 most significantly associated SNPs were genotyped individually in the same sample set. All 192 SNPs that still had significant P-values were genotyped in a second independent set of 297 samples for replication. The significant P-values were replicated in nine SNPs, with combined P-values between 3 × 10−3 and 1 × 10−4. This study suggests that the phenotypic variability in 35delG homozygous patients cannot be explained by the effect of one major modifier gene. Significantly associated SNPs may reflect a small modifying effect on the phenotype. Increasing the power of the study will be of greatest importance to confirm these results. PMID:18985073

  20. Inheritance of a temperature-modified phenotype of the short antennae (sa) mutation in a moth, Ephestia kuehniella (Lepidoptera: Pyralidae).

    PubMed

    Pavelka, J; Koudelová, J

    2001-01-01

    The autosomal recessive mutation short antennae (sa) causes considerable shortening of antennae in male and female Mediterranean flour moths (Ephestia kuehniella Zeller). However, the sa phenotype can be suppressed by several physical factors, making sa moths indistinguishable from wild-type moths (sa(WT)). This can be done by subjecting larva and pupa to a higher temperature (25 degrees C), to lithium ions, or to an alternate electric field. The first half of pupal development was found to be the sensitive period for the sa(WT) phenotype. The sa(WT) phenotype is stable and cannot be reverted to the original sa type by physical or chemical factors. The sa(WT) phenotype is transmitted to future generations. When crossed with typical sa moths, the sa(WT) phenotype is inherited either as a dominant character if carried by males or a semidominant character if carried by females. We compared proteins of the ejaculate, accessory gland secretions, and spermatophore in sa, sa(WT), and wild-type males and found considerable differences between sperm proteins of sa(WT), sa, and wild-type males. The sa(WT) phenotype influences the mating success of males: sa(WT) males mated successfully with any females, whereas typical sa males were less successful in mating and then mainly with females of the same phenotype.

  1. DNA polymorphisms in the controlling region of the human haptoglobin genes: a molecular explanation for the haptoglobin 2-1 modified phenotype.

    PubMed Central

    Maeda, N

    1991-01-01

    A haptoglobin 2-1 modified (Hp2-1mod) phenotype results when the amount of Hp2 polypeptide synthesized in Hp2/Hp1 heterozygotes is less than that of Hp1 polypeptide. Cloned Hp2 DNA from an individual with the Hp2-1mod phenotype is here shown to have a C in place of the normal A at nucleotide position -61 in one of the interleukin-6 (IL-6) responsive elements of the haptoglobin promoter region. Direct sequencing of the haptoglobin promoter region, amplified by PCR, from DNA from unrelated American blacks showed a C at -61 in all of 10 individuals with the Hp2-1mod phenotype, in two of four with a "possible Hp2-1mod" phenotype, but in none of 15 with the Hp2-1 phenotype. Thus the -61C mutation in the Hp2-61C allele is strongly associated with the Hp2-1mod phenotype. Sequencing results also show that there are three other promoter sequences in the population studied; each can be associated with either Hp2 or Hp1. The variability seen in the Hp2-1mod phenotype, a variability which ranges from close to Hp2-1 to close to Hp1-1, can be explained, in part, by the existence of several Hp2 alleles differing in their promoters--and possibly, in part, by differences in the promoters of the accompanying Hp1 allele. A further part of the variability may be the consequence of differences in the way that the Hp2-61C and the Hp2 alleles respond to the IL-6-dependent factor during an acute-phase response. Images Figure 2 Figure 3 PMID:2063867

  2. Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis.

    PubMed

    Emond, Mary J; Louie, Tin; Emerson, Julia; Zhao, Wei; Mathias, Rasika A; Knowles, Michael R; Wright, Fred A; Rieder, Mark J; Tabor, Holly K; Nickerson, Deborah A; Barnes, Kathleen C; Gibson, Ronald L; Bamshad, Michael J

    2012-07-08

    Exome sequencing has become a powerful and effective strategy for the discovery of genes underlying Mendelian disorders. However, use of exome sequencing to identify variants associated with complex traits has been more challenging, partly because the sample sizes needed for adequate power may be very large. One strategy to increase efficiency is to sequence individuals who are at both ends of a phenotype distribution (those with extreme phenotypes). Because the frequency of alleles that contribute to the trait are enriched in one or both phenotype extremes, a modest sample size can potentially be used to identify novel candidate genes and/or alleles. As part of the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP), we used an extreme phenotype study design to discover that variants in DCTN4, encoding a dynactin protein, are associated with time to first P. aeruginosa airway infection, chronic P. aeruginosa infection and mucoid P. aeruginosa in individuals with cystic fibrosis.

  3. Identification of Atg2 and ArfGAP1 as Candidate Genetic Modifiers of the Eye Pigmentation Phenotype of Adaptor Protein-3 (AP-3) Mutants in Drosophila melanogaster.

    PubMed

    Rodriguez-Fernandez, Imilce A; Dell'Angelica, Esteban C

    2015-01-01

    The Adaptor Protein (AP)-3 complex is an evolutionary conserved, molecular sorting device that mediates the intracellular trafficking of proteins to lysosomes and related organelles. Genetic defects in AP-3 subunits lead to impaired biogenesis of lysosome-related organelles (LROs) such as mammalian melanosomes and insect eye pigment granules. In this work, we have performed a forward screening for genetic modifiers of AP-3 function in the fruit fly, Drosophila melanogaster. Specifically, we have tested collections of large multi-gene deletions--which together covered most of the autosomal chromosomes-to identify chromosomal regions that, when deleted in single copy, enhanced or ameliorated the eye pigmentation phenotype of two independent AP-3 subunit mutants. Fine-mapping led us to define two non-overlapping, relatively small critical regions within fly chromosome 3. The first critical region included the Atg2 gene, which encodes a conserved protein involved in autophagy. Loss of one functional copy of Atg2 ameliorated the pigmentation defects of mutants in AP-3 subunits as well as in two other genes previously implicated in LRO biogenesis, namely Blos1 and lightoid, and even increased the eye pigment content of wild-type flies. The second critical region included the ArfGAP1 gene, which encodes a conserved GTPase-activating protein with specificity towards GTPases of the Arf family. Loss of a single functional copy of the ArfGAP1 gene ameliorated the pigmentation phenotype of AP-3 mutants but did not to modify the eye pigmentation of wild-type flies or mutants in Blos1 or lightoid. Strikingly, loss of the second functional copy of the gene did not modify the phenotype of AP-3 mutants any further but elicited early lethality in males and abnormal eye morphology when combined with mutations in Blos1 and lightoid, respectively. These results provide genetic evidence for new functional links connecting the machinery for biogenesis of LROs with molecules implicated in

  4. Human dendritic cell subsets from spleen and blood are similar in phenotype and function but modified by donor health status.

    PubMed

    Mittag, Diana; Proietto, Anna I; Loudovaris, Thomas; Mannering, Stuart I; Vremec, David; Shortman, Ken; Wu, Li; Harrison, Leonard C

    2011-06-01

    Mouse dendritic cells (DC) have been extensively studied in various tissues, especially spleen, and they comprise subsets with distinct developmental origins, surface phenotypes, and functions. Considerably less is known about human DC due to their rarity in blood and inaccessibility of other human tissues. The study of DC in human blood has revealed four subsets distinct in phenotype and function. In this study, we describe four equivalent DC subsets in human spleen obtained from deceased organ donors. We identify three conventional DC subsets characterized by surface expression of CD1b/c, CD141, and CD16, and one plasmacytoid DC subset characterized by CD304 expression. Human DC subsets in spleen were very similar to those in human blood with respect to surface phenotype, TLR and transcription factor expression, capacity to stimulate T cells, cytokine secretion, and cross-presentation of exogenous Ag. However, organ donor health status, in particular treatment with corticosteroid methylprednisolone and brain death, may affect DC phenotype and function. DC T cell stimulatory capacity was reduced but DC were qualitatively unchanged in methylprednisolone-treated deceased organ donor spleen compared with healthy donor blood. Overall, our findings indicate that human blood DC closely resemble human spleen DC. Furthermore, we confirm parallels between human and mouse DC subsets in phenotype and function, but also identify differences in transcription factor and TLR expression as well as functional properties. In particular, the hallmark functions of mouse CD8α(+) DC subsets, that is, IL-12p70 secretion and cross-presentation, are not confined to the equivalent human CD141(+) DC but are shared by CD1b/c(+) and CD16(+) DC subsets.

  5. Detection of KPC Carbapenemase in Pseudomonas aeruginosa Isolated From Clinical Samples Using Modified Hodge Test and Boronic Acid Phenotypic Methods and Their Comparison With the Polymerase Chain Reaction

    PubMed Central

    Falahat, Saeed; Shojapour, Mana; Sadeghi, Abdorrahim

    2016-01-01

    Background Bacterial resistance to antibiotics has become a major source of concern for public health. Pseudomonas aeruginosa strains are important opportunistic pathogens. These bacteria have a high resistance to a wide range of existing antimicrobials and antibiotics. Objectives The present study was performed to evaluate the frequency of KPC in P. aeruginosa isolated from clinical samples of educational hospitals of Arak University of Medical Sciences, using the mentioned phenotypic and genotypic methods. Materials and Methods One hundred and eight non-duplicate clinical isolates of P. aeruginosa were collected from hospitals of Arak University of Medical Sciences, Arak, Iran. Antibacterial susceptibility was determined by the disk diffusion method. KPC production was confirmed by the Modified Hodge Test (MHT), which is a phenotypic test, and combined-disk test with boronic acid and the Polymerase Chain Reaction (PCR). Results In the present study, 13 isolates (12%) of P. aeruginosa were positive for KPC, using PCR. Comparison of the two phenotypic methods used in this study showed that boronic acid is more sensitive than MHT in identification of KPC-producing strains (84.6% vs. 77%). Conclusions Utilization of reliable methods for identifying carbapenemase-producing strains and determining their antibiotic resistance pattern could have a very important role in treatment of infections caused by these strains. A substantial amount of P. aeruginosa isolated from clinical samples of hospitals in Arak (Iran) produce KPC carbapenemase. Due to their low specificity, MHT and boronic acid phenotypic methods could not completely identify KPC-producing P. aeruginosa. However, the sensitivity of boronic acid phenotypic method in detection of KPC was higher than MHT. PMID:27800140

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

    PubMed Central

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

    2015-01-01

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

  7. A candidate gene approach to identify modifiers of the palatal phenotype in 22q11.2 deletion syndrome patients

    PubMed Central

    Widdershoven, Josine C.C.; Bowser, Mark; Sheridan, Molly B.; McDonald-McGinn, Donna M.; Zackai, Elaine H.; Solot, Cynthia B.; Kirschner, Richard E.; Beemer, Frits A.; Morrow, Bernice E.; Devoto, Marcella; Emanuel, Beverly S.

    2014-01-01

    Objective Palatal anomalies are one of the identifying features of 22q11.2 deletion syndrome (22q11.2DS) affecting about one third of patients. To identify genetic variants that increase the risk of cleft or palatal anomalies in 22q11.2DS patients, we performed a candidate gene association study in 101 patients with 22q11.2DS genotyped with the Affymetrix genome-wide human SNP array 6.0. Methods Patients from Children's Hospital of Philadelphia, USA and Wilhelmina Children's Hospital Utrecht, The Netherlands were stratified based on palatal phenotype (overt cleft, submucosal cleft, bifid uvula). SNPs in 21 candidate genes for cleft palate were analyzed for genotype-phenotype association. In addition, TBX1 sequencing was carried out. Quality control and association analyses were conducted using the software package PLINK. Results Genotype and phenotype data of 101 unrelated patients (63 non-cleft subjects (62.4%), 38 cleft subjects (37.6%)) were analyzed. A Total of 39 SNPs on 10 genes demonstrated a p-value ≤0.05 prior to correction. The most significant SNPs were found on FGF10. However none of the SNPs remained significant after correcting for multiple testing. Conclusions Although these results are promising, analysis of additional samples will be required to confirm that variants in these regions influence risk for cleft palate or palatal anomalies in 22q11.2DS patients. PMID:23121717

  8. A candidate gene approach to identify modifiers of the palatal phenotype in 22q11.2 deletion syndrome patients.

    PubMed

    Widdershoven, Josine C C; Bowser, Mark; Sheridan, Molly B; McDonald-McGinn, Donna M; Zackai, Elaine H; Solot, Cynthia B; Kirschner, Richard E; Beemer, Frits A; Morrow, Bernice E; Devoto, Marcella; Emanuel, Beverly S

    2013-01-01

    Palatal anomalies are one of the identifying features of 22q11.2 deletion syndrome (22q11.2DS) affecting about one third of patients. To identify genetic variants that increase the risk of cleft or palatal anomalies in 22q11.2DS patients, we performed a candidate gene association study in 101 patients with 22q11.2DS genotyped with the Affymetrix genome-wide human SNP array 6.0. Patients from Children's Hospital of Philadelphia, USA and Wilhelmina Children's Hospital Utrecht, The Netherlands were stratified based on palatal phenotype (overt cleft, submucosal cleft, bifid uvula). SNPs in 21 candidate genes for cleft palate were analyzed for genotype-phenotype association. In addition, TBX1 sequencing was carried out. Quality control and association analyses were conducted using the software package PLINK. Genotype and phenotype data of 101 unrelated patients (63 non-cleft subjects (62.4%), 38 cleft subjects (37.6%)) were analyzed. A Total of 39 SNPs on 10 genes demonstrated a p-value ≤0.05 prior to correction. The most significant SNPs were found on FGF10. However none of the SNPs remained significant after correcting for multiple testing. Although these results are promising, analysis of additional samples will be required to confirm that variants in these regions influence risk for cleft palate or palatal anomalies in 22q11.2DS patients. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  9. Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes.

    PubMed

    Coppieters, Frauke; Casteels, Ingele; Meire, Françoise; De Jaegere, Sarah; Hooghe, Sally; van Regemorter, Nicole; Van Esch, Hilde; Matuleviciene, Ausra; Nunes, Luis; Meersschaut, Valérie; Walraedt, Sophie; Standaert, Lieve; Coucke, Paul; Hoeben, Heidi; Kroes, Hester Y; Vande Walle, Johan; de Ravel, Thomy; Leroy, Bart P; De Baere, Elfride

    2010-10-01

    Leber Congenital Amaurosis (LCA), the most severe inherited retinal dystrophy, is genetically heterogeneous, with 14 genes accounting for 70% of patients. Here, 91 LCA probands underwent LCA chip analysis and subsequent sequencing of 6 genes (CEP290, CRB1, RPE65, GUCY2D, AIPL1and CRX), revealing mutations in 69% of the cohort, with major involvement of CEP290 (30%). In addition, 11 patients with early-onset retinal dystrophy (EORD) and 13 patients with Senior-Loken syndrome (SLS), LCA-Joubert syndrome (LCA-JS) or cerebello-oculo-renal syndrome (CORS) were included. Exhaustive re-inspection of the overall phenotypes in our LCA cohort revealed novel insights mainly regarding the CEP290-related phenotype. The AHI1 gene was screened as a candidate modifier gene in three patients with the same CEP290 genotype but different neurological involvement. Interestingly, a heterozygous novel AHI1 mutation, p.Asn811Lys, was found in the most severely affected patient. Moreover, AHI1 screening in five other patients with CEP290-related disease and neurological involvement revealed a second novel missense variant, p.His758Pro, in one LCA patient with mild mental retardation and autism. These two AHI1 mutations might thus represent neurological modifiers of CEP290-related disease.

  10. A systematic screen for dominant second-site modifiers of Merlin/NF2 phenotypes reveals an interaction with blistered/DSRF and scribbler.

    PubMed Central

    LaJeunesse, D R; McCartney, B M; Fehon, R G

    2001-01-01

    Merlin, the Drosophila homologue of the human tumor suppressor gene Neurofibromatosis 2 (NF2), is required for the regulation of cell proliferation and differentiation. To better understand the cellular functions of the NF2 gene product, Merlin, recent work has concentrated on identifying proteins with which it interacts either physically or functionally. In this article, we describe genetic screens designed to isolate second-site modifiers of Merlin phenotypes from which we have identified five multiallelic complementation groups that modify both loss-of-function and dominant-negative Merlin phenotypes. Three of these groups, Group IIa/scribbler (also known as brakeless), Group IIc/blistered, and Group IId/net, are known genes, while two appear to be novel. In addition, two genes, Group IIa/scribbler and Group IIc/blistered, alter Merlin subcellular localization in epithelial and neuronal tissues, suggesting that they regulate Merlin trafficking or function. Furthermore, we show that mutations in scribbler and blistered display second-site noncomplementation with one another. These results suggest that Merlin, blistered, and scribbler function together in a common pathway to regulate Drosophila wing epithelial development. PMID:11404331

  11. Genetic Screening of LCA in Belgium: Predominance of CEP290 and Identification of Potential Modifier Alleles in AHI1 of CEP290-related Phenotypes

    PubMed Central

    Coppieters, Frauke; Casteels, Ingele; Meire, Françoise; De Jaegere, Sarah; Hooghe, Sally; van Regemorter, Nicole; Van Esch, Hilde; Matulevičienė, Aušra; Nunes, Luis; Meersschaut, Valérie; Walraedt, Sophie; Standaert, Lieve; Coucke, Paul; Hoeben, Heidi; Kroes, Hester Y; Vande Walle, Johan; de Ravel, Thomy; Leroy, Bart P; De Baere, Elfride

    2010-01-01

    Leber Congenital Amaurosis (LCA), the most severe inherited retinal dystrophy, is genetically heterogeneous, with 14 genes accounting for 70% of patients. Here, 91 LCA probands underwent LCA chip analysis and subsequent sequencing of 6 genes (CEP290, CRB1, RPE65, GUCY2D, AIPL1and CRX), revealing mutations in 69% of the cohort, with major involvement of CEP290 (30%). In addition, 11 patients with early-onset retinal dystrophy (EORD) and 13 patients with Senior-Loken syndrome (SLS), LCA-Joubert syndrome (LCA-JS) or cerebello-oculo-renal syndrome (CORS) were included. Exhaustive re-inspection of the overall phenotypes in our LCA cohort revealed novel insights mainly regarding the CEP290-related phenotype. The AHI1 gene was screened as a candidate modifier gene in three patients with the same CEP290 genotype but different neurological involvement. Interestingly, a heterozygous novel AHI1 mutation, p.Asn811Lys, was found in the most severely affected patient. Moreover, AHI1 screening in five other patients with CEP290-related disease and neurological involvement revealed a second novel missense variant, p.His758Pro, in one LCA patient with mild mental retardation and autism. These two AHI1 mutations might thus represent neurological modifiers of CEP290-related disease. © 2010 Wiley-Liss, Inc. PMID:20683928

  12. Loci on murine chromosomes 7 and 13 that modify the phenotype of the NOA mouse, an animal model of atopic dermatitis.

    PubMed

    Watanabe, O; Tamari, M; Natori, K; Onouchi, Y; Shiomoto, Y; Hiraoka, I; Nakamura, Y

    2001-01-01

    The NOA (Naruto Research Institute Otsuka Atrichia) mouse is an animal model of allergic or atopic dermatitis, a condition characterized by ulcerative skin lesions with accumulation of mast cells and increased serum IgE. We reported earlier that a major gene responsible for dermatitis in the NOA mouse lay in the middle of chromosome 14, and that the incidence of disease clearly differed according to parental strain; the mode of inheritance was autosomal recessive with incomplete penetrance. In the study reported here, we searched for genes that might modify the NOA phenotype, and we identified two candidate loci that appeared to contain genes capable of modifying atopic or allergic dermatitis, one in the middle of chromosome 7 (chi2 = 14.66; P = 0.00013 for D7Mit62) and the other in the telomeric region of chromosome 13 (chi2 = 15.352; P = 0.000089 for D13Mit147). These loci correspond to regions of synteny in human chromosomes where linkages to asthma, atopy, or related phenotypes, such as serum IgE levels, have been documented.

  13. Biochemical evidence for a mitochondrial genetic modifier in the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation.

    PubMed

    Jiang, Pingping; Liang, Min; Zhang, Chaofan; Zhao, Xiaoxu; He, Qiufen; Cui, Limei; Liu, Xiaoling; Sun, Yan-Hong; Fu, Qun; Ji, Yanchun; Bai, Yidong; Huang, Taosheng; Guan, Min-Xin

    2016-08-15

    Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disease. Mitochondrial modifiers are proposed to modify the phenotypic expression of primary LHON-associated mitochondrial DNA (mtDNA) mutations. In this study, we demonstrated that the LHON susceptibility allele (m.14502T > C, p. 58I > V) in the ND6 gene modulated the phenotypic expression of primary LHON-associated m.11778G > A mutation. Twenty-two Han Chinese pedigrees carrying m.14502T > C and m.11778G > A mutations exhibited significantly higher penetrance of optic neuropathy than those carrying only m.11778G > A mutation. We performed functional assays using the cybrid cell models, generated by fusing mtDNA-less ρ(o) cells with enucleated cells from LHON patients carrying both m.11778G > A and m.14502T > C mutations, only m.14502T > C or m.11778G > A mutation and a control belonging to the same mtDNA haplogroup. These cybrids cell lines bearing m.14502T > C mutation exhibited mild effects on mitochondrial functions compared with those carrying only m.11778G > A mutation. However, more severe mitochondrial dysfunctions were observed in cell lines bearing both m.14502T > C and m.11778G > A mutations than those carrying only m.11778G > A or m.14502T > C mutation. In particular, the m.14502T > C mutation altered assemble of complex I, thereby aggravating the respiratory phenotypes associated with m.11778G > A mutation, resulted in a more defective complex I. Furthermore, more reductions in the levels of mitochondrial ATP and increasing production of reactive oxygen species were also observed in mutant cells bearing both m.14502T > C and m.11778G > A mutation than those carrying only 11778G > A mutation. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between primary and secondary mtDNA mutations.

  14. A base substitution in the promoter associated with the human haptoglobin 2-1 modified phenotype decreases transcriptional activity and responsiveness to interleukin-6 in human hepatoma cells

    SciTech Connect

    Grant, D.J.; Maeda, N. )

    1993-05-01

    An A-to-C base substitution at nucleotide position -61 in the promoter region of the human haptoglobin gene (Hp) has been shown to be strongly associated with the haptoglobin 2-1 modified (Hp2-1mod) phenotype. In order to investigate whether this base substitution is the cause of reduced expression of the Hp[sup 2] allele relative to the Hp[sup 1] allele in individuals with the Hp2-1mod phenotype, the authors used the chloramphenicol acetyl transferase (CAT) expression system to evaluate promoter function. In HepG2 cells, which normally express their endogenous haptoglobin genes, CAT plasmid constructs with the -61C base change in the promoter had about 10-fold-lower transcriptional activity after transfection than did the Hp control construct. The -61C substitution also rendered the construct unresponsive to treatment by interleukin-6 after transfection into Hep3B2 cells, which normally do not express haptoglobin but do so in response to stimulation by acute-phase reactants. In addition, two base substitutions, T to A and A to G, at positions -104 and -55G, respectively, in the promoter region of the Hp[sup 1] allele, are also associated with the Hp2-1mod phenotype. CAT constructs with both substitutions (-104A-55G) and with one substitution (-55G) showed activity similar to that in the Hp control when transfected into both HepG2 and Hep3B2 cells, although interleukin-6 induction was less than with the Hp control construct. These results further support the hypothesis that the Hp2-1mod phenotype results, in part, from the -61C mutation in the promoter region of the Hp[sup 2] gene.

  15. BODE-index, modified BODE-index and ADO-score in chronic obstructive pulmonary disease: relationship with COPD phenotypes and CT lung density changes.

    PubMed

    Camiciottoli, Gianna; Bigazzi, Francesca; Bartolucci, Maurizio; Cestelli, Lucia; Paoletti, Matteo; Diciotti, Stefano; Cavigli, Edoardo; Magni, Chiara; Buonasera, Luigi; Mascalchi, Mario; Pistolesi, Massimo

    2012-06-01

    COPD is a heterogeneous disorder whose assessment is going to be increasingly multidimensional. Grading systems such as BODE (Body-Mass Index, Obstruction, Dyspnea, Exercise), mBODE (BODE modified in grading of walked distance), ADO (Age, Dyspnea, Obstruction) are proposed to assess COPD severity and outcome. Computed tomography (CT) is deemed to reflect COPD lung pathologic changes. We studied the relationship of multidimensional grading systems (MGS) with clinically determined COPD phenotypes and CT lung density. Seventy-two patients underwent clinical and chest x-ray evaluation, pulmonary function tests (PFT), 6-minute walking test (6MWT) to derive: predominant COPD clinical phenotype, BODE, mBODE, ADO. Inspiratory and expiratory CT was performed to calculate mean lung attenuation (MLA), relative area with density below-950 HU at inspiration (RAI(-950)), and below -910 HU at expiration (RAE(-910)). MGS, PFT, and CT data were compared between bronchial versus emphysematous COPD phenotype. MGS were correlated with CT data. The prediction of CT density by means of MGS was investigated by direct and stepwise multivariate regression. MGS did not differ in clinically determined COPD phenotypes. BODE was more closely related and better predicted CT findings than mBODE and ADO; the better predictive model was obtained for CT expiratory data; stepwise regression models of CT data did not include 6MWT distance; the dyspnea score MRC was included only to predict RA-950 and RA-910 which quantify emphysema extent. BODE reflect COPD severity better than other MGS, but not its clinical heterogeneity. 6MWT does not significantly increase BODE predictivity of CT lung density changes.

  16. Placental phenotype and resource allocation to fetal growth are modified by the timing and degree of hypoxia during mouse pregnancy

    PubMed Central

    Higgins, J. S.; Vaughan, O. R.; Fernandez de Liger, E.; Fowden, A. L.

    2015-01-01

    Key points Hypoxia is a major cause of fetal growth restriction, particularly at high altitude, although little is known about its effects on placental phenotype and resource allocation to fetal growth.In the present study, maternal hypoxia induced morphological and functional changes in the mouse placenta, which depended on the timing and severity of hypoxia, as well as the degree of maternal hypophagia.Hypoxia at 13% inspired oxygen induced beneficial changes in placental morphology, nutrient transport and metabolic signalling pathways associated with little or no change in fetal growth, irrespective of gestational age.Hypoxia at 10% inspired oxygen adversely affected placental phenotype and resulted in severe fetal growth restriction, which was due partly to maternal hypophagia.There is a threshold between 13% and 10% inspired oxygen, corresponding to altitudes of ∼3700 m and 5800 m, respectively, at which the mouse placenta no longer adapts to support fetal resource allocation. This has implications for high altitude human pregnancies. Abstract The placenta adapts its transport capacity to nutritional cues developmentally, although relatively little is known about placental transport phenotype in response to hypoxia, a major cause of fetal growth restriction. The present study determined the effects of both moderate hypoxia (13% inspired O2) between days (D)11 and D16 or D14 and D19 of pregnancy and severe hypoxia (10% inspired O2) from D14 to D19 on placental morphology, transport capacity and fetal growth on D16 and D19 (term∼D20.5), relative to normoxic mice in 21% O2. Placental morphology adapted beneficially to 13% O2; fetal capillary volume increased at both ages, exchange area increased at D16 and exchange barrier thickness reduced at D19. Exposure to 13% O2 had no effect on placental nutrient transport on D16 but increased placental uptake and clearance of 3H‐methyl‐d‐glucose at D19. By contrast, 10% O2 impaired fetal vascularity

  17. Identification of Atg2 and ArfGAP1 as Candidate Genetic Modifiers of the Eye Pigmentation Phenotype of Adaptor Protein-3 (AP-3) Mutants in Drosophila melanogaster

    PubMed Central

    Rodriguez-Fernandez, Imilce A.; Dell’Angelica, Esteban C.

    2015-01-01

    The Adaptor Protein (AP)-3 complex is an evolutionary conserved, molecular sorting device that mediates the intracellular trafficking of proteins to lysosomes and related organelles. Genetic defects in AP-3 subunits lead to impaired biogenesis of lysosome-related organelles (LROs) such as mammalian melanosomes and insect eye pigment granules. In this work, we have performed a forward screening for genetic modifiers of AP-3 function in the fruit fly, Drosophila melanogaster. Specifically, we have tested collections of large multi-gene deletions–which together covered most of the autosomal chromosomes–to identify chromosomal regions that, when deleted in single copy, enhanced or ameliorated the eye pigmentation phenotype of two independent AP-3 subunit mutants. Fine-mapping led us to define two non-overlapping, relatively small critical regions within fly chromosome 3. The first critical region included the Atg2 gene, which encodes a conserved protein involved in autophagy. Loss of one functional copy of Atg2 ameliorated the pigmentation defects of mutants in AP-3 subunits as well as in two other genes previously implicated in LRO biogenesis, namely Blos1 and lightoid, and even increased the eye pigment content of wild-type flies. The second critical region included the ArfGAP1 gene, which encodes a conserved GTPase-activating protein with specificity towards GTPases of the Arf family. Loss of a single functional copy of the ArfGAP1 gene ameliorated the pigmentation phenotype of AP-3 mutants but did not to modify the eye pigmentation of wild-type flies or mutants in Blos1 or lightoid. Strikingly, loss of the second functional copy of the gene did not modify the phenotype of AP-3 mutants any further but elicited early lethality in males and abnormal eye morphology when combined with mutations in Blos1 and lightoid, respectively. These results provide genetic evidence for new functional links connecting the machinery for biogenesis of LROs with molecules implicated

  18. A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS Alleles and Uncovers a Specific Genetic Interaction between osm-3 and nphp-4

    PubMed Central

    Williams, Corey L.; Pieczynski, Jay N.; Roszczynialski, Kelly N.; Covington, Jannese E.; Malarkey, Erik B.; Yoder, Bradley K.

    2016-01-01

    Nephronophthisis (NPHP) is a ciliopathy in which genetic modifiers may underlie the variable penetrance of clinical features. To identify modifiers, a screen was conducted on C. elegans nphp-4(tm925) mutants. Mutations in ten loci exacerbating nphp-4(tm925) ciliary defects were obtained. Four loci have been identified, three of which are established ciliopathy genes mks-1, mks-2, and mks-5. The fourth allele (yhw66) is a missense mutation (S316F) in OSM-3, a kinesin required for cilia distal segment assembly. While osm-3(yhw66) mutants alone have no overt cilia phenotype, nphp-4(tm925);osm-3(yhw66) double mutants lack distal segments and are dye-filling (Dyf) and osmotic avoidance (Osm) defective, similar to osm-3(mn357) null mutants. In osm-3(yhw66) mutants anterograde intraflagellar transport (IFT) velocity is reduced. Furthermore, expression of OSM-3(S316F)::GFP reduced IFT velocities in nphp-4(tm925) mutants, but not in wild type animals. In silico analysis indicates the S316F mutation may affect a phosphorylation site. Putative phospho-null OSM-3(S316F) and phospho-mimetic OSM-3(S316D) proteins accumulate at the cilia base and tip respectively. FRAP analysis indicates that the cilia entry rate of OSM-3(S316F) is slower than OSM-3 and that in the presence of OSM-3(S316F), OSM-3 and OSM-3(S316D) rates decrease. In the presence OSM-3::GFP or OSM-3(S316D)::GFP, OSM-3(S316F)::tdTomato redistributes along the cilium and accumulates in the cilia tip. OSM-3(S316F) and OSM-3(S316D) are functional as they restore cilia distal segment formation in osm-3(mn357) null mutants; however, only OSM-3(S316F) rescues the osm-3(mn357) null Dyf phenotype. Despite rescue of cilia length in osm-3(mn357) null mutants, neither OSM-3(S316F) nor OSM-3(S316D) restores ciliary defects in nphp-4(tm925);osm-3(yhw66) double mutants. Thus, these OSM-3 mutations cause NPHP-4 dependent and independent phenotypes. These data indicate that in addition to regulating cilia protein entry or exit

  19. Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet

    PubMed Central

    Curtin, Karen; Slattery, Martha L.; Ulrich, Cornelia M.; Bigler, Jeannette; Levin, Theodore R.; Wolff, Roger K.; Albertsen, Hans; Potter, John D.; Samowitz, Wade S.

    2008-01-01

    This study investigated associations between CpG island methylator phenotype (CIMP) colon cancer and genetic polymorphisms relevant to one-carbon metabolism and thus, potentially the provision of methyl groups and risk of colon cancer. Data from a large, population-based case–control study (916 incident colon cancer cases and 1972 matched controls) were used. Candidate polymorphisms in methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), transcobalamin II (TCNII), methionine synthase (MTR), reduced folate carrier (RFC), methylene-tetrahydrofolate dehydrogenase 1 (MTHFD1), dihydrofolate reductase (DHFR) and alcohol dehydrogenase 3 (ADH3) were evaluated. CIMP− or CIMP+ phenotype was based on five CpG island markers: MINT1, MINT2, MINT31, p16 and MLH1. The influence of specific dietary factors (folate, methionine, vitamin B12 and alcohol) on these associations was also analyzed. We hypothesized that polymorphisms involved in the provision of methyl groups would be associated with CIMP+ tumors (two or more of five markers methylated), potentially modified by diet. Few associations specific to CIMP+ tumors were observed overall, which does not support the hypothesis that the provision of methyl groups is important in defining a methylator phenotype. However, our data suggest that genetic polymorphisms in MTHFR 1298A > C, interacting with diet, may be involved in the development of highly CpG-methylated colon cancers. AC and CC genotypes in conjunction with a high-risk dietary pattern (low folate and methionine intake and high alcohol use) were associated with CIMP+ (OR = 2.1, 95% CI = 1.3–3.4 versus AA/high risk; P-interaction = 0.03). These results provide only limited support for a role of polymorphisms in one-carbon metabolism in the etiology of CIMP colon cancer. PMID:17449906

  20. Adoptive transfer of heme oxygenase-1 (HO-1)-modified macrophages rescues the nuclear factor erythroid 2-related factor (Nrf2) antiinflammatory phenotype in liver ischemia/reperfusion injury.

    PubMed

    Huang, Jing; Shen, Xiu-Da; Yue, Shi; Zhu, Jianjun; Gao, Feng; Zhai, Yuan; Busuttil, Ronald W; Ke, Bibo; Kupiec-Weglinski, Jerzy W

    2014-10-14

    Macrophages are instrumental in the pathophysiology of liver ischemia/reperfusion injury (IRI). Although Nrf2 regulates macrophage-specific heme oxygenase-1 (HO-1) antioxidant defense, it remains unknown whether HO-1 induction might rescue macrophage Nrf2-dependent antiinflammatory functions. This study explores the mechanisms by which the Nrf2-HO-1 axis regulates sterile hepatic inflammation responses after adoptive transfer of ex vivo modified HO-1 overexpressing bone marrow-derived macrophages (BMMs). Livers in Nrf2-deficient mice preconditioned with Ad-HO-1 BMMs, but not Ad-β-Gal-BMMs, ameliorated liver IRI (at 6 h of reperfusion after 90 min of warm ischemia), evidenced by improved hepatocellular function (serum alanine aminotransferase [sALT] levels) and preserved hepatic architecture (Suzuki histological score). Treatment with Ad-HO-1 BMMs decreased neutrophil accumulation, proinflammatory mediators and hepatocellular necrosis/apoptosis in ischemic livers. Moreover, Ad-HO-1 transfection of Nrf2-deficient BMMs suppressed M1 (Nos2(+)) while promoting the M2 (Mrc-1/Arg-1(+)) phenotype. Unlike in controls, Ad-HO-1 BMMs increased the expression of Notch1, Hes1, phosphorylation of Stat3 and Akt in IR-stressed Nrf2-deficient livers as well as in lipopolysaccharide (LPS)-stimulated BMMs. Thus, adoptive transfer of ex vivo generated Ad-HO-1 BMMs rescued Nrf2-dependent antiinflammatory phenotype by promoting Notch1/Hes1/Stat3 signaling and reprogramming macrophages toward the M2 phenotype. These findings provide the rationale for a novel clinically attractive strategy to manage IR liver inflammation/damage.

  1. A Novel Zebrafish ret Heterozygous Model of Hirschsprung Disease Identifies a Functional Role for mapk10 as a Modifier of Enteric Nervous System Phenotype Severity

    PubMed Central

    Kawakami, Koichi; Pachnis, Vassilis

    2016-01-01

    Hirschsprung disease (HSCR) is characterized by absence of enteric neurons from the distal colon and severe intestinal dysmotility. To understand the pathophysiology and genetics of HSCR we developed a unique zebrafish model that allows combined genetic, developmental and in vivo physiological studies. We show that ret mutant zebrafish exhibit cellular, physiological and genetic features of HSCR, including absence of intestinal neurons, reduced peristalsis, and varying phenotype expressivity in the heterozygous state. We perform live imaging experiments using a UAS-GAL4 binary genetic system to drive fluorescent protein expression in ENS progenitors. We demonstrate that ENS progenitors migrate at reduced speed in ret heterozygous embryos, without changes in proliferation or survival, establishing this as a principal pathogenic mechanism for distal aganglionosis. We show, using live imaging of actual intestinal movements, that intestinal motility is severely compromised in ret mutants, and partially impaired in ret heterozygous larvae, and establish a clear correlation between neuron position and organised intestinal motility. We exploited the partially penetrant ret heterozygous phenotype as a sensitised background to test the influence of a candidate modifier gene. We generated mapk10 loss-of-function mutants, which show reduced numbers of enteric neurons. Significantly, we show that introduction of mapk10 mutations into ret heterozygotes enhanced the ENS deficit, supporting MAPK10 as a HSCR susceptibility locus. Our studies demonstrate that ret heterozygous zebrafish is a sensitized model, with many significant advantages over existing murine models, to explore the pathophysiology and complex genetics of HSCR. PMID:27902697

  2. Modified CLSI Extended-Spectrum β-Lactamase (ESBL) Confirmatory Test for Phenotypic Detection of ESBLs among Enterobacteriaceae Producing Various β-Lactamases

    PubMed Central

    Poulou, Aggeliki; Grivakou, Evgenia; Vrioni, Georgia; Koumaki, Vassiliki; Pittaras, Theodoros; Pournaras, Spyros

    2014-01-01

    The worldwide dissemination of Enterobacteriaceae producing AmpC β-lactamases and carbapenemases makes difficult the phenotypic detection of extended-spectrum β-lactamases (ESBLs), as they may be masked by these additional enzymes. A modification of the CLSI ESBL confirmatory test was developed and evaluated in a comparative study for its ability to successfully detect ESBLs among Enterobacteriaceae producing various carbapenemases (Klebsiella pneumoniae carbapenemase [KPC], VIM, NDM, and OXA-48) and plasmidic or derepressed AmpCs. The modified CLSI ESBL confirmatory test was performed with cefotaxime and ceftazidime disks with and without clavulanate, on which both boronic acid (BA) and EDTA were dispensed. A total of 162 genotypically confirmed ESBL-positive Enterobacteriaceae isolates (83 carbapenemase/ESBL producers, 25 AmpC/ESBL producers, and 54 ESBL-only producers) were examined. For comparison, 139 genotypically confirmed ESBL-negative Enterobacteriaceae isolates (94 of them possessed carbapenemases and 20 possessed AmpCs) were also tested. The standard CLSI ESBL confirmatory test was positive for 106 of the 162 ESBL producers (sensitivity, 65.4%) and showed false-positive results for 4 of the 139 non-ESBL producers (specificity, 97.1%). The modified CLSI ESBL confirmatory test detected 158 of 162 ESBL producers (sensitivity, 97.5%) and showed no false-positive results for non-ESBL producers (specificity, 100%). The findings of the study demonstrate that the modified CLSI ESBL confirmatory test using antibiotic disks containing both BA and EDTA accurately detects ESBLs in Enterobacteriaceae regardless of the coexistence of additional β-lactam resistance mechanisms. PMID:24574283

  3. Modified CLSI extended-spectrum β-lactamase (ESBL) confirmatory test for phenotypic detection of ESBLs among Enterobacteriaceae producing various β-lactamases.

    PubMed

    Poulou, Aggeliki; Grivakou, Evgenia; Vrioni, Georgia; Koumaki, Vassiliki; Pittaras, Theodoros; Pournaras, Spyros; Tsakris, Athanassios

    2014-05-01

    The worldwide dissemination of Enterobacteriaceae producing AmpC β-lactamases and carbapenemases makes difficult the phenotypic detection of extended-spectrum β-lactamases (ESBLs), as they may be masked by these additional enzymes. A modification of the CLSI ESBL confirmatory test was developed and evaluated in a comparative study for its ability to successfully detect ESBLs among Enterobacteriaceae producing various carbapenemases (Klebsiella pneumoniae carbapenemase [KPC], VIM, NDM, and OXA-48) and plasmidic or derepressed AmpCs. The modified CLSI ESBL confirmatory test was performed with cefotaxime and ceftazidime disks with and without clavulanate, on which both boronic acid (BA) and EDTA were dispensed. A total of 162 genotypically confirmed ESBL-positive Enterobacteriaceae isolates (83 carbapenemase/ESBL producers, 25 AmpC/ESBL producers, and 54 ESBL-only producers) were examined. For comparison, 139 genotypically confirmed ESBL-negative Enterobacteriaceae isolates (94 of them possessed carbapenemases and 20 possessed AmpCs) were also tested. The standard CLSI ESBL confirmatory test was positive for 106 of the 162 ESBL producers (sensitivity, 65.4%) and showed false-positive results for 4 of the 139 non-ESBL producers (specificity, 97.1%). The modified CLSI ESBL confirmatory test detected 158 of 162 ESBL producers (sensitivity, 97.5%) and showed no false-positive results for non-ESBL producers (specificity, 100%). The findings of the study demonstrate that the modified CLSI ESBL confirmatory test using antibiotic disks containing both BA and EDTA accurately detects ESBLs in Enterobacteriaceae regardless of the coexistence of additional β-lactam resistance mechanisms.

  4. Monozygotic twins discordant for recessive dystrophic epidermolysis bullosa phenotype highlight the role of TGF-β signalling in modifying disease severity.

    PubMed

    Odorisio, Teresa; Di Salvio, Michela; Orecchia, Angela; Di Zenzo, Giovanni; Piccinni, Eugenia; Cianfarani, Francesca; Travaglione, Antonella; Uva, Paolo; Bellei, Barbara; Conti, Andrea; Zambruno, Giovanna; Castiglia, Daniele

    2014-08-01

    Recessive dystrophic epidermolysis bullosa (RDEB) is a genodermatosis characterized by fragile skin forming blisters that heal invariably with scars. It is due to mutations in the COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils connecting the cutaneous basement membrane to the dermis. Identical COL7A1 mutations often result in inter- and intra-familial disease variability, suggesting that additional modifiers contribute to RDEB course. Here, we studied a monozygotic twin pair with RDEB presenting markedly different phenotypic manifestations, while expressing similar amounts of collagen VII. Genome-wide expression analysis in twins' fibroblasts showed differential expression of genes associated with TGF-β pathway inhibition. In particular, decorin, a skin matrix component with anti-fibrotic properties, was found to be more expressed in the less affected twin. Accordingly, fibroblasts from the more affected sibling manifested a profibrotic and contractile phenotype characterized by enhanced α-smooth muscle actin and plasminogen activator inhibitor 1 expression, collagen I release and collagen lattice contraction. These cells also produced increased amounts of proinflammatory cytokines interleukin 6 and monocyte chemoattractant protein-1. Both TGF-β canonical (Smads) and non-canonical (MAPKs) pathways were basally more activated in the fibroblasts of the more affected twin. The profibrotic behaviour of these fibroblasts was suppressed by decorin delivery to cells. Our data show that the amount of type VII collagen is not the only determinant of RDEB clinical severity, and indicate an involvement of TGF-β pathways in modulating disease variability. Moreover, our findings identify decorin as a possible anti-fibrotic/inflammatory agent for RDEB therapeutic intervention.

  5. Silent polymorphisms in the RYR1 gene do not modify the phenotype of the p.4898 I>T pathogenic mutation in central core disease: a case report

    PubMed Central

    2014-01-01

    Background Central core disease is a congenital myopathy, characterized by presence of central core-like areas in muscle fibers. Patients have mild or moderate weakness, hypotonia and motor developmental delay. The disease is caused by mutations in the human ryanodine receptor gene (RYR1), which encodes a calcium-release channel. Since the RYR1 gene is huge, containing 106 exons, mutation screening has been limited to three ‘hot spots’, with particular attention to the C-terminal region. Recent next- generation sequencing methods are now identifying multiple numbers of variants in patients, in which interpretation and phenotype prevision is difficult. Case presentation In a Brazilian Caucasian family, clinical, histopathological and molecular analysis identified a new case of central core disease in a 48-year female. Sanger sequencing of the C-terminal region of the RYR1 gene identified two different missense mutations: c.14256 A > C polymorphism in exon 98 and c.14693 T > C in exon 102, which have already been described as pathogenic. Trans-position of the 2 mutations was confirmed because patient’s daughter, mother and sister carried only the exon 98’s mutation, a synonymous variant that was subsequently found in the frequency of 013–0,05 of alleles. Further next generation sequencing study of the whole RYR1 gene in the patient revealed the presence of additional 5 common silent polymorphisms in homozygosis and 8 polymorphisms in heterozygosis. Conclusions Considering that patient’s relatives showed no pathologic phenotype, and the phenotype presented by the patient is within the range observed in other central core disease patients with the same mutation, it was concluded that the c.14256 A > C polymorphism alone is not responsible for disease, and the associated additional silent polymorphisms are not acting as modifiers of the primary pathogenic mutation in the affected patient. The case described above illustrates the present reality where

  6. Antibacterial and antibiotic-resistance modifying activity of the extracts and compounds from Nauclea pobeguinii against Gram-negative multi-drug resistant phenotypes.

    PubMed

    Seukep, Jackson A; Sandjo, Louis P; Ngadjui, Bonaventure T; Kuete, Victor

    2016-07-07

    Multi-drug resistance of Gram-negative bacteria constitutes a major obstacle in the antibacterial fight worldwide. The discovery of new and effective antimicrobials and/or resistance modulators is necessary to combat the spread of resistance or to reverse the multi-drug resistance. In this study, we investigated the antibacterial and antibiotic-resistance modifying activities against 29 Gram-negative bacteria including multi-drug resistant (MDR) phenotypes of the methanol extracts from Nauclea pobeguiinii leaves (NPL), Nauclea pobeguiinii bark (NPB) and six compounds from the bark extract, identified as 3-acetoxy-11-oxo-urs-12-ene (1), p-coumaric acid (2), citric acid trimethyl ester (3), resveratrol (4), resveratrol β- D -glucopyranoside (5) and strictosamide (6). The broth microdilution method was used to determine the minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) of crude extracts and compounds as well as the antibiotic-resistance modifying effects of MPB and 4. MIC determinations indicate values ranging from 32-1024 μg/mL for NPB and NPL on 89.7 % and 69.0 % of the tested bacterial strains respectively. MIC values below 100 μg/mL were obtained with NPB against Escherichia coli ATCC10536, AG100 and Enterobacter aerogenes CM64 strains. The lowest MIC value for crude extracts of 32 μg/mL was obtained with NPB against E. coli ATCC10536. Compound 4 was active all tested bacteria, whilst 1, 3 and 6 displayed weak and selective inhibitory effects. The corresponding MIC value (16 μg/mL) was obtained with 4 against Klebsiella pneumoniae KP55 strain. Synergistic effects of the combination of NPB with chloramphenicol (CHL), kanamycin (KAN) as well as that of compound 4 with streptomycin (STR) and ciprofloxacin (CIP) were observed. The present study provides information on the possible use of Nauclea pobeguinii and compound 4 in the control of Gram-negative bacterial infections including MDR phenotypes. It also indicates

  7. Genetic Modifiers of Sickle Cell Disease: A Genotype-Phenotype Relationship Study in a Cohort of 82 Children on Mayotte Island.

    PubMed

    Muszlak, Mathias; Pissard, Serge; Badens, Catherine; Chamouine, Abdourahim; Maillard, Olivier; Thuret, Isabelle

    2015-01-01

    Sickle cell disease presents a great clinical variability that remains largely misunderstood. New disease protective genetic modifiers acting mainly through an increased Hb F level have recently been described. We studied relations between clinical and hematological phenotypes and known sickle cell disease genetic modifiers in patients from Mayotte Island, a remote French territory located in the Indian Ocean. Eighty-two children with sickle cell disease were enrolled; their median age was 5.9 years (range 1-18). Clinical and hematological features of sickle cell disease were retrospectively collected. Genetic studies included determination of β-globin genotypes [Hb SS, Hb S-β(0)-thalassemia (Hb S-β(0)-thal), Hb S-β(+)-thal], β(S)-globin locus haplotype, α-thalassemia (α-thal), and single nucleotide polymorphisms (SNPs) located in quantitative trait loci for Hb F expression (XmnI polymorphism, BCL11A rs4671393 and rs11886868, intergenic region of HBS1L-MYB rs28384513, rs4895441 and rs9399137). Univariate and multivariate analyses were conducted. Twenty-eight percent of the patients had Hb S-β-thal (eight different mutations in 21 patients), 55.0% had the -α(3.7) (rightward) deletion and 88.0% of the homozygous Hb SS patients were carrying a homozygous Bantu haplotype. In the multivariate model, the prognosis role of the SNP BCL11A rs4671393 was confirmed in the studied population showing a significant association with an elevated Hb F level and with a low hospitalization rate. The -α(3.7) deletion, XmnI polymorphism and intergenic region HBS1L-MYB SNPs were not significantly linked to any clinical criteria of severity. This report, the first to describe the main features of children with sickle cell disease on Mayotte Island, highlights the protective effect of the BCL11A polymorphism in this population.

  8. The Power of Human Protective Modifiers: PLS3 and CORO1C Unravel Impaired Endocytosis in Spinal Muscular Atrophy and Rescue SMA Phenotype.

    PubMed

    Hosseinibarkooie, Seyyedmohsen; Peters, Miriam; Torres-Benito, Laura; Rastetter, Raphael H; Hupperich, Kristina; Hoffmann, Andrea; Mendoza-Ferreira, Natalia; Kaczmarek, Anna; Janzen, Eva; Milbradt, Janine; Lamkemeyer, Tobias; Rigo, Frank; Bennett, C Frank; Guschlbauer, Christoph; Büschges, Ansgar; Hammerschmidt, Matthias; Riessland, Markus; Kye, Min Jeong; Clemen, Christoph S; Wirth, Brunhilde

    2016-09-01

    Homozygous loss of SMN1 causes spinal muscular atrophy (SMA), the most common and devastating childhood genetic motor-neuron disease. The copy gene SMN2 produces only ∼10% functional SMN protein, insufficient to counteract development of SMA. In contrast, the human genetic modifier plastin 3 (PLS3), an actin-binding and -bundling protein, fully protects against SMA in SMN1-deleted individuals carrying 3-4 SMN2 copies. Here, we demonstrate that the combinatorial effect of suboptimal SMN antisense oligonucleotide treatment and PLS3 overexpression-a situation resembling the human condition in asymptomatic SMN1-deleted individuals-rescues survival (from 14 to >250 days) and motoric abilities in a severe SMA mouse model. Because PLS3 knockout in yeast impairs endocytosis, we hypothesized that disturbed endocytosis might be a key cellular mechanism underlying impaired neurotransmission and neuromuscular junction maintenance in SMA. Indeed, SMN deficit dramatically reduced endocytosis, which was restored to normal levels by PLS3 overexpression. Upon low-frequency electro-stimulation, endocytotic FM1-43 (SynaptoGreen) uptake in the presynaptic terminal of neuromuscular junctions was restored to control levels in SMA-PLS3 mice. Moreover, proteomics and biochemical analysis revealed CORO1C, another F-actin binding protein, whose direct binding to PLS3 is dependent on calcium. Similar to PLS3 overexpression, CORO1C overexpression restored fluid-phase endocytosis in SMN-knockdown cells by elevating F-actin amounts and rescued the axonal truncation and branching phenotype in Smn-depleted zebrafish. Our findings emphasize the power of genetic modifiers to unravel the cellular pathomechanisms underlying SMA and the power of combinatorial therapy based on splice correction of SMN2 and endocytosis improvement to efficiently treat SMA. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  9. Randomly detected genetically modified (GM) maize (Zea mays L.) near a transport route revealed a fragile 45S rDNA phenotype.

    PubMed

    Waminal, Nomar Espinosa; Ryu, Ki Hyun; Choi, Sun-Hee; Kim, Hyun Hee

    2013-01-01

    Monitoring of genetically modified (GM) crops has been emphasized to prevent their potential effects on the environment and human health. Monitoring of the inadvertent dispersal of transgenic maize in several fields and transport routes in Korea was carried out by qualitative multiplex PCR, and molecular analyses were conducted to identify the events of the collected GM maize. Cytogenetic investigations through fluorescence in situ hybridization (FISH) of the GM maize were performed to check for possible changes in the 45S rDNA cluster because this cluster was reported to be sensitive to replication and transcription stress. Three GM maize kernels were collected from a transport route near Incheon port, Korea, and each was found to contain NK603, stacked MON863 x NK603, and stacked NK603 x MON810 inserts, respectively. Cytogenetic analysis of the GM maize containing the stacked NK603 x MON810 insert revealed two normal compact 5S rDNA signals, but the 45S rDNA showed a fragile phenotype, demonstrating a "beads-on-a-string" fragmentation pattern, which seems to be a consequence of genetic modification. Implications of the 45S rDNA cluster fragility in GM maize are also discussed.

  10. Randomly Detected Genetically Modified (GM) Maize (Zea mays L.) near a Transport Route Revealed a Fragile 45S rDNA Phenotype

    PubMed Central

    Waminal, Nomar Espinosa; Ryu, Ki Hyun; Choi, Sun-Hee; Kim, Hyun Hee

    2013-01-01

    Monitoring of genetically modified (GM) crops has been emphasized to prevent their potential effects on the environment and human health. Monitoring of the inadvertent dispersal of transgenic maize in several fields and transport routes in Korea was carried out by qualitative multiplex PCR, and molecular analyses were conducted to identify the events of the collected GM maize. Cytogenetic investigations through fluorescence in situ hybridization (FISH) of the GM maize were performed to check for possible changes in the 45S rDNA cluster because this cluster was reported to be sensitive to replication and transcription stress. Three GM maize kernels were collected from a transport route near Incheon port, Korea, and each was found to contain NK603, stacked MON863 x NK603, and stacked NK603 x MON810 inserts, respectively. Cytogenetic analysis of the GM maize containing the stacked NK603 x MON810 insert revealed two normal compact 5S rDNA signals, but the 45S rDNA showed a fragile phenotype, demonstrating a “beads-on-a-string” fragmentation pattern, which seems to be a consequence of genetic modification. Implications of the 45S rDNA cluster fragility in GM maize are also discussed. PMID:24040165

  11. Antibacterial and antibiotic resistance modifying activity of the extracts from Allanblackia gabonensis, Combretum molle and Gladiolus quartinianus against Gram-negative bacteria including multi-drug resistant phenotypes.

    PubMed

    Fankam, Aimé G; Kuiate, Jules R; Kuete, Victor

    2015-06-30

    Bacterial resistance to antibiotics is becoming a serious problem worldwide. The discovery of new and effective antimicrobials and/or resistance modulators is necessary to tackle the spread of resistance or to reverse the multi-drug resistance. We investigated the antibacterial and antibiotic-resistance modifying activities of the methanol extracts from Allanblackia gabonensis, Gladiolus quartinianus and Combretum molle against 29 Gram-negative bacteria including multi-drug resistant (MDR) phenotypes. The broth microdilution method was used to determine the minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) of the samples meanwhile the standard phytochemical methods were used for the preliminary phytochemical screening of the plant extracts. Phytochemical analysis showed the presence of alkaloids, flavonoids, phenols and tannins in all studied extracts. Other chemical classes of secondary metabolites were selectively presents. Extracts from A. gabonensis and C. molle displayed a broad spectrum of activity with MICs varying from 16 to 1024 μg/mL against about 72.41% of the tested bacteria. The extract from the fruits of A. gabonensis had the best activity, with MIC values below 100 μg/mL on 37.9% of tested bacteria. Percentages of antibiotic-modulating effects ranging from 67 to 100% were observed against tested MDR bacteria when combining the leaves extract from C. molle (at MIC/2 and MIC/4) with chloramphenicol, kanamycin, streptomycin and tetracycline. The overall results of the present study provide information for the possible use of the studied plant, especially Allanblackia gabonensis and Combretum molle in the control of Gram-negative bacterial infections including MDR species as antibacterials as well as resistance modulators.

  12. Specific polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression

    PubMed Central

    Borrego, S.; Saez, M. E.; Ruiz, A.; Gimm, O.; Lopez-Alonso, M.; Antinolo, G.; Eng, C.

    1999-01-01

    Hirschsprung disease (HSCR) is a common genetic disorder presenting with functional intestinal obstruction secondary to enteric aganglionosis. HSCR can be familial or sporadic. Although five putative susceptibility genes have been identified, only germline mutations in the RET proto-oncogene account for a significant minority (up to 50%) of familial HSCR; 3% of sporadic HSCR in a population based series carry RET mutations. From 1998 to February 1999, we prospectively ascertained 64 cases of sporadic HSCR from the western Andalusia region. To determine if polymorphic sequence variants within RET could act as low penetrance predisposing alleles, we examined allelic frequencies at seven polymorphic loci in this population based series. Whether allele frequencies differed from those in the control population were determined by either chi-squared analysis or Fisher's exact test. For two sequence variants, A45A (c 135G→A) (exon 2) and L769L (c 2307T→G) (exon 13), the rarer polymorphic allele was over-represented among HSCR cases versus controls (p<0.0006). In contrast, two other polymorphisms, G691S (c 2071C→A) (exon 11) and S904S (c 2712C→G) (exon 15), were under-represented in the HSCR patients compared to controls (p=0.02). Polymorphisms in the RET proto-oncogene appear to predispose to HSCR in a complex, low penetrance fashion and may also modify phenotypic expression.


Keywords: polymorphism; low penetrance alleles; neurocristopathy; chromosome 10 PMID:10528857

  13. Effects of modifying agents on conformity of enzyme phenotype and proliferative potential in focal preneoplastic and neoplastic liver cell lesions in rats.

    PubMed

    Tsuda, H; Ozaki, K; Uwagawa, S; Yamaguchi, S; Hakoi, K; Aoki, T; Kato, T; Sato, K; Ito, N

    1992-11-01

    Development of preneoplastic lesions in the rat liver under the influence of various modifiers was investigated with particular attention to changes in simultaneous expression of altered enzyme phenotype within the lesions (conformity) and proliferation potential. Degree of conformity of marker enzymes such as glutathione S-transferase placental form (GST-P), glucose-6-phosphate dehydrogenase (G6PD), glucose-6-phosphatase, adenosine triphosphatase and gamma-glutamyltranspeptidase was compared with levels of 5-bromo-2-deoxyuridine labeling. After initiation with diethylnitrosamine, rats were administered the hepatopromoter sodium phenobarbital (PB, 0.05%), the antioxidant ethoxyquin (EQ, 0.5%), or a peroxisome proliferator, clofibrate (CF, 1.0%) or di(2-ethylhexyl)-phthalate (0.3%) and killed at week 16 or 32. The PB promoting regimen was clearly associated with increase in the numbers of high conformity class lesions simultaneously expressing three to five enzymes, and elevated proliferation potential. The inhibitor, EQ, in contrast, brought about a time-dependent decrease in conformity so that only 1 or 2 alterations were most commonly observed at week 32. Lesion populations in the peroxisome proliferator- and especially CF-treated cases were characterized by obvious dissociation between degree of conformity and proliferative status. Such treatment-dependent differences were not always correlated with the size of the lesion. The results thus suggested that the conformity and proliferation potential of preneoplastic lesions are dependent on modification treatment. Overall, GST-P was found to be the most reliable marker, although G6PD was less influenced in the peroxisome proliferator cases.

  14. Allelic variants of the amylose extender mutation of maize demonstrate phenotypic variation in starch structure resulting from modified protein–protein interactions

    PubMed Central

    Liu, Fushan; Ahmed, Zaheer; Lee, Elizabeth A.; Donner, Elizabeth; Liu, Qiang; Ahmed, Regina; Morell, Matthew K.; Emes, Michael J.; Tetlow, Ian J.

    2012-01-01

    amylose extender (ae−) starches characteristically have modified starch granule morphology resulting from amylopectin with reduced branch frequency and longer glucan chains in clusters, caused by the loss of activity of the major starch branching enzyme (SBE), which in maize endosperm is SBEIIb. A recent study with ae− maize lacking the SBEIIb protein (termed ae1.1 herein) showed that novel protein–protein interactions between enzymes of starch biosynthesis in the amyloplast could explain the starch phenotype of the ae1.1 mutant. The present study examined an allelic variant of the ae− mutation, ae1.2, which expresses a catalytically inactive form of SBEIIb. The catalytically inactive SBEIIb in ae1.2 lacks a 28 amino acid peptide (Val272–Pro299) and is unable to bind to amylopectin. Analysis of starch from ae1.2 revealed altered granule morphology and physicochemical characteristics distinct from those of the ae1.1 mutant as well as the wild-type, including altered apparent amylose content and gelatinization properties. Starch from ae1.2 had fewer intermediate length glucan chains (degree of polymerization 16–20) than ae1.1. Biochemical analysis of ae1.2 showed that there were differences in the organization and assembly of protein complexes of starch biosynthetic enzymes in comparison with ae1.1 (and wild-type) amyloplasts, which were also reflected in the composition of starch granule-bound proteins. The formation of stromal protein complexes in the wild-type and ae1.2 was strongly enhanced by ATP, and broken by phosphatase treatment, indicating a role for protein phosphorylation in their assembly. Labelling experiments with [γ-32P]ATP showed that the inactive form of SBEIIb in ae1.2 was phosphorylated, both in the monomeric form and in association with starch synthase isoforms. Although the inactive SBEIIb was unable to bind starch directly, it was strongly associated with the starch granule, reinforcing the conclusion that its presence in the

  15. Estimating rice yield related traits and quantitative trait loci analysis under different nitrogen treatments using a simple tower-based field phenotyping system with modified single-lens reflex cameras

    NASA Astrophysics Data System (ADS)

    Naito, Hiroki; Ogawa, Satoshi; Valencia, Milton Orlando; Mohri, Hiroki; Urano, Yutaka; Hosoi, Fumiki; Shimizu, Yo; Chavez, Alba Lucia; Ishitani, Manabu; Selvaraj, Michael Gomez; Omasa, Kenji

    2017-03-01

    Application of field based high-throughput phenotyping (FB-HTP) methods for monitoring plant performance in real field conditions has a high potential to accelerate the breeding process. In this paper, we discuss the use of a simple tower based remote sensing platform using modified single-lens reflex cameras for phenotyping yield traits in rice under different nitrogen (N) treatments over three years. This tower based phenotyping platform has the advantages of simplicity, ease and stability in terms of introduction, maintenance and continual operation under field conditions. Out of six phenological stages of rice analyzed, the flowering stage was the most useful in the estimation of yield performance under field conditions. We found a high correlation between several vegetation indices (simple ratio (SR), normalized difference vegetation index (NDVI), transformed vegetation index (TVI), corrected transformed vegetation index (CTVI), soil-adjusted vegetation index (SAVI) and modified soil-adjusted vegetation index (MSAVI)) and multiple yield traits (panicle number, grain weight and shoot biomass) across a three trials. Among all of the indices studied, SR exhibited the best performance in regards to the estimation of grain weight (R2 = 0.80). Under our tower-based field phenotyping system (TBFPS), we identified quantitative trait loci (QTL) for yield related traits using a mapping population of chromosome segment substitution lines (CSSLs) and a single nucleotide polymorphism data set. Our findings suggest the TBFPS can be useful for the estimation of yield performance during early crop development. This can be a major opportunity for rice breeders whom desire high throughput phenotypic selection for yield performance traits.

  16. Exome Sequencing of Phenotypic Extremes Identifies CAV2 and TMC6 as Interacting Modifiers of Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis

    PubMed Central

    Emond, Mary J.; Louie, Tin; Emerson, Julia; Chong, Jessica X.; Mathias, Rasika A.; Knowles, Michael R.; Rieder, Mark J.; Tabor, Holly K.; Nickerson, Debbie A.; Barnes, Kathleen C.; GO, Lung; Gibson, Ronald L.; Bamshad, Michael J.

    2015-01-01

    Discovery of rare or low frequency variants in exome or genome data that are associated with complex traits often will require use of very large sample sizes to achieve adequate statistical power. For a fixed sample size, sequencing of individuals sampled from the tails of a phenotype distribution (i.e., extreme phenotypes design) maximizes power and this approach was recently validated empirically with the discovery of variants in DCTN4 that influence the natural history of P. aeruginosa airway infection in persons with cystic fibrosis (CF; MIM219700). The increasing availability of large exome/genome sequence datasets that serve as proxies for population-based controls affords the opportunity to test an alternative, potentially more powerful and generalizable strategy, in which the frequency of rare variants in a single extreme phenotypic group is compared to a control group (i.e., extreme phenotype vs. control population design). As proof-of-principle, we applied this approach to search for variants associated with risk for age-of-onset of chronic P. aeruginosa airway infection among individuals with CF and identified variants in CAV2 and TMC6 that were significantly associated with group status. These results were validated using a large, prospective, longitudinal CF cohort and confirmed a significant association of a variant in CAV2 with increased age-of-onset of P. aeruginosa airway infection (hazard ratio = 0.48, 95% CI=[0.32, 0.88]) and variants in TMC6 with diminished age-of-onset of P. aeruginosa airway infection (HR = 5.4, 95% CI=[2.2, 13.5]) A strong interaction between CAV2 and TMC6 variants was observed (HR=12.1, 95% CI=[3.8, 39]) for children with the deleterious TMC6 variant and without the CAV2 protective variant. Neither gene showed a significant association using an extreme phenotypes design, and conditions for which the power of an extreme phenotype vs. control population design was greater than that for the extreme phenotypes design were

  17. Modifiable exposures to air pollutants related to asthma phenotypes in the first year of life in children of the EDEN mother-child cohort study

    PubMed Central

    2013-01-01

    Background Studies have shown diverse strength of evidence for the associations between air pollutants and childhood asthma, but these associations have scarcely been documented in the early life. The purpose of this study was to evaluate the impacts of various air pollutants on the development of asthma phenotypes in the first year of life. Methods Adjusted odds ratios were estimated to assess the relationships between exposures to air pollutants and single and multi-dimensional asthma phenotypes in the first year of life in children of the EDEN mother-child cohort study (n = 1,765 mother-child pairs). The Generalized Estimating Equation (GEE) model was used to determine the associations between prenatal maternal smoking and in utero exposure to traffic-related air pollution and asthma phenotypes (data were collected when children were at birth, and at 4, 8 and 12 months of age). Adjusted Population Attributable Risk (aPAR) was estimated to measure the impacts of air pollutants on health outcomes. Results In the first year of life, both single and multi-dimensional asthma phenotypes were positively related to heavy parental smoking, traffic-related air pollution and dampness, but negatively associated with contact with cats and domestic wood heating. Adjusted odds ratios (aORs) for traffic-related air pollution were the highest [1.71 (95% Confidence Interval (CI): 1.08-2.72) for ever doctor-diagnosed asthma, 1.44 (95% CI: 1.05-1.99) for bronchiolitis with wheezing, 2.01 (95% CI: 1.23-3.30) for doctor-diagnosed asthma with a history of bronchiolitis]. The aPARs based on these aORs were 13.52%, 9.39%, and 17.78%, respectively. Results persisted for prenatal maternal smoking and in utero exposure to traffic-related air pollution, although statistically significant associations were observed only with the asthma phenotype of ever bronchiolitis. Conclusions After adjusting for potential confounders, traffic-related air pollution in utero life and in the first year

  18. Human TRMU encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclear modifier gene for the phenotypic expression of the deafness-associated 12S rRNA mutations

    SciTech Connect

    Yan Qingfeng; Bykhovskaya, Yelena; Li Ronghua; Mengesha, Emebet; Shohat, Mordechai; Estivill, Xavier; Fischel-Ghodsian, Nathan; Guan Minxin . E-mail: min-xin.guan@chmcc.org

    2006-04-21

    Nuclear modifier genes have been proposed to modulate the phenotypic manifestation of human mitochondrial 12S rRNA A1491G mutation associated with deafness in many families world-wide. Here we identified and characterized the putative nuclear modifier gene TRMU encoding a highly conserved mitochondrial protein related to tRNA modification. A 1937 bp TRMU cDNA has been isolated and the genomic organization of TRMU has been elucidated. The human TRMU gene containing 11 exons encodes a 421 residue protein with a strong homology to the TRMU-like proteins of bacteria and other homologs. TRMU is ubiquitously expressed in various tissues, but abundantly in tissues with high metabolic rates including heart, liver, kidney, and brain. Immunofluorescence analysis of human 143B cells expressing TRMU-GFP fusion protein demonstrated that the human Trmu localizes and functions in mitochondrion. Furthermore, we show that in families with the deafness-associated 12S rRNA A1491G mutation there is highly suggestive linkage and linkage disequilibrium between microsatellite markers adjacent to TRMU and the presence of deafness. These observations suggest that human TRMU may modulate the phenotypic manifestation of the deafness-associated mitochondrial 12S rRNA mutations.

  19. Biochemical Evidence for a Nuclear Modifier Allele (A10S) in TRMU (Methylaminomethyl-2-thiouridylate-methyltransferase) Related to Mitochondrial tRNA Modification in the Phenotypic Manifestation of Deafness-associated 12S rRNA Mutation.

    PubMed

    Meng, Feilong; Cang, Xiaohui; Peng, Yanyan; Li, Ronghua; Zhang, Zhengyue; Li, Fushan; Fan, Qingqing; Guan, Anna S; Fischel-Ghosian, Nathan; Zhao, Xiaoli; Guan, Min-Xin

    2017-02-17

    Nuclear modifier gene(s) was proposed to modulate the phenotypic expression of mitochondrial DNA mutation(s). Our previous investigations revealed that a nuclear modifier allele (A10S) in TRMU (methylaminomethyl-2-thiouridylate-methyltransferase) related to tRNA modification interacts with 12S rRNA 1555A→G mutation to cause deafness. The A10S mutation resided at a highly conserved residue of the N-terminal sequence. It was hypothesized that the A10S mutation altered the structure and function of TRMU, thereby causing mitochondrial dysfunction. Using molecular dynamics simulations, we showed that the A10S mutation introduced the Ser(10) dynamic electrostatic interaction with the Lys(106) residue of helix 4 within the catalytic domain of TRMU. The Western blotting analysis displayed the reduced levels of TRMU in mutant cells carrying the A10S mutation. The thermal shift assay revealed the Tm value of mutant TRMU protein, lower than that of the wild-type counterpart. The A10S mutation caused marked decreases in 2-thiouridine modification of U34 of tRNA(Lys), tRNA(Glu) and tRNA(Gln) However, the A10S mutation mildly increased the aminoacylated efficiency of tRNAs. The altered 2-thiouridine modification worsened the impairment of mitochondrial translation associated with the m.1555A→G mutation. The defective translation resulted in the reduced activities of mitochondrial respiration chains. The respiratory deficiency caused the reduction of mitochondrial ATP production and elevated the production of reactive oxidative species. As a result, mutated TRMU worsened mitochondrial dysfunctions associated with m.1555A→G mutation, exceeding the threshold for expressing a deafness phenotype. Our findings provided new insights into the pathophysiology of maternally inherited deafness that was manifested by interaction between mtDNA mutation and nuclear modifier gene. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring

    PubMed Central

    Short, A K; Fennell, K A; Perreau, V M; Fox, A; O'Bryan, M K; Kim, J H; Bredy, T W; Pang, T Y; Hannan, A J

    2016-01-01

    Recent studies have suggested that physiological and behavioral traits may be transgenerationally inherited through the paternal lineage, possibly via non-genomic signals derived from the sperm. To investigate how paternal stress might influence offspring behavioral phenotypes, a model of hypothalamic–pituitary–adrenal (HPA) axis dysregulation was used. Male breeders were administered water supplemented with corticosterone (CORT) for 4 weeks before mating with untreated female mice. Female, but not male, F1 offspring of CORT-treated fathers displayed altered fear extinction at 2 weeks of age. Only male F1 offspring exhibited altered patterns of ultrasonic vocalization at postnatal day 3 and, as adults, showed decreased time in open on the elevated-plus maze and time in light on the light–dark apparatus, suggesting a hyperanxiety-like behavioral phenotype due to paternal CORT treatment. Interestingly, expression of the paternally imprinted gene Igf2 was increased in the hippocampus of F1 male offspring but downregulated in female offspring. Male and female F2 offspring displayed increased time spent in the open arm of the elevated-plus maze, suggesting lower levels of anxiety compared with control animals. Only male F2 offspring showed increased immobility time on the forced-swim test and increased latency to feed on the novelty-supressed feeding test, suggesting a depression-like phenotype in these animals. Collectively, these data provide evidence that paternal CORT treatment alters anxiety and depression-related behaviors across multiple generations. Analysis of the small RNA profile in sperm from CORT-treated males revealed marked effects on the expression of small noncoding RNAs. Sperm from CORT-treated males contained elevated levels of three microRNAs, miR-98, miR-144 and miR-190b, which are predicted to interact with multiple growth factors, including Igf2 and Bdnf. Sustained elevation of glucocorticoids is therefore involved in the transmission of

  1. Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study

    PubMed Central

    Hamroun, Dalil; Varet, Hugo; Fabbro, Marianne; Rougier, Felix; Amarof, Khadija; Arne Bes, Marie-Christine; Bedat-Millet, Anne-Laure; Behin, Anthony; Bellance, Remi; Bouhour, Françoise; Boutte, Celia; Boyer, François; Campana-Salort, Emmanuelle; Chapon, Françoise; Cintas, Pascal; Desnuelle, Claude; Deschamps, Romain; Drouin-Garraud, Valerie; Ferrer, Xavier; Gervais-Bernard, Helene; Ghorab, Karima; Laforet, Pascal; Magot, Armelle; Magy, Laurent; Menard, Dominique; Minot, Marie-Christine; Nadaj-Pakleza, Aleksandra; Pellieux, Sybille; Pereon, Yann; Preudhomme, Marguerite; Pouget, Jean; Sacconi, Sabrina; Sole, Guilhem; Stojkovich, Tanya; Tiffreau, Vincent; Urtizberea, Andoni; Vial, Christophe; Zagnoli, Fabien; Caranhac, Gilbert; Bourlier, Claude; Riviere, Gerard; Geille, Alain; Gherardi, Romain K.; Eymard, Bruno; Puymirat, Jack; Katsahian, Sandrine; Bassez, Guillaume

    2016-01-01

    Background Myotonic Dystrophy type 1 (DM1) is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity. Methods We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18y) from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Téléthon DM1 survey (n = 970), and morbidity and mortality using the French National Health Service Database (n = 3301). Results Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate. Conclusion Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials. PMID:26849574

  2. The exome sequencing identified the mutation in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as a nuclear modifier for the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation.

    PubMed

    Jiang, Pingping; Jin, Xiaofen; Peng, Yanyan; Wang, Meng; Liu, Hao; Liu, Xiaoling; Zhang, Zengjun; Ji, Yanchun; Zhang, Juanjuan; Liang, Min; Zhao, Fuxin; Sun, Yan-Hong; Zhang, Minglian; Zhou, Xiangtian; Chen, Ye; Mo, Jun Qin; Huang, Taosheng; Qu, Jia; Guan, Min-Xin

    2016-02-01

    Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder. Nuclear modifier genes are proposed to modify the phenotypic expression of LHON-associated mitochondrial DNA (mtDNA) mutations. By using an exome sequencing approach, we identified a LHON susceptibility allele (c.572G>T, p.191Gly>Val) in YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase, which interacts with m.11778G>A mutation to cause visual failure. We performed functional assays by using lymphoblastoid cell lines derived from members of Chinese families (asymptomatic individuals carrying m.11778G>A mutation, or both m.11778G>A and heterozygous p.191Gly>Val mutations and symptomatic subjects harboring m.11778G>A and homozygous p.191Gly>Val mutations) and controls lacking these mutations. The 191Gly>Val mutation reduced the YARS2 protein level in the mutant cells. The aminoacylated efficiency and steady-state level of tRNA(Tyr) were markedly decreased in the cell lines derived from patients both carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The failure in tRNA(Tyr) metabolism impaired mitochondrial translation, especially for polypeptides with high content of tyrosine codon such as ND4, ND5, ND6 and COX2 in cells lines carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The YARS2 p.191Gly>Val mutation worsened the respiratory phenotypes associated with m.11778G>A mutation, especially reducing activities of complexes I and IV. The respiratory deficiency altered the efficiency of mitochondrial ATP synthesis and increased the production of reactive oxygen species. Thus, mutated YARS2 aggravates mitochondrial dysfunctions associated with the m.11778G>A mutation, exceeding the threshold for the expression of blindness phenotype. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutation and mutated nuclear-modifier YARS2.

  3. Clock Genes Explain a Large Proportion of Phenotypic Variance in Systolic Blood Pressure and This Control Is Not Modified by Environmental Temperature.

    PubMed

    Dashti, Hassan S; Aslibekyan, Stella; Scheer, Frank A J L; Smith, Caren E; Lamon-Fava, Stefania; Jacques, Paul; Lai, Chao-Qiang; Tucker, Katherine L; Arnett, Donna K; Ordovás, José M

    2016-01-01

    Diurnal variation in blood pressure (BP) is regulated, in part, by an endogenous circadian clock; however, few human studies have identified associations between clock genes and BP. Accounting for environmental temperature may be necessary to correct for seasonal bias. We examined whether environmental temperature on the day of participants' assessment was associated with BP, using adjusted linear regression models in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) (n = 819) and the Boston Puerto Rican Health Study (BPRHS) (n = 1,248) cohorts. We estimated phenotypic variance in BP by 18 clock genes and examined individual single-nucleotide polymorphism (SNP) associations with BP using an additive genetic model, with further consideration of environmental temperature. In GOLDN, each additional 1 °C increase in environmental temperature was associated with 0.18 mm Hg lower systolic BP [SBP; β ± SE = -0.18 ± 0.05 mm Hg; P = 0.0001] and 0.10mm Hg lower diastolic BP [DBP; -0.10 ± 0.03 mm Hg; P = 0.001]. Similar results were seen in the BPRHS for SBP only. Clock genes explained a statistically significant proportion of the variance in SBP [V G/V P ± SE = 0.071 ± 0.03; P = 0.001] in GOLDN, but not in the BPRHS, and we did not observe associations between individual SNPs and BP. Environmental temperature did not influence the identified genetic associations. We identified clock genes that explained a statistically significant proportion of the phenotypic variance in SBP, supporting the importance of the circadian pathway underlying cardiac physiology. Although temperature was associated with BP, it did not affect results with genetic markers in either study. Therefore, it does not appear that temperature measures are necessary for interpreting associations between clock genes and BP. Trials related to this study were registered at clinicaltrials.gov as NCT00083369 (Genetic and Environmental Determinants of Triglycerides) and NCT01231958 (Boston Puerto

  4. Disabling of the erbB Pathway Followed by IFN-γ Modifies Phenotype and Enhances Genotoxic Eradication of Breast Tumors

    PubMed Central

    Nagai, Yasuhiro; Tsuchiya, Hiromichi; Runkle, E. Aaron; Young, Peter D.; Ji, Mei Q.; Norton, Larry; Drebin, Jeffrey A.; Zhang, Hongtao; Greene, Mark I.

    2015-01-01

    Summary Reversion of the malignant phenotype of erbB2-transformed cells can be driven by anti-erbB2/neu monoclonal antibodies (mAb), which disrupt the receptor's kinase activity. We examined the biologic effects of IFN-γ alone or after anti-erbB2/neu mAb treatment of erbB2-positive cells. IFN-γ had no effect on its own. Treatment of the tumors with anti-erbB2/neu mAb followed by IFN-γ led to dramatic inhibition of tumor growth in vitro and in vivo with minimal mAb dosing. Sequential therapy enhanced the effects of chemotherapy. Moreover, IFN-γ with mAb treatment of mice with IFNγR knock down tumors did not demonstrate marked synergistic eradication effects, indicating an unexpected role of IFN-γ on the tumor itself. Additionally, mAb and IFN-γ treatment also in duced immune host responses that enhanced tumor eradication. Biochemical analyses identified loss of Snail expression in tumor cells, reflecting diminution of tumor stem cell-like properties as a consequence of altered activity of GSK3-β and KLF molecules. PMID:26365188

  5. Molecular phenotyping of lignin-modified tobacco reveals associated changes in cell-wall metabolism, primary metabolism, stress metabolism and photorespiration.

    PubMed

    Dauwe, Rebecca; Morreel, Kris; Goeminne, Geert; Gielen, Birgit; Rohde, Antje; Van Beeumen, Jos; Ralph, John; Boudet, Alain-Michel; Kopka, Joachim; Rochange, Soizic F; Halpin, Claire; Messens, Eric; Boerjan, Wout

    2007-10-01

    Lignin is an important component of secondarily thickened cell walls. Cinnamoyl CoA reductase (CCR) and cinnamyl alcohol dehydrogenase (CAD) are two key enzymes that catalyse the penultimate and last steps in the biosynthesis of the monolignols. Downregulation of CCR in tobacco (Nicotiana tabacum) has been shown to reduce lignin content, whereas lignin in tobacco downregulated for CAD incorporates more aldehydes. We show that altering the expression of either or both genes in tobacco has far-reaching consequences on the transcriptome and metabolome. cDNA-amplified fragment length polymorphism-based transcript profiling, combined with HPLC and GC-MS-based metabolite profiling, revealed differential transcripts and metabolites within monolignol biosynthesis, as well as a substantial network of interactions between monolignol and other metabolic pathways. In general, in all transgenic lines, the phenylpropanoid biosynthetic pathway was downregulated, whereas starch mobilization was upregulated. CCR-downregulated lines were characterized by changes at the level of detoxification and carbohydrate metabolism, whereas the molecular phenotype of CAD-downregulated tobacco was enriched in transcript of light- and cell-wall-related genes. In addition, the transcript and metabolite data suggested photo-oxidative stress and increased photorespiration, mainly in the CCR-downregulated lines. These predicted effects on the photosynthetic apparatus were subsequently confirmed physiologically by fluorescence and gas-exchange measurements. Our data provide a molecular picture of a plant's response to altered monolignol biosynthesis.

  6. Hereditary hemochromatosis type 1 phenotype modifiers in Italian patients. The controversial role of variants in HAMP, BMP2, FTL and SLC40A1 genes.

    PubMed

    Radio, Francesca Clementina; Majore, Silvia; Aurizi, Caterina; Sorge, Fiammetta; Biolcati, Gianfranco; Bernabini, Sara; Giotti, Irene; Torricelli, Francesca; Giannarelli, Diana; De Bernardo, Carmelilia; Grammatico, Paola

    2015-06-01

    Hereditary hemochromatosis (HH) is a heterogeneous disorder of iron metabolism. The most common form of the disease is Classic or type 1 HH, mainly caused by a biallelic missense p.Cys282Tyr (c.845G>A) mutation in the HFE gene. However, the penetrance of p.Cys282Tyr/p.Cys282Tyr genotype is incomplete in terms of both biochemical and clinical expressivity. Lack of penetrance is thought to be caused by several genetic and environmental factors. Recently, a lot of evidences on HH genetic modifiers were produced, often without conclusive results. We investigated 6 polymorphisms (rs10421768 in HAMP gene, rs235756 in BMP2 gene, rs2230267 in FTL gene, rs1439816 in SLC40A1 gene, rs41295942 in TFR2 gene and rs2111833 in TMPRSS6 gene) with uncertain function in order to further evaluate their role in an independent cohort of 109 HH type 1 patients. Our results make it likely the role of rs10421768, rs235756, rs2230267 and rs1439816 polymorphisms, respectively in HAMP, BMP2, FTL and SLC40A1 genes in HH expressivity. In addition, previous and our findings support a hypothetical multifactorial model of HH, characterized by a principal gene (HFE in HH type 1) and minor genetic and environmental factors that still have to be fully elucidated.

  7. Lack of CCR5 modifies glial phenotypes and population of the nigral dopaminergic neurons, but not MPTP-induced dopaminergic neurodegeneration.

    PubMed

    Choi, Dong-Young; Lee, Myung Koo; Hong, Jin Tae

    2013-01-01

    Constitutive expression of C-C chemokine receptor (CCR) 5 has been detected in astrocytes, microglia and neurons, but its physiological roles in the central nervous system are obscure. The bidirectional interactions between neuron and glial cells through CCR5 and its ligands were thought to be crucial for maintaining normal neuronal activities. No study has described function of CCR5 in the dopaminergic neurodegeneration in Parkinson's disease. In order to examine effects of CCR5 on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration, we employed CCR5 wild type (WT) and knockout (KO) mice. Immunostainings for tyrosine hydroxylase (TH) exhibited that CCR5 KO mice had lower number of TH-positive neurons even in the absence of MPTP. Difference in MPTP (15mg/kg×4 times, 2hr interval)-mediated loss of TH-positive neurons was subtle between CCR5 WT and KO mice, but there was larger dopamine depletion, behavioral impairments and microglial activation in CCR5 deficient mice. Intriguingly, CCR5 KO brains contained higher immunoreactivity for monoamine oxidase (MAO) B which was mainly localized within astrocytes. In agreement with upregulation of MAO B, concentration of MPP+ was higher in the substantia nigra and striatum of CCR5 KO mice after MPTP injection. We found remarkable activation of p38 MAPK in CCR5 deficient mice, which positively regulates MAO B expression. These results indicate that CCR5 deficiency modifies the nigrostriatal dopaminergic neuronal system and bidirectional interaction between neurons and glial cells via CCR5 might be important for dopaminergic neuronal survival.

  8. Frequent phosphodiesterase 11A gene (PDE11A) defects in patients with Carney complex (CNC) caused by PRKAR1A mutations: PDE11A may contribute to adrenal and testicular tumors in CNC as a modifier of the phenotype.

    PubMed

    Libé, Rossella; Horvath, Anelia; Vezzosi, Delphine; Fratticci, Amato; Coste, Joel; Perlemoine, Karine; Ragazzon, Bruno; Guillaud-Bataille, Marine; Groussin, Lionel; Clauser, Eric; Raffin-Sanson, Marie-Laure; Siegel, Jennifer; Moran, Jason; Drori-Herishanu, Limor; Faucz, Fabio Rueda; Lodish, Maya; Nesterova, Maria; Bertagna, Xavier; Bertherat, Jerome; Stratakis, Constantine A

    2011-01-01

    Carney complex (CNC) is an autosomal dominant multiple neoplasia, caused mostly by inactivating mutations of the regulatory subunit 1A of the protein kinase A (PRKAR1A). Primary pigmented nodular adrenocortical disease (PPNAD) is the most frequent endocrine manifestation of CNC with a great inter-individual variability. Germline, protein-truncating mutations of phosphodiesterase type 11A (PDE11A) have been described to predispose to a variety of endocrine tumors, including adrenal and testicular tumors. Our objective was to investigate the role of PDE11A as a possible gene modifier of the phenotype in a series of 150 patients with CNC. A higher frequency of PDE11A variants in patients with CNC compared with healthy controls was found (25.3 vs. 6.8%, P < 0.0001). Among CNC patients, those with PPNAD were significantly more frequently carriers of PDE11A variants compared with patients without PPNAD (30.8 vs. 13%, P = 0.025). Furthermore, men with PPNAD were significantly more frequently carriers of PDE11A sequence variants (40.7%) than women with PPNAD (27.3%) (P < 0.001). A higher frequency of PDE11A sequence variants was also found in patients with large-cell calcifying Sertoli cell tumors (LCCSCT) compared with those without LCCSCT (50 vs. 10%, P = 0.0056). PDE11A variants were significantly associated with the copresence of PPNAD and LCCSCT in men: 81 vs. 20%, P < 0.004). The simultaneous inactivation of PRKAR1A and PDE11A by small inhibitory RNA led to an increase in cAMP-regulatory element-mediated transcriptional activity under basal conditions and after stimulation by forskolin. We demonstrate, in a large cohort of CNC patients, a high frequency of PDE11A variants, suggesting that PDE11A is a genetic modifying factor for the development of testicular and adrenal tumors in patients with germline PRKAR1A mutation.

  9. Mouse phenotyping.

    PubMed

    Fuchs, Helmut; Gailus-Durner, Valérie; Adler, Thure; Aguilar-Pimentel, Juan Antonio; Becker, Lore; Calzada-Wack, Julia; Da Silva-Buttkus, Patricia; Neff, Frauke; Götz, Alexander; Hans, Wolfgang; Hölter, Sabine M; Horsch, Marion; Kastenmüller, Gabi; Kemter, Elisabeth; Lengger, Christoph; Maier, Holger; Matloka, Mikolaj; Möller, Gabriele; Naton, Beatrix; Prehn, Cornelia; Puk, Oliver; Rácz, Ildikó; Rathkolb, Birgit; Römisch-Margl, Werner; Rozman, Jan; Wang-Sattler, Rui; Schrewe, Anja; Stöger, Claudia; Tost, Monica; Adamski, Jerzy; Aigner, Bernhard; Beckers, Johannes; Behrendt, Heidrun; Busch, Dirk H; Esposito, Irene; Graw, Jochen; Illig, Thomas; Ivandic, Boris; Klingenspor, Martin; Klopstock, Thomas; Kremmer, Elisabeth; Mempel, Martin; Neschen, Susanne; Ollert, Markus; Schulz, Holger; Suhre, Karsten; Wolf, Eckhard; Wurst, Wolfgang; Zimmer, Andreas; Hrabě de Angelis, Martin

    2011-02-01

    Model organisms like the mouse are important tools to learn more about gene function in man. Within the last 20 years many mutant mouse lines have been generated by different methods such as ENU mutagenesis, constitutive and conditional knock-out approaches, knock-down, introduction of human genes, and knock-in techniques, thus creating models which mimic human conditions. Due to pleiotropic effects, one gene may have different functions in different organ systems or time points during development. Therefore mutant mouse lines have to be phenotyped comprehensively in a highly standardized manner to enable the detection of phenotypes which might otherwise remain hidden. The German Mouse Clinic (GMC) has been established at the Helmholtz Zentrum München as a phenotyping platform with open access to the scientific community (www.mousclinic.de; [1]). The GMC is a member of the EUMODIC consortium which created the European standard workflow EMPReSSslim for the systemic phenotyping of mouse models (http://www.eumodic.org/[2]). Copyright © 2010 Elsevier Inc. All rights reserved.

  10. Mitochondrial COX2 G7598A mutation may have a modifying role in the phenotypic manifestation of aminoglycoside antibiotic-induced deafness associated with 12S rRNA A1555G mutation in a Han Chinese pedigree.

    PubMed

    Chen, Tianbin; Liu, Qicai; Jiang, Ling; Liu, Can; Ou, Qishui

    2013-02-01

    Recent studies suggest that certain mitochondrial haplogroup markers and some specific variants in mitochondrial haplogroup may also influence the phenotypic expression of particular mitochondrial disorders. In this report, the clinical, genetic, and molecular characterization were identified in a Chinese pedigree with the aminoglycoside antibiotic (AmAn)-induced deafness and nonsyndromic hearing loss (NSHL). The pathogenic gene responsible for this hereditary NSHL pedigree was determined by Microarray chip, which possessed the nine NSHL hot-spot mutations, including GJB2 (35delG, 176dell6bp, 235de1C, and 299delAT), GJB3 (538C>T), SLC26A4 (IVS7-2A>G and 2168A>G), and mitochondrial DNA (mtDNA) 12S rRNA (C1494T and A1555G). Only the homoplasmic A1555G mutation was detected, which was confirmed by direct sequencing. Also, real-time amplification refractory mutation system quantitative polymerase chain reaction methodology was performed to calculate the A1555G mutation load. The proband's complete mtDNA genome were amplified and direct sequencing was performed to determine the mitochondrial haplogroup and private mutations. The proband's mitochondrial haplogroup belonges to M7b1 and a private mutation MTCOX2 G7598A (p.Ala 5 Thr) is found. Phylogenetic analysis of COX2 polypeptide sequences demonstrates that the alanine residue is relatively conserved, but owing to the missense mutation (p.Ala 5 Thr), its side chain hydrophobicity will be changed, and what is more, as it is adjacent to a glutamine residue, which is highly conserved and hydrophilic, in an evolutionary stable domain; G7598A (p.Ala 5 Thr) may alter the protein secondary structure and physiological function of COX2 and, thus, aggravate the mitochondrial dysfunction conferred by the A1555G mutation. Furthermore, the G7598A mutation is absent in 100 unrelated healthy controls; therefore, G7598A (p.Ala 5 Thr) in the mitochondrial haplogoup M7b1 may have a modifying role, enhancing its penetrance and severity

  11. Dynamic Changes in the Intracellular Association of Selected Rab Small GTPases with MHC Class II and DM during Dendritic Cell Maturation.

    PubMed

    Pérez-Montesinos, Gibrán; López-Ortega, Orestes; Piedra-Reyes, Jessica; Bonifaz, Laura C; Moreno, José

    2017-01-01

    Antigen processing for presentation by major histocompatibility complex class II (MHCII) molecules requires the latter to travel through the endocytic pathway together with its chaperons: the invariant chain (Ii) and DM. Nevertheless, the nature of the compartments where MHCII molecules travel to acquire peptides lacks definition regarding molecules involved in intracellular vesicular trafficking, such as Rab small GTPases. We aimed to define which Rab proteins are present during the intracellular transport of MHCII, DM, and Ii through the endocytic pathway on their route to the cell surface during dendritic cell (DC) maturation. We examined, by means of three-color confocal microscopy, the association of MHCII, DM, and Ii with Rab5, Rab7, Rab9, and Rab11 during the maturation of bone marrow-derived or spleen DC in response to LPS as an inflammatory stimulus. Prior to the stage of immature DC, MHCII migrated from diffuse small cytoplasmic vesicles, predominantly Rab5+Rab7- and Rab5+Rab7+ into a pericentriolar Rab5+Rab7+Rab9+ cluster, with Rab11+ areas. As DC reached the mature phenotype, MHCII left the pericentriolar endocytic compartments toward the cell surface in Rab11+ and Rab9+Rab11+ vesicles. The invariant chain and MHCII transport pathways were not identical. DM and MHCII appeared to arrive to pericentriolar endocytic compartments of immature DC through partially different routes. The association of MHCII molecules with distinct Rab GTPases during DC maturation suggests that after leaving the biosynthetic pathway, MHCII sequentially traffic from typical early endosomes to multivesicular late endosomes to finally arrive at the cell surface in Rab11+ recycling-type endosomes. In immature DCs, DM encounters transiently MHCII in the Rab5+Rab7+Rab9+ compartments, to remain there in mature DC.

  12. Dynamic Changes in the Intracellular Association of Selected Rab Small GTPases with MHC Class II and DM during Dendritic Cell Maturation

    PubMed Central

    Pérez-Montesinos, Gibrán; López-Ortega, Orestes; Piedra-Reyes, Jessica; Bonifaz, Laura C.; Moreno, José

    2017-01-01

    Antigen processing for presentation by major histocompatibility complex class II (MHCII) molecules requires the latter to travel through the endocytic pathway together with its chaperons: the invariant chain (Ii) and DM. Nevertheless, the nature of the compartments where MHCII molecules travel to acquire peptides lacks definition regarding molecules involved in intracellular vesicular trafficking, such as Rab small GTPases. We aimed to define which Rab proteins are present during the intracellular transport of MHCII, DM, and Ii through the endocytic pathway on their route to the cell surface during dendritic cell (DC) maturation. We examined, by means of three-color confocal microscopy, the association of MHCII, DM, and Ii with Rab5, Rab7, Rab9, and Rab11 during the maturation of bone marrow-derived or spleen DC in response to LPS as an inflammatory stimulus. Prior to the stage of immature DC, MHCII migrated from diffuse small cytoplasmic vesicles, predominantly Rab5+Rab7− and Rab5+Rab7+ into a pericentriolar Rab5+Rab7+Rab9+ cluster, with Rab11+ areas. As DC reached the mature phenotype, MHCII left the pericentriolar endocytic compartments toward the cell surface in Rab11+ and Rab9+Rab11+ vesicles. The invariant chain and MHCII transport pathways were not identical. DM and MHCII appeared to arrive to pericentriolar endocytic compartments of immature DC through partially different routes. The association of MHCII molecules with distinct Rab GTPases during DC maturation suggests that after leaving the biosynthetic pathway, MHCII sequentially traffic from typical early endosomes to multivesicular late endosomes to finally arrive at the cell surface in Rab11+ recycling-type endosomes. In immature DCs, DM encounters transiently MHCII in the Rab5+Rab7+Rab9+ compartments, to remain there in mature DC. PMID:28396666

  13. Large phenotype jumps in biomolecular evolution

    NASA Astrophysics Data System (ADS)

    Bardou, F.; Jaeger, L.

    2004-03-01

    By defining the phenotype of a biopolymer by its active three-dimensional shape, and its genotype by its primary sequence, we propose a model that predicts and characterizes the statistical distribution of a population of biopolymers with a specific phenotype that originated from a given genotypic sequence by a single mutational event. Depending on the ratio g0 that characterizes the spread of potential energies of the mutated population with respect to temperature, three different statistical regimes have been identified. We suggest that biopolymers found in nature are in a critical regime with g0≃1 6, corresponding to a broad, but not too broad, phenotypic distribution resembling a truncated Lévy flight. Thus the biopolymer phenotype can be considerably modified in just a few mutations. The proposed model is in good agreement with the experimental distribution of activities determined for a population of single mutants of a group-I ribozyme.

  14. Modified cyanobacteria

    DOEpatents

    Vermaas, Willem F J.

    2014-06-17

    Disclosed is a modified photoautotrophic bacterium comprising genes of interest that are modified in terms of their expression and/or coding region sequence, wherein modification of the genes of interest increases production of a desired product in the bacterium relative to the amount of the desired product production in a photoautotrophic bacterium that is not modified with respect to the genes of interest.

  15. Histopathology reveals correlative and unique phenotypes in a high-throughput mouse phenotyping screen.

    PubMed

    Adissu, Hibret A; Estabel, Jeanne; Sunter, David; Tuck, Elizabeth; Hooks, Yvette; Carragher, Damian M; Clarke, Kay; Karp, Natasha A; Newbigging, Susan; Jones, Nora; Morikawa, Lily; White, Jacqueline K; McKerlie, Colin

    2014-05-01

    The Mouse Genetics Project (MGP) at the Wellcome Trust Sanger Institute aims to generate and phenotype over 800 genetically modified mouse lines over the next 5 years to gain a better understanding of mammalian gene function and provide an invaluable resource to the scientific community for follow-up studies. Phenotyping includes the generation of a standardized biobank of paraffin-embedded tissues for each mouse line, but histopathology is not routinely performed. In collaboration with the Pathology Core of the Centre for Modeling Human Disease (CMHD) we report the utility of histopathology in a high-throughput primary phenotyping screen. Histopathology was assessed in an unbiased selection of 50 mouse lines with (n=30) or without (n=20) clinical phenotypes detected by the standard MGP primary phenotyping screen. Our findings revealed that histopathology added correlating morphological data in 19 of 30 lines (63.3%) in which the primary screen detected a phenotype. In addition, seven of the 50 lines (14%) presented significant histopathology findings that were not associated with or predicted by the standard primary screen. Three of these seven lines had no clinical phenotype detected by the standard primary screen. Incidental and strain-associated background lesions were present in all mutant lines with good concordance to wild-type controls. These findings demonstrate the complementary and unique contribution of histopathology to high-throughput primary phenotyping of mutant mice.

  16. Histopathology reveals correlative and unique phenotypes in a high-throughput mouse phenotyping screen

    PubMed Central

    Adissu, Hibret A.; Estabel, Jeanne; Sunter, David; Tuck, Elizabeth; Hooks, Yvette; Carragher, Damian M.; Clarke, Kay; Karp, Natasha A.; Project, Sanger Mouse Genetics; Newbigging, Susan; Jones, Nora; Morikawa, Lily; White, Jacqueline K.; McKerlie, Colin

    2014-01-01

    The Mouse Genetics Project (MGP) at the Wellcome Trust Sanger Institute aims to generate and phenotype over 800 genetically modified mouse lines over the next 5 years to gain a better understanding of mammalian gene function and provide an invaluable resource to the scientific community for follow-up studies. Phenotyping includes the generation of a standardized biobank of paraffin-embedded tissues for each mouse line, but histopathology is not routinely performed. In collaboration with the Pathology Core of the Centre for Modeling Human Disease (CMHD) we report the utility of histopathology in a high-throughput primary phenotyping screen. Histopathology was assessed in an unbiased selection of 50 mouse lines with (n=30) or without (n=20) clinical phenotypes detected by the standard MGP primary phenotyping screen. Our findings revealed that histopathology added correlating morphological data in 19 of 30 lines (63.3%) in which the primary screen detected a phenotype. In addition, seven of the 50 lines (14%) presented significant histopathology findings that were not associated with or predicted by the standard primary screen. Three of these seven lines had no clinical phenotype detected by the standard primary screen. Incidental and strain-associated background lesions were present in all mutant lines with good concordance to wild-type controls. These findings demonstrate the complementary and unique contribution of histopathology to high-throughput primary phenotyping of mutant mice. PMID:24652767

  17. Para Bombay phenotype--a case report.

    PubMed

    Mathai, J; Sulochana, P V; Sathyabhama, S

    1997-10-01

    Bombay phenotype is peculiar in that red cells are not agglutinated by antisera A, B or H; while serum contains anti A, B and H. Existence of modifying genes at independent loci with variable expression of ABO genes is postulated. We report here a case of partial suppression where antigens could be detected by elution tests and unlike classical Bombay type, normal amount of appropriate blood group substances were present in saliva. This case of para Bombay phenotype was detected as a result of discrepancy in cell and serum group ng. This highlights the importance of both forward and reverse grouping in ABO testing.

  18. In-silico identification of phenotype-biased functional modules

    PubMed Central

    2012-01-01

    Background Phenotypes exhibited by microorganisms can be useful for several purposes, e.g., ethanol as an alternate fuel. Sometimes, the target phenotype maybe required in combination with other phenotypes, in order to be useful, for e.g., an industrial process may require that the organism survive in an anaerobic, alcohol rich environment and be able to feed on both hexose and pentose sugars to produce ethanol. This combination of traits may not be available in any existing organism or if they do exist, the mechanisms involved in the phenotype-expression may not be efficient enough to be useful. Thus, it may be required to genetically modify microorganisms. However, before any genetic modification can take place, it is important to identify the underlying cellular subsystems responsible for the expression of the target phenotype. Results In this paper, we develop a method to identify statistically significant and phenotypically-biased functional modules. The method can compare the organismal network information from hundreds of phenotype expressing and phenotype non-expressing organisms to identify cellular subsystems that are more prone to occur in phenotype-expressing organisms than in phenotype non-expressing organisms. We have provided literature evidence that the phenotype-biased modules identified for phenotypes such as hydrogen production (dark and light fermentation), respiration, gram-positive, gram-negative and motility, are indeed phenotype-related. Conclusion Thus we have proposed a methodology to identify phenotype-biased cellular subsystems. We have shown the effectiveness of our methodology by applying it to several target phenotypes. The code and all supplemental files can be downloaded from (http://freescience.org/cs/phenotype-biased-biclusters/). PMID:22759578

  19. Respiratory Syncytial Virus Modified by Deletions of the NS2 Gene and Amino Acid S1313 of the L Polymerase Protein Is a Temperature-Sensitive, Live-Attenuated Vaccine Candidate That Is Phenotypically Stable at Physiological Temperature

    PubMed Central

    Luongo, Cindy; Winter, Christine C.; Collins, Peter L.

    2013-01-01

    Human respiratory syncytial virus (RSV) is the leading viral cause of lower respiratory tract disease in infants and children worldwide. In previous work to develop point mutations in RSV with improved genetic stability, we observed that an attenuating mutation at amino acid position 1321 in the L polymerase protein was subject to deattenuation by a spontaneous second-site compensatory mutation at position 1313 (C. Luongo, C. C. Winter, P. L. Collins, and U. J. Buchholz, J. Virol. 86:10792–10804, 2012). In the present study, we found that deletion of position 1313 (Δ1313), irrespective of the presence of an attenuating mutation at position 1321, provided a new attenuating mutation. RSV bearing Δ1313 replicated in cell culture as efficiently as wild-type virus at 32°C, was restricted for replication at 37°C, and was restricted 50-fold and 150-fold in the upper and lower respiratory tracts, respectively, of mice. We combined the Δ1313 deletion with the previously described, attenuating NS2 gene deletion (ΔNS2) to produce the recombinant live-attenuated RSV vaccine candidate ΔNS2/Δ1313. During in vitro stress tests involving serial passage at incrementally increasing temperatures, a second-site compensatory mutation was detected in close proximity of Δ1313, namely, I1314T. This site was genetically and phenotypically stabilized by an I1314L substitution. Combination of I1314L with ΔNS2/Δ1313 yielded a virus, ΔNS2/Δ1313/1314L, with genetic stability at physiological temperature. This stabilized vaccine candidate was moderately temperature sensitive and had a level of restriction in chimpanzees comparable to that of MEDI-559, a promising RSV vaccine candidate that presently is in clinical trials but lacks stabilized attenuating mutations. The level of attenuation and genetic stability identify ΔNS2/Δ1313/1314L as a promising candidate for evaluation in pediatric phase I studies. PMID:23236065

  20. Phenotype definition in epilepsy.

    PubMed

    Winawer, Melodie R

    2006-05-01

    Phenotype definition consists of the use of epidemiologic, biological, molecular, or computational methods to systematically select features of a disorder that might result from distinct genetic influences. By carefully defining the target phenotype, or dividing the sample by phenotypic characteristics, we can hope to narrow the range of genes that influence risk for the trait in the study population, thereby increasing the likelihood of finding them. In this article, fundamental issues that arise in phenotyping in epilepsy and other disorders are reviewed, and factors complicating genotype-phenotype correlation are discussed. Methods of data collection, analysis, and interpretation are addressed, focusing on epidemiologic studies. With this foundation in place, the epilepsy subtypes and clinical features that appear to have a genetic basis are described, and the epidemiologic studies that have provided evidence for the heritability of these phenotypic characteristics, supporting their use in future genetic investigations, are reviewed. Finally, several molecular approaches to phenotype definition are discussed, in which the molecular defect, rather than the clinical phenotype, is used as a starting point.

  1. Phenotypic switching in bacteria

    NASA Astrophysics Data System (ADS)

    Merrin, Jack

    Living matter is a non-equilibrium system in which many components work in parallel to perpetuate themselves through a fluctuating environment. Physiological states or functionalities revealed by a particular environment are called phenotypes. Transitions between phenotypes may occur either spontaneously or via interaction with the environment. Even in the same environment, genetically identical bacteria can exhibit different phenotypes of a continuous or discrete nature. In this thesis, we pursued three lines of investigation into discrete phenotypic heterogeneity in bacterial populations: the quantitative characterization of the so-called bacterial persistence, a theoretical model of phenotypic switching based on those measurements, and the design of artificial genetic networks which implement this model. Persistence is the phenotype of a subpopulation of bacteria with a reduced sensitivity to antibiotics. We developed a microfluidic apparatus, which allowed us to monitor the growth rates of individual cells while applying repeated cycles of antibiotic treatments. We were able to identify distinct phenotypes (normal and persistent) and characterize the stochastic transitions between them. We also found that phenotypic heterogeneity was present prior to any environmental cue such as antibiotic exposure. Motivated by the experiments with persisters, we formulated a theoretical model describing the dynamic behavior of several discrete phenotypes in a periodically varying environment. This theoretical framework allowed us to quantitatively predict the fitness of dynamic populations and to compare survival strategies according to environmental time-symmetries. These calculations suggested that persistence is a strategy used by bacterial populations to adapt to fluctuating environments. Knowledge of the phenotypic transition rates for persistence may provide statistical information about the typical environments of bacteria. We also describe a design of artificial

  2. Phenotypic approaches to drought in cassava: review.

    PubMed

    Okogbenin, Emmanuel; Setter, Tim L; Ferguson, Morag; Mutegi, Rose; Ceballos, Hernan; Olasanmi, Bunmi; Fregene, Martin

    2013-01-01

    Cassava is an important crop in Africa, Asia, Latin America, and the Caribbean. Cassava can be produced adequately in drought conditions making it the ideal food security crop in marginal environments. Although cassava can tolerate drought stress, it can be genetically improved to enhance productivity in such environments. Drought adaptation studies in over three decades in cassava have identified relevant mechanisms which have been explored in conventional breeding. Drought is a quantitative trait and its multigenic nature makes it very challenging to effectively manipulate and combine genes in breeding for rapid genetic gain and selection process. Cassava has a long growth cycle of 12-18 months which invariably contributes to a long breeding scheme for the crop. Modern breeding using advances in genomics and improved genotyping, is facilitating the dissection and genetic analysis of complex traits including drought tolerance, thus helping to better elucidate and understand the genetic basis of such traits. A beneficial goal of new innovative breeding strategies is to shorten the breeding cycle using minimized, efficient or fast phenotyping protocols. While high throughput genotyping have been achieved, this is rarely the case for phenotyping for drought adaptation. Some of the storage root phenotyping in cassava are often done very late in the evaluation cycle making selection process very slow. This paper highlights some modified traits suitable for early-growth phase phenotyping that may be used to reduce drought phenotyping cycle in cassava. Such modified traits can significantly complement the high throughput genotyping procedures to fast track breeding of improved drought tolerant varieties. The need for metabolite profiling, improved phenomics to take advantage of next generation sequencing technologies and high throughput phenotyping are basic steps for future direction to improve genetic gain and maximize speed for drought tolerance breeding.

  3. Phenotypic approaches to drought in cassava: review

    PubMed Central

    Okogbenin, Emmanuel; Setter, Tim L.; Ferguson, Morag; Mutegi, Rose; Ceballos, Hernan; Olasanmi, Bunmi; Fregene, Martin

    2012-01-01

    Cassava is an important crop in Africa, Asia, Latin America, and the Caribbean. Cassava can be produced adequately in drought conditions making it the ideal food security crop in marginal environments. Although cassava can tolerate drought stress, it can be genetically improved to enhance productivity in such environments. Drought adaptation studies in over three decades in cassava have identified relevant mechanisms which have been explored in conventional breeding. Drought is a quantitative trait and its multigenic nature makes it very challenging to effectively manipulate and combine genes in breeding for rapid genetic gain and selection process. Cassava has a long growth cycle of 12–18 months which invariably contributes to a long breeding scheme for the crop. Modern breeding using advances in genomics and improved genotyping, is facilitating the dissection and genetic analysis of complex traits including drought tolerance, thus helping to better elucidate and understand the genetic basis of such traits. A beneficial goal of new innovative breeding strategies is to shorten the breeding cycle using minimized, efficient or fast phenotyping protocols. While high throughput genotyping have been achieved, this is rarely the case for phenotyping for drought adaptation. Some of the storage root phenotyping in cassava are often done very late in the evaluation cycle making selection process very slow. This paper highlights some modified traits suitable for early-growth phase phenotyping that may be used to reduce drought phenotyping cycle in cassava. Such modified traits can significantly complement the high throughput genotyping procedures to fast track breeding of improved drought tolerant varieties. The need for metabolite profiling, improved phenomics to take advantage of next generation sequencing technologies and high throughput phenotyping are basic steps for future direction to improve genetic gain and maximize speed for drought tolerance breeding. PMID

  4. Macrophage phenotypes in atherosclerosis.

    PubMed

    Colin, Sophie; Chinetti-Gbaguidi, Giulia; Staels, Bart

    2014-11-01

    Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the development and progression of atherosclerosis, macrophages are fundamental contributors. For nearly a decade, the phenotypic heterogeneity and plasticity of macrophages has been studied. In atherosclerotic lesions, macrophages are submitted to a large variety of micro-environmental signals, such as oxidized lipids and cytokines, which influence the phenotypic polarization and activation of macrophages resulting in a dynamic plasticity. The macrophage phenotype spectrum is characterized, at the extremes, by the classical M1 macrophages induced by T-helper 1 (Th-1) cytokines and by the alternative M2 macrophages induced by Th-2 cytokines. M2 macrophages can be further classified into M2a, M2b, M2c, and M2d subtypes. More recently, additional plaque-specific macrophage phenotypes have been identified, termed as Mox, Mhem, and M4. Understanding the mechanisms and functional consequences of the phenotypic heterogeneity of macrophages will contribute to determine their potential role in lesion development and plaque stability. Furthermore, research on macrophage plasticity could lead to novel therapeutic approaches to counteract cardiovascular diseases such as atherosclerosis. The present review summarizes our current knowledge on macrophage subsets in atherosclerotic plaques and mechanism behind the modulation of the macrophage phenotype.

  5. Biolog phenotype microarrays.

    PubMed

    Shea, April; Wolcott, Mark; Daefler, Simon; Rozak, David A

    2012-01-01

    Phenotype microarrays nicely complement traditional genomic, transcriptomic, and proteomic analysis by offering opportunities for researchers to ground microbial systems analysis and modeling in a broad yet quantitative assessment of the organism's physiological response to different metabolites and environments. Biolog phenotype assays achieve this by coupling tetrazolium dyes with minimally defined nutrients to measure the impact of hundreds of carbon, nitrogen, phosphorous, and sulfur sources on redox reactions that result from compound-induced effects on the electron transport chain. Over the years, we have used Biolog's reproducible and highly sensitive assays to distinguish closely related bacterial isolates, to understand their metabolic differences, and to model their metabolic behavior using flux balance analysis. This chapter describes Biolog phenotype microarray system components, reagents, and methods, particularly as they apply to bacterial identification, characterization, and metabolic analysis.

  6. Modified SEAGULL

    NASA Technical Reports Server (NTRS)

    Salas, M. D.; Kuehn, M. S.

    1994-01-01

    Original version of program incorporated into program SRGULL (LEW-15093) for use on National Aero-Space Plane project, its duty being to model forebody, inlet, and nozzle portions of vehicle. However, real-gas chemistry effects in hypersonic flow fields limited accuracy of that version, because it assumed perfect-gas properties. As a result, SEAGULL modified according to real-gas equilibrium-chemistry methodology. This program analyzes two-dimensional, hypersonic flows of real gases. Modified version of SEAGULL maintains as much of original program as possible, and retains ability to execute original perfect-gas version.

  7. Down Syndrome: Cognitive Phenotype

    ERIC Educational Resources Information Center

    Silverman, Wayne

    2007-01-01

    Down syndrome is the most prevalent cause of intellectual impairment associated with a genetic anomaly, in this case, trisomy of chromosome 21. It affects both physical and cognitive development and produces a characteristic phenotype, although affected individuals vary considerably with respect to severity of specific impairments. Studies…

  8. Down Syndrome: Cognitive Phenotype

    ERIC Educational Resources Information Center

    Silverman, Wayne

    2007-01-01

    Down syndrome is the most prevalent cause of intellectual impairment associated with a genetic anomaly, in this case, trisomy of chromosome 21. It affects both physical and cognitive development and produces a characteristic phenotype, although affected individuals vary considerably with respect to severity of specific impairments. Studies…

  9. Genetic Modifiers of Sickle Cell Disease

    PubMed Central

    Steinberg, Martin H.; Sebastiani, Paola

    2015-01-01

    Sickle cell anemia is associated with unusual clinical heterogeneity for a Mendelian disorder. Fetal hemoglobin concentration and coincident ∝ thalassemia, both which directly affect the sickle erythrocyte, are the major modulators of the phenotype of disease. Understanding the genetics underlying the heritable subphenotypes of sickle cell anemia would be prognostically useful, could inform personalized therapeutics, and might help the discovery of new “druggable” pathophysiologic targets. Genotype-phenotype association studies have been used to identify novel genetic modifiers. In the future, whole genome sequencing with its promise of discovering hitherto unsuspected variants could add to our understanding of the genetic modifiers of this disease. PMID:22641398

  10. Modifiability Tactics

    DTIC Science & Technology

    2007-09-01

    about purchasing paper copies of SEI reports, please visit the publications portion of our Web site (http://www.sei.cmu.edu/ publications /pubweb.html...architects need to understand how architectural tactics and patterns relate and how to use them effectively. In this report, we explore the relation ...architecture transformations that support the achievement of modifiability [Bass 2003]. In this report, we relate coupling and cohesion to tactics

  11. Glyoxalase I drives epithelial-to-mesenchymal transition via argpyrimidine-modified Hsp70, miR-21 and SMAD signalling in human bronchial cells BEAS-2B chronically exposed to crystalline silica Min-U-Sil 5: Transformation into a neoplastic-like phenotype.

    PubMed

    Antognelli, Cinzia; Gambelunghe, Angela; Muzi, Giacomo; Talesa, Vincenzo Nicola

    2016-03-01

    Glyoxalase I (Glo1) is the main scavenging enzyme of methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs). AGEs are known to control multiple biological processes, including epithelial to mesenchymal transition (EMT), a multistep phenomenon associated with cell transformation, playing a major role in a variety of diseases, including cancer. Crystalline silica is a well-known occupational health hazard, responsible for a great number of human pulmonary diseases, such as silicosis. There is still much debate concerning the carcinogenic role of crystalline silica, mainly due to the lack of a causal demonstration between silica exposure and carcinogenesis. It has been suggested that EMT might play a role in crystalline silica-induced lung neoplastic transformation. The aim of this study was to investigate whether, and by means of which mechanism, the antiglycation defence Glo1 is involved in Min-U-Sil 5 (MS5) crystalline silica-induced EMT in BEAS-2B human bronchial epithelial cells chronically exposed, and whether this is associated with the beginning of a neoplastic-like transformation process. By using gene silencing/overexpression and scavenging/inhibitory agents, we demonstrated that MS5 induced hydrogen peroxide-mediated c-Jun-dependent Glo1 up-regulation which resulted in a decrease in the Argpyrimidine-modified Hsp70 protein level which triggered EMT in a novel mechanism involving miR-21 and SMAD signalling. The observed EMT was associated with a neoplastic-like phenotype. The results obtained provide a causal in vitro demonstration of the MS5 pro-carcinogenic transforming role and more importantly they provide new insights into the mechanisms involved in this process, thus opening new paths in research concerning the in vivo study of the carcinogenic potential of crystalline silica.

  12. Optimization and phenotype allocation.

    PubMed

    Jost, Jürgen; Wang, Ying

    2014-01-01

    We study the phenotype allocation problem for the stochastic evolution of a multitype population in a random environment. Our underlying model is a multitype Galton–Watson branching process in a random environment. In the multitype branching model, different types denote different phenotypes of offspring, and offspring distributions denote the allocation strategies. Two possible optimization targets are considered: the long-term growth rate of the population conditioned on nonextinction, and the extinction probability of the lineage. In a simple and biologically motivated case, we derive an explicit formula for the long-term growth rate using the random Perron–Frobenius theorem, and we give an approximation to the extinction probability by a method similar to that developed by Wilkinson. Then we obtain the optimal strategies that maximize the long-term growth rate or minimize the approximate extinction probability, respectively, in a numerical example. It turns out that different optimality criteria can lead to different strategies.

  13. Single cell dynamic phenotyping

    PubMed Central

    Patsch, Katherin; Chiu, Chi-Li; Engeln, Mark; Agus, David B.; Mallick, Parag; Mumenthaler, Shannon M.; Ruderman, Daniel

    2016-01-01

    Live cell imaging has improved our ability to measure phenotypic heterogeneity. However, bottlenecks in imaging and image processing often make it difficult to differentiate interesting biological behavior from technical artifact. Thus there is a need for new methods that improve data quality without sacrificing throughput. Here we present a 3-step workflow to improve dynamic phenotype measurements of heterogeneous cell populations. We provide guidelines for image acquisition, phenotype tracking, and data filtering to remove erroneous cell tracks using the novel Tracking Aberration Measure (TrAM). Our workflow is broadly applicable across imaging platforms and analysis software. By applying this workflow to cancer cell assays, we reduced aberrant cell track prevalence from 17% to 2%. The cost of this improvement was removing 15% of the well-tracked cells. This enabled detection of significant motility differences between cell lines. Similarly, we avoided detecting a false change in translocation kinetics by eliminating the true cause: varied proportions of unresponsive cells. Finally, by systematically seeking heterogeneous behaviors, we detected subpopulations that otherwise could have been missed, including early apoptotic events and pre-mitotic cells. We provide optimized protocols for specific applications and step-by-step guidelines for adapting them to a variety of biological systems. PMID:27708391

  14. [Phenotype specific therapy of COPD].

    PubMed

    Rothe, Thomas

    2014-12-10

    COPD is not a homogenous disease but consists of at least four different phenotypes: Emphysema, COPD with chronic bronchitis, asthma-COPD overlap syndrome (ACOS), and COPD with recurrent exacerbations. With differentiation, treatment can be designed phenotype-specific. Some modern drugs are not indicated in all phenotypes.

  15. Cardiac sodium channel mutations: why so many phenotypes?

    PubMed Central

    Liu, Man; Yang, Kai-Chien; Dudley, Samuel C.

    2016-01-01

    Mutations of the cardiac sodium channel (Nav1.5) can induce gain or loss of channel function. Gain-of-function mutations can cause long QT syndrome type 3 and possibly atrial fibrillation, whereas loss-of-function mutations are associated with a variety of phenotypes, such as Brugada syndrome, cardiac conduction disease, sick sinus syndrome, and possibly dilated cardiomyopathy. The phenotypes produced by Nav1.5 mutations vary according to the direct effect of the mutation on channel biophysics, but also with age, sex, body temperature, and between regions of the heart. This phenotypic variability makes genotype–phenotype correlations difficult. In this Perspectives article, we propose that phenotypic variability not ascribed to mutation-dependent changes in channel function might be the result of additional modifiers of channel behaviour, such as other genetic variation and alterations in transcription, RNA processing, translation, post-translational modifications, and protein degradation. Consideration of these modifiers might help to improve genotype–phenotype correlations and lead to new therapeutic strategies. PMID:24958080

  16. `Weak A' phenotypes

    PubMed Central

    Cartron, J. P.; Gerbal, A.; Hughes-Jones, N. C.; Salmon, C.

    1974-01-01

    Thirty-five weak A samples including fourteen A3, eight Ax, seven Aend, three Am and three Ae1 were studied in order to determine their A antigen site density, using an IgG anti-A labelled with 125I. The values obtained ranged between 30,000 A antigen sites for A3 individuals, and 700 sites for the Ae1 red cells. The hierarchy of values observed made it possible to establish a quantitative relationship between the red cell agglutinability of these phenotypes measured under standard conditions, and their antigen site density. PMID:4435836

  17. The cellular microscopy phenotype ontology.

    PubMed

    Jupp, Simon; Malone, James; Burdett, Tony; Heriche, Jean-Karim; Williams, Eleanor; Ellenberg, Jan; Parkinson, Helen; Rustici, Gabriella

    2016-01-01

    Phenotypic data derived from high content screening is currently annotated using free-text, thus preventing the integration of independent datasets, including those generated in different biological domains, such as cell lines, mouse and human tissues. We present the Cellular Microscopy Phenotype Ontology (CMPO), a species neutral ontology for describing phenotypic observations relating to the whole cell, cellular components, cellular processes and cell populations. CMPO is compatible with related ontology efforts, allowing for future cross-species integration of phenotypic data. CMPO was developed following a curator-driven approach where phenotype data were annotated by expert biologists following the Entity-Quality (EQ) pattern. These EQs were subsequently transformed into new CMPO terms following an established post composition process. CMPO is currently being utilized to annotate phenotypes associated with high content screening datasets stored in several image repositories including the Image Data Repository (IDR), MitoSys project database and the Cellular Phenotype Database to facilitate data browsing and discoverability.

  18. Bioimaging for quantitative phenotype analysis.

    PubMed

    Chen, Weiyang; Xia, Xian; Huang, Yi; Chen, Xingwei; Han, Jing-Dong J

    2016-06-01

    With the development of bio-imaging techniques, an increasing number of studies apply these techniques to generate a myriad of image data. Its applications range from quantification of cellular, tissue, organismal and behavioral phenotypes of model organisms, to human facial phenotypes. The bio-imaging approaches to automatically detect, quantify, and profile phenotypic changes related to specific biological questions open new doors to studying phenotype-genotype associations and to precisely evaluating molecular changes associated with quantitative phenotypes. Here, we review major applications of bioimage-based quantitative phenotype analysis. Specifically, we describe the biological questions and experimental needs addressable by these analyses, computational techniques and tools that are available in these contexts, and the new perspectives on phenotype-genotype association uncovered by such analyses.

  19. Quantification of Microbial Phenotypes

    PubMed Central

    Martínez, Verónica S.; Krömer, Jens O.

    2016-01-01

    Metabolite profiling technologies have improved to generate close to quantitative metabolomics data, which can be employed to quantitatively describe the metabolic phenotype of an organism. Here, we review the current technologies available for quantitative metabolomics, present their advantages and drawbacks, and the current challenges to generate fully quantitative metabolomics data. Metabolomics data can be integrated into metabolic networks using thermodynamic principles to constrain the directionality of reactions. Here we explain how to estimate Gibbs energy under physiological conditions, including examples of the estimations, and the different methods for thermodynamics-based network analysis. The fundamentals of the methods and how to perform the analyses are described. Finally, an example applying quantitative metabolomics to a yeast model by 13C fluxomics and thermodynamics-based network analysis is presented. The example shows that (1) these two methods are complementary to each other; and (2) there is a need to take into account Gibbs energy errors. Better estimations of metabolic phenotypes will be obtained when further constraints are included in the analysis. PMID:27941694

  20. [Detection of resistance phenotypes in gram-negative bacteria].

    PubMed

    Navarro, Ferran; Calvo, Jorge; Cantón, Rafael; Fernández-Cuenca, Felipe; Mirelis, Beatriz

    2011-01-01

    Detecting resistance in gram-negative microorganisms has a strong clinical and epidemiological impact, but there is still a great deal of debate about the most sensitive phenotypic method and whether in vitro susceptibility results should be interpreted. The present work reviews the phenotypes and mechanisms of resistance to beta-lactams, quinolones and aminoglycosides in gram-negative bacilli and also revises the different phenotypic methods used for their detection. A clinical interpretation of in vitro susceptibility results is also discussed. Extended-spectrum and inhibitor resistant beta-lactamases, AmpC type beta-lactamases and carbapenemases are thoroughly reviewed. As regards quinolones, the resistance mediated both by plasmids and by mutations in the DNA gyrase and the topoisomerase IV genes is also reviewed. This report includes resistance patterns to aminoglycosides caused by modifying enzymes. Phenotypic detection of beta-lactam resistance in Neisseria spp. and Haemophilus influenzae is also reviewed in a separate section.

  1. An ontology for microbial phenotypes.

    PubMed

    Chibucos, Marcus C; Zweifel, Adrienne E; Herrera, Jonathan C; Meza, William; Eslamfam, Shabnam; Uetz, Peter; Siegele, Deborah A; Hu, James C; Giglio, Michelle G

    2014-11-30

    Phenotypic data are routinely used to elucidate gene function in organisms amenable to genetic manipulation. However, previous to this work, there was no generalizable system in place for the structured storage and retrieval of phenotypic information for bacteria. The Ontology of Microbial Phenotypes (OMP) has been created to standardize the capture of such phenotypic information from microbes. OMP has been built on the foundations of the Basic Formal Ontology and the Phenotype and Trait Ontology. Terms have logical definitions that can facilitate computational searching of phenotypes and their associated genes. OMP can be accessed via a wiki page as well as downloaded from SourceForge. Initial annotations with OMP are being made for Escherichia coli using a wiki-based annotation capture system. New OMP terms are being concurrently developed as annotation proceeds. We anticipate that diverse groups studying microbial genetics and associated phenotypes will employ OMP for standardizing microbial phenotype annotation, much as the Gene Ontology has standardized gene product annotation. The resulting OMP resource and associated annotations will facilitate prediction of phenotypes for unknown genes and result in new experimental characterization of phenotypes and functions.

  2. Plants having modified response to ethylene

    DOEpatents

    Meyerowitz, Elliott M.; Chang, Caren; Bleecker, Anthony B.

    1997-01-01

    The invention includes transformed plants having at least one cell transformed with a modified ETR nucleic acid. Such plants have a phenotype characterized by a decrease in the response of at least one transformed plant cell to ethylene as compared to a plant not containing the transformed plant cell. Tissue and/or temporal specificity for expression of the modified ETR nucleic acid is controlled by selecting appropriate expression regulation sequences to target the location and/or time of expression of the transformed nucleic acid. The plants are made by transforming at least one plant cell with an appropriate modified ETR nucleic acid, regenerating plants from one or more of the transformed plant cells and selecting at least one plant having the desired phenotype.

  3. Plants having modified response to ethylene

    DOEpatents

    Meyerowitz, Elliot M.; Chang, Caren; Bleecker, Anthony B.

    1998-01-01

    The invention includes transformed plants having at least one cell transformed with a modified ETR nucleic acid. Such plants have a phenotype characterized by a decrease in the response of at least one transformed plant cell to ethylene as compared to a plant not containing the transformed plant cell. Tissue and/or temporal specificity for expression of the modified ETR nucleic acid is controlled by selecting appropriate expression regulation sequences to target the location and/or time of expression of the transformed nucleic acid. The plants are made by transforming at least one plant cell with an appropriate modified ETR nucleic acid, regenerating plants from one or more of the transformed plant cells and selecting at least one plant having the desired phenotype.

  4. Plants having modified response to ethylene

    DOEpatents

    Meyerowitz, E.M.; Chang, C.; Bleecker, A.B.

    1998-10-20

    The invention includes transformed plants having at least one cell transformed with a modified ETR nucleic acid. Such plants have a phenotype characterized by a decrease in the response of at least one transformed plant cell to ethylene as compared to a plant not containing the transformed plant cell. Tissue and/or temporal specificity for expression of the modified ETR nucleic acid is controlled by selecting appropriate expression regulation sequences to target the location and/or time of expression of the transformed nucleic acid. The plants are made by transforming at least one plant cell with an appropriate modified ETR nucleic acid, regenerating plants from one or more of the transformed plant cells and selecting at least one plant having the desired phenotype. 67 figs.

  5. Plants having modified response to ethylene

    DOEpatents

    Meyerowitz, E.M.; Chang, C.; Bleecker, A.B.

    1997-11-18

    The invention includes transformed plants having at least one cell transformed with a modified ETR nucleic acid. Such plants have a phenotype characterized by a decrease in the response of at least one transformed plant cell to ethylene as compared to a plant not containing the transformed plant cell. Tissue and/or temporal specificity for expression of the modified ETR nucleic acid is controlled by selecting appropriate expression regulation sequences to target the location and/or time of expression of the transformed nucleic acid. The plants are made by transforming at least one plant cell with an appropriate modified ETR nucleic acid, regenerating plants from one or more of the transformed plant cells and selecting at least one plant having the desired phenotype. 31 figs.

  6. High-throughput mouse phenotyping.

    PubMed

    Gates, Hilary; Mallon, Ann-Marie; Brown, Steve D M

    2011-04-01

    Comprehensive phenotyping will be required to reveal the pleiotropic functions of a gene and to uncover the wider role of genetic loci within diverse biological systems. The challenge will be to devise phenotyping approaches to characterise the thousands of mutants that are being generated as part of international efforts to acquire a mutant for every gene in the mouse genome. In order to acquire robust datasets of broad based phenotypes from mouse mutants it is necessary to design and implement pipelines that incorporate standardised phenotyping platforms that are validated across diverse mouse genetics centres or mouse clinics. We describe here the rationale and methodology behind one phenotyping pipeline, EMPReSSslim, that was designed as part of the work of the EUMORPHIA and EUMODIC consortia, and which exemplifies some of the challenges facing large-scale phenotyping. EMPReSSslim captures a broad range of data on diverse biological systems, from biochemical to physiological amongst others. Data capture and dissemination is pivotal to the operation of large-scale phenotyping pipelines, including the definition of parameters integral to each phenotyping test and the associated ontological descriptions. EMPReSSslim data is displayed within the EuroPhenome database, where a variety of tools are available to allow the user to search for interesting biological or clinical phenotypes.

  7. EHR Big Data Deep Phenotyping

    PubMed Central

    Lenert, L.; Lopez-Campos, G.

    2014-01-01

    Summary Objectives Given the quickening speed of discovery of variant disease drivers from combined patient genotype and phenotype data, the objective is to provide methodology using big data technology to support the definition of deep phenotypes in medical records. Methods As the vast stores of genomic information increase with next generation sequencing, the importance of deep phenotyping increases. The growth of genomic data and adoption of Electronic Health Records (EHR) in medicine provides a unique opportunity to integrate phenotype and genotype data into medical records. The method by which collections of clinical findings and other health related data are leveraged to form meaningful phenotypes is an active area of research. Longitudinal data stored in EHRs provide a wealth of information that can be used to construct phenotypes of patients. We focus on a practical problem around data integration for deep phenotype identification within EHR data. The use of big data approaches are described that enable scalable markup of EHR events that can be used for semantic and temporal similarity analysis to support the identification of phenotype and genotype relationships. Conclusions Stead and colleagues’ 2005 concept of using light standards to increase the productivity of software systems by riding on the wave of hardware/processing power is described as a harbinger for designing future healthcare systems. The big data solution, using flexible markup, provides a route to improved utilization of processing power for organizing patient records in genotype and phenotype research. PMID:25123744

  8. Plant Phenotype Characterization System

    SciTech Connect

    Daniel W McDonald; Ronald B Michaels

    2005-09-09

    This report is the final scientific report for the DOE Inventions and Innovations Project: Plant Phenotype Characterization System, DE-FG36-04GO14334. The period of performance was September 30, 2004 through July 15, 2005. The project objective is to demonstrate the viability of a new scientific instrument concept for the study of plant root systems. The root systems of plants are thought to be important in plant yield and thus important to DOE goals in renewable energy sources. The scientific study and understanding of plant root systems is hampered by the difficulty in observing root activity and the inadequacy of existing root study instrumentation options. We have demonstrated a high throughput, non-invasive, high resolution technique for visualizing plant root systems in-situ. Our approach is based upon low-energy x-ray radiography and the use of containers and substrates (artificial soil) which are virtually transparent to x-rays. The system allows us to germinate and grow plant specimens in our containers and substrates and to generate x-ray images of the developing root system over time. The same plant can be imaged at different times in its development. The system can be used for root studies in plant physiology, plant morphology, plant breeding, plant functional genomics and plant genotype screening.

  9. Identification of Loci Modulating the Cardiovascular and Skeletal Phenotypes of Marfan Syndrome in Mice

    PubMed Central

    Fernandes, Gustavo R.; Massironi, Silvia M. G.; Pereira, Lygia V.

    2016-01-01

    Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue, affecting mostly the skeletal, ocular and cardiovascular systems, caused by mutations in the FBN1 gene. The existence of modifier genes has been postulated based on the wide clinical variability of manifestations in patients, even among those with the same FBN1 mutation. Although isogenic mouse models of the disease were fundamental in dissecting the molecular mechanism of pathogenesis, they do not address the effect of genetic background on the disease phenotype. Here, we use a new mouse model, mgΔloxPneo, which presents different phenotype severity dependent on the genetic backgrounds, to identify genes involved in modulating MFS phenotype. F2 heterozygotes showed wide phenotypic variability, with no correlations between phenotypic severities of the different affected systems, indicating that each has its specific set of modifier genes. Individual analysis of the phenotypes, with SNP microarrays, identified two suggestive QTL each to the cardiovascular and skeletal, and one significant QTL to the skeletal phenotype. Epistatic interactions between the QTL account for 47.4% and 53.5% of variation in the skeletal and cardiovascular phenotypes, respectively. This is the first study that maps modifier loci for MFS, showing the complex genetic architecture underlying the disease. PMID:26927851

  10. Global phenotypic characterization of bacteria

    PubMed Central

    Bochner, Barry R

    2009-01-01

    The measure of the quality of a systems biology model is how well it can reproduce and predict the behaviors of a biological system such as a microbial cell. In recent years, these models have been built up in layers, and each layer has been growing in sophistication and accuracy in parallel with a global data set to challenge and validate the models in predicting the content or activities of genes (genomics), proteins (proteomics), metabolites (metabolomics), and ultimately cell phenotypes (phenomics). This review focuses on the latter, the phenotypes of microbial cells. The development of Phenotype MicroArrays, which attempt to give a global view of cellular phenotypes, is described. In addition to their use in fleshing out and validating systems biology models, there are many other uses of this global phenotyping technology in basic and applied microbiology research, which are also described. PMID:19054113

  11. Emerging molecular phenotypes of asthma

    PubMed Central

    Ray, Anuradha; Oriss, Timothy B.

    2014-01-01

    Although asthma has long been considered a heterogeneous disease, attempts to define subgroups of asthma have been limited. In recent years, both clinical and statistical approaches have been utilized to better merge clinical characteristics, biology, and genetics. These combined characteristics have been used to define phenotypes of asthma, the observable characteristics of a patient determined by the interaction of genes and environment. Identification of consistent clinical phenotypes has now been reported across studies. Now the addition of various 'omics and identification of specific molecular pathways have moved the concept of clinical phenotypes toward the concept of molecular phenotypes. The importance of these molecular phenotypes is being confirmed through the integration of molecularly targeted biological therapies. Thus the global term asthma is poised to become obsolete, being replaced by terms that more specifically identify the pathology associated with the disease. PMID:25326577

  12. Congenital erythropoietic porphyria: mutation update and correlations between genotype and phenotype.

    PubMed

    Ged, C; Moreau-Gaudry, F; Richard, E; Robert-Richard, E; de Verneuil, H

    2009-02-16

    High quality genotype/phenotype analysis is a difficult issue in rare genetic diseases such as congenital erythropoietic porphyria (CEP) or Günther's disease, a heme biosynthesis defect due to uroporphyrinogen III synthase deficiency. The historical background and the main phenotypic features of the disease are depicted together with an update of published mutants and genotype/phenotype correlations. General rules concerning the prediction of disease severity are drawn as a guide for patient management and therapeutic choices. The phenotypic heterogeneity of the disease is presented in relation with a likely influence of modifying factors, either genetic or acquired.

  13. Discordant phenotype in siblings with X-linked agammaglobulinemia

    SciTech Connect

    Bykowsky, M.J.; Veksler, K.S.; Sullivan, K.E.

    1996-03-01

    X-linked agammaglobulinemia (XLA) is a congenital humoral immunodeficiency caused by a defect in a B-cell-specific signaling molecule, Btk. There has been little concordance of phenotype with genotype in this disorder, and defects in Btk cause immunodeficiencies that range from mild impairment to complete inability to produce antibodies. The factors modifying the phenotype of XLA are not understood. The current study is the first description of two male siblings with identical T{sup 134}{yields}C mutations in the translation initiation ATG of Btk who have different clinical phenotypes as well as different laboratory phenotypes. The proband lacks immunoglobulins and B cells and has recurrent infections, while the elder, affected brother has normal levels of IgG and IgM and very few infections. Both have undetectable levels of Btk kinase activity in circulating mononuclear cells. Complete sequencing of Btk gene transcripts in both brothers revealed no additional mutations to account for the discordant phenotypes. This description provides unequivocal evidence that the phenotype of XLA is influenced by factors additional to the Btk gene. 39 refs., 3 figs., 3 tabs.

  14. Root Traits and Phenotyping Strategies for Plant Improvement.

    PubMed

    Paez-Garcia, Ana; Motes, Christy M; Scheible, Wolf-Rüdiger; Chen, Rujin; Blancaflor, Elison B; Monteros, Maria J

    2015-06-15

    Roots are crucial for nutrient and water acquisition and can be targeted to enhance plant productivity under a broad range of growing conditions. A current challenge for plant breeding is the limited ability to phenotype and select for desirable root characteristics due to their underground location. Plant breeding efforts aimed at modifying root traits can result in novel, more stress-tolerant crops and increased yield by enhancing the capacity of the plant for soil exploration and, thus, water and nutrient acquisition. Available approaches for root phenotyping in laboratory, greenhouse and field encompass simple agar plates to labor-intensive root digging (i.e., shovelomics) and soil boring methods, the construction of underground root observation stations and sophisticated computer-assisted root imaging. Here, we summarize root architectural traits relevant to crop productivity, survey root phenotyping strategies and describe their advantages, limitations and practical value for crop and forage breeding programs.

  15. Root Traits and Phenotyping Strategies for Plant Improvement

    PubMed Central

    Paez-Garcia, Ana; Motes, Christy M.; Scheible, Wolf-Rüdiger; Chen, Rujin; Blancaflor, Elison B.; Monteros, Maria J.

    2015-01-01

    Roots are crucial for nutrient and water acquisition and can be targeted to enhance plant productivity under a broad range of growing conditions. A current challenge for plant breeding is the limited ability to phenotype and select for desirable root characteristics due to their underground location. Plant breeding efforts aimed at modifying root traits can result in novel, more stress-tolerant crops and increased yield by enhancing the capacity of the plant for soil exploration and, thus, water and nutrient acquisition. Available approaches for root phenotyping in laboratory, greenhouse and field encompass simple agar plates to labor-intensive root digging (i.e., shovelomics) and soil boring methods, the construction of underground root observation stations and sophisticated computer-assisted root imaging. Here, we summarize root architectural traits relevant to crop productivity, survey root phenotyping strategies and describe their advantages, limitations and practical value for crop and forage breeding programs. PMID:27135332

  16. Mouse Genetic Background Influences the Dental Phenotype

    PubMed Central

    Li, Yong; Konicki, William S.; Wright, J. Timothy; Suggs, Cynthia; Xue, Hui; Kuehl, Melissa A.; Kulkarni, Ashok B.; Gibson, Carolyn W.

    2014-01-01

    Dental enamel covers the crown of the vertebrate tooth and is considered to be the hardest tissue in the body. Enamel develops during secretion of an extracellular matrix by ameloblast cells in the tooth germ, prior to eruption of the tooth into the oral cavity. Secreted enamel proteins direct mineralization patterns during the maturation stage of amelogenesis as the tooth prepares to erupt. The amelogenins are the most abundant enamel proteins, and are required for normal enamel development. Phenotypic differences were observed between incisors from individual Amelx (Amelogenin) null mice that had a mixed 129xC57BL/6J genetic background, and between inbred wld-type (WT) mice with different genetic backgrounds (C57BL/6J, C3H/HEJ, FVB/NJ). We hypothesized this could be due to modifier genes, as human patients with a mutation in an enamel protein gene causing the enamel defect amelogenesis imperfecta (AI) also can have varied appearance of dentitions within a kindred. Enamel density measurements varied for all WT inbred strains midway during incisor development. Enamel thickness varied between some WT strains and, unexpectedly, dentin density varied extensively between incisors and molars of all WT and Amelx null strains studied. WT FVB/NJ incisors were more similar to Amelx null than to the other WT strains in incisor height/weight ratio and pattern of enamel mineralization. Strain-specific differences led to the conclusion that modifier genes may be implicated in determining both normal development and severity of enamel appearance in AI mouse models and may in future studies be related to phenotypic heterogeneity within human AI kindreds reported in the literature. PMID:24732779

  17. Finding our way through phenotypes.

    PubMed

    Deans, Andrew R; Lewis, Suzanna E; Huala, Eva; Anzaldo, Salvatore S; Ashburner, Michael; Balhoff, James P; Blackburn, David C; Blake, Judith A; Burleigh, J Gordon; Chanet, Bruno; Cooper, Laurel D; Courtot, Mélanie; Csösz, Sándor; Cui, Hong; Dahdul, Wasila; Das, Sandip; Dececchi, T Alexander; Dettai, Agnes; Diogo, Rui; Druzinsky, Robert E; Dumontier, Michel; Franz, Nico M; Friedrich, Frank; Gkoutos, George V; Haendel, Melissa; Harmon, Luke J; Hayamizu, Terry F; He, Yongqun; Hines, Heather M; Ibrahim, Nizar; Jackson, Laura M; Jaiswal, Pankaj; James-Zorn, Christina; Köhler, Sebastian; Lecointre, Guillaume; Lapp, Hilmar; Lawrence, Carolyn J; Le Novère, Nicolas; Lundberg, John G; Macklin, James; Mast, Austin R; Midford, Peter E; Mikó, István; Mungall, Christopher J; Oellrich, Anika; Osumi-Sutherland, David; Parkinson, Helen; Ramírez, Martín J; Richter, Stefan; Robinson, Peter N; Ruttenberg, Alan; Schulz, Katja S; Segerdell, Erik; Seltmann, Katja C; Sharkey, Michael J; Smith, Aaron D; Smith, Barry; Specht, Chelsea D; Squires, R Burke; Thacker, Robert W; Thessen, Anne; Fernandez-Triana, Jose; Vihinen, Mauno; Vize, Peter D; Vogt, Lars; Wall, Christine E; Walls, Ramona L; Westerfeld, Monte; Wharton, Robert A; Wirkner, Christian S; Woolley, James B; Yoder, Matthew J; Zorn, Aaron M; Mabee, Paula

    2015-01-01

    Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility.

  18. Finding Our Way through Phenotypes

    PubMed Central

    Deans, Andrew R.; Lewis, Suzanna E.; Huala, Eva; Anzaldo, Salvatore S.; Ashburner, Michael; Balhoff, James P.; Blackburn, David C.; Blake, Judith A.; Burleigh, J. Gordon; Chanet, Bruno; Cooper, Laurel D.; Courtot, Mélanie; Csösz, Sándor; Cui, Hong; Dahdul, Wasila; Das, Sandip; Dececchi, T. Alexander; Dettai, Agnes; Diogo, Rui; Druzinsky, Robert E.; Dumontier, Michel; Franz, Nico M.; Friedrich, Frank; Gkoutos, George V.; Haendel, Melissa; Harmon, Luke J.; Hayamizu, Terry F.; He, Yongqun; Hines, Heather M.; Ibrahim, Nizar; Jackson, Laura M.; Jaiswal, Pankaj; James-Zorn, Christina; Köhler, Sebastian; Lecointre, Guillaume; Lapp, Hilmar; Lawrence, Carolyn J.; Le Novère, Nicolas; Lundberg, John G.; Macklin, James; Mast, Austin R.; Midford, Peter E.; Mikó, István; Mungall, Christopher J.; Oellrich, Anika; Osumi-Sutherland, David; Parkinson, Helen; Ramírez, Martín J.; Richter, Stefan; Robinson, Peter N.; Ruttenberg, Alan; Schulz, Katja S.; Segerdell, Erik; Seltmann, Katja C.; Sharkey, Michael J.; Smith, Aaron D.; Smith, Barry; Specht, Chelsea D.; Squires, R. Burke; Thacker, Robert W.; Thessen, Anne; Fernandez-Triana, Jose; Vihinen, Mauno; Vize, Peter D.; Vogt, Lars; Wall, Christine E.; Walls, Ramona L.; Westerfeld, Monte; Wharton, Robert A.; Wirkner, Christian S.; Woolley, James B.; Yoder, Matthew J.; Zorn, Aaron M.; Mabee, Paula

    2015-01-01

    Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility. PMID:25562316

  19. The digital revolution in phenotyping

    PubMed Central

    Oellrich, Anika; Collier, Nigel; Groza, Tudor; Rebholz-Schuhmann, Dietrich; Shah, Nigam; Bodenreider, Olivier; Boland, Mary Regina; Georgiev, Ivo; Liu, Hongfang; Livingston, Kevin; Luna, Augustin; Mallon, Ann-Marie; Manda, Prashanti; Robinson, Peter N.; Rustici, Gabriella; Simon, Michelle; Wang, Liqin; Winnenburg, Rainer; Dumontier, Michel

    2016-01-01

    Phenotypes have gained increased notoriety in the clinical and biological domain owing to their application in numerous areas such as the discovery of disease genes and drug targets, phylogenetics and pharmacogenomics. Phenotypes, defined as observable characteristics of organisms, can be seen as one of the bridges that lead to a translation of experimental findings into clinical applications and thereby support ‘bench to bedside’ efforts. However, to build this translational bridge, a common and universal understanding of phenotypes is required that goes beyond domain-specific definitions. To achieve this ambitious goal, a digital revolution is ongoing that enables the encoding of data in computer-readable formats and the data storage in specialized repositories, ready for integration, enabling translational research. While phenome research is an ongoing endeavor, the true potential hidden in the currently available data still needs to be unlocked, offering exciting opportunities for the forthcoming years. Here, we provide insights into the state-of-the-art in digital phenotyping, by means of representing, acquiring and analyzing phenotype data. In addition, we provide visions of this field for future research work that could enable better applications of phenotype data. PMID:26420780

  20. Reciprocal phenotypic plasticity in a predator-prey interaction between larval amphibians.

    PubMed

    Kishida, Osamu; Mizuta, Yuuki; Nishimura, Kinya

    2006-06-01

    In biological interactions, phenotypic change in interacting organisms induced by their interaction partners causes a substantial shift in some environmental factor of the partners, which may subsequently change their phenotype in response to that modified environmental factor. Few examples of such arms-race-like plastic responses, known as reciprocal phenotypic plasticity, have been identified in predator-prey interactions. We experimentally identified a reciprocal defensive plastic response of a prey species against a predator with a predaceous phenotype using a model system of close predator-prey interaction. Rana pirica tadpoles (the prey species) were reared with larvae of the salamander Hynobius retardatus (the predator species) having either a predaceous or a typical, nonpredaceous phenotype. The H. retardatus larvae with the predaceous phenotype, which is known to be induced by the presence of R. pirica tadpoles, induced a more defensive phenotype in the tadpoles than did larvae with the typical phenotype. The result suggests that the reciprocal phenotypic plasticity of R. pirica tadpoles is in response to a phenotype-specific signal under a close-signal recognition process.

  1. Refining mimicry: phenotypic variation tracks the local optimum.

    PubMed

    Mérot, Claire; Le Poul, Yann; Théry, Marc; Joron, Mathieu

    2016-07-01

    Müllerian mimicry between chemically defended preys is a textbook example of natural selection favouring phenotypic convergence onto a shared warning signal. Studies of mimicry have concentrated on deciphering the ecological and genetic underpinnings of dramatic switches in mimicry association, producing a well-known mosaic distribution of mimicry patterns across geography. However, little is known about the accuracy of resemblance between natural comimics when the local phenotypic optimum varies. In this study, using analyses of wing shape, pattern and hue, we quantify multimodal phenotypic similarity between butterfly comimics sharing the so-called postman pattern in different localities with varying species composition. We show that subtle but consistent variation between populations of the localized species, Heliconius timareta thelxinoe, enhance resemblance to the abundant comimics which drive the mimicry in each locality. Those results suggest that rarer comimics track the changes in the phenotypic optimum caused by gradual changes in the composition of the mimicry community, providing insights into the process by which intraspecific diversity of mimetic pattern may arise. Furthermore, our results suggest a multimodal evolution of similarity, with coordinated convergence in different features of the phenotype such as wing outline, pattern and hue. Finally, multilocus genotyping allows estimating local hybridization rates between H. timareta and comimic H. melpomene in different populations, raising the hypothesis that mimicry refinement between closely related comimics may be enhanced by adaptive introgression at loci modifying the accuracy of resemblance. © 2016 The Authors. Journal of Animal Ecology © 2016 British Ecological Society.

  2. Epigenetic reversion of breast carcinoma phenotype is accompaniedby DNA sequestration

    SciTech Connect

    Sandal, Tone; Valyi-Nagy, Klara; Spencer, Virginia A.; Folberg,Robert; Bissell, Mina J.; Maniotis, Andrew J.

    2006-07-19

    The importance of microenvironment and context in regulation of tissue-specific genes is finally well established. DNA exposure to, or sequestration from, nucleases can be used to detect differences in higher order chromatin structure in intact cells without disturbing cellular or tissue architecture. To investigate the relationship between chromatin organization and tumor phenotype, we utilized an established 3-D assay where normal and malignant human breast cells can be easily distinguished by the morphology of the structures they make (acinus-like vs tumor-like, respectively). We show that these phenotypes can be distinguished also by sensitivity to AluI digestion where the malignant cells are resistant to digestion relative to non-malignant cells. Reversion of the T4-2 breast cancer cells by either cAMP analogs, or a phospatidylinositol 3-kinase (P13K) inhibitor not only reverted the phenotype, but also the chromatin sensitivity to AluI. By using different cAMP-analogs, we show that the cAMP-induced phenotypic reversion, polarization, and shift in DNA organization act through a cAMP-dependent-protein-kinase A-coupled signaling pathway. Importantly, inhibitory antibody to fibronectin also reverted the malignant phenotype, polarized the acini, and changed chromatin sequestration. These experiments show not only that modifying the tumor microenvironment can alter the organization of tumor cells but also that architecture of the tissues and the global chromatin organization are coupled and yet highly plastic.

  3. [Effects of pregnancy and changes in body weight on polycystic ovary syndrome phenotypes according to the Rotterdam criteria].

    PubMed

    Echiburú, Bárbara; Ladrón de Guevara, Amanda; Pereira, Cecilia; Pérez, Constanza; Michael, Pía; Crisosto, Nicolás; Sir-Petermann, Teresa

    2014-08-01

    Polycystic Ovary Syndrome (PCOS) is tightly associated with insulin resistance and obesity and characterized by hyperandrogenism, chronic oligo-anovulation and polycystic ovarian morphology when fully expressed. The 2003 Rotterdam consensus proposed that two or three of these features were necessary to make the diagnosis, which generated four phenotypes. Several studies have suggested that these phenotypes could differ in their metabolic and endocrine characteristics and that they could vary in the same patient when analyzed throughout life. To determine if the initial classification of PCOS phenotypes is modified by different physiological conditions. We performed a non-concurrent prospective analysis of 88 women with PCOS according to the Rotterdam criteria. The effect of physiological conditions such as changes in body weight, pregnancy and ageing more than five years on PCOS phenotype expression was analyzed. Twenty four percent of women became pregnant, 37% decreased and 24% increased their body weight during follow up. These conditions modified significantly the proportion of the different phenotypes (c2 = 32.2, p < 0.001). For instance, weight reduction was associated with a change to a better phenotype (p = 0.047) and even a normalization of the PCOS condition in 27% of the patients. On the other hand, an increase in body weight modifying body mass index in one unit, conferred an 8% probability of changing to a worst phenotype. Pregnancy and changes in body weight significantly modify PCOS phenotypes.

  4. Putative modifier genes in mevalonate kinase deficiency.

    PubMed

    Marcuzzi, Annalisa; Vozzi, Diego; Girardelli, Martina; Tricarico, Paola Maura; Knowles, Alessandra; Crovella, Sergio; Vuch, Josef; Tommasini, Alberto; Piscianz, Elisa; Bianco, Anna Monica

    2016-04-01

    Mevalonate kinase deficiency (MKD) is an autosomal recessive auto‑inflammatory disease, caused by impairment of the mevalonate pathway. Although the molecular mechanism remains to be elucidated, there is clinical evidence suggesting that other regulatory genes may be involved in determining the phenotype. The identification of novel target genes may explain non‑homogeneous genotype‑phenotype correlations, and provide evidence in support of the hypothesis that novel regulatory genes predispose or amplify deregulation of the mevalonate pathway in this orphan disease. In the present study, DNA samples were obtained from five patients with MKD, which were then analyzed using whole exome sequencing. A missense variation in the PEX11γ gene was observed in homozygosis in P2, possibly correlating with visual blurring. The UNG rare gene variant was detected in homozygosis in P5, without correlating with a specific clinical phenotype. A number of other variants were found in the five analyzed DNA samples from the MKD patients, however no correlation with the phenotype was established. The results of the presents study suggested that further analysis, using next generation sequencing approaches, is required on a larger sample size of patients with MKD, who share the same MVK mutations and exhibit 'extreme' clinical phenotypes. As MVK mutations may be associated with MKD, the identification of specific modifier genes may assist in providing an earlier diagnosis.

  5. Phenotypic heterogeneity promotes adaptive evolution

    PubMed Central

    Nevozhay, Dmitry; Kalapis, Dorottya; Lázár, Viktória; Csörgő, Bálint; Nyerges, Ákos; Szamecz, Béla; Fekete, Gergely; Papp, Balázs; Araújo, Hugo; Oliveira, José L.; Moura, Gabriela; Santos, Manuel A. S.; Székely Jr, Tamás; Balázsi, Gábor

    2017-01-01

    Genetically identical cells frequently display substantial heterogeneity in gene expression, cellular morphology and physiology. It has been suggested that by rapidly generating a subpopulation with novel phenotypic traits, phenotypic heterogeneity (or plasticity) accelerates the rate of adaptive evolution in populations facing extreme environmental challenges. This issue is important as cell-to-cell phenotypic heterogeneity may initiate key steps in microbial evolution of drug resistance and cancer progression. Here, we study how stochastic transitions between cellular states influence evolutionary adaptation to a stressful environment in yeast Saccharomyces cerevisiae. We developed inducible synthetic gene circuits that generate varying degrees of expression stochasticity of an antifungal resistance gene. We initiated laboratory evolutionary experiments with genotypes carrying different versions of the genetic circuit by exposing the corresponding populations to gradually increasing antifungal stress. Phenotypic heterogeneity altered the evolutionary dynamics by transforming the adaptive landscape that relates genotype to fitness. Specifically, it enhanced the adaptive value of beneficial mutations through synergism between cell-to-cell variability and genetic variation. Our work demonstrates that phenotypic heterogeneity is an evolving trait when populations face a chronic selection pressure. It shapes evolutionary trajectories at the genomic level and facilitates evolutionary rescue from a deteriorating environmental stress. PMID:28486496

  6. In pursuit of taste phenotypes.

    PubMed

    Green, Barry G

    2013-05-01

    Notable progress has been made relating individual differences in bitter taste sensitivity to specific alleles and TAS2R receptors, but psychophysical evidence of reliable phenotypes for other tastes has been more elusive. In this issue, Wise and Breslin report a study of individual differences in threshold sensitivity to sour and salty taste, which, though failing to find clear phenotypes, exemplifies the type of approach and analysis necessary to disentangle sources of variance inherent in the psychophysical measures applied from those attributable to true differences in sensitivity. Methodological and theoretical lessons that can be taken from this work are discussed in the context of the early and dramatic evidence of chemosensory phenotypes that belied the complexity of taste receptor genetics and focused attention solely on peripheral determinants of sensitivity.

  7. Optofluidic Detection for Cellular Phenotyping

    PubMed Central

    Tung, Yi-Chung; Huang, Nien-Tsu; Oh, Bo-Ram; Patra, Bishnubrata; Pan, Chi-Chun; Qiu, Teng; Paul, K. Chu; Zhang, Wenjun; Kurabayashi, Katsuo

    2012-01-01

    Quantitative analysis of the output of processes and molecular interactions within a single cell is highly critical to the advancement of accurate disease screening and personalized medicine. Optical detection is one of the most broadly adapted measurement methods in biological and clinical assays and serves cellular phenotyping. Recently, microfluidics has obtained increasing attention due to several advantages, such as small sample and reagent volumes, very high throughput, and accurate flow control in the spatial and temporal domains. Optofluidics, which is the attempt to integrate optics with microfluidic, shows great promise to enable on-chip phenotypic measurements with high precision, sensitivity, specificity, and simplicity. This paper reviews the most recent developments of optofluidic technologies for cellular phenotyping optical detection. PMID:22854915

  8. Systemic first-line phenotyping.

    PubMed

    Gailus-Durner, Valérie; Fuchs, Helmut; Adler, Thure; Aguilar Pimentel, Antonio; Becker, Lore; Bolle, Ines; Calzada-Wack, Julia; Dalke, Claudia; Ehrhardt, Nicole; Ferwagner, Barbara; Hans, Wolfgang; Hölter, Sabine M; Hölzlwimmer, Gabriele; Horsch, Marion; Javaheri, Anahita; Kallnik, Magdalena; Kling, Eva; Lengger, Christoph; Mörth, Corinna; Mossbrugger, Ilona; Naton, Beatrix; Prehn, Cornelia; Puk, Oliver; Rathkolb, Birgit; Rozman, Jan; Schrewe, Anja; Thiele, Frank; Adamski, Jerzy; Aigner, Bernhard; Behrendt, Heidrun; Busch, Dirk H; Favor, Jack; Graw, Jochen; Heldmaier, Gerhard; Ivandic, Boris; Katus, Hugo; Klingenspor, Martin; Klopstock, Thomas; Kremmer, Elisabeth; Ollert, Markus; Quintanilla-Martinez, Leticia; Schulz, Holger; Wolf, Eckhard; Wurst, Wolfgang; de Angelis, Martin Hrabé

    2009-01-01

    With the completion of the mouse genome sequence an essential task for biomedical sciences in the twenty-first century will be the generation and functional analysis of mouse models for every gene in the mammalian genome. More than 30,000 mutations in ES cells will be engineered and thousands of mouse disease models will become available over the coming years by the collaborative effort of the International Mouse Knockout Consortium. In order to realize the full value of the mouse models proper characterization, archiving and dissemination of mouse disease models to the research community have to be performed. Phenotyping centers (mouse clinics) provide the necessary capacity, broad expertise, equipment, and infrastructure to carry out large-scale systemic first-line phenotyping. Using the example of the German Mouse Clinic (GMC) we will introduce the reader to the different aspects of the organization of a mouse clinic and present selected methods used in first-line phenotyping.

  9. Capturing phenotypic heterogeneity in MPS I: results of an international consensus procedure.

    PubMed

    de Ru, Minke H; Teunissen, Quirine Ga; van der Lee, Johanna H; Beck, Michael; Bodamer, Olaf A; Clarke, Lorne A; Hollak, Carla E; Lin, Shuan-Pei; Rojas, Maria-Verónica Muñoz; Pastores, Gregory M; Raiman, Julian A; Scarpa, Maurizio; Treacy, Eileen P; Tylki-Szymanska, Anna; Wraith, J Edmond; Zeman, Jiri; Wijburg, Frits A

    2012-04-23

    Mucopolysaccharidosis type I (MPS I) is traditionally divided into three phenotypes: the severe Hurler (MPS I-H) phenotype, the intermediate Hurler-Scheie (MPS I-H/S) phenotype and the attenuated Scheie (MPS I-S) phenotype. However, there are no clear criteria for delineating the different phenotypes. Because decisions about optimal treatment (enzyme replacement therapy or hematopoietic stem cell transplantation) need to be made quickly and depend on the presumed phenotype, an assessment of phenotypic severity should be performed soon after diagnosis. Therefore, a numerical severity scale for classifying different MPS I phenotypes at diagnosis based on clinical signs and symptoms was developed. A consensus procedure based on a combined modified Delphi method and a nominal group technique was undertaken. It consisted of two written rounds and a face-to-face meeting. Sixteen MPS I experts participated in the process. The main goal was to identify the most important indicators of phenotypic severity and include these in a numerical severity scale. The correlation between the median subjective expert MPS I rating and the scores derived from this severity scale was used as an indicator of validity. Full consensus was reached on six key clinical items for assessing severity: age of onset of signs and symptoms, developmental delay, joint stiffness/arthropathy/contractures, kyphosis, cardiomyopathy and large head/frontal bossing. Due to the remarkably large variability in the expert MPS I assessments, however, a reliable numerical scale could not be constructed. Because of this variability, such a scale would always result in patients whose calculated severity score differed unacceptably from the median expert severity score, which was considered to be the 'gold standard'. Although consensus was reached on the six key items for assessing phenotypic severity in MPS I, expert opinion on phenotypic severity at diagnosis proved to be highly variable. This subjectivity

  10. Identification of extreme motor phenotypes in Huntington's disease.

    PubMed

    Braisch, Ulrike; Hay, Birgit; Muche, Rainer; Rothenbacher, Dietrich; Landwehrmeyer, G Bernhard; Long, Jeffrey D; Orth, Michael

    2017-04-01

    The manifestation of motor signs in Huntington's disease (HD) has a well-known inverse relationship with HTT CAG repeat length, but the prediction is far from perfect. The probability of finding disease modifiers is enhanced in individuals with extreme HD phenotypes. We aimed to identify extreme HD motor phenotypes conditional on CAG and age, such as patients with very early or very late onset of motor manifestation. Retrospective data were available from 1,218 healthy controls and 9,743 HD participants with CAG repeats ≥40, and a total of about 30,000 visits. Boundaries (2.5% and 97.5% quantiles) for extreme motor phenotypes (UHDRS total motor score (TMS) and motor age-at-onset) were estimated using quantile regression for longitudinal data. More than 15% of HD participants had an extreme TMS phenotype for at least one visit. In contrast, only about 4% of participants were consistent TMS extremes at two or more visits. Data from healthy controls revealed an upper cut-off of 13 for the TMS representing the extreme of motor ratings for a normal aging population. In HD, boundaries of motor age-at-onset based on diagnostic confidence or derived from the TMS data cut-off in controls were similar. In summary, a UHDRS TMS of more than 13 in an individual carrying the HD mutation indicates a high likelihood of motor manifestations of HD irrespective of CAG repeat length or age. The identification of motor phenotype extremes can be useful in the search for disease modifiers, for example, genetic or environmental such as medication. © 2016 Wiley Periodicals, Inc.

  11. Genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies.

    PubMed

    Hightower, Rylie M; Alexander, Matthew S

    2017-09-06

    Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next-generation sequencing has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes, including age of loss of ambulation, steroid responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. This review highlights recent findings on genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. Muscle Nerve, 2017. © 2017 Wiley Periodicals, Inc.

  12. Modifier genes: Moving from pathogenesis to therapy.

    PubMed

    McCabe, Edward R B

    2017-09-01

    This commentary will focus on how we can use our knowledge about the complexity of human disease and its pathogenesis to identify novel approaches to therapy. We know that even for single gene Mendelian disorders, patients with identical mutations often have different presentations and outcomes. This lack of genotype-phenotype correlation led us and others to examine the roles of modifier genes in the context of biological networks. These investigations have utilized vertebrate and invertebrate model organisms. Since one of the goals of research on modifier genes and networks is to identify novel therapeutic targets, the challenges to patient access and compliance because of the high costs of medications for rare genetic diseases must be recognized. A recent article explored protective modifiers, including plastin 3 (PLS3) and coronin 1C (CORO1C), in spinal muscular atrophy (SMA). SMA is an autosomal recessive deficit of survival motor neuron protein (SMN) caused by mutations in SMN1. However, the severity of SMA is determined primarily by the number of SMN2 copies, and this results in significant phenotypic variability. PLS3 was upregulated in siblings who were asymptomatic compared with those who had SMA2 or SMA3, but identical homozygous SMN1 deletions and equal numbers of SMN2 copies. CORO1C was identified by interrogation of the PLS3 interactome. Overexpression of these proteins rescued endocytosis in SMA models. In addition, antisense RNA for upregulation of SMN2 protein expression is being developed as another way of modifying the SMA phenotype. These investigations suggest the practical application of protective modifiers to rescue SMA phenotypes. Other examples of the potential therapeutic value of novel protective modifiers will be discussed, including in Duchenne muscular dystrophy and glycerol kinase deficiency. This work shows that while we live in an exciting era of genomic sequencing, a functional understanding of biology, the impact of its

  13. Steroid responsiveness and wheezing phenotypes.

    PubMed

    Ducharme, Francine M; Krajinovic, Maja

    2011-09-01

    Oral corticosteroids are the cornerstone of management of acute moderate or severe asthma whilst preventive inhaled corticosteroids are the mainstay of the preventive management of children with asthma. Yet, variation in the magnitude of response to corticosteroids has been observed. There is increasing evidence that preschool-aged children with viral-induced asthma may display a certain degree of corticosteroid resistance, requiring higher doses of corticosteroids to overcome it. The identification of determinants of responsiveness is complicated by design issues, including heterogeneous populations of children with asthma and bronchiolitis or of children with viral-induced and multi-trigger asthma phenotypes in published trials. Potential key determinants of responsiveness may include age, trigger, phenotype, tobacco smoke exposure and genotype. The mechanistic pathway for corticoresistance may originate from a gene-environment interaction, leading to non-eosinophilic airway inflammation. The clinician should carefully confirm the diagnosis of asthma and ascertain the phenotype to select appropriate phenotype-specific therapy. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. Genetic Homozygosity and Phenotypic Variability in Craniosynostotic Rabbits.

    PubMed

    Gilbert, James R; Cray, James J; Kreithen, Amy; Marazita, Mary L; Cooper, Gregory M; Losee, Joseph E; Siegel, Michael I; Mooney, Mark P

    2017-01-01

      Craniosynostosis ranges in severity from single suture involvement with prenatal onset to multiple suture involvement with postnatal onset. The present study was designed to test the hypothesis that increasing homozygosity may be responsible for more severe phenotypic expression by examining the relationship between inbreeding and phenotypic expression in synostotic rabbits.   Data were obtained from 173 litters and 209 rabbits with familial craniosynostosis. Five distinct phenotypes were identified (normal n = 62; unicoronal delayed onset synostosis (DOS) n = 47; bicoronal DOS n = 21; unicoronal early onset synostosis (EOS) n = 26, and bicoronal EOS n= 53). Wright's coefficients of inbreeding (CI) were calculated using CompuPed software. Radiographs were taken at 10, 25, 42, 84, and 126 days of age to assess coronal suture, craniofacial, and skeletal growth. The relationship between CI and growth data was assessed using correlation coefficients.   Mean CIs ranged from 15.68 (±2.22) in normal rabbits to 25.89 (±5.03) in bicoronal DOS, to 36.29 (±2.10) in unicoronal EOS to 42.85 (±2.10) in bicoronal EOS rabbits. Significant differences were noted among groups (F = 11.48; P < .001). Significant negative correlations were noted between CI and sutural and craniofacial growth at 25 (r = -.45, P < .001; and r = -.66, P < .001) through 126 (r = -.40, P < .001 and r = -.46, P < .001) days of age.   While the synostotic phenotype is inherited in an autosomal dominant fashion in these rabbits, increasing homozygosity is associated with more severely affected phenotypes. These findings suggest that an accumulation of additional, modifier genes may determine the severity of the synostotic phenotype in rabbits.

  15. Distinct clinical phenotypes of airways disease defined by cluster analysis.

    PubMed

    Weatherall, M; Travers, J; Shirtcliffe, P M; Marsh, S E; Williams, M V; Nowitz, M R; Aldington, S; Beasley, R

    2009-10-01

    Airways disease is currently classified using diagnostic labels such as asthma, chronic bronchitis and emphysema. The current definitions of these classifications may not reflect the phenotypes of airways disease in the community, which may have differing disease processes, clinical features or responses to treatment. The aim of the present study was to use cluster analysis to explore clinical phenotypes in a community population with airways disease. A random population sample of 25-75-yr-old adults underwent detailed investigation, including a clinical questionnaire, pulmonary function tests, nitric oxide measurements, blood tests and chest computed tomography. Cluster analysis was performed on the subgroup with current respiratory symptoms or obstructive spirometric results. Subjects with a complete dataset (n = 175) were included in the cluster analysis. Five clusters were identified with the following characteristics: cluster 1: severe and markedly variable airflow obstruction with features of atopic asthma, chronic bronchitis and emphysema; cluster 2: features of emphysema alone; cluster 3: atopic asthma with eosinophilic airways inflammation; cluster 4: mild airflow obstruction without other dominant phenotypic features; and cluster 5: chronic bronchitis in nonsmokers. Five distinct clinical phenotypes of airflow obstruction were identified. If confirmed in other populations, these findings may form the basis of a modified taxonomy for the disorders of airways obstruction.

  16. Effect of genetic background on the dystrophic phenotype in mdx mice

    PubMed Central

    Coley, William D.; Bogdanik, Laurent; Vila, Maria Candida; Yu, Qing; Van Der Meulen, Jack H.; Rayavarapu, Sree; Novak, James S.; Nearing, Marie; Quinn, James L.; Saunders, Allison; Dolan, Connor; Andrews, Whitney; Lammert, Catherine; Austin, Andrew; Partridge, Terence A.; Cox, Gregory A.; Lutz, Cathleen; Nagaraju, Kanneboyina

    2016-01-01

    Genetic background significantly affects phenotype in multiple mouse models of human diseases, including muscular dystrophy. This phenotypic variability is partly attributed to genetic modifiers that regulate the disease process. Studies have demonstrated that introduction of the γ-sarcoglycan-null allele onto the DBA/2J background confers a more severe muscular dystrophy phenotype than the original strain, demonstrating the presence of genetic modifier loci in the DBA/2J background. To characterize the phenotype of dystrophin deficiency on the DBA/2J background, we created and phenotyped DBA/2J-congenic Dmdmdx mice (D2-mdx) and compared them with the original, C57BL/10ScSn-Dmdmdx (B10-mdx) model. These strains were compared with their respective control strains at multiple time points between 6 and 52 weeks of age. Skeletal and cardiac muscle function, inflammation, regeneration, histology and biochemistry were characterized. We found that D2-mdx mice showed significantly reduced skeletal muscle function as early as 7 weeks and reduced cardiac function by 28 weeks, suggesting that the disease phenotype is more severe than in B10-mdx mice. In addition, D2-mdx mice showed fewer central myonuclei and increased calcifications in the skeletal muscle, heart and diaphragm at 7 weeks, suggesting that their pathology is different from the B10-mdx mice. The new D2-mdx model with an earlier onset and more pronounced dystrophy phenotype may be useful for evaluating therapies that target cardiac and skeletal muscle function in dystrophin-deficient mice. Our data align the D2-mdx with Duchenne muscular dystrophy patients with the LTBP4 genetic modifier, making it one of the few instances of cross-species genetic modifiers of monogenic traits. PMID:26566673

  17. Microtubule stabilising peptides rescue tau phenotypes in-vivo

    PubMed Central

    Quraishe, Shmma; Sealey, Megan; Cranfield, Louise; Mudher, Amritpal

    2016-01-01

    The microtubule cytoskeleton is a highly dynamic, filamentous network underpinning cellular structure and function. In Alzheimer’s disease, the microtubule cytoskeleton is compromised, leading to neuronal dysfunction and eventually cell death. There are currently no disease-modifying therapies to slow down or halt disease progression. However, microtubule stabilisation is a promising therapeutic strategy that is being explored. We previously investigated the disease-modifying potential of a microtubule-stabilising peptide NAP (NAPVSIPQ) in a well-established Drosophila model of tauopathy characterised by microtubule breakdown and axonal transport deficits. NAP prevented as well as reversed these phenotypes even after they had become established. In this study, we investigate the neuroprotective capabilities of an analogous peptide SAL (SALLRSIPA). We found that SAL mimicked NAP’s protective effects, by preventing axonal transport disruption and improving behavioural deficits, suggesting both NAP and SAL may act via a common mechanism. Both peptides contain a putative ‘SIP’ (Ser-Ile-Pro) domain that is important for interactions with microtubule end-binding proteins. Our data suggests this domain may be central to the microtubule stabilising function of both peptides and the mechanism by which they rescue phenotypes in this model of tauopathy. Our observations support microtubule stabilisation as a promising disease-modifying therapeutic strategy for tauopathies like Alzheimer’s disease. PMID:27910888

  18. Diverse phenotypic expression of NPHP4 mutations in four siblings.

    PubMed

    Bakkaloğlu, Sevcan A; Kandur, Yaşar; Bedir-Demirdağ, Tuğba; Işık-Gönül, İpek; Hildebrandt, Friedhelm

    2014-01-01

    Nephronophthisis (NPHP) is an autosomal recessive disease characterized by renal tubular basement membrane disruption, interstitial fibrosis and tubular cysts that progresses to end-stage kidney disease (ESKD). There are also characteristic extrarenal manifestations. Mutations of more than thirteen genes that can cause NPHP have been identified. We herein report four siblings from a consanguineous family, who carried the same NPHP4 mutations but presented with different disease phenotypes ranging from enuresis nocturna to ESKD. Diluted urine and echogenic kidneys in ultrasound examination were consistent, which is typical for 100% of the NPHP cases that have been described. Chronic kidney disease developed in the older two brothers. The observed phenotypic differences are likely to be related to environmental and epigenetic factors, oligogenic inheritance and modifier genes affecting the age of presentation of signs and symptoms. NPHP should be considered as an important cause of CKD in children, which insidiously progresses to ESKD, with no specific therapy available.

  19. Characterizing visible and invisible cell wall mutant phenotypes.

    PubMed

    Carpita, Nicholas C; McCann, Maureen C

    2015-07-01

    About 10% of a plant's genome is devoted to generating the protein machinery to synthesize, remodel, and deconstruct the cell wall. High-throughput genome sequencing technologies have enabled a reasonably complete inventory of wall-related genes that can be assembled into families of common evolutionary origin. Assigning function to each gene family member has been aided immensely by identification of mutants with visible phenotypes or by chemical and spectroscopic analysis of mutants with 'invisible' phenotypes of modified cell wall composition and architecture that do not otherwise affect plant growth or development. This review connects the inference of gene function on the basis of deviation from the wild type in genetic functional analyses to insights provided by modern analytical techniques that have brought us ever closer to elucidating the sequence structures of the major polysaccharide components of the plant cell wall.

  20. Phenotypic deconstruction of gene circuitry

    NASA Astrophysics Data System (ADS)

    Lomnitz, Jason G.; Savageau, Michael A.

    2013-06-01

    It remains a challenge to obtain a global perspective on the behavioral repertoire of complex nonlinear gene circuits. In this paper, we describe a method for deconstructing complex systems into nonlinear sub-systems, based on mathematically defined phenotypes, which are then represented within a system design space that allows the repertoire of qualitatively distinct phenotypes of the complex system to be identified, enumerated, and analyzed. This method efficiently characterizes large regions of system design space and quickly generates alternative hypotheses for experimental testing. We describe the motivation and strategy in general terms, illustrate its use with a detailed example involving a two-gene circuit with a rich repertoire of dynamic behavior, and discuss experimental means of navigating the system design space.

  1. Identifying neurocognitive phenotypes in autism.

    PubMed Central

    Tager-Flusberg, Helen; Joseph, Robert M

    2003-01-01

    Autism is a complex disorder that is heterogeneous both in its phenotypic expression and its etiology. The search for genes associated with autism and the neurobiological mechanisms that underlie its behavioural symptoms has been hampered by this heterogeneity. Recent studies indicate that within autism, there may be distinct subgroups that can be defined based on differences in neurocognitive profiles. This paper presents evidence for two kinds of subtypes in autism that are defined on the basis of language profiles and on the basis of cognitive profiles. The implications for genetic and neurobiological studies of these subgroups are discussed, with special reference to evidence relating these cognitive phenotypes to volumetric studies of brain size and organization in autism. PMID:12639328

  2. Geno- and phenotypic resistance tests.

    PubMed

    1998-09-01

    There are two types of experimental drug resistance tests, genotypic and phenotypic, that may be able to determine a person's level of resistance to certain HIV drugs. Genotypic resistance testing seeks mutations in the genetic structure of HIV. The analysis is typically conducted from a blood test, and several methods may be used to read the blood sample including a machine that reads gene sequences, a line probe assay, and the GeneChip, which scans blood samples into a computer. Phenotypic resistance testing assesses the quantity of a drug necessary to suppress the virus in a laboratory setting. Both tests require a patient to have a viral load over 1,000 HIV RNA copies, and both are relatively expensive. Neither test can predict which treatments will definitely be successful, as the results are likely to be subjective, depending on the laboratory. Pros and cons for each type of test are listed. Availability, cost, and contact information are provided.

  3. Automated phenotyping of permanent crops

    NASA Astrophysics Data System (ADS)

    McPeek, K. Thomas; Steddom, Karl; Zamudio, Joseph; Pant, Paras; Mullenbach, Tyler

    2017-05-01

    AGERpoint is defining a new technology space for the growers' industry by introducing novel applications for sensor technology and data analysis to growers of permanent crops. Serving data to a state-of-the-art analytics engine from a cutting edge sensor platform, a new paradigm in precision agriculture is being developed that allows growers to understand the unique needs of each tree, bush or vine in their operation. Autonomous aerial and terrestrial vehicles equipped with multiple varieties of remote sensing technologies give AGERpoint the ability to measure key morphological and spectral features of permanent crops. This work demonstrates how such phenotypic measurements combined with machine learning algorithms can be used to determine the variety of crops (e.g., almond and pecan trees). This phenotypic and varietal information represents the first step in enabling growers with the ability to tailor their management practices to individual plants and maximize their economic productivity.

  4. Phenotyping jasmonate regulation of senescence.

    PubMed

    Seltmann, Martin A; Berger, Susanne

    2013-01-01

    Osmotic stress induces several senescence-like processes in leaves, such as specific changes in gene expression and yellowing. These processes are dependent on the accumulation of jasmonates and on intact jasmonate signaling. This chapter describes the treatment of Arabidopsis thaliana leaves with sorbitol as an osmotic stress agent and the determination of the elicited phenotypes encompassing chlorophyll loss, degradation of plastidial membrane lipids, and induction of genes regulated by senescence and jasmonate.

  5. Wine Expertise Predicts Taste Phenotype

    PubMed Central

    Hayes, John E; Pickering, Gary J

    2011-01-01

    Taste phenotypes have long been studied in relation to alcohol intake, dependence, and family history, with contradictory findings. However, on balance – with appropriate caveats about populations tested, outcomes measured and psychophysical methods used – an association between variation in taste responsiveness and some alcohol behaviors is supported. Recent work suggests super-tasting (operationalized via propylthiouracil (PROP) bitterness) not only associates with heightened response but also with more acute discrimination between stimuli. Here, we explore relationships between food and beverage adventurousness and taste phenotype. A convenience sample of wine drinkers (n=330) were recruited in Ontario and phenotyped for PROP bitterness via filter paper disk. They also filled out a short questionnaire regarding willingness to try new foods, alcoholic beverages and wines as well as level of wine involvement, which was used to classify them as a wine expert (n=110) or wine consumer (n=220). In univariate logisitic models, food adventurousness predicted trying new wines and beverages but not expertise. Likewise, wine expertise predicted willingness to try new wines and beverages but not foods. In separate multivariate logistic models, willingness to try new wines and beverages was predicted by expertise and food adventurousness but not PROP. However, mean PROP bitterness was higher among wine experts than wine consumers, and the conditional distribution functions differed between experts and consumers. In contrast, PROP means and distributions did not differ with food adventurousness. These data suggest individuals may self-select for specific professions based on sensory ability (i.e., an active gene-environment correlation) but phenotype does not explain willingness to try new stimuli. PMID:22888174

  6. Wine Expertise Predicts Taste Phenotype.

    PubMed

    Hayes, John E; Pickering, Gary J

    2012-03-01

    Taste phenotypes have long been studied in relation to alcohol intake, dependence, and family history, with contradictory findings. However, on balance - with appropriate caveats about populations tested, outcomes measured and psychophysical methods used - an association between variation in taste responsiveness and some alcohol behaviors is supported. Recent work suggests super-tasting (operationalized via propylthiouracil (PROP) bitterness) not only associates with heightened response but also with more acute discrimination between stimuli. Here, we explore relationships between food and beverage adventurousness and taste phenotype. A convenience sample of wine drinkers (n=330) were recruited in Ontario and phenotyped for PROP bitterness via filter paper disk. They also filled out a short questionnaire regarding willingness to try new foods, alcoholic beverages and wines as well as level of wine involvement, which was used to classify them as a wine expert (n=110) or wine consumer (n=220). In univariate logisitic models, food adventurousness predicted trying new wines and beverages but not expertise. Likewise, wine expertise predicted willingness to try new wines and beverages but not foods. In separate multivariate logistic models, willingness to try new wines and beverages was predicted by expertise and food adventurousness but not PROP. However, mean PROP bitterness was higher among wine experts than wine consumers, and the conditional distribution functions differed between experts and consumers. In contrast, PROP means and distributions did not differ with food adventurousness. These data suggest individuals may self-select for specific professions based on sensory ability (i.e., an active gene-environment correlation) but phenotype does not explain willingness to try new stimuli.

  7. Phenotypic variation in LADD syndrome.

    PubMed Central

    Thompson, E; Pembrey, M; Graham, J M

    1985-01-01

    A mother and son are reported with chronic dacrocystitis, cup shaped ears, hearing loss, abnormal teeth, and poor formation of saliva and tears. They are similar to previously reported cases of lacrimo-auriculo-dento-digital (LADD) syndrome. The variability of expression of this autosomal dominant syndrome is discussed, and it is suggested that poor saliva and tear formation be added to the phenotype. Images PMID:4078868

  8. Animal models of RLS phenotypes.

    PubMed

    Allen, Richard P; Donelson, Nathan C; Jones, Byron C; Li, Yuqing; Manconi, Mauro; Rye, David B; Sanyal, Subhabrata; Winkelmann, Juliane

    2017-03-01

    Restless legs syndrome (RLS) is a complex disorder that involves sensory and motor systems. The major pathophysiology of RLS is low iron concentration in the substantia nigra containing the cell bodies of dopamine neurons that project to the striatum, an area that is crucial for modulating movement. People who have RLS often present with normal iron values outside the brain; recent studies implicate several genes are involved in the syndrome. Like most complex diseases, animal models usually do not faithfully capture the full phenotypic spectrum of "disease," which is a uniquely human construct. Nonetheless, animal models have proven useful in helping to unravel the complex pathophysiology of diseases such as RLS and suggesting novel treatment paradigms. For example, hypothesis-independent genome-wide association studies (GWAS) have identified several genes as increasing the risk for RLS, including BTBD9. Independently, the murine homolog Btbd9 was identified as a candidate gene for iron regulation in the midbrain in mice. The relevance of the phenotype of another of the GWAS identified genes, MEIS1, has also been explored. The role of Btbd9 in iron regulation and RLS-like behaviors has been further evaluated in mice carrying a null mutation of the gene and in fruit flies when the BTBD9 protein is degraded. The BTBD9 and MEIS1 stories originate from human GWAS research, supported by work in a genetic reference population of mice (forward genetics) and further verified in mice, fish flies, and worms. Finally, the role of genetics is further supported by an inbred mouse strain that displays many of the phenotypic characteristics of RLS. The role of animal models of RLS phenotypes is also extended to include periodic limb movements.

  9. Statistical models for trisomic phenotypes

    SciTech Connect

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

    1996-01-01

    Certain genetic disorders are rare in the general population but more common in individuals with specific trisomies, which suggests that the genes involved in the etiology of these disorders may be located on the trisomic chromosome. As with all aneuploid syndromes, however, a considerable degree of variation exists within each phenotype so that any given trait is present only among a subset of the trisomic population. We have previously presented a simple gene-dosage model to explain this phenotypic variation and developed a strategy to map genes for such traits. The mapping strategy does not depend on the simple model but works in theory under any model that predicts that affected individuals have an increased likelihood of disomic homozygosity at the trait locus. This paper explores the robustness of our mapping method by investigating what kinds of models give an expected increase in disomic homozygosity. We describe a number of basic statistical models for trisomic phenotypes. Some of these are logical extensions of standard models for disomic phenotypes, and some are more specific to trisomy. Where possible, we discuss genetic mechanisms applicable to each model. We investigate which models and which parameter values give an expected increase in disomic homozygosity in individuals with the trait. Finally, we determine the sample sizes required to identify the increased disomic homozygosity under each model. Most of the models we explore yield detectable increases in disomic homozygosity for some reasonable range of parameter values, usually corresponding to smaller trait frequencies. It therefore appears that our mapping method should be effective for a wide variety of moderately infrequent traits, even though the exact mode of inheritance is unlikely to be known. 21 refs., 8 figs., 1 tab.

  10. Adaptive evolution of molecular phenotypes

    NASA Astrophysics Data System (ADS)

    Held, Torsten; Nourmohammad, Armita; Lässig, Michael

    2014-09-01

    Molecular phenotypes link genomic information with organismic functions, fitness, and evolution. Quantitative traits are complex phenotypes that depend on multiple genomic loci. In this paper, we study the adaptive evolution of a quantitative trait under time-dependent selection, which arises from environmental changes or through fitness interactions with other co-evolving phenotypes. We analyze a model of trait evolution under mutations and genetic drift in a single-peak fitness seascape. The fitness peak performs a constrained random walk in the trait amplitude, which determines the time-dependent trait optimum in a given population. We derive analytical expressions for the distribution of the time-dependent trait divergence between populations and of the trait diversity within populations. Based on this solution, we develop a method to infer adaptive evolution of quantitative traits. Specifically, we show that the ratio of the average trait divergence and the diversity is a universal function of evolutionary time, which predicts the stabilizing strength and the driving rate of the fitness seascape. From an information-theoretic point of view, this function measures the macro-evolutionary entropy in a population ensemble, which determines the predictability of the evolutionary process. Our solution also quantifies two key characteristics of adapting populations: the cumulative fitness flux, which measures the total amount of adaptation, and the adaptive load, which is the fitness cost due to a population's lag behind the fitness peak.

  11. Polydactyly: phenotypes, genetics and classification.

    PubMed

    Malik, S

    2014-03-01

    Polydactyly is one of the most common hereditary limb malformations featuring additional digits in hands and/or feet. It constituted the highest proportion among the congenital limb defects in various epidemiological surveys. Polydactyly, primarily presenting as an additional pre-axial or post-axial digit of autopod, is a highly heterogeneous condition and depicts broad inter- and intra-familial clinical variability. There is a plethora of polydactyly classification methods reported in the medical literature which approach the heterogeneity in polydactyly in various ways. In this communication, well-characterized, non-syndromic polydactylies in humans are reviewed. The cardinal features, phenotypic variability and molecular advances of each type have been presented. Polydactyly at cellular and developmental levels is mainly a failure in the control of digit number. Interestingly, GLI3 and SHH (ZRS/SHH enhancer), two antagonistic factors known to modulate digit number and identity during development, have also been implicated in polydactyly. Mutations in GLI3 and ZRS/SHH cause overlapping polydactyly phenotypes highlighting shared molecular cascades in the etiology of additional digits, and thus suggesting the lumping of at least six distinct polydactyly entities. However, owing to the extreme phenotypic and clinical heterogeneity witnessed in polydactyly a substantial genetic heterogeneity is expected across different populations and ethnic groups.

  12. Exacerbation phenotyping in chronic obstructive pulmonary disease.

    PubMed

    MacDonald, Martin; Korman, Tony; King, Paul; Hamza, Kais; Bardin, Philip

    2013-11-01

    Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are crucial events but causes remain poorly defined. A method to clinically 'phenotype' AECOPD have been proposed, and 52 hospitalized chronic obstructive pulmonary disease exacerbations according to underlying aetiology have now been prospectively phenotyped. Multiple exacerbation phenotypes were identified. A subpopulation coinfected with virus and bacteria had a significantly longer length of hospital stay, and this pilot study indicates that exacerbation phenotyping may be advantageous.

  13. Multivariate Analysis of Genotype–Phenotype Association

    PubMed Central

    Mitteroecker, Philipp; Cheverud, James M.; Pavlicev, Mihaela

    2016-01-01

    With the advent of modern imaging and measurement technology, complex phenotypes are increasingly represented by large numbers of measurements, which may not bear biological meaning one by one. For such multivariate phenotypes, studying the pairwise associations between all measurements and all alleles is highly inefficient and prevents insight into the genetic pattern underlying the observed phenotypes. We present a new method for identifying patterns of allelic variation (genetic latent variables) that are maximally associated—in terms of effect size—with patterns of phenotypic variation (phenotypic latent variables). This multivariate genotype–phenotype mapping (MGP) separates phenotypic features under strong genetic control from less genetically determined features and thus permits an analysis of the multivariate structure of genotype–phenotype association, including its dimensionality and the clustering of genetic and phenotypic variables within this association. Different variants of MGP maximize different measures of genotype–phenotype association: genetic effect, genetic variance, or heritability. In an application to a mouse sample, scored for 353 SNPs and 11 phenotypic traits, the first dimension of genetic and phenotypic latent variables accounted for >70% of genetic variation present in all 11 measurements; 43% of variation in this phenotypic pattern was explained by the corresponding genetic latent variable. The first three dimensions together sufficed to account for almost 90% of genetic variation in the measurements and for all the interpretable genotype–phenotype association. Each dimension can be tested as a whole against the hypothesis of no association, thereby reducing the number of statistical tests from 7766 to 3—the maximal number of meaningful independent tests. Important alleles can be selected based on their effect size (additive or nonadditive effect on the phenotypic latent variable). This low dimensionality of the

  14. Multivariate Analysis of Genotype-Phenotype Association.

    PubMed

    Mitteroecker, Philipp; Cheverud, James M; Pavlicev, Mihaela

    2016-04-01

    With the advent of modern imaging and measurement technology, complex phenotypes are increasingly represented by large numbers of measurements, which may not bear biological meaning one by one. For such multivariate phenotypes, studying the pairwise associations between all measurements and all alleles is highly inefficient and prevents insight into the genetic pattern underlying the observed phenotypes. We present a new method for identifying patterns of allelic variation (genetic latent variables) that are maximally associated-in terms of effect size-with patterns of phenotypic variation (phenotypic latent variables). This multivariate genotype-phenotype mapping (MGP) separates phenotypic features under strong genetic control from less genetically determined features and thus permits an analysis of the multivariate structure of genotype-phenotype association, including its dimensionality and the clustering of genetic and phenotypic variables within this association. Different variants of MGP maximize different measures of genotype-phenotype association: genetic effect, genetic variance, or heritability. In an application to a mouse sample, scored for 353 SNPs and 11 phenotypic traits, the first dimension of genetic and phenotypic latent variables accounted for >70% of genetic variation present in all 11 measurements; 43% of variation in this phenotypic pattern was explained by the corresponding genetic latent variable. The first three dimensions together sufficed to account for almost 90% of genetic variation in the measurements and for all the interpretable genotype-phenotype association. Each dimension can be tested as a whole against the hypothesis of no association, thereby reducing the number of statistical tests from 7766 to 3-the maximal number of meaningful independent tests. Important alleles can be selected based on their effect size (additive or nonadditive effect on the phenotypic latent variable). This low dimensionality of the genotype-phenotype map

  15. Atypical Ligon Lintless-2 Phenotype in Cotton

    USDA-ARS?s Scientific Manuscript database

    The mutant Li2 is reported to be a dominant single gene mutation in cotton, Gossypium hirsutum L. It has normal vegetative phenotypic morphology and the phenotype of the seed cotton is reported to be fuzzy seed with short fibers. The objective of this research was to report on atypical phenotypes ob...

  16. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities

    PubMed Central

    Tchkonia, Tamara; Zhu, Yi; van Deursen, Jan; Campisi, Judith; Kirkland, James L.

    2013-01-01

    Aging is the largest risk factor for most chronic diseases, which account for the majority of morbidity and health care expenditures in developed nations. New findings suggest that aging is a modifiable risk factor, and it may be feasible to delay age-related diseases as a group by modulating fundamental aging mechanisms. One such mechanism is cellular senescence, which can cause chronic inflammation through the senescence-associated secretory phenotype (SASP). We review the mechanisms that induce senescence and the SASP, their associations with chronic disease and frailty, therapeutic opportunities based on targeting senescent cells and the SASP, and potential paths to developing clinical interventions. PMID:23454759

  17. Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis.

    PubMed

    Lo, Sarah M; Choi, Murim; Liu, Jun; Jain, Dhanpat; Boot, Rolf G; Kallemeijn, Wouter W; Aerts, Johannes M F G; Pashankar, Farzana; Kupfer, Gary M; Mane, Shrikant; Lifton, Richard P; Mistry, Pramod K

    2012-05-17

    Gaucher disease (GD), an inherited macrophage glycosphingolipidosis, manifests with an extraordinary variety of phenotypes that show imperfect correlation with mutations in the GBA gene. In addition to the classic manifestations, patients suffer from increased susceptibility to hematologic and nonhematologic malignancies. The mechanism(s) underlying malignancy in GD is not known, but is postulated to be secondary to macrophage dysfunction and immune dysregulation arising from lysosomal accumulation of glucocerebroside. However, there is weak correlation between GD/cancer phenotype and the systemic burden of glucocerebroside-laden macrophages. Therefore, we hypothesized that genetic modifier(s) may underlie the GD/cancer phenotype. In the present study, the genetic basis of GD/T-cell acute lymphoblastic lymphoma in 2 affected siblings was deciphered through genomic analysis. GBA gene sequencing revealed homozygosity for a novel mutation, D137N. Whole-exome capture and massively parallel sequencing combined with homozygosity mapping identified a homozygous novel mutation in the MSH6 gene that leads to constitutional mismatch repair deficiency syndrome and increased cancer risk. Enzyme studies demonstrated that the D137N mutation in GBA is a pathogenic mutation, and immunohistochemistry confirmed the absence of the MSH6 protein. Therefore, precise phenotype annotation followed by individual genome analysis has the potential to identify genetic modifiers of GD, facilitate personalized management, and provide novel insights into disease pathophysiology.

  18. Alteration of fibroblast phenotype by asbestos-induced autoantibodies.

    PubMed

    Pfau, Jean C; Li, Sheng'ai; Holland, Sara; Sentissi, Jami J

    2011-06-01

    Pulmonary fibrosis is a relentlessly progressive disease for which the etiology can be idiopathic or associated with environmental or occupational exposures. There is not a clear explanation for the chronic and progressive nature of the disease, leaving treatment and prevention options limited. However, there is increasing evidence of an autoimmune component, since fibrotic diseases are often accompanied by production of autoantibodies. Because exposure to silicates such as silica and asbestos can lead to both autoantibodies and pulmonary/pleural fibrosis, these exposures provide an excellent tool for examining the relationship between these outcomes. This study explored the possibility that autoantibodies induced by asbestos exposure in mice would affect fibroblast phenotype. L929 fibroblasts and primary lung fibroblasts were treated with serum IgG from asbestos- or saline-treated mice, and tested for binding using cell-based ELISA, and for phenotypic changes using immunofluorescence, laser scanning cytometry and Sirius Red collagen assay. Autoantibodies in the serum of C57Bl/6 mice exposed to asbestos (but not sera from untreated mice) bound to mouse fibroblasts. The autoantibodies induced differentiation to a myofibroblast phenotype, as demonstrated by increased expression of smooth muscle α-actin (SMA), which was lost when the serum was cleared of IgG. Cells treated with purified IgG of exposed mice produced excess collagen. Using ELISA, we tested serum antibody binding to DNA topoisomerase (Topo) I, vimentin, TGFβ-R, and PDGF-Rα. Antibodies to DNA Topo I and to PDGF-Rα were detected, both of which have been shown by others to be able to affect fibroblast phenotype. The anti-fibroblast antibodies (AFA) also induced STAT-1 activation, implicating the PDGF-R pathway as part of the response to AFA binding. These data support the hypothesis that asbestos induces AFA that modify fibroblast phenotype, and suggest a mechanism whereby autoantibodies may mediate

  19. Using genetic networks and homology to understand the evolution of phenotypic traits.

    PubMed

    McCune, Amy R; Schimenti, John C

    2012-03-01

    Homology can have different meanings for different kinds of biologists. A phylogenetic view holds that homology, defined by common ancestry, is rigorously identified through phylogenetic analysis. Such homologies are taxic homologies (=synapomorphies). A second interpretation, "biological homology" emphasizes common ancestry through the continuity of genetic information underlying phenotypic traits, and is favored by some developmental geneticists. A third kind of homology, deep homology, was recently defined as "the sharing of the genetic regulatory apparatus used to build morphologically and phylogenetically disparate features." Here we explain the commonality among these three versions of homology. We argue that biological homology, as evidenced by a conserved gene regulatory network giving a trait its "essential identity" (a Character Identity Network or "ChIN") must also be a taxic homology. In cases where a phenotypic trait has been modified over the course of evolution such that homology (taxic) is obscured (e.g. jaws are modified gill arches), a shared underlying ChIN provides evidence of this transformation. Deep homologies, where molecular and cellular components of a phenotypic trait precede the trait itself (are phylogenetically deep relative to the trait), are also taxic homologies, undisguised. Deep homologies inspire particular interest for understanding the evolutionary assembly of phenotypic traits. Mapping these deeply homologous building blocks on a phylogeny reveals the sequential steps leading to the origin of phenotypic novelties. Finally, we discuss how new genomic technologies will revolutionize the comparative genomic study of non-model organisms in a phylogenetic context, necessary to understand the evolution of phenotypic traits.

  20. Organ system heterogeneity DB: a database for the visualization of phenotypes at the organ system level.

    PubMed

    Mannil, Deepthi; Vogt, Ingo; Prinz, Jeanette; Campillos, Monica

    2015-01-01

    Perturbations of mammalian organisms including diseases, drug treatments and gene perturbations in mice affect organ systems differently. Some perturbations impair relatively few organ systems while others lead to highly heterogeneous or systemic effects. Organ System Heterogeneity DB (http://mips.helmholtz-muenchen.de/Organ_System_Heterogeneity/) provides information on the phenotypic effects of 4865 human diseases, 1667 drugs and 5361 genetically modified mouse models on 26 different organ systems. Disease symptoms, drug side effects and mouse phenotypes are mapped to the System Organ Class (SOC) level of the Medical Dictionary of Regulatory Activities (MedDRA). Then, the organ system heterogeneity value, a measurement of the systemic impact of a perturbation, is calculated from the relative frequency of phenotypic features across all SOCs. For perturbations of interest, the database displays the distribution of phenotypic effects across organ systems along with the heterogeneity value and the distance between organ system distributions. In this way, it allows, in an easy and comprehensible fashion, the comparison of the phenotypic organ system distributions of diseases, drugs and their corresponding genetically modified mouse models of associated disease genes and drug targets. The Organ System Heterogeneity DB is thus a platform for the visualization and comparison of organ system level phenotypic effects of drugs, diseases and genes.

  1. Organ system heterogeneity DB: a database for the visualization of phenotypes at the organ system level

    PubMed Central

    Mannil, Deepthi; Vogt, Ingo; Prinz, Jeanette; Campillos, Monica

    2015-01-01

    Perturbations of mammalian organisms including diseases, drug treatments and gene perturbations in mice affect organ systems differently. Some perturbations impair relatively few organ systems while others lead to highly heterogeneous or systemic effects. Organ System Heterogeneity DB (http://mips.helmholtz-muenchen.de/Organ_System_Heterogeneity/) provides information on the phenotypic effects of 4865 human diseases, 1667 drugs and 5361 genetically modified mouse models on 26 different organ systems. Disease symptoms, drug side effects and mouse phenotypes are mapped to the System Organ Class (SOC) level of the Medical Dictionary of Regulatory Activities (MedDRA). Then, the organ system heterogeneity value, a measurement of the systemic impact of a perturbation, is calculated from the relative frequency of phenotypic features across all SOCs. For perturbations of interest, the database displays the distribution of phenotypic effects across organ systems along with the heterogeneity value and the distance between organ system distributions. In this way, it allows, in an easy and comprehensible fashion, the comparison of the phenotypic organ system distributions of diseases, drugs and their corresponding genetically modified mouse models of associated disease genes and drug targets. The Organ System Heterogeneity DB is thus a platform for the visualization and comparison of organ system level phenotypic effects of drugs, diseases and genes. PMID:25313158

  2. NIH Mouse Metabolic Phenotyping Centers: the power of centralized phenotyping

    PubMed Central

    Kent Lloyd, K. C.; Cline, Gary W.; Wasserman, David H.

    2013-01-01

    The Mouse Metabolic Phenotyping Centers (MMPCs) were founded in 2001 by the National Institutes of Health (NIH) to advance biomedical research by providing the scientific community with standardized, high-quality phenotyping services for mouse models of diabetes, obesity, and their complications. The intent is to allow researchers to take optimum advantage of the many new mouse models produced in labs and in high-throughput public efforts. The six MMPCs are located at universities around the country and perform complex metabolic tests in intact mice and hormone and analyte assays in tissues on a fee-for-service basis. Testing is subsidized by the NIH in order to reduce the barriers for mouse researchers. Although data derived from these tests belong to the researcher submitting mice or tissues, these data are archived after publication in a public database run by the MMPC Coordinating and Bioinformatics Unit. It is hoped that data from experiments performed in many mouse models of metabolic diseases, using standard protocols, will be useful in understanding the nature of these complex disorders. The current areas of expertise include energy balance and body composition, insulin action and secretion, whole-body and tissue carbohydrate and lipid metabolism, cardiovascular and renal function, and metabolic pathway kinetics. In addition to providing services, the MMPC staff provides expertise and advice to researchers, and works to develop and refine test protocols to best meet the community’s needs in light of current scientific developments. Test technology is disseminated by publications and through annual courses. PMID:22940748

  3. Global Phenotypic Screening for Antimalarials

    PubMed Central

    Guiguemde, W. Armand; Shelat, Anang A.; Garcia-Bustos, Jose F.; Diagana, Thierry; Gamo, Francisco-Javier; Guy, R. Kiplin

    2012-01-01

    Malaria, a devastating infectious disease caused by Plasmodium spp., leads to roughly 655,000 deaths per year, mostly of African children. To compound the problem, drug resistance has emerged to all classical antimalarials and may be emerging for artemisinin-based combination therapies. To address the need for new antimalarials with novel mechanisms, several groups carried out phenotypic screening campaigns to identify compounds inhibiting growth of the blood stages of Plasmodium falciparum. In this review, we describe the characterization of these compounds, explore currently ongoing strategies to develop lead molecules, and endorse the concept of a “malaria box” of publicly accessible active compounds. PMID:22284359

  4. [Plasticity of the cellular phenotype].

    PubMed

    Chneiweiss, Hervé

    2011-01-01

    The tragical consequences of the Hiroshima and Nagasaki atomic bombs in 1945 were to lead to the discovery of hematopoietic stem cells and their phenotypic plasticity, in response to environmental factors. These concepts were much later extended to the founding cells of other tissues. In the following collection of articles, the mechanisms underlying this plasticity, at the frontiers of developmental biology and oncology, are illustrated in the case of various cell types of neural origin and of some tumours. © Société de Biologie, 2011.

  5. Phenotype of normal hairline maturation.

    PubMed

    Rassman, William R; Pak, Jae P; Kim, Jino

    2013-08-01

    Hairlines change shape with age, starting at birth. A good head of hair is frequently present some time after ages 3 to 5 years. The look of childhood has its corresponding hairline, and, as the child grows and develops into adulthood, facial morphology migrate changes from a childlike look to a more mature look. This article discusses the dynamics of hairline evolution and the phenotypic variations of the front and side hairlines in men and women. A modeling system is introduced that provides a common language to define the various anatomic points of the full range of hairlines.

  6. The Human Phenotype Ontology in 2017

    PubMed Central

    Köhler, Sebastian; Vasilevsky, Nicole A.; Engelstad, Mark; Foster, Erin; McMurry, Julie; Aymé, Ségolène; Baynam, Gareth; Bello, Susan M.; Boerkoel, Cornelius F.; Boycott, Kym M.; Brudno, Michael; Buske, Orion J.; Chinnery, Patrick F.; Cipriani, Valentina; Connell, Laureen E.; Dawkins, Hugh J.S.; DeMare, Laura E.; Devereau, Andrew D.; de Vries, Bert B.A.; Firth, Helen V.; Freson, Kathleen; Greene, Daniel; Hamosh, Ada; Helbig, Ingo; Hum, Courtney; Jähn, Johanna A.; James, Roger; Krause, Roland; F. Laulederkind, Stanley J.; Lochmüller, Hanns; Lyon, Gholson J.; Ogishima, Soichi; Olry, Annie; Ouwehand, Willem H.; Pontikos, Nikolas; Rath, Ana; Schaefer, Franz; Scott, Richard H.; Segal, Michael; Sergouniotis, Panagiotis I.; Sever, Richard; Smith, Cynthia L.; Straub, Volker; Thompson, Rachel; Turner, Catherine; Turro, Ernest; Veltman, Marijcke W.M.; Vulliamy, Tom; Yu, Jing; von Ziegenweidt, Julie; Zankl, Andreas; Züchner, Stephan; Zemojtel, Tomasz; Jacobsen, Julius O.B.; Groza, Tudor; Smedley, Damian; Mungall, Christopher J.; Haendel, Melissa; Robinson, Peter N.

    2017-01-01

    Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology. PMID:27899602

  7. The Human Phenotype Ontology in 2017.

    PubMed

    Köhler, Sebastian; Vasilevsky, Nicole A; Engelstad, Mark; Foster, Erin; McMurry, Julie; Aymé, Ségolène; Baynam, Gareth; Bello, Susan M; Boerkoel, Cornelius F; Boycott, Kym M; Brudno, Michael; Buske, Orion J; Chinnery, Patrick F; Cipriani, Valentina; Connell, Laureen E; Dawkins, Hugh J S; DeMare, Laura E; Devereau, Andrew D; de Vries, Bert B A; Firth, Helen V; Freson, Kathleen; Greene, Daniel; Hamosh, Ada; Helbig, Ingo; Hum, Courtney; Jähn, Johanna A; James, Roger; Krause, Roland; F Laulederkind, Stanley J; Lochmüller, Hanns; Lyon, Gholson J; Ogishima, Soichi; Olry, Annie; Ouwehand, Willem H; Pontikos, Nikolas; Rath, Ana; Schaefer, Franz; Scott, Richard H; Segal, Michael; Sergouniotis, Panagiotis I; Sever, Richard; Smith, Cynthia L; Straub, Volker; Thompson, Rachel; Turner, Catherine; Turro, Ernest; Veltman, Marijcke W M; Vulliamy, Tom; Yu, Jing; von Ziegenweidt, Julie; Zankl, Andreas; Züchner, Stephan; Zemojtel, Tomasz; Jacobsen, Julius O B; Groza, Tudor; Smedley, Damian; Mungall, Christopher J; Haendel, Melissa; Robinson, Peter N

    2017-01-04

    Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.

  8. Modifying Curriculum. Module.

    ERIC Educational Resources Information Center

    Petch, Beverly

    This module on modifying curriculum is 1 in a series of 10 modules written for vocational education teacher education programs. It is designed to prepare the learner to identify the varying learning styles of learners and to modify curriculum by providing alternative techniques for curriculum modification. Introductory materials include the…

  9. Phenotyping bananas for drought resistance

    PubMed Central

    Ravi, Iyyakkutty; Uma, Subbaraya; Vaganan, Muthu Mayil; Mustaffa, Mohamed M.

    2012-01-01

    Drought has emerged as one of the major constraints in banana production. Its effects are pronounced substantially in the tropics and sub-tropics of the world due to climate change. Bananas are quite sensitive to drought; however, genotypes with “B” genome are more tolerant to abiotic stresses than those solely based on “A” genome. In particular, bananas with “ABB” genomes are more tolerant to drought and other abiotic stresses than other genotypes. A good phenotyping plan is a prerequisite for any improvement program for targeted traits. In the present article, known drought tolerant traits of other crop plants are validated in bananas with different genomic backgrounds and presented. Since, banana is recalcitrant to breeding, strategies for making hybrids between different genomic backgrounds are also discussed. Stomatal conductance, cell membrane stability (CMS), leaf emergence rate, rate of leaf senescence, RWC, and bunch yield under soil moisture deficit stress are some of the traits associated with drought tolerance. Among these stress bunch yield under drought should be given top priority for phenotyping. In the light of recently released Musa genome draft sequence, the molecular breeders may have interest in developing molecular markers for drought resistance. PMID:23443573

  10. Exceptional cognitive ability: the phenotype.

    PubMed

    Lubinski, David

    2009-07-01

    Characterizing the outcomes related to the phenotype of exceptional cognitive abilities has been feasible in recent years due to the availability of large samples of intellectually precocious adolescents identified by modern talent searches that have been followed-up longitudinally over multiple decades. The level and pattern of cognitive abilities, even among participants within the top 1% of general intellectual ability, are related to differential developmental trajectories and important life accomplishments: The likelihood of earning a doctorate, earning exceptional compensation, publishing novels, securing patents, and earning tenure at a top university (and the academic disciplines within which tenure is most likely to occur) all vary as a function of individual differences in cognitive abilities assessed decades earlier. Individual differences that distinguish the able (top 1 in 100) from the exceptionally able (top 1 in 10,000) during early adolescence matter in life, and, given the heritability of general intelligence, they suggest that understanding the genetic and environmental origins of exceptional abilities should be a high priority for behavior genetic research, especially because the results for extreme groups could differ from the rest of the population. In addition to enhancing our understanding of the etiology of general intelligence at the extreme, such inquiry may also reveal fundamental determinants of specific abilities, like mathematical versus verbal reasoning, and the distinctive phenotypes that contrasting ability patterns are most likely to eventuate in at extraordinary levels.

  11. Phenotypic variability in Patau syndrome.

    PubMed

    Caba, Lavinia; Rusu, Cristina; Butnariu, Lacramioara; Panzaru, Monica; Braha, Elena; Volosciuc, M; Popescu, Roxana; Gramescu, Mihaela; Bujoran, C; Martiniuc, Violeta; Covic, M; Gorduza, E V

    2013-01-01

    Patau syndrome has an incidence of 1/10.000-20.000, the clinical diagnosis being suggested by the triad cleft lip and palate, microphthalmia/anophthalmia and postaxial polydactyly. Most frequent cytogenetic abnormality is free and homogeneous trisomy 13 (80.0%), rarely being detected trisomy mosaics or Robertsonian translocations. The objective of the study was to identify phenotypic features of trisomy 13. The retrospective study was conducted on a trial group of 14 cases diagnosed cytogenetically with trisomy 13 between January 2000 and December 2012 at lasi Medical Genetics Centre. Of the 14 cases, 3 were evaluated pathologically (two aborted foetuses and one stillborn), 8 cases were detected in the neonatal period, and 3 in infancy. Clinical diagnosis was supported by the identification of a model of abnormal development, mainly characterized by: maxillary cleft (lip and palate--5 cases; lip--1 case), ocular abnormalities (microphthalmia/anophthalmia--7 cases; cyclopia--1 case), postaxial polydactyly (7 cases), scalp defects (6 cases), congenital heart anomalies (10 cases, 6 patients with atrial septal defect), complete holoprosencephaly (4 cases), ear abnormalities (11 cases), broad nasal root (10 cases). An important issue in confirming the phenotypic variability of Patau syndrome is that the classic clinical triad was identified only in one case. Patau syndrome is a disease with variable expression and is characterized by a pattern of abnormal prenatal development characterized by facial dysmorphia, polydactyly and severe birth defects (heart, brain) that generate an increased in utero and perinatal mortality.

  12. Phenotypic plasticity in bacterial plasmids.

    PubMed Central

    Turner, Paul E

    2004-01-01

    Plasmid pB15 was previously shown to evolve increased horizontal (infectious) transfer at the expense of reduced vertical (intergenerational) transfer and vice versa, a key trade-off assumed in theories of parasite virulence. Whereas the models predict that susceptible host abundance should determine which mode of transfer is selectively favored, host density failed to mediate the trade-off in pB15. One possibility is that the plasmid's transfer deviates from the assumption that horizontal spread (conjugation) occurs in direct proportion to cell density. I tested this hypothesis using Escherichia coli/pB15 associations in laboratory serial culture. Contrary to most models of plasmid transfer kinetics, my data show that pB15 invades static (nonshaking) bacterial cultures only at intermediate densities. The results can be explained by phenotypic plasticity in traits governing plasmid transfer. As cells become more numerous, the plasmid's conjugative transfer unexpectedly declines, while the trade-off between transmission routes causes vertical transfer to increase. Thus, at intermediate densities the plasmid's horizontal transfer can offset selection against plasmid-bearing cells, but at high densities pB15 conjugates so poorly that it cannot invade. I discuss adaptive vs. nonadaptive causes for the phenotypic plasticity, as well as potential mechanisms that may lead to complex transfer dynamics of plasmids in liquid environments. PMID:15166133

  13. A quantitative neural network approach to understanding aging phenotypes

    PubMed Central

    Ash, Jessica A.; Rapp, Peter R.

    2015-01-01

    Basic research on neurocognitive aging has traditionally adopted a reductionist approach in the search for the basis of cognitive preservation versus decline. However, increasing evidence suggests that a network level understanding of the brain can provide additional novel insight into the structural and functional organization from which complex behavior and dysfunction emerge. Using graph theory as a mathematical framework to characterize neural networks, recent data suggest that alterations in structural and functional networks may contribute to individual differences in cognitive phenotypes in advanced aging. This paper reviews literature that defines network changes in healthy and pathological aging phenotypes, while highlighting the substantial overlap in key features and patterns observed across aging phenotypes. Consistent with current efforts in this area, here we outline one analytic strategy that attempts to quantify graph theory metrics more precisely, with the goal of improving diagnostic sensitivity and predictive accuracy for differential trajectories in neurocognitive aging. Ultimately, such an approach may yield useful measures for gauging the efficacy of potential preventative interventions and disease modifying treatments early in the course of aging. PMID:24548925

  14. Virus Infection Suppresses Nicotiana benthamiana Adaptive Phenotypic Plasticity

    PubMed Central

    Bedhomme, Stéphanie; Elena, Santiago F.

    2011-01-01

    Competition and parasitism are two important selective forces that shape life-histories, migration rates and population dynamics. Recently, it has been shown in various pathosystems that parasites can modify intraspecific competition, thus generating an indirect cost of parasitism. Here, we investigated if this phenomenon was present in a plant-potyvirus system using two viruses of different virulence (Tobacco etch virus and Turnip mosaic virus). Moreover, we asked if parasitism interacted with the shade avoidance syndrome, the plant-specific phenotypic plasticity in response to intraspecific competition. Our results indicate that the modification of intraspecific competition by parasitism is not present in the Nicotiana benthamiana – potyvirus system and suggests that this phenomenon is not universal but depends on the peculiarities of each pathosystem. However, whereas the healthy N. benthamiana presented a clear shade avoidance syndrome, this phenotypic plasticity totally disappeared when the plants were infected with TEV and TuMV, very likely resulting in a fitness loss and being another form of indirect cost of parasitism. This result suggests that the suppression or the alteration of adaptive phenotypic plasticity might be a component of virulence that is often overlooked. PMID:21359142

  15. Phenotypic heterogeneity and genotypic instability in coupled cellular arrays

    NASA Astrophysics Data System (ADS)

    Klevecz, Robert R.

    1998-12-01

    The dynamic origins of phenotypic heterogeneity and genotypic instability and hypermutation have been investigated in simulated tissues comprised of 900-25 600 cells each represented by initially identical Rossler attractors running in the chaotic domain. This attractor, representing the cell cycle behavior of individual cells in the array, has previously been used to model the dynamic behavior of mammalian cells in culture. In these tissue constructs, the behavior of an individual cell is modified by its interactions with its immediate neighbors as a consequence of diffusive coupling through one of the variables. Differentiation within the initially identical population of attractors is manifested as a position dependent set of novel stable trajectories in phase space that are revealed through the use of return maps. These self-mapping patterns, which we define as the phenotype of the cell, are periodic and stable over a considerable period of time. A comparison of tissues whose individual cell cycle attractor phases describe an archimedean spiral with those that exhibit S-T chaos, or turbulence, suggests that the heterogeneous phenotype of tumor tissues is better modeled by turbulence. Instability in the spiral array exists primarily at the boundary between periodic regions of differing phase and trajectory, and involves infrequent excursions by these boundary cells away from their stables trajectories. Such instabilities are hypothesized to play an important role in the amplification, hypermutation, and gene conversion events seen in certain normal biological tissues and tumors.

  16. Virus infection suppresses Nicotiana benthamiana adaptive phenotypic plasticity.

    PubMed

    Bedhomme, Stéphanie; Elena, Santiago F

    2011-02-17

    Competition and parasitism are two important selective forces that shape life-histories, migration rates and population dynamics. Recently, it has been shown in various pathosystems that parasites can modify intraspecific competition, thus generating an indirect cost of parasitism. Here, we investigated if this phenomenon was present in a plant-potyvirus system using two viruses of different virulence (Tobacco etch virus and Turnip mosaic virus). Moreover, we asked if parasitism interacted with the shade avoidance syndrome, the plant-specific phenotypic plasticity in response to intraspecific competition. Our results indicate that the modification of intraspecific competition by parasitism is not present in the Nicotiana benthamiana--potyvirus system and suggests that this phenomenon is not universal but depends on the peculiarities of each pathosystem. However, whereas the healthy N. benthamiana presented a clear shade avoidance syndrome, this phenotypic plasticity totally disappeared when the plants were infected with TEV and TuMV, very likely resulting in a fitness loss and being another form of indirect cost of parasitism. This result suggests that the suppression or the alteration of adaptive phenotypic plasticity might be a component of virulence that is often overlooked.

  17. Environmental and genetic modulation of the phenotypic expression of antibiotic resistance.

    PubMed

    Hughes, Diarmaid; Andersson, Dan I

    2017-03-08

    Antibiotic resistance can be acquired by mutation or horizontal transfer of a resistance gene, and generally an acquired mechanism results in a predictable increase in phenotypic resistance. However, recent findings suggest that the environment and/or the genetic context can modify the phenotypic expression of specific resistance genes/mutations. An important implication from these findings is that a given genotype does not always result in the expected phenotype. This dissociation of genotype and phenotype has important consequences for clinical bacteriology and for our ability to predict resistance phenotypes from genetics and DNA sequences. A related problem concerns the degree to which the genes/mutations currently identified in vitro can fully explain the in vivo resistance phenotype, or whether there is a significant additional amount of presently unknown mutations/genes (genetic 'dark matter') that could contribute to resistance in clinical isolates. Finally, a very important question is whether/how we can identify the genetic features that contribute to making a successful pathogen, and predict why some resistant clones are very successful and spread globally? In this review, we describe different environmental and genetic factors that influence phenotypic expression of antibiotic resistance genes/mutations and how this information is needed to understand why particular resistant clones spread worldwide and to what extent we can use DNA sequences to predict evolutionary success.

  18. Environmental and genetic modulation of the phenotypic expression of antibiotic resistance

    PubMed Central

    Andersson, Dan I

    2017-01-01

    Abstract Antibiotic resistance can be acquired by mutation or horizontal transfer of a resistance gene, and generally an acquired mechanism results in a predictable increase in phenotypic resistance. However, recent findings suggest that the environment and/or the genetic context can modify the phenotypic expression of specific resistance genes/mutations. An important implication from these findings is that a given genotype does not always result in the expected phenotype. This dissociation of genotype and phenotype has important consequences for clinical bacteriology and for our ability to predict resistance phenotypes from genetics and DNA sequences. A related problem concerns the degree to which the genes/mutations currently identified in vitro can fully explain the in vivo resistance phenotype, or whether there is a significant additional amount of presently unknown mutations/genes (genetic ‘dark matter’) that could contribute to resistance in clinical isolates. Finally, a very important question is whether/how we can identify the genetic features that contribute to making a successful pathogen, and predict why some resistant clones are very successful and spread globally? In this review, we describe different environmental and genetic factors that influence phenotypic expression of antibiotic resistance genes/mutations and how this information is needed to understand why particular resistant clones spread worldwide and to what extent we can use DNA sequences to predict evolutionary success. PMID:28333270

  19. Modifying toxicokinetics with antidotes.

    PubMed

    Baud, F J; Borron, S W; Bismuth, C

    1995-12-01

    Five approaches may be described through which antidotes can modify toxicokinetics: (1) Decreased bioavailability of the toxins; (2) Cellular redistribution of the toxin in the organism; (3) Promotion of elimination in an unchanged form; (4) Slowing of metabolic activation pathways; (5) Acceleration of metabolic deactivation pathways. However, the ability to modify toxicokinetics with a new treatment, while demonstrating an understanding of the mechanism of action, must never be construed to be, in and of itself, the goal of therapy. The ultimate evaluation of an antidote modifying toxicokinetics is strictly clinical.

  20. Genetic modifier loci of mouse Mfrp(rd6) identified by quantitative trait locus analysis.

    PubMed

    Won, Jungyeon; Charette, Jeremy R; Philip, Vivek M; Stearns, Timothy M; Zhang, Weidong; Naggert, Jürgen K; Krebs, Mark P; Nishina, Patsy M

    2014-01-01

    The identification of genes that modify pathological ocular phenotypes in mouse models may improve our understanding of disease mechanisms and lead to new treatment strategies. Here, we identify modifier loci affecting photoreceptor cell loss in homozygous Mfrp(rd6) mice, which exhibit a slowly progressive photoreceptor degeneration. A cohort of 63 F2 homozygous Mfrp(rd6) mice from a (B6.C3Ga-Mfrp(rd6)/J × CAST/EiJ) F1 intercross exhibited a variable number of cell bodies in the retinal outer nuclear layer at 20 weeks of age. Mice were genotyped with a panel of single nucleotide polymorphism markers, and genotypes were correlated with phenotype by quantitative trait locus (QTL) analysis to map modifier loci. A genome-wide scan revealed a statistically significant, protective candidate locus on CAST/EiJ Chromosome 1 and suggestive modifier loci on Chromosomes 6 and 11. Multiple regression analysis of a three-QTL model indicated that the modifier loci on Chromosomes 1 and 6 together account for 26% of the observed phenotypic variation, while the modifier locus on Chromosome 11 explains only an additional 4%. Our findings indicate that the severity of the Mfrp(rd6) retinal degenerative phenotype in mice depends on the strain genetic background and that a significant modifier locus on CAST/EiJ Chromosome 1 protects against Mfrp(rd6)-associated photoreceptor loss.

  1. Genetic and environmental modifiers of Wilson disease.

    PubMed

    Medici, Valentina; Weiss, Karl-Heinz

    2017-01-01

    Wilson disease (WD) is characterized by remarkable variety in its phenotypic presentation. Patients with WD can present with hepatic, neurologic, and psychiatric symptoms combined in different and unpredictable ways. Importantly, no convincing phenotype-genotype correlation has ever been identified, opening the possibility that other genes, aside from ATPase copper-transporting beta (ATP7B), are involved in the pathogenesis of this condition. In addition, modifier genes, or genes that can affect the expression of other genes, may be involved. Clinical and basic science data indicate that environmental and dietary factors can potentially modify gene expression in WD and, consequently, its clinical presentation and course. In particular, previously studied genes include copper metabolism domain-containing 1 (COMMD1), antioxidant 1 copper chaperone (ATOX1), X-linked inhibitor of apoptosis (XIAP), apolipoprotein E (APOE), hemochromatosis (HFE), and 5,10-methylenetetrahydrofolate reductase (MTHFR). Dietary factors include iron and methyl group donors which could affect methionine metabolism and epigenetic mechanisms of gene expression regulation. Most of the work conducted in this field is in its initial stages but it has the potential to change the diagnosis and treatment of WD. © 2017 Elsevier B.V. All rights reserved.

  2. Adrenoleukodystrophy: phenotypic variability and implications for therapy.

    PubMed

    Moser, H W; Moser, A B; Smith, K D; Bergin, A; Borel, J; Shankroff, J; Stine, O C; Merette, C; Ott, J; Krivit, W

    1992-01-01

    X-linked adrenoleukodystrophy (ALD) is a relatively common disorder that shows a great deal of phenotypic variability. Approximately half of the patients have the rapidly progressive childhood cerebral form that is associated with an inflammatory response in brain and leads to total disability or death during the first decade. Twenty five per cent or more of the patients have adrenomyeloneuropathy (AMN), a form that progresses slowly, involves the spinal cord mainly, shows little or no inflammatory response, manifests in adulthood, and is compatible with a near-normal life span. The two forms of the disease occur frequently within the same kindreds and nuclear families. Segregation analysis based on 3862 individuals in 89 kindreds points to the existence of an autosomal modifier locus with a likelihood ratio of 20:1. In addition, we present preliminary results of three types of therapy. Two hundred and four patients have received a dietary regimen that combines the administration of oils containing mono-unsaturated fatty acids (oleic and erucic) with the restricted intake of very long-chain fatty acids. This regimen normalizes the levels of satured very long-chain fatty acids in plasma within 4 weeks. It appears to improve peripheral nerve function in patients with AMN, and a large-scale trial is in progress to determine whether it can prevent the onset of neurological involvement in patients who have the biochemical abnormality of ALD but are neurologically intact. We report early results of bone marrow transplantation in 14 patients. There is encouraging but still preliminary evidence that transplantation can arrest the progression of the disease in patients with mild neurological involvement. There is urgent need to develop methods to combat the rapid progression of the cerebral forms of the disease, which so far has resisted therapeutic intervention, including immunosuppression or the administration of immunoglobulin.

  3. Estrogen, inflammation, and platelet phenotype.

    PubMed

    Miller, Virginia M; Jayachandran, Muthuvel; Hashimoto, Kazumori; Heit, John A; Owen, Whyte G

    2008-01-01

    Although exogenous estrogenic therapies increase the risk of thrombosis, the effects of estrogen on formed elements of blood are uncertain. This article examines the genomic and nongenomic actions of estrogen on platelet phenotype that may contribute to increased thrombotic risk. To determine aggregation, secretion, protein expression, and thrombin generation, platelets were collected from experimental animals of varying hormonal status and from women enrolled in the Kronos Early Estrogen Prevention Study. Estrogen receptor beta predominates in circulating platelets. Estrogenic treatment in ovariectomized animals decreased platelet aggregation and adenosine triphosphate (ATP) secretion. However, acute exposure to 17beta-estradiol did not reverse decreases in platelet ATP secretion invoked by lipopolysaccharide. Thrombin generation was positively correlated to the number of circulating microvesicles expressing phosphatidylserine. Assessing the effect of estrogen treatments on blood platelets may lead to new ways of identifying women at risk for adverse thrombotic events with such therapies.

  4. Phenotypic plasticity and experimental evolution.

    PubMed

    Garland, Theodore; Kelly, Scott A

    2006-06-01

    Natural or artificial selection that favors higher values of a particular trait within a given population should engender an evolutionary response that increases the mean value of the trait. For this prediction to hold, the phenotypic variance of the trait must be caused in part by additive effects of alleles segregating in the population, and also the trait must not be too strongly genetically correlated with other traits that are under selection. Another prediction, rarely discussed in the literature, is that directional selection should favor alleles that increase phenotypic plasticity in the direction of selection, where phenotypic plasticity is defined as the ability of one genotype to produce more than one phenotype when exposed to different environments. This prediction has received relatively little empirical attention. Nonetheless, many laboratory experiments impose selection regimes that could allow for the evolution of enhanced plasticity (e.g. desiccation trials with Drosophila that last for several hours or days). We review one example that involved culturing of Drosophila on lemon for multiple generations and then tested for enhanced plasticity of detoxifying enzymes. We also review an example with vertebrates that involves selective breeding for high voluntary activity levels in house mice, targeting wheel-running behavior on days 5+6 of a 6-day wheel exposure. This selection regime allows for the possibility of wheel running itself or subordinate traits that support such running to increase in plasticity over days 1-4 of wheel access. Indeed, some traits, such as the concentration of the glucose transporter GLUT4 in gastrocnemius muscle, do show enhanced plasticity in the selected lines over a 5-6 day period. In several experiments we have housed mice from both the Selected (S) and Control (C) lines with or without wheel access for several weeks to test for differences in plasticity (training effects). A variety of patterns were observed, including

  5. Phenotypic checkpoints regulate neuronal development.

    PubMed

    Ben-Ari, Yehezkel; Spitzer, Nicholas C

    2010-11-01

    Nervous system development proceeds by sequential gene expression mediated by cascades of transcription factors in parallel with sequences of patterned network activity driven by receptors and ion channels. These sequences are cell type- and developmental stage-dependent and modulated by paracrine actions of substances released by neurons and glia. How and to what extent these sequences interact to enable neuronal network development is not understood. Recent evidence demonstrates that CNS development requires intermediate stages of differentiation providing functional feedback that influences gene expression. We suggest that embryonic neuronal functions constitute a series of phenotypic checkpoint signatures; neurons failing to express these functions are delayed or developmentally arrested. Such checkpoints are likely to be a general feature of neuronal development and constitute presymptomatic signatures of neurological disorders when they go awry.

  6. Epithelial phenotype in total sclerocornea

    PubMed Central

    Yeh, Lung-Kun; Chen, Hung-Chi; Chang, Anna Marie; Ho, Yi-Ju; Chang, Shirley H.L.; Yang, Unique

    2014-01-01

    Purpose To understand whether the epithelial phenotype in total sclerocornea is corneal or conjunctival in origin. Methods Four cases of total sclerocornea (male:female = 1:3; mean age = 5.4±4.3; 1–11 years old) who received penetrating keratoplasty (PKP) at our hospital between 2008 and 2011 were included. Corneal buttons obtained during PKP were used for transmission electron microscopy (TEM) as well as immunoconfocal microscopy for cytokeratins 3, 12, and 13, goblet cell mucin MUC5AC, connexin 43, stem cell markers p63 and ABCG2, laminin-5, and fibronectin. Results After a mean follow-up period of 38.8±14.0 (12–54) months, the grafts remained clear in half of the patients. TEM examination revealed a markedly attenuated Bowman’s layer in the scleralized corneas, with irregular and variably thinned collagen lamellar layers, and disorganization and random distribution of collagen fibrils, which were much larger in diameter compared with a normal cornea. Immunoconfocal microscopy showed that keratin 3 was expressed in all four patients, while p63, ABCG2, and MUC5AC were all absent. Cornea-specific keratin 12 was universally expressed in Patients 1 to 3, while mucosa (including conjunctiva)-specific keratin 13 was negative in these patients. Interestingly, keratin 12 and 13 were expressed in Patient 4 in a mutually exclusive manner. Linear expression of laminin-5 in the basement membrane zone and similar expression of fibronectin were observed. Conclusions The epithelia in total sclerocornea are essentially corneal in phenotype, but in the event of massive corneal angiogenesis, invasion by the conjunctival epithelium is possible. PMID:24744607

  7. FYPO: the fission yeast phenotype ontology.

    PubMed

    Harris, Midori A; Lock, Antonia; Bähler, Jürg; Oliver, Stephen G; Wood, Valerie

    2013-07-01

    To provide consistent computable descriptions of phenotype data, PomBase is developing a formal ontology of phenotypes observed in fission yeast. The fission yeast phenotype ontology (FYPO) is a modular ontology that uses several existing ontologies from the open biological and biomedical ontologies (OBO) collection as building blocks, including the phenotypic quality ontology PATO, the Gene Ontology and Chemical Entities of Biological Interest. Modular ontology development facilitates partially automated effective organization of detailed phenotype descriptions with complex relationships to each other and to underlying biological phenomena. As a result, FYPO supports sophisticated querying, computational analysis and comparison between different experiments and even between species. FYPO releases are available from the Subversion repository at the PomBase SourceForge project page (https://sourceforge.net/p/pombase/code/HEAD/tree/phenotype_ontology/). The current version of FYPO is also available on the OBO Foundry Web site (http://obofoundry.org/).

  8. Cystic fibrosis modifier genes.

    PubMed Central

    Davies, Jane; Alton, Eric; Griesenbach, Uta

    2005-01-01

    Since the recognition that CFTR genotype was not a good predictor of pulmonary disease severity in CF, several candidate modifier genes have been identified. It is unlikely that a single modifier gene will be found, but more probable that several haplotypes in combination may contribute, which in itself presents a major methodological challenge. The aims of such studies are to increase our understanding of disease pathogenesis, to aid prognosis and ultimately to lead to the development of novel treatments. PMID:16025767

  9. Geographic atrophy phenotype identification by cluster analysis.

    PubMed

    Monés, Jordi; Biarnés, Marc

    2017-07-20

    To identify ocular phenotypes in patients with geographic atrophy secondary to age-related macular degeneration (GA) using a data-driven cluster analysis. This was a retrospective analysis of data from a prospective, natural history study of patients with GA who were followed for ≥6 months. Cluster analysis was used to identify subgroups within the population based on the presence of several phenotypic features: soft drusen, reticular pseudodrusen (RPD), primary foveal atrophy, increased fundus autofluorescence (FAF), greyish FAF appearance and subfoveal choroidal thickness (SFCT). A comparison of features between the subgroups was conducted, and a qualitative description of the new phenotypes was proposed. The atrophy growth rate between phenotypes was then compared. Data were analysed from 77 eyes of 77 patients with GA. Cluster analysis identified three groups: phenotype 1 was characterised by high soft drusen load, foveal atrophy and slow growth; phenotype 3 showed high RPD load, extrafoveal and greyish FAF appearance and thin SFCT; the characteristics of phenotype 2 were midway between phenotypes 1 and 3. Phenotypes differed in all measured features (p≤0.013), with decreases in the presence of soft drusen, foveal atrophy and SFCT seen from phenotypes 1 to 3 and corresponding increases in high RPD load, high FAF and greyish FAF appearance. Atrophy growth rate differed between phenotypes 1, 2 and 3 (0.63, 1.91 and 1.73 mm(2)/year, respectively, p=0.0005). Cluster analysis identified three distinct phenotypes in GA. One of them showed a particularly slow growth pattern. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  10. The cognitive phenotype of spina bifida meningomyelocele.

    PubMed

    Dennis, Maureen; Barnes, Marcia A

    2010-01-01

    A cognitive phenotype is a product of both assets and deficits that specifies what individuals with spina bifida meningomyelocele (SBM) can and cannot do and why they can or cannot do it. In this article, we review the cognitive phenotype of SBM and describe the processing assets and deficits that cut within and across content domains, sensory modality, and material, including studies from our laboratory and other investigations. We discuss some implications of the SBM cognitive phenotype for assessment, rehabilitation, and research.

  11. Biological response modifiers

    SciTech Connect

    Weller, R.E.

    1991-10-01

    Much of what used to be called immunotherapy is now included in the term biological response modifiers. Biological response modifiers (BRMs) are defined as those agents or approaches that modify the relationship between the tumor and host by modifying the host's biological response to tumor cells with resultant therapeutic effects.'' Most of the early work with BRMs centered around observations of spontaneous tumor regression and the association of tumor regression with concurrent bacterial infections. The BRM can modify the host response in the following ways: Increase the host's antitumor responses through augmentation and/or restoration of effector mechanisms or mediators of the host's defense or decrease the deleterious component by the host's reaction; Increase the host's defenses by the administration of natural biologics (or the synthetic derivatives thereof) as effectors or mediators of an antitumor response; Augment the host's response to modified tumor cells or vaccines, which might stimulate a greater response by the host or increase tumor-cell sensitivity to an existing response; Decrease the transformation and/or increase differentiation (maturation) of tumor cells; or Increase the ability of the host to tolerate damage by cytotoxic modalities of cancer treatment.

  12. Biological response modifiers

    SciTech Connect

    Weller, R.E.

    1988-10-01

    Much of what used to be called immunotherapy is now included in the term biological response modifiers. Biological response modifiers (BRMs) are those agents or approaches that modify the relationship between the tumor and host by modifying the host's biological response to tumor cells with resultant therapeutic effects. Most of the early work with BRMs centered around observations of spontaneous tumor regression and the association of tumor regression with concurrent bacterial infections. The BRM can modify the host response by increasing the host's antitumor responses through augmentation and/or restoration of effector mechanisms or mediators of the host's defense or decrease the deleterious component by the host's reaction, increasing the host's defenses by the administration of natural biologics (or the synthetic derivatives thereof) as effectors or mediators of an antitumor response, augmenting the host's response to modified tumor cells or vaccines, which might stimulate a greater response by the host or increase tumor-cell sensitivity to an existing response, decreasing the transformation and/or increase differentiation (maturation) of tumor cells, or increasing the ability of the host to tolerate damage by cytotoxic modalities of cancer treatment.

  13. Latent phenotypes pervade gene regulatory circuits

    PubMed Central

    2014-01-01

    Background Latent phenotypes are non-adaptive byproducts of adaptive phenotypes. They exist in biological systems as different as promiscuous enzymes and genome-scale metabolic reaction networks, and can give rise to evolutionary adaptations and innovations. We know little about their prevalence in the gene expression phenotypes of regulatory circuits, important sources of evolutionary innovations. Results Here, we study a space of more than sixteen million three-gene model regulatory circuits, where each circuit is represented by a genotype, and has one or more functions embodied in one or more gene expression phenotypes. We find that the majority of circuits with single functions have latent expression phenotypes. Moreover, the set of circuits with a given spectrum of functions has a repertoire of latent phenotypes that is much larger than that of any one circuit. Most of this latent repertoire can be easily accessed through a series of small genetic changes that preserve a circuit’s main functions. Both circuits and gene expression phenotypes that are robust to genetic change are associated with a greater number of latent phenotypes. Conclusions Our observations suggest that latent phenotypes are pervasive in regulatory circuits, and may thus be an important source of evolutionary adaptations and innovations involving gene regulation. PMID:24884746

  14. Latent phenotypes pervade gene regulatory circuits.

    PubMed

    Payne, Joshua L; Wagner, Andreas

    2014-05-30

    Latent phenotypes are non-adaptive byproducts of adaptive phenotypes. They exist in biological systems as different as promiscuous enzymes and genome-scale metabolic reaction networks, and can give rise to evolutionary adaptations and innovations. We know little about their prevalence in the gene expression phenotypes of regulatory circuits, important sources of evolutionary innovations. Here, we study a space of more than sixteen million three-gene model regulatory circuits, where each circuit is represented by a genotype, and has one or more functions embodied in one or more gene expression phenotypes. We find that the majority of circuits with single functions have latent expression phenotypes. Moreover, the set of circuits with a given spectrum of functions has a repertoire of latent phenotypes that is much larger than that of any one circuit. Most of this latent repertoire can be easily accessed through a series of small genetic changes that preserve a circuit's main functions. Both circuits and gene expression phenotypes that are robust to genetic change are associated with a greater number of latent phenotypes. Our observations suggest that latent phenotypes are pervasive in regulatory circuits, and may thus be an important source of evolutionary adaptations and innovations involving gene regulation.

  15. [Intermediate phenotype studies in psychiatric disorder].

    PubMed

    Hashimoto, Ryota

    2016-02-01

    The concept of intermediate phenotype was proposed by Dr. Weinberger of the National Institute of Mental Health (NIMH). The risk genes for mental disorders define intermediate phenotypes, neurobiological characteristics observed in psychiatric disorders, and intermediate phenotypes increase the risk of mental disorders. The author worked at Dr. Weinberger's laboratory, and after returning home, introduced the concept to Japan, creating a term "Chukanhyogengata" to translate "intermediate phenotype". Intermediate phenotype has been proposed as a tool for the identification of risk genes for mental disorders, spreading the concept as a biomarker for the bridging between genes and behaviors. Intermediate phenotype studies later became one of the main pillars of psychiatric research. As a large number of data and samples are needed for intermediate phenotype research, we built a research resource database that combines the brain phenotype and bioresources. We performed genome-wide association analysis of cognitive decline in schizophrenia and identified the DEGS2 gene using this sample. This research resource database was developed for a multicenter study by COCORO (Cognitive Genetics Collaborative Research Organization). COCORO carried out genome-wide association analysis of the gray matter volume of the superior temporal gyrus and identified genome-wide significant loci. In this paper, we introduce the concept and history of intermediate phenotype study of mental illness and the latest trends. We hope to contribute to the future development of mental illness research through translational research.

  16. Phenotypic screening: the future of antibody discovery.

    PubMed

    Gonzalez-Munoz, Andrea L; Minter, Ralph R; Rust, Steven J

    2016-01-01

    Most antibody therapeutics have been isolated from high throughput target-based screening. However, as the number of validated targets diminishes and the target space becomes increasingly competitive, alternative strategies, such as phenotypic screening, are gaining momentum. Here, we review successful phenotypic screens, including those used to isolate antibodies against cancer and infectious agents. We also consider exciting advances in the expression and phenotypic screening of antibody repertoires in single cell autocrine systems. As technologies continue to develop, we believe that antibody phenotypic screening will increase further in popularity and has the potential to provide the next generation of therapeutic antibodies.

  17. The phenotypic variance gradient - a novel concept.

    PubMed

    Pertoldi, Cino; Bundgaard, Jørgen; Loeschcke, Volker; Barker, James Stuart Flinton

    2014-11-01

    Evolutionary ecologists commonly use reaction norms, which show the range of phenotypes produced by a set of genotypes exposed to different environments, to quantify the degree of phenotypic variance and the magnitude of plasticity of morphometric and life-history traits. Significant differences among the values of the slopes of the reaction norms are interpreted as significant differences in phenotypic plasticity, whereas significant differences among phenotypic variances (variance or coefficient of variation) are interpreted as differences in the degree of developmental instability or canalization. We highlight some potential problems with this approach to quantifying phenotypic variance and suggest a novel and more informative way to plot reaction norms: namely "a plot of log (variance) on the y-axis versus log (mean) on the x-axis, with a reference line added". This approach gives an immediate impression of how the degree of phenotypic variance varies across an environmental gradient, taking into account the consequences of the scaling effect of the variance with the mean. The evolutionary implications of the variation in the degree of phenotypic variance, which we call a "phenotypic variance gradient", are discussed together with its potential interactions with variation in the degree of phenotypic plasticity and canalization.

  18. Interoperability between phenotype and anatomy ontologies

    PubMed Central

    Hoehndorf, Robert; Oellrich, Anika; Rebholz-Schuhmann, Dietrich

    2010-01-01

    Motivation: Phenotypic information is important for the analysis of the molecular mechanisms underlying disease. A formal ontological representation of phenotypic information can help to identify, interpret and infer phenotypic traits based on experimental findings. The methods that are currently used to represent data and information about phenotypes fail to make the semantics of the phenotypic trait explicit and do not interoperate with ontologies of anatomy and other domains. Therefore, valuable resources for the analysis of phenotype studies remain unconnected and inaccessible to automated analysis and reasoning. Results: We provide a framework to formalize phenotypic descriptions and make their semantics explicit. Based on this formalization, we provide the means to integrate phenotypic descriptions with ontologies of other domains, in particular anatomy and physiology. We demonstrate how our framework leads to the capability to represent disease phenotypes, perform powerful queries that were not possible before and infer additional knowledge. Availability: http://bioonto.de/pmwiki.php/Main/PheneOntology Contact: rh497@cam.ac.uk PMID:20971987

  19. Phenotype of Normal Spirometry in an Aging Population

    PubMed Central

    McAvay, Gail; Van Ness, Peter H.; Casaburi, Richard; Jensen, Robert L.; MacIntyre, Neil; Gill, Thomas M.; Yaggi, H. Klar; Concato, John

    2015-01-01

    Rationale: In aging populations, the commonly used Global Initiative for Chronic Obstructive Lung Disease (GOLD) may misclassify normal spirometry as respiratory impairment (airflow obstruction and restrictive pattern), including the presumption of respiratory disease (chronic obstructive pulmonary disease [COPD]). Objectives: To evaluate the phenotype of normal spirometry as defined by a new approach from the Global Lung Initiative (GLI), overall and across GOLD spirometric categories. Methods: Using data from COPDGene (n = 10,131; ages 45–81; smoking history, ≥10 pack-years), we evaluated spirometry and multiple phenotypes, including dyspnea severity (Modified Medical Research Council grade 0–4), health-related quality of life (St. George’s Respiratory Questionnaire total score), 6-minute-walk distance, bronchodilator reversibility (FEV1 % change), computed tomography–measured percentage of lung with emphysema (% emphysema) and gas trapping (% gas trapping), and small airway dimensions (square root of the wall area for a standardized airway with an internal perimeter of 10 mm). Measurements and Main Results: Among 5,100 participants with GLI-defined normal spirometry, GOLD identified respiratory impairment in 1,146 (22.5%), including a restrictive pattern in 464 (9.1%), mild COPD in 380 (7.5%), moderate COPD in 302 (5.9%), and severe COPD in none. Overall, the phenotype of GLI-defined normal spirometry included normal adjusted mean values for dyspnea grade (0.8), St. George’s Respiratory Questionnaire (15.9), 6-minute-walk distance (1,424 ft [434 m]), bronchodilator reversibility (2.7%), % emphysema (0.9%), % gas trapping (10.7%), and square root of the wall area for a standardized airway with an internal perimeter of 10 mm (3.65 mm); corresponding 95% confidence intervals were similarly normal. These phenotypes remained normal for GLI-defined normal spirometry across GOLD spirometric categories. Conclusions: GLI-defined normal spirometry, even

  20. Sickle Cell Disease in the Post Genomic Era: A Monogenic Disease with a Polygenic Phenotype

    PubMed Central

    Driss, A; Asare, KO; Hibbert, JM; Gee, BE; Adamkiewicz, TV; Stiles, JK

    2009-01-01

    More than half a century after the discovery of the molecular basis of Sickle Cell Disease (SCD), the causes of the phenotypic heterogeneity of the disease remain unclear. This heterogeneity manifests with different clinical outcomes such as stroke, vaso-occlusive episodes, acute chest syndrome, avascular necrosis, leg ulcers, priapism and retinopathy. These outcomes cannot be explained by the single mutation in the beta-globin gene alone but may be attributed to genetic modifiers and environmental effects. Recent advances in the post human genome sequence era have opened the door for the identification of novel genetic modifiers in SCD. Studies are showing that phenotypes of SCD seem to be modulated by polymorphisms in genes that are involved in inflammation, cell–cell interaction and modulators of oxidant injury and nitric oxide biology. The discovery of genes implicated in different phenotypes will help understanding of the physiopathology of the disease and aid in establishing targeted cures. However, caution is needed in asserting that genetic modifiers are the cause of all SCD phenotypes, because there are other factors such as genetic background of the population, environmental components, socio-economics and psychology that can play significant roles in the clinical heterogeneity. PMID:20401335

  1. Wild worm embryogenesis harbors ubiquitous polygenic modifier variation

    PubMed Central

    Paaby, Annalise B; White, Amelia G; Riccardi, David D; Gunsalus, Kristin C; Piano, Fabio; Rockman, Matthew V

    2015-01-01

    Embryogenesis is an essential and stereotypic process that nevertheless evolves among species. Its essentiality may favor the accumulation of cryptic genetic variation (CGV) that has no effect in the wild-type but that enhances or suppresses the effects of rare disruptions to gene function. Here, we adapted a classical modifier screen to interrogate the alleles segregating in natural populations of Caenorhabditis elegans: we induced gene knockdowns and used quantitative genetic methodology to examine how segregating variants modify the penetrance of embryonic lethality. Each perturbation revealed CGV, indicating that wild-type genomes harbor myriad genetic modifiers that may have little effect individually but which in aggregate can dramatically influence penetrance. Phenotypes were mediated by many modifiers, indicating high polygenicity, but the alleles tend to act very specifically, indicating low pleiotropy. Our findings demonstrate the extent of conditional functionality in complex trait architecture. DOI: http://dx.doi.org/10.7554/eLife.09178.001 PMID:26297805

  2. Capturing phenotypic heterogeneity in MPS I: results of an international consensus procedure

    PubMed Central

    2012-01-01

    Background Mucopolysaccharidosis type I (MPS I) is traditionally divided into three phenotypes: the severe Hurler (MPS I-H) phenotype, the intermediate Hurler-Scheie (MPS I-H/S) phenotype and the attenuated Scheie (MPS I-S) phenotype. However, there are no clear criteria for delineating the different phenotypes. Because decisions about optimal treatment (enzyme replacement therapy or hematopoietic stem cell transplantation) need to be made quickly and depend on the presumed phenotype, an assessment of phenotypic severity should be performed soon after diagnosis. Therefore, a numerical severity scale for classifying different MPS I phenotypes at diagnosis based on clinical signs and symptoms was developed. Methods A consensus procedure based on a combined modified Delphi method and a nominal group technique was undertaken. It consisted of two written rounds and a face-to-face meeting. Sixteen MPS I experts participated in the process. The main goal was to identify the most important indicators of phenotypic severity and include these in a numerical severity scale. The correlation between the median subjective expert MPS I rating and the scores derived from this severity scale was used as an indicator of validity. Results Full consensus was reached on six key clinical items for assessing severity: age of onset of signs and symptoms, developmental delay, joint stiffness/arthropathy/contractures, kyphosis, cardiomyopathy and large head/frontal bossing. Due to the remarkably large variability in the expert MPS I assessments, however, a reliable numerical scale could not be constructed. Because of this variability, such a scale would always result in patients whose calculated severity score differed unacceptably from the median expert severity score, which was considered to be the 'gold standard'. Conclusions Although consensus was reached on the six key items for assessing phenotypic severity in MPS I, expert opinion on phenotypic severity at diagnosis proved to be

  3. Modified blank ammunition injuries.

    PubMed

    Ogunc, Gokhan I; Ozer, M Tahir; Coskun, Kagan; Uzar, Ali Ihsan

    2009-12-15

    Blank firing weapons are designed only for discharging blank ammunition cartridges. Because they are cost-effective, are easily accessible and can be modified to live firearms plus their unclear legal situation in Turkish Law makes them very popular in Turkey. 2004 through 2008, a total of 1115 modified blank weapons were seized in Turkey. Blank firing weapons are easily modified by owners, making them suitable for discharging live firearm ammunition or modified blank ammunitions. Two common methods are used for modification of blank weapons. After the modification, these weapons can discharge the live ammunition. However, due to compositional durability problems with these types of weapons; the main trend is to use the modified blank ammunitions rather than live firearm ammunition fired from modified blank firing weapons. In this study, two types of modified blank weapons and two types of modified blank cartridges were tested on three different target models. Each of the models' shooting side was coated with 1.3+/-2 mm thickness chrome tanned cowhide as a skin simulant. The first model was only coated with skin simulant. The second model was coated with skin simulant and 100% cotton police shirt. The third model was coated with skin simulant and jean denim. After the literature evaluation four high risky anatomic locations (the neck area; the eyes; the thorax area and inguinal area) were pointed out for the steel and lead projectiles are discharged from the modified blank weapons especially in close range (0-50 cm). The target models were designed for these anatomic locations. For the target models six Transparent Ballistic Candle blocks (TCB) were prepared and divided into two test groups. The first group tests were performed with lead projectiles and second group with steel projectile. The shortest penetration depth (lead projectile: 4.358 cm; steel projectile 8.032 cm) was recorded in the skin simulant and jean denim coated block for both groups. In both groups

  4. Aminoglycoside Modifying Enzymes

    PubMed Central

    Ramirez, Maria S.; Tolmasky, Marcelo E.

    2010-01-01

    Aminoglycosides have been an essential component of the armamentarium in the treatment of life-threatening infections. Unfortunately, their efficacy has been reduced by the surge and dissemination of resistance. In some cases the levels of resistance reached the point that rendered them virtually useless. Among many known mechanisms of resistance to aminoglycosides, enzymatic modification is the most prevalent in the clinical setting. Aminoglycoside modifying enzymes catalyze the modification at different −OH or −NH2 groups of the 2-deoxystreptamine nucleus or the sugar moieties and can be nucleotidyltranferases, phosphotransferases, or acetyltransferases. The number of aminoglycoside modifying enzymes identified to date as well as the genetic environments where the coding genes are located is impressive and there is virtually no bacteria that is unable to support enzymatic resistance to aminoglycosides. Aside from the development of new aminoglycosides refractory to as many as possible modifying enzymes there are currently two main strategies being pursued to overcome the action of aminoglycoside modifying enzymes. Their successful development would extend the useful life of existing antibiotics that have proven effective in the treatment of infections. These strategies consist of the development of inhibitors of the enzymatic action or of the expression of the modifying enzymes. PMID:20833577

  5. The need for agriculture phenotyping: "moving from genotype to phenotype".

    PubMed

    Boggess, Mark V; Lippolis, John D; Hurkman, William J; Fagerquist, Clifton K; Briggs, Steve P; Gomes, Aldrin V; Righetti, Pier Giorgio; Bala, Kumar

    2013-11-20

    Increase in the world population has called for the increased demand for agricultural productivity. Traditional methods to augment crop and animal production are facing exacerbating pressures in keeping up with population growth. This challenge has in turn led to the transformational change in the use of biotechnology tools to meet increased productivity for both plant and animal systems. Although many challenges exist, the use of proteomic techniques to understand agricultural problems is steadily increasing. This review discusses the impact of genomics, proteomics, metabolomics and phenotypes on plant, animal and bacterial systems to achieve global food security and safety and we highlight examples of intra and extra mural research work that is currently being done to increase agricultural productivity. This review focuses on the global demand for increased agricultural productivity arising from population growth and how we can address this challenge using biotechnology. With a population well above seven billion humans, in a very unbalanced nutritional state (20% overweight, 20% risking starvation) drastic measures have to be taken at the political, infrastructure and scientific levels. While we cannot influence politics, it is our duty as scientists to see what can be done to feed humanity. Hence we highlight the transformational change in the use of biotechnology tools over traditional methods to increase agricultural productivity (plant and animal). Specifically, this review deals at length on how a three-pronged attack, namely combined genomics, proteomics and metabolomics, can help to ensure global food security and safety. This article is part of a Special Issue entitled: Translational Plant Proteomics. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Emerging semantics to link phenotype and environment

    DOE PAGES

    Thessen, Anne E.; Bunker, Daniel E.; Buttigieg, Pier Luigi; ...

    2015-12-14

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies aremore » well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. Lastly, in this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments.« less

  7. Disc degeneration-related clinical phenotypes.

    PubMed

    Battié, Michele C; Lazáry, Aron; Fairbank, Jeremy; Eisenstein, Stephen; Heywood, Chris; Brayda-Bruno, Marco; Varga, Péter Pál; McCall, Iain

    2014-06-01

    The phenotype, or observable trait of interest, is at the core of studies identifying associated genetic variants and their functional pathways, as well as diagnostics. Yet, despite remarkable technological developments in genotyping and progress in genetic research, relatively little attention has been paid to the equally important issue of phenotype. This is especially true for disc degeneration-related disorders, and the concept of degenerative disc disease, in particular, where there is little consensus or uniformity of definition. Greater attention and rigour are clearly needed in the development of disc degeneration-related clinical phenotypes if we are to see more rapid advancements in knowledge of this area. When selecting phenotypes, a basic decision is whether to focus directly on the complex clinical phenotype (e.g. the clinical syndrome of spinal stenosis), which is ultimately of interest, or an intermediate phenotype (e.g. dural sac cross-sectional area). While both have advantages, it cannot be assumed that associated gene variants will be similarly relevant to both. Among other considerations are factors influencing phenotype identification, comorbidities that are often present, and measurement issues. Genodisc, the European research consortium project on disc-related clinical pathologies has adopted a strategy that will allow for the careful characterisation and examination of both the complex clinical phenotypes of interest and their components.

  8. The Cognitive Phenotype of Spina Bifida Meningomyelocele

    ERIC Educational Resources Information Center

    Dennis, Maureen; Barnes, Marcia A.

    2010-01-01

    A cognitive phenotype is a product of both assets and deficits that specifies what individuals with spina bifida meningomyelocele (SBM) can and cannot do and why they can or cannot do it. In this article, we review the cognitive phenotype of SBM and describe the processing assets and deficits that cut within and across content domains, sensory…

  9. Imaging Prostate Cancer (PCa) Phenotype and Evolution

    DTIC Science & Technology

    2016-10-01

    1 AWARD NUMBER: W81XWH-13-1-0386 TITLE: Imaging Prostate Cancer (PCa) Phenotype and Evolution PRINCIPAL INVESTIGATOR: Jason A. Koutcher...also tumor macrophages, suggesting that DFP may have a dual activity on tumors Jason A. Koutcher Imaging Prostate Cancer (PCa) Phenotype and Evolution

  10. Auditory Phenotype of Smith-Magenis Syndrome

    ERIC Educational Resources Information Center

    Brendal, Megan A.; King, Kelly A.; Zalewski, Christopher K.; Finucane, Brenda M.; Introne, Wendy; Brewer, Carmen C.; Smith, Ann C. M.

    2017-01-01

    Purpose: The purpose of this study was to describe the auditory phenotype of a large cohort with Smith-Magenis syndrome (SMS), a rare disorder including physical anomalies, cognitive deficits, sleep disturbances, and a distinct behavioral phenotype. Method: Hearing-related data were collected for 133 individuals with SMS aged 1-49 years. Audiogram…

  11. Effects of polyandry on male phenotypic diversity.

    PubMed

    Barbosa, M; Dornelas, M; Magurran, A E

    2010-11-01

    Polyandry has the potential to affect the distribution of phenotypes and to shape the direction of sexual selection. Here, we explore this potential using Trinidadian guppies as a model system and ask whether polyandry leads to directional and/or diversifying selection of male phenotypic traits. In this study, we compare the phenotypic diversity of offspring from multiply and singly sired broods. To quantify phenotypic diversity, we first combine phenotypic traits using multivariate methods, and then take the dispersion of individuals in multivariate space as our measure of diversity. We show that, when each trait is examined separately, polyandry generates offspring with a higher proportion of bright coloration, indicating directional selection. However, our multivariate approach reveals that this directionality is accompanied by an increase in phenotypic diversity. These results suggest that polyandry (i) selects for the production of sons with the preferred brighter colour phenotypes whereas (ii) enhancing the diversity of male sexual traits. Promoting phenotypic diversity may be advantageous in coping with environmental and reproductive variability by increasing long-term fitness. © 2010 The Authors. Journal Compilation © 2010 European Society For Evolutionary Biology.

  12. The Neuroanatomy of the Autistic Phenotype

    ERIC Educational Resources Information Center

    Fahim, Cherine; Meguid, Nagwa A.; Nashaat, Neveen H.; Yoon, Uicheul; Mancini-Marie, Adham; Evans, Alan C.

    2012-01-01

    The autism phenotype is associated with an excess of brain volume due in part to decreased pruning during development. Here we aimed at assessing brain volume early in development to further elucidate previous findings in autism and determine whether this pattern is restricted to idiopathic autism or shared within the autistic phenotype (fragile X…

  13. The Cognitive Phenotype of Spina Bifida Meningomyelocele

    ERIC Educational Resources Information Center

    Dennis, Maureen; Barnes, Marcia A.

    2010-01-01

    A cognitive phenotype is a product of both assets and deficits that specifies what individuals with spina bifida meningomyelocele (SBM) can and cannot do and why they can or cannot do it. In this article, we review the cognitive phenotype of SBM and describe the processing assets and deficits that cut within and across content domains, sensory…

  14. Daddy issues: paternal effects on phenotype.

    PubMed

    Rando, Oliver J

    2012-11-09

    The once popular and then heretical idea that ancestral environment can affect the phenotype of future generations is coming back into vogue due to advances in the field of epigenetic inheritance. How paternal environmental conditions influence the phenotype of progeny is now a tractable question, and researchers are exploring potential mechanisms underlying such effects.

  15. The Neuroanatomy of the Autistic Phenotype

    ERIC Educational Resources Information Center

    Fahim, Cherine; Meguid, Nagwa A.; Nashaat, Neveen H.; Yoon, Uicheul; Mancini-Marie, Adham; Evans, Alan C.

    2012-01-01

    The autism phenotype is associated with an excess of brain volume due in part to decreased pruning during development. Here we aimed at assessing brain volume early in development to further elucidate previous findings in autism and determine whether this pattern is restricted to idiopathic autism or shared within the autistic phenotype (fragile X…

  16. Emerging semantics to link phenotype and environment.

    PubMed

    Thessen, Anne E; Bunker, Daniel E; Buttigieg, Pier Luigi; Cooper, Laurel D; Dahdul, Wasila M; Domisch, Sami; Franz, Nico M; Jaiswal, Pankaj; Lawrence-Dill, Carolyn J; Midford, Peter E; Mungall, Christopher J; Ramírez, Martín J; Specht, Chelsea D; Vogt, Lars; Vos, Rutger Aldo; Walls, Ramona L; White, Jeffrey W; Zhang, Guanyang; Deans, Andrew R; Huala, Eva; Lewis, Suzanna E; Mabee, Paula M

    2015-01-01

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies are well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. In this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments.

  17. Long-term phenotypic evolution of bacteria.

    PubMed

    Plata, Germán; Henry, Christopher S; Vitkup, Dennis

    2015-01-15

    For many decades comparative analyses of protein sequences and structures have been used to investigate fundamental principles of molecular evolution. In contrast, relatively little is known about the long-term evolution of species' phenotypic and genetic properties. This represents an important gap in our understanding of evolution, as exactly these proprieties play key roles in natural selection and adaptation to diverse environments. Here we perform a comparative analysis of bacterial growth and gene deletion phenotypes using hundreds of genome-scale metabolic models. Overall, bacterial phenotypic evolution can be described by a two-stage process with a rapid initial phenotypic diversification followed by a slow long-term exponential divergence. The observed average divergence trend, with approximately similar fractions of phenotypic properties changing per unit time, continues for billions of years. We experimentally confirm the predicted divergence trend using the phenotypic profiles of 40 diverse bacterial species across more than 60 growth conditions. Our analysis suggests that, at long evolutionary distances, gene essentiality is significantly more conserved than the ability to utilize different nutrients, while synthetic lethality is significantly less conserved. We also find that although a rapid phenotypic evolution is sometimes observed within the same species, a transition from high to low phenotypic similarity occurs primarily at the genus level.

  18. Emerging semantics to link phenotype and environment

    SciTech Connect

    Thessen, Anne E.; Bunker, Daniel E.; Buttigieg, Pier Luigi; Cooper, Laurel D.; Dahdul, Wasila M.; Domisch, Sami; Franz, Nico M.; Jaiswal, Pankaj; Lawrence-Dill, Carolyn J.; Midford, Peter E.; Mungall, Christopher J.; Ramirez, Martin J.; Specht, Chelsea D.; Vogt, Lars; Vos, Rutger Aldo; Walls, Ramona L.; White, Jeffrey W.; Zhang, Guanyang; Deans, Andrew R.; Huala, Eva; Lewis, Suzanna E.; Mabee, Paula M.

    2015-12-14

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies are well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. Lastly, in this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments.

  19. Emerging semantics to link phenotype and environment

    PubMed Central

    Bunker, Daniel E.; Buttigieg, Pier Luigi; Cooper, Laurel D.; Dahdul, Wasila M.; Domisch, Sami; Franz, Nico M.; Jaiswal, Pankaj; Lawrence-Dill, Carolyn J.; Midford, Peter E.; Mungall, Christopher J.; Ramírez, Martín J.; Specht, Chelsea D.; Vogt, Lars; Vos, Rutger Aldo; Walls, Ramona L.; White, Jeffrey W.; Zhang, Guanyang; Deans, Andrew R.; Huala, Eva; Lewis, Suzanna E.; Mabee, Paula M.

    2015-01-01

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies are well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. In this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments. PMID:26713234

  20. ICAM-1: isoforms and phenotypes.

    PubMed

    Ramos, Theresa N; Bullard, Daniel C; Barnum, Scott R

    2014-05-15

    ICAM-1 plays an important role in leukocyte trafficking, immunological synapse formation, and numerous cellular immune responses. Although considered a single glycoprotein, there are multiple membrane-bound and soluble ICAM-1 isoforms that arise from alternative splicing and proteolytic cleavage during inflammatory responses. The function and expression of these isoforms on various cell types are poorly understood. In the generation of ICAM-1-deficient mice, two isoform-deficient ICAM-1 mutants were inadvertently produced as a result of alternative splicing. These mice, along with true ICAM-1-deficient mice and newly generated ICAM-1-transgenic mice, have provided the opportunity to begin examining the role of ICAM-1 isoforms (singly or in combination) in various disease settings. In this review, we highlight the sharply contrasting disease phenotypes using ICAM-1 isoform mutant mice. These studies demonstrate that ICAM-1 immunobiology is highly complex but that individual isoforms, aside from the full-length molecule, make significant contributions to disease development and pathogenesis.

  1. ICAM-1: Isoforms and Phenotypes

    PubMed Central

    Ramos, Theresa N.; Bullard, Daniel C.; Barnum, Scott R.

    2014-01-01

    Intercellular adhesion molecule-1 (ICAM-1) plays an important role in leukocyte trafficking, immunological synapse formation and, numerous cellular immune responses. Although considered a single glycoprotein, there are multiple membrane bound and soluble ICAM-1 isoforms which arise from alternative splicing and proteolytic cleavage during inflammatory responses. The function and expression of these isoforms on various cell types is poorly understood. In the generation of ICAM-1-deficient mice, two isoform-deficient ICAM-1 mutants were inadvertently produced due to alternative splicing. These mice along with true ICAM-1-deficient mice and newly generated ICAM-1 transgenic mice have provided the opportunity to begin examining the role of ICAM-1 isoforms (singly or in combination) in various disease settings. In this review we highlight the sharply contrasting disease phenotypes using ICAM-1 isoform mutant mice. These studies demonstrate that ICAM-1 immunobiology is highly complex but that individual isoforms, aside from the full-length molecule, make significant contributions to disease development and pathogenesis. PMID:24795464

  2. Adjusting Phenotypes by Noise Control

    PubMed Central

    Kim, Kyung H.; Sauro, Herbert M.

    2012-01-01

    Genetically identical cells can show phenotypic variability. This is often caused by stochastic events that originate from randomness in biochemical processes involving in gene expression and other extrinsic cellular processes. From an engineering perspective, there have been efforts focused on theory and experiments to control noise levels by perturbing and replacing gene network components. However, systematic methods for noise control are lacking mainly due to the intractable mathematical structure of noise propagation through reaction networks. Here, we provide a numerical analysis method by quantifying the parametric sensitivity of noise characteristics at the level of the linear noise approximation. Our analysis is readily applicable to various types of noise control and to different types of system; for example, we can orthogonally control the mean and noise levels and can control system dynamics such as noisy oscillations. As an illustration we applied our method to HIV and yeast gene expression systems and metabolic networks. The oscillatory signal control was applied to p53 oscillations from DNA damage. Furthermore, we showed that the efficiency of orthogonal control can be enhanced by applying extrinsic noise and feedback. Our noise control analysis can be applied to any stochastic model belonging to continuous time Markovian systems such as biological and chemical reaction systems, and even computer and social networks. We anticipate the proposed analysis to be a useful tool for designing and controlling synthetic gene networks. PMID:22253584

  3. Bronchiectasis: Phenotyping a Complex Disease.

    PubMed

    Chalmers, James D

    2017-03-15

    Bronchiectasis is a long-neglected disease currently experiencing a surge in interest. It is a highly complex condition with numerous aetiologies, co-morbidities and a heterogeneous disease presentation and clinical course. The past few years have seen major advances in our understanding of the disease, primarily through large real-life cohort studies. The main outcomes of interest in bronchiectasis are symptoms, exacerbations, treatment response, disease progression and death. We are now more able to identify clearly the radiological, clinical, microbiological and inflammatory contributors to these outcomes. Over the past couple of years, multidimensional scoring systems such as the Bronchiectasis Severity Index have been introduced to predict disease severity and mortality. Although there are currently no licensed therapies for bronchiectasis, an increasing number of clinical trials are planned or ongoing. While this emerging evidence is awaited, bronchiectasis guidelines will continue to be informed largely by real-life evidence from observational studies and patient registries. Key developments in the bronchiectasis field include the establishment of international disease registries and characterisation of disease phenotypes using cluster analysis and biological data.

  4. The autonomic phenotype of rumination.

    PubMed

    Ottaviani, Cristina; Shapiro, David; Davydov, Dmitry M; Goldstein, Iris B; Mills, Paul J

    2009-06-01

    Recent studies suggest that ruminative thoughts may be mediators of the prolonged physiological effects of stress. We hypothesized that autonomic dysregulation plays a role in the relation between rumination and health. Rumination was induced by an anger-recall task in 45 healthy subjects. Heart rate variability (HRV), baroreflex sensitivity (BRS), and baroreflex effectiveness index (BEI) change scores were evaluated to obtain the autonomic phenotype of rumination. Personality traits and endothelial activation were examined for their relation to autonomic responses during rumination. Degree of endothelial activation was assessed by circulating soluble intercellular adhesion molecule-1 (sICAM-1). Vagal withdrawal during rumination was greater for women than men. Larger decreases in the high frequency component of HRV were associated with higher levels of anger-in, depression, and sICAM-1 levels. BRS reactivity was negatively related to trait anxiety. BEI reactivity was positively related to anger-in, hostility, anxiety, and depression. Lower BEI and BRS recovery were associated with lower social desirability and higher anger-out, anxiety, and depression. Findings suggest that the autonomic dysregulation that characterizes rumination plays a role in the relationships between personality and cardiovascular health.

  5. Phenotypic plasticity in freshwater picocyanobacteria.

    PubMed

    Huber, Paula; Diovisalvi, Nadia; Ferraro, Marcela; Metz, Sebastián; Lagomarsino, Leonardo; Llames, María Eugenia; Royo-Llonch, Marta; Bustingorry, José; Escaray, Roberto; Acinas, Silvia G; Gasol, Josep M; Unrein, Fernando

    2017-03-01

    Picocyanobacteria can occur as single-cell (Pcy) or as colonies (CPcy). Published evidence suggests that some Pcy strains have the capability to aggregate under certain culture conditions, however this has not been demonstrated to occur in natural environments. We investigated whether the Pcy and CPcy belong to the same species (i.e. phylotype), and the factors that determine their morphological and genetic variability in a hypertrophic shallow lake dominated by picocyanobacteria. Six main different morphologies and >30 phylotypes were observed. All sequences retrieved belonged to the 'Anathece + Cyanobium' clade (Synechococcales) that are known to have the capability of aggregation/disaggregation. The temporal variation of picocyanobacteria morphotype composition was weakly correlated with the DGGE temporal pattern, and could be explained by the composition of the zooplankton assemblage. Laboratory experiments confirmed that the small cladoceran Bosmina favoured the dominance of CPcy, i.e. Cyanodictyon doubled the size of the colonies when present, most likely through the aggregation of single-cell picocyanobacteria into colonies. Flow cytometry cell sorting and 16S rRNA + ITS sequencing of the Pcy and CPcy cytometrically-defined populations revealed that some phylotypes could be found in both sorted populations, suggesting phenotypic plasticity in which various Synechococcales phylotypes could be found in situ either as single-cells or as colonies.

  6. Phenotypic screening for developmental neurotoxicity ...

    EPA Pesticide Factsheets

    There are large numbers of environmental chemicals with little or no available information on their toxicity, including developmental neurotoxicity. Because of the resource-intensive nature of traditional animal tests, high-throughput (HTP) methods that can rapidly evaluate chemicals for the potential to affect the developing brain are being explored. Typically, HTP screening uses biochemical and molecular assays to detect the interaction of a chemical with a known target or molecular initiating event (e.g., the mechanism of action). For developmental neurotoxicity, however, the mechanism(s) is often unknown. Thus, we have developed assays for detecting chemical effects on the key events of neurodevelopment at the cellular level (e.g., proliferation, differentiation, neurite growth, synaptogenesis, network formation). Cell-based assays provide a test system at a level of biological complexity that encompasses many potential neurotoxic mechanisms. For example, phenotypic assessment of neurite outgrowth at the cellular level can detect chemicals that target kinases, ion channels, or esterases at the molecular level. The results from cell-based assays can be placed in a conceptual framework using an Adverse Outcome Pathway (AOP) which links molecular, cellular, and organ level effects with apical measures of developmental neurotoxicity. Testing a wide range of concentrations allows for the distinction between selective effects on neurodevelopmental and non-specific

  7. Physiological phenotyping of plants for crop improvement.

    PubMed

    Ghanem, Michel Edmond; Marrou, Hélène; Sinclair, Thomas R

    2015-03-01

    Future progress in crop breeding requires a new emphasis in plant physiological phenotyping for specific, well-defined traits. Success in physiological phenotyping to identify parents for use in breeding efforts for improved cultivars has been achieved by employing a multi-tier screening approach with different levels of sophistication and trait resolution. Subsequently, cultivar development required an integrated mix of classical breeding approaches and one or more tiers of phenotyping to identify genotypes expressing the desired trait. The role of high throughput systems can be useful; here, we emphasize that this approach is likely to offer useful results at an initial tier of phenotyping and will need to be complemented with more directed tiers of phenotyping. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. The Nature of Stable Insomnia Phenotypes

    PubMed Central

    Pillai, Vivek; Roth, Thomas; Drake, Christopher L.

    2015-01-01

    Study Objectives: We examined the 1-y stability of four insomnia symptom profiles: sleep onset insomnia; sleep maintenance insomnia; combined onset and maintenance insomnia; and neither criterion (i.e., insomnia cases that do not meet quantitative thresholds for onset or maintenance problems). Insomnia cases that exhibited the same symptom profile over a 1-y period were considered to be phenotypes, and were compared in terms of clinical and demographic characteristics. Design: Longitudinal. Setting: Urban, community-based. Participants: Nine hundred fifty-four adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition based current insomnia (46.6 ± 12.6 y; 69.4% female). Interventions: None. Measurements and results: At baseline, participants were divided into four symptom profile groups based on quantitative criteria. Follow-up assessment 1 y later revealed that approximately 60% of participants retained the same symptom profile, and were hence judged to be phenotypes. Stability varied significantly by phenotype, such that sleep onset insomnia (SOI) was the least stable (42%), whereas combined insomnia (CI) was the most stable (69%). Baseline symptom groups (cross-sectionally defined) differed significantly across various clinical indices, including daytime impairment, depression, and anxiety. Importantly, however, a comparison of stable phenotypes (longitudinally defined) did not reveal any differences in impairment or comorbid psychopathology. Another interesting finding was that whereas all other insomnia phenotypes showed evidence of an elevated wake drive both at night and during the day, the “neither criterion” phenotype did not; this latter phenotype exhibited significantly higher daytime sleepiness despite subthreshold onset and maintenance difficulties. Conclusions: By adopting a stringent, stability-based definition, this study offers timely and important data on the longitudinal trajectory of specific insomnia phenotypes. With

  9. Detection of Mutually Exclusive Mosaicism in a Girl with Genotype-Phenotype Discrepancies

    PubMed Central

    Luo, Minjie; Mulchandani, Surabhi; Dubbs, Holly A.; Swarr, Daniel; Pyle, Louise; Zackai, Elaine H.; Spinner, Nancy B.; Conlin, Laura K.

    2015-01-01

    Discordance between clinical phenotype and genotype has multiple causes, including mosaicism. Phenotypes can be modified due to tissue distribution, or the presence of multiple abnormal cell lines with different genomic contributions. We have studied a 20-month-old female whose main phenotypes were failure to thrive, developmental delay, and patchy skin pigmentation. Initial chromosome and SNP microarray analysis of her blood revealed a non-mosaic ~24 Mb duplication of 15q25.1q26.3 resulting from the unbalanced translocation of terminal 15q to the short arm of chromosome 15. The most common feature associated with distal trisomy 15q is prenatal and postnatal overgrowth, which was not consistent with this patient’s phenotype. The phenotypic discordance, in combination with the patchy skin pigmentation, suggested the presence of mosaicism. Further analysis of skin biopsies from both hyper- and hypopigmented regions confirmed the presence of an additional cell line with the short arm of chromosome X deleted and replaced by the entire long arm of chromosome 15. The Xp deletion, consistent with a variant Turner Syndrome diagnosis, better explained the patient’s phenotype. Parental studies revealed that the alterations in both cell lines were de novo and the duplicated distal 15q and the deleted Xp were from different parental origins, suggesting a mitotic event. The possible mechanism for the occurrence of two mutually exclusive structural rearrangements with both involving the long arm of chromosome 15 is discussed. PMID:26198585

  10. Invasive ecosystem engineer selects for different phenotypes of an associated native species.

    PubMed

    Wright, Jeffrey T; Gribben, Paul E; Byers, James E; Monro, Keyne

    2012-06-01

    Invasive habitat-forming ecosystem engineers modify the abiotic environment and thus represent a major perturbation to many ecosystems. Because native species often persist in these invaded habitats but have no shared history with the ecosystem engineer, the engineer may impose novel selective pressure on native species. In this study, we used a phenotypic selection framework to determine whether an invasive habitat-forming ecosystem engineer (the seaweed Caulerpa taxifolia) selects for different phenotypes of a common co-occurring native species (the bivalve Anadara trapezia). Compared to unvegetated habitat, Caulerpa habitat has lower water flow, lower dissolved oxygen, and sediments are more silty and anoxic. We determined the performance consequences of variation in key functional traits that may be affected by these abiotic changes (shell morphology, gill mass, and palp mass) for Anadara transplanted into Caulerpa and unvegetated habitat. Both linear and nonlinear performance gradients in Anadara differed between habitats, and these gradients were stronger in Caulerpa compared to unvegetated sediment. Moreover, in Caulerpa alternate phenotypes performed well, and these phenotypes were different from the dominant phenotype in unvegetated sediment. By demonstrating that phenotype-performance gradients differ between habitats, we have highlighted a role for Caulerpa as an agent of selection on native species.

  11. Rethinking phenotypic plasticity and its consequences for individuals, populations and species

    PubMed Central

    Forsman, A

    2015-01-01

    Much research has been devoted to identify the conditions under which selection favours flexible individuals or genotypes that are able to modify their growth, development and behaviour in response to environmental cues, to unravel the mechanisms of plasticity and to explore its influence on patterns of diversity among individuals, populations and species. The consequences of developmental plasticity and phenotypic flexibility for the performance and ecological success of populations and species have attracted a comparatively limited but currently growing interest. Here, I re-emphasize that an increased understanding of the roles of plasticity in these contexts requires a ‘whole organism' (rather than ‘single trait') approach, taking into consideration that organisms are integrated complex phenotypes. I further argue that plasticity and genetic polymorphism should be analysed and discussed within a common framework. I summarize predictions from theory on how phenotypic variation stemming from developmental plasticity and phenotypic flexibility may affect different aspects of population-level performance. I argue that it is important to distinguish between effects associated with greater interindividual phenotypic variation resulting from plasticity, and effects mediated by variation among individuals in the capacity to express plasticity and flexibility as such. Finally, I claim that rigorous testing of predictions requires methods that allow for quantifying and comparing whole organism plasticity, as well as the ability to experimentally manipulate the level of and capacity for developmental plasticity and phenotypic flexibility independent of genetic variation. PMID:25293873

  12. Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes.

    PubMed

    Loviglio, M N; Leleu, M; Männik, K; Passeggeri, M; Giannuzzi, G; van der Werf, I; Waszak, S M; Zazhytska, M; Roberts-Caldeira, I; Gheldof, N; Migliavacca, E; Alfaiz, A A; Hippolyte, L; Maillard, A M; Van Dijck, A; Kooy, R F; Sanlaville, D; Rosenfeld, J A; Shaffer, L G; Andrieux, J; Marshall, C; Scherer, S W; Shen, Y; Gusella, J F; Thorsteinsdottir, U; Thorleifsson, G; Dermitzakis, E T; Deplancke, B; Beckmann, J S; Rougemont, J; Jacquemont, S; Reymond, A

    2016-05-31

    Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.Molecular Psychiatry advance online publication, 31 May 2016; doi:10.1038/mp.2016.84.

  13. Refined Phenotyping of Modic Changes

    PubMed Central

    Määttä, Juhani H.; Karppinen, Jaro; Paananen, Markus; Bow, Cora; Luk, Keith D.K.; Cheung, Kenneth M.C.; Samartzis, Dino

    2016-01-01

    Abstract Low back pain (LBP) is the world's most disabling condition. Modic changes (MC) are vertebral bone marrow changes adjacent to the endplates as noted on magnetic resonance imaging. The associations of specific MC types and patterns with prolonged, severe LBP and disability remain speculative. This study assessed the relationship of prolonged, severe LBP and back-related disability, with the presence and morphology of lumbar MC in a large cross-sectional population-based study of Southern Chinese. We addressed the topographical and morphological dimensions of MC along with other magnetic resonance imaging phenotypes (eg, disc degeneration and displacement) on the basis of axial T1 and sagittal T2-weighted imaging of L1-S1. Prolonged severe LBP was defined as LBP lasting ≥30 days during the past year, and a visual analog scale severest pain intensity of at least 6/10. An Oswestry Disability Index score of 15% was regarded as significant disability. We also assessed subject demographics, occupation, and lifestyle factors. In total, 1142 subjects (63% females, mean age 53 years) were assessed. Of these, 282 (24.7%) had MC (7.1% type I, 17.6% type II). MC subjects were older (P = 0.003), had more frequent disc displacements (P < 0.001) and greater degree of disc degeneration (P < 0.001) than non-MC subjects. In adjusted models, any MC (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.01–2.18), MC affecting whole anterior-posterior length (OR 1.62, 95% CI 1.04–2.51), and MC affecting 2/3 posterior length (OR 2.79, 95% CI 1.17–6.65) were associated with prolonged severe LBP. Type I MC tended to associate with pain more strongly than type II MC (OR 1.80, 95% CI 0.94–3.44 vs OR 1.36, 95% CI 0.88–2.09, respectively). Any MC (OR 1.47, 95% CI 1.04–2.10), type II MC (OR 1.56, 95% CI 1.06–2.31), MC affecting 2/3 posterior length (OR 2.96, 95% CI 1.27–6.89), and extensive MC (OR 1.95, 95% CI 1.21–3.15) were associated with disability

  14. Targeting phenotypically tolerant Mycobacterium tuberculosis

    PubMed Central

    Gold, Ben; Nathan, Carl

    2016-01-01

    While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in a clinical setting. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of post-treatment relapse. Some promising drugs to treat tuberculosis, such as rifampicin and bedaquiline, only kill nonreplicating M. tuberculosis in vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores. However, few of these compounds were tested under conditions that would exclude the impact of adsorbed compound acting during the recovery phase of

  15. Modifying Cookbook Labs.

    ERIC Educational Resources Information Center

    Clark, Robert, L.; Clough, Michael P.; Berg, Craig A.

    2000-01-01

    Modifies an extended lab activity from a cookbook approach for determining the percent mass of water in copper sulfate pentahydrate crystals to one which incorporates students' prior knowledge, engenders active mental struggling with prior knowledge and new experiences, and encourages metacognition. (Contains 12 references.) (ASK)

  16. Modifying Cookbook Labs.

    ERIC Educational Resources Information Center

    Clark, Robert, L.; Clough, Michael P.; Berg, Craig A.

    2000-01-01

    Modifies an extended lab activity from a cookbook approach for determining the percent mass of water in copper sulfate pentahydrate crystals to one which incorporates students' prior knowledge, engenders active mental struggling with prior knowledge and new experiences, and encourages metacognition. (Contains 12 references.) (ASK)

  17. Modified Embedded Atom Method

    SciTech Connect

    Rudd, R. E.

    2012-08-01

    Interatomic force and energy calculation subroutine to be used with the molecular dynamics simulation code LAMMPS (Ref a.). The code evaluated the total energy and atomic forces (energy gradient) according to a cubic spline-based variant (Ref b.) of the Modified Embedded Atom Method (MEAM) with a additional Stillinger-Weber (SW) contribution.

  18. Evolution of molecular phenotypes under stabilizing selection

    NASA Astrophysics Data System (ADS)

    Nourmohammad, Armita; Schiffels, Stephan; Lässig, Michael

    2013-01-01

    Molecular phenotypes are important links between genomic information and organismic functions, fitness, and evolution. Complex phenotypes, which are also called quantitative traits, often depend on multiple genomic loci. Their evolution builds on genome evolution in a complicated way, which involves selection, genetic drift, mutations and recombination. Here we develop a coarse-grained evolutionary statistics for phenotypes, which decouples from details of the underlying genotypes. We derive approximate evolution equations for the distribution of phenotype values within and across populations. This dynamics covers evolutionary processes at high and low recombination rates, that is, it applies to sexual and asexual populations. In a fitness landscape with a single optimal phenotype value, the phenotypic diversity within populations and the divergence between populations reach evolutionary equilibria, which describe stabilizing selection. We compute the equilibrium distributions of both quantities analytically and we show that the ratio of mean divergence and diversity depends on the strength of selection in a universal way: it is largely independent of the phenotype’s genomic encoding and of the recombination rate. This establishes a new method for the inference of selection on molecular phenotypes beyond the genome level. We discuss the implications of our findings for the predictability of evolutionary processes.

  19. [Phenotypic heterogeneity of chronic obstructive pulmonary disease].

    PubMed

    Garcia-Aymerich, Judith; Agustí, Alvar; Barberà, Joan A; Belda, José; Farrero, Eva; Ferrer, Antoni; Ferrer, Jaume; Gáldiz, Juan B; Gea, Joaquim; Gómez, Federico P; Monsó, Eduard; Morera, Josep; Roca, Josep; Sauleda, Jaume; Antó, Josep M

    2009-03-01

    A functional definition of chronic obstructive pulmonary disease (COPD) based on airflow limitation has largely dominated the field. However, a view has emerged that COPD involves a complex array of cellular, organic, functional, and clinical events, with a growing interest in disentangling the phenotypic heterogeneity of COPD. The present review is based on the opinion of the authors, who have extensive research experience in several aspects of COPD. The starting assumption of the review is that current knowledge on the pathophysiology and clinical features of COPD allows us to classify phenotypic information in terms of the following dimensions: respiratory symptoms and health status, acute exacerbations, lung function, structural changes, local and systemic inflammation, and systemic effects. Twenty-six phenotypic traits were identified and assigned to one of the 6 dimensions. For each dimension, a summary is provided of the best evidence on the relationships among phenotypic traits, in particular among those corresponding to different dimensions, and on the relationship between these traits and relevant events in the natural history of COPD. The information has been organized graphically into a phenotypic matrix where each cell representing a pair of phenotypic traits is linked to relevant references. The information provided has the potential to increase our understanding of the heterogeneity of COPD phenotypes and help us plan future studies on aspects that are as yet unexplored.

  20. Transcriptome transfer produces a predictable cellular phenotype

    PubMed Central

    Sul, Jai-Yoon; Wu, Chia-wen K.; Zeng, Fanyi; Jochems, Jeanine; Lee, Miler T.; Kim, Tae Kyung; Peritz, Tiina; Buckley, Peter; Cappelleri, David J.; Maronski, Margaret; Kim, Minsun; Kumar, Vijay; Meaney, David; Kim, Junhyong; Eberwine, James

    2009-01-01

    Cellular phenotype is the conglomerate of multiple cellular processes involving gene and protein expression that result in the elaboration of a cell's particular morphology and function. It has been thought that differentiated postmitotic cells have their genomes hard wired, with little ability for phenotypic plasticity. Here we show that transfer of the transcriptome from differentiated rat astrocytes into a nondividing differentiated rat neuron resulted in the conversion of the neuron into a functional astrocyte-like cell in a time-dependent manner. This single-cell study permits high resolution of molecular and functional components that underlie phenotype identity. The RNA population from astrocytes contains RNAs in the appropriate relative abundances that give rise to regulatory RNAs and translated proteins that enable astrocyte identity. When transferred into the postmitotic neuron, the astrocyte RNA population converts 44% of the neuronal host cells into the destination astrocyte-like phenotype. In support of this observation, quantitative measures of cellular morphology, single-cell PCR, single-cell microarray, and single-cell functional analyses have been performed. The host-cell phenotypic changes develop over many weeks and are persistent. We call this process of RNA-induced phenotype changes, transcriptome-induced phenotype remodeling. PMID:19380745

  1. Phenoscape: Identifying Candidate Genes for Evolutionary Phenotypes

    PubMed Central

    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. Metabolomic phenotyping of a cloned pig model

    PubMed Central

    2011-01-01

    Background Pigs are widely used as models for human physiological changes in intervention studies, because of the close resemblance between human and porcine physiology and the high degree of experimental control when using an animal model. Cloned animals have, in principle, identical genotypes and possibly also phenotypes and this offer an extra level of experimental control which could possibly make them a desirable tool for intervention studies. Therefore, in the present study, we address how phenotype and phenotypic variation is affected by cloning, through comparison of cloned pigs and normal outbred pigs. Results The metabolic phenotype of cloned pigs (n = 5) was for the first time elucidated by nuclear magnetic resonance (NMR)-based metabolomic analysis of multiple bio-fluids including plasma, bile and urine. The metabolic phenotype of the cloned pigs was compared with normal outbred pigs (n = 6) by multivariate data analysis, which revealed differences in the metabolic phenotypes. Plasma lactate was higher for cloned vs control pigs, while multiple metabolites were altered in the bile. However a lower inter-individual variability for cloned pigs compared with control pigs could not be established. Conclusions From the present study we conclude that cloned and normal outbred pigs are phenotypically different. However, it cannot be concluded that the use of cloned animals will reduce the inter-individual variation in intervention studies, though this is based on a limited number of animals. PMID:21859467

  3. Phenotyping: targeting genotype's rich cousin for diagnosis.

    PubMed

    Baynam, Gareth; Walters, Mark; Claes, Peter; Kung, Stefanie; LeSouef, Peter; Dawkins, Hugh; Bellgard, Matthew; Girdea, Marta; Brudno, Michael; Robinson, Peter; Zankl, Andreas; Groza, Tudor; Gillett, David; Goldblatt, Jack

    2015-04-01

    There are many current and evolving tools to assist clinicians in their daily work of phenotyping. In medicine, the term 'phenotype' is usually taken to mean some deviation from normal morphology, physiology and behaviour. It is ascertained via history, examination and investigations, and a primary aim is diagnosis. Therefore, doctors are, by necessity, expert 'phenotypers'. There is an inherent and partially realised power in phenotypic information that when harnessed can improve patient care. Furthermore, phenotyping developments are increasingly important in an era of rapid advances in genomic technology. Fortunately, there is an expanding network of phenotyping tools that are poised for clinical translation. These tools will preferentially be implemented to mirror clinical workflows and to integrate with advances in genomic and information-sharing technologies. This will synergise with and augment the clinical acumen of medical practitioners. We outline key enablers of the ascertainment, integration and interrogation of clinical phenotype by using genetic diseases, particularly rare ones, as a theme. Successes from the test bed or rare diseases will support approaches to common disease. © 2014 The Authors. Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

  4. Distribution of phenotypes among Bacillus thuringiensis strains.

    PubMed

    Martin, Phyllis A W; Gundersen-Rindal, Dawn E; Blackburn, Michael B

    2010-06-01

    An extensive collection of Bacillus thuringiensis isolates from around the world were phenotypically profiled using standard biochemical tests. Six phenotypic traits occurred in 20-86% of the isolates and were useful in distinguishing isolates: production of urease (U; 20.5% of isolates), hydrolysis of esculin (E; 32.3% of isolates), acid production from salicin (A; 37.4% of isolates), acid production from sucrose (S; 34.0% of isolates), production of phospholipase C or lecithinase (L; 79.7% of isolates), and hydrolysis of starch (T; 85.8% of isolates). With the exception of acid production from salicin and hydrolysis of esculin, which were associated, the traits assorted independently. Of the 64 possible combinations of these six phenotypic characteristics, 15 combinations accounted for ca. 80% of all isolates, with the most common phenotype being TL (23.6% of isolates). Surprisingly, while the biochemical traits generally assorted independently, certain phenotypic traits associated with the parasporal crystal were correlated with certain combinations of biochemical traits. Crystals that remained attached to spores (which tended to be non-toxic to insects) were highly correlated with the phenotypes that included both L and S. Among the 15 most abundant phenotypes characterizing B. thuringiensis strains, amorphous crystals were associated with TLE, TL, T, and Ø (the absence of positive tested biochemical traits). Amorphous crystal types displayed a distinct bias toward toxicity to dipteran insects. Although all common phenotypes included B. thuringiensis isolates producing bipyramidal crystals toxic to lepidopteran insects, those with the highest abundance of these toxic crystals displayed phenotypes TLU, TLUA, TLUAE, and TLAE.

  5. The nature of stable insomnia phenotypes.

    PubMed

    Pillai, Vivek; Roth, Thomas; Drake, Christopher L

    2015-01-01

    We examined the 1-y stability of four insomnia symptom profiles: sleep onset insomnia; sleep maintenance insomnia; combined onset and maintenance insomnia; and neither criterion (i.e., insomnia cases that do not meet quantitative thresholds for onset or maintenance problems). Insomnia cases that exhibited the same symptom profile over a 1-y period were considered to be phenotypes, and were compared in terms of clinical and demographic characteristics. Longitudinal. Urban, community-based. Nine hundred fifty-four adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition based current insomnia (46.6 ± 12.6 y; 69.4% female). None. At baseline, participants were divided into four symptom profile groups based on quantitative criteria. Follow-up assessment 1 y later revealed that approximately 60% of participants retained the same symptom profile, and were hence judged to be phenotypes. Stability varied significantly by phenotype, such that sleep onset insomnia (SOI) was the least stable (42%), whereas combined insomnia (CI) was the most stable (69%). Baseline symptom groups (cross-sectionally defined) differed significantly across various clinical indices, including daytime impairment, depression, and anxiety. Importantly, however, a comparison of stable phenotypes (longitudinally defined) did not reveal any differences in impairment or comorbid psychopathology. Another interesting finding was that whereas all other insomnia phenotypes showed evidence of an elevated wake drive both at night and during the day, the 'neither criterion' phenotype did not; this latter phenotype exhibited significantly higher daytime sleepiness despite subthreshold onset and maintenance difficulties. By adopting a stringent, stability-based definition, this study offers timely and important data on the longitudinal trajectory of specific insomnia phenotypes. With the exception of daytime sleepiness, few clinical differences are apparent across stable phenotypes.

  6. Development of a phenotypic susceptibility assay for HIV-1 integrase inhibitors.

    PubMed

    Heger, Eva; Theis, Alexandra Andrée; Remmel, Klaus; Walter, Hauke; Pironti, Alejandro; Knops, Elena; Di Cristanziano, Veronica; Jensen, Björn; Esser, Stefan; Kaiser, Rolf; Lübke, Nadine

    2016-12-01

    Phenotypic resistance analysis is an indispensable method for determination of HIV-1 resistance and cross-resistance to novel drug compounds. Since integrase inhibitors are essential components of recent antiretroviral combination therapies, phenotypic resistance data, in conjunction with the corresponding genotypes, are needed for improving rules-based and data-driven tools for resistance prediction, such as HIV-Grade and geno2pheno[integrase]. For generation of phenotypic resistance data to recent integrase inhibitors, a recombinant phenotypic integrase susceptibility assay was established. For validation purposes, the phenotypic resistance to raltegravir, elvitegravir and dolutegravir of nine subtype-B virus strains, isolated from integrase inhibitor-naïve and raltegravir-treated patients was determined. Genotypic resistance analysis identified four virus strains harbouring RAL resistance-associated mutations. Phenotypic resistance analysis was performed as follows. The HIV-1 integrase genes were cloned into a modified pNL4-3 vector and transfected into 293T cells for the generation of recombinant virus. The integrase-inhibitor susceptibility of the recombinant viruses was determined via an indicator cell line. While raltegravir resistance profiles presented a high cross-resistance to elvitegravir, dolutegravir maintained in-vitro activity in spite of the Y143R and N155H mutations, confirming the strong activity of dolutegravir against raltegravir-resistant viruses. Solely a Q148H+G140S variant presented reduced susceptibility to dolutegravir. In conclusion, our phenotypic susceptibility assay permits resistance analysis of the integrase gene of patient-derived viruses for integrase inhibitors by replication-competent recombinants. Thus, this assay can be used to analyze phenotypic drug resistance of integrase inhibitors in vitro. It provides the possibility to determine the impact of newly appearing mutational patterns to drug resistance of recent integrase

  7. Phenotypic plasticity in the range-margin population of the lycaenid butterfly Zizeeria maha

    PubMed Central

    2010-01-01

    Background Many butterfly species have been experiencing the northward range expansion and physiological adaptation, probably due to climate warming. Here, we document an extraordinary field case of a species of lycaenid butterfly, Zizeeria maha, for which plastic phenotypes of wing color-patterns were revealed at the population level in the course of range expansion. Furthermore, we examined whether this outbreak of phenotypic changes was able to be reproduced in a laboratory. Results In the recently expanded northern range margins of this species, more than 10% of the Z. maha population exhibited characteristic color-pattern modifications on the ventral wings for three years. We physiologically reproduced similar phenotypes by an artificial cold-shock treatment of a normal southern population, and furthermore, we genetically reproduced a similar phenotype after selective breeding of a normal population for ten generations, demonstrating that the cold-shock-induced phenotype was heritable and partially assimilated genetically in the breeding line. Similar genetic process might have occurred in the previous and recent range-margin populations as well. Relatively minor modifications expressed in the tenth generation of the breeding line together with other data suggest a role of founder effect in this field case. Conclusions Our results support the notion that the outbreak of the modified phenotypes in the recent range-margin population was primed by the revelation of plastic phenotypes in response to temperature stress and by the subsequent genetic process in the previous range-margin population, followed by migration and temporal establishment of genetically unstable founders in the recent range margins. This case presents not only an evolutionary role of phenotypic plasticity in the field but also a novel evolutionary aspect of range expansion at the species level. PMID:20718993

  8. Stochastic developmental variation, an epigenetic source of phenotypic diversity with far-reaching biological consequences.

    PubMed

    Vogt, Günter

    2015-03-01

    pathogens are asexuals that exploit this third source of phenotypic variation to modify infectivity and resistance to antibiotics. Since SDV affects all types of organisms and almost all aspects of life, it urgently requires more intense research and a better integration into biological thinking.

  9. Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome.

    PubMed

    Calhoun, Jeffrey D; Hawkins, Nicole A; Zachwieja, Nicole J; Kearney, Jennifer A

    2017-08-01

    Dravet syndrome, an early onset epileptic encephalopathy, is most often caused by de novo mutation of the neuronal voltage-gated sodium channel gene SCN1A. Mouse models with deletion of Scn1a recapitulate Dravet syndrome phenotypes, including spontaneous generalized tonic-clonic seizures, susceptibility to seizures induced by elevated body temperature, and elevated risk of sudden unexpected death in epilepsy. Importantly, the epilepsy phenotype of Dravet mouse models is highly strain-dependent, suggesting a strong influence of genetic modifiers. We previously identified Cacna1g, encoding the Cav3.1 subunit of the T-type calcium channel family, as an epilepsy modifier in the Scn2a(Q54) transgenic epilepsy mouse model. In this study, we asked whether transgenic alteration of Cacna1g expression modifies severity of the Scn1a(+/-) Dravet phenotype. Scn1a(+/-) mice with decreased Cacna1g expression showed partial amelioration of disease phenotypes with improved survival and reduced spontaneous seizure frequency. However, reduced Cacna1g expression did not alter susceptibility to hyperthermia-induced seizures. Transgenic elevation of Cacna1g expression had no effect on the Scn1a(+/-) epilepsy phenotype. These results provide support for Cacna1g as a genetic modifier in a mouse model of Dravet syndrome and suggest that Cav3.1 may be a potential molecular target for therapeutic intervention in patients. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  10. Phenotypic plasticity and evolution by genetic assimilation.

    PubMed

    Pigliucci, Massimo; Murren, Courtney J; Schlichting, Carl D

    2006-06-01

    In addition to considerable debate in the recent evolutionary literature about the limits of the Modern Synthesis of the 1930s and 1940s, there has also been theoretical and empirical interest in a variety of new and not so new concepts such as phenotypic plasticity, genetic assimilation and phenotypic accommodation. Here we consider examples of the arguments and counter-arguments that have shaped this discussion. We suggest that much of the controversy hinges on several misunderstandings, including unwarranted fears of a general attempt at overthrowing the Modern Synthesis paradigm, and some fundamental conceptual confusion about the proper roles of phenotypic plasticity and natural selection within evolutionary theory.

  11. Important discoveries from analysing bacterial phenotypes

    PubMed Central

    Bochner, Barry R; Giovannetti, Luciana; Viti, Carlo

    2008-01-01

    The ability to test hundreds to thousands of cellular phenotypes in a single experiment has opened up new avenues of investigation and exploration and led to important discoveries in very diverse applications of microbiological research and development. The information provided by global phenotyping is complementary to, and often more easily interpretable than information provided by global molecular analytical methods such as gene chips and proteomics. This report summarizes advances presented by scientists brought together to share their experiences and knowledge gained with high-throughput phenotyping. PMID:18681942

  12. Cattle phenotypes can disguise their maternal ancestry.

    PubMed

    Srirattana, Kanokwan; McCosker, Kieren; Schatz, Tim; St John, Justin C

    2017-06-26

    Cattle are bred for, amongst other factors, specific traits, including parasite resistance and adaptation to climate. However, the influence and inheritance of mitochondrial DNA (mtDNA) are not usually considered in breeding programmes. In this study, we analysed the mtDNA profiles of cattle from Victoria (VIC), southern Australia, which is a temperate climate, and the Northern Territory (NT), the northern part of Australia, which has a tropical climate, to determine if the mtDNA profiles of these cattle are indicative of breed and phenotype, and whether these profiles are appropriate for their environments. A phylogenetic tree of the full mtDNA sequences of different breeds of cattle, which were obtained from the NCBI database, showed that the mtDNA profiles of cattle do not always reflect their phenotype as some cattle with Bos taurus phenotypes had Bos indicus mtDNA, whilst some cattle with Bos indicus phenotypes had Bos taurus mtDNA. Using D-loop sequencing, we were able to contrast the phenotypes and mtDNA profiles from different species of cattle from the 2 distinct cattle breeding regions of Australia. We found that 67 of the 121 cattle with Bos indicus phenotypes from NT (55.4%) had Bos taurus mtDNA. In VIC, 92 of the 225 cattle with Bos taurus phenotypes (40.9%) possessed Bos indicus mtDNA. When focusing on oocytes from cattle with the Bos taurus phenotype in VIC, their respective oocytes with Bos indicus mtDNA had significantly lower levels of mtDNA copy number compared with oocytes possessing Bos taurus mtDNA (P < 0.01). However, embryos derived from oocytes with Bos indicus mtDNA had the same ability to develop to the blastocyst stage and the levels of mtDNA copy number in their blastocysts were similar to blastocysts derived from oocytes harbouring Bos taurus mtDNA. Nevertheless, oocytes originating from the Bos indicus phenotype exhibited lower developmental potential due to low mtDNA copy number when compared with oocytes from cattle with a Bos

  13. Phenotype-driven strategies for exome prioritization of human Mendelian disease genes.

    PubMed

    Smedley, Damian; Robinson, Peter N

    2015-01-01

    Whole exome sequencing has altered the way in which rare diseases are diagnosed and disease genes identified. Hundreds of novel disease-associated genes have been characterized by whole exome sequencing in the past five years, yet the identification of disease-causing mutations is often challenging because of the large number of rare variants that are being revealed. Gene prioritization aims to rank the most probable candidate genes towards the top of a list of potentially pathogenic variants. A promising new approach involves the computational comparison of the phenotypic abnormalities of the individual being investigated with those previously associated with human diseases or genetically modified model organisms. In this review, we compare and contrast the strengths and weaknesses of current phenotype-driven computational algorithms, including Phevor, Phen-Gen, eXtasy and two algorithms developed by our groups called PhenIX and Exomiser. Computational phenotype analysis can substantially improve the performance of exome analysis pipelines.

  14. Modeling tumor predisposing FH mutations in yeast: effects on fumarase activity, growth phenotype and gene expression profile.

    PubMed

    Kokko, Antti; Ylisaukko-Oja, Sanna S K; Kiuru, Maija; Takatalo, Maarit S; Salmikangas, Paula; Tuimala, Jarno; Arango, Diego; Karhu, Auli; Aaltonen, Lauri A; Jäntti, Jussi

    2006-03-15

    Heterozygous mutations in the fumarase (FH) gene cause the tumor predisposition syndrome hereditary leiomyomatosis and renal cell cancer (MIM 605839). While most families segregate a benign phenotype of multiple leiomyomas, others display a phenotype with early-onset renal cancer and leiomyosarcoma. Modifier genes may play a role in this, but an alternative explanation is simple genotype-phenotype association. FH mutations predisposing to cancer appear to be truncating or in fully conserved amino acids, suggesting that mutations severely affecting FH activity might predispose to malignancy. In the present study, we analyzed 2 conserved fumarase mutations in yeast. H153R has been described in 3 cancer predisposition families; whereas all 3 reported K187R families have displayed the benign phenotype. Examining H153R and K187R should clarify whether cancer-related FH mutations differ from their benign phenotype-associated counterparts. Yeast strains containing the 2 mutations, and knockout and wild type (WT) references, were created and the growth phenotypes studied on selected carbon sources to assess mitochondrial function. Additionally, Fum1 protein production and activity were measured, and the strains were subjected to transcriptional profiling. On nonfermentable lactate medium, the fumarase knockout strains did not grow, whereas the mutants showed no differences, as compared to WT yeast. Although both mutant strains produced fumarase, a considerable decrease in enzyme activity was seen in mutants with respect to WT. Transcription of the majority of Krebs cycle enzymes was downregulated in response to mutations in fumarase. In conclusion, both mutants displayed some, albeit greatly reduced, fumarase activity. This activity was sufficient to support normal growth on nonfermentable carbon source, unlike the deletion phenotype, demonstrating the significance of the residual activity. The findings support the hypothesis that modifier gene(s), rather than phenotype

  15. Variable phenotypes associated with aromatase (CYP19) insufficiency in humans

    PubMed Central

    Lin, Lin; Ercan, Oya; Raza, Jamal; Burren, Christine P.; Creighton, Sarah M.; Auchus, Richard J.; Dattani, Mehul T.; Achermann, John C.

    2007-01-01

    Context The P450 enzyme aromatase (CYP19) plays a crucial role in the endocrine and paracrine biosynthesis of estrogens from androgens in many diverse estrogen-responsive tissues. Complete aromatase deficiency has been reported in a small number of 46,XX girls with genital ambiguity and absent pubertal development, but it is unknown whether non-classic phenotypes exist. Objective The objective of the study was to determine whether variant forms of aromatase insufficiency can occur in humans. Patients Four patients (46,XX) from three kindred with variable degrees of androgenization and pubertal failure. Methods Mutational analysis of CYP19 and assay of enzyme activity. Results Aromatase insufficiency resulting in genital ambiguity at birth, but with variable breast development at puberty (B2-B4), occurred in 46,XX patients from two kindred who harbored point mutations or single codon deletions (R435C, F234del). Absent puberty with minimal androgenization at birth was found in one girl with a deletion involving exon5 of CYP19 (exon5del), which would be predicted to lead to an in-frame deletion of 59 amino acids from the enzyme. Functional studies revealed low residual aromatase activity in the cases where breast development occurred. Conclusions These studies demonstrate that aromatase mutations can produce variable or “non-classic” phenotypes in humans. Low residual aromatase activity may be sufficient for breast and uterine development to occur at puberty, despite significant androgenization in utero. Such phenotypic variability may be influenced further by modifying factors, such as non-classic pathways of estrogen synthesis, variability in co-regulators, or differences in androgen responsiveness. PMID:17164303

  16. Parasites alter the pathological phenotype of lupus nephritis.

    PubMed

    Miyake, Katsuhisa; Adachi, Keishi; Watanabe, Maho; Sasatomi, Yoshie; Ogahara, Satoru; Abe, Yasuhiro; Ito, Kenji; Dan Justin, Yombo K; Saito, Takao; Nakashima, Hitoshi; Hamano, Shinjiro

    2014-12-01

    Lupus nephritis is one of the most serious complications of systemic lupus erythematosus and manifests with considerable phenotypic and histological heterogeneity. In particular, diffuse proliferative lupus nephritis (DPLN) and membranous lupus nephritis (MLN) represent morphologic forms that are polar opposites. DPLN is associated with autoimmune responses dominated by Th1 immune response associated with high levels of interferon (IFN)-γ. In contrast, a Th2 cytokine response is associated with the pathogenesis of MLN. MRL/lpr mice develop human LN-like immune complex-associated nephritis and provide a suitable histological model for human DPLN. Infection with Schistosoma mansoni skewed a Th2-type immune response induction and IL-10 in MRL/lpr mice, drastically changing the pathophysiology of glomerulonephritis from DPLN to MLN accompanied by increased IgG1 and IgE in the sera. T cells in 32-week-old MRL/lpr mice infected with S. mansoni expressed significantly more IL-4 and IL-10 than T cells of uninfected mice; T cells with IFN-γ were comparable between infected and uninfected MR/lpr mice. Thus, the helminthic infection modified the cytokine microenvironment and altered the pathological phenotype of autoimmune nephritis.

  17. Parasites alter the pathological phenotype of lupus nephritis

    PubMed Central

    Miyake, Katsuhisa; Adachi, Keishi; Watanabe, Maho; Sasatomi, Yoshie; Ogahara, Satoru; Abe, Yasuhiro; Ito, Kenji; Dan Justin, Yombo K.; Saito, Takao

    2014-01-01

    lpr Lupus nephritis is one of the most serious complications of systemic lupus erythematosus and manifests with considerable phenotypic and histological heterogeneity. In particular, diffuse proliferative lupus nephritis (DPLN) and membranous lupus nephritis (MLN) represent morphologic forms that are polar opposites. DPLN is associated with autoimmune responses dominated by Th1 immune response associated with high levels of interferon (IFN)-γ. In contrast, a Th2 cytokine response is associated with the pathogenesis of MLN. MRL/lpr mice develop human LN-like immune complex-associated nephritis and provide a suitable histological model for human DPLN. Infection with Schistosoma mansoni skewed a Th2-type immune response induction and IL-10 in MRL/lpr mice, drastically changing the pathophysiology of glomerulonephritis from DPLN to MLN accompanied by increased IgG1 and IgE in the sera. T cells in 32-week-old MRL/lpr mice infected with S. mansoni expressed significantly more IL-4 and IL-10 than T cells of uninfected mice; T cells with IFN-γ were comparable between infected and uninfected MR/lpr mice. Thus, the helminthic infection modified the cytokine microenvironment and altered the pathological phenotype of autoimmune nephritis. PMID:24957876

  18. Different phenotypes in identical twins with cerebrotendinous xanthomatosis: case series.

    PubMed

    Zádori, Dénes; Szpisjak, László; Madar, László; Varga, Viktória Evelin; Csányi, Bernadett; Bencsik, Krisztina; Balogh, István; Harangi, Mariann; Kereszty, Éva; Vécsei, László; Klivényi, Péter

    2017-03-01

    Cerebrotendinous xanthomatosis (CTX) is a rare, genetically determined error of metabolism. The characteristic clinical symptoms are diarrhea, juvenile cataracts, tendon xanthomas and neuropsychiatric alterations. The aim of this study is to present a pair of identical adult twins with considerable differences in the severity of phenotype. With regards to neuropsychiatric symptoms, the predominant features were severe Parkinsonism and moderate cognitive dysfunctions in the more-affected individual, whereas these alterations in the less-affected patient were only very mild and mild, respectively. The characteristic increase in the concentrations of serum cholestanol and the lesion volumes in dentate nuclei in the brain assessed with magnetic resonance imaging were quite similar in both cases. The lifestyle conditions, including eating habits of the twin pair, were quite similar as well; therefore, currently unknown genetic modifiers or certain epigenetic factors may be responsible for the differences in severity of phenotype. This case series serves as the first description of an identical twin pair with CTX presenting heterogeneous clinical features.

  19. Phenotypic Plasticity and Selection: Nonexclusive Mechanisms of Adaptation

    PubMed Central

    Grenier, S.; Barre, P.; Litrico, I.

    2016-01-01

    Selection and plasticity are two mechanisms that allow the adaptation of a population to a changing environment. Interaction between these nonexclusive mechanisms must be considered if we are to understand population survival. This review discusses the ways in which plasticity and selection can interact, based on a review of the literature on selection and phenotypic plasticity in the evolution of populations. The link between selection and phenotypic plasticity is analysed at the level of the individual. Plasticity can affect an individual's response to selection and so may modify the end result of genetic diversity evolution at population level. Genetic diversity increases the ability of populations or communities to adapt to new environmental conditions. Adaptive plasticity increases individual fitness. However this effect must be viewed from the perspective of the costs of plasticity, although these are not easy to estimate. It is becoming necessary to engage in new experimental research to demonstrate the combined effects of selection and plasticity for adaptation and their consequences on the evolution of genetic diversity. PMID:27313957

  20. Using Genetic Networks and Homology to Understand the Evolution of Phenotypic Traits

    PubMed Central

    McCune, Amy R; Schimenti, John C

    2012-01-01

    Homology can have different meanings for different kinds of biologists. A phylogenetic view holds that homology, defined by common ancestry, is rigorously identified through phylogenetic analysis. Such homologies are taxic homologies (=synapomorphies). A second interpretation, “biological homology” emphasizes common ancestry through the continuity of genetic information underlying phenotypic traits, and is favored by some developmental geneticists. A third kind of homology, deep homology, was recently defined as “the sharing of the genetic regulatory apparatus used to build morphologically and phylogenetically disparate features.” Here we explain the commonality among these three versions of homology. We argue that biological homology, as evidenced by a conserved gene regulatory network giving a trait its “essential identity” (a Character Identity Network or “ChIN”) must also be a taxic homology. In cases where a phenotypic trait has been modified over the course of evolution such that homology (taxic) is obscured (e.g. jaws are modified gill arches), a shared underlying ChIN provides evidence of this transformation. Deep homologies, where molecular and cellular components of a phenotypic trait precede the trait itself (are phylogenetically deep relative to the trait), are also taxic homologies, undisguised. Deep homologies inspire particular interest for understanding the evolutionary assembly of phenotypic traits. Mapping these deeply homologous building blocks on a phylogeny reveals the sequential steps leading to the origin of phenotypic novelties. Finally, we discuss how new genomic technologies will revolutionize the comparative genomic study of non-model organisms in a phylogenetic context, necessary to understand the evolution of phenotypic traits. PMID:22942677

  1. Complex Small-Molecule Architectures Regulate Phenotypic Plasticity in a Nematode**

    PubMed Central

    Bose, Neelanjan; Ogawa, Akira; von Reuss, Stephan H.; Yim, Joshua J.; Ragsdale, Erik J.; Sommer, Ralf J.; Schroeder, Frank C.

    2013-01-01

    Microorganisms and plants produce a large diversity of secondary metabolites, whereas analyses of metazoan metabolomes have yielded comparatively few types of small molecules. We show that the nematode Pristionchus pacificus constructs elaborate molecular architectures from modified building blocks of primary metabolism, including an unusual xylopyranose-based nucleoside. These compounds act as signaling molecules controlling adult phenotypic plasticity and development and provide striking examples for modular generation of structural diversity in metazoans. PMID:23161728

  2. Phenotypic Assessment and the Discovery of Topiramate

    PubMed Central

    2016-01-01

    The role of phenotypic assessment in drug discovery is discussed, along with the discovery and development of TOPAMAX (topiramate), a billion-dollar molecule for the treatment of epilepsy and migraine. PMID:27437073

  3. Probing genetic overlap among complex human phenotypes.

    PubMed

    Rzhetsky, Andrey; Wajngurt, David; Park, Naeun; Zheng, Tian

    2007-07-10

    Geneticists and epidemiologists often observe that certain hereditary disorders cooccur in individual patients significantly more (or significantly less) frequently than expected, suggesting there is a genetic variation that predisposes its bearer to multiple disorders, or that protects against some disorders while predisposing to others. We suggest that, by using a large number of phenotypic observations about multiple disorders and an appropriate statistical model, we can infer genetic overlaps between phenotypes. Our proof-of-concept analysis of 1.5 million patient records and 161 disorders indicates that disease phenotypes form a highly connected network of strong pairwise correlations. Our modeling approach, under appropriate assumptions, allows us to estimate from these correlations the size of putative genetic overlaps. For example, we suggest that autism, bipolar disorder, and schizophrenia share significant genetic overlaps. Our disease network hypothesis can be immediately exploited in the design of genetic mapping approaches that involve joint linkage or association analyses of multiple seemingly disparate phenotypes.

  4. The behavioural phenotype of Angelman syndrome.

    PubMed

    Horsler, K; Oliver, C

    2006-01-01

    The purpose of this review is to examine the notion of a behavioural phenotype for Angelman syndrome and identify methodological and conceptual influences on the accepted presentation. Studies examining the behavioural characteristics associated with Angelman syndrome are reviewed and methodology is described. Potential bias in the description of the phenotype emerges with the use of case and cohort studies with the absence of comparison groups. A trend in the literature from a direct gene effect to a socially mediated effect on laughter is evident. Evidence for a behavioural phenotype of Angelman syndrome has begun to emerge. However, by adopting the concept of a 'behavioural phenotype', attention may become biased towards the underlying biological basis of the syndrome, with developmental and environmental factors being overlooked.

  5. Modified Faraday cup

    DOEpatents

    Elmer, J.W.; Teruya, A.T.; O`Brien, D.W.

    1996-09-10

    A tomographic technique for measuring the current density distribution in electron beams using electron beam profile data acquired from a modified Faraday cup to create an image of the current density in high and low power beams is disclosed. The modified Faraday cup includes a narrow slit and is rotated by a stepper motor and can be moved in the x, y and z directions. The beam is swept across the slit perpendicular thereto and controlled by deflection coils, and the slit rotated such that waveforms are taken every few degrees from 0{degree} to 360{degree} and the waveforms are recorded by a digitizing storage oscilloscope. Two-dimensional and three-dimensional images of the current density distribution in the beam can be reconstructed by computer tomography from this information, providing quantitative information about the beam focus and alignment. 12 figs.

  6. Modified Faraday cup

    DOEpatents

    Elmer, John W.; Teruya, Alan T.; O'Brien, Dennis W.

    1996-01-01

    A tomographic technique for measuring the current density distribution in electron beams using electron beam profile data acquired from a modified Faraday cup to create an image of the current density in high and low power beams. The modified Faraday cup includes a narrow slit and is rotated by a stepper motor and can be moved in the x, y and z directions. The beam is swept across the slit perpendicular thereto and controlled by deflection coils, and the slit rotated such that waveforms are taken every few degrees form 0.degree. to 360.degree. and the waveforms are recorded by a digitizing storage oscilloscope. Two-din-tensional and three-dimensional images of the current density distribution in the beam can be reconstructed by computer tomography from this information, providing quantitative information about the beam focus and alignment.

  7. Genetically modified bacteriophages.

    PubMed

    Sagona, Antonia P; Grigonyte, Aurelija M; MacDonald, Paul R; Jaramillo, Alfonso

    2016-04-18

    Phages or bacteriophages, viruses that infect and replicate inside bacteria, are the most abundant microorganisms on earth. The realization that antibiotic resistance poses a substantial risk to the world's health and global economy is revitalizing phage therapy as a potential solution. The increasing ease by which phage genomes can be modified, owing to the influx of new technologies, has led to an expansion of their natural capabilities, and a reduced dependence on phage isolation from environmental sources. This review will discuss the way synthetic biology has accelerated the construction of genetically modified phages and will describe the wide range of their applications. It will further provide insight into the societal and economic benefits that derive from the use of recombinant phages in various sectors, from health to biodetection, biocontrol and the food industry.

  8. Phenotype Standardization for Statin-Induced Myotoxicity

    PubMed Central

    Alfirevic, A; Neely, D; Armitage, J; Chinoy, H; Cooper, R G; Laaksonen, R; Carr, D F; Bloch, K M; Fahy, J; Hanson, A; Yue, Q-Y; Wadelius, M; Maitland-van Der Zee, A H; Voora, D; Psaty, B M; Palmer, C N A; Pirmohamed, M

    2014-01-01

    Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy. PMID:24897241

  9. Mining phenotypes for gene function prediction

    PubMed Central

    Groth, Philip; Weiss, Bertram; Pohlenz, Hans-Dieter; Leser, Ulf

    2008-01-01

    Background Health and disease of organisms are reflected in their phenotypes. Often, a genetic component to a disease is discovered only after clearly defining its phenotype. In the past years, many technologies to systematically generate phenotypes in a high-throughput manner, such as RNA interference or gene knock-out, have been developed and used to decipher functions for genes. However, there have been relatively few efforts to make use of phenotype data beyond the single genotype-phenotype relationships. Results We present results on a study where we use a large set of phenotype data – in textual form – to predict gene annotation. To this end, we use text clustering to group genes based on their phenotype descriptions. We show that these clusters correlate well with several indicators for biological coherence in gene groups, such as functional annotations from the Gene Ontology (GO) and protein-protein interactions. We exploit these clusters for predicting gene function by carrying over annotations from well-annotated genes to other, less-characterized genes in the same cluster. For a subset of groups selected by applying objective criteria, we can predict GO-term annotations from the biological process sub-ontology with up to 72.6% precision and 16.7% recall, as evaluated by cross-validation. We manually verified some of these clusters and found them to exhibit high biological coherence, e.g. a group containing all available antennal Drosophila odorant receptors despite inconsistent GO-annotations. Conclusion The intrinsic nature of phenotypes to visibly reflect genetic activity underlines their usefulness in inferring new gene functions. Thus, systematically analyzing these data on a large scale offers many possibilities for inferring functional annotation of genes. We show that text clustering can play an important role in this process. PMID:18315868

  10. A database of Caenorhabditis elegans behavioral phenotypes.

    PubMed

    Yemini, Eviatar; Jucikas, Tadas; Grundy, Laura J; Brown, André E X; Schafer, William R

    2013-09-01

    Using low-cost automated tracking microscopes, we have generated a behavioral database for 305 Caenorhabditis elegans strains, including 76 mutants with no previously described phenotype. The growing database currently consists of 9,203 short videos segmented to extract behavior and morphology features, and these videos and feature data are available online for further analysis. The database also includes summary statistics for 702 measures with statistical comparisons to wild-type controls so that phenotypes can be identified and understood by users.

  11. Phenotype standardization for statin-induced myotoxicity.

    PubMed

    Alfirevic, A; Neely, D; Armitage, J; Chinoy, H; Cooper, R G; Laaksonen, R; Carr, D F; Bloch, K M; Fahy, J; Hanson, A; Yue, Q-Y; Wadelius, M; Maitland-van Der Zee, A H; Voora, D; Psaty, B M; Palmer, C N A; Pirmohamed, M

    2014-10-01

    Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.

  12. A database of C. elegans behavioral phenotypes

    PubMed Central

    Yemini, Eviatar; Jucikas, Tadas; Grundy, Laura J.; Brown, André E.X.; Schafer, William R.

    2014-01-01

    Using low-cost automated tracking microscopes, we have generated a behavioral database for 305 C. elegans strains, including 76 mutants with no previously described phenotype. The database consists of 9,203 short videos segmented to extract behavior and morphology features that are available online for further analysis. The database also includes summary statistics for 702 measures with statistical comparisons to wild-type controls so that phenotypes can be identified and understood by users. PMID:23852451

  13. Modified entropic force

    SciTech Connect

    Gao Changjun

    2010-04-15

    The theory of statistical thermodynamics tells us the equipartition law of energy does not hold in the limit of very low temperatures. It is found the Debye model is very successful in explaining the experimental results for most of the solid objects. Motivated by this fact, we modify the entropic force formula which is proposed very recently. Since the Unruh temperature is proportional to the strength of the gravitational field, so the modified entropic force formula is an extension of the Newtonian gravity to the weak field. On the contrary, general relativity extends Newtonian gravity to the strong field case. Corresponding to Debye temperature, there exists a Debye acceleration g{sub D}. It is found the Debye acceleration is g{sub D}=10{sup -15} N kg{sup -1}. This acceleration is very much smaller than the gravitational acceleration 10{sup -4} N kg{sup -1} which is felt by Neptune and the gravitational acceleration 10{sup -10} N kg{sup -1} felt by the Sun. Therefore, the modified entropic force can be very well approximated by the Newtonian gravity in the Solar System and in the Galaxy. With this Debye acceleration, we find the current cosmic speeding up can be explained without invoking any kind of dark energy.

  14. Biochemical basis of prolidase deficiency. Polypeptide and RNA phenotypes and the relation to clinical phenotypes.

    PubMed Central

    Endo, F; Tanoue, A; Kitano, A; Arata, J; Danks, D M; Lapière, C M; Sei, Y; Wadman, S K; Matsuda, I

    1990-01-01

    Cultured skin fibroblasts or lymphoblastoid cells from eight patients with clinical symptoms of prolidase deficiency were analyzed in terms of enzyme activity, presence of material crossreacting with specific antibodies, biosynthesis of the polypeptide, and mRNA corresponding to the enzyme. There are at least two enzymes that hydrolyze imidodipeptides in these cells and these two enzymes could be separated by an immunochemical procedure. The specific assay for prolidase showed that the enzyme activity was virtually absent in six cell strains and was markedly reduced in two (less than 3% of controls). The activities of the labile enzyme that did not immunoprecipitate with the anti-prolidase antibody were decreased in the cells (30-60% of controls). Cell strains with residual activities of prolidase had immunological polypeptides crossreacting with a Mr 56,000, similar to findings in the normal enzyme. The polypeptide biosynthesis in these cells and the controls was similar. Northern blot analyses revealed the presence of mRNA in the polypeptide-positive cells, yet it was absent in the polypeptide-negative cells. The substrate specificities analyzed in the partially purified enzymes from the polypeptide-positive cell strains differed, presumably due to different mutations. Thus, there seems to be a molecular heterogeneity in prolidase deficiency. There was no apparent relation between the clinical symptoms and the biochemical phenotypes, except that mental retardation was present in the polypeptide-negative patients. The activities of the labile enzyme may not be a major factor in modifying the clinical symptoms. Images PMID:1688567

  15. The Genetics of Phenotypic Plasticity. XIV. Coevolution.

    PubMed

    Scheiner, Samuel M; Gomulkiewicz, Richard; Holt, Robert D

    2015-05-01

    Plastic changes in organisms' phenotypes can result from either abiotic or biotic effectors. Biotic effectors create the potential for a coevolutionary dynamic. Through the use of individual-based simulations, we examined the coevolutionary dynamic of two species that are phenotypically plastic. We explored two modes of biotic and abiotic interactions: ecological interactions that determine the form of natural selection and developmental interactions that determine phenotypes. Overall, coevolution had a larger effect on the evolution of phenotypic plasticity than plasticity had on the outcome of coevolution. Effects on the evolution of plasticity were greater when the fitness-maximizing coevolutionary outcomes were antagonistic between the species pair (predator-prey interactions) than when those outcomes were augmenting (competitive or mutualistic). Overall, evolution in the context of biotic interactions reduced selection for plasticity even when trait development was responding to just the abiotic environment. Thus, the evolution of phenotypic plasticity must always be interpreted in the full context of a species' ecology. Our results show how the merging of two theory domains--coevolution and phenotypic plasticity--can deepen our understanding of both and point to new empirical research.

  16. [Variant phenotype of Lesch-Nyhan syndrome].

    PubMed

    Torres Jiménez, Rosa; García García, Marta; García Puig, Juan

    2011-01-29

    Lesch-Nyhan syndrome (LNS) and LNS variants are due to mutations in the HPRT1 gene causing HPRT enzymatic activity deficiency. We report a patient presenting a variant phenotype and a major genetic defect. The mutation has been previously reported as always associated with complete Lesch-Nyhan phenotype. We analyzed the presence of complete HPRT mRNA in this patient, in two patients with the complete Lesch Nyhan syndrome phenotype, and in control subjects. We found a minor amount of normal HPRT mRNA in the present patient but also in the two patients with splice mutation and the complete Lesch Nyhan syndrome phenotype. To our knowledge, this patient is the first report of a major genetic defect, with no detectable enzymatic activity, and a partial HPRT deficiency phenotype. Our results question the hypothesis of a normally spliced HPRT cDNA as the sole cause of the patient partial phenotype. Copyright © 2010 Elsevier España, S.L. All rights reserved.

  17. Phenotypes of refractory/severe asthma.

    PubMed

    Bush, Andrew; Fleming, Louise

    2011-09-01

    The acid test of phenotyping is that it leads either to a clinically useful or mechanistically important insight. Phenotypes may change over time, but the exact definition of a phenotype shift is unclear. Methods of phenotyping are either investigator driven, in which a priori prejudices are applied to the data, or (semi) objective, in which mathematical techniques or systems biology approaches are applied to the dataset. However, the composition of the dataset is driven by investigator prejudice. Phenotyping is likely most useful in severe asthma, because mild and moderate asthma responds to simple treatments, and no great subtlety is required. Our non-evidence based approach is to define the subpopulation of genuine severe, therapy-resistant asthmatics from the generality of problematic severe asthma. We then investigate them invasively with bronchoscopy and a steroid trial using intramuscular triamcinolone to determine the nature of any inflammatory process; whether inflammation and symptoms are concordant or discordant; whether the inflammatory process is steroid resistant or sensitive; and whether the child has persistent airflow limitation. Other possibly relevant phenotypes include the child with severe exacerbations; brittle asthma; and severe asthma with fungal sensitization. Severe, therapy resistant asthma is a disparate disease, and only international uniform approaches, carefully characterising the children as a prelude to focussed clinical trials will allow progress to be made, and vindicate (or otherwise) our suggested approach.

  18. Phenotypic consequences of aneuploidy in Arabidopsis thaliana.

    PubMed

    Henry, Isabelle M; Dilkes, Brian P; Miller, Eric S; Burkart-Waco, Diana; Comai, Luca

    2010-12-01

    Aneuploid cells are characterized by incomplete chromosome sets. The resulting imbalance in gene dosage has phenotypic consequences that are specific to each karyotype. Even in the case of Down syndrome, the most viable and studied form of human aneuploidy, the mechanisms underlying the connected phenotypes remain mostly unclear. Because of their tolerance to aneuploidy, plants provide a powerful system for a genome-wide investigation of aneuploid syndromes, an approach that is not feasible in animal systems. Indeed, in many plant species, populations of aneuploid individuals can be easily obtained from triploid individuals. We phenotyped a population of Arabidopsis thaliana aneuploid individuals containing 25 different karyotypes. Even in this highly heterogeneous population, we demonstrate that certain traits are strongly associated with the dosage of specific chromosome types and that chromosomal effects can be additive. Further, we identified subtle developmental phenotypes expressed in the diploid progeny of aneuploid parent(s) but not in euploid controls from diploid lineages. These results indicate long-term phenotypic consequences of aneuploidy that can persist after chromosomal balance has been restored. We verified the diploid nature of these individuals by whole-genome sequencing and discuss the possibility that trans-generational phenotypic effects stem from epigenetic modifications passed from aneuploid parents to their diploid progeny.

  19. Phenotypic Consequences of Aneuploidy in Arabidopsis thaliana

    PubMed Central

    Henry, Isabelle M.; Dilkes, Brian P.; Miller, Eric S.; Burkart-Waco, Diana; Comai, Luca

    2010-01-01

    Aneuploid cells are characterized by incomplete chromosome sets. The resulting imbalance in gene dosage has phenotypic consequences that are specific to each karyotype. Even in the case of Down syndrome, the most viable and studied form of human aneuploidy, the mechanisms underlying the connected phenotypes remain mostly unclear. Because of their tolerance to aneuploidy, plants provide a powerful system for a genome-wide investigation of aneuploid syndromes, an approach that is not feasible in animal systems. Indeed, in many plant species, populations of aneuploid individuals can be easily obtained from triploid individuals. We phenotyped a population of Arabidopsis thaliana aneuploid individuals containing 25 different karyotypes. Even in this highly heterogeneous population, we demonstrate that certain traits are strongly associated with the dosage of specific chromosome types and that chromosomal effects can be additive. Further, we identified subtle developmental phenotypes expressed in the diploid progeny of aneuploid parent(s) but not in euploid controls from diploid lineages. These results indicate long-term phenotypic consequences of aneuploidy that can persist after chromosomal balance has been restored. We verified the diploid nature of these individuals by whole-genome sequencing and discuss the possibility that trans-generational phenotypic effects stem from epigenetic modifications passed from aneuploid parents to their diploid progeny. PMID:20876566

  20. Geographically multifarious phenotypic divergence during speciation

    PubMed Central

    Gompert, Zachariah; Lucas, Lauren K; Nice, Chris C; Fordyce, James A; Alex Buerkle, C; Forister, Matthew L

    2013-01-01

    Speciation is an important evolutionary process that occurs when barriers to gene flow evolve between previously panmictic populations. Although individual barriers to gene flow have been studied extensively, we know relatively little regarding the number of barriers that isolate species or whether these barriers are polymorphic within species. Herein, we use a series of field and lab experiments to quantify phenotypic divergence and identify possible barriers to gene flow between the butterfly species Lycaeides idas and Lycaeides melissa. We found evidence that L. idas and L. melissa have diverged along multiple phenotypic axes. Specifically, we identified major phenotypic differences in female oviposition preference and diapause initiation, and more moderate divergence in mate preference. Multiple phenotypic differences might operate as barriers to gene flow, as shown by correlations between genetic distance and phenotypic divergence and patterns of phenotypic variation in admixed Lycaeides populations. Although some of these traits differed primarily between species (e.g., diapause initiation), several traits also varied among conspecific populations (e.g., male mate preference and oviposition preference). PMID:23532669

  1. Advanced phenotyping and phenotype data analysis for the study of plant growth and development

    PubMed Central

    Rahaman, Md. Matiur; Chen, Dijun; Gillani, Zeeshan; Klukas, Christian; Chen, Ming

    2015-01-01

    Due to an increase in the consumption of food, feed, fuel and to meet global food security needs for the rapidly growing human population, there is a necessity to breed high yielding crops that can adapt to the future climate changes, particularly in developing countries. To solve these global challenges, novel approaches are required to identify quantitative phenotypes and to explain the genetic basis of agriculturally important traits. These advances will facilitate the screening of germplasm with high performance characteristics in resource-limited environments. Recently, plant phenomics has offered and integrated a suite of new technologies, and we are on a path to improve the description of complex plant phenotypes. High-throughput phenotyping platforms have also been developed that capture phenotype data from plants in a non-destructive manner. In this review, we discuss recent developments of high-throughput plant phenotyping infrastructure including imaging techniques and corresponding principles for phenotype data analysis. PMID:26322060

  2. Disease-modifying genes and monogenic disorders: experience in cystic fibrosis.

    PubMed

    Gallati, Sabina

    2014-01-01

    The mechanisms responsible for the determination of phenotypes are still not well understood; however, it has become apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of Mendelian disorders. Significant advances in genetic technologies and molecular medicine allow huge amounts of information to be generated from individual samples within a reasonable time frame. This review focuses on the role of modifier genes using the example of cystic fibrosis, the most common lethal autosomal recessive disorder in the white population, and discusses the advantages and limitations of candidate gene approaches versus genome-wide association studies. Moreover, the implications of modifier gene research for other monogenic disorders, as well as its significance for diagnostic, prognostic, and therapeutic approaches are summarized. Increasing insight into modifying mechanisms opens up new perspectives, dispelling the idea of genetic disorders being caused by one single gene.

  3. Low level ozone exposure induces airways inflammation and modifies cell surface phenotypes in healthy humans

    EPA Science Inventory

    Background: The effects of low level ozone exposure (0.08 ppm) on pulmonary function in healthy young adults are well known, however much less is known about the inflammatory and immuno-modulatory effects oflow level ozone in the airways. Techniques such as induced sputum and flo...

  4. Low level ozone exposure induces airways inflammation and modifies cell surface phenotypes in healthy humans

    EPA Science Inventory

    Background: The effects of low level ozone exposure (0.08 ppm) on pulmonary function in healthy young adults are well known, however much less is known about the inflammatory and immuno-modulatory effects oflow level ozone in the airways. Techniques such as induced sputum and flo...

  5. A method for analysis of phenotypic change for phenotypes described by high-dimensional data

    PubMed Central

    Collyer, M L; Sekora, D J; Adams, D C

    2015-01-01

    The analysis of phenotypic change is important for several evolutionary biology disciplines, including phenotypic plasticity, evolutionary developmental biology, morphological evolution, physiological evolution, evolutionary ecology and behavioral evolution. It is common for researchers in these disciplines to work with multivariate phenotypic data. When phenotypic variables exceed the number of research subjects—data called ‘high-dimensional data'—researchers are confronted with analytical challenges. Parametric tests that require high observation to variable ratios present a paradox for researchers, as eliminating variables potentially reduces effect sizes for comparative analyses, yet test statistics require more observations than variables. This problem is exacerbated with data that describe ‘multidimensional' phenotypes, whereby a description of phenotype requires high-dimensional data. For example, landmark-based geometric morphometric data use the Cartesian coordinates of (potentially) many anatomical landmarks to describe organismal shape. Collectively such shape variables describe organism shape, although the analysis of each variable, independently, offers little benefit for addressing biological questions. Here we present a nonparametric method of evaluating effect size that is not constrained by the number of phenotypic variables, and motivate its use with example analyses of phenotypic change using geometric morphometric data. Our examples contrast different characterizations of body shape for a desert fish species, associated with measuring and comparing sexual dimorphism between two populations. We demonstrate that using more phenotypic variables can increase effect sizes, and allow for stronger inferences. PMID:25204302

  6. The International Mouse Phenotyping Consortium: past and future perspectives on mouse phenotyping

    PubMed Central

    Moore, Mark W.

    2013-01-01

    Determining the function of all mammalian genes remains a major challenge for the biomedical science community in the 21st century. The goal of the International Mouse Phenotyping Consortium (IMPC) over the next 10 years is to undertake broad-based phenotyping of 20,000 mouse genes, providing an unprecedented insight into mammalian gene function. This short article explores the drivers for large-scale mouse phenotyping and provides an overview of the aims and processes involved in IMPC mouse production and phenotyping. PMID:22940749

  7. Potential variance affecting homeotic Ultrabithorax and Antennapedia phenotypes in Drosophila melanogaster.

    PubMed Central

    Gibson, G; Wemple, M; van Helden, S

    1999-01-01

    Introgression of homeotic mutations into wild-type genetic backgrounds results in a wide variety of phenotypes and implies that major effect modifiers of extreme phenotypes are not uncommon in natural populations of Drosophila. A composite interval mapping procedure was used to demonstrate that one major effect locus accounts for three-quarters of the variance for haltere to wing margin transformation in Ultrabithorax flies, yet has no obvious effect on wild-type development. Several other genetic backgrounds result in enlargement of the haltere significantly beyond the normal range of haploinsufficient phenotypes, suggesting genetic variation in cofactors that mediate homeotic protein function. Introgression of Antennapedia produces lines with heritable phenotypes ranging from almost complete suppression to perfect antennal leg formation, as well as transformations that are restricted to either the distal or proximal portion of the appendage. It is argued that the existence of "potential" variance, which is genetic variation whose effects are not observable in wild-type individuals, is a prerequisite for the uncoupling of genetic from phenotypic divergence. PMID:10049924

  8. The evolution of phenotypic plasticity: genealogy of a debate in genetics.

    PubMed

    Nicoglou, Antonine

    2015-04-01

    The paper describes the context and the origin of a particular debate that concerns the evolution of phenotypic plasticity. In 1965, British biologist A. D. Bradshaw proposed a widely cited model intended to explain the evolution of norms of reaction, based on his studies of plant populations. Bradshaw's model went beyond the notion of the "adaptive norm of reaction" discussed before him by Dobzhansky and Schmalhausen by suggesting that "plasticity"--the ability of a phenotype to be modified by the environment--should be genetically determined. To prove Bradshaw's hypothesis, it became necessary for some authors to identify the pressures exerted by natural selection on phenotypic plasticity in particular traits, and thus to model its evolution. In this paper, I contrast two different views, based on quantitative genetic models, proposed in the mid-1980s: Russell Lande and Sara Via's conception of phenotypic plasticity, which assumes that the evolution of plasticity is linked to the evolution of the plastic trait itself, and Samuel Scheiner and Richard Lyman's view, which assumes that the evolution of plasticity is independent from the evolution of the trait. I show how the origin of this specific debate, and different assumptions about the evolution of phenotypic plasticity, depended on Bradshaw's definition of plasticity and the context of quantitative genetics. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Improved exome prioritization of disease genes through cross-species phenotype comparison

    PubMed Central

    Robinson, Peter N.; Köhler, Sebastian; Oellrich, Anika; Wang, Kai; Mungall, Christopher J.; Lewis, Suzanna E.; Washington, Nicole; Bauer, Sebastian; Seelow, Dominik; Krawitz, Peter; Gilissen, Christian; Haendel, Melissa; Smedley, Damian

    2014-01-01

    Numerous new disease-gene associations have been identified by whole-exome sequencing studies in the last few years. However, many cases remain unsolved due to the sheer number of candidate variants remaining after common filtering strategies such as removing low quality and common variants and those deemed unlikely to be pathogenic. The observation that each of our genomes contains about 100 genuine loss-of-function variants makes identification of the causative mutation problematic when using these strategies alone. We propose using the wealth of genotype to phenotype data that already exists from model organism studies to assess the potential impact of these exome variants. Here, we introduce PHenotypic Interpretation of Variants in Exomes (PHIVE), an algorithm that integrates the calculation of phenotype similarity between human diseases and genetically modified mouse models with evaluation of the variants according to allele frequency, pathogenicity, and mode of inheritance approaches in our Exomiser tool. Large-scale validation of PHIVE analysis using 100,000 exomes containing known mutations demonstrated a substantial improvement (up to 54.1-fold) over purely variant-based (frequency and pathogenicity) methods with the correct gene recalled as the top hit in up to 83% of samples, corresponding to an area under the ROC curve of >95%. We conclude that incorporation of phenotype data can play a vital role in translational bioinformatics and propose that exome sequencing projects should systematically capture clinical phenotypes to take advantage of the strategy presented here. PMID:24162188

  10. Phenotype-based clustering of glycosylation-related genes by RNAi-mediated gene silencing.

    PubMed

    Yamamoto-Hino, Miki; Yoshida, Hideki; Ichimiya, Tomomi; Sakamura, Sho; Maeda, Megumi; Kimura, Yoshinobu; Sasaki, Norihiko; Aoki-Kinoshita, Kiyoko F; Kinoshita-Toyoda, Akiko; Toyoda, Hidenao; Ueda, Ryu; Nishihara, Shoko; Goto, Satoshi

    2015-06-01

    Glycan structures are synthesized by a series of reactions conducted by glycosylation-related (GR) proteins such as glycosyltransferases, glycan-modifying enzymes, and nucleotide-sugar transporters. For example, the common core region of glycosaminoglycans (GAGs) is sequentially synthesized by peptide-O-xylosyltransferase, β1,4-galactosyltransferase I, β1,3-galactosyltransferase II, and β1,3-glucuronyltransferase. This raises the possibility that functional impairment of GR proteins involved in synthesis of the same glycan might result in the same phenotypic abnormality. To examine this possibility, comprehensive silencing of genes encoding GR and proteoglycan core proteins was conducted in Drosophila. Drosophila GR candidate genes (125) were classified into five functional groups for synthesis of GAGs, N-linked, O-linked, Notch-related, and unknown glycans. Spatiotemporally regulated silencing caused a range of malformed phenotypes that fell into three types: extra veins, thick veins, and depigmentation. The clustered phenotypes reflected the biosynthetic pathways of GAGs, Fringe-dependent glycan on Notch, and glycans placed at or near nonreducing ends (herein termed terminal domains of glycans). Based on the phenotypic clustering, CG33145 was predicted to be involved in formation of terminal domains. Our further analysis showed that CG33145 exhibited galactosyltransferase activity in synthesis of terminal N-linked glycans. Phenotypic clustering, therefore, has potential for the functional prediction of novel GR genes. © 2015 The Authors. Genes to Cells published by Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.

  11. iBeetle-Base: a database for RNAi phenotypes in the red flour beetle Tribolium castaneum.

    PubMed

    Dönitz, Jürgen; Schmitt-Engel, Christian; Grossmann, Daniela; Gerischer, Lizzy; Tech, Maike; Schoppmeier, Michael; Klingler, Martin; Bucher, Gregor

    2015-01-01

    The iBeetle-Base (http://ibeetle-base.uni-goettingen.de) makes available annotations of RNAi phenotypes, which were gathered in a large scale RNAi screen in the red flour beetle Tribolium castaneum (iBeetle screen). In addition, it provides access to sequence information and links for all Tribolium castaneum genes. The iBeetle-Base contains the annotations of phenotypes of several thousands of genes knocked down during embryonic and metamorphic epidermis and muscle development in addition to phenotypes linked to oogenesis and stink gland biology. The phenotypes are described according to the EQM (entity, quality, modifier) system using controlled vocabularies and the Tribolium morphological ontology (TrOn). Furthermore, images linked to the respective annotations are provided. The data are searchable either for specific phenotypes using a complex 'search for morphological defects' or a 'quick search' for gene names and IDs. The red flour beetle Tribolium castaneum has become an important model system for insect functional genetics and is a representative of the most species rich taxon, the Coleoptera, which comprise several devastating pests. It is used for studying insect typical development, the evolution of development and for research on metabolism and pest control. Besides Drosophila, Tribolium is the first insect model organism where large scale unbiased screens have been performed.

  12. Factors influencing disease phenotype and penetrance in HFE haemochromatosis.

    PubMed

    Rochette, J; Le Gac, G; Lassoued, K; Férec, C; Robson, K J H

    2010-09-01

    Haemochromatosis is predominantly associated with the HFE p.C282Y homozygous genotype, which is present in approximately 1 in 200 people of Northern European origin. However, not all p.C282Y homozygotes develop clinical features of haemochromatosis, and not all p.C282Y homozygotes even present abnormal iron parameters justifying venesection therapy. This situation was not apparent from initial genotype/phenotype correlation studies as there was a selection bias of patients. Only those patients with a significant iron burden were included in these early studies. It is now largely accepted that the p.C282Y/p.C282Y genotype is necessary for the development of HFE haemochromatosis. However, this genotype provides few clues as to why certain symptoms are associated with the disease. Expression of iron overload in people with this genotype depends on the complex interplay of environmental factors and modifier genes. In this review, we restrict our discussion to work done in humans giving examples of animal models where this has helped clarify our understanding. We discuss penetrance, explaining that this concept normally does not apply to autosomal recessive disorders, and discuss the usefulness of different biochemical markers in ascertaining iron burden. Hepcidin, a peptide synthesized primarily by the liver, has been identified as the central regulator in iron homeostasis. Consequently, understanding its regulation is the key. We conclude that the main goal now is to identify important modifiers that have a significant and unambiguous effect on iron storage.

  13. Rare variant association test with multiple phenotypes.

    PubMed

    Lee, Selyeong; Won, Sungho; Kim, Young Jin; Kim, Yongkang; Kim, Bong-Jo; Park, Taesung

    2017-04-01

    Although genome-wide association studies (GWAS) have now discovered thousands of genetic variants associated with common traits, such variants cannot explain the large degree of "missing heritability," likely due to rare variants. The advent of next generation sequencing technology has allowed rare variant detection and association with common traits, often by investigating specific genomic regions for rare variant effects on a trait. Although multiple correlated phenotypes are often concurrently observed in GWAS, most studies analyze only single phenotypes, which may lessen statistical power. To increase power, multivariate analyses, which consider correlations between multiple phenotypes, can be used. However, few existing multivariant analyses can identify rare variants for assessing multiple phenotypes. Here, we propose Multivariate Association Analysis using Score Statistics (MAAUSS), to identify rare variants associated with multiple phenotypes, based on the widely used sequence kernel association test (SKAT) for a single phenotype. We applied MAAUSS to whole exome sequencing (WES) data from a Korean population of 1,058 subjects to discover genes associated with multiple traits of liver function. We then assessed validation of those genes by a replication study, using an independent dataset of 3,445 individuals. Notably, we detected the gene ZNF620 among five significant genes. We then performed a simulation study to compare MAAUSS's performance with existing methods. Overall, MAAUSS successfully conserved type 1 error rates and in many cases had a higher power than the existing methods. This study illustrates a feasible and straightforward approach for identifying rare variants correlated with multiple phenotypes, with likely relevance to missing heritability.

  14. Molecular Genetic Studies of Complex Phenotypes

    PubMed Central

    Marian, A.J.

    2012-01-01

    The approach to molecular genetic studies of complex phenotypes has evolved considerably during the recent years. The candidate gene approach, restricted to analysis of a few single nucleotide polymorphisms (SNPs) in a modest number of cases and controls, has been supplanted by the unbiased approach of Genome-Wide Association Studies (GWAS), wherein a large number of tagger SNPs are typed in a large number of individuals. GWAS, which are designed upon the common disease- common variant hypothesis (CD-CV), have identified a large number of SNPs and loci for complex phenotypes. However, alleles identified through GWAS are typically not causative but rather in linkage disequilibrium (LD) with the true causal variants. The common alleles, which may not capture the uncommon and rare variants, account only for a fraction of heritability of the complex traits. Hence, the focus is being shifted to rare variants – common disease (RV-CD) hypothesis, surmising that rare variants exert large effect sizes on the phenotype. In conjunctional with this conceptual shift technological advances in DNA sequencing techniques have dramatically enhanced whole genome or whole exome sequencing capacity. The sequencing approach affords identification of not only the rare but also the common variants. The approach – whether used in complementation with GWAS or as a stand-alone approach - could define the genetic architecture of the complex phenotypes. Robust phenotyping and large-scale sequencing studies are essential to extract the information content of the vast number of DNA sequence variants (DSVs) in the genome. To garner meaningful clinical information and link the genotype to a phenotype, identification and characterization of a very large number of causal fields beyond the information content of DNA sequence variants would be necessary. This review provides an update on the current progress and limitations in identifying DSVs that are associated with phenotypic effects. PMID

  15. Surface modified aerogel monoliths

    NASA Technical Reports Server (NTRS)

    Leventis, Nicholas (Inventor); Johnston, James C. (Inventor); Kuczmarski, Maria A. (Inventor); Meador, Mary Ann B. (Inventor)

    2013-01-01

    This invention comprises reinforced aerogel monoliths such as silica aerogels having a polymer coating on its outer geometric surface boundary, and to the method of preparing said aerogel monoliths. The polymer coatings on the aerogel monoliths are derived from polymer precursors selected from the group consisting of isocyanates as a precursor, precursors of epoxies, and precursors of polyimides. The coated aerogel monoliths can be modified further by encapsulating the aerogel with the polymer precursor reinforced with fibers such as carbon or glass fibers to obtain mechanically reinforced composite encapsulated aerogel monoliths.

  16. Histone Modifiers in Cancer

    PubMed Central

    Cohen, Idan; Poręba, Elżbieta; Kamieniarz, Kinga; Schneider, Robert

    2011-01-01

    Covalent modifications of histones can regulate all DNA-dependent processes. In the last few years, it has become more and more evident that histone modifications are key players in the regulation of chromatin states and dynamics as well as in gene expression. Therefore, histone modifications and the enzymatic machineries that set them are crucial regulators that can control cellular proliferation, differentiation, plasticity, and malignancy processes. This review discusses the biology and biochemistry of covalent histone posttranslational modifications (PTMs) and evaluates the dual role of their modifiers in cancer: as oncogenes that can initiate and amplify tumorigenesis or as tumor suppressors. PMID:21941619

  17. Modified harmony search

    NASA Astrophysics Data System (ADS)

    Mohamed, Najihah; Lutfi Amri Ramli, Ahmad; Majid, Ahmad Abd; Piah, Abd Rahni Mt

    2017-09-01

    A metaheuristic algorithm, called Harmony Search is quite highly applied in optimizing parameters in many areas. HS is a derivative-free real parameter optimization algorithm, and draws an inspiration from the musical improvisation process of searching for a perfect state of harmony. Propose in this paper Modified Harmony Search for solving optimization problems, which employs a concept from genetic algorithm method and particle swarm optimization for generating new solution vectors that enhances the performance of HS algorithm. The performances of MHS and HS are investigated on ten benchmark optimization problems in order to make a comparison to reflect the efficiency of the MHS in terms of final accuracy, convergence speed and robustness.

  18. Modified arthroscopic Brostrom procedure.

    PubMed

    Lui, Tun Hing

    2015-09-01

    The open modified Brostrom anatomic repair technique is widely accepted as the reference standard for lateral ankle stabilization. However, there is high incidence of intra-articular pathologies associated with chronic lateral ankle instability which may not be addressed by an isolated open Brostrom procedure. Arthroscopic Brostrom procedure with suture anchor has been described for anatomic repair of chronic lateral ankle instability and management of intra-articular lesions. However, the complication rates seemed to be higher than open Brostrom procedure. Modification of the arthroscopic Brostrom procedure with the use of bone tunnel may reduce the risk of certain complications.

  19. Modeling RASopathies with Genetically Modified Mouse Models.

    PubMed

    Hernández-Porras, Isabel; Guerra, Carmen

    2017-01-01

    The RAS/MAPK signaling pathway plays key roles in development, cell survival and proliferation, as well as in cancer pathogenesis. Molecular genetic studies have identified a group of developmental syndromes, the RASopathies, caused by germ line mutations in this pathway. The syndromes included within this classification are neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML, formerly known as LEOPARD syndrome), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome (LS, NF1-like syndrome), capillary malformation-arteriovenous malformation syndrome (CM-AVM), and hereditary gingival fibromatosis (HGF) type 1. Although these syndromes present specific molecular alterations, they are characterized by a large spectrum of functional and morphological abnormalities, which include heart defects, short stature, neurocognitive impairment, craniofacial malformations, and, in some cases, cancer predisposition. The development of genetically modified animals, such as mice (Mus musculus), flies (Drosophila melanogaster), and zebrafish (Danio rerio), has been instrumental in elucidating the molecular and cellular bases of these syndromes. Moreover, these models can also be used to determine tumor predisposition, the impact of different genetic backgrounds on the variable phenotypes found among the patients and to evaluate preventative and therapeutic strategies. Here, we review a wide range of genetically modified mouse models used in the study of RASopathies and the potential application of novel technologies, which hopefully will help us resolve open questions in the field.

  20. Pragmatic Aspects of Scalar Modifiers

    ERIC Educational Resources Information Center

    Sawada, Osamu

    2010-01-01

    This dissertation investigates the pragmatic aspects of scalar modifiers from the standpoint of the interface between semantics and pragmatics, focusing on (i) the (non) parallelism between the truth-conditional scalar modifiers and the non-truth-conditional scalar modifiers, (ii) the compositionality and dimensionality of non-truth-conditional…

  1. Phenotypic plasticity and diversity in insects

    PubMed Central

    Moczek, Armin P.

    2010-01-01

    Phenotypic plasticity in general and polyphenic development in particular are thought to play important roles in organismal diversification and evolutionary innovation. Focusing on the evolutionary developmental biology of insects, and specifically that of horned beetles, I explore the avenues by which phenotypic plasticity and polyphenic development have mediated the origins of novelty and diversity. Specifically, I argue that phenotypic plasticity generates novel targets for evolutionary processes to act on, as well as brings about trade-offs during development and evolution, thereby diversifying evolutionary trajectories available to natural populations. Lastly, I examine the notion that in those cases in which phenotypic plasticity is underlain by modularity in gene expression, it results in a fundamental trade-off between degree of plasticity and mutation accumulation. On one hand, this trade-off limits the extent of plasticity that can be accommodated by modularity of gene expression. On the other hand, it causes genes whose expression is specific to rare environments to accumulate greater variation within species, providing the opportunity for faster divergence and diversification between species, compared with genes expressed across environments. Phenotypic plasticity therefore contributes to organismal diversification on a variety of levels of biological organization, thereby facilitating the evolution of novel traits, new species and complex life cycles. PMID:20083635

  2. Serum Biochemical Phenotypes in the Domestic Dog.

    PubMed

    Chang, Yu-Mei; Hadox, Erin; Szladovits, Balazs; Garden, Oliver A

    2016-01-01

    The serum or plasma biochemical profile is essential in the diagnosis and monitoring of systemic disease in veterinary medicine, but current reference intervals typically take no account of breed-specific differences. Breed-specific hematological phenotypes have been documented in the domestic dog, but little has been published on serum biochemical phenotypes in this species. Serum biochemical profiles of dogs in which all measurements fell within the existing reference intervals were retrieved from a large veterinary database. Serum biochemical profiles from 3045 dogs were retrieved, of which 1495 had an accompanying normal glucose concentration. Sixty pure breeds plus a mixed breed control group were represented by at least 10 individuals. All analytes, except for sodium, chloride and glucose, showed variation with age. Total protein, globulin, potassium, chloride, creatinine, cholesterol, total bilirubin, ALT, CK, amylase, and lipase varied between sexes. Neutering status significantly impacted all analytes except albumin, sodium, calcium, urea, and glucose. Principal component analysis of serum biochemical data revealed 36 pure breeds with distinctive phenotypes. Furthermore, comparative analysis identified 23 breeds with significant differences from the mixed breed group in all biochemical analytes except urea and glucose. Eighteen breeds were identified by both principal component and comparative analysis. Tentative reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis and represented by at least 120 individuals. This is the first large-scale analysis of breed-specific serum biochemical phenotypes in the domestic dog and highlights potential genetic components of biochemical traits in this species.

  3. Overeating phenotypes in overweight and obese children.

    PubMed

    Boutelle, Kerri N; Peterson, Carol B; Crosby, Ross D; Rydell, Sarah A; Zucker, Nancy; Harnack, Lisa

    2014-05-01

    The purpose of this study was to identify overeating phenotypes and their correlates in overweight and obese children. One hundred and seventeen treatment-seeking overweight and obese 8-12year-old children and their parents completed the study. Children completed an eating in the absence of hunger (EAH) paradigm, the Eating Disorder Examination interview, and measurements of height and weight. Parents and children completed questionnaires that evaluated satiety responsiveness, food responsiveness, negative affect eating, external eating and eating in the absence of hunger. Latent profile analysis was used to identify heterogeneity in overeating phenotypes in the child participants. Latent classes were then compared on measures of demographics, obesity status and nutritional intake. Three latent classes of overweight and obese children were identified: High Satiety Responsive, High Food Responsive, and Moderate Satiety and Food Responsive. Results indicated that the High Food Responsive group had higher BMI and BMI-Z scores compared to the High Satiety Responsive group. No differences were found among classes in demographics or nutritional intake. This study identified three overeating phenotypes, supporting the heterogeneity of eating patterns associated with overweight and obesity in treatment-seeking children. These finding suggest that these phenotypes can potentially be used to identify high risk groups, inform prevention and intervention targets, and develop specific treatments for these behavioral phenotypes.

  4. Understanding Genotypes and Phenotypes in Epileptic Encephalopathies

    PubMed Central

    Helbig, Ingo; Tayoun, Abou Ahmad N.

    2016-01-01

    Epileptic encephalopathies are severe often intractable seizure disorders where epileptiform abnormalities contribute to a progressive disturbance in brain function. Often, epileptic encephalopathies start in childhood and are accompanied by developmental delay and various neurological and non-neurological comorbidities. In recent years, this concept has become virtually synonymous with a group of severe childhood epilepsies including West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, and several other severe childhood epilepsies for which genetic factors are increasingly recognized. In the last 5 years, the field has seen a virtual explosion of gene discovery, raising the number of bona fide genes and possible candidate genes for epileptic encephalopathies to more than 70 genes, explaining 20-25% of all cases with severe early-onset epilepsies that had otherwise no identifiable causes. This review will focus on the phenotypic variability as a characteristic aspect of genetic epilepsies. For many genetic epilepsies, the phenotypic presentation can be broad, even in patients with identical genetic alterations. Furthermore, patients with different genetic etiologies can have seemingly similar clinical presentations, such as in Dravet syndrome. While most patients carry mutations in SCN1A, similar phenotypes can be seen in patients with mutations in PCDH19, CHD2, SCN8A, or in rare cases GABRA1 and STXBP1. In addition to the genotypic and phenotypic heterogeneity, both benign phenotypes and severe encephalopathies have been recognized in an increasing number of genetic epilepsies, raising the question whether these conditions represent a fluid continuum or distinct entities. PMID:27781027

  5. Delineating the GRIN1 phenotypic spectrum

    PubMed Central

    Geider, Kirsten; Helbig, Katherine L.; Heyne, Henrike O.; Schütz, Hannah; Hentschel, Julia; Courage, Carolina; Depienne, Christel; Nava, Caroline; Heron, Delphine; Møller, Rikke S.; Hjalgrim, Helle; Lal, Dennis; Neubauer, Bernd A.; Nürnberg, Peter; Thiele, Holger; Kurlemann, Gerhard; Arnold, Georgianne L.; Bhambhani, Vikas; Bartholdi, Deborah; Pedurupillay, Christeen Ramane J.; Misceo, Doriana; Frengen, Eirik; Strømme, Petter; Dlugos, Dennis J.; Doherty, Emily S.; Bijlsma, Emilia K.; Ruivenkamp, Claudia A.; Hoffer, Mariette J.V.; Goldstein, Amy; Rajan, Deepa S.; Narayanan, Vinodh; Ramsey, Keri; Belnap, Newell; Schrauwen, Isabelle; Richholt, Ryan; Koeleman, Bobby P.C.; Sá, Joaquim; Mendonça, Carla; de Kovel, Carolien G.F.; Weckhuysen, Sarah; Hardies, Katia; De Jonghe, Peter; De Meirleir, Linda; Milh, Mathieu; Badens, Catherine; Lebrun, Marine; Busa, Tiffany; Francannet, Christine; Piton, Amélie; Riesch, Erik; Biskup, Saskia; Vogt, Heinrich; Dorn, Thomas; Helbig, Ingo; Michaud, Jacques L.; Laube, Bodo; Syrbe, Steffen

    2016-01-01

    Objective: To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology. Methods: We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes. Results: We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families. Conclusions: De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders. PMID:27164704

  6. Phenotypic plasticity and diversity in insects.

    PubMed

    Moczek, Armin P

    2010-02-27

    Phenotypic plasticity in general and polyphenic development in particular are thought to play important roles in organismal diversification and evolutionary innovation. Focusing on the evolutionary developmental biology of insects, and specifically that of horned beetles, I explore the avenues by which phenotypic plasticity and polyphenic development have mediated the origins of novelty and diversity. Specifically, I argue that phenotypic plasticity generates novel targets for evolutionary processes to act on, as well as brings about trade-offs during development and evolution, thereby diversifying evolutionary trajectories available to natural populations. Lastly, I examine the notion that in those cases in which phenotypic plasticity is underlain by modularity in gene expression, it results in a fundamental trade-off between degree of plasticity and mutation accumulation. On one hand, this trade-off limits the extent of plasticity that can be accommodated by modularity of gene expression. On the other hand, it causes genes whose expression is specific to rare environments to accumulate greater variation within species, providing the opportunity for faster divergence and diversification between species, compared with genes expressed across environments. Phenotypic plasticity therefore contributes to organismal diversification on a variety of levels of biological organization, thereby facilitating the evolution of novel traits, new species and complex life cycles.

  7. Vascular smooth muscle phenotypic diversity and function

    PubMed Central

    2010-01-01

    The control of force production in vascular smooth muscle is critical to the normal regulation of blood flow and pressure, and altered regulation is common to diseases such as hypertension, heart failure, and ischemia. A great deal has been learned about imbalances in vasoconstrictor and vasodilator signals, e.g., angiotensin, endothelin, norepinephrine, and nitric oxide, that regulate vascular tone in normal and disease contexts. In contrast there has been limited study of how the phenotypic state of the vascular smooth muscle cell may influence the contractile response to these signaling pathways dependent upon the developmental, tissue-specific (vascular bed) or disease context. Smooth, skeletal, and cardiac muscle lineages are traditionally classified into fast or slow sublineages based on rates of contraction and relaxation, recognizing that this simple dichotomy vastly underrepresents muscle phenotypic diversity. A great deal has been learned about developmental specification of the striated muscle sublineages and their phenotypic interconversions in the mature animal under the control of mechanical load, neural input, and hormones. In contrast there has been relatively limited study of smooth muscle contractile phenotypic diversity. This is surprising given the number of diseases in which smooth muscle contractile dysfunction plays a key role. This review focuses on smooth muscle contractile phenotypic diversity in the vascular system, how it is generated, and how it may determine vascular function in developmental and disease contexts. PMID:20736412

  8. Phenotypic switching in gene regulatory networks.

    PubMed

    Thomas, Philipp; Popović, Nikola; Grima, Ramon

    2014-05-13

    Noise in gene expression can lead to reversible phenotypic switching. Several experimental studies have shown that the abundance distributions of proteins in a population of isogenic cells may display multiple distinct maxima. Each of these maxima may be associated with a subpopulation of a particular phenotype, the quantification of which is important for understanding cellular decision-making. Here, we devise a methodology which allows us to quantify multimodal gene expression distributions and single-cell power spectra in gene regulatory networks. Extending the commonly used linear noise approximation, we rigorously show that, in the limit of slow promoter dynamics, these distributions can be systematically approximated as a mixture of Gaussian components in a wide class of networks. The resulting closed-form approximation provides a practical tool for studying complex nonlinear gene regulatory networks that have thus far been amenable only to stochastic simulation. We demonstrate the applicability of our approach in a number of genetic networks, uncovering previously unidentified dynamical characteristics associated with phenotypic switching. Specifically, we elucidate how the interplay of transcriptional and translational regulation can be exploited to control the multimodality of gene expression distributions in two-promoter networks. We demonstrate how phenotypic switching leads to birhythmical expression in a genetic oscillator, and to hysteresis in phenotypic induction, thus highlighting the ability of regulatory networks to retain memory.

  9. The new mutation theory of phenotypic evolution

    PubMed Central

    Nei, Masatoshi

    2007-01-01

    Recent studies of developmental biology have shown that the genes controlling phenotypic characters expressed in the early stage of development are highly conserved and that recent evolutionary changes have occurred primarily in the characters expressed in later stages of development. Even the genes controlling the latter characters are generally conserved, but there is a large component of neutral or nearly neutral genetic variation within and between closely related species. Phenotypic evolution occurs primarily by mutation of genes that interact with one another in the developmental process. The enormous amount of phenotypic diversity among different phyla or classes of organisms is a product of accumulation of novel mutations and their conservation that have facilitated adaptation to different environments. Novel mutations may be incorporated into the genome by natural selection (elimination of preexisting genotypes) or by random processes such as genetic and genomic drift. However, once the mutations are incorporated into the genome, they may generate developmental constraints that will affect the future direction of phenotypic evolution. It appears that the driving force of phenotypic evolution is mutation, and natural selection is of secondary importance. PMID:17640887

  10. Serum Biochemical Phenotypes in the Domestic Dog

    PubMed Central

    Chang, Yu-Mei; Hadox, Erin; Szladovits, Balazs; Garden, Oliver A.

    2016-01-01

    The serum or plasma biochemical profile is essential in the diagnosis and monitoring of systemic disease in veterinary medicine, but current reference intervals typically take no account of breed-specific differences. Breed-specific hematological phenotypes have been documented in the domestic dog, but little has been published on serum biochemical phenotypes in this species. Serum biochemical profiles of dogs in which all measurements fell within the existing reference intervals were retrieved from a large veterinary database. Serum biochemical profiles from 3045 dogs were retrieved, of which 1495 had an accompanying normal glucose concentration. Sixty pure breeds plus a mixed breed control group were represented by at least 10 individuals. All analytes, except for sodium, chloride and glucose, showed variation with age. Total protein, globulin, potassium, chloride, creatinine, cholesterol, total bilirubin, ALT, CK, amylase, and lipase varied between sexes. Neutering status significantly impacted all analytes except albumin, sodium, calcium, urea, and glucose. Principal component analysis of serum biochemical data revealed 36 pure breeds with distinctive phenotypes. Furthermore, comparative analysis identified 23 breeds with significant differences from the mixed breed group in all biochemical analytes except urea and glucose. Eighteen breeds were identified by both principal component and comparative analysis. Tentative reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis and represented by at least 120 individuals. This is the first large-scale analysis of breed-specific serum biochemical phenotypes in the domestic dog and highlights potential genetic components of biochemical traits in this species. PMID:26919479

  11. Modifying Radiation Damage

    PubMed Central

    Kim, Kwanghee; McBride, William H.

    2011-01-01

    Radiation leaves a fairly characteristic footprint in biological materials, but this is rapidly all but obliterated by the canonical biological responses to the radiation damage. The innate immune recognition systems that sense “danger” through direct radiation damage and through associated collateral damage set in motion a chain of events that, in a tissue compromised by radiation, often unwittingly result in oscillating waves of molecular and cellular responses as tissues attempt to heal. Understanding “nature’s whispers” that inform on these processes will lead to novel forms of intervention targeted more precisely towards modifying them in an appropriate and timely fashion so as to improve the healing process and prevent or mitigate the development of acute and late effects of normal tissue radiation damage, whether it be accidental, as a result of a terrorist incident, or of therapeutic treatment of cancer. Here we attempt to discuss some of the non-free radical scavenging mechanisms that modify radiation responses and comment on where we see them within a conceptual framework of an evolving radiation-induced lesion. PMID:20583981

  12. Genotype-phenotype relationship in mucopolysaccharidosis II: predictive power of IDS variants for the neuronopathic phenotype.

    PubMed

    Vollebregt, Audrey A M; Hoogeveen-Westerveld, Marianne; Kroos, Marian A; Oussoren, Esmee; Plug, Iris; Ruijter, George J; van der Ploeg, Ans T; Pijnappel, W W M Pim

    2017-10-01

    Mucopolysaccharidosis type II (MPS II) is caused by variants in the iduronate-2-sulphatase gene (IDS). Patients can be either neuronopathic with intellectual disability, or non-neuronopathic. Few studies have reported on the IDS genotype-phenotype relationship and on the molecular effects involved. We addressed this in a cohort study of Dutch patients with MPS II. Intellectual performance was assessed for school performance, behaviour, and intelligence. Urinary glycosaminoglycans were quantified by mass spectrometry. IDS variants were analysed in expression studies for enzymatic activity and processing by immunoblotting. Six patients had a non-neuronopathic phenotype and 11 a neuronopathic phenotype, three of whom had epilepsy. Total deletion of IDS invariably resulted in the neuronopathic phenotype. Phenotypes of seven known IDS variants were consistent with the literature. Expression studies of nine variants were novel and showed impaired IDS enzymatic activity, aberrant intracellular processing, and elevated urinary excretion of heparan sulphate and dermatan sulphate irrespective of the MPS II phenotype. We speculate that very low or cell-type-specific IDS residual activity is sufficient to prevent the neuronal phenotype of MPS II. Whereas the molecular effects of IDS variants do not distinguish between MPS II phenotypes, the IDS genotype is a strong predictor. © 2017 Mac Keith Press.

  13. Comprehensive detection of genes causing a phenotype using phenotype sequencing and pathway analysis.

    PubMed

    Harper, Marc; Gronenberg, Luisa; Liao, James; Lee, Christopher

    2014-01-01

    Discovering all the genetic causes of a phenotype is an important goal in functional genomics. We combine an experimental design for detecting independent genetic causes of a phenotype with a high-throughput sequencing analysis that maximizes sensitivity for comprehensively identifying them. Testing this approach on a set of 24 mutant strains generated for a metabolic phenotype with many known genetic causes, we show that this pathway-based phenotype sequencing analysis greatly improves sensitivity of detection compared with previous methods, and reveals a wide range of pathways that can cause this phenotype. We demonstrate our approach on a metabolic re-engineering phenotype, the PEP/OAA metabolic node in E. coli, which is crucial to a substantial number of metabolic pathways and under renewed interest for biofuel research. Out of 2157 mutations in these strains, pathway-phenoseq discriminated just five gene groups (12 genes) as statistically significant causes of the phenotype. Experimentally, these five gene groups, and the next two high-scoring pathway-phenoseq groups, either have a clear connection to the PEP metabolite level or offer an alternative path of producing oxaloacetate (OAA), and thus clearly explain the phenotype. These high-scoring gene groups also show strong evidence of positive selection pressure, compared with strictly neutral selection in the rest of the genome.

  14. A network-based phenotype mapping approach to identify genes that modulate drug response phenotypes

    PubMed Central

    Cairns, Junmei; Ung, Choong Yong; da Rocha, Edroaldo Lummertz; Zhang, Cheng; Correia, Cristina; Weinshilboum, Richard; Wang, Liewei; Li, Hu

    2016-01-01

    To better address the problem of drug resistance during cancer chemotherapy and explore the possibility of manipulating drug response phenotypes, we developed a network-based phenotype mapping approach (P-Map) to identify gene candidates that upon perturbed can alter sensitivity to drugs. We used basal transcriptomics data from a panel of human lymphoblastoid cell lines (LCL) to infer drug response networks (DRNs) that are responsible for conferring response phenotypes for anthracycline and taxane, two common anticancer agents use in clinics. We further tested selected gene candidates that interact with phenotypic differentially expressed genes (PDEGs), which are up-regulated genes in LCL for a given class of drug response phenotype in triple-negative breast cancer (TNBC) cells. Our results indicate that it is possible to manipulate a drug response phenotype, from resistant to sensitive or vice versa, by perturbing gene candidates in DRNs and suggest plausible mechanisms regulating directionality of drug response sensitivity. More important, the current work highlights a new way to formulate systems-based therapeutic design: supplementing therapeutics that aim to target disease culprits with phenotypic modulators capable of altering DRN properties with the goal to re-sensitize resistant phenotypes. PMID:27841317

  15. First insights into the genotype–phenotype map of phenotypic stability in rye

    PubMed Central

    Wang, Yu; Mette, Michael Florian; Miedaner, Thomas; Wilde, Peer; Reif, Jochen C.; Zhao, Yusheng

    2015-01-01

    Improving phenotypic stability of crops is pivotal for coping with the detrimental impacts of climate change. The goal of this study was to gain first insights into the genetic architecture of phenotypic stability in cereals. To this end, we determined grain yield, thousand kernel weight, test weight, falling number, and both protein and soluble pentosan content for two large bi-parental rye populations connected through one common parent and grown in multi-environmental field trials involving more than 15 000 yield plots. Based on these extensive phenotypic data, we calculated parameters for static and dynamic phenotypic stability of the different traits and applied linkage mapping using whole-genome molecular marker profiles. While we observed an absence of large-effect quantitative trait loci (QTLs) underlying yield stability, large and stable QTLs were found for phenotypic stability of test weight, soluble pentosan content, and falling number. Applying genome-wide selection, which in contrast to marker-assisted selection also takes into account loci with small-effect sizes, considerably increased the accuracy of prediction of phenotypic stability for all traits by exploiting both genetic relatedness and linkage between single-nucleotide polymorphisms and QTLs. We conclude that breeding for crop phenotypic stability can be improved in related populations using genomic selection approaches established upon extensive phenotypic data. PMID:25873667

  16. Application of phenotypic microarrays to environmental microbiology

    SciTech Connect

    Borglin, sharon; Joyner, Dominique; DeAngelis, Kristen; Khudyakov, Jane; D'haeseleer, Patrik; Joachimiak, Marcin; Hazen, Terry C; Fagan, Lisa Anne

    2012-01-01

    Environmental organisms are extremely diverse and only a small fraction has been successfully cultured in the laboratory. Culture in micro wells provides a method for rapid screening of a wide variety of growth conditions and commercially available plates contain a large number of substrates, nutrient sources, and inhibitors, which can provide an assessment of the phenotype of an organism. This review describes applications of phenotype arrays to anaerobic and thermophilic microorganisms, use of the plates in stress response studies, in development of culture media for newly discovered strains, and for assessment of phenotype of environmental communities. Also discussed are considerations and challenges in data interpretation and visualization, including data normalization, statistics, and curve fitting.

  17. Rational elicitation of cold-sensitive phenotypes

    PubMed Central

    Baliga, Chetana; Majhi, Sandipan; Mondal, Kajari; Bhattacharjee, Antara; Varadarajan, Raghavan

    2016-01-01

    Cold-sensitive phenotypes have helped us understand macromolecular assembly and biological phenomena, yet few attempts have been made to understand the basis of cold sensitivity or to elicit it by design. We report a method for rational design of cold-sensitive phenotypes. The method involves generation of partial loss-of-function mutants, at either buried or functional sites, coupled with selective overexpression strategies. The only essential input is amino acid sequence, although available structural information can be used as well. The method has been used to elicit cold-sensitive mutants of a variety of proteins, both monomeric and dimeric, and in multiple organisms, namely Escherichia coli, Saccharomyces cerevisiae, and Drosophila melanogaster. This simple, yet effective technique of inducing cold sensitivity eliminates the need for complex mutations and provides a plausible molecular mechanism for eliciting cold-sensitive phenotypes. PMID:27091994

  18. Semi-supervised Learning for Phenotyping Tasks.

    PubMed

    Dligach, Dmitriy; Miller, Timothy; Savova, Guergana K

    2015-01-01

    Supervised learning is the dominant approach to automatic electronic health records-based phenotyping, but it is expensive due to the cost of manual chart review. Semi-supervised learning takes advantage of both scarce labeled and plentiful unlabeled data. In this work, we study a family of semi-supervised learning algorithms based on Expectation Maximization (EM) in the context of several phenotyping tasks. We first experiment with the basic EM algorithm. When the modeling assumptions are violated, basic EM leads to inaccurate parameter estimation. Augmented EM attenuates this shortcoming by introducing a weighting factor that downweights the unlabeled data. Cross-validation does not always lead to the best setting of the weighting factor and other heuristic methods may be preferred. We show that accurate phenotyping models can be trained with only a few hundred labeled (and a large number of unlabeled) examples, potentially providing substantial savings in the amount of the required manual chart review.

  19. Phenotype-Driven Therapeutics in Severe Asthma.

    PubMed

    Opina, Maria Theresa D; Moore, Wendy C

    2017-02-01

    Inhaled corticosteroids are the mainstay of asthma treatment using a step-up approach with incremental dosing and additional controller medications in order to achieve symptom control and prevent exacerbations. While most patients respond well to this treatment approach, some patients remain refractory despite high doses of inhaled corticosteroids and a long-acting β-agonist. The problem lies in the heterogeneity of severe asthma, which is further supported by the emergence of severe asthma phenotypes. This heterogeneity contributes to the variability in treatment response. Randomized controlled trials involving add-on therapies in poorly controlled asthma have challenged the idea of a "one size fits all" approach targeting specific phenotypes in their subject selection. This review discusses severe asthma phenotypes from unbiased clustering approaches and the most recent scientific evidence on novel treatments to provide a guide in personalizing severe asthma treatment.

  20. High-throughput hyperdimensional vertebrate phenotyping

    PubMed Central

    Pardo-Martin, Carlos; Allalou, Amin; Medina, Jaime; Eimon, Peter M.; Wählby, Carolina; Yanik, Mehmet Fatih

    2013-01-01

    Most gene mutations and biologically active molecules cause complex responses in animals that cannot be predicted by cell culture models. Yet animal studies remain too slow and their analyses are often limited to only a few readouts. Here we demonstrate high-throughput optical projection tomography with micrometer resolution and hyperdimensional screening of entire vertebrates in tens of seconds using a simple fluidic system. Hundreds of independent morphological features and complex phenotypes are automatically captured in three dimensions with unprecedented speed and detail in semi-transparent zebrafish larvae. By clustering quantitative phenotypic signatures, we can detect and classify even subtle alterations in many biological processes simultaneously. We term our approach hyperdimensional in vivo phenotyping (HIP). To illustrate the power of HIP, we have analyzed the effects of several classes of teratogens on cartilage formation using 200 independent morphological measurements and identified similarities and differences that correlate well with their known mechanisms of actions in mammals. PMID:23403568

  1. Effect of phenotypic variation on kin selection

    PubMed Central

    Boyd, Robert; Richerson, Peter J.

    1980-01-01

    An expression for the equilibrium of the mean phenotypic value of a quantitative character is derived for a model in which the fitness of an individual depends on its own phenotype and the mean phenotypic value of a group of related individuals. When selection is weak the equilibrium mean is well predicted by Hamilton's k > 1/r rule (k is the ratio of mean fitness gained by recipient of altruistic behavior to mean fitness lost by donor; r is mean coefficient of relationship between donor and recipient). When selection is strong, however, the equilibrium mean depends on the heritability of the character. Low heritability can lead to substantially more “altruism” than predicted by the k > 1/r rule. PMID:16592940

  2. Impact of the LDL subfraction phenotype on Lp-PLA2 distribution, LDL modification and HDL composition in type 2 diabetes

    PubMed Central

    2013-01-01

    Background Qualitative alterations of lipoproteins underlie the high incidence of atherosclerosis in diabetes. The objective of this study was to assess the impact of low-density lipoprotein (LDL) subfraction phenotype on the qualitative characteristics of LDL and high-density lipoprotein (HDL) in patients with type 2 diabetes. Methods One hundred twenty two patients with type 2 diabetes in poor glycemic control and 54 healthy subjects were included in the study. Patients were classified according to their LDL subfraction phenotype. Seventy-seven patients presented phenotype A whereas 45 had phenotype B. All control subjects showed phenotype A. Several forms of modified LDL, HDL composition and the activity and distribution of lipoprotein-associated phospholipase A2 (Lp-PLA2) were analyzed. Results Oxidized LDL, glycated LDL and electronegative LDL were increased in both groups of patients compared with the control group. Patients with phenotype B had increased oxidized LDL and glycated LDL concentration than patients with phenotype A. HDL composition was abnormal in patients with diabetes, being these abnormalities more marked in patients with phenotype B. Total Lp-PLA2 activity was higher in phenotype B than in phenotype A or in control subjects. The distribution of Lp-PLA2 between HDL and apoB-containing lipoproteins differed in patients with phenotype A and phenotype B, with higher activity associated to apoB-containing lipoproteins in the latter. Conclusions The presence of LDL subfraction phenotype B is associated with increased oxidized LDL, glycated LDL and Lp-PLA2 activity associated to apoB-containing lipoproteins, as well as with abnormal HDL composition. PMID:23915379

  3. Impact of the LDL subfraction phenotype on Lp-PLA2 distribution, LDL modification and HDL composition in type 2 diabetes.

    PubMed

    Sánchez-Quesada, Jose Luis; Vinagre, Irene; De Juan-Franco, Elena; Sánchez-Hernández, Juan; Bonet-Marques, Rosa; Blanco-Vaca, Francisco; Ordóñez-Llanos, Jordi; Pérez, Antonio

    2013-08-05

    Qualitative alterations of lipoproteins underlie the high incidence of atherosclerosis in diabetes. The objective of this study was to assess the impact of low-density lipoprotein (LDL) subfraction phenotype on the qualitative characteristics of LDL and high-density lipoprotein (HDL) in patients with type 2 diabetes. One hundred twenty two patients with type 2 diabetes in poor glycemic control and 54 healthy subjects were included in the study. Patients were classified according to their LDL subfraction phenotype. Seventy-seven patients presented phenotype A whereas 45 had phenotype B. All control subjects showed phenotype A. Several forms of modified LDL, HDL composition and the activity and distribution of lipoprotein-associated phospholipase A2 (Lp-PLA2) were analyzed. Oxidized LDL, glycated LDL and electronegative LDL were increased in both groups of patients compared with the control group. Patients with phenotype B had increased oxidized LDL and glycated LDL concentration than patients with phenotype A. HDL composition was abnormal in patients with diabetes, being these abnormalities more marked in patients with phenotype B. Total Lp-PLA2 activity was higher in phenotype B than in phenotype A or in control subjects. The distribution of Lp-PLA2 between HDL and apoB-containing lipoproteins differed in patients with phenotype A and phenotype B, with higher activity associated to apoB-containing lipoproteins in the latter. The presence of LDL subfraction phenotype B is associated with increased oxidized LDL, glycated LDL and Lp-PLA2 activity associated to apoB-containing lipoproteins, as well as with abnormal HDL composition.

  4. The Phenotype of Spontaneous Preterm Birth: Application of a Clinical Phenotyping Tool

    PubMed Central

    Manuck, Tracy A.; Esplin, M. Sean; Biggio, Joseph; Bukowski, Radek; Parry, Samuel; Zhang, Heping; Varner, Michael W.; Andrews, William; Saade, George; Sadovsky, Yoel; Reddy, Uma M.; Ilekis, John

    2015-01-01

    Objective Spontaneous preterm birth (SPTB) is a complex condition that is likely a final common pathway with multiple possible etiologies. We hypothesized that a comprehensive classification system could appropriately group women with similar STPB etiologies, and provide an explanation, at least in part, for the disparities in SPTB associated with race and gestational age at delivery. Study Design Planned analysis of a multicenter, prospective study of singleton SPTB. Women with SPTB < 34 weeks were included. We defined 9 potential SPTB phenotypes based on clinical data, including infection/inflammation, maternal stress, decidual hemorrhage, uterine distention, cervical insufficiency, placental dysfunction, premature rupture of the membranes, maternal comorbidities, and familial factors. Each woman was evaluated for each phenotype. Delivery gestational age was compared between those with and without each phenotype. Phenotype profiles were also compared between women with very early (20.0–27.9 weeks) SPTB vs. those with early SPTB (28.0–34.0 weeks), and between African-American and Caucasian women. Statistical analysis was by t-test and chi-square as appropriate. Results The phenotyping tool was applied to 1025 women with SPTB who delivered at a mean 30.0 (+/− 3.2) weeks gestation. Of these, 800 (78%) had ≥2 phenotypes. Only 43 (4.2%) had no phenotypes. The 281 women with early SPTB were more likely to have infection/inflammation, decidual hemorrhage, and cervical insufficiency phenotypes (all p≤0.001). African-American women had more maternal stress and cervical insufficiency but less decidual hemorrhage and placental dysfunction compared to Caucasian women (all p<0.05). Gestational age at delivery decreased as the number of phenotypes present increased. Conclusions Precise SPTB phenotyping classifies women with SPTB and identifies specific differences between very early and early SPTB and between African-Americans and Caucasians. PMID:25687564

  5. Phenotypic Responses of a Stoloniferous Clonal Plant Buchloe dactyloides to Scale-Dependent Nutrient Heterogeneity

    PubMed Central

    Han, Lei; Liu, Jun-Xiang; Sun, Zhen-Yuan

    2013-01-01

    Clonal plants could modify phenotypic responses to nutrients heterogeneously distributed both in space and time by physiological integration. It will take times to do phenotypic responses to modifications which are various in different growth periods. An optimal phenotype is reached when there is a match between nutrient conditions and foraging ability. A single plantlet of Buchloe dactyloides with two stolons was transplanted into heterogeneous nutrient conditions. One stolon grew in homogeneous nutrient patch, while the other cultured in different scales of heterogeneous nutrient patches. As compared to the other nutrient treatment, heterogeneous nutrient treatments with small scale of 25×25 cm resulted in a higher biomass, and larger number of ramets, clumps and stolons in B. dactyloides at both genet and clonal fragment levels. Significant differences of number of ramets, clumps and stolons were detected at the rapid growth stage, but not in the early stage of the experiment. Foraging ability was more efficient in heterogeneous than in homogeneous nutrient conditions as assessed by higher root mass and root to shoot ratio. Different nutrient treatments did not prompt significant differences in internode and root length. Physiological integration significantly increased biomass, but did not influence other growth or morphological characters. These results suggest that physiological integration modifies phenotypic plasticity of B. dactyloides for efficient foraging of nutrients in heterogeneous nutrient conditions. These effects are more pronounced at genet and clonal fragment levels when the patch scale is 25×25 cm. Time is a key factor when phenotypic plasticity of B. dactyloides in heterogeneous nutrient conditions is examined. PMID:23826285

  6. Developmental thermal plasticity of prey modifies the impact of predation.

    PubMed

    Seebacher, Frank; Grigaltchik, Veronica S

    2015-05-01

    Environmental conditions during embryonic development can influence the mean expression of phenotypes as well as phenotypic responses to environmental change later in life. The resulting phenotypes may be better matched to their environment and more resilient to environmental change, including human-induced climate change. However, whether plasticity does improve success in an ecological context is unresolved. In a microcosm experiment, we show that developmental plasticity in embryos of the frog Limnodynastes peronii is beneficial by increasing survivorship of tadpoles in the presence of predators when egg incubation (15 or 25°C) and tadpole acclimation temperature in microcosms (15 or 25°C) coincided at 15°C. Tadpoles that survived predation were smaller, and had faster burst swimming speeds than those kept in no-predator control conditions, but only at high (25°C) egg incubation or subsequent microcosm temperatures. Metabolic rates were determined by a three-way interaction between incubation and microcosm temperatures and predation; maximal glycolytic and mitochondrial metabolic capacities (enzyme activities) were lower in survivors from predation compared with controls, particularly when eggs were incubated at 25°C. We show that thermal conditions experienced during early development are ecologically relevant by modulating survivorship from predation. Importantly, developmental thermal plasticity also impacts population phenotypes indirectly by modifying species interactions and the selection pressure imposed by predation.

  7. Lung cancer stem cells—characteristics, phenotype

    PubMed Central

    George, Rachel; Sethi, Tariq

    2016-01-01

    Lung cancer remains a major cause of cancer-related deaths worldwide with unfavourable prognosis mainly due to the late stage of disease at presentation. High incidence and disease recurrence rates are a fact despite advances in treatment. Ongoing experimental and clinical observations suggest that the malignant phenotype in lung cancer is sustained by lung cancer stem cells (CSCs) which are putative stem cells situated throughout the airways that have the potential of initiating lung cancer formation. These cells share the common characteristic of increased proliferation and differentiation, long life span and resistance to chemotherapy and radiation therapy. This review summarises the current knowledge on their characteristics and phenotype. PMID:27413709

  8. Phenotypically heterogeneous populations in spatially heterogeneous environments

    NASA Astrophysics Data System (ADS)

    Patra, Pintu; Klumpp, Stefan

    2014-03-01

    The spatial expansion of a population in a nonuniform environment may benefit from phenotypic heterogeneity with interconverting subpopulations using different survival strategies. We analyze the crossing of an antibiotic-containing environment by a bacterial population consisting of rapidly growing normal cells and slow-growing, but antibiotic-tolerant persister cells. The dynamics of crossing is characterized by mean first arrival times and is found to be surprisingly complex. It displays three distinct regimes with different scaling behavior that can be understood based on an analytical approximation. Our results suggest that a phenotypically heterogeneous population has a fitness advantage in nonuniform environments and can spread more rapidly than a homogeneous population.

  9. Genetics of alcoholism using intermediate phenotypes.

    PubMed

    Enoch, Mary-Anne; Schuckit, Marc A; Johnson, Bankole A; Goldman, David

    2003-02-01

    This article represents the proceedings of a symposium at the 2002 meeting of the Research Society on Alcoholism in San Francisco, CA. It was organized by Mary-Anne Enoch and David Goldman and chaired by David Goldman. The presentations were (1) Two functional polymorphisms and their intermediate phenotypes in complex behaviors: COMT/executive cognition and anxiety and HTT/anxiety, by David Goldman; (2) Role of the EEG in determining genetic risk for alcoholism and anxiety disorders, by Mary-Anne Enoch; (3) The response to alcohol as an intermediate phenotype for alcoholism, by Marc A. Schuckit; and (4) Pharmacogenomic approaches to alcoholism treatment: toward a hypothesis, by Bankole A. Johnson.

  10. The search for modifier genes in Huntington disease - Multifactorial aspects of a monogenic disorder.

    PubMed

    Arning, Larissa

    2016-12-01

    It is becoming increasingly evident that the underlying mutation of a single locus is often insufficient for the prediction of the comprehensive phenotype in human Mendelian disorders, implicating that there is no clear distinction between monogenic and complex traits. By definition, monogenic traits show a classic pattern of inheritance and are strongly influenced by variation within a single gene. However, many Mendelian traits that result in genetic disorders can have phenotypes that differ in subtle or profound ways such as severity, onset age and other associated phenotypic characteristics. Among the factors that may explain these differences in disease expression are modifier genes. This review focuses on the role of modifier genes using the example of Huntington Disease (HD), an autosomal dominantly transmitted, progressive neurodegenerative disorder. The advantages and limitations of candidate gene approaches versus genome-wide association studies (GWAS) as well as its implications for diagnostic, prognostic, and therapeutic interventions are discussed.

  11. Polysaccharide biological response modifiers.

    PubMed

    Leung, M Y K; Liu, C; Koon, J C M; Fung, K P

    2006-06-15

    Biological response modifiers (BRMs) are substances which augment immune response. BRMs can be cytokines which are produced endogenously in our body by immune cells or derivatives of bacteria, fungi, brown algae, Aloe vera and photosynthetic plants. Such exogeneous derivatives (exogeneous BRMs) can be nucleic acid (CpG), lipid (lipotechoic acid), protein or polysaccharide in nature. The receptors for these exogeneous BRMs are pattern recognition receptors. The binding of exogeneous BRMs to pattern recognition receptors triggers immune response. Exogenous BRMs have been reported to have anti-viral, anti-bacterial, anti-fungal, anti-parasitic, and anti-tumor activities. Among different exogeneous BRMs, polysaccharide BRMs have the widest occurrence in nature. Some polysaccharide BRMs have been tested for their therapeutic properties in human clinical trials. An overview of current understandings of polysaccharide BRMs is summarized in this review.

  12. Modified clay sorbents

    DOEpatents

    Fogler, H. Scott; Srinivasan, Keeran R.

    1990-01-01

    A novel modified clay sorbent and method of treating industrial effluents to remove trace pollutants, such as dioxins, biphenyls, and polyaromatics such as benzo(a)pyrene and pentachlorophenol. The novel clay sorbent has a composite structure in which the interlayer space of an expandable clay, such as smectite, is filled with polyvalent or multivalent inorganic cations which forces weaker surfactant cations to locate on the surface of the clay in such an orientation that the resulting composite is hydrophilic in nature. A specific example is cetylpyridinium-hydroxy aluminum-montmorillonite. In certain embodiments, a non-expanding clay, such as kaolinite, is used and surfactant cations are necessarily located on an external surface of the clay. A specific example is cetylpyridinium-kaolinite.

  13. Modified Composite Materials Workshop

    NASA Technical Reports Server (NTRS)

    Dicus, D. L. (Compiler)

    1978-01-01

    The reduction or elimination of the hazard which results from accidental release of graphite fibers from composite materials was studied at a workshop. At the workshop, groups were organized to consider six topics: epoxy modifications, epoxy replacement, fiber modifications, fiber coatings and new fibers, hybrids, and fiber release testing. Because of the time required to develop a new material and acquire a design data base, most of the workers concluded that a modified composite material would require about four to five years of development and testing before it could be applied to aircraft structures. The hybrid working group considered that some hybrid composites which reduce the risk of accidental fiber release might be put into service over the near term. The fiber release testing working group recommended a coordinated effort to define a suitable laboratory test.

  14. Why genetically modified crops?

    PubMed

    Jones, Jonathan D G

    2011-05-13

    This paper is intended to convey the message of the talk I gave at the Theo Murphy meeting at the Kavli Centre in July 2010. It, like the talk, is polemical, and conveys the exasperation felt by a practitioner of genetically modified (GM) plant science at its widespread misrepresentation. I argue that sustainable intensification of agriculture, using GM as well as other technologies, reduces its environmental impact by reducing pesticide applications and conserving soil carbon by enabling low till methods. Current technologies (primarily insect resistance and herbicide tolerance) have been beneficial. Moreover, the near-term pipeline of new GM methods and traits to enhance our diet, increase crop yields and reduce losses to disease is substantial. It would be perverse to spurn this approach at a time when we need every tool in the toolbox to ensure adequate food production in the short, medium and long term.

  15. Coevolutionary dynamics of phenotypic diversity and contingent cooperation.

    PubMed

    Wu, Te; Wang, Long; Fu, Feng

    2017-01-01

    Phenotypic diversity is considered beneficial to the evolution of contingent cooperation, in which cooperators channel their help preferentially towards others of similar phenotypes. However, it remains largely unclear how phenotypic variation arises in the first place and thus leads to the construction of phenotypic complexity. Here we propose a mathematical model to study the coevolutionary dynamics of phenotypic diversity and contingent cooperation. Unlike previous models, our model does not assume any prescribed level of phenotypic diversity, but rather lets it be an evolvable trait. Each individual expresses one phenotype at a time and only the phenotypes expressed are visible to others. Moreover, individuals can differ in their potential of phenotypic variation, which is characterized by the number of distinct phenotypes they can randomly switch to. Each individual incurs a cost proportional to the number of potentially expressible phenotypes so as to retain phenotypic variation and expression. Our results show that phenotypic diversity coevolves with contingent cooperation under a wide range of conditions and that there exists an optimal level of phenotypic diversity best promoting contingent cooperation. It pays for contingent cooperators to elevate their potential of phenotypic variation, thereby increasing their opportunities of establishing cooperation via novel phenotypes, as these new phenotypes serve as secret tags that are difficult for defector to discover and chase after. We also find that evolved high levels of phenotypic diversity can occasionally collapse due to the invasion of defector mutants, suggesting that cooperation and phenotypic diversity can mutually reinforce each other. Thus, our results provide new insights into better understanding the coevolution of cooperation and phenotypic diversity.

  16. Coevolutionary dynamics of phenotypic diversity and contingent cooperation

    PubMed Central

    Wang, Long

    2017-01-01

    Phenotypic diversity is considered beneficial to the evolution of contingent cooperation, in which cooperators channel their help preferentially towards others of similar phenotypes. However, it remains largely unclear how phenotypic variation arises in the first place and thus leads to the construction of phenotypic complexity. Here we propose a mathematical model to study the coevolutionary dynamics of phenotypic diversity and contingent cooperation. Unlike previous models, our model does not assume any prescribed level of phenotypic diversity, but rather lets it be an evolvable trait. Each individual expresses one phenotype at a time and only the phenotypes expressed are visible to others. Moreover, individuals can differ in their potential of phenotypic variation, which is characterized by the number of distinct phenotypes they can randomly switch to. Each individual incurs a cost proportional to the number of potentially expressible phenotypes so as to retain phenotypic variation and expression. Our results show that phenotypic diversity coevolves with contingent cooperation under a wide range of conditions and that there exists an optimal level of phenotypic diversity best promoting contingent cooperation. It pays for contingent cooperators to elevate their potential of phenotypic variation, thereby increasing their opportunities of establishing cooperation via novel phenotypes, as these new phenotypes serve as secret tags that are difficult for defector to discover and chase after. We also find that evolved high levels of phenotypic diversity can occasionally collapse due to the invasion of defector mutants, suggesting that cooperation and phenotypic diversity can mutually reinforce each other. Thus, our results provide new insights into better understanding the coevolution of cooperation and phenotypic diversity. PMID:28141806

  17. Discovery of the gray phenotype and white-gray-opaque tristable phenotypic transitions in Candida dubliniensis.

    PubMed

    Yue, Huizhen; Hu, Jian; Guan, Guobo; Tao, Li; Du, Han; Li, Houmin; Huang, Guanghua

    2016-04-02

    Candida dubliniensis is closely related to Candida albicans, a major causative agent of candidiasis, and is primarily associated with oral colonization and infection in human immunodeficiency virus (HIV)-positive patients. Despite the high similarity of genomic and phenotypic features between the 2 species, C. dubliniensis is much less virulent and less prevalent than C. albicans. The ability to change morphological phenotypes is a striking feature of Candida species and is linked to virulence. In this study, we report a novel phenotype, the gray phenotype, in C. dubliniensis. Together with the previously reported white and opaque cell types, the gray phenotype forms a tristable phenotypic switching system in C. dubliniensis that is similar to the white-gray-opaque tristable switching system in C. albicans. Gray cells of C. dubliniensis are similar to their counterparts in C. albicans in terms of several biological aspects including cellular morphology, mating competence, and genetic regulatory mechanisms. However, the gray phenotypes of the 2 species have some distinguishing features. For example, the secreted aspartyl protease (Sap) activity is induced by bovine serum albumin (BSA) in gray cells of C. albicans, but not in gray cells of C. dubliniensis. Taken together, our results demonstrate that the biological features and regulatory mechanisms of white-gray-opaque tristable transitions are largely conserved in the 2 pathogenic Candida species.

  18. Discovery of the gray phenotype and white-gray-opaque tristable phenotypic transitions in Candida dubliniensis

    PubMed Central

    Yue, Huizhen; Hu, Jian; Guan, Guobo; Tao, Li; Du, Han; Li, Houmin; Huang, Guanghua

    2016-01-01

    ABSTRACt Candida dubliniensis is closely related to Candida albicans, a major causative agent of candidiasis, and is primarily associated with oral colonization and infection in human immunodeficiency virus (HIV)-positive patients. Despite the high similarity of genomic and phenotypic features between the 2 species, C. dubliniensis is much less virulent and less prevalent than C. albicans. The ability to change morphological phenotypes is a striking feature of Candida species and is linked to virulence. In this study, we report a novel phenotype, the gray phenotype, in C. dubliniensis. Together with the previously reported white and opaque cell types, the gray phenotype forms a tristable phenotypic switching system in C. dubliniensis that is similar to the white-gray-opaque tristable switching system in C. albicans. Gray cells of C. dubliniensis are similar to their counterparts in C. albicans in terms of several biological aspects including cellular morphology, mating competence, and genetic regulatory mechanisms. However, the gray phenotypes of the 2 species have some distinguishing features. For example, the secreted aspartyl protease (Sap) activity is induced by bovine serum albumin (BSA) in gray cells of C. albicans, but not in gray cells of C. dubliniensis. Taken together, our results demonstrate that the biological features and regulatory mechanisms of white-gray-opaque tristable transitions are largely conserved in the 2 pathogenic Candida species. PMID:26714067

  19. A New Method to Infer Causal Phenotype Networks Using QTL and Phenotypic Information

    PubMed Central

    Wang, Huange; van Eeuwijk, Fred A.

    2014-01-01

    In the context of genetics and breeding research on multiple phenotypic traits, reconstructing the directional or causal structure between phenotypic traits is a prerequisite for quantifying the effects of genetic interventions on the traits. Current approaches mainly exploit the genetic effects at quantitative trait loci (QTLs) to learn about causal relationships among phenotypic traits. A requirement for using these approaches is that at least one unique QTL has been identified for each trait studied. However, in practice, especially for molecular phenotypes such as metabolites, this prerequisite is often not met due to limited sample sizes, high noise levels and small QTL effects. Here, we present a novel heuristic search algorithm called the QTL+phenotype supervised orientation (QPSO) algorithm to infer causal directions for edges in undirected phenotype networks. The two main advantages of this algorithm are: first, it does not require QTLs for each and every trait; second, it takes into account associated phenotypic interactions in addition to detected QTLs when orienting undirected edges between traits. We evaluate and compare the performance of QPSO with another state-of-the-art approach, the QTL-directed dependency graph (QDG) algorithm. Simulation results show that our method has broader applicability and leads to more accurate overall orientations. We also illustrate our method with a real-life example involving 24 metabolites and a few major QTLs measured on an association panel of 93 tomato cultivars. Matlab source code implementing the proposed algorithm is freely available upon request. PMID:25144184

  20. A new method to infer causal phenotype networks using QTL and phenotypic information.

    PubMed

    Wang, Huange; van Eeuwijk, Fred A

    2014-01-01

    In the context of genetics and breeding research on multiple phenotypic traits, reconstructing the directional or causal structure between phenotypic traits is a prerequisite for quantifying the effects of genetic interventions on the traits. Current approaches mainly exploit the genetic effects at quantitative trait loci (QTLs) to learn about causal relationships among phenotypic traits. A requirement for using these approaches is that at least one unique QTL has been identified for each trait studied. However, in practice, especially for molecular phenotypes such as metabolites, this prerequisite is often not met due to limited sample sizes, high noise levels and small QTL effects. Here, we present a novel heuristic search algorithm called the QTL+phenotype supervised orientation (QPSO) algorithm to infer causal directions for edges in undirected phenotype networks. The two main advantages of this algorithm are: first, it does not require QTLs for each and every trait; second, it takes into account associated phenotypic interactions in addition to detected QTLs when orienting undirected edges between traits. We evaluate and compare the performance of QPSO with another state-of-the-art approach, the QTL-directed dependency graph (QDG) algorithm. Simulation results show that our method has broader applicability and leads to more accurate overall orientations. We also illustrate our method with a real-life example involving 24 metabolites and a few major QTLs measured on an association panel of 93 tomato cultivars. Matlab source code implementing the proposed algorithm is freely available upon request.

  1. Parasitism and phenotypic change in colonial hosts.

    PubMed

    Hartikainen, Hanna; Fontes, Inês; Okamura, Beth

    2013-09-01

    Changes in host phenotype are often attributed to manipulation that enables parasites to complete trophic transmission cycles. We characterized changes in host phenotype in a colonial host–endoparasite system that lacks trophic transmission (the freshwater bryozoan Fredericella sultana and myxozoan parasite Tetracapsuloides bryosalmonae). We show that parasitism exerts opposing phenotypic effects at the colony and module levels. Thus, overt infection (the development of infectious spores in the host body cavity) was linked to a reduction in colony size and growth rate, while colony modules exhibited a form of gigantism. Larger modules may support larger parasite sacs and increase metabolite availability to the parasite. Host metabolic rates were lower in overtly infected relative to uninfected hosts that were not investing in propagule production. This suggests a role for direct resource competition and active parasite manipulation (castration) in driving the expression of the infected phenotype. The malformed offspring (statoblasts) of infected colonies had greatly reduced hatching success. Coupled with the severe reduction in statoblast production this suggests that vertical transmission is rare in overtly infected modules. We show that although the parasite can occasionally infect statoblasts during overt infections, no infections were detected in the surviving mature offspring, suggesting that during overt infections, horizontal transmission incurs a trade-off with vertical transmission.

  2. Cognitive Phenotype of Velocardiofacial Syndrome: A Review

    ERIC Educational Resources Information Center

    Furniss, Frederick; Biswas, Asit B.; Gumber, Rohit; Singh, Niraj

    2011-01-01

    The behavioural phenotype of velocardiofacial syndrome (VCFS), one of the most common human multiple anomaly syndromes, includes developmental disabilities, frequently including intellectual disability (ID) and high risk of diagnosis of psychotic disorders including schizophrenia. VCFS may offer a model of the relationship between ID and risk of…

  3. Radiofrequency treatment alters cancer cell phenotype

    NASA Astrophysics Data System (ADS)

    Ware, Matthew J.; Tinger, Sophia; Colbert, Kevin L.; Corr, Stuart J.; Rees, Paul; Koshkina, Nadezhda; Curley, Steven; Summers, H. D.; Godin, Biana

    2015-07-01

    The importance of evaluating physical cues in cancer research is gradually being realized. Assessment of cancer cell physical appearance, or phenotype, may provide information on changes in cellular behavior, including migratory or communicative changes. These characteristics are intrinsically different between malignant and non-malignant cells and change in response to therapy or in the progression of the disease. Here, we report that pancreatic cancer cell phenotype was altered in response to a physical method for cancer therapy, a non-invasive radiofrequency (RF) treatment, which is currently being developed for human trials. We provide a battery of tests to explore these phenotype characteristics. Our data show that cell topography, morphology, motility, adhesion and division change as a result of the treatment. These may have consequences for tissue architecture, for diffusion of anti-cancer therapeutics and cancer cell susceptibility within the tumor. Clear phenotypical differences were observed between cancerous and normal cells in both their untreated states and in their response to RF therapy. We also report, for the first time, a transfer of microsized particles through tunneling nanotubes, which were produced by cancer cells in response to RF therapy. Additionally, we provide evidence that various sub-populations of cancer cells heterogeneously respond to RF treatment.

  4. Macrophage Phenotype in Liver Injury and Repair.

    PubMed

    Sun, Y-Y; Li, X-F; Meng, X-M; Huang, C; Zhang, L; Li, J

    2017-03-01

    Macrophages hold a critical position in the pathogenesis of liver injury and repair, in which their infiltrations is regarded as a main feature for both acute and chronic liver diseases. It is noted that, based on the distinct phenotypes and origins, hepatic macrophages are capable of clearing pathogens, promoting/or inhibiting liver inflammation, while regulating liver fibrosis and fibrolysis through interplaying with hepatocytes and hepatic stellate cells (HSC) via releasing different types of pro- or anti-inflammatory cytokines and growth factors. Macrophages are typically categorized into M1 or M2 phenotypes by adapting to local microenvironment during the progression of liver injury. In most occasions, M1 macrophages play a pro-inflammatory role in liver injury, while M2 macrophages exert an anti-inflammatory or pro-fibrotic role during liver repair and fibrosis. In this review, we focused on the up-to-date information about the phenotypic and functional plasticity of the macrophages and discussed the detailed mechanisms through which the phenotypes and functions of macrophages are regulated in different stages of liver injury and repair. Moreover, their roles in determining the fate of liver diseases were also summarized. Finally, the macrophage-targeted therapies against liver diseases were also be evaluated.

  5. Phenotyping jasmonate regulation of root growth.

    PubMed

    Kellermeier, Fabian; Amtmann, Anna

    2013-01-01

    Root architecture is a complex and highly plastic feature of higher plants. Direct treatments with jasmonates and alterations in jasmonate signaling have been shown to elicit a range of root phenotypes. Here, we describe a fast, noninvasive, and semiautomatic method to monitor root architectural responses to environmental stimuli using plant tissue culture and the software tool EZ-RHIZO.

  6. Usefulness of descriptors in phenotyping germplasm collections

    USDA-ARS?s Scientific Manuscript database

    A large number of crop germplasm collections are maintained within the U.S. National Plant Germplasm System (NPGS). For each of these crop collections, Crop Germplasm committees (CGC), crop curators, and collection staff have established extensive lists of descriptors or phenotypic traits by which t...

  7. PRIMARY CILIARY DYSKINESIA: DIAGNOSTIC AND PHENOTYPIC FEATURES

    EPA Science Inventory

    Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormalities in ciliary structure/function. We hypothesized that the major clinical and biologic phenotypic markers of the disease could be evaluated by studying a cohort of subjects suspected of having PCD. ...

  8. The Behavioural Phenotype of Angelman Syndrome

    ERIC Educational Resources Information Center

    Horsler, K.; Oliver, C.

    2006-01-01

    Background: The purpose of this review is to examine the notion of a behavioural phenotype for Angelman syndrome and identify methodological and conceptual influences on the accepted presentation. Methods: Studies examining the behavioural characteristics associated with Angelman syndrome are reviewed and methodology is described. Results:…

  9. Phenotype as Agent for Epigenetic Inheritance

    PubMed Central

    Torday, John S.; Miller, William B.

    2016-01-01

    The conventional understanding of phenotype is as a derivative of descent with modification through Darwinian random mutation and natural selection. Recent research has revealed Lamarckian inheritance as a major transgenerational mechanism for environmental action on genomes whose extent is determined, in significant part, by germ line cells during meiosis and subsequent stages of embryological development. In consequence, the role of phenotype can productively be reconsidered. The possibility that phenotype is directed towards the effective acquisition of epigenetic marks in consistent reciprocation with the environment during the life cycle of an organism is explored. It is proposed that phenotype is an active agent in niche construction for the active acquisition of epigenetic marks as a dominant evolutionary mechanism rather than a consequence of Darwinian selection towards reproductive success. The reproductive phase of the life cycle can then be appraised as a robust framework in which epigenetic inheritance is entrained to affect growth and development in continued reciprocal responsiveness to environmental stresses. Furthermore, as first principles of physiology determine the limits of epigenetic inheritance, a coherent justification can thereby be provided for the obligate return of all multicellular eukaryotes to the unicellular state. PMID:27399791

  10. The Behavioural Phenotype of Angelman Syndrome

    ERIC Educational Resources Information Center

    Horsler, K.; Oliver, C.

    2006-01-01

    Background: The purpose of this review is to examine the notion of a behavioural phenotype for Angelman syndrome and identify methodological and conceptual influences on the accepted presentation. Methods: Studies examining the behavioural characteristics associated with Angelman syndrome are reviewed and methodology is described. Results:…

  11. Evolutionary engineering of industrially important microbial phenotypes.

    PubMed

    Sauer, U

    2001-01-01

    The tremendous complexity of dynamic interactions in cellular systems often impedes practical applications of metabolic engineering that are largely based on available molecular or functional knowledge. In contrast, evolutionary engineering follows nature's 'engineering' principle by variation and selection. Thus, it is a complementary strategy that offers compelling scientific and applied advantages for strain development and process optimization, provided a desired phenotype is amenable to direct or indirect selection. In addition to simple empirical strain development by random mutation and direct selection on plates, evolutionary engineering also encompasses recombination and continuous evolution of large populations over many generations. Two distinct evolutionary engineering applications are likely to gain more relevance in the future: first, as an integral component in metabolic engineering of strains with improved phenotypes, and second, to elucidate the molecular basis of desired phenotypes for subsequent transfer to other hosts. The latter will profit from the broader availability of recently developed methodologies for global response analysis at the genetic and metabolic level. These methodologies facilitate identification of the molecular basis of evolved phenotypes. It is anticipated that, together with novel analytical techniques, bioinformatics, and computer modeling of cellular functions and activities, evolutionary engineering is likely to find its place in the metabolic engineer's toolbox for research and strain development. This review presents evolutionary engineering of whole cells as an emerging methodology that draws on the latest advances from a wide range of scientific and technical disciplines.

  12. Behavioural Phenotypes in Disability Research: Historical Perspectives

    ERIC Educational Resources Information Center

    Goodey, C. F.

    2006-01-01

    Western medicine has a long history of accounting for behaviour by reducing the body to ultimate explanatory entities. In pre-modern medicine these were invisible "animal spirits" circulating the body. In modern medicine, they are "genes". Both raise questions. The psychological phenotype is defined by human consensus, varying according to time…

  13. Restoration of normal phenotype in cancer cells

    DOEpatents

    Bissell, M.J.; Weaver, V.M.

    1998-12-08

    A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying {beta}{sub 1} integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive. 14 figs.

  14. Towards a multidimensional healthy ageing phenotype.

    PubMed

    Mount, Sarah; Lara, Jose; Schols, Annemie M W J; Mathers, John C

    2016-11-01

    There is great interest in developing tools to measure healthy ageing and to identify early stages of health impairment, which may guide the implementation of interventions to prevent or delay the development of disease, disability, and mortality. Here, we review the most recent developments directed to operationalize, and test, definitions of healthy ageing. There is lack of consensus about how to define healthy ageing and, unsurprisingly, diversity in the instruments for its measurement. However, progress is being made in describing and in devising tools to capture the healthy ageing phenotype. Attempts to measure healthy ageing have relied primarily on cross-sectional data collected in older people. More recent studies have assessed the healthy ageing phenotype using markers of multiple functional domains and have used longitudinal data to model the dynamics and trajectories of healthy ageing. Given the complexity of the ageing process, no single measure is able to predict the ageing trajectory. Current attempts to operationalize the healthy ageing phenotype have relied on markers and data from earlier cohort studies and are limited by the tools used to collect data in those studies. Such data are often unsuitable to detect early subtle declines in function and/or are inappropriate for use in younger old adults. Future studies employing more objective and novel markers of healthy ageing are likely to offer opportunities to define and operationalize the healthy ageing phenotype.

  15. Cognitive Phenotype of Velocardiofacial Syndrome: A Review

    ERIC Educational Resources Information Center

    Furniss, Frederick; Biswas, Asit B.; Gumber, Rohit; Singh, Niraj

    2011-01-01

    The behavioural phenotype of velocardiofacial syndrome (VCFS), one of the most common human multiple anomaly syndromes, includes developmental disabilities, frequently including intellectual disability (ID) and high risk of diagnosis of psychotic disorders including schizophrenia. VCFS may offer a model of the relationship between ID and risk of…

  16. PRIMARY CILIARY DYSKINESIA: DIAGNOSTIC AND PHENOTYPIC FEATURES

    EPA Science Inventory

    Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormalities in ciliary structure/function. We hypothesized that the major clinical and biologic phenotypic markers of the disease could be evaluated by studying a cohort of subjects suspected of having PCD. ...

  17. The Relativity of Genotypes and Phenotypes.

    ERIC Educational Resources Information Center

    Willie, Charles Vert

    1995-01-01

    Asserts that Herrnstein and Murray's "The Bell Curve" (1994) is an attempt to influence and control public discourse about public policy and inequality. It examines four of the book's flaws in classification, analyses, research, and its failure to recognize intelligence as having both genotypic and phenotypic manifestations. (GR)

  18. Diverse application of MRI for mouse phenotyping.

    PubMed

    Wu, Yijen L; Lo, Cecilia W

    2017-06-01

    Small animal models, particularly mouse models, of human diseases are becoming an indispensable tool for biomedical research. Studies in animal models have provided important insights into the etiology of diseases and accelerated the development of therapeutic strategies. Detailed phenotypic characterization is essential, both for the development of such animal models and mechanistic studies into disease pathogenesis and testing the efficacy of experimental therapeutics. MRI is a versatile and noninvasive imaging modality with excellent penetration depth, tissue coverage, and soft tissue contrast. MRI, being a multi-modal imaging modality, together with proven imaging protocols and availability of good contrast agents, is ideally suited for phenotyping mutant mouse models. Here we describe the applications of MRI for phenotyping structural birth defects involving the brain, heart, and kidney in mice. The versatility of MRI and its ease of use are well suited to meet the rapidly increasing demands for mouse phenotyping in the coming age of functional genomics. Birth Defects Research 109:758-770, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  19. Phenotypic plasticity with instantaneous but delayed switches.

    PubMed

    Utz, Margarete; Jeschke, Jonathan M; Loeschcke, Volker; Gabriel, Wilfried

    2014-01-07

    Phenotypic plasticity is a widespread phenomenon, allowing organisms to better adapt to changing environments. Most empirical and theoretical studies are restricted to irreversible plasticity where the expression of a specific phenotype is mostly determined during development. However, reversible plasticity is not uncommon; here, organisms are able to switch back and forth between phenotypes. We present two optimization models for the fitness of (i) non-plastic, (ii) irreversibly plastic, and (iii) reversibly plastic genotypes in a fluctuating environment. In one model, the fitness values of an organism during different life phases act together multiplicatively (so as to consider traits that are related to survival). The other model additionally considers additive effects (corresponding to traits related to fecundity). Both models yield qualitatively similar results. If the only costs of reversible plasticity are due to temporal maladaptation while switching between phenotypes, reversibility is virtually always advantageous over irreversibility, especially for slow environmental fluctuations. If reversibility implies an overall decreased fitness, then irreversibility is advantageous if the environment fluctuates quickly or if stress events last relatively short. Our results are supported by observations from different types of organisms and have implications for many basic and applied research questions, e.g., on invasive alien species.

  20. Phenotype Information Retrieval for Existing GWAS Studies.

    PubMed

    Alipanah, Neda; Lin, Ko-Wei; Venkatesh, Vinay; Farzaneh, Seena; Kim, Hyeon-Eui

    2013-01-01

    The database of Genotypes and Phenotypes (dbGaP) is archiving the results of different Genome Wide Association Studies (GWAS). dbGaP has a multitude of phenotype variables, but they are not harmonized across studies. We proposed a method to standardize phenotype variables by classifying similar variables based on semantic distances. We first extracted variables description, enriched them using domain knowledge, and computed the distances among them. We used clustering techniques to classify the most similar variables. We used domain experts to audit clusters, annotated the clusters with appropriate labels, and used re-clustering to build a semantically-driven Genotypes and Phenotypes (sdGaP) ontology using the UMLS semantic network and metathesaurus. The sdGaP ontology allowed us to expand user queries and retrieve information using a semantic metric called density measure (DM). We illustrated the potential improvement of information retrieval using the sdGaP ontology in one search scenario using the variables from the Cleveland Family Study.

  1. Restoration of normal phenotype in cancer cells

    DOEpatents

    Bissell, Mina J.; Weaver, Valerie M.

    1998-01-01

    A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying .beta..sub.1 integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive.

  2. Engineering complex phenotypes in industrial strains.

    PubMed

    Patnaik, Ranjan

    2008-01-01

    The global demand is rising for greener manufacturing processes that are cost-competitive and available in a timely manner. This has led to the development of a series of new tools and integrative platforms enabling rapid engineering of complex phenotypes in industrial microbes. By blending "old classical methods" of strain isolation with "newer approaches" of cell engineering, researchers are demonstrating the ability to stack multiple complex phenotypes in industrial hosts with some level of certainty. Newer tools for dissecting the genotype-phenotype correlation include association analysis (Precision Engineering), multiSCale Analysis of Library Enrichment (SCALE) in competition experiments, whole-genome transcriptional analysis, and proteomics and metabolomics technology. These newer and older tools of metabolic engineering and synthetic biology when combined with recent whole cell engineering approaches like whole genome shuffling, global transciptome machinery engineering, and directed evolutionary engineering, provide a powerful platform for engineering complex phenotypes in industrial strains. This review attempts to highlight and compare these newer tools and approaches with traditional strain isolation procedures as it applies to genome engineering with examples taken from literature.

  3. Phenotypic mutant library: potential for gene discovery

    USDA-ARS?s Scientific Manuscript database

    The rapid development of high throughput and affordable Next- Generation Sequencing (NGS) techniques has renewed interest in gene discovery using forward genetics. The conventional forward genetic approach starts with isolation of mutants with a phenotype of interest, mapping the mutation within a s...

  4. Biodiversity of spoilage lactobacilli: phenotypic characterisation.

    PubMed

    Sanders, J W; Oomes, S J C M; Membré, J-M; Wegkamp, A; Wels, M

    2015-02-01

    Preventing food spoilage is a challenge for the food industry, especially when applying mild preservation methods and when avoiding the use of preservatives. Therefore, it is essential to explore the boundaries of preservation by better understanding the causative microbes, their phenotypic behaviour and their genetic makeup. Traditionally in food microbiology, single strains or small sets of selected strains are studied. Here a collection of 120 strains of 6 different spoilage related Lactobacillus species and a multitude of sources was prepared and their growth characteristics determined in 384-well plates by optical density measurements (OD) over 20 days, for 20 carbon source-related phenotypic parameters and 25 preservation-related phenotypic parameters. Growth under all conditions was highly strain specific and there was no correlation of phenotypes at the species level. On average Lactobacillus brevis strains were amongst the most robust whereas Lactobacillus fructivorans strains had a much narrower growth range. The biodiversity data allowed the definition of preservation boundaries on the basis of the number of Lactobacillus strains that reached a threshold OD, which is different from current methods that are based on growth ability or growth rate of a few selected strains. Genetic information on these microbes and a correlation study will improve the mechanistic understanding of preservation resistance and this will support the future development of superior screening and preservation methods.

  5. Characterizing the ADHD Phenotype for Genetic Studies

    ERIC Educational Resources Information Center

    Stevenson, Jim; Asherson, Phil; Hay, David; Levy, Florence; Swanson, Jim; Thapar, Anita; Willcutt, Erik

    2005-01-01

    The genetic study of ADHD has made considerable progress. Further developments in the field will be reliant in part on identifying the most appropriate phenotypes for genetic analysis. The use of both categorical and dimensional measures of symptoms related to ADHD has been productive. The use of multiple reporters is a valuable feature of the…

  6. Behavioural Phenotypes in Disability Research: Historical Perspectives

    ERIC Educational Resources Information Center

    Goodey, C. F.

    2006-01-01

    Western medicine has a long history of accounting for behaviour by reducing the body to ultimate explanatory entities. In pre-modern medicine these were invisible "animal spirits" circulating the body. In modern medicine, they are "genes". Both raise questions. The psychological phenotype is defined by human consensus, varying according to time…

  7. Radiofrequency treatment alters cancer cell phenotype

    PubMed Central

    Ware, Matthew J.; Tinger, Sophia; Colbert, Kevin L.; Corr, Stuart J.; Rees, Paul; Koshkina, Nadezhda; Curley, Steven; Summers, H. D.; Godin, Biana

    2015-01-01

    The importance of evaluating physical cues in cancer research is gradually being realized. Assessment of cancer cell physical appearance, or phenotype, may provide information on changes in cellular behavior, including migratory or communicative changes. These characteristics are intrinsically different between malignant and non-malignant cells and change in response to therapy or in the progression of the disease. Here, we report that pancreatic cancer cell phenotype was altered in response to a physical method for cancer therapy, a non-invasive radiofrequency (RF) treatment, which is currently being developed for human trials. We provide a battery of tests to explore these phenotype characteristics. Our data show that cell topography, morphology, motility, adhesion and division change as a result of the treatment. These may have consequences for tissue architecture, for diffusion of anti-cancer therapeutics and cancer cell susceptibility within the tumor. Clear phenotypical differences were observed between cancerous and normal cells in both their untreated states and in their response to RF therapy. We also report, for the first time, a transfer of microsized particles through tunneling nanotubes, which were produced by cancer cells in response to RF therapy. Additionally, we provide evidence that various sub-populations of cancer cells heterogeneously respond to RF treatment. PMID:26165830

  8. Phenotypic spandrel: absolute discrimination and ligand antagonism

    NASA Astrophysics Data System (ADS)

    François, Paul; Hemery, Mathieu; Johnson, Kyle A.; Saunders, Laura N.

    2016-12-01

    We consider the general problem of sensitive and specific discrimination between biochemical species. An important instance is immune discrimination between self and not-self, where it is also observed experimentally that ligands just below the discrimination threshold negatively impact response, a phenomenon called antagonism. We characterize mathematically the generic properties of such discrimination, first relating it to biochemical adaptation. Then, based on basic biochemical rules, we establish that, surprisingly, antagonism is a generic consequence of any strictly specific discrimination made independently from ligand concentration. Thus antagonism constitutes a ‘phenotypic spandrel’: a phenotype existing as a necessary by-product of another phenotype. We exhibit a simple analytic model of discrimination displaying antagonism, where antagonism strength is linear in distance from the detection threshold. This contrasts with traditional proofreading based models where antagonism vanishes far from threshold and thus displays an inverted hierarchy of antagonism compared to simpler models. The phenotypic spandrel studied here is expected to structure many decision pathways such as immune detection mediated by TCRs and FCɛRIs, as well as endocrine signalling/disruption.

  9. Alcohol consumption, Lewis phenotypes, and risk of ischemic heart disease

    SciTech Connect

    Hein, H.O.; Suadicani, P.; Gyntelberg, F. . Epidemiological Research Unit); Sorenson, H. . Dept. of Chemical Immunology); Hein, H.O. . Dept. of Internal Medicine)

    1993-02-13

    The authors have previously found an increased risk of ischemic heart disease (IHD) in men with the Lewis phenotype Le(a[minus]b[minus]) and suggested that the Lewis blood group has a close genetic relation with insulin resistance. The authors have investigated whether any conventional risk factors explain the increased risk in Le(a[minus]b[minus]) men. 3,383 men aged 53-75 years were examined in 1985-86, and morbidity and mortality during the next 4 years were recorded. At baseline, the authors excluded 343 men with a history of myocardial infarction, angina pectoris, intermittent claudication, or stroke. The potential risk factors examined were alcohol consumption, physical activity, tobacco smoking, serum cotinine, serum lipids, body-mass index, blood pressure, prevalence of hypertension and non-insulin-dependent diabetes mellitus, and social class. In 280 (9.6%) men with Le(a[minus]b[minus]), alcohol was the only risk factor significantly associated with risk of IHD. There was a significant inverse dose-effect relation between alcohol consumption and risk; trend tests, with adjustment for age, were significant for fatal IHD (p=0.02), all IHD (p=0.03), and all causes of death (p=0.02). In 2649 (90.4%) men with other phenotypes, there was a limited negative association with alcohol consumption. In Le(a[minus]b[minus]) men, a group genetically at high risk of IHD, alcohol consumption seems to be especially protective. The authors suggest that alcohol consumption may modify insulin resistance in Le(a[minus]b[minus]) men.

  10. Metabolomics to Unveil and Understand Phenotypic Diversity between Pathogen Populations

    PubMed Central

    t'Kindt, Ruben; Scheltema, Richard A.; Jankevics, Andris; Brunker, Kirstyn; Rijal, Suman; Dujardin, Jean-Claude; Breitling, Rainer; Watson, David G.; Coombs, Graham H.; Decuypere, Saskia

    2010-01-01

    Leishmaniasis is a debilitating disease caused by the parasite Leishmania. There is extensive clinical polymorphism, including variable responsiveness to treatment. We study Leishmania donovani parasites isolated from visceral leishmaniasis patients in Nepal that responded differently to antimonial treatment due to differing intrinsic drug sensitivity of the parasites. Here, we present a proof-of-principle study in which we applied a metabolomics pipeline specifically developed for L. donovani to characterize the global metabolic differences between antimonial-sensitive and antimonial-resistant L. donovani isolates. Clones of drug-sensitive and drug-resistant parasite isolates from clinical samples were cultured in vitro and harvested for metabolomics analysis. The relative abundance of 340 metabolites was determined by ZIC-HILIC chromatography coupled to LTQ-Orbitrap mass spectrometry. Our measurements cover approximately 20% of the predicted core metabolome of Leishmania and additionally detected a large number of lipids. Drug-sensitive and drug-resistant parasites showed distinct metabolic profiles, and unsupervised clustering and principal component analysis clearly distinguished the two phenotypes. For 100 metabolites, the detected intensity differed more than three-fold between the 2 phenotypes. Many of these were in specific areas of lipid metabolism, suggesting that the membrane composition of the drug-resistant parasites is extensively modified. Untargeted metabolomics has been applied on clinical Leishmania isolates to uncover major metabolic differences between drug-sensitive and drug-resistant isolates. The identified major differences provide novel insights into the mechanisms involved in resistance to antimonial drugs, and facilitate investigations using targeted approaches to unravel the key changes mediating drug resistance. PMID:21152055

  11. Differential impact of lactose/lactase phenotype on colonic microflora

    PubMed Central

    Szilagyi, Andrew; Shrier, Ian; Heilpern, Debra; Je, Jung Sung; Park, Sunghoon; Chong, George; Lalonde, Catherine; Cote, Louis-Francois; Lee, Byong

    2010-01-01

    BACKGROUND: The ability to digest lactose divides the world’s population into two phenotypes that may be risk variability markers for several diseases. Prebiotic effects likely favour lactose maldigesters who experience lactose spilling into their colon. OBJECTIVE: To evaluate the effects of fixed-dose lactose solutions on fecal bifidobacteria and lactobacilli in digesters and maldigesters, and to determine whether the concept of a difference in ability to digest lactose is supported. METHODS: A four-week study was performed in 23 lactose mal-digesters and 18 digesters. Following two weeks of dairy food withdrawal, subjects ingested 25 g of lactose twice a day for two weeks. Stool bifidobacteria and lactobacilli counts pre- and postintervention were measured as the primary outcome. For secondary outcomes, total anaerobes, Enterobacteriaceae, beta-galactosidase and N-acetyl-beta-D-glucosaminidase activity in stool, as well as breath hydrogen and symptoms following lactose challenge tests, were measured. RESULTS: Lactose maldigesters had a mean change difference (0.72 log10 colony forming units/g stool; P=0.04) in bifidobacteria counts compared with lactose digesters. Lactobacilli counts were increased, but not significantly. Nevertheless, reduced breath hydrogen after lactose ingestion correlated with lactobacilli (r=−0.5; P<0.001). Reduced total breath hydrogen and symptom scores together, with a rise in fecal enzymes after intervention, were appropriate, but not significant. CONCLUSIONS: Despite failure to achieve full colonic adaptation, the present study provided evidence for a differential impact of lactose on microflora depending on genetic lactase status. A prebiotic effect was evident in lactose maldigesters but not in lactose digesters. This may play a role in modifying the mechanisms of certain disease risks related to dairy food consumption between the two phenotypes. PMID:20559580

  12. Phenotypes influencing low physical activity in maintenance dialysis.

    PubMed

    Panaye, Marine; Kolko-Labadens, Anne; Lasseur, Catherine; Paillasseur, Jean-Louis; Guillodo, Marie Paule; Levannier, Martial; Teta, Daniel; Fouque, Denis

    2015-01-01

    The "Pas à Pas" initiative aimed at evaluating the weekly physical activity (PA) and its determinants in a large cohort of dialysis patients. Physical inactivity is a risk factor for mortality in maintenance dialysis patients and is still poorly documented in this population. A prospective national epidemiological study was performed. A total of 1,163 patients on maintenance dialysis (hemodialysis and peritoneal dialysis) were included. PA was recorded during seven consecutive days using a pedometer to measure daily step numbers. Median age was 63 years (Q1 51-Q3 75). Sixty-three percent were sedentary (<5000 steps/day) with a median of 3,688 steps/day (1,866-6,271)]. PA level was similar between hemodialysis patients and those on peritoneal dialysis (3,693 steps [1,896-6,307] vs. 3,320 [1,478-5,926], P = .33). In hemodialysis patients, PA was lower on dialysis days compared with nondialysis days (2,912 [1,439-5,232] vs. 4,054 [2,136-7,108], respectively, P < .01). PA gradually decreased with age, 57% being sedentary between 50 and 65 years and 83% of patients after 80 years. Beyond this age effect, we identified, for the first time, specific phenotypes of patients with lower PA, such as inflammation, cardiovascular disease, protein energy wasting, obesity, and diabetes. By contrast, previous kidney transplantation and a higher muscle mass were associated with higher PA. Dialysis patients present a very low level of PA with high sedentary. Acting on patient's modifiable phenotypes may help to increase PA to improve morbidity, mortality, and quality of life. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  13. The relative contribution of environmental and genetic factors to phenotypic variation in familial Mediterranean fever (FMF).

    PubMed

    Ben-Zvi, Ilan; Brandt, Benny; Berkun, Yackov; Lidar, Merav; Livneh, Avi

    2012-01-10

    Familial Mediterranean fever (FMF) is an autosomal recessive disease, caused by mutations in the FMF gene MEFV (MEditerranean FeVer). It has a large phenotypic diversity even in patients with similar genotypes. Despite evidence that environmental factors (EFs) and genetic factors, including MEFV mutations (such as M694V, E148Q) and background modifier genes (MGs), affect the clinical manifestations of FMF, the relative contribution of each remains unknown. To investigate the relative contribution of environmental and genetic factors to the phenotype of FMF, we compared the intra-pair clinical concordance of 10 mono and 7 dizygotic twins with FMF. The part played by EFs was determined by the phenotypic discordance of the monozygous twins, and the MGs effect was determined by deducing the environmental effect, computed for MZ twins, from the phenotypic discordance of the dizygous twins. The mean±SD of intra-pair concordance was higher in the MZ than in DZ twin group (88.1±13.2 vs. 70.7±14.1 respectively, P value<0.05). Based on the concordance in clinical manifestations in MZ and DZ twins, the environmental effect on the phenotype of FMF is estimated as 11.9%±6.6% and the MGs effect as 17.4%±15.5% in average. In FMF the phenotype is affected by MEFV mutations, MGs and EFs in an estimated ratio of about 6:1.5:1 respectively. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Phenotypic plasticity changes correlations of traits following experimental introductions of Trinidadian guppies (Poecilia reticulata).

    PubMed

    Handelsman, Corey A; Ruell, Emily W; Torres-Dowdall, Julián; Ghalambor, Cameron K

    2014-11-01

    Colonization of novel environments can alter selective pressures and act as a catalyst for rapid evolution in nature. Theory and empirical studies suggest that the ability of a population to exhibit an adaptive evolutionary response to novel selection pressures should reflect the presence of sufficient additive genetic variance and covariance for individual and correlated traits. As correlated traits should not respond to selection independently, the structure of correlations of traits can bias or constrain adaptive evolution. Models of how multiple correlated traits respond to selection often assume spatial and temporal stability of trait-correlations within populations. Yet, trait-correlations can also be plastic in response to environmental variation. Phenotypic plasticity, the ability of a single genotype to produce different phenotypes across environments, is of particular interest because it can induce population-wide changes in the combination of traits exposed to selection and change the trajectory of evolutionary divergence. We tested the ability of phenotypic plasticity to modify trait-correlations by comparing phenotypic variance and covariance in the body-shapes of four experimental populations of Trinidadian guppies (Poecilia reticulata) to their ancestral population. We found that phenotypic plasticity produced both adaptive and novel aspects of body-shape, which was repeated in all four experimental populations. Further, phenotypic plasticity changed patterns of covariance among morphological characters. These findings suggest our ability to make inferences about patterns of divergence based on correlations of traits in extant populations may be limited if novel environments not only induce plasticity in multiple traits, but also change the correlations among the traits. © The Author 2014. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

  15. Effect of culture medium on propagation and phenotype of corneal stroma-derived stem cells.

    PubMed

    Sidney, Laura E; Branch, Matthew J; Dua, Harminder S; Hopkinson, Andrew

    2015-12-01

    The limbal area of the corneal stroma has been identified as a source of mesenchymal-like stem cells, which have potential for exploitation as a cell therapy. However, the optimal culture conditions are disputed and few direct media comparisons have been performed. In this report, we evaluated several media types to identify the optimal for inducing an in vitro stem cell phenotype. Primary human corneal stroma-derived stem cells (CSSCs) were extracted from corneoscleral rims. Culture in seven different media types was compared: Dulbecco's modified Eagle's medium (DMEM) with 10% fetal bovine serum (FBS); M199 with 20% FBS; DMEM-F12 with 20% serum replacement, basic fibroblast growth factor and leukemia inhibitory factor (SCM); endothelial growth medium (EGM); semi-solid MethoCult; serum-free keratinocyte medium (K-SFM); and StemPro-34. Effects on proliferation, morphology, protein and messenger RNA expression were evaluated. All media supported proliferation of CSSCs with the exception of K-SFM and StemPro-34. Morphology differed between media: DMEM produced large cells, whereas EGM produced very small cells. Culture in M199 produced a typical mesenchymal stromal cell phenotype with high expression of CD105, CD90 and CD73 but not CD34. Culture in SCM produced a phenotype more reminiscent of a progenitor cell type with expression of CD34, ABCG2, SSEA-4 and PAX6. Culture medium can significantly influence CSSC phenotype. SCM produced a cell phenotype closest to that of a pluripotent stem cell, and we consider it to be the most appropriate for development as a clinical-grade medium for the production of CSSC phenotypes suitable for cell therapy. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  16. Down syndrome individuals with Alzheimer's disease have a distinct neuroinflammatory phenotype compared to sporadic Alzheimer's disease.

    PubMed

    Wilcock, Donna M; Hurban, Jennifer; Helman, Alex M; Sudduth, Tiffany L; McCarty, Katie L; Beckett, Tina L; Ferrell, Joshua C; Murphy, M Paul; Abner, Erin L; Schmitt, Frederick A; Head, Elizabeth

    2015-09-01

    Down syndrome (DS) is the most common genetic cause of intellectual disability and is primarily caused by the triplication of chromosome 21. The overexpression of amyloid precursor protein gene may be sufficient to drive Alzheimer's disease (AD) neuropathology that is observed in virtually all individuals with DS by the age of 40 years. There is relatively little information about inflammation in the DS brain and how the genetics of DS may alter inflammatory responses and modify the course of AD pathogenesis in this disorder. Using the macrophage classification system of M1, M2a, M2b, and M2c inflammatory phenotypes, we have shown that the early stages of AD are associated with a bias toward an M1 or M2a phenotype. In later stages of AD, markers of M1, M2a and M2c are elevated. We now report the inflammatory phenotype in a DS autopsy series to compare this with the progression in sporadic AD. Tissue from young DS cases (under 40 years of age, pre-AD) show a bias toward M1 and M2b states with little M2a or M2c observed. Older DS cases (over 40 with AD pathology) show a distinct bias toward an M2b phenotype. Importantly, this is distinct from sporadic AD where the M2b phenotype has been rarely, if ever observed in postmortem studies. Stimulated by immune complex activation of microglial cells and toll-like receptor activation, the M2b phenotype represents a unique neuroinflammatory state in diseased brain and may have significant implications for therapeutic intervention for persons with DS.

  17. DMP1 C-Terminal Mutant Mice Recapture the Human ARHR Tooth Phenotype

    PubMed Central

    Jiang, Baichun; Cao, Zhengguo; Lu, Yongbo; Janik, Carol; Lauziere, Stephanie; Xie, Yixia; Poliard, Anne; Qin, Chunlin; Ward, Leanne M; Feng, Jian Q

    2010-01-01

    DMP1 mutations in autosomal recessive hypophosphatemic rickets (ARHR) patients and mice lacking Dmp1 display an overlapping pathophysiology, such as hypophosphatemia. However, subtle differences exist between the mouse model and human ARHR patients. These differences could be due to a species specificity of human versus mouse, or it may be that the mutant DMP1 in humans maintains partial function of DMP1. In this study we report a deformed tooth phenotype in a human DMP1 deletion mutation case. Unexpectedly, the deletion of nucleotides 1484 to 1490 (c.1484_1490delCTATCAC, delMut, resulting in replacement of the last 18 residues with 33 random amino acids) showed a severe dentin and enamel defect similar to a dentinogenesis imperfecta (DI) III–like phenotype. To address the molecular mechanism behind this phenotype, we generated delMut transgenic mice with the endogenous Dmp1 gene removed. These mutant mice did not recapture the abnormal phenotype observed in the human patient but displayed a mild rachitic tooth phenotype in comparison with that in the Dmp1-null mice, suggesting that the DI III–like phenotype may be due to an as-yet-undetermined acquired gene modifier. The mechanism studies showed that the mutant fragment maintains partial function of DMP1 such as stimulating MAP kinase signaling in vitro. Last, the in vitro and in vivo data support a role of odontoblasts in the control of fibroblast growth factor 23 (FGF-23) regulation during early postnatal development, although this regulation on Pi homeostasis is likely limited. © 2010 American Society for Bone and Mineral Research. PMID:20499360

  18. In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis

    PubMed Central

    Génin, Emmanuelle; Férec, Claude

    2017-01-01

    Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance. PMID:28339466

  19. In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis.

    PubMed

    Trouvé, Pascal; Génin, Emmanuelle; Férec, Claude

    2017-01-01

    Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance.

  20. Genetically modified mouse models addressing gonadotropin function.

    PubMed

    Ratner, Laura D; Rulli, Susana B; Huhtaniemi, Ilpo T

    2014-03-01

    The development of genetically modified animals has been useful to understand the mechanisms involved in the regulation of the gonadotropin function. It is well known that alterations in the secretion of a single hormone is capable of producing profound reproductive abnormalities. Human chorionic gonadotropin (hCG) is a glycoprotein hormone normally secreted by the human placenta, and structurally and functionally it is related to pituitary LH. LH and hCG bind to the same LH/hCG receptor, and hCG is often used as an analog of LH to boost gonadotropin action. There are many physiological and pathological conditions where LH/hCG levels and actions are elevated. In order to understand how elevated LH/hCG levels may impact on the hypothalamic-pituitary-gonadal axis we have developed a transgenic mouse model with chronic hCG hypersecretion. Female mice develop many gonadal and extragonadal phenotypes including obesity, infertility, hyperprolactinemia, and pituitary and mammary gland tumors. This article summarizes recent findings on the mechanisms involved in pituitary gland tumorigenesis and hyperprolactinemia in the female mice hypersecreting hCG, in particular the relationship of progesterone with the hyperprolactinemic condition of the model. In addition, we describe the role of hyperprolactinemia as the main cause of infertility and the phenotypic abnormalities in these mice, and the use of dopamine agonists bromocriptine and cabergoline to normalize these conditions. Copyright © 2014 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  1. Plants having modified response to ethylene by transformation with an ETR nucleic acid

    DOEpatents

    Meyerowitz, Elliott M.; Chang, Caren; Bleecker, Anthony B.

    2001-01-01

    The invention includes transformed plants having at least one cell transformed with a modified ETR nucleic acid. Such plants have a phenotype characterized by a decrease in the response of at least one transformed plant cell to ethylene as compared to a plant not containing the transformed plant cell. Tissue and/or temporal specificity for expression of the modified ETR nucleic acid is controlled by selecting appropriate expression regulation sequences to target the location and/or time of expression of the transformed nucleic acid. The plants are made by transforming at least one plant cell with an appropriate modified ETR nucleic acid, regenerating plants from one or more of the transformed plant cells and selecting at least one plant having the desired phenotype.

  2. Distinguishing modified gravity models

    SciTech Connect

    Brax, Philippe

    2015-10-01

    Modified gravity models with screening in local environments appear in three different guises: chameleon, K-mouflage and Vainshtein mechanisms. We propose to look for differences between these classes of models by considering cosmological observations at low redshift. In particular, we analyse the redshift dependence of the fine structure constant and the proton to electron mass ratio in each of these scenarios. When the absorption lines belong to unscreened regions of space such as dwarf galaxies, a time variation would be present for chameleons. For both K-mouflage and Vainshtein mechanisms, the cosmological time variation of the scalar field is not suppressed in both unscreened and screened environments, therefore enhancing the variation of constants and their detection prospect. We also consider the time variation of the redshift of distant objects using their spectrocopic velocities. We find that models of the K-mouflage and Vainshtein types have very different spectroscopic velocities as a function of redshift and that their differences with the Λ-CDM template should be within reach of the future ELT-HIRES observations.

  3. [Biotechnology using modified microorganisms].

    PubMed

    Deshayes, A F

    1992-11-01

    Few microorganisms, as compare to their high diversity, are used for human needs. They can produce molecules of interest, process fermentation, protect crops, treat wastes or clean environment. Molecular technics and genetic engineering are new tools offer to geneticists which breed microorganisms for years. Using them, it is now possible, theoretically, to introduce any gene in any organism. Some examples are given concerning genetic modifications in yeasts and lactic acid bacteria to optimize agrofood processes and to improve nutritive and flavour characteristics of fermented products like bread, beer, wine, cheese, meat, vegetable juices... In spite of scientific and industrial interest of the new technologies, limiting factors can explain that genetically modified microorganisms are not routinely used in agrofood yet. First, risks assessment on human health and environment are still in debate, but their is a consensus, within the scientific community, to consider that new characteristics of improved microorganisms are more important than the technics used for their construction. Second, regulations turn out to impose constraints susceptible to discourage technological innovations. At least, the public perception about the new technologies appears, actually, as the major factor to limit their development.

  4. Phenotypic equilibrium as probabilistic convergence in multi-phenotype cell population dynamics

    PubMed Central

    Jiang, Da-Quan; Zhou, Da

    2017-01-01

    We consider the cell population dynamics with n different phenotypes. Both the Markovian branching process model (stochastic model) and the ordinary differential equation (ODE) system model (deterministic model) are presented, and exploited to investigate the dynamics of the phenotypic proportions. We will prove that in both models, these proportions will tend to constants regardless of initial population states (“phenotypic equilibrium”) under weak conditions, which explains the experimental phenomenon in Gupta et al.’s paper. We also prove that Gupta et al.’s explanation is the ODE model under a special assumption. As an application, we will give sufficient and necessary conditions under which the proportion of one phenotype tends to 0 (die out) or 1 (dominate). We also extend our results to non-Markovian cases. PMID:28182672

  5. Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters

    PubMed Central

    Bröer, Stefan; Bailey, Charles G.; Kowalczuk, Sonja; Ng, Cynthia; Vanslambrouck, Jessica M.; Rodgers, Helen; Auray-Blais, Christiane; Cavanaugh, Juleen A.; Bröer, Angelika; Rasko, John E.J.

    2008-01-01

    Iminoglycinuria (IG) is an autosomal recessive abnormality of renal transport of glycine and the imino acids proline and hydroxyproline, but the specific genetic defect(s) have not been determined. Similarly, although the related disorder hyperglycinuria (HG) without iminoaciduria has been attributed to heterozygosity of a putative defective glycine, proline, and hydroxyproline transporter, confirming the underlying genetic defect(s) has been difficult. Here we applied a candidate gene sequencing approach in 7 families first identified through newborn IG screening programs. Both inheritance and functional studies identified the gene encoding the proton amino acid transporter SLC36A2 (PAT2) as the major gene responsible for IG in these families, and its inheritance was consistent with a classical semidominant pattern in which 2 inherited nonfunctional alleles conferred the IG phenotype, while 1 nonfunctional allele was sufficient to confer the HG phenotype. Mutations in SLC36A2 that retained residual transport activity resulted in the IG phenotype when combined with mutations in the gene encoding the imino acid transporter SLC6A20 (IMINO). Additional mutations were identified in the genes encoding the putative glycine transporter SLC6A18 (XT2) and the neutral amino acid transporter SLC6A19 (B0AT1) in families with either IG or HG, suggesting that mutations in the genes encoding these transporters may also contribute to these phenotypes. In summary, although recognized as apparently simple Mendelian disorders, IG and HG exhibit complex molecular explanations depending on a major gene and accompanying modifier genes. PMID:19033659

  6. Is rate of skin wound healing associated with aging or longevity phenotype?

    PubMed

    Yanai, Hagai; Budovsky, Arie; Tacutu, Robi; Fraifeld, Vadim E

    2011-12-01

    Wound healing (WH) is a fundamental biological process. Is it associated with a longevity or aging phenotype? In an attempt to answer this question, we compared the established mouse models with genetically modified life span and also an altered rate of WH in the skin. Our analysis showed that the rate of skin WH in advanced ages (but not in the young animals) may be used as a marker for biological age, i.e., to be indicative of the longevity or aging phenotype. The ability to preserve the rate of skin WH up to an old age appears to be associated with a longevity phenotype, whereas a decline in WH-with an aging phenotype. In the young, this relationship is more complex and might even be inversed. While the aging process is likely to cause wounds to heal slowly, an altered WH rate in younger animals could indicate a different cellular proliferation and/or migration capacity, which is likely to affect other major processes such as the onset and progression of cancer. As a point for future studies on WH and longevity, using only young animals might yield confusing or misleading results, and therefore including older animals in the analysis is encouraged.

  7. Metabolic profiles to define the genome: can we hear the phenotypes?

    PubMed Central

    Griffin, Julian L

    2004-01-01

    There is an increased reliance on genetically modified organisms as a functional genomic tool to elucidate the role of genes and their protein products. Despite this, many models do not express the expected phenotype thought to be associated with the gene or protein. There is thus an increased need to further define the phenotype resultant from a genetic modification to understand how the transcriptional or proteomic network may conspire to alter the expected phenotype. This is best typified by the description of the silent phenotype in genetic manipulations of yeast. High-resolution proton nuclear magnetic resonance ((1)H NMR) spectroscopy provides an ideal mechanism for the profiling of metabolites within biofluids, tissue extracts or, with recent advances, intact tissues. These metabolic datasets can be readily mined using a range of pattern recognition techniques, including hierarchical cluster analysis, principal components analysis, partial least squares and neural networks, with the combined approach being termed metabolomics. This review describes the application of NMR-based metabolomics or metabonomics to genetic and chemical interventions in a number of different species, demonstrating the versatility of such an approach, as well as suggesting how it may be integrated with other "omic" technologies. PMID:15306403

  8. Not in their genes: phenotypic flexibility, behavioural traditions and cultural evolution in wild bonnet macaques.

    PubMed

    Sinha, Anindya

    2005-02-01

    Phenotypic flexibility, or the within-genotype, context-dependent, variation in behaviour expressed by single reproductively mature individuals during their lifetimes, often impart a selective advantage to organisms and profoundly influence their survival and reproduction. Another phenomenon apparently not under direct genetic control is behavioural inheritance whereby higher animals are able to acquire information from the behaviour of others by social learning, and, through their own modified behaviour, transmit such information between individuals and across generations. Behavioural information transfer of this nature thus represents another form of inheritance that operates in many animals in tandem with the more basic genetic system. This paper examines the impact that phenotypic flexibility, behavioural inheritance and socially transmitted cultural traditions may have in shaping the structure and dynamics of a primate society--that of the bonnet macaque (Macaca radiata), a primate species endemic to peninsular India. Three principal issues are considered: the role of phenotypic flexibility in shaping social behaviour, the occurrence of individual behavioural traits leading to the establishment of social traditions, and the appearance of cultural evolution amidst such social traditions. Although more prolonged observations are required, these initial findings suggest that phenotypic plasticity, behavioural inheritance and cultural traditions may be much more widespread among primates than have previously been assumed but may have escaped attention due to a preoccupation with genetic inheritance in zoological thinking.

  9. Phenotype Determines Nanoparticle Uptake by Human Macrophages from Liver and Blood.

    PubMed

    MacParland, Sonya A; Tsoi, Kim M; Ouyang, Ben; Ma, Xue-Zhong; Manuel, Justin; Fawaz, Ali; Ostrowski, Mario A; Alman, Benjamin A; Zilman, Anton; Chan, Warren C W; McGilvray, Ian D

    2017-01-17

    A significant challenge to delivering therapeutic doses of nanoparticles to targeted disease sites is the fact that most nanoparticles become trapped in the liver. Liver-resident macrophages, or Kupffer cells, are key cells in the hepatic sequestration of nanoparticles. However, the precise role that the macrophage phenotype plays in nanoparticle uptake is unknown. Here, we show that the human macrophage phenotype modulates hard nanoparticle uptake. Using gold nanoparticles, we examined uptake by human monocyte-derived macrophages that had been driven to a "regulatory" M2 phenotype or an "inflammatory" M1 phenotype and found that M2-type macrophages preferentially take up nanoparticles, with a clear hierarchy among the subtypes (M2c > M2 > M2a > M2b > M1). We also found that stimuli such as LPS/IFN-γ rather than with more "regulatory" stimuli such as TGF-β/IL-10 reduce per cell macrophage nanoparticle uptake by an average of 40%. Primary human Kupffer cells were found to display heterogeneous expression of M1 and M2 markers, and Kupffer cells expressing higher levels of M2 markers (CD163) take up significantly more nanoparticles than Kupffer cells expressing lower levels of surface CD163. Our results demonstrate that hepatic inflammatory microenvironments should be considered when studying liver sequestration of nanoparticles, and that modifying the hepatic microenvironment might offer a tool for enhancing or decreasing this sequestration. Our findings also suggest that models examining the nanoparticle/macrophage interaction should include studies with primary tissue macrophages.

  10. Phenotypic and evolutionary consequences of social behaviours: interactions among individuals affect direct genetic effects.

    PubMed

    Trubenová, Barbora; Hager, Reinmar

    2012-01-01

    Traditional quantitative genetics assumes that an individual's phenotype is determined by both genetic and environmental factors. For many animals, part of the environment is social and provided by parents and other interacting partners. When expression of genes in social partners affects trait expression in a focal individual, indirect genetic effects occur. In this study, we explore the effects of indirect genetic effects on the magnitude and range of phenotypic values in a focal individual in a multi-member model analyzing three possible classes of interactions between individuals. We show that social interactions may not only cause indirect genetic effects but can also modify direct genetic effects. Furthermore, we demonstrate that both direct and indirect genetic effects substantially alter the range of phenotypic values, particularly when a focal trait can influence its own expression via interactions with traits in other individuals. We derive a function predicting the relative importance of direct versus indirect genetic effects. Our model reveals that both direct and indirect genetic effects can depend to a large extent on both group size and interaction strength, altering group mean phenotype and variance. This may lead to scenarios where between group variation is much higher than within group variation despite similar underlying genetic properties, potentially affecting the level of selection. Our analysis highlights key properties of indirect genetic effects with important consequences for trait evolution, the level of selection and potentially speciation.

  11. Host Genotype and Gut Microbiome Modulate Insulin Secretion and Diet-Induced Metabolic Phenotypes.

    PubMed

    Kreznar, Julia H; Keller, Mark P; Traeger, Lindsay L; Rabaglia, Mary E; Schueler, Kathryn L; Stapleton, Donald S; Zhao, Wen; Vivas, Eugenio I; Yandell, Brian S; Broman, Aimee Teo; Hagenbuch, Bruno; Attie, Alan D; Rey, Federico E

    2017-02-14

    Genetic variation drives phenotypic diversity and influences the predisposition to metabolic disease. Here, we characterize the metabolic phenotypes of eight genetically distinct inbred mouse strains in response to a high-fat/high-sucrose diet. We found significant variation in diabetes-related phenotypes and gut microbiota composition among the different mouse strains in response to the dietary challenge and identified taxa associated with these traits. Follow-up microbiota transplant experiments showed that altering the composition of the gut microbiota modifies strain-specific susceptibility to diet-induced metabolic disease. Animals harboring microbial communities with enhanced capacity for processing dietary sugars and for generating hydrophobic bile acids showed increased susceptibility to metabolic disease. Notably, differences in glucose-stimulated insulin secretion between different mouse strains were partially recapitulated via gut microbiota transfer. Our results suggest that the gut microbiome contributes to the genetic and phenotypic diversity observed among mouse strains and provide a link between the gut microbiome and insulin secretion.

  12. [Genotype/phenotype correlation in autism: genetic models and phenotypic characterization].

    PubMed

    Bonnet-Brilhault, F

    2011-02-01

    Autism spectrum disorders are a class of conditions categorized by communication problems, ritualistic behaviors, and deficits in social behaviors. This class of disorders merges a heterogeneous group of neurodevelopmental disorders regarding some phenotypic and probably physiopathological aspects. Genetic basis is well admitted, however, considering phenotypic and genotypic heterogeneity, correspondences between genotype and phenotype have yet to be established. To better identify such correspondences, genetic models have to be identified and phenotypic markers have to be characterized. Recent insights show that a variety of genetic mechanisms may be involved in autism spectrum disorders, i.e. single gene disorders, copy number variations and polygenic mechanisms. These current genetic models are described. Regarding clinical aspects, several approaches can be used in genetic studies. Nosographical approach, especially with the concept of autism spectrum disorders, merges a large group of disorders with clinical heterogeneity and may fail to identify clear genotype/phenotype correlations. Dimensional approach referred in genetic studies to the notion of "Broad Autism Phenotype" related to a constellation of language, personality, and social-behavioral features present in relatives that mirror the symptom domains of autism, but are much milder in expression. Studies of this broad autism phenotype may provide a potentially important complementary approach for detecting the genes involved in these domains. However, control population used in those studies need to be well characterized too. Identification of endophenotypes seems to offer more promising results. Endophenotypes, which are supposed to be more proximal markers of gene action in the same biological pathway, linking genes and complex clinical symptoms, are thought to be less genetically complex than the broader disease phenotype, indexing a limited aspect of genetic risk for the disorder as a whole. However

  13. Belief propagation in genotype-phenotype networks.

    PubMed

    Moharil, Janhavi; May, Paul; Gaile, Daniel P; Blair, Rachael Hageman

    2016-03-01

    Graphical models have proven to be a valuable tool for connecting genotypes and phenotypes. Structural learning of phenotype-genotype networks has received considerable attention in the post-genome era. In recent years, a dozen different methods have emerged for network inference, which leverage natural variation that arises in certain genetic populations. The structure of the network itself can be used to form hypotheses based on the inferred direct and indirect network relationships, but represents a premature endpoint to the graphical analyses. In this work, we extend this endpoint. We examine the unexplored problem of perturbing a given network structure, and quantifying the system-wide effects on the network in a node-wise manner. The perturbation is achieved through the setting of values of phenotype node(s), which may reflect an inhibition or activation, and propagating this information through the entire network. We leverage belief propagation methods in Conditional Gaussian Bayesian Networks (CG-BNs), in order to absorb and propagate phenotypic evidence through the network. We show that the modeling assumptions adopted for genotype-phenotype networks represent an important sub-class of CG-BNs, which possess properties that ensure exact inference in the propagation scheme. The system-wide effects of the perturbation are quantified in a node-wise manner through the comparison of perturbed and unperturbed marginal distributions using a symmetric Kullback-Leibler divergence. Applications to kidney and skin cancer expression quantitative trait loci (eQTL) data from different mus musculus populations are presented. System-wide effects in the network were predicted and visualized across a spectrum of evidence. Sub-pathways and regions of the network responded in concert, suggesting co-regulation and coordination throughout the network in response to phenotypic changes. We demonstrate how these predicted system-wide effects can be examined in connection with

  14. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data.

    PubMed

    Köhler, Sebastian; Doelken, Sandra C; Mungall, Christopher J; Bauer, Sebastian; Firth, Helen V; Bailleul-Forestier, Isabelle; Black, Graeme C M; Brown, Danielle L; Brudno, Michael; Campbell, Jennifer; FitzPatrick, David R; Eppig, Janan T; Jackson, Andrew P; Freson, Kathleen; Girdea, Marta; Helbig, Ingo; Hurst, Jane A; Jähn, Johanna; Jackson, Laird G; Kelly, Anne M; Ledbetter, David H; Mansour, Sahar; Martin, Christa L; Moss, Celia; Mumford, Andrew; Ouwehand, Willem H; Park, Soo-Mi; Riggs, Erin Rooney; Scott, Richard H; Sisodiya, Sanjay; Van Vooren, Steven; Wapner, Ronald J; Wilkie, Andrew O M; Wright, Caroline F; Vulto-van Silfhout, Anneke T; de Leeuw, Nicole; de Vries, Bert B A; Washingthon, Nicole L; Smith, Cynthia L; Westerfield, Monte; Schofield, Paul; Ruef, Barbara J; Gkoutos, Georgios V; Haendel, Melissa; Smedley, Damian; Lewis, Suzanna E; Robinson, Peter N

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.

  15. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

    PubMed Central

    Köhler, Sebastian; Doelken, Sandra C.; Mungall, Christopher J.; Bauer, Sebastian; Firth, Helen V.; Bailleul-Forestier, Isabelle; Black, Graeme C. M.; Brown, Danielle L.; Brudno, Michael; Campbell, Jennifer; FitzPatrick, David R.; Eppig, Janan T.; Jackson, Andrew P.; Freson, Kathleen; Girdea, Marta; Helbig, Ingo; Hurst, Jane A.; Jähn, Johanna; Jackson, Laird G.; Kelly, Anne M.; Ledbetter, David H.; Mansour, Sahar; Martin, Christa L.; Moss, Celia; Mumford, Andrew; Ouwehand, Willem H.; Park, Soo-Mi; Riggs, Erin Rooney; Scott, Richard H.; Sisodiya, Sanjay; Vooren, Steven Van; Wapner, Ronald J.; Wilkie, Andrew O. M.; Wright, Caroline F.; Vulto-van Silfhout, Anneke T.; de Leeuw, Nicole; de Vries, Bert B. A.; Washingthon, Nicole L.; Smith, Cynthia L.; Westerfield, Monte; Schofield, Paul; Ruef, Barbara J.; Gkoutos, Georgios V.; Haendel, Melissa; Smedley, Damian; Lewis, Suzanna E.; Robinson, Peter N.

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online. PMID:24217912

  16. On a modified electrodynamics.

    PubMed

    Reiss, H R

    2012-09-01

    A modification of electrodynamics is proposed, motivated by previously unremarked paradoxes that can occur in the standard formulation. It is shown by specific examples that gauge transformations exist that radically alter the nature of a problem, even while maintaining the values of many measurable quantities. In one example, a system with energy conservation is transformed to a system where energy is not conserved. The second example possesses a ponderomotive potential in one gauge, but this important measurable quantity does not appear in the gauge-transformed system. A resolution of the paradoxes comes from noting that the change in total action arising from the interaction term in the Lagrangian density cannot always be neglected, contrary to the usual assumption. The problem arises from the information lost by employing an adiabatic cutoff of the field. This is not necessary. Its replacement by a requirement that the total action should not change with a gauge transformation amounts to a supplementary condition for gauge invariance that can be employed to preserve the physical character of the problem. It is shown that the adiabatic cutoff procedure can also be eliminated in the construction of quantum transition amplitudes, thus retaining consistency between the way in which asymptotic conditions are applied in electrodynamics and in quantum mechanics. The 'gauge-invariant electrodynamics' of Schwinger is shown to depend on an ansatz equivalent to the condition found here for maintenance of the ponderomotive potential in a gauge transformation. Among the altered viewpoints required by the modified electrodynamics, in addition to the rejection of the adiabatic cutoff, is the recognition that the electric and magnetic fields do not completely determine a physical problem, and that the electromagnetic potentials supply additional information that is required for completeness of electrodynamics.

  17. On a modified electrodynamics

    PubMed Central

    Reiss, H.R.

    2012-01-01

    A modification of electrodynamics is proposed, motivated by previously unremarked paradoxes that can occur in the standard formulation. It is shown by specific examples that gauge transformations exist that radically alter the nature of a problem, even while maintaining the values of many measurable quantities. In one example, a system with energy conservation is transformed to a system where energy is not conserved. The second example possesses a ponderomotive potential in one gauge, but this important measurable quantity does not appear in the gauge-transformed system. A resolution of the paradoxes comes from noting that the change in total action arising from the interaction term in the Lagrangian density cannot always be neglected, contrary to the usual assumption. The problem arises from the information lost by employing an adiabatic cutoff of the field. This is not necessary. Its replacement by a requirement that the total action should not change with a gauge transformation amounts to a supplementary condition for gauge invariance that can be employed to preserve the physical character of the problem. It is shown that the adiabatic cutoff procedure can also be eliminated in the construction of quantum transition amplitudes, thus retaining consistency between the way in which asymptotic conditions are applied in electrodynamics and in quantum mechanics. The ‘gauge-invariant electrodynamics’ of Schwinger is shown to depend on an ansatz equivalent to the condition found here for maintenance of the ponderomotive potential in a gauge transformation. Among the altered viewpoints required by the modified electrodynamics, in addition to the rejection of the adiabatic cutoff, is the recognition that the electric and magnetic fields do not completely determine a physical problem, and that the electromagnetic potentials supply additional information that is required for completeness of electrodynamics. PMID:23105173

  18. Epigenetic modulators promote mesenchymal stem cell phenotype switches.

    PubMed

    Alexanian, Arshak R

    2015-07-01

    Discoveries in recent years have suggested that some tissue specific adult stem cells in mammals might have the ability to differentiate into cell types from different germ layers. This phenomenon has been referred to as stem cell transdifferentiation or plasticity. Despite controversy, the current consensus holds that transdifferentiation does occur in mammals, but only within a limited range. Understanding the mechanisms that underlie the switches in phenotype and development of the methods that will promote such type of conversions can open up endless possibilities for regenerative medicine. Epigenetic control contributes to various processes that lead to cellular plasticity and DNA and histone covalent modifications play a key role in these processes. Recently, we have been able to convert human mesenchymal stem cells (hMSCs) into neural-like cells by exposing cells to epigenetic modifiers and neural inducing factors. The goal of this study was to investigate the stability and plasticity of these transdifferentiated cells. To this end, neurally induced MSCs (NI-hMSCs) were exposed to adipocyte inducing factors. Grown for 24-48 h in fat induction media NI-hMSCs reversed their morphology into fibroblast-like cells and regained their proliferative properties. After 3 weeks approximately 6% of hMSCs differentiated into multilocular or plurivacuolar adipocyte cells that demonstrated by Oil Red O staining. Re-exposure of these cultures or the purified adipocytes to neural induction medium induced the cells to re-differentiate into neuronal-like cells. These data suggest that cell plasticity can be manipulated by the combination of small molecule modulators of chromatin modifying enzymes and specific cell signaling pathways.

  19. Intein-modified enzymes, their production and industrial applications

    DOEpatents

    Apgar, James; Lessard, Philip; Raab, Michael R.; Shen, Binzhang; Lazar, Gabor; de la Vega, Humberto

    2016-10-11

    A method of predicting an intein insertion site in a protein that will lead to a switching phenotype is provided. The method includes identifying a plurality of C/T/S sites within the protein; selecting from the plurality of C/T/S/ sites those that are ranked 0.75 or higher by a support vector machine, within ten angstroms of the active site of the protein, and at or near a loop-.beta.-sheet junction or a loop-.alpha.-helix junction. A method of controlling protein activity and hosts including proteins with controlled activity are also provided. Also, intein modified proteins and plants containing intein modified proteins are provided.

  20. Genetically modified foods and allergy.

    PubMed

    Lee, T H; Ho, H K; Leung, T F

    2017-06-01

    2015 marked the 25th anniversary of the commercial use and availability of genetically modified crops. The area of planted biotech crops cultivated globally occupies a cumulative two billion hectares, equivalent to twice the land size of China or the United States. Foods derived from genetically modified plants are widely consumed in many countries and genetically modified soybean protein is extensively used in processed foods throughout the industrialised countries. Genetically modified food technology offers a possible solution to meet current and future challenges in food and medicine. Yet there is a strong undercurrent of anxiety that genetically modified foods are unsafe for human consumption, sometimes fuelled by criticisms based on little or no firm evidence. This has resulted in some countries turning away food destined for famine relief because of the perceived health risks of genetically modified foods. The major concerns include their possible allergenicity and toxicity despite the vigorous testing of genetically modified foods prior to marketing approval. It is imperative that scientists engage the public in a constructive evidence-based dialogue to address these concerns. At the same time, improved validated ways to test the safety of new foods should be developed. A post-launch strategy should be established routinely to allay concerns. Mandatory labelling of genetically modified ingredients should be adopted for the sake of transparency. Such ingredient listing and information facilitate tracing and recall if required.

  1. Nominal Modifiers in Mandarin Chinese.

    ERIC Educational Resources Information Center

    Hou, John Y.

    In the surface structure of Chinese nominal modifiers (quantifiers, determiners, adjectives, measure phrase, relative clause, etc.) may occur either before or after a modified noun. In most of the transformational studies of Chinese syntax (e.g. Cheng 1966; Hashimoto 1966; Mei 1972; Tai 1973; Teng 1974), it has been assumed that such NP's have the…

  2. Phenotypic variation among brothers with the McLeod neuroacanthocytosis syndrome.

    PubMed

    Walker, Ruth H; Jung, Hans H; Tison, François; Lee, Soohee; Danek, Adrian

    2007-01-15

    McLeod syndrome is an X-linked multisystem disorder affecting red blood cells, the peripheral and central nervous systems, and skeletal and cardiac muscle. No clear correlations of the clinical findings with the genotype of XK mutations have yet been uncovered. Here, we report the clinical features and progression in 10 affected brothers from 4 families with McLeod syndrome. There is significant variation in clinical presentation within families, including in causes of morbidity and mortality. This phenotypic variation, despite shared mutations, suggests the action of disease-modifying factors that may explain some of the difficulties with genotype-phenotype correlation in McLeod syndrome. (c) 2006 Movement Disorder Society.

  3. Effects of poor hygiene on cytokine phenotypes in children in the tropics.

    PubMed

    Figueiredo, C A; Amorim, L D; Vaca, M; Chico, M E; Campos, A C; Barreto, M L; Cooper, P J

    2016-01-01

    We describe immune phenotypes (innate and adaptive cytokines) according to environmental exposure using latent class analysis. A total of 310 schoolchildren living in Ecuador were assayed for spontaneous cytokine production as well as mitogen (SEB)-stimulated cytokines in whole blood cultures. We collected data on environmental exposures by questionnaire and on intestinal parasites by examination of stool samples. Latent class analysis (LCA) was used to group children according to their innate (IL-6, IL-8, IL-10 and TNF-α) and adaptive (IL-5, IL-13, IL-17, IFN-γ and IL-10) cytokine profile. We also conducted multiple-group LCA and LCA with covariates to evaluate the effect of predictors on profile membership. We identified both hyporesponsive and Th2-modified immune phenotypes produced by peripheral blood leukocytes (PBLs) that were associated with intestinal worms and birth order, providing insights into how poor hygiene mediates immunologic effects on immune-mediated diseases.

  4. Tuning the range and stability of multiple phenotypic states with coupled positive-negative feedback loops.

    PubMed

    Avendaño, Maier S; Leidy, Chad; Pedraza, Juan M

    2013-01-01

    Positive feedback loops can produce multistability, resulting in different phenotypic states. However, many transcription networks contain counteracting positive and negative feedbacks. Here we explore the dynamics of an interlinked positive and negative feedback motif based on the galactose-uptake control system of Saccharomyces cerevisiae modified to make the strength of each feedback externally controllable. Our results show that although the positive feedback loop determines the range of bistability and the width of the regions where intermediate activation is possible, the transition rates between states are mostly sensitive to the negative feedback strength. Thus, our results suggest that the function of the negative loop in this motif is to allow separate tuning of the range and transition rates between phenotypic states. This could enhance fitness by allowing improved matching of the stochastic switching to the frequency of environmental changes.

  5. A broad phenotypic screen identifies novel phenotypes driven by a single mutant allele in Huntington's disease CAG knock-in mice.

    PubMed

    Hölter, Sabine M; Stromberg, Mary; Kovalenko, Marina; Garrett, Lillian; Glasl, Lisa; Lopez, Edith; Guide, Jolene; Götz, Alexander; Hans, Wolfgang; Becker, Lore; Rathkolb, Birgit; Rozman, Jan; Schrewed, Anja; Klingenspor, Martin; Klopstock, Thomas; Schulz, Holger; Wolf, Eckhard; Wursta, Wolfgang; Gillis, Tammy; Wakimoto, Hiroko; Seidman, Jonathan; MacDonald, Marcy E; Cotman, Susan; Gailus-Durner, Valérie; Fuchs, Helmut; de Angelis, Martin Hrabě; Lee, Jong-Min; Wheeler, Vanessa C

    2013-01-01

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.

  6. A Broad Phenotypic Screen Identifies Novel Phenotypes Driven by a Single Mutant Allele in Huntington’s Disease CAG Knock-In Mice

    PubMed Central

    Kovalenko, Marina; Garrett, Lillian; Glasl, Lisa; Lopez, Edith; Guide, Jolene; Götz, Alexander; Hans, Wolfgang; Becker, Lore; Rathkolb, Birgit; Rozman, Jan; Schrewed, Anja; Klingenspor, Martin; Klopstock, Thomas; Schulz, Holger; Wolf, Eckhard; Wursta, Wolfgang; Gillis, Tammy; Wakimoto, Hiroko; Seidman, Jonathan; MacDonald, Marcy E.; Cotman, Susan; Gailus-Durner, Valérie; Fuchs, Helmut; de Angelis, Martin Hrabě; Lee, Jong-Min; Wheeler, Vanessa C.

    2013-01-01

    Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing. PMID:24278347

  7. Chromosome imbalance, normal phenotype, and imprinting.

    PubMed Central

    Bortotto, L; Piovan, E; Furlan, R; Rivera, H; Zuffardi, O

    1990-01-01

    A duplication of the sub-bands 1q42.11 and 1q42.12 was found in a boy and his mother. The proband has short stature (around the 10th centile) but a normal phenotype and psychomotor development. His mother is also asymptomatic. We found 30 published cases of normal subjects with an imbalance of autosomal euchromatic material. In these cases the imbalance involved either only one G positive band or a G positive and a G negative band. Thus the absence of a phenotypic effect cannot always be ascribed to the deficiency in the G positive bands of coding DNA. Moreover, in some cases, the method of transmission of the chromosome abnormality was such that an imprinting effect could be postulated. Images PMID:2231652

  8. Multiple Phenotypic Changes Define Neutrophil Priming.

    PubMed

    Miralda, Irina; Uriarte, Silvia M; McLeish, Kenneth R

    2017-01-01

    Exposure to pro-inflammatory cytokines, chemokines, mitochondrial contents, and bacterial and viral products induces neutrophils to transition from a basal state into a primed one, which is currently defined as an enhanced response to activating stimuli. Although, typically associated with enhanced generation of reactive oxygen species (ROS) by the NADPH oxidase, primed neutrophils show enhanced responsiveness of exocytosis, NET formation, and chemotaxis. Phenotypic changes associated with priming also include activation of a subset of functions, including adhesion, transcription, metabolism, and rate of apoptosis. This review summarizes the breadth of phenotypic changes associated with priming and reviews current knowledge of the molecular mechanisms behind those changes. We conclude that the current definition of priming is too restrictive. Priming represents a combination of enhanced responsiveness and activated functions that regulate both adaptive and innate immune responses.

  9. Advances in Human B Cell Phenotypic Profiling

    PubMed Central

    Kaminski, Denise A.; Wei, Chungwen; Qian, Yu; Rosenberg, Alexander F.; Sanz, Ignacio

    2012-01-01

    To advance our understanding and treatment of disease, research immunologists have been called-upon to place more centralized emphasis on impactful human studies. Such endeavors will inevitably require large-scale study execution and data management regulation (“Big Biology”), necessitating standardized and reliable metrics of immune status and function. A well-known example setting this large-scale effort in-motion is identifying correlations between eventual disease outcome and T lymphocyte phenotype in large HIV-patient cohorts using multiparameter flow cytometry. However, infection, immunodeficiency, and autoimmunity are also characterized by correlative and functional contributions of B lymphocytes, which to-date have received much less attention in the human Big Biology enterprise. Here, we review progress in human B cell phenotyping, analysis, and bioinformatics tools that constitute valuable resources for the B cell research community to effectively join in this effort. PMID:23087687

  10. Animal biometrics: quantifying and detecting phenotypic appearance.

    PubMed

    Kühl, Hjalmar S; Burghardt, Tilo

    2013-07-01

    Animal biometrics is an emerging field that develops quantified approaches for representing and detecting the phenotypic appearance of species, individuals, behaviors, and morphological traits. It operates at the intersection between pattern recognition, ecology, and information sciences, producing computerized systems for phenotypic measurement and interpretation. Animal biometrics can benefit a wide range of disciplines, including biogeography, population ecology, and behavioral research. Currently, real-world applications are gaining momentum, augmenting the quantity and quality of ecological data collection and processing. However, to advance animal biometrics will require integration of methodologies among the scientific disciplines involved. Such efforts will be worthwhile because the great potential of this approach rests with the formal abstraction of phenomics, to create tractable interfaces between different organizational levels of life.

  11. Trisomy 4 mosaicism: Delineation of the phenotype.

    PubMed

    Bouman, Arjan; van der Kevie-Kersemaekers, Anne-Marie; Huijsdens-van Amsterdam, Karin; Dahhan, Nordin; Knegt, Lia; Vansenne, Fleur; Cobben, Jan Maarten

    2016-04-01

    Trisomy 4 mosaicism in liveborns is very rare. We describe a 17-month-old girl with trisomy 4 mosaicism. Clinical findings in this patient are compared to previously reported patients. Based on the few descriptions available in the literature the common phenotype of trisomy 4 mosaicism seems to consist of IUGR, low birth weight/length/OFC, congenital heart defects, characteristic thumb anomalies (aplasia/hypoplasia), skin abnormalities (hypo-/hyperpigmentation), several dysmorphic features, and likely some degree of intellectual disability. When trisomy 4 mosaicism is suspected clinicians should be aware that a normal karyotype in lymphocytes does not exclude mosaicism for trisomy 4. This report contributes to a further delineation of the phenotype associated with trisomy 4 mosaicism.

  12. New genes as drivers of phenotypic evolution

    PubMed Central

    Chen, Sidi; Krinsky, Benjamin H.; Long, Manyuan

    2014-01-01

    During the course of evolution, genomes acquire novel genetic elements as sources of functional and phenotypic diversity, including new genes that originated in recent evolution. In the past few years, substantial progress has been made in understanding the evolution and phenotypic effects of new genes. In particular, an emerging picture is that new genes, despite being present in the genomes of only a subset of species, can rapidly evolve indispensable roles in fundamental biological processes, including development, reproduction, brain function and behaviour. The molecular underpinnings of how new genes can develop these roles are starting to be characterized. These recent discoveries yield fresh insights into our broad understanding of biological diversity at refined resolution. PMID:23949544

  13. Phenotypic Signatures Arising from Unbalanced Bacterial Growth

    PubMed Central

    Tan, Cheemeng; Smith, Robert Phillip; Tsai, Ming-Chi; Schwartz, Russell; You, Lingchong

    2014-01-01

    Fluctuations in the growth rate of a bacterial culture during unbalanced growth are generally considered undesirable in quantitative studies of bacterial physiology. Under well-controlled experimental conditions, however, these fluctuations are not random but instead reflect the interplay between intra-cellular networks underlying bacterial growth and the growth environment. Therefore, these fluctuations could be considered quantitative phenotypes of the bacteria under a specific growth condition. Here, we present a method to identify “phenotypic signatures” by time-frequency analysis of unbalanced growth curves measured with high temporal resolution. The signatures are then applied to differentiate amongst different bacterial strains or the same strain under different growth conditions, and to identify the essential architecture of the gene network underlying the observed growth dynamics. Our method has implications for both basic understanding of bacterial physiology and for the classification of bacterial strains. PMID:25101949

  14. Evolution of environmental cues for phenotypic plasticity.

    PubMed

    Chevin, Luis-Miguel; Lande, Russell

    2015-10-01

    Phenotypically plastic characters may respond to multiple variables in their environment, but the evolutionary consequences of this phenomenon have rarely been addressed theoretically. We model the evolution of linear reaction norms in response to several correlated environmental variables, in a population undergoing stationary environmental fluctuations. At evolutionary equilibrium, the linear combination of environmental variables that acts as a developmental cue for the plastic trait is the multivariate best linear predictor of changes in the optimum. However, the reaction norm with respect to any single environmental variable may exhibit nonintuitive patterns. Apparently maladaptive, or hyperadaptive plasticity can evolve with respect to single environmental variables, and costs of plasticity may increase, rather than reduce, plasticity in response to some variables. We also find conditions for the evolution of an indirect environmental indicator that affects expression of a plastic phenotype, despite not influencing natural selection on it.

  15. New genes as drivers of phenotypic evolution.

    PubMed

    Chen, Sidi; Krinsky, Benjamin H; Long, Manyuan

    2013-09-01

    During the course of evolution, genomes acquire novel genetic elements as sources of functional and phenotypic diversity, including new genes that originated in recent evolution. In the past few years, substantial progress has been made in understanding the evolution and phenotypic effects of new genes. In particular, an emerging picture is that new genes, despite being present in the genomes of only a subset of species, can rapidly evolve indispensable roles in fundamental biological processes, including development, reproduction, brain function and behaviour. The molecular underpinnings of how new genes can develop these roles are starting to be characterized. These recent discoveries yield fresh insights into our broad understanding of biological diversity at refined resolution.

  16. Causal Phenotype Discovery via Deep Networks

    PubMed Central

    Kale, David C.; Che, Zhengping; Bahadori, Mohammad Taha; Li, Wenzhe; Liu, Yan; Wetzel, Randall

    2015-01-01

    The rapid growth of digital health databases has attracted many researchers interested in using modern computational methods to discover and model patterns of health and illness in a research program known as computational phenotyping. Much of the work in this area has focused on traditional statistical learning paradigms, such as classification, prediction, clustering, pattern mining. In this paper, we propose a related but different paradigm called causal phenotype discovery, which aims to discover latent representations of illness that are causally predictive. We illustrate this idea with a two-stage framework that combines the latent representation learning power of deep neural networks with state-of-the-art tools from causal inference. We apply this framework to two large ICU time series data sets and show that it can learn features that are predictively useful, that capture complex physiologic patterns associated with critical illnesses, and that are potentially more clinically meaningful than manually designed features. PMID:26958203

  17. The phenotype range of achondrogenesis 1A.

    PubMed

    Grigelioniene, Giedre; Geiberger, Stefan; Papadogiannakis, Nikos; Mäkitie, Outi; Nishimura, Gen; Nordgren, Ann; Conner, Peter

    2013-10-01

    Achondrogenesis 1A (ACG1A; OMIM 200600) is an autosomal recessive perinatally lethal skeletal dysplasia comprising intrauterine growth failure, micromelia, minor facial anomalies, deficient ossification of the skull, absent or extremely defective spinal ossification, short beaded ribs, and short deformed long bones with a stellate appearance. ACG1A is caused by mutations in the TRIP11 gene, resulting in deficiency of the Golgi microtubule associated protein 210. In this study we describe dizygotic twins with a clinical and radiological phenotype of ACG1A who were homozygous for a novel nonsense mutation in the TRIP11 gene. In addition, another patient with a milder manifestation, not readily distinguishable from those of other lethal skeletal dysplasias, was found to be a compound heterozygote for a nonsense mutation and a deletion of the 3' end of the TRIP11 gene. We conclude that mutations of the TRIP11 gene may encompass a wider phenotypic range than previously recognized.

  18. How epigenomics brings phenotype into being.

    PubMed

    Martín-Subero, Jose Ignacio

    2011-09-01

    After sequencing the human genome, it has become clear that genetic information alone is not sufficient to understand phenotypic manifestations. The way the DNA code is translated into function depends not only on its sequence but also on the interaction with environmental factors. It is in this intersection where the science of epigenetics plays a crucial role. Epigenetic mechanisms like DNA methylation and histone modifications are essential for multiple physiological processes like development, establishment of tissue identity, imprinting, X-chromosome inactivation, chromosomal stability and gene transcription regulation. Additionally, environmental factors like nutrition or maternal behavior in early childhood are able to induce epigenetic changes. This short review aims at summarizing the role of epigenetics in multiple aspects of biology and medicine, including development, cancer, non-tumoral diseases, environmentally induced phenotypic changes, and also in inheritance and evolution.

  19. Multiple Phenotypic Changes Define Neutrophil Priming

    PubMed Central

    Miralda, Irina; Uriarte, Silvia M.; McLeish, Kenneth R.

    2017-01-01

    Exposure to pro-inflammatory cytokines, chemokines, mitochondrial contents, and bacterial and viral products induces neutrophils to transition from a basal state into a primed one, which is currently defined as an enhanced response to activating stimuli. Although, typically associated with enhanced generation of reactive oxygen species (ROS) by the NADPH oxidase, primed neutrophils show enhanced responsiveness of exocytosis, NET formation, and chemotaxis. Phenotypic changes associated with priming also include activation of a subset of functions, including adhesion, transcription, metabolism, and rate of apoptosis. This review summarizes the breadth of phenotypic changes associated with priming and reviews current knowledge of the molecular mechanisms behind those changes. We conclude that the current definition of priming is too restrictive. Priming represents a combination of enhanced responsiveness and activated functions that regulate both adaptive and innate immune responses. PMID:28611952

  20. [Research progress of epigenetic transgenerational phenotype].

    PubMed

    Kexue, Ma; Keshi, Ma; Xingzi, Xi

    2014-05-01

    The epigenome undergoes a reprogramming process during gametogenesis and early embryogenesis. Therefore, it is believed that epigenetic information cannot be transmitted across generations. However, the occurrence of epigenetic transgenerational phenotype suggests that certain epigenetic marks may escape reprogramming. Although the existence of such a mode of inheritance has been controversial, there is increasing evidence that epigenetic memory does occur in mammals. Due to the reversibility of epigenetic modification, the epigenome is easily changed by a variety of environ-mental factors, such as chemicals, nutrition and behaviour. Therefore, it provides a potential mechanism for the transgenerational transmission of the impact of environmental factors. The purpose of this review is to introduce the concept of epi-genetic transgenerational phenotype, to discuss the epigenetic reprogramming and the molecular mechanism of epigenetic transgenerational transmission, and to list some environmental factors that are associated with epigenetic transgenerational diseases.

  1. Modified Gravity and Coupled Quintessence

    NASA Astrophysics Data System (ADS)

    Wetterich, Christof

    The distinction between modified gravity and quintessence or dynamical dark energy is difficult. Many models of modified gravity are equivalent to models of coupled quintessence by virtue of variable transformations. This makes an observational differentiation between modified gravity and dark energy very hard. For example, the additional scalar degree of freedom in f(R)-gravity or non-local gravity can be interpreted as the cosmon of quintessence. Nevertheless, modified gravity can shed light on questions of interpretation, naturalness and simplicity. We present a simple model where gravity is modified by a field dependent Planck mass. It leads to a universe with a cold and slow beginning. This cosmology can be continued to the infinite past such that no big bang singularity occurs. All observables can be described equivalently in a hot big bang picture with inflation and early dark energy.

  2. Phenotyping maize for adaptation to drought

    PubMed Central

    Araus, Jose L.; Serret, María D.; Edmeades, Gregory O.

    2012-01-01

    The need of a better adaptation of crops to drought is an issue of increasing urgency. However, enhancing the tolerance of maize has, therefore, proved to be somewhat elusive in terms of plant breeding. In that context, proper phenotyping remains as one of the main factors limiting breeding advance. Topics covered by this review include the conceptual framework for identifying secondary traits associated with yield response to drought and how to measure these secondary traits in practice. PMID:22934056

  3. Genomic Analysis of the Opi− Phenotype

    PubMed Central

    Hancock, Leandria C.; Behta, Ryan P.; Lopes, John M.

    2006-01-01

    Most of the phospholipid biosynthetic genes of Saccharomyces cerevisiae are coordinately regulated in response to inositol and choline. Inositol affects the intracellular levels of phosphatidic acid (PA). Opi1p is a repressor of the phospholipid biosynthetic genes and specifically binds PA in the endoplasmic reticulum. In the presence of inositol, PA levels decrease, releasing Opi1p into the nucleus where it represses transcription. The opi1 mutant overproduces and excretes inositol into the growth medium in the absence of inositol and choline (Opi− phenotype). To better understand the mechanism of Opi1p repression, the viable yeast deletion set was screened to identify Opi− mutants. In total, 89 Opi− mutants were identified, of which 7 were previously known to have the Opi− phenotype. The Opi− mutant collection included genes with roles in phospholipid biosynthesis, transcription, protein processing/synthesis, and protein trafficking. Included in this set were all nonessential components of the NuA4 HAT complex and six proteins in the Rpd3p–Sin3p HDAC complex. It has previously been shown that defects in phosphatidylcholine synthesis (cho2 and opi3) yield the Opi− phenotype because of a buildup of PA. However, in this case the Opi− phenotype is conditional because PA can be shuttled through a salvage pathway (Kennedy pathway) by adding choline to the growth medium. Seven new mutants present in the Opi− collection (fun26, kex1, nup84, tps1, mrpl38, mrpl49, and opi10/yol032w) were also suppressed by choline, suggesting that these affect PC synthesis. Regulation in response to inositol is also coordinated with the unfolded protein response (UPR). Consistent with this, several Opi− mutants were found to affect the UPR (yhi9, ede1, and vps74). PMID:16582425

  4. Asthma phenotypes in inner-city children.

    PubMed

    Zoratti, Edward M; Krouse, Rebecca Z; Babineau, Denise C; Pongracic, Jacqueline A; O'Connor, George T; Wood, Robert A; Khurana Hershey, Gurjit K; Kercsmar, Carolyn M; Gruchalla, Rebecca S; Kattan, Meyer; Teach, Stephen J; Sigelman, Steven M; Gergen, Peter J; Togias, Alkis; Visness, Cynthia M; Busse, William W; Liu, Andrew H

    2016-10-01

    Children with asthma in low-income urban areas have high morbidity. Phenotypic analysis in these children is lacking, but may identify characteristics to inform successful tailored management approaches. We sought to identify distinct asthma phenotypes among inner-city children receiving guidelines-based management. Nine inner-city asthma consortium centers enrolled 717 children aged 6 to 17 years. Data were collected at baseline and prospectively every 2 months for 1 year. Participants' asthma and rhinitis were optimally managed by study physicians on the basis of guidelines. Cluster analysis using 50 baseline and 12 longitudinal variables was performed in 616 participants completing 4 or more follow-up visits. Five clusters (designated A through E) were distinguished by indicators of asthma and rhinitis severity, pulmonary physiology, allergy (sensitization and total serum IgE), and allergic inflammation. In comparison to other clusters, cluster A was distinguished by lower allergy/inflammation, minimally symptomatic asthma and rhinitis, and normal pulmonary physiology. Cluster B had highly symptomatic asthma despite high step-level treatment, lower allergy and inflammation, and mildly altered pulmonary physiology. Cluster C had minimally symptomatic asthma and rhinitis, intermediate allergy and inflammation, and mildly impaired pulmonary physiology. Clusters D and E exhibited progressively higher asthma and rhinitis symptoms and allergy/inflammation. Cluster E had the most symptomatic asthma while receiving high step-level treatment and had the highest total serum IgE level (median, 733 kU/L), blood eosinophil count (median, 400 cells/mm(3)), and allergen sensitizations (15 of 22 tested). Allergy distinguishes asthma phenotypes in urban children. Severe asthma often coclusters with highly allergic children. However, a symptomatic phenotype with little allergy or allergic inflammation was identified. Copyright © 2016 American Academy of Allergy, Asthma

  5. Using ontologies to describe mouse phenotypes

    PubMed Central

    Gkoutos, Georgios V; Green, Eain CJ; Mallon, Ann-Marie; Hancock, John M; Davidson, Duncan

    2005-01-01

    The mouse is an important model of human genetic disease. Describing phenotypes of mutant mice in a standard, structured manner that will facilitate data mining is a major challenge for bioinformatics. Here we describe a novel, compositional approach to this problem which combines core ontologies from a variety of sources. This produces a framework with greater flexibility, power and economy than previous approaches. We discuss some of the issues this approach raises. PMID:15642100

  6. Multiple pterygium syndrome: evolution of the phenotype.

    PubMed Central

    Thompson, E M; Donnai, D; Baraitser, M; Hall, C M; Pembrey, M E; Fixsen, J

    1987-01-01

    The clinical features of the multiple pterygium syndrome are multiple congenital joint contractures, multiple skin webs, camptodactyly, vertebral anomalies, short stature, ptosis, and antimongoloid eye slant. We present 11 new cases to show the evolution of the full phenotype from birth and to confirm autosomal recessive inheritance. We emphasise morbidity secondary to respiratory impairment and that conductive deafness may be part of the syndrome. Images PMID:3430553

  7. Molecular basis of weak D phenotypes.

    PubMed

    Wagner, F F; Gassner, C; Müller, T H; Schönitzer, D; Schunter, F; Flegel, W A

    1999-01-01

    A Rhesus D (RhD) red blood cell phenotype with a weak expression of the D antigen occurs in 0.2% to 1% of whites and is called weak D, formerly Du. Red blood cells of weak D phenotype have a much reduced number of presumably complete D antigens that were repeatedly reported to carry the amino acid sequence of the regular RhD protein. The molecular cause of weak D was unknown. To evaluate the molecular cause of weak D, we devised a method to sequence all 10 RHD exons. Among weak D samples, we found a total of 16 different molecular weak D types plus two alleles characteristic of partial D. The amino acid substitutions of weak D types were located in intracellular and transmembraneous protein segments and clustered in four regions of the protein (amino acid positions 2 to 13, around 149, 179 to 225, and 267 to 397). Based on sequencing, polymerase chain reaction-restriction fragment length polymorphism and polymerase chain reaction using sequence-specific priming, none of 161 weak D samples investigated showed a normal RHD exon sequence. We concluded, that in contrast to the current published dogma most, if not all, weak D phenotypes carry altered RhD proteins, suggesting a causal relationship. Our results showed means to specifically detect and to classify weak D. The genotyping of weak D may guide Rhesus negative transfusion policy for such molecular weak D types that were prone to develop anti-D.

  8. Psychiatric phenotypes in chronic traumatic encephalopathy.

    PubMed

    Mahar, Ian; Alosco, Michael L; McKee, Ann C

    2017-09-06

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder involving cognitive, motor, and psychiatrically-relevant symptoms resulting from repetitive head impacts. Psychiatric phenotypes of CTE, including depression and suicidality, present particular challenges for CTE research, given that the diagnosis requires postmortem neuropathological examination. The pathognomonic lesion of CTE is the perivascular accumulation of hyperphosphorylated tau (ptau) protein at the depths of cortical sulci. These lesions are found in the earliest disease stages, and with advancing pathological severity, ptau deposition occurs in widespread brain regions in a four-stage scheme of severity. We review the psychiatric phenotypes of individuals neuropathologically diagnosed with CTE, and suggest that earlier CTE stages hold particular interest for psychiatric CTE research. In the early CTE stages, there is ptau pathology in frontal cortex and axonal loss in the frontal white matter, followed by progressive ptau neurofibrillary degeneration in the amygdala and hippocampus. Neuropathological changes in the frontal and medial temporal lobes may underlie psychiatric phenotypes. Additional insight into the association between CTE pathology and psychiatric sequelae may come from advancements in in vivo methods of CTE detection. Further epidemiological, clinical, and postmortem studies are needed to validate the nature of psychiatric sequelae in CTE. Copyright © 2017. Published by Elsevier Ltd.

  9. The phenotypic spectrum of congenital Zika syndrome.

    PubMed

    Del Campo, Miguel; Feitosa, Ian M L; Ribeiro, Erlane M; Horovitz, Dafne D G; Pessoa, André L S; França, Giovanny V A; García-Alix, Alfredo; Doriqui, Maria J R; Wanderley, Hector Y C; Sanseverino, Maria V T; Neri, João I C F; Pina-Neto, João M; Santos, Emerson S; Verçosa, Islane; Cernach, Mirlene C S P; Medeiros, Paula F V; Kerbage, Saile C; Silva, André A; van der Linden, Vanessa; Martelli, Celina M T; Cordeiro, Marli T; Dhalia, Rafael; Vianna, Fernanda S L; Victora, Cesar G; Cavalcanti, Denise P; Schuler-Faccini, Lavinia

    2017-04-01

    In October 2015, Zika virus (ZIKV) outbreak the Brazilian Ministry of Health (MoH). In response, the Brazilian Society of Medical Genetics established a task force (SBGM-ZETF) to study the phenotype of infants born with microcephaly due to ZIKV congenital infection and delineate the phenotypic spectrum of this newly recognized teratogen. This study was based on the clinical evaluation and neuroimaging of 83 infants born during the period from July, 2015 to March, 2016 and registered by the SBGM-ZETF. All 83 infants had significant findings on neuroimaging consistent with ZIKV congenital infection and 12 had confirmed ZIKV IgM in CSF. A recognizable phenotype of microcephaly, anomalies of the shape of skull and redundancy of the scalp consistent with the Fetal Brain Disruption Sequence (FBDS) was present in 70% of infants, but was most often subtle. In addition, features consistent with fetal immobility, ranging from dimples (30.1%), distal hand/finger contractures (20.5%), and feet malpositions (15.7%), to generalized arthrogryposis (9.6%), were present in these infants. Some cases had milder microcephaly or even a normal head circumference (HC), and other less distinctive findings. The detailed observation of the dysmorphic and neurologic features in these infants provides insight into the mechanisms and timings of the brain disruption and the sequence of developmental anomalies that may occur after prenatal infection by the ZIKV. © 2017 Wiley Periodicals, Inc.

  10. Cluster analysis in phenotyping a Portuguese population.

    PubMed

    Loureiro, C C; Sa-Couto, P; Todo-Bom, A; Bousquet, J

    2015-09-03

    Unbiased cluster analysis using clinical parameters has identified asthma phenotypes. Adding inflammatory biomarkers to this analysis provided a better insight into the disease mechanisms. This approach has not yet been applied to asthmatic Portuguese patients. To identify phenotypes of asthma using cluster analysis in a Portuguese asthmatic population treated in secondary medical care. Consecutive patients with asthma were recruited from the outpatient clinic. Patients were optimally treated according to GINA guidelines and enrolled in the study. Procedures were performed according to a standard evaluation of asthma. Phenotypes were identified by cluster analysis using Ward's clustering method. Of the 72 patients enrolled, 57 had full data and were included for cluster analysis. Distribution was set in 5 clusters described as follows: cluster (C) 1, early onset mild allergic asthma; C2, moderate allergic asthma, with long evolution, female prevalence and mixed inflammation; C3, allergic brittle asthma in young females with early disease onset and no evidence of inflammation; C4, severe asthma in obese females with late disease onset, highly symptomatic despite low Th2 inflammation; C5, severe asthma with chronic airflow obstruction, late disease onset and eosinophilic inflammation. In our study population, the identified clusters were mainly coincident with other larger-scale cluster analysis. Variables such as age at disease onset, obesity, lung function, FeNO (Th2 biomarker) and disease severity were important for cluster distinction. Copyright © 2015. Published by Elsevier España, S.L.U.

  11. Abaxial Greening Phenotype in Hybrid Aspen

    PubMed Central

    Nowak, Julia S.; Douglas, Carl J.; Cronk, Quentin C.B.

    2013-01-01

    The typical angiosperm leaf, as in Arabidopsis, is bifacial consisting of top (adaxial) and bottom (abaxial) surfaces readily distinguishable by the underlying cell type (palisade and spongy mesophyll, respectively). Species of the genus Populus have leaves that are either conventionally bifacial or isobilateral. Isobilateral leaves have palisade mesophyll on the top and bottom of the leaf, making the two sides virtually indistinguishable at the macroscopic level. In poplars this has been termed the “abaxial greening” phenotype. Previous work has implicated ASYMMETRIC LEAVES1 (AS1) as an essential determinant of palisade mesophyll development. This gene, as well as other genes (84 in all) putatively involved in setting the dorsiventral axis of leaves, were investigated in two Populus species: black cottonwood (Populus trichocarpa) and hybrid aspen (P. tremula x tremuloides), representative of each leaf type (bifacial and isobilateral, respectively). Poplar orthologs of AS1 have significantly higher expression in aspen leaf blade and lower in the petiole, suggestive of a potential role in the isobilateral leaf phenotype consistent with the previously observed phenotypes. Furthermore, an ABERRANT TESTA SHAPE (ATS) ortholog has significantly lower expression in aspen leaf tissue, also suggesting a possible contribution of this gene to abaxial greening. PMID:27137376

  12. Phenotypic variability of Cat-Eye syndrome.

    PubMed

    Berends, M J; Tan-Sindhunata, G; Leegte, B; van Essen, A J

    2001-01-01

    Cat-Eye syndrome (CES) is a disorder with a variable pattern of multiple congenital anomalies of which coloboma of the iris and anal atresia are the best known. CES is cytogenetically characterised by the presence of an extra bisatellited marker chromosome, which represents an inverted dicentric duplication of a part of chromosome 22 (inv dup(22)). We report on three CES-patients who carry an inv dup(22) diagnosed with FISH studies. They show remarkable phenotypic variability. The cause of this variability is unknown. Furthermore, we review clinical features of 71 reported patients. Only 41% of the CES-patients have the combination of iris coloboma, anal anomalies and pre-auricular anomalies. Therefore, almost 60% of the CES-patients are hard to recognize by their phenotype alone. Mild to moderate mental retardation was found in 32% (16/50) of the cases. Mental retardation occurs more frequently in male CES-patients. There is no apparent phenotypic difference between mentally retarded and mentally normal CES-patients.

  13. Abaxial Greening Phenotype in Hybrid Aspen.

    PubMed

    Nowak, Julia S; Douglas, Carl J; Cronk, Quentin C B

    2013-04-24

    The typical angiosperm leaf, as in Arabidopsis, is bifacial consisting of top (adaxial) and bottom (abaxial) surfaces readily distinguishable by the underlying cell type (palisade and spongy mesophyll, respectively). Species of the genus Populus have leaves that are either conventionally bifacial or isobilateral. Isobilateral leaves have palisade mesophyll on the top and bottom of the leaf, making the two sides virtually indistinguishable at the macroscopic level. In poplars this has been termed the "abaxial greening" phenotype. Previous work has implicated ASYMMETRIC LEAVES1 (AS1) as an essential determinant of palisade mesophyll development. This gene, as well as other genes (84 in all) putatively involved in setting the dorsiventral axis of leaves, were investigated in two Populus species: black cottonwood (Populus trichocarpa) and hybrid aspen (P. tremula x tremuloides), representative of each leaf type (bifacial and isobilateral, respectively). Poplar orthologs of AS1 have significantly higher expression in aspen leaf blade and lower in the petiole, suggestive of a potential role in the isobilateral leaf phenotype consistent with the previously observed phenotypes. Furthermore, an ABERRANT TESTA SHAPE (ATS) ortholog has significantly lower expression in aspen leaf tissue, also suggesting a possible contribution of this gene to abaxial greening.

  14. Phenotypic Variability in the Coccolithophore Emiliania huxleyi

    PubMed Central

    Lebrato, Mario; Stoll, Heather M.; Iglesias-Rodriguez, Debora; Müller, Marius N.; Méndez-Vicente, Ana; Oschlies, Andreas

    2016-01-01

    Coccolithophores are a vital part of oceanic phytoplankton assemblages that produce organic matter and calcium carbonate (CaCO3) containing traces of other elements (i.e. Sr and Mg). Their associated carbon export from the euphotic zone to the oceans' interior plays a crucial role in CO2 feedback mechanisms and biogeochemical cycles. The coccolithophore Emiliania huxleyi has been widely studied as a model organism to understand physiological, biogeochemical, and ecological processes in marine sciences. Here, we show the inter-strain variability in physiological and biogeochemical traits in 13 strains of E. huxleyi from various biogeographical provinces obtained from culture collections commonly used in the literature. Our results demonstrate that inter-strain genetic variability has greater potential to induce larger phenotypic differences than the phenotypic plasticity of single strains cultured under a broad range of variable environmental conditions. The range of variation found in physiological parameters and calcite Sr:Ca highlights the need to reconsider phenotypic variability in paleoproxy calibrations and model parameterizations to adequately translate findings from single strain laboratory experiments to the real ocean. PMID:27348427

  15. Olfactory phenotypic expression unveils human aging

    PubMed Central

    Mazzatenta, Andrea; Cellerino, Alessandro; Origlia, Nicola; Barloscio, Davide; Sartucci, Ferdinando; Giulio, Camillo Di; Domenici, Luciano

    2016-01-01

    The mechanism of the natural aging of olfaction and its declinein the absence of any overt disease conditions remains unclear. Here, we investigated this mechanism through measurement of one of the parameters of olfactory function, the absolute threshold, in a healthy population from childhood to old age. The absolute olfactory threshold data were collected from an Italian observational study with 622 participants aged 5-105 years. A subjective testing procedure of constant stimuli was used, which was also compared to the ‘staircase’ method, with the calculation of the reliability. The n-butanol stimulus was used as an ascending series of nine molar concentrations that were monitored using an electronic nose. The data were analyzed using nonparametric statistics because of the multimodal distribution. We show that the age-related variations in the absolute olfactory threshold are not continuous; instead, there are multiple olfactory phenotypes. Three distinct age-related phenotypes were defined, termed as ‘juvenile’, ‘mature’ and ‘elder’. The frequency of these three phenotypes depends on age. Our data suggest that the sense of smell does not decrease linearly with aging. Our findings provide the basis for further understanding of olfactory loss as an anticipatory sign of aging and neurodegenerative processes. PMID:27027240

  16. Dietary composition programmes placental phenotype in mice.

    PubMed

    Coan, P M; Vaughan, O R; McCarthy, J; Mactier, C; Burton, G J; Constância, M; Fowden, A L

    2011-07-15

    Dietary composition during pregnancy influences fetal and adult phenotype but its effects on placental phenotype remain largely unknown. Using molecular, morphological and functional analyses, placental nutrient transfer capacity was examined in mice fed isocaloric diets containing 23%, 18% or 9% casein (C) during pregnancy. At day 16, placental transfer of glucose, but not methyl-aminoisobutyric acid (MeAIB), was greater in C18 and C9 than C23 mice, in association with increased placental expression of the glucose transporter Slc2a1/GLUT1, and the growth factor Igf2. At day 19, placental glucose transport remained high in C9 mice while MeAIB transfer was less in C18 than C23 mice, despite greater placental weights in C18 and C9 than C23 mice. Placental System A amino acid transporter expression correlated with protein intake at day 19. Relative growth of transport verses endocrine zones of the placenta was influenced by diet at both ages without changing the absolute volume of the transport surface. Fetal weight was unaffected by diet at day 16 but was reduced in C9 animals by day 19. Morphological and functional adaptations in placental phenotype, therefore, occur to optimise nutrient transfer when dietary composition is varied, even subtly. This has important implications for the intrauterine programming of life expectancy.

  17. Phenotypic Heterogeneity of Monogenic Frontotemporal Dementia

    PubMed Central

    Benussi, Alberto; Padovani, Alessandro; Borroni, Barbara

    2015-01-01

    Frontotemporal dementia (FTD) is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment, and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e., the behavioral variant of FTD, the agrammatic variant of primary progressive aphasia, and the semantic variant of PPA. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD–MND). A family history of dementia is found in 40% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Genetic studies have identified several genes associated with monogenic FTD: microtubule-associated protein tau, progranulin, TAR DNA-binding protein 43, valosin-containing protein, charged multivesicular body protein 2B, fused in sarcoma, and the hexanucleotide repeat expansion in intron 1 of the chromosome 9 open reading frame 72. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation. The objective of the present work is to review and evaluate available literature data in order to highlight recent advances in clinical, biological, and neuroimaging features of monogenic frontotemporal lobar degeneration and try to identify different mechanisms underlying the extreme phenotypic heterogeneity that characterizes this disease. PMID:26388768

  18. Auditory Phenotype of Smith-Magenis Syndrome.

    PubMed

    Brendal, Megan A; King, Kelly A; Zalewski, Christopher K; Finucane, Brenda M; Introne, Wendy; Brewer, Carmen C; Smith, Ann C M

    2017-04-14

    The purpose of this study was to describe the auditory phenotype of a large cohort with Smith-Magenis syndrome (SMS), a rare disorder including physical anomalies, cognitive deficits, sleep disturbances, and a distinct behavioral phenotype. Hearing-related data were collected for 133 individuals with SMS aged 1-49 years. Audiogram data (97 participants) were used for cross-sectional and longitudinal analyses. Caregivers completed a sound sensitivity survey for 98 individuals with SMS and a control group of 24 unaffected siblings. Nearly 80% of participants with interpretable audiograms (n = 76) had hearing loss, which was typically slight to mild in degree. When hearing loss type could be determined (40 participants), sensorineural hearing loss (48.1%) occurred most often in participants aged 11-49 years. Conductive hearing loss (35.2%) was typically observed in children aged 1-10 years. A pattern of fluctuating and progressive hearing decline was documented. Hyperacusis was reported in 73.5% of participants with SMS compared with 12.5% of unaffected siblings. This study offers the most comprehensive characterization of the auditory phenotype of SMS to date. The auditory profile in SMS is multifaceted and can include a previously unreported manifestation of hyperacusis. Routine audiologic surveillance is recommended as part of standard clinical care.

  19. Forbidden phenotypes and the limits of evolution

    PubMed Central

    Vermeij, Geerat J.

    2015-01-01

    Evolution has produced an astonishing array of organisms, but does it have limits and, if so, how are these overcome and how have they changed over the course of time? Here, I review models for describing and explaining existing diversity, and then explore parts of the evolutionary tree that remain empty. In an analysis of 32 forbidden states among eukaryotes, identified in major clades and in the three great habitat realms of water, land and air, I argue that no phenotypic constraint is absolute, that most constraints reflect a limited time–energy budget available to individual organisms, that natural selection is ultimately responsible for both imposing and overcoming constraints, including those normally ascribed to developmental patterns of construction and phylogenetic conservatism, and that increases in adaptive versatility in major clades together with accompanying new ecological opportunities have eliminated many constraints. Phenotypes that were inaccessible during the Early Palaeozoic era have evolved during later periods while very few adaptive states have disappeared. The filling of phenotypic space has proceeded cumulatively in three overlapping phases characterized by diversification at the biochemical, morphological and cultural levels. PMID:26640643

  20. Zebrafish phenotypic screen identifies novel Notch antagonists.

    PubMed

    Velaithan, Vithya; Okuda, Kazuhide Shaun; Ng, Mei Fong; Samat, Norazwana; Leong, Sze Wei; Faudzi, Siti Munirah Mohd; Abas, Faridah; Shaari, Khozirah; Cheong, Sok Ching; Tan, Pei Jean; Patel, Vyomesh

    2017-04-01

    Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27(KIP1). Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.

  1. Topological Phenotypes in Complex Leaf Venation Networks

    NASA Astrophysics Data System (ADS)

    Ronellenfitsch, Henrik; Lasser, Jana; Daly, Douglas; Katifori, Eleni

    2015-03-01

    The leaves of vascular plants contain highly complex venation networks consisting of recursively nested, hierarchically organized loops. We analyze the topology of the venation of leaves from ca. 200 species belonging to ca. 10 families, defining topological metrics that quantify the hierarchical nestedness of the network cycles. We find that most of the venation variability can be described by a two dimensional phenotypic space, where one dimension consists of a linear combination of geometrical metrics and the other dimension of topological, previously uncharacterized metrics. We show how this new topological dimension in the phenotypic space significantly improves identification of leaves from fragments, by calculating a ``leaf fingerprint'' from the topology and geometry of the higher order veins. Further, we present a simple model suggesting that the topological phenotypic traits can be explained by noise effects and variations in the timing of higher order vein developmental events. This work opens the path to (a) new quantitative identification techniques for leaves which go beyond simple geometric traits such as vein density and (b) topological quantification of other planar or almost planar networks such as arterial vaculature in the neocortex and lung tissue.

  2. Signaling in Regulation of Podocyte Phenotypes

    PubMed Central

    Chuang, Peter Y.; He, John C.

    2010-01-01

    The kidney podocyte is a terminally differentiated and highly specialized cell. The function of the glomerular filtration barrier depends on the integrity of the podocyte. Podocyte injury and loss have been observed in human and experimental models of glomerular diseases. Three major podocyte phenotypes have been described in glomerular diseases: effacement, apoptosis, and proliferation. Here, we highlight the signaling cascades that are responsible for the manifestation of these pathologic phenotypes. The integrity of the podocyte foot process is determined by the interaction of nephrin with proteins in the slit diaphragm complex, the regulation of actin dynamics by the Rho family of GTPases, and the transduction of extracellular signals through focal adhesion complexes. Activation of the p38 mitogen-activated protein kinase and transforming growth factor-β 1 causes podocyte apoptosis. Phosphoinositide 3-kinase and its downstream target AKT protect podocytes from apoptosis. In human immunodeficiency virus-associated nephropathy, Src-dependent activation of Stat3, mitogen- activated protein kinase 1,2, and hypoxia-inducible factor 2α is an important driver of podocyte proliferation. At the level of intracellular signaling, it appears that different extracellular signals can converge onto a few pathways to induce changes in the phenotype of podocytes. PMID:19142027

  3. Phenotypic and dermatological manifestations in Down Syndrome.

    PubMed

    Sureshbabu, Rengasamy; Kumari, Rashmi; Ranugha, Subramaniam; Sathyamoorthy, Ramanathan; Udayashankar, Carounanidy; Oudeacoumar, Paquirissamy

    2011-02-15

    Down syndrome (DS) is associated with various uncommon dermatological disorders and increased frequency of some common dermatoses. This study was conducted over a 2-year period to evaluate the frequency of phenotypic and dermatologic manifestations in patients with Down syndrome in south India. The most common phenotypic manifestations that characterize DS include the epicanthic fold (93.7%), brachicephaly (90.6%), flat nasal bridge (84.2%), upward angle of eyes (83.2%), wide gap between first and second toe (81.1%), clinodactyly (77.9%), small nose (74.7%), short broad neck (72.6%), single palmar crease (61.1%), increased nuchal skin fold (61.1%), and fissured tongue (52.6%). The most common dermatological manifestation seen in patients with DS were lichenification, xerosis, dental anomaly, fine, sparse hair, and delayed dentition. Alopecia areata was seen in 9.4 percent of patients and tended to be severe. Infections were relatively less common in our study. Our study has highlighted many phenotypic features and dermatoses, which may help provide better care for patients and counseling to the families.

  4. A population-based approach to define body-composition phenotypes.

    PubMed

    Prado, Carla M M; Siervo, Mario; Mire, Emily; Heymsfield, Steven B; Stephan, Blossom C M; Broyles, Stephanie; Smith, Steven R; Wells, Jonathan C K; Katzmarzyk, Peter T

    2014-06-01

    Abnormal body compositions such as high adiposity (HA), low muscle mass (LM), or a combination of the 2 [high adiposity with low muscle mass (HA-LM)] are relevant phenotypes, but data on their prevalence and impact on health are still limited. This is largely because of a lack of a consensus definition for these conditions. Of particular interest is the HA-LM phenotype, also termed "sarcopenic obesity," which may confer greater health risk. We propose a new approach for operationalizing abnormal body-composition phenotypes in a representative adult population. Whole-body dual-energy X-ray absorptiometry data obtained from the 1999-2004 NHANES were analyzed for 13,236 subjects aged ≥18 y (maximum weight and height of 136 kg and 1.96 m, respectively). Sex- and body mass index (BMI)-specific decile groups of appendicular skeletal muscle index (ASMI; kg/m²) and fat mass index (FMI; kg/m²) were developed. Cutoffs for HA and LM were incorporated into a diagnostic framework to characterize 4 specific body-composition phenotypes-low adiposity with high muscle mass, high adiposity with high muscle mass, low adiposity with low muscle mass, and HA-LM-and a subclassification of the phenotypes into classes I, II, and III. Abnormal phenotypes were prevalent across the age spectrum and BMI categories. The association between ASMI or FMI and age was modified by sex and BMI. The prevalence of HA-LM in the whole sample was 10.3% in women and 15.2% in men. The prevalence of all subclasses of HA-LM in obese women and men was 14.7% and 22.9%, respectively. HA-LM class III was more prevalent in obese men (2.3%) than in obese women (0.3%). We developed sex- and BMI-specific reference curves to harmonize the classification of body-composition phenotypes. The application of this classification will be particularly useful in the identification of cases of sarcopenic obesity. The association of these phenotypes with metabolic deregulation and increased disease risk awaits verification.

  5. Genetic variants and early cigarette smoking and nicotine dependence phenotypes in adolescents.

    PubMed

    O'Loughlin, Jennifer; Sylvestre, Marie-Pierre; Labbe, Aurélie; Low, Nancy C; Roy-Gagnon, Marie-Hélène; Dugas, Erika N; Karp, Igor; Engert, James C

    2014-01-01

    While the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes. In a prospective study of 1294 adolescents aged 12-13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7-8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator). The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value <0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and self-medication phenotypes were both 0.076. Because the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3). Dopaminergic pathways may be salient during early smoking and the development of ND.

  6. Study of modifiers factors associated to mitochondrial mutations in individuals with hearing impairment

    SciTech Connect

    Sousa de Moraes, Vanessa Cristine; Alexandrino, Fabiana; Andrade, Paula Baloni; Camara, Marilia Fontenele; Sartorato, Edi Lucia

    2009-04-03

    Hearing impairment is the most prevalent sensorial deficit in the general population. Congenital deafness occurs in about 1 in 1000 live births, of which approximately 50% has hereditary cause in development countries. Non-syndromic deafness can be caused by mutations in both nuclear and mitochondrial genes. Mutations in mtDNA have been