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PubMed2004

Porcine reproductive and respiratory syndrome virus field isolates differ in in vitro interferon phenotypes.

Type I interferons (IFN-alpha and -beta) play an important role in the innate host defense against viral infection by inducing antiviral responses. In addition to direct antiviral activities, type I IFN serves as an important link between the innate and adaptive immune response through multiple mechanisms. Therefore, the outcome of a viral infection can be affected by IFN induction and the IFN sensitivity of a virus. North American porcine reproductive and respiratory syndrome virus (PRRSV) field isolates were studied with regard to IFN-alpha sensitivity and induction in order to understand the role of type I IFN in PRRSV pathogenesis. PRRSV isolates were differentially sensitive to porcine recombinant IFN-alpha (rIFN-alpha) and varied in their ability to induce IFN-alpha in porcine alveolar macrophages (PAM) cultures as measured by a porcine IFN-alpha specific ELISA on cell culture supernatants. Fifty-two plaques were purified from three PRRSV isolates (numbers 3, 7, and 12) and tested for IFN sensitivity and IFN induction. Plaque-derived populations were composed of heterogeneous populations in terms of IFN-inducing capacity and sensitivity to rIFN-alpha. When macrophages infected with isolates 3, 7, or 12 were treated with polycytidylic acid (polyI:C), IFN-alpha production was enhanced. Cells infected with isolate 3 and treated with polyI:C showed the most consistent and strongest enhancement of IFN-alpha production. It was demonstrated that the relatively low concentrations of IFN-alpha produced by isolate 3 contributed to the enhanced IFN-alpha synthesis in response to polyI:C. Isolates 7 and 12 significantly suppressed the enhanced IFN-alpha production by isolate 3 in polyI:C treated cells. To determine if suppression was at the level of IFN-alpha transcription, quantitative RT-PCR was performed for IFN-alpha mRNA and compared to GAPDH and cyclophilin mRNA quantification. However, the relative number of IFN-alpha transcript copies did not correlate with IFN-alpha protein levels, suggesting a post-transcriptional mechanism of suppression. In summary, these results demonstrate that PRRSV field isolates differ both in IFN-alpha sensitivity and induction. Furthermore, a PRRSV field isolate strongly enhance polyI:C-induced IFN-alpha production in PAM cultures and this priming effect was suppressed by other PRRSV isolates.

Animals↗
PubMed2002

Finding genes for bipolar disorder in the functional genomics era: from convergent functional genomics to phenomics and back.

Psychiatric genetics, while promising to unravel the mechanisms of psychiatric disorders, has proven to be a challenging field. Psychiatric disorders, like other common genetic traits, are complex and heterogeneous. Psychiatric genetics has also suffered from a lack of quantifiable, biology-based phenotypes. However, the field is currently at an opportune moment. The work of various investigators is on the verge of paying rich dividends. Efforts at positional cloning are being greatly accelerated by the fruits of the Human Genome Project. New tools of functional genomics, such as expression profiling and proteomics, are being applied to animal models. These two methods can complement each other in an approach we have termed convergent functional genomics. Lastly, improvements in the measurement of biologically distinct endophenotypes--or phenomic--will lead to a better understanding of the mapping of genes to phenotypes in both animal and human systems.

Journal Article↗
PubMed2001

Molecular analyses of methyl-coenzyme M reductase alpha-subunit (mcrA) genes in rice field soil and enrichment cultures reveal the methanogenic phenotype of a novel archaeal lineage.

The diversity of methanogen-specific methyl-coenzyme M reductase alpha-subunit (mcrA/mrtA) genes in Italian rice field soil was analysed using a combination of molecular techniques and enrichment cultures. From 75 mcrA/mrtA clones retrieved from rice field soil, 52 were related to members of the Methanosarcinaceae, Methanosaetaceae and Methanobacteriaceae. However, 19 and four clones formed two novel clusters of deeply branching mcrA sequences, respectively, which could not be affiliated to known methanogens. A new methanogen-specific fingerprinting assay based on terminal restriction fragment length polymorphism (T-RFLP) analysis of fluorescently labelled polymerase chain reaction (PCR) products allowed us to distinguish all environmental mcrA/mrtA sequences via group-specific Sau96I restriction sites. Even genes for the isoenzyme methyl-coenzyme M reductase two (mrtA) of Methanobacteriaceae present in rice field soil were represented by a unique 470 bp terminal restriction fragment (T-RF). Both cloning and T-RFLP analysis indicated a significant representation of novel environmental mcrA sequences in rice field soil (238 bp T-RF). To identify these mcrA sequences, methanogenic enrichment cultures with rice field soil as inoculum were established with H2/CO2 as substrates at a temperature of 50 degrees C, and these were monitored using molecular tools. In subsequent transfers of these enrichment cultures, cloning and T-RFLP analysis detected predominantly SSU rRNA genes of rice cluster I (RC-I), an uncultivated euryarchaeotal lineage discovered previously in anoxic rice field soil. In parallel, both mcrA cloning and T-RFLP analyses of the enrichment culture identified the more frequent cluster of novel environmental mcrA sequences as belonging to members of RC-I. Thus, we could demonstrate the genotype and phenotype of RC-I Archaea by the presence of a catabolic gene in a methanogenic enrichment culture before the isolation of pure cultures.

Archaea↗
PubMedDate not supplied

Field homology as a way to reconcile genetic and developmental variability with adult homology.

The theoretical and developmental fundament of field homology is here examined, particularly as applied by the authors to comparative neurobiology. Preliminary considerations explore conceptual differences between sameness (homology) and similarity. The source of sameness (the biological evolutionary relationship properly sought in homology analysis) is thought to lie in morphostatic evolutionary and morphogenetic processes, which constrain organismal variation at the level of its fundamental structural organization (Bauplan). This occurs via regulation of the branching mode of the morphogenetic sequence or epigenetic landscape. Of fundamental importance in this context is the role of developmental (morphogenetic) fields. The latter concept is analyzed in its general properties and is postulated to underpin the stability of the developing Bauplan down to the ultimate conserved details. Developmental fields subdivide during ontogenesis into ever smaller fields in a complex hierarchy, defining at each stage the developmental entities which are subjected to regulatory, morphostatic effects via the genome and indirect phenotypic selection. These fields thus represent the natural characters for considerations of embryonic homology, and underlie adult homology, rather than arbitrarily selected embryonic parts. Field subdivision proceeds into the constitution of individually specified cell populations. Field regulatory properties, however, do not extend to all differentiation phenomena observed in embryos. This means there is a limit to the applicability of field homology analysis, leaving space for biological variation and convergence outside of proper homology relationships. Genetic and developmental variability are compensated by the regulatory functions of the developmental fields insofar as they relate to correct Bauplan construction. These ideas suggest the convenience of a more systematic use of field homology methods, which start with appropriately identified developmental fields to expand knowledge on adult homology (sameness) and eventually also on accessory structural and functional similarities or differences.

Aging↗
PubMed2004

In silico screening of a saturated mutation library of tomato.

A comprehensive mutant population is a basic resource for exploring gene function. We developed an isogenic tomato 'mutation library' in the genetic background of the inbred variety M82. A total of 13 000 M(2) families, derived from EMS (ethyl methane sulfonate) and fast-neutron mutagenesis, were visually phenotyped in the field and categorized into a morphological catalog that includes 15 primary and 48 secondary categories. Currently, 3417 mutations have been cataloged; among them are most of the previously described phenotypes from the monogenic mutant collection of The Tomato Genetics Resource Center, and over a thousand new mutants, with multiple alleles per locus. The phenotypic database indicates that most mutations fall into more than a single category (pleiotropic), with some organs such as leaves more prone to alterations than others. All data and images can be searched and accessed in the Solanaceae Genome Network (SGN) on a site called 'The Genes That Make Tomatoes' (http://zamir.sgn.cornell.edu/mutants/).

Crosses, Genetic↗
PubMed2006

Wild mouse open field behavior is embedded within the multidimensional data space spanned by laboratory inbred strains.

The vast majority of studies on mouse behavior are performed on laboratory mouse strains (Mus laboratorius), while studies of wild-mouse behavior are relatively rare. An interesting question is the relationship between the phenotypes of M. laboratorius and the phenotypes of their wild ancestors. It is commonly believed, often in the absence of hard evidence, that the behavior of wild mice exceeds by far, in terms of repertoire richness, magnitude of variables and variability of behavioral measures, the behavior of the classical inbred strains. Having phenotyped the open field behavior (OF) of eight of the commonly used laboratory inbred strains, two wild-derived strains and a group of first-generation-in-captivity local wild mice (Mus musculus domesticus), we show that contrary to common belief, wild-mouse OF behavior is moderate, both in terms of end-point values and in terms of their variability, being embedded within the multidimensional data space spanned by laboratory inbred strains. The implication could be that whereas natural selection favors moderate locomotor behavior in wild mice, the inbreeding process tends to generate in mice, in some of the features, extreme and more variable behavior.

Animals↗
PubMed2026

Genome-wide association study combined with multi-assay phenotyping identifies a novel anthracnose resistance locus in apple.

BACKGROUND: Apple anthracnose, a disease complex that includes Glomerella leaf spot (GLS) and bitter rot caused by Colletotrichum species, is a major disease affecting apple production worldwide. In this study, we combined multi-year field evaluations with controlled inoculation assays to identify genomic regions associated with anthracnose resistance in apple. RESULTS: A total of 440 apple genotypes, including 411 F₁ progenies derived from six parental crosses and 29 cultivars, were evaluated under natural orchard conditions and through artificial fruit and leaf inoculation assays using wound and non-wound methods. Disease severity varied substantially between years, particularly under contrasting environmental conditions, indicating strong genotype-by-environment interactions. Genome-wide association analysis (GWAS) using field-derived disease severity scores from 2019 identified a significant quantitative trait locus (QTL) on chromosome 15 (~ 31.8 Mb) associated with reduced anthracnose severity. This locus was distinct from the previously reported Rgls/MdTNL1 region on chromosome 15 (~ 2-5 Mb), suggesting the presence of a novel resistance-associated locus. In contrast, no genome-wide significant associations were detected from artificial inoculation datasets. CONCLUSIONS: These findings demonstrate the importance of field-based, multi-environment phenotyping for detecting field-relevant resistance loci and improving understanding of the genetic architecture underlying anthracnose resistance in apple.

Malus↗
PubMed2003

Differences between genotyping and phenotyping methods for assessing apolipoprotein(a) size polymorphisms.

The aim of the present study was to analyze, on a double-blind basis, the relationships between the apolipoprotein(a) (apo(a)) gene and protein size polymorphisms in healthy volunteers (n = 99) and patients with premature myocardial infarction (n = 91). Apo(a) genotypes were determined by pulse-field electrophoresis and phenotypes were separated by sodium dodecyl sulfate-agarose gel electrophoresis. Results showed that phenotyping overestimated apo(a) size with respect to genotyping (mean (SD) = 3.7 (3.4) kringle units; p < 0.001) in subjects with a double-band genotype, although both measurements were highly correlated (r = 0.83; p < 0.001). We also observed that the protein band in subjects with a single-band phenotype was related more closely to the smallest allele than to the largest allele band. The correlation of plasma lipoprotein(a) (Lp(a)) concentration was stronger with the phenotype than with the genotype. We hypothesize that post-translational modifications in the apo(a) molecule may be the most plausible explanation for the discrepancies observed. In conclusion, the present study highlights the dissimilarities between phenotyping and genotyping methods for the measurement of apo(a) size and suggests that laboratories should carefully consider these relationships and the transfer of results between such methodologies.

Age of Onset↗
PubMed1987

Immunohistology in the identification of tumour types.

Recently developed immunohistological techniques coupled with the advent of the monoclonal antibody era have revolutionized diagnostic tumour pathology. The search for a tumour specific marker has not been fulfilled; however, judicious use of panels of antibodies recognizing tissue differentiation antigens has enabled separation of morphologically indistinct tumours where this was not previously possible. This same approach has proved useful for identifying site of origin in small tumour biopsy specimens, in aspirates of malignant cells from body fluids and in micrometastases. Lymphoma phenotyping is the field where the greatest advances have been made. This is because of the diverse range of antibodies available in this area and the widespread cooperation in characterizing and clustering these antibodies that has occurred at the three international workshops on leucocyte antigens. Less dramatic, but nevertheless appreciable advances have been made in the field of solid tumours, using antibodies to differentiation products or organ specific products to identify the site of origin of a carcinoma or sarcoma. The identification of consistent production of aberrant differentiation products also provides a promising approach to tumour identification. The recognition of changed antigenic phenotype in preinvasive neoplastic cells offers a means of early, more objective, diagnostic assessment of these lesions.

Antibodies, Monoclonal↗
PubMed1986

Pharmacogenetics of dextromethorphan O-demethylation in man.

The metabolism of dextromethorphan has been investigated from the aspect of genetically determined intersubject differences of oxidative drug metabolism in man. For this purpose, the urinary elimination of dextromethorphan and dextrorphan, which is the major O-demethylated metabolite in urine, has been studied in selected drug hydroxylation phenotypes. Dextromethorphan O-demethylation co-segregates with polymorphic debrisoquine hydroxylation, whereas no such co-segregation exists with the independently controlled mephenytoin polymorphism in man. The urinary dextromethorphan over dextrorphan metabolic ratio was validated for linearity of O-demethylation vs dose administered, and for varying urine collection intervals at different urinary pH values. A 94% repeatability of the dextromethorphan metabolic ratio could be established in extensive and poor metabolizer phenotypes. In a preliminary study, different rates of N-, O- and N,O- demethylation of dextromethorphan to yield D-methoxymorphinane, dextrorphan and D-hydroxymorphinane, respectively, were found in extensive- (Sprague-Dawley) and poor-metabolizer (female dark Agouti) rat strains. The observed interphenotype differences in man and the interstrain variations in an experimental animal model indicate that dextromethorphan O-demethylation is catalysed by the debrisoquine-type cytochrome P-450 isozyme. Therefore, the common genetic control of debrisoquine and dextromethorphan metabolism indicates that dextromethorphan might be used as a safe and innocuous substitute for debrisoquine in future routine phenotyping in the field of human pharmacogenetics of oxidative drug metabolism.

Adult↗
PubMed2004

High-quality male field crickets invest heavily in sexual display but die young.

Only high-quality males can bear the costs of an extreme sexual display. As a consequence, such males are not only more attractive, but they often live longer than average. Recent theory predicts, however, that high-quality males should sometimes invest so heavily in sexual displays that they die sooner than lower quality males. We manipulated the phenotypic quality of field crickets, Teleogryllus commodus, by altering the protein content of their diet. Here we show that nymphs and adult females reared on a high-protein diet lived longer than those on a low-protein diet. In contrast, adult males reared on a high-protein diet died sooner than those on low-protein diets because they invested more energy in calling during early adulthood. Our findings uphold the theoretical prediction that the relationship between longevity and sexual advertisement may be dynamic (that is, either positive or negative), depending on local conditions such as resource availability. Moreover, they caution the use of longevity as a proxy for fitness in sexual selection studies, and suggest avenues for future research on the relationship between sexual attractiveness and ageing.

Aging↗
PubMed2000

Nonlinear response of the immune system to power-frequency magnetic fields.

Studies of the effects of power-frequency electromagnetic fields (EMFs) on the immune and other body systems produced positive and negative results, and this pattern was usually interpreted to indicate the absence of real effects. However, if the biological effects of EMFs were governed by nonlinear laws, deterministic responses to fields could occur that were both real and inconsistent, thereby leading to both types of results. The hypothesis of real inconsistent effects due to EMFs was tested by exposing mice to 1 G, 60 Hz for 1-105 days and observing the effect on 20 immune parameters, using flow cytometry and functional assays. The data were evaluated by means of a novel statistical procedure that avoided averaging away oppositely directed changes in different animals, which we perceived to be the problem in some of the earlier EMF studies. The reliability of the procedure was shown using appropriate controls. In three independent experiments involving exposure for 21 or more days, the field altered lymphoid phenotype even though the changes in individual immune parameters were inconsistent. When the data were evaluated using traditional linear statistical methods, no significant difference in any immune parameter was found. We were able to mimic the results by sampling from known chaotic systems, suggesting that deterministic chaos could explain the effect of fields on the immune system. We conclude that exposure to power-frequency fields produced changes in the immune system that were both real and inconsistent.

Animals↗
PubMed2006

Modifier genes and sickle cell anemia.

PURPOSE OF REVIEW: With the completion of the human genome project and HapMap, previously unknown genetic polymorphisms associated with disease have been observed. This review highlights genetic polymorphisms that have provided insight into the pathophysiology underlying the many phenotypes of sickle cell disease. RECENT FINDINGS: The phenotypes of sickle cell disease are likely to be modulated by polymorphisms in genes that are involved in inflammation, cell-cell interaction, and nitric oxide biology. Case-control studies are beginning to define the relationships between single-nucleotide polymorphisms in candidate genes and the many subphenotypes of sickle cell anemia. A common theme emerging from these studies is that single-nucleotide polymorphisms in genes of the transforming growth factor-beta/bone morphogenetic protein and a few other genes such as Klotho are associated with several subphenotypes of sickle cell disease. SUMMARY: Genomic medicine is merging with clinical practice as our understanding of the structure and variability of the human genome increases. Patients with diseases caused by identical mutations in a single gene - sickle cell anemia is a prime example - can have clinical courses very different from one another, and when environmental influences are removed the phenotypic heterogeneity of mendelian single-gene disorders is best explained by single-nucleotide polymorphisms in genes that modulate the disease phenotype. As this field expands, insights will be gained into complex epistatic factors that influence the clinical presentation of sickle cell disease, enabling physicians to better predict and manage the many complications of this disease.

Anemia, Sickle Cell↗
PubMedDate not supplied

Mammalian development in a changing environment: exposure to endocrine disruptors reveals the developmental plasticity of steroid-hormone target organs.

Recent findings in the field of environmental endocrine disruption have revealed that developmental exposure to estrogenic chemicals induces morphological, functional, and behavioral anomalies associated with reproduction. The aim of the present study was to determine the effects of in utero exposure to low doses of the estrogenic chemical bisphenol A (BPA) on the development of the female reproductive tissues and mammary glands in CD-1 mice. Humans are exposed to BPA, which leaches from dental materials and plastic food and beverage containers. Here we report that prenatal exposure to BPA induces alterations in tissue organization within the ovaries and mammary glands and disrupts estrous cyclicity in adulthood. Because estrogen receptors are expressed developmentally in these estrogen-target organs, we propose that BPA may directly affect the expression of genes involved in their morphogenesis. In addition, alterations in the sexual differentiation of the brain, and thus the hypothalamic-pituitary-gonadal axis, may further contribute to the observed phenotype. The emerging field of endocrine disruptors promises to provide new insights into the mechanisms underlying the development of hormone-target organs and demonstrates that the environment plays important roles in the making of phenotypes.

Animals↗
PubMed2005

Complex organization of mouse and rat suprachiasmatic nucleus.

The suprachiasmatic nucleus, site of the dominant mammalian circadian clock, contains a variety of different neurons that tend to form groups within the nucleus. The present investigation used single and multiple label tract tracing and immunofluorescence methods to evaluate the relative locations of the neuron groups and to compare them with the distributions of the three major afferent projections, the retinohypothalamic tract, geniculohypothalamic tract and the serotonergic pathway from the median raphe nucleus. The suprachiasmatic nucleus has a complex order characterized by peptidergic cell groups (vasopressin, gastrin releasing peptide, vasoactive intestinal polypeptide, calbindin, calretinin, corticotrophin releasing factor and enkephalin) that, in most cases, substantially overlap. The retinohypothalamic tract projects bilaterally to virtually all the suprachiasmatic nucleus in both rat (predominantly contralateral) and mouse (symmetric) and its terminal field overlaps that for the geniculohypothalamic tract, but with distinctions visible according to density criteria; neither provides more than sparse innervation of the dorsomedial suprachiasmatic nucleus. In the mouse, the serotonergic terminal field is densest medially and ventrally, but is also distributed elsewhere with varying density. The serotonergic terminal plexus in the rat is densest centromedially and largely, but not completely, overlaps the complete distribution of retinal terminals with density much reduced in the lateral suprachiasmatic nucleus. The locations of vasopressin neurons, retinohypothalamic tract terminals and serotonergic (mouse, rat) or geniculohypothalamic tract (rat) provide evidence for three clear, but not exclusionary, sectors of the suprachiasmatic nucleus. The data, in conjunction with emerging knowledge concerning rhythmically dynamic changes in the size of regions of neuropeptide gene expression in suprachiasmatic nucleus cells, support the view that suprachiasmatic nucleus organization is more complex than a simple "core" and "shell" arrangement. While generalizations about suprachiasmatic nucleus organization can be made with respect to location of cell phenotypes or terminal fields, oversimplification may hinder, rather than facilitate, understanding of suprachiasmatic nucleus structure-function relationships.

Afferent Pathways↗
PubMed2005

Dominant optic atrophy caused by a novel OPA1 splice site mutation (IVS20+1G-->A) associated with intron retention.

Dominant optic atrophy (DOA) is the most common form of inherited primary optic neuropathy. The purpose of the current study was to report a novel OPA1 splice site mutation and investigate the impact of the mutation on pre-mRNA splicing in a female proband and her father diagnosed with DOA. We evaluated visual acuity, retinal fundi and kinetic visual fields. Color vision phenotypes were determined using the Farnsworth Panel D-15 and the Farnsworth-Munsell 100-hue tests. All 28 coding exons of the OPA1 gene were analyzed with polymerase chain reaction (PCR) amplification and direct sequencing. Total RNA extraction from white blood cells followed by reverse transcription-PCR (RT-PCR) was performed. We identified a novel heterozygous G to A mutation at position +1 of intron 20 (g.IVS20+1G-->A) in both patients. RT-PCR analysis revealed that the first 25 bp from intron 20 plus exon 20 were spliced onto exon 21. No difference in expression of mutant and wild-type transcripts was found within the linear range of amplification. Clinically, both patients exhibited reduced visual acuities, pallor of optic discs, decreased sensitivities of central visual fields and blue-yellow color vision defects. Previously, only one mechanism (skipping of exon) of pre-mRNA splicing defects has been reported among OPA1 splice site mutations. Our study demonstrates that the mechanism of intron retention is a novel type of pre-mRNA splicing defects. The mutant transcript with a premature termination codon is likely to encode a truncated protein, due to a translational frameshift (V672fsX675), that lacks 289 amino acids of the C-terminal end. Therefore, it is suggested that haploinsufficiency underlies DOA in the patients. However, we could not exclude the possibility that the truncated protein has a dominant negative activity because the mutant transcript is insusceptible to nonsense-mediated mRNA decay.

Adult↗
PubMed2004

The quantitative genetics of floral trait variation in Lobelia: potential constraints on adaptive evolution.

Although pollinator-mediated natural selection has been measured on many floral traits and in many species, the extent to which selection is constrained from producing optimal floral phenotypes is less frequently studied. In particular, negative correlations between flower size and flower number are hypothesized to be a major constraint on the evolution of floral displays, yet few empirical studies have documented such a trade-off. To determine the potential for genetic constraints on the adaptive evolution of floral displays, I estimated the quantitative genetic basis of floral trait variation in two populations of Lobelia siphilitica. Restricted maximum likelihood (REML) analyses of greenhouse-grown half-sib families were used to estimate genetic variances and covariances for flower number and six measures of flower size. There was significant genetic variation for all seven floral traits in both populations. Flower number was negatively genetically correlated with four measures of flower size in one population and three measures in the other. When the genetic variance-covariance matrices were combined with field estimates of phenotypic selection gradients, the predicted multivariate evolutionary response was less than or opposite in sign to the selection gradient for flower number and five of six measures of flower size, suggesting genetic constraints on the evolution of these traits. More generally, my results indicate that the adaptive evolution of floral displays can be constrained by trade-offs between flower size and number, as has been assumed by many theoretical models of floral evolution.

Adaptation, Biological↗