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PubMed2006

Searching for hemostatic modifier genes affecting the phenotype of mice with very low levels of FVII.

FVII(tTA/-) mice are heterozygous for the FVII- null allele and a gene-targeted allele expressing very low levels of FVII. Approximately half the FVII(tTA/-) in a mixed C57Bl/6:129x1/SVJ background survive much longer than mice in a C57Bl/6 background, suggesting that genetic background affects the survival of mice expressing very low levels of FVII. A lineage of long-term surviving FVII(tTA/-) mice in a predominantly C57Bl/6 background was generated by selecting 16 weeks or older FVII(tTA/-) males and breeding them with C57Bl/6 FVII+/- females. It is postulated that these mice maintain 129x1/SVJ alleles at putative hemostatic modifier loci necessary for the survival of mice expressing very low levels of FVII. A SNP genomic scan was performed on DNA from long-term surviving FVII(tTA/-) mice. The scan identified 8 regions enriched for 129x1/SVJ sequences that might contain putative hemostatic modifier genes.

Animals↗
PubMedDate not supplied

Trinucleotide repeat expansions: do they contribute to bipolar disorder?

It has long been known that bipolar disorder has a true but complex genetic background. Reports on genetic anticipation in bipolar disorder opened the way to a new approach for genetic studies. Indeed, anticipation, a decreasing age at onset, and/or increasing disease severity in successive generations, were recently explained by an expansion of trinucleotide repeats in monogenic diseases like Huntington's disease and Fragile X syndrome. The involvement of trinucleotide repeat expansions in bipolar disorder received even more support when studies reported association of large CAG/CTG repeats with bipolar disorder. Even though a large number of studies have been conducted, this association is still unexplained. Here, we review the studies investigating the trinucleotide repeat expansion hypothesis in bipolar disorder. Studies on anticipation, on association of anonymous large CAG/CTG repeats and on specific trinucleotide repeats are critically analysed and discussed, showing a field with precipitate conclusions or inconclusive results. The analysis suggests that there are indications, though disputable, supporting the trinucleotide repeat expansion hypothesis in bipolar disorder, but no conclusive evidence has been hitherto provided.

Bipolar Disorder↗
PubMed2004

The effects of ketamine vary among inbred mouse strains and mimic schizophrenia for the P80, but not P20 or N40 auditory ERP components.

N-methyl-D-aspartate (NMDA) antagonists produce behavioral and electrophysiological effects similar to schizophrenia. The mouse P20, N40, and P80 event related potential (ERP) components were analyzed for genetic variance among inbred strains and ketamine-induced differences to model abnormalities in the P50, N100, and P200 in schizophrenia. Ketamine increased P20/N40 amplitude and decreased P80 amplitude. Therefore, the effects of ketamine in mice are inconsistent with alterations in the corresponding P50 and N100 in schizophrenia, suggesting that NMDA receptor dysfunction may not underlie abnormalities of these components in schizophrenia. However, the effects of ketamine on the mouse P80 were consistent with P200 ERP changes in schizophrenia and support the hypothesis that NMDA dysfunction may contribute to some neuronal abnormalities in schizophrenia. The current study lays the groundwork for defining the role of NMDA-mediated transmission for specific aspects of neuronal processing that vary with genetic background. Future studies could use transcription profiling to clarify such interactions between genetic background, specific neuronal circuits, and transmitter systems.

Animals↗
PubMed2001

Modifier genes in mice and humans.

An emerging theme of studies with spontaneous, engineered and induced mutant mice is that phenotypes often depend on genetic background, implying that genetic modifiers have a role in guiding the functional consequences of genetic variation. Understanding the molecular and cellular basis by which modifier genes exert their influence will provide insights into developmental and physiological pathways that are critical to fundamental biological processes, as well as into novel targets for therapeutic interventions in human diseases.

Animals↗
PubMed1990

HLA- and H-2-associated variations of intra- and extracellular magnesium content.

Erythrocyte and plasma magnesium (EMg, PMg) levels have been shown to be genetically controlled in human and mouse. The possible association of these genetic factors with the major histocompatibility complex (MHC) (HLA and H-2) was investigated. Among unrelated adult male blood donors, HLA-B35 carriers have PMg (P less than 0.01) and EMg (P less than 0.0005) levels lower than those of noncarriers, while HLA-B38 carriers exhibit a significant (P less than 0.05) increase of both PMg and EMg levels when compared to the other individuals. Furthermore, HLA identical sibs have EMg values more similar than those of HLA different sibs. In the mouse, erythrocyte (P less than 0.001), plasma (P less than 0.001), liver (P less than 0.03), and spleen (P less than 0.04) Mg contents vary significantly according to H-2, with higher values being found in H-2k than in H-2q or H-2b congenic strains. However, non-MHC genes also have an influence on erythrocyte (P less than 10(-10], plasma (P less than 10(-10], spleen (P less than 10(-5], and kidney (P less than 10(-6] Mg contents as shown by differences between H-2 identical strains, which differ by the C3H and B10 genetic backgrounds. In conclusion, genetic factors controlling intra- and extracellular Mg levels are composed of at least three components: MHC (HLA and H-2)-associated genes, non-MHC genes, and tissue factors modulating the respective importance of the first two sets of factors. The mechanisms underlying this genetic system are discussed.

Adult↗
PubMed2004

Identification of a variant "Rome clone" of methicillin-resistant Staphylococcus aureus with decreased susceptibility to vancomycin, responsible for an outbreak in an intensive care unit.

We describe the identification of a variant of the "Rome clone" of methicillin-resistant Staphylococcus aureus (MRSA), responsible for an outbreak involving 5 patients in a Cardiac Surgery Intensive Care Unit (CS-ICU) of a tertiary-care University Hospital in Rome. All strains isolated from patients and from nasal swabs obtained from four members of the CS-ICU personnel, belonged to the same identified clone. The characteristics of this clone were: (1) resistance to ampicillin, oxacillin, gentamicin, ciprofloxacin, erythromycin, clindamycin, rifampin, spectinomycin, and tetracycline; (2) vancomycin and teicoplanin MICs respectively of 2 and 4 mg/L; (3) heteroresistant subpopulations in the presence of 4 and 6 mg/L of vancomycin (10(-3) and 10(-5), respectively); (4) clonal type I::J::C determined following an established protocol (mec A::Tn 554 ::PFGE); (5) sequence type ST247 (3-3-1-12-4-4-16), obtained by multilocus sequence typing (MLST); and (6) the staphylococcal cassette chromosome mec (SCC) IA, obtained by multiplex PCR method. This new strain had different characteristics from the epidemic clone circulating in the same hospital from 1997 and designed "Rome clone," which was susceptible to erythromycin, clindamycin, and spectinomycin and belonged to the II::NH::C genetic background. A high genetic similarity between this Rome clone and the previously classified Archaic and Iberian clones was found, because they shared the same allelic profile (ST247), probably originating from the same S. aureus ancestor of the Iberian MRSA strains. Therefore, the strains responsible for the outbreak, with vancomycin MICs 2-4 mg/L, are variant clones, showing the genotype of the "Rome clone," the ST247 in association with SCC mec type IA (ST247-MRSA-IA), and are characterized by a uniform susceptibility to fosfomycin.

Anti-Bacterial Agents↗
PubMed2000

Schizosaccharomyces pombe Ste7p is required for both promotion and withholding of the entry to meiosis.

The fission yeast ste7 mutant cannot mate and undergo meiosis, but shows no defect in vegetative growth. We cloned and characterized the ste7 gene. The deduced ste7 gene product (Ste7p) was a protein of 569 amino acids with no significant similarity to other proteins. Transcription of ste7 was induced by nutrient starvation via the function of the transcription factor Ste11p. Disruption of the ste7 gene blocked both conjugation and meiosis, showing that Ste7p plays a positive role in these two processes, probably activating the pheromone signal pathway. Unexpectedly, overexpression of ste7(+) promoted conjugation but inhibited meiosis in wild-type cells. The temperature-sensitive pat1-114 mutant underwent ectopic conjugation at the semirestrictive temperature when its genetic background was ste7(+), whereas the same mutant initiated haploid meiosis when its genetic background was ste7Delta. Two-hybrid analysis suggested that Ste7p interacts physically with both Pat1p and Mei2p, which together constitute the major switch to initiate meiosis. Ste7p tagged with green fluorescent protein accumulated in haploid cells under nutrient starvation until they completed conjugation, but this protein disappeared when they were to enter meiosis. These observations suggest that Ste7p may have a function to suppress the onset of meiosis until the conjugation process has been duly completed.

Amino Acid Sequence↗
PubMed2004

A model of global cerebral ischemia in C57 BL/6 mice.

A reproducible model of global cerebral ischemia in mice is essential for elucidating the molecular mechanism of ischemic neuronal injury. Such a model is particularly important in the mouse because many genetically engineered mutant animals are available. In C57BL/6 and SV129/EMS mice, we evaluated a three-vessel occlusion model. Occlusion of the basilar artery with a miniature clip was followed by bilateral carotid occlusion. The mean cortical cerebral blood flow was reduced to less than 10% of the preischemic value, and the mean anoxic depolarization was attained within 1 minute. In C57BL/6 mice, there was CA1 hippocampal neuronal degeneration 4 days after ischemia. Neuronal damage depended upon ischemic duration: the surviving neuronal count was 78.5 +/- 8.5% after 8-minute ischemia and 8.4 +/- 12.7% after 14-minute ischemia. In SV129/EMS mice, similar neuronal degeneration was not observed after 14-minute ischemia. The global ischemia model in C57BL/6 mice showed high reproducibility and consistent neuronal injury in the CA1 sector, indicating that comparison of ischemic outcome between wild-type and mutant mice could provide meaningful data using the C57BL/6 genetic background. Strain differences in this study highlight the need for consideration of genetic background when evaluating ischemia experiments in mice.

Animals↗
PubMed2006

Assessing the need for certainty in users of a clinical genetic health service.

AIM: This paper presents a study investigating the need for closure in users of a genetic health service. BACKGROUND: Genetic healthcare services are used by people who are concerned about a genetic condition in the family. Many clients expect information about the condition, risk assessment and discussion of options available to minimize the impact of the condition on the family. Some use the information to try to obtain certainty or cognitive closure. The psychological theory termed 'need for cognitive closure' explains individual differences in motivation to seek information. The tendency to seek closure can be measured by the Need for Closure Scale, which has five sub-scales: preference for order, preference for predictability, discomfort with ambiguity, decisiveness and closed-mindedness. METHODS: Clients who were referred to our genetic service in 1998 were approached before personal contact with staff of the genetic service. Fifty-two people completed the need for closure scale questionnaire. Six months after the genetic consultation, participants were asked to complete the questionnaire again (n = 45). The data were statistically analysed using Cronbach's alpha, paired t-tests and independent t-tests. RESULTS: There were no statistically significant differences in Need for Closure Scale scores in this cohort before and after the genetic consultation. Participants scored highly on the preference for order and discomfort with ambiguity sub-scales, but scores for closed-mindedness were low. Intolerance of ambiguity was statistically significantly higher in participants whose main concerns centred on their children. CONCLUSIONS: This psychological theory can help healthcare professionals to understand the motivation of clients who seek information from genetic services, and enhance understanding of those who avoid using the service. It cannot be assumed that additional knowledge is helpful to all clients, nor that knowledge of bad news is necessarily an adverse event if prior uncertainty has existed.

Adolescent↗
PubMed2005

Constraints on the evolution of adaptive phenotypic plasticity in plants.

The high potential fitness benefit of phenotypic plasticity tempts us to expect phenotypic plasticity as a frequent adaptation to environmental heterogeneity. Examples of proven adaptive plasticity in plants, however, are scarce and most plastic responses actually may be 'passive' rather than adaptive. This suggests that frequently requirements for the evolution of adaptive plasticity are not met or that such evolution is impeded by constraints. Here we outline requirements and potential constraints for the evolution of adaptive phenotypic plasticity, identify open questions, and propose new research approaches. Important open questions concern the genetic background of plasticity, genetic variation in plasticity, selection for plasticity in natural habitats, and the nature and occurrence of costs and limits of plasticity. Especially promising tools to address these questions are selection gradient analysis, meta-analysis of studies on genotype-by-environment interactions, QTL analysis, cDNA-microarray scanning and quantitative PCR to quantify gene expression, and two-dimensional gel electrophoresis to quantify protein expression. Studying plasticity along the pathway from gene expression to the phenotype and its relationship with fitness will help us to better understand why adaptive plasticity is not more universal, and to more realistically predict the evolution of plastic responses to environmental change.

Adaptation, Physiological↗
PubMed2005

Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility.

Mutations of the conserved residues of influenza virus neuraminidase (NA) that are associated with NA inhibitor (NAI) resistance decrease the sialidase activity and/or stability of the NA, thus compromising viral fitness. In fact, clinically derived NAI-resistant variants with different NA mutations have shown different transmissibilities in ferrets (M. L. Herlocher, R. Truscon, S. Elias, H. Yen, N. A. Roberts, S. E. Ohmit, and A. S. Monto, J. Infect. Dis. 190:1627-1630, 2004). Molecular characterization of mutant viruses that have a homogeneous genetic background is required to determine the effect of single mutations at conserved NA residues. We generated recombinant viruses containing either the wild-type NA (RG WT virus) or a single amino acid change at NA residue 119 (RG E119V-NA virus) or 292 (RG R292K-NA virus) in the A/Wuhan/359/95 (H3N2) influenza virus background by reverse genetics. Both mutants showed decreased sensitivity to oseltamivir carboxylate, and the RG R292K-NA virus showed cross-resistance to zanamivir. We also observed differences between the two mutants in NA enzymatic activity and thermostability. The R292K mutation caused greater reduction of sialidase activity and thermostability than the E119V mutation. The NA defect caused by the R292K mutation was associated with compromised growth and transmissibility, whereas the growth and transmissibility of the RG E119V-NA virus were comparable to those of RG WT virus. Our results suggest that NAI-resistant influenza virus variants may differ substantially in fitness and transmissibility, depending on different levels of NA functional loss.

Acetamides↗
PubMed2003

Ethanol tolerance in the yeast Saccharomyces cerevisiae is dependent on cellular oleic acid content.

In this investigation, we examined the effects of different unsaturated fatty acid compositions of Saccharomyces cerevisiae on the growth-inhibiting effects of ethanol. The unsaturated fatty acid (UFA) composition of S. cerevisiae is relatively simple, consisting almost exclusively of the mono-UFAs palmitoleic acid (Delta(9)Z-C(16:1)) and oleic acid (Delta(9)Z-C(18:1)), with the former predominating. Both UFAs are formed in S. cerevisiae by the oxygen- and NADH-dependent desaturation of palmitic acid (C(16:0)) and stearic acid (C(18:0)), respectively, catalyzed by a single integral membrane desaturase encoded by the OLE1 gene. We systematically altered the UFA composition of yeast cells in a uniform genetic background (i) by genetic complementation of a desaturase-deficient ole1 knockout strain with cDNA expression constructs encoding insect desaturases with distinct regioselectivities (i.e., Delta(9) and Delta(11)) and substrate chain-length preferences (i.e., C(16:0) and C(18:0)); and, (ii) by supplementation of the same strain with synthetic mono-UFAs. Both experimental approaches demonstrated that oleic acid is the most efficacious UFA in overcoming the toxic effects of ethanol in growing yeast cells. Furthermore, the only other UFA tested that conferred a nominal degree of ethanol tolerance is cis-vaccenic acid (Delta(11)Z-C(18:1)), whereas neither Delta(11)Z-C(16:1) nor palmitoleic acid (Delta(9)Z-C(16:1)) conferred any ethanol tolerance. We also showed that the most ethanol-tolerant transformant, which expresses the insect desaturase TniNPVE, produces twice as much oleic acid as palmitoleic acid in the absence of ethanol and undergoes a fourfold increase in the ratio of oleic acid to palmitoleic acid in response to exposure to 5% ethanol. These findings are consistent with the hypothesis that ethanol tolerance in yeast results from incorporation of oleic acid into lipid membranes, effecting a compensatory decrease in membrane fluidity that counteracts the fluidizing effects of ethanol.

Animals↗
PubMed1993

Clonal analysis of Escherichia coli of serogroups O9, O20, and O101 isolated from Australian pigs with neonatal diarrhea.

The genetic diversity of 87 isolates of Escherichia coli recovered from Australian pigs with neonatal diarrhea was examined by multilocus enzyme electrophoresis. The isolates were of serogroups O9, O20, and O101, and although most isolates lacked K88(F4), K99(F5), 987P(F6), and F41 fimbriae, they were considered to be involved in the etiology of the diarrhea. The isolates were extremely diverse, considering their origin from a single pathological condition in one country. There were estimated to be 18, 16, and 12 clones of the three respective serogroups in the collection, with serogroup diversities of 0.387, 0.448, and 0.275, respectively. Comparison with the results previously obtained for isolates from piglets with postweaning diarrhea suggested that bacteria from piglets with these two conditions did not come from any particular common genetic background. The overall genetic diversity for the combined collection was the same as that reported by others for representative isolates selected from throughout the species (0.47). The current results indicate that if isolates of these O groups are involved in porcine diarrhea, their pathogenicity is directly linked to their O somatic antigen type and is not simply due to the wide distribution of a small number of virulent clones.

Animals↗
PubMed2003

Generation of influenza A viruses with chimeric (type A/B) hemagglutinins.

To gain insight into the intertypic incompatibility between type A and B influenza viruses, we focused on the hemagglutinin (HA) gene, systematically studying the compatibility of chimeric (type A/B) HAs with a type A genetic background. An attempt to generate a reassortant containing an intact type B HA segment in a type A virus background by reverse genetics was unsuccessful despite transcription of the type B HA segment by the type A polymerase complex. Although a type A virus with a chimeric HA segment comprising the entire coding sequence of the type B HA flanked by the noncoding sequence of the type A HA was viable, it replicated only marginally. Other chimeric viruses contained type A/B HAs possessing the type A noncoding region together with either the signal peptide or transmembrane/cytoplasmic region of type A virus or both, with the remaining regions derived from the type B HA. Each of these viruses grew to median tissue culture infectious doses of more than 10(5) per ml, but those with more type A HA regions replicated better, suggesting protein-protein interactions or increased HA segment incorporation into virions as contributing factors in the efficient growth of this series of viruses. All of these chimeric (A/B) HA viruses were attenuated in mice compared with wild-type A or B viruses. All animals intranasally immunized with a chimeric virus survived upon challenge with a lethal dose of wild-type type B virus. These results suggest a framework for the design of a novel live vaccine virus.

Animals↗
PubMed2004

Isolation of antibiotic-resistant and antimetabolite-resistant mutants of Frankia strains EuI1c and Cc1.17.

Antibiotic-resistant and antimetabolite-resistant mutants of the nitrogen-fixing symbiotic bacterium Frankia were isolated to provide strains with genetic backgrounds amenable to genetic analysis. The lethal and mutagenic effects of ethyl methanesulfonate (EMS) and UV light on four Frankia strains were investigated. UV irradiation or EMS treatment of strain EuI1c cells resulted in the formation of two different colony types: rough and smooth. The smooth colonies were conditional sporulation mutants. In the case of EMS-induced cells of strain Cc1.17, resistance to lincomycin, ampicillin, and 5-fluorouracil occurred at a frequency of 1 x 10(-5), 1 x 10(-5), and 4 x 10(-5), respectively. The lincomycin-resistant mutants produced a yellow-tan pigment that was released into the growth medium. Resistance to tetracycline and lincomycin with EMS-induced cells of strain EuI1c occurred at a frequency of 3.2 x 10(-3) and 4.7 x 10(-4), respectively. These strains will be useful for the development of genetic methods for Frankia.

Anti-Bacterial Agents↗
PubMed2004

Quantitative trait locus mapping of genetic modifiers of metabolic syndrome and atherosclerosis in low-density lipoprotein receptor-deficient mice: identification of a locus for metabolic syndrome and increased atherosclerosis on chromosome 4.

OBJECTIVE: The purpose of this study was to examine genetic factors responsible for metabolic syndrome and atherosclerosis in a setting of low-density lipoprotein (LDL) receptor deficiency in a cross between C57BL/6J (B6) and PERA/Ei (PERA) inbred mouse strains. METHODS AND RESULTS: Comparison of metabolic phenotypes in B6 and PERA strains revealed the PERA genetic background to be dramatically more susceptible to hyperleptinemia, hyperglycemia, hypertriglyceridemia, elevated insulin levels, and body fat increase than the B6 background. To facilitate genetic analysis, metabolic syndrome-related traits and atherosclerotic lesion area were measured in 167 [(PERAxB6.129S7-Ldlr(tm1Her))xB6.129S7-Ldlr(tm1Her)]N2 male and female backcross mice that were homozygous for the Ldlr null allele. Quantitative trait locus analysis was performed using 153 polymorphic microsatellite markers spanning the genome. On chromosome 4, we identified a locus influencing plasma triglyceride, insulin, and leptin concentrations, body weight, and atherosclerosis. Several other genetic loci were identified with separate effects on plasma insulin, body weight, high-density lipoprotein cholesterol, and atherosclerosis. CONCLUSIONS: The PERA strain is highly susceptible to the development of metabolic syndrome after feeding a Western-type diet. This susceptibility is due, in part, to a locus on murine chromosome 4 in which PERA alleles predispose to adiposity, increased insulin, and accelerated atherogenesis in the absence of marked hyperlipidemia.

Animals↗
PubMed2000

Variation of candidate genes in triglyceride metabolism.

After more than a decade of study, investigators are grappling for a consensus regarding the relationship between variation in candidate genes and plasma triglyceride concentration. Certain variants of LPL--both rare variants, in the case of loss-of-function mutations in kindreds with chylomicronemia, and common variants, in the case of the D9N and N291S variants--appear to be fairly consistently associated with an elevated plasma triglyceride level. In addition, the variation of the recognition site for Sstl within the 3'-untranslated region of APOC3 has consistently shown an association with a variation in plasma triglycerides. The LPL and APOC3 variants thus have at least a chance in future clinical applications, but this will require more study. Common variants of some other promising candidate genes, such as HL, have not shown as consistent an association with the variation in plasma triglyceride level. Finally, studies of variants of newer candidates, such as the mitochondrial genome, LMNA, and IL-6, indicate that many different genes might be important determinants of plasma triglyceride concentration in the general population. As always, the associations of genes with a complex intermediate trait such as plasma triglyceride level depend upon interactions with modulatory factors such as genetic background and/or secondary genetic effects, in addition to the effects of gender, age, hormone replacement, and postprandial status. A key attribute for increasing confidence in the biologic or potential clinical validity of the associations of candidate gene variation with plasma triglyceride will be the development of assays that will provide a more direct mechanistic link between the genetic variant and the elevated plasma triglyceride.

Coronary Disease↗
PubMed2006

Sporadic ALS is not associated with VAPB gene mutations in Southern Italy.

Mutations in the Cu/Zn superoxide dismutase (Sod1) gene have been reported to cause adult-onset autosomal dominant Amyotrophic Lateral Sclerosis (FALS). In sporadic cases (SALS) de novo mutations in the Sod1 gene have occasionally been observed. The recent finding of a mutation in the VAMP/synaptobrevin-associated membrane protein B (VAPB) gene as the cause of amyotrophic lateral sclerosis (ALS8), prompted us to investigate the entire coding region of this gene in SALS patients. One hundred twenty-five unrelated patients with adult-onset ALS and 150 healthy sex-age-matched subjects with the same genetic background were analyzed. Genetic analysis for all exons of the VAPB gene by DHPLC revealed 5 variant profiles in 83 out of 125 SALS patients. Direct sequencing of these PCR products revealed 3 nucleotide substitutions. Two of these were found within intron 3 of the gene, harbouring 4 variant DHPLC profiles. The third nucleotide variation (Asp130Glu) was the only substitution present in the coding region of the VAPB gene, and it occurred within exon 4. It was found in three patients out of 125. The frequency of the detected exon variation in the VAPB gene was not significantly different between patients and controls. In conclusion, our study suggests that VAPB mutations are not a common cause of adult-onset SALS.

Adult↗