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Results for “Phenotype modifier”

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PubMed1967

A new Vi-phage-type of Salmonella typhi and preparation of the typing phage.

A new Vi-phage-type of Salmonella typhi, type F(7), isolated in Poland in 1963, is described. The homologous typing phage was prepared from phage F(1). The new Vi-phage-type belongs to the F group and its "precursor" is type F(1). No temperate type-determining phage has so far been isolated from this phage-type. The homologous typing phage F(7) is a phenotypically modified host-range mutant of Vi-phage II; its phenotype is F(1) and the genotype is that found in phage 35, and is related to phage C(11).

Bacteriophage Typing↗

PubMed1982

Characterization of N-type and dually permissive cells segregated from mouse fibroblasts whose Fv-1 phenotype could be modified by another independently segregating gene(s).

Though the inbred DDD mouse strain is essentially of the N type, the primary culture of this strain was about 100-fold more sensitive to B-tropic WN1802B virus than were the typical N-type strains (C3H/He, C57L, etc.). After cloning, DDD mouse cells segregated two types of cells, typical N-type cells and cells lacking in Fv-1 restriction. As both types of cells so far tested retained glucose-6-phosphatase-1 coded by a locus closely linked to Fv-1 and genetic cross experiments indicated the presence of a gene(s) modifying the Fv-1 phenotype, variation in Fv-1 restriction could presumably be brought about by genetic changes in a gene(s) other than Fv-1 itself. N-type and dually permissive cell clones were similarly established from the inbred G mouse. Compositions of polypeptides labeled with [35S]methionine in the N-type and dually permissive cells of DDD and G mouse origins were compared by two-dimensional gel electrophoresis. The polypeptide maps of these cells were similar except for a few spots. Among these dissimilar spots, a spot of about 20,000 daltons with a pI of about 5.5 was always present in N-type cells, whereas it was absent in dually permissive cells. In DDD mouse-derived clones, a proportional relation was observed between the intensity of the spot and the restriction to the B-tropic virus.

Animals↗

PubMed1994

Selection at the diazinon resistance locus in overwintering populations of Lucilia cuprina (the Australian sheep blowfly).

In excess of 70 per cent mortality is observed during the overwintering stage of the life cycle of L. cuprina. The mortality is selective in the absence of a fitness modifier; phenotypes resistant to diazinon overwinter less successfully than susceptibles. In the presence of the modifier the overwintering success of all genotypes is similar. The effect is dominant. Laboratory and field experiments show that selection against resistant individuals increases with time in arrested development. The relevance of these results to the evolution of insecticide resistance is discussed.

Animals↗

PubMed1989

Neurotransmitter phenotype plasticity in cultured dissociated adult rat dorsal root ganglia: an immunocytochemical study.

Culturing sympathetic ganglion neurons in vitro may modify phenotypic expression of some neurotransmitters. For dorsal root ganglia (DRG), contradictory results have been reported; most studies have used immature material. We have therefore performed a detailed immunocytochemical analysis of the transmitter content of cultured adult rat DRG neurons. To demonstrate possible modifications of neurotransmitter phenotypes, we have compared the results obtained with the same techniques on neurons cultured for 3 days and on freshly dissociated DRG cells. Also, the transmitter profile of cultured neurons was compared with that known from in situ studies. Out of 22 antigens studied, 20 were detected in cultured DRG neurons. All of them were expressed in small and/or intermediate-sized cells. Large neurons only contained CGRP, VIP, NPY, beta-END, ENK, and GABA. The percentage of immunostained neurons varied for the various antisera: less than 10% of cultured neurons were positive for ENK, beta-LPH, beta-END, DYN, VASO, and OXY; 10-30% for SOM, CCK, CAT, and SP; and greater than 30% for NPY, CRF, GLU, NT, VIP, GABA, GRP, CGRP, 5-HT, and TRH. In the latter two groups of transmitters (except CGRP), the proportion of immunoreactive neurons was by far larger in cultured than in freshly dissociated DRG. The most pronounced (greater than 25%) increase in the proportion of positively stained neurons after culturing was observed for the GRP, CRF, TRH, and 5-HT antisera. Serotonin was the only transmitter identified in cultured but not in freshly dissociated cells. These data indicate, on one hand, that various antigens, for example, CAT, GABA, NT, TRH, NPY, beta-LPH, and beta-END, which up to now have not been described in DRG in situ, can be detected immunocytochemically a few hours after dissociation of adult rat DRG. On the other hand, several transmitters, for example, VIP, NPY, SP, GABA, GLU, NT, GRP, CRF, TRH, and 5-HT, are expressed in a significantly higher proportion of cells in cultured than in freshly dissociated preparations. This might reflect a change in the phenotypic expression of transmitters due to the new environment generated by the culture conditions, a hypothesis that can be tested by measuring specific mRNA levels. Moreover, considering the plasticity and multipotentiality of their transmitter phenotype, cultured adult DRG neurons might represent an interesting material for autografts into the injured central nervous system.

Animals↗

PubMed1999

A Drosophila Axin homolog, Daxin, inhibits Wnt signaling.

The vertebrate Axin protein, the product of the mouse fused gene, binds to beta-catenin to inhibit Wnt signaling. We have identified a homolog of Axin in Drosophila, Daxin. Using double-stranded RNA interference, we generated loss-of-function phenotypes that are similar to overexpression of the Drosophila Wnt gene wingless (wg). Overexpression of Daxin produces phenotypes similar to loss of wg. In addition, we show that Daxin overexpression can modify phenotypes elicited by wg and another Drosophila Wnt gene, DWnt-2. Using immunoprecipitation of endogenous Daxin protein from embryos we show that Daxin interacts with Armadillo and Zeste-white 3. The loss-of-function and overexpression phenotypes show that Daxin, like its mammalian counterpart, acts as a negative regulator of wg/Wnt signaling.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Chimerism in grapevines: implications for cultivar identity, ancestry and genetic improvement.

In the course of DNA profiling of grapevine cultivars using microsatellite loci we have occasionally observed more than two alleles at a locus in some individuals and have identified periclinal chimerism as the source of such anomalies. This phenomenon in long-lived clonally propagated crops, such as grapevine, which contains historically ancient cultivars, may have a role in clonal differences and affect cultivar identification and pedigree analysis. Here we show that when the two cell layers of a periclinal chimera, Pinot Meunier, are separated by passage through somatic embryogenesis the regenerated plants not only have distinct DNA profiles which are different from those of the parent plant but also have novel phenotypes. Recovery of these phenotypes indicates that additional genetic differences can exist between the two cell layers and that the Pinot Meunier phenotype is due to the interaction of genetically distinct cell layers. It appears that grapevine chimerism can not only modify phenotype but can also impact on grapevine improvement as both genetic transformation and conventional breeding strategies separate mutations in the L1 and L2 cell layers.

Journal Article↗

PubMed1997

Genetic disorders of cardiac morphogenesis. The DiGeorge and velocardiofacial syndromes.

The phenotype associated with a 22q11 deletion is highly variable and still under investigation. Of particular interest to cardiologists and cardiac developmental biologists is the finding that many patients with a 22q11 deletion have conotruncal cardiac defects and aortic arch anomalies. Despite the phenotypic variability, the vast majority of patients have a similar large deletion spanning approximately 2 megabases. The low-frequency repeated sequences at either end of the commonly deleted region may be responsible for the size of the deletion and account for the instability of this chromosomal region. Molecular studies of patients with the DGS/VCFS phenotype and unique chromosomal rearrangements have allowed a minimal critical region for the disease to be defined. Multiple genes have been identified in the minimal critical and larger deleted region. These genes are being investigated for their potential role in the disease pathophysiology by screening for mutations in nondeleted patients with the phenotype and by analysis of the pattern of expression in the developing mouse embryo. Further experimentation in the mouse mammalian model system will be of great utility to help determine whether haploinsufficiency of one critical gene or several genes within the DGCR results in the disease phenotype. Modifying factors, both genetic and environmental, must also be considered. Further investigation into the disease mechanism leading to the DGS/VCFS phenotype will hopefully further our understanding of cardiac development and disease.

Chromosome Deletion↗

PubMed2000

The androgen receptor exon 1 trinucleotide repeat does not act as a modifier of the age of presentation in breast cancer.

The CAG repeat in exon 1 of the androgen receptor (AR) genes has been postulated as both a susceptibility allele and phenotypic modifier in BRCA1-associated breast cancers. We have analysed this repeat in a set of 178 breast cancer cases who have been selected only for age of presentation at 65 years or less. No effect of repeat length on age of presentation was found and there was no association between repeat length and family history. In combination with the data from other workers, our findings suggest that the androgen receptor repeat does not act as a modifier gene or susceptibility locus outside the context of the hereditary breast/ovarian cancer syndrome.

Adult↗

PubMed1997

Rufous oculocutaneous albinism in southern African Blacks is caused by mutations in the TYRP1 gene.

Oculocutaneous albinism (OCA) is the most common autosomal recessive disorder among southern African Blacks. There are three forms that account for almost all OCA types in this region. Tyrosinase-positive OCA (OCA2), which is the most common, affects approximately 1/3,900 newborns and has a carrier frequency of approximately 1/33. It is caused by mutations in the P gene on chromosome 15. Brown OCA (BOCA) and rufous OCA (ROCA) account for the majority of the remaining phenotypes. The prevalence of BOCA is unknown, but for ROCA it is approximately 1/8,500. Linkage analysis performed on nine ROCA families showed that ROCA was linked to an intragenic marker at the TYRP1 locus (maximum LOD score = 3.80 at straight theta=.00). Mutation analysis of 19 unrelated ROCA individuals revealed a nonsense mutation at codon 166 (S166X) in 17 (45%) of 38 ROCA chromosomes, and a second mutation (368delA) was found in an additional 19 (50%) of 38 chromosomes; mutations were not identified in the remaining 2 ROCA chromosomes. In one family, two siblings with a phenotypically unclassified form of albinism were found to be compound heterozygotes for mutations (S166X/368delA) at the TYRP1 locus and were heterozygous for a common 2.7-kb deletion in the P gene. These findings have highlighted the influence of genetic background on phenotype, in which the genotype at one locus can be influenced by the genotype at a second locus, leading to a modified phenotype. ROCA, which in southern African Blacks is caused by mutations in the TYRP1 gene, therefore should be referred to as "OCA3," since this is the third locus that has been shown to cause an OCA phenotype in humans.

Africa, Southern↗

PubMed2002

Modifier genes in haemophilia: their expansion in the human genome.

Mutations in factor VIII and IX genes have a determinant effect on the severity of haemophilia. Modulation of clinical manifestations depends on other genetic factors, including modifier genes. In the context of haemophilia, such genes could be the ones involved in thrombophilia. Factor V Leiden and prothrombin 20210A were studied as possible phenotypic modifiers. Inhibitor development after therapeutic factor replacement depends on the type of mutation and on the genetic factors related to the immune response of each patient. The study of all these variants in haemophiliacs constitutes an important step in prevention, prognosis and therapeutic alternatives of the disease.

Factor VIII↗

PubMed2006

A sex-linked allele, autosomal modifiers and temperature-dependence appear to regulate melanism in male mosquitofish (Gambusia holbrooki).

About 1% of male mosquitofish (Gambusia holbrooki) express melanic (mottled-black) body coloration, which differs dramatically from the wild-type, silvery-gray coloration. Here, I report on the genetic inheritance pattern of melanic coloration, which indicates Y-linkage, and at least one autosomal modifier. Phenotypic expression of melanism is also affected by temperature. Expression is constitutive (temperature insensitive) in some populations, inducible (temperature sensitive) in others. Constitutive and inducible expression occur among geographically proximal populations. However, males from any single population demonstrate the same constitutive or inducible expression pattern as one another. The F1 males from inter-population crosses demonstrate temperature-related expression patterns like their sires'. As well, the sex ratio of melanic males' progeny differs among populations. Here, inter-population crosses demonstrate a sex-ratio bias in the same direction as intra-population crosses of the sire population. About 20% of the male progeny of melanic sires express the wild-type phenotype. These silver F1 males sire only silver offspring, suggestive of loss of the melanin gene in F1 males from crossover between sex chromosomes, or control by additional modifiers, or involvement of additional factors. In nature, melanic males persist at very low frequencies. The data collected here on heritability indicate that genetic factors contribute to the rarity of melanic male mosquitofish.

Animals↗

PubMed2004

Reference intervals for thiopurine S-methyltransferase activity in red blood cells using 6-thioguanine as substrate and rapid non-extraction liquid chromatography.

BACKGROUND: Although widely used, thiopurine drugs have a narrow therapeutic index and treatment can result in life-threatening toxicity, the basis being pharmacogenetic variation in thiopurine metabolism by thiopurine S-methyltransferase (TPMT). We recently developed a modified phenotyping assay to determine TPMT activity in red blood cells. Here we describe improvements to the method and establish reference intervals in a large prospective study. METHODS: A modified enzyme assay for TPMT activity is reported. It uses 6-thioguanine as substrate with heat treatment of the incubate to stop the reaction and precipitate protein prior to high-performance liquid chromatographic (HPLC) analysis. Measurement of the reaction product, 6-methylthioguanine (6-MTG), uses HPLC with fluorimetric detection. RESULTS: The assay shows excellent characteristics, with clear discrimination of patients who are deficient in TPMT activity (< 5 nmol 6-MTG per g Hb per h) from heterozygotes (5-24 nmol 6-MTG per g Hb per h) and patients with normal activity (>25 nmol 6-MTG per g Hb per h). CONCLUSION: A modified TPMT assay is described which is suited for routine analysis in a regional centre. The method overcomes the need for extraction and has speeded up the chromatographic determination of 6-MTG, enabling large numbers of samples to be analysed. A prospective study of 1000 individuals has established the distribution of TPMT activity using the assay.

Adolescent↗

PubMed2004

Phenotypic variability associated with Arg26Gln mutation in caveolin3.

Caveolin3 (CAV3) is a protein associated with dystrophin, dystrophin-associated glycoproteins, and dysferlin. Mutations in the CAV3 gene result in certain autosomal-dominant inherited diseases, namely, rippling muscle disease (RMD), limb-girdle muscular dystrophy type 1C (LGMD1C), distal myopathy, and hyperCKemia. In this report we show that a previously reported family with RMD has a mutation in the CAV3 gene. Affected individuals had either a characteristic RMD phenotype, a combination of RMD and LGMD1C phenotypes, or a LGMD1C phenotype, but one mutation carrier was asymptomatic at age 86 years. This phenotypic variability associated with mutations in CAV3 has been reported previously but only in a few families. It is important to remember the significant phenotypic variability associated with CAV3 mutations when counseling families with these mutations. These observations also suggest the presence of factors independent of the CAV3 gene locus that modify phenotype.

Aged↗

PubMed1999

Transcriptional down-regulation of the rabbit pulmonary artery endothelin B receptor during phenotypic modulation.

1. We confirmed that endothelium-independent contraction of the rabbit pulmonary artery (RPA) is mediated through both an endothelin A (ET(A)R) and endothelin B (ET(B2)R) receptor. 2. The response of endothelium-denuded RPA rings to endothelin-1 (ET-1, pD2 = 7.84 +/- 0.03) was only partially inhibited by BQ123 (10 microM), an ET(A)R antagonist. 3. Pretreatment with 1 nM sarafotoxin S6c (S6c), an ET(B)R agonist, desensitized the ET(B2)R and significantly attenuated the response to ET-3 (pD2 = 7.40 +/- 0.02 before, <6.50 after S6c). 4. Pretreatment with S6c had little effect on the response to ET-1, but BQ123 (10 microM) caused a parallel shift to the right of the residual ETAR-mediated response to ET-1 (pD2 = 7.84 +/- 0.03 before S6c, 7.93 +/- 0.03 after S6c, 6.81 +/- 0.05 after BQ123). 5. Binding of radiolabelled ET-1 to early passage cultures of RPA vascular smooth muscle cells (VSMC) displayed two patterns of competitive displacement characteristic of the ET(A)R (BQ123 pIC50 = 8.73 +/- 0.05) or ET(B2)R (S6c pIC50 = 10.15). 6. Competitive displacement experiments using membranes from late passage VSMC confirmed only the presence of the ET(A)R (ET-1 pIC50 = 9.3, BQ123 pIC50 = 8.0, S6c pIC50 < 6.0). 7. The ET(A)R was functionally active and coupled to rises in intracellular calcium which exhibited prolonged homologous desensitization. 8. Using a reverse transcriptase polymerase chain reaction for the rabbit ET(B2)R, we demonstrated the absence of mRNA expression in phenotypically modified VSMC. 9. We conclude that the ET(B2)R expressed by VSMC which mediates contraction of RPA is rapidly down-regulated at the transcriptional level during phenotypic modulation in vitro.

Animals↗

PubMed1998

The system of phytochromes: photobiophysics and photobiochemistry in vivo.

Phytochrome is a key photoregulation pigment in plants which determines the strategy of their development throughout their life cycle. The major achievement in the recent investigations of the pigment is the discovery of its structural and functional heterogeneity: existence of a family of phytochromes (phyA-phyE) differing by the apoprotein was demonstrated. We approach this problem by investigating the chromophore component of the pigment with the use of the developed method of in vivo low-temperature fluorescence spectroscopy of phytochrome. In etiolated plants, phytochrome fluorescence was detected and attributed to its red-light absorbing form (Pr) and the first photoproduct (lumi-R), and a scheme of the photoreaction in phytochrome, a distinction of which is the activation barrier in the excited state, was put forward. It was found that the spectroscopic and photochemical characteristics of Pr depend on the plant species and phytochrome mutants and overexpressors used, on localization of the pigment in organs and tissues, plant age, effect of preillumination and other physiological factors. This variability of the parameters was interpreted as the existence of at least two phenomenological Pr populations, which differ by their spectroscopic characteristics and activation parameters of the Pr --> lumi-R photoreaction (in particular, by the extent of the Pr --> lumi-R photoconversion at low temperatures, gamma1): the longer-wavelength major and variable by its content in plant tissues Pr' with gamma1 = 0.5 and the shorter-wavelength minor relatively constant Pr" with gamma1 < or = 0.05. The analysis of the phytochrome mutants and overexpressors allows a conclusion that phytochrome A (phyA), which dominates in etiolated seedlings, is presented by two isoforms attributed to Pr' and Pr" (phyA' and phyA", respectively). Phytochrome B (phyB) accounts for less than 10% of the total phytochrome fluorescence and belongs to the Pr" type. It is also characterized by the relatively low extent of the Pr photoconversion into the far-red-light absorbing physiologically active phytochrome form, Pfr. Fluorescence of the minor phytochromes (phyC-phyE) is negligible. The recently discovered phytochrome of the cyanobacterium Synechocystis also belongs to the phenomenological Pr" type. PhyA' is a light-labile and soluble fraction, while phyA" is a relatively light-stable and, possibly, membrane (protein)-associated. Experiments with transgenic tobacco plants overexpressing full-length and C- and N-terminally truncated oat phytochrome A suggest that phyA' and phyA" might differ by the post-translational modification of the small N-terminal segment (amino acid residues 7-69) of the pigment. PhyA' is likely to be active in the de-etiolation processes while phyA" together with phyB, in green plants as revealed by the experiments on transgenic potato plants and phytochrome mutants of Arabidopsis and pea with altered levels of phytochromes A and B and modified phenotypes. And finally, within phyA', there are three subpopulations which are, possibly, different conformers of the chromophore. Thus, there is a hierarchical system of phytochromes which include: (i) different phytochromes; (ii) their post-translationally modified states and (iii) conformers within one molecular type. Its existence might be the rationale for the multiplicity of the photoregulation reactions in plants mediated by phytochrome.

Biochemical Phenomena↗

PubMed2002

DiGeorge syndrome: the use of model organisms to dissect complex genetics.

The research interest in DiGeorge syndrome (DGS) is partly due to its clinical importance. However, fundamental questions of genetics and developmental biology related to DGS are inspiring investigators to experiment with model systems. Most DGS cases are caused by a heterozygous chromosomal deletion del22q11, and the search for haploinsufficient genes has been successful in mice and led to the discovery of Tbx1 as a major player in the development of the pharyngeal arches and pouches. Whether TBX1 is haploinsufficient in humans, as several other T-box genes are, is yet to be proven. The puzzling clinical variability in patients with del22q11 is also being addressed in model organisms. Consistent with clinical data, experiments in mice indicate that genetics can only explain part of the phenotypic variability. The recent identification of phenotypic modifiers further underscores the complex genetics of this syndrome.

Animals↗

PubMed2002

Genetic modifiers of otocephalic phenotypes in Otx2 heterozygous mutant mice.

Mice heterozygous for the Otx2 mutation display a craniofacial malformation, known as otocephaly or agnathia-holoprosencephaly complex. The severity of the phenotype is dependent on the genetic background of a C57BL/6 (B6) strain; most of the offspring of Otx2 knock-out chimeras, which are equivalent to the F(1) of CBA and B6 strains, backcrossed with B6 females display reduction or loss of mandible, whereas those backcrossed with CBA females do not show noticeable phenotype at birth. The availability of phenotypically disparate strains renders identification of Otx2 modifier loci possible. In this study, a backcross of chimera with B6 was generated and genome-wide scans were conducted with polymorphic markers for non-mendelian distribution of alleles in Otx2 heterozygous mutant mice displaying abnormalities in the lower jaw. We identified one significant locus, Otmf18, between D18Mit68 and D18Mit120 on chromosomes 18, linked to the mandibular phenotype (LOD score 3.33). A similar replication experiment using a second backcross (N3) mouse demonstrated the presence of another significant locus, Otmf2 between D2Mit164 and D2Mit282 on chromosome 2, linked to the mandibular phenotype (LOD score 3.93). These two modifiers account for the distribution of the craniofacial malformations by the genetic effect between B6 and CBA strains. Moreover, Otmf2 contain a candidate gene for several diseases in mice and humans. These genetic studies involving an otocephalic mouse model appear to provide new insights into mechanistic pathways of craniofacial development. Furthermore, these experiments offer a powerful approach with respect to identification and characterization of candidate genes that may contribute to human agnathia-holoprosencephaly complex diseases.

Animals↗

PubMed1972

Isolation and classification of extranuclear mutants of Neurospora crassa.

Four extranuclear mutants, [exn-1], [exn-2],[exn-4], and [stp-C], were obtained from N-methyl-N'-nitro-N-nitrosoguanidine-treated conidia and mycelium of Neurospora crassa. The three exn mutants grow with a pronounced lag from conidia and ascospores and are female fertile, whereas [stp-C] has a stop-start growth phenotype and is female sterile. The mitochondria from all four mutants are deficient in cytochromes a+a(3) and b, but contain an excess of cytochrome c. On the basis of growth and fertility, nuclear suppressors and complementation in heteroplasmons, 16 of the extranuclear mutants now available in Neurospora can be divided into three groups. Group I consists of 8 female-fertile variants with both poky-like growth and cytochrome defects. Their slow growth is suppressed by the nuclear factor, f, but not by a second nuclear suppressor, su-1([mi-3]). They complement with group III mutants in mixed cytoplasmons. Group II is represented by a single variant, [mi-3]. It is phenotypically modified by the su-1([mi-3]) factor, but not by f. Its unique cytochrome spectrum shows a deficiency of cytochrome a, but c and b are present. It complements in heteroplasmons with group I and III mutants. Group III included 7 female-sterile variants with stopper growth phenotypes and the same cytochrome defects as group I. Group III mutants complement both with group I and II isolates, but they are unaffected by either f or su-1.

Crosses, Genetic↗