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At least 145 records · Page 8Linked to original sources
PubMed2002

Genetic dissection of the human leukocyte antigen region by use of haplotypes of Tasmanians with multiple sclerosis.

Association of multiple sclerosis (MS) with the human leukocyte antigen (HLA) class II haplotype DRB1*1501-DQB1*0602 is the most consistently replicated finding of genetic studies of the disease. However, the high level of linkage disequilibrium (LD) in the HLA region has hindered the identification of other loci that single-marker tests for association are unlikely to resolve. In order to address this issue, we generated haplotypes spanning 14.754 Mb (5 cM) across the entire HLA region. The haplotypes, which were inferred by genotyping relatives of 152 patients with MS and 105 unaffected control subjects of Tasmanian ancestry, define a genomic segment from D6S276 to D6S291, including 13 microsatellite markers integrated with allele-typing data for DRB1 and DQB1. Association to the DRB1*1501-DQB1*0602 haplotype was replicated. In addition, we found that the class I/extended class I region, defined by a genomic segment of approximately 400 kb between MOGCA and D6S265, harbors genes that independently increase risk of, or provide protection from, MS. Log-linear modeling analysis of constituent haplotypes that represent genomic regions containing class I (MOGCA-D6S265), class III (TNFa-TNFd-D6S273), and class II (DRB1-DQB1) genes indicated that having class I and class II susceptibility variants on the same haplotype provides an additive effect on risk. Moreover, we found no evidence for a disease locus in the class III region defined by a 150-kb genomic segment containing the TNF locus and 14 other genes. A global overview of LD performed using GOLD identified two discrete blocks of LD in the HLA region that correspond well with previous findings. We propose that the analysis of haplotypes, by use of the types of approaches outlined in the present article, should make it possible to more accurately define the contribution of the HLA to MS.

Alleles↗
PubMed1999

Genetic dissection of Sle pathogenesis: Sle3 on murine chromosome 7 impacts T cell activation, differentiation, and cell death.

Polyclonal, generalized T cell defects, as well as Ag-specific Th clones, are likely to contribute to pathology in murine lupus, but the genetic bases for these mechanisms remain unknown. Mapping studies indicate that loci on chromosomes 1 (Sle1), 4 (Sle2), 7 (Sle3), and 17 (Sle4) confer disease susceptibility in the NZM2410 lupus strain. B6.NZMc7 mice are C57BL/6 (B6) mice congenic for the NZM2410-derived chromosome 7 susceptibility interval, bearing Sle3. Compared with B6 controls, B6.NZMc7 mice exhibit elevated CD4:CD8 ratios (2.0 vs 1.34 in 1- to 3-mo-old spleens); an age-dependent accumulation of activated CD4+ T cells (33.4% vs 21.9% in 9- to 12-mo-old spleens); a more diffuse splenic architecture; and a stronger immune response to T-dependent, but not T-independent, Ags. In vitro, Sle3-bearing T cells show stronger proliferation, increased expansion of CD4+ T cells, and reduced apoptosis (with or without anti-Fas) following stimulation with anti-CD3. With age, the B cells in this strain acquire an activated phenotype. Thus, the NZM2410 allele of Sle3 appears to impact generalized T cell activation, and this may be causally related to the low grade, polyclonal serum autoantibodies seen in this strain. Epistatic interactions with other loci may be required to transform this relatively benign phenotype into overt autoimmunity, as seen in the NZM2410 strain.

Animals↗
PubMed1998

Genetic dissection of murine susceptibilities to liver and lung tumors based on the two-stage concept of carcinogenesis.

Inbred mouse strains exhibit strain-specific susceptibilities to spontaneous and induced tumors, indicating that the individual risks for neoplastic development are largely under genetic control. Recent advances in linkage analysis have made it routine to chromosomally map the mouse genes responsible for the strain variations in tumor susceptibility using segregating crosses. It is also possible to characterize their biological functions using the positional information. These types of studies are still severely hampered for human cases due to the remarkable genetic heterogeneity and impossibility of experimental crosses. In this article, previous work on genetic susceptibility to mouse liver and lung tumors is reviewed in view of the classical two-stage concept of carcinogenesis. According to this central concept, the tumor susceptibility genes should affect either the first stage, 'initiation', or the second stage, 'promotion', or both. At least some genes seem to be specifically involved in initiation or promotion, in line with the fact that initiation and promotion are due, to a certain extent, to independent mechanisms. This notion should be also applicable to human carcinogenesis and may provide important clues for prevention of initiation and promotion in populations with a genetic predisposition for cancer development.

Animals↗
PubMed1995

Genetic dissection of the molecular mechanisms of transmitter vesicle release during synaptic transmission.

Over the last few years there has been rapid progress in our understanding of the molecular mechanisms of synaptic transmission. This advance is largely due to the convergence of biochemical and genetic approaches to identify a discrete set of synaptic proteins associated with transmitter vesicles and their specialized fusion sites in the presynaptic membrane. The fruitfly, Drosophila melanogaster, is an attractive system to further such studies where we can combine sophisticated molecular genetic manipulations with direct observation of synaptic phenotypes at the well-characterized neuromuscular junction (NMJ). So far, five essential synaptic proteins have been identified in Drosophila and genetically modified or removed from the synapse: synaptotagmin, synaptobrevin (also called VAMP), syntaxin, Rop (Drosophila n-sec1 homologue) and cysteine string protein (csp). We are presently characterizing the functional roles of these identified proteins using electrophysiological and ultrastructural analyses of genetic mutants. In this article I review our current knowledge of these five proteins in Drosophila and discuss their possible functional roles in the molecular machinery governing synaptic transmission.

Animals↗
PubMed1994

Genetic dissection of consolidated memory in Drosophila.

Behavioral and pharmacological experiments in many animal species have suggested that memory is consolidated from an initial, disruptable form into a long-lasting, stable form within a few hours after training. We combined these traditional approaches with genetic analyses in Drosophila to show that consolidated memory of conditioned (learned) odor avoidance 1 day after extended training consisted of two genetically distinct, functionally independent memory components: anesthesia-resistant memory (ARM) and long-term memory (LTM). ARM decayed away within 4 days, was resistant to hypothermic disruption, was insensitive to the protein synthesis inhibitor cycloheximide (CXM), and was disrupted by the radish single-gene mutation. LTM showed no appreciable decay over 7 days, was sensitive to CXM, and was not disrupted by the radish mutation.

Animals↗
PubMed1998

Genetic dissection of SLE pathogenesis. Sle1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnucleosomes.

One of the hallmarks of SLE is the loss of tolerance to chromatin. The genes and mechanisms that trigger this loss of tolerance remain unknown. Our genetic studies in the NZM2410 lupus strain have implicated genomic intervals on chromosomes 1 (Sle1), 4 (Sle2), and 7 (Sle3) as conferring strong lupus susceptibility. Interestingly, B6 mice that are congenic for Sle1 (B6.NZMc1) have elevated IgG antichromatin Abs. This study explores the antinuclear antibody fine specificities and underlying cellular defects in these mice. On the B6 background, Sle1 by itself is sufficient to generate a robust, spontaneous antichromatin Ab response, staining Hep-2 nuclei homogeneously, and reacting primarily with H2A/H2B/DNA subnucleosomes. This targeted immune response peaks at 7-9 mo of age, affects both sexes with equally high penetrance (> 75%), and interestingly, does not "spread" to other subnucleosomal chromatin components. Sle1 also leads to an expanded pool of histone-reactive T cells, which may have a role in driving the anti-H2A/H2B/DNA B cells. However, these mice do not exhibit any generalized immunological defects or quantitative aberrations in lymphocyte apoptosis. We hypothesize that Sle1 may lead to the presentation of chromatin in an immunogenic fashion, or directly impact tolerance of chromatin-specific B cells.

Animals↗
PubMed2002

Genetic dissection of pathotype-specific resistance to ascochyta blight disease in chickpea (Cicer arietinum L.) using microsatellite markers.

Ascochyta blight is an economically important disease of chickpea caused by the fungus Ascochyta rabiei. The fungus shows considerable variation for pathogenicity in nature. However, studies on the genetics of pathotype-specific resistance are not available for this plant-pathosystem. The chickpea landrace ILC 3279 has resistance to pathotype I and II of the pathogen. In order to understand the inheritance of pathotype-specific resistance in this crop, both Mendelian and quantitative trait loci analyses were performed using a set of intraspecific, recombinant inbred lines derived from a cross between the susceptible accession ILC 1272 and the resistant ILC 3279, and microsatellite markers. We identified and mapped a major locus (ar1, mapped on linkage group 2), which confers resistance to pathotype I, and two independent recessive major loci (ar2a, mapped on linkage group 2 and ar2b, mapped on linkage group 4), with complementary gene action conferring resistance to pathotype II. Out of two pathotype II-specific resistance loci, one (ar2a) linked very closely with the pathotype I-specific resistance locus, indicating a clustering of resistance genes in that region of the chickpea genome.

Ascomycota↗
PubMedDate not supplied

Genetic dissection of a major Fusarium head blight QTL in tetraploid wheat.

The devastating effect of Fusarium head blight (FHB) caused by Fusarium graminearum has led to significant financial losses across the Upper Midwest of the USA. These losses have spurred the need for research in biological, chemical, and genetic control methods for this disease. To date, most of the research on FHB resistance has concentrated on hexaploid wheat (Triticum aestivum L.) lines originating from China. Other sources of resistance to FHB would be desirable. One other source of resistance for both hexaploid wheat and tetraploid durum wheat (T. turgidum L. var. durum) is the wild tetraploid, T. turgidum L. var. dicoccoides (T. dicoccoides). Previous analysis of the 'Langdon'-T. dicoccoides chromosome substitution lines, LDN(Dic), indicated that the chromosome 3A substitution line expresses moderate levels of resistance to FHB. LDN(Dic-3A) recombinant inbred chromosome lines (RICL) were used to generate a linkage map of chromosome 3A with 19 molecular markers spanning a distance of 155.2 cM. The individual RICL and controls were screened for their FHB phenotype in two greenhouse seasons. Analysis of 83 RICL identified a single major quantitative trait locus, Qfhs.ndsu-3AS, that explains 37% of the phenotypic or 55% of the genetic variation for FHB resistance. A microsatellite locus, Xgwm2, is tightly linked to the highest point of the QTL peak. A region of the LDN (Dic-3A) chromosome associated with the QTL for FHB resistance encompasses a 29.3 cM region from Xmwg14 to Xbcd828.

Chromosome Mapping↗
PubMed2005

Genetic dissection of gene expression observed in whole blood samples of elderly Danish twins.

The microarray technique is an important tool in gene expression analysis to study the activities of thousands of genes measured by their transcript levels under disease or laboratory controlled experimental conditions. Recent studies have suggested a genetic component in the variations of gene expression thus indicating the important role of genetic control over gene activities. In this study, we analyze and report the twin correlation on gene expression in whole blood samples of six female Danish twin pairs aged from 81 to 85 years. We studied the expression phenotype by treating the measured gene expression as a quantitative trait and introducing analytical approaches including the traditional twin methods in population genetics and the multivariate statistical methods. Using this combinatory approach, we were able to estimate and compare the twin correlation on the expression phenotype while accounting for systematic influence in microarray experiments. Analyses on our twin data detected a significant correlation on the expression levels of the actively regulated genes in both monozygotic and dizygotic twins, which is more pronounced in monozygotic twins. Gene ontology analysis has shown that these actively regulated genes are predominantly involved in defense and immune responses against antigenic stimulus. In conclusion, the correlation patterns revealed in our twin data provide evidence of the existence of a heritable mechanism in gene expression regulation persistently functioning even in aged subjects.

Aged↗
PubMed1998

Experimental strategies for the genetic dissection of complex traits in animal models.

Current success in detecting complex trait loci in general, and quantitative trait loci (QTLs) using model organisms in particular, has attracted major biological and biomedical interest. The potential ability to identify genes and their function provides opportunities for new diagnostics and treatments of complex genetic diseases. Despite the success in gene mapping, however, cloning of complex trait loci or QTLs is not straightforward. A major obstacle lies in achieving fine mapping resolution for the detected loci. Compared to the rapid development of sophisticated statistical and molecular tools, development and analysis of experimental designs for various stages in QTL mapping experiments have barely been considered. In this study, novel and existing experimental strategies for QTL analysis are presented and evaluated.

Animals↗
PubMed2002

Genetic dissection of femur breaking strength in a large population (MRL/MpJ x SJL/J) of F2 Mice: single QTL effects, epistasis, and pleiotropy.

Bone breaking strength is an ultimate measurement of the risk of fracture. For a practical reason, bone mineral density (BMD) has been commonly used for predicting the risk instead. To identify genetic loci influencing femur-breaking strength (FBS), which was measured by three-point bending using an Instron DynaMight Low-Force Testing System, the whole-genome scan was carried out using 119 polymorphic markers in 633 (MRLxSJL) F2 female mice. We identified six significant quantitative trait loci (QTL) affecting bone breaking strength on chromosomes 1, 2, 8, 9, 10, and 17, which together explained 23% of F2 variance. Of those, the QTL on chromosomes 2, 8, and 10 seem to be unique to bone breaking strength, whereas the remaining three QTL are concordant with femur BMD QTL. Genetic analysis suggests that, of these six FBS QTL, three influence BMD, two influence bone quality, and one influences bone size. We detected multiple significant epistatic interactions for FBS, which accounts for half (14.6%) of F2 variance compared with significant single QTL effects. We found evidence that pleiotropic effect might represent a common genetic mechanism to coordinately regulate bone-related phenotypes. Pleiotropic analysis also suggests that our current threshold level for significant QTL may be too high to detect biologically significant QTL with small effect. Together with epistatic interactions, these undetected small QTL could explain 30% of genetic variance that remains unaccounted for in this study (heritability estimate for FBS is 68%). Our findings in single QTL effects, epistasis, and pleiotropy demonstrate that partially overlapped but distinct combinations of genetic loci in MRL/MpJ and SJL/J inbred strains of mice regulate bone strength and bone density. Identification of the genes unique to FBS may have an impact on prediction of osteoporosis in human.

Animals↗
PubMed1995

Genetic dissection of intersubunit contacts within human protein kinase CK2.

The activity of the catalytic alpha subunits of protein kinase CK2 is modulated by interaction with the regulatory beta subunits. In order to define the domains involved in intersubunit contacts, we have applied the two-hybrid system, which a is yeast-based genetic method for the detection of protein-protein interactions in vivo. The data demonstrate that the alpha and beta subunits interact with each other and that the beta subunits, but not the alpha subunits, are able to self-associate. This suggests that the beta subunits play a bridging role in the architecture of the CK2 holoenzyme by linking two alpha:beta heterodimers into a tetrameric complex. Analysis of truncated alpha and beta subunits was used to delimit the subregions necessary for complex formation. The data reveal that the beta subunit is modular in structure, with the two fully separable domains involved in homomeric beta:beta and heteromeric alpha:beta interactions, respectively. Also, beta subunits lacking the autophosphorylation sites in the N termini are able to associate with both the alpha and beta subunits. Furthermore, we find that the N terminus and the evolutionarily less conserved C terminus of the alpha subunit are dispensable for establishing heterodimeric alpha:beta structures.

Base Sequence↗
PubMed1991

From genes to tensile forces: genetic dissection of contractile protein assembly and function in Drosophila melanogaster.

Myofibrils, the contractile organelles of skeletal muscle, are highly ordered and precisely regulated actomyosin networks. Investigations of myofibril assembly are revealing the cellular mechanisms by which contractile components are arranged and regulated. In order to facilitate this research we have developed formal molecular genetics for myofibrillar proteins of Drosophila flight muscle. Presently, mutations can be used systematically to perturb or eliminate any of the classical myofibrillar proteins within these fibers, and the in vivo consequences can be conveniently evaluated using protein electrophoresis, electron microscopy, or by assaying flight performance. Here we review some recent progress.

Animals↗
PubMed2005

Developmental, molecular, and genetic dissection of INa in vivo in embryonic zebrafish sensory neurons.

The presence of multiple Nav1 isotypes within a neuron and the lack of specific blockers hamper identification of the in vivo roles of sodium current (INa) components, especially during embryonic stages. To identify the functional properties of INa components in vivo in developing neurons, we took a molecular genetic approach. Embryonic zebrafish Rohon-Beard (RB) mechanosensory neurons express two different sodium channel isotypes: Nav1.1 and Nav1.6. To examine the properties of Nav1.1- and Nav1.6-encoded currents in RB cells at different developmental stages, we eliminated the contribution of Nav1.6 and Nav1.1 channels, respectively, using an antisense morpholino (MO) approach. MOs were injected into one-cell stage embryos, and RB sodium currents were recorded using patch-clamp techniques in both conventional whole cell mode as well from nucleated patches. Only a subset of RB cells appeared to be affected by the Nav1.1MO. Overall, the effect of the Nav1.1MO was a small 25% average reduction in current amplitude. Further, Nav1.1MO effects were most pronounced in RB cells of younger embryos. In contrast, the effects of the Nav1.6 MO were observed in all cells and increased as development proceeded. These results indicated that developmental upregulation of RB INa entailed an increase in the number of functional Nav1.6 channels. In addition, analysis of voltage-dependent steady-state activation and inactivation parameters revealed that specific functional properties of channels were also developmentally regulated. Finally, analysis of macho mutants indicated that developmental upregulation of INa was absent in RB cells. These results indicate that MOs are a useful tool for the molecular dissection and analysis of ion channel function in vivo.

Age Factors↗
PubMed1993

The molecular and genetic dissection of the retinoid signalling pathway.

Retinoids are derivatives of vitamin A (retinol) that exert a wide variety of profound effects on vertebrate development, cellular differentiation and homeostasis. How these simple molecules can exert such pleiotropic effects has recently been an area of intensive investigation. A complex array of combinatorial effects is beginning to emerge from molecular and genetic studies, which may ultimately account for the pleiotropic effects of retinoids.

Animals↗
PubMed1992

Genetic dissection of autoimmune type I diabetes in the BB rat.

The BB rat is among the best models of insulin-dependent diabetes mellitus--with onset and pathogenesis closely resembling the human disease. One unusual feature is a severe T-cell lymphopenia, which appears to be inherited as a recessive trait controlled by a single gene, Lyp. Based on genetic analysis of several crosses, we show that development of diabetes involves at least three genes: Lyp, which is tightly linked to the neuropeptide Y (Npy) gene on chromosome 4, a gene linked to the major histocompatibility complex (MHC) on chromosome 20, and a third unmapped gene for which the Fischer rat strain carries an allele conferring resistance.

Animals↗
PubMed1992

Genetic dissection of cyclophilin function. Saturation mutagenesis of the Drosophila cyclophilin homolog ninaA.

Cyclophilins, the intracellular receptors for the widely used immunosuppressant cyclosporin A have been found to be peptidyl-prolyl cis/trans isomerases and have been implicated in intracellular protein folding and trafficking. The Drosophila ninaA gene encodes a photoreceptor-specific cyclophilin homolog involved in rhodopsin biogenesis. ninaA mutants have a 90% reduction in the levels of Rh1 rhodopsin. To gain insight into the role of cyclophilins in vivo, we carried out a genetic screen designed to identify functionally important regions in the ninaA protein. Over 700,000 mutagenized flies were screened for a visible ninaA phenotype and 70 independent mutations in ninaA were isolated and characterized. These mutations provide a detailed dissection of the structure/function relationships in cyclophilin. We also show that mammalian cyclophilins engineered to contain missense mutations found in two temperature-sensitive ninaA alleles display temperature-sensitive prolyl cis/trans isomerase activity.

Alleles↗