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PubMed2003

[Mapping quantitative trait loci associated with rice grain shape based on an indica/japonica backcross population].

Appearance of rice grain represents a major character of rice quality in many rice-producing areas of the world, especially in hybrid rice production in China. In this study, we conducted a molecular marker-based genetic analysis of the traits that are determinants of the appearance quality of rice grains, including grain length, grain width and grain shape (measured as grain length to grain width ratio). Two typical indica/japonica varieties Balilla and Nantehao(NTH) were selected to construct Balilla/NTH//Balilla backcross population containing 142 individuals. In the population, grain length, grain width and grain shape all conform to the normal distribution with certain transgressive segregation. It can be deduced that all of three traits were controlled by some quantitative trait loci (QTLs). In order to explore the QTLs effect, number and location, a linkage map consisting of 108 SSR markers based on the backcross population was constructed, and QTLs mapping was carried out for grain length, grain width and grain shape. A QTL, qGL-12, was detected for grain length at the interval RM101-RM270 on chromosome 12, its additive effect was 0.26 mm, and can explain 16.7% genetic variation. As for grain width trait, two QTLs were found, qGW-2 located at RM154-RM211 interval on chromosome 2, and qGW-3 at interval RM257-RM175 on chromosome 3, accounting for 11.5% and 16.6% genetic variation, respectively. The alleles at qGW-2 and qGW-3 from parent Balilla can increase grain width by 0.10 mm and 0.12 mm. For grain shape, 3 QTLs, qLW-2, qLW-6 and qLW-7 were found, located on chromosome 2, 6, and 7, respectively. qLW-2 and qLW-7 had positive effect, and they can explain 12.7% and 18.3% genetic variation, while qLW-6 had negative effect and contributed 11.5% genetic variation to the backcross population. The prospects of application of linkage relationship between SSR marker and QTLs in marker based selection (MAS) in rice breeding, and the improvement of grain shape and rice appearance quality were discussed.

Chromosome Mapping↗
PubMed1996

A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities.

Drosophila patched is a segment polarity gene required for the correct patterning of larval segments and imaginal discs during fly development and has a close functional relationship with hedgehog. We have isolated a complete human PATCHED cDNA sequence, which encodes a putative protein of 1296 amino acids, and displays 39% identity and 60% similarity to the Drosophila PATCHED protein. Hydropathy analysis suggests that human PATCHED is an integral membrane protein with a pattern of hydrophobic and hydrophilic stretches nearly identical to that of Drosophila patched. In the developing mouse embryo, patched is initially detected within the ventral neural tube and later in the somites and limb buds. Expression in the limb buds is restricted to the posterior ectoderm surrounding the zone of polarizing activity. The results show that patched is expressed in target tissues of sonic hedgehog, a murine homolog of Drosophila hedgehog suggesting that patched/hedgehog interactions have been conserved during evolution. Human PATCHED maps to human chromosome 9q22.3, the candidate region for the nevoid basal cell carcinoma syndrome. Patched expression is compatible with the congenital defects observed in the nevoid basal cell carcinoma syndrome.

Amino Acid Sequence↗
PubMed2000

Chromosomal mapping of osteopenia-associated quantitative trait loci using closely related mouse strains.

Peak bone mineral density (BMD) is a highly heritable trait in humans and is currently the best predictor of skeletal fragility underlying osteoporosis. The SAMP6 mouse strain displays unusually low BMD at maturity, and age-dependent osteopenia associated with defective osteoblastogenesis. To identify quantitative trait loci (QTLs) influencing bone density, we constructed crosses between SAMP6 and either AKR/J or SAMP6, two related mouse strains of higher peak BMD. Due to common ancestry of these strains, intercross parents differed at only 39-40% of 227 highly-polymorphic genotyping markers, thus restricting our search to this informative portion of the genome and reducing the number of mice required for QTL significance. Using dual energy X-ray absorptiometry (DEXA), we measured spinal BMD in F2 cross progeny at 4 months of age, and selectively genotyped those in the highest and lowest quartiles for BMD. Based on linear regression of bone density on genotype, including Composite Interval Mapping to enhance mapping precision while adjusting for effects of distal markers, we identified multiple QTLs significantly affecting spinal BMD; these were mapped to regions of chromosomes 2 (two sites, one confirmed in both crosses), 7, 11, 13 and 16. One of these loci had been previously identified as a significant bone-density QTL, while 3 substantiate QTLs suggested by a low-power study of 24 recombinant-inbred mouse lines. Such recurrent appearance of QTLs, especially in crosses involving distantly-related strains, implies that polymorphism at these loci may be favored by evolution and might underlie variation in peak bone density among humans.

Absorptiometry, Photon↗
PubMed1998

Mapping a disease locus by allelic association.

Allelic association provides a means to map disease genes that, in a dense map of polymorphic markers, has considerably higher resolution than linkage methods. We describe here a composite likelihood estimate of location for a disease gene against a high-resolution marker map by using allele frequencies at linked loci. Data may be family-based, as in the transmission disequilibrium test, or from a case-control study. chi2 tests, logarithm of odds, standard errors, and information weights are provided. The method is illustrated by analysis of published cystic fibrosis haplotypes, in which DeltaF508 is more accurately localized than by other association studies. This differs from current approaches by adopting a more general Malecot model for isolation by distance, where distance here is between marker and disease locus, allowance for errors in the map and model, and freedom from assumptions about demography, systematic pressures, and the ratio of physical to genetic distance. When these assumptions are introduced the number of generations since the original mutation may be estimated, but this is not required to determine location and its standard error, so that evidence from allelic association may be efficiently combined with linkage evidence to identify a region for positional cloning of a disease gene.

Alleles↗
PubMed2002

Mapping myasthenia gravis-associated T cell epitopes on human acetylcholine receptors in HLA transgenic mice.

Susceptibility to myasthenia gravis (MG) is positively linked to expression of HLA-DQ8 and DR3 molecules and negatively linked to expression of the DQ6 molecule. To elucidate the molecular basis of this association, we have induced experimental autoimmune MG (EAMG) in mice transgenic for HLA-DQ8, DQ6, and DR3, and in DQ8xDQ6 and DQ8xDR3 F(1) transgenic mice, by immunization with human acetylcholine receptor (H-AChR) in CFA. Mice expressing transgenes for one or both of the HLA class II molecules positively associated with MG (DQ8 and DR3) developed EAMG. T cells from DQ8 transgenic mice responded well to three cytoplasmic peptide sequences of H-AChR (alpha320-337, alpha304-322, and alpha419-437), of which the response to alpha320-337 was the most intense. DR3 transgenic mice also responded to this sequence very strongly. H-AChR- and alpha320-337 peptide-specific lymphocyte responses were restricted by HLA class II molecules. Disease resistance in DQ6 transgenic mice was associated with reduced synthesis of anti-AChR IgG, IgG(2b), and IgG(2c) Ab's and reduced IL-2 and IFN-gamma secretion by H-AChR- and peptide alpha320-337-specific lymphocytes. Finally, we show that DQ8 imparts susceptibility to EAMG and responsiveness to an epitope within the sequence alpha320-337 as a dominant trait.

Amino Acid Sequence↗
PubMed2002

Naturally occurring human autoantibodies recognize a fetal brain antigen identified as microtubulus associated protein 1B.

We have recently reported naturally occurring autoantibodies against a large fetal brain antigen (FBA). Now we describe the process of purification and identification of this particular FBA. The brains of newborn rabbits were solubilized and purified with preparative gel electrophoresis. The protein fractions were concentrated and desalted and the fractions were tested by a known positive serum. On membrane digestion of the FBA-band gave a twelve amino acid sequence that resulted in best identity score for mouse, rat and human microtubule-associated protein (MAP) 1B: a member of the microtubule-associated protein family. Monoclonal anti-MAP1B recognized a band in immunoblots of the brain homogenate and of the partially purified fractions with the same electrophoretic mobility as that recognized by a known anti-FBA positive serum. When adult rabbit brain was used as an antigen, the anti-MAP1B failed to recognize any bands on immunoblots. MAP lB has not been previously known as an autoantigen, even though many structural proteins of the neuronal cytoskeleton are known to be targets of naturally occurring autoantibodies. MAP 1B is a functionally important regulatory protein in the developing brain; thus autoantibodies against MAP1B may affect the normal development.

Animals↗
PubMed2001

Abundant expression of the microtubule-associated protein, ensconsin (E-MAP-115), alters the cellular response to Taxol.

Correlation between expression level of a microtubule-associated protein called ensconsin (E-MAP-115) and degree of Taxol sensitivity in several cultured cell lines prompted us to investigate potential cause-and-effect relationships between ensconsin level and Taxol action. We used human MCF-7 or HeLa cells, which are sensitive to low Taxol concentrations (LD(50) of 30-35 and 3.5 nM, respectively) to prepare stably transfected populations of cells expressing heterogeneous levels of ensconsin chimeras, either green fluorescent protein (GFP) conjugated to full-length ensconsin (GFP-Ensc) or to ensconsin's microtubule-binding domain (GFP-EMTB). Both a subjective microscopic assay, i.e., scoring fluorescence of GFP-ensconsin chimeras following Taxol treatment, and a quantitative immunobiochemical assay, i.e., measuring level of GFP-ensconsin chimera in cells surviving treatment with Taxol, showed that cells expressing higher levels of GFP-ensconsin chimera were killed more readily by Taxol concentrations approaching the LD(50). In contrast, in TC-7 cells, which are relatively insensitive to Taxol (LD(50) > 600 nM), high-level expression of GFP-EMTB conferred no significant susceptibility to killing by Taxol. However, heightening the Taxol sensitivity of GFP-EMTB-TC-7 cells by pre-incubating cells with the p-glycoprotein inhibitor, verapamil, did result in selective killing of cells highly expressing GFP-EMTB. Taken together, results obtained in MCF-7, HeLa, and TC-7 cells suggest that elevated ensconsin level bestowed a selective disadvantage upon Taxol-sensitive cells. To probe potential mechanisms by which ensconsin could alter the Taxol response, we isolated microtubules from HeLa cells that were or were not pretreated with Taxol. In vivo Taxol treatment significantly tightened microtubule-binding of ensconsin, suggesting that Taxol alters ensconsin's microtubule-binding properties and may, in turn, alter the Taxol response of the microtubules. Our data support the hypothesis that Taxol works synergistically or in concert with microtubule-binding proteins in bringing about deleterious effects on the microtubule cytoskeleton.

Animals↗
PubMed2002

Induction of apoptosis in rat ventral prostate by finasteride is associated with alteration in MAP kinase pathways and Bcl-2 related family of proteins.

Finasteride is widely used in treatment of symptomatic benign prostatic hyperplasia. Treatment of rats with finasteride caused a significant decrease in ventral prostate weight and intraprostatic dihydrotestosterone levels while intraprostatic testosterone levels were increased. Finasteride inhibited Akt-1 and MAPK expression while expression of PTEN was significantly increased only at 100 mg dose. Basal phosphorylation of c-Raf, MEK1/2, MAPK and the transcription factor Elk-1 was significantly reduced by finasteride. The rate of prostate epithelial apoptosis is equivalent to 0.1+/-0.03, 0.6+/-0.18%, 0.92+/-0.24% and 1.42+/-0.3% on treatments with 0, 1, 10 and 100 mg finasteride per kg body weight, respectively. Concomitantly, these treatments led to a 2.5-, 4.0- and 4.0-fold increase in Bad while a slight decrease in Bax was observed. Similar elevations were also observed in Bcl-xs levels which increased by 9.8-, 10- and 12-fold respectively in the finasteride treatments as compared to controls. Bcl-xL levels in ventral prostates treated with 1, 10 and 100 mg finasteride were approximately 30, 30 and 26% of control, respectively. Significant reduction in Bcl-2 expression was observed only at the dose of 100 mg/kg body weight. These findings suggest that modulation of MAP kinase and Akt expression, Bcl-xL, Bcl-xs, Bcl-2 and Bad proteins by finasteride may be, in part, responsible for the anti-proliferative and apoptotic effect of this drug seen clinically and in animal models.

Animals↗
PubMed1995

Molecular mapping of 21 features associated with partial monosomy 21: involvement of the APP-SOD1 region.

We compared the phenotypes, karyotypes, and molecular data for six cases of partial monosomy 21. Regions of chromosome 21, the deletion of which corresponds to particular features of monosomy 21, were thereby defined. Five such regions were identified for 21 features. Ten of the features could be assigned to the region flanked by genes APP and SOD1: six facial features, transverse palmar crease, arthrogryposis-like symptoms, hypertonia, and contribution to mental retardation. This region, covering the interface of bands 21q21-21q22.1, is 4.7-6.4 Mb long and contains the gene encoding the glutamate receptor subunit GluR5 (GRIK1).

Adolescent↗
PubMed1993

Chromosomal mapping of genetic locus associated with thymus-size enlargement in BUF/Mna rats.

The thymoma-prone rat of the BUF/Mna strain is a useful model for human thymoma. In this strain thymoma development is regulated by a single autosomal susceptible gene, Tsr-1. At pre-thymoma age, BUF/Mna rats have extremely large thymuses, when compared to those of other strains of rats. Genetic studies in crosses between BUF/Mna rats with large thymuses and WKY/NCrj rats with small thymuses suggested the presence of a major autosomal gene, Ten-1, which contributes to thymus enlargement in a backcross population. Linkage studies between Ten-1 and microsatellite markers in backcross rats of (WKY/NCrj x BUF/Mna)F1 x BUF/Mna have led to the localization of Ten-1 in chromosome 1. This result may provide an approach to clone Tsr-1, which could be allelic to Ten-1.

Animals↗
PubMed1995

Mapping of the intermolecular association of human T cell leukaemia/lymphotropic virus type I p12I and the vacuolar H+-ATPase 16 kDa subunit protein.

The p12I protein, a small hydrophobic protein encoded by the human T cell leukaemia/lymphotropic virus type I pX region, contains a proline-rich region located between two putative transmembrane (TM) domains. The p12I protein is associated with cellular endomembranes, and physically binds to the 16 kDa subunit of the vacuolar H+-ATPase proton pump. To investigate the nature of the 16 kDa and p12I interaction and to determine the oncogenic domain of p12I, we constructed p12I mutant proteins in which various portions of the TM domains were deleted, as well as p12I mutant containing a single amino acid substitution. These mutants were tested for binding to the 16 kDa subunit of the vacuolar H+-ATPase in HeLa/Tat cells and for the capability to potentiate transformation by bovine papillomavirus type 1 E5 oncoprotein in mouse C127 cells. The results indicated that both TM domains of the p12I protein were dispensable for its interaction with the 16 kDa protein, whereas partial or complete deletion of the proline-rich region resulted in decreased or no binding of the p12I protein to the 16 kDa subunit. Immunofluorescence analysis of HeLa/Tat cells transfected with the p12I mutants showed that deletion of the proline-rich region did not alter the subcellular localization of these mutant p12I proteins, suggesting direct involvement of the proline-rich domain in binding rather than the failure of these p12I mutants to reach the appropriate cellular compartment. Mapping of 16 kDa subunit mutants in binding with p12I protein suggested that molecular determinants located between the second and third TM domain of the 16 kDa protein might be involved in this interaction. Finally, most of the p12I mutants lost the ability to potentiate transformation of C127 cells indicating that binding of p12I to the 16 kDa subunit does not directly correlate with oncogenicity.

Animals↗
PubMed2026

A novel reusable transcriptome-wide association study workflow used to map key genes linked to important cattle traits.

Transcriptome-wide association studies (TWAS) are a powerful approach for studying the genes underlying complex traits by directly integrating GWAS and gene expression datasets. In cattle, they have been previously applied to identify genes driving fertility, milk production, and health. However, these studies have also highlighted several challenges, from difficulties in reproducing these complex analyses to limitations from poor genotype calls, especially when called directly from RNA sequencing data. To address these and other challenges, for the H2020 BovReg Project, we have developed a streamlined, species-agnostic, and reusable Nextflow TWAS workflow to integrate transcriptomic and GWAS summary statistic datasets. Our workflow first generates accurate genotype calls and gene expression prediction models from transcriptomic datasets and then applies these tools to impute gene expression levels into GWAS cohorts, enabling the association of genes with traits of interest. We explore optimal strategies for calling genetic variants directly from transcriptomic data and illustrate that using imputation approaches specifically designed for low-pass sequencing data can improve variant calling over previously adopted methods. We demonstrate the utility of our TWAS workflow by applying it to both novel and publicly available GWAS cohorts for cattle, detecting novel gene-trait associations for complex traits. Using a new transcriptome annotation of the cattle genome generated for the BovReg project we also illustrate how previously un-assayable associations can be detected. The results and the workflow we present, provide a new resource for the community and contribute to a better understanding of the molecular drivers of complex traits in cattle with the goal of eventually leveraging this information in future breeding decisions.

Animals↗
PubMed1983

Mapping of cholinergic neurons associated with rat supraoptic nucleus: combined immunocytochemical and histochemical identification.

Recent electrophysiological experiments have suggested that electrical stimulation of an area dorsolateral to the rat supraoptic nucleus (SON) activates a cholinergic pathway to the vasopressin neurons of the SON. As no detailed information is available concerning the distribution and projections of the cholinergic neurons in this area, we have sought to provide this using a combination of choline acetyltransferase (ChAT) immunocytochemistry and acetylcholinesterase (AChE) histochemistry. In some cases, these techniques were applied to the same neurons. Almost all neurons just outside of the SON that showed ChAT-like immunoreactivity also stained densely for AChE. These cells were distributed in a region dorsolateral to the SON. Light, punctate AChE staining around SON neurons was observed predominantly in the more ventral and posterior parts of the nucleus and were suggestive of synaptic terminals. Cholinergic fibres were found to enter the SON mainly from a lateral direction, turning in an anterior or posterior direction inside the nucleus. These results support the conclusion of earlier studies that the major cholinergic input to the SON arises in its immediate vicinity. We hypothesize that these ChAT/AChE-positive neurons are those responsible for cholinergically mediated, osmotically-stimulated release of vasopressin.

Acetylcholinesterase↗
PubMed2005

Effects of EGF and bFGF on expression of microtubule-associated protein tau and MAP-2 mRNA in human umbilical cord mononuclear cells.

The aim of this study was to explore the regulatory effects of cytokines, such as EGF and bFGF, on expression of the neural-specific molecules tau and MAP2 mRNA in mononuclear cells (MNCs) derived from human umbilical cord blood (UCB). Phenotypic changes were monitored by inverse phase-contrast microscopy. Tau and MAP2 mRNA were determined by reverse-transcriptase polymerase chain reaction (RT-PCR). Tau and MAP2-positive cells were determined by immunocytochemistry. The expression of tau mRNA was negative in uncultured cells, but MAP2 mRNA was positive; in cultured cells, tau protein mRNA expression was positive, MAP2 mRNA expression was upregulated by EGF+bFGF, EGF and bFGF compared to the control group (no cytokines). EGF+bFGF had a greater effect on MAP2 mRNA expression than EGF or bFGF alone. The same upregulatory tendency was noted for tau mRNA expression. It is concluded that MNCs derived from human UCB cells may express some neural specific molecules that can be upregulated by cytokines, especially EGF and bFGF together.

Cell Differentiation↗
PubMed1987

MAP2 and tau segregate into dendritic and axonal domains after the elaboration of morphologically distinct neurites: an immunocytochemical study of cultured rat cerebrum.

We sought to determine whether the strict segregation of MAP2 and tau into somatodendritic and axonal compartments in situ was maintained in dissociated neuronal cultures of the rat cerebrum. Cultures grown under serum-free conditions were immunolabeled with monoclonal antibodies specific for MAP2 and tau. At 14 d after plating, a clear distinction between MAP2- and tau-immunoreactive neurites was apparent. MAP2-immunoreactive neurites were relatively short, thick, tapering, and branched. Tau-immunoreactive neurites formed a crisscrossing meshwork of long, fine-caliber neurites, which, in more densely plated cultures, had a tendency to form thick, ropelike fascicles. Unlike the MAP2 pattern, tau antibodies labeled somata only lightly. Since distinct populations of neurites were labeled with the 2 antibodies, we sought to observe the development of the topographically distinct compartments by double-labeled immunocytochemistry with both polyclonal and monoclonal antibodies to MAP2 and tau. Cells observed within the first 8 hr after plating demonstrated equally intense MAP2 and tau immunoreactivity in a coextensive distribution throughout the cell body and initial neurites. By 16 hr, some neurites began to assume dendritic and axonal features; however, many such processes contained reaction product for both MAP2 and tau. Beginning at this time, neurites that appeared axonal showed a progressively weaker reaction with MAP2 antibodies, and neurites that appeared dendritic showed a progressively weaker reaction with tau antibodies. In most neurites the diminution appeared to occur uniformly over the entire extent of the neurite. During this transformation period there were occasional axon-like neurites that contained MAP2 immunoreactivity proximally, while tau immunoreactivity extended over the entire length of the neurite. We conclude that neurons in culture are able to compartmentalize MAP2 and tau into their appropriate processes and only attain an apparently homogeneous population of one of these MAPs after the neuron has assumed dendritic and axonal features. The analysis also lends indirect support to the hypothesis that microtubule-associated proteins (MAPs) form this association at the distal extent of the growing neurite.

Animals↗
PubMed2004

Optimal designs for linkage disequilibrium mapping and candidate gene association tests in livestock populations.

Simulation was used to evaluate the performance of different selective genotyping strategies when using linkage disequilibrium across large half-sib families to position a QTL within a previously defined genomic region. Strategies examined included standard selective genotyping and different approaches of discordant and concordant sib selection applied to arbitrary or selected families. Strategies were compared as a function of effect and frequency of QTL alleles, heritability, and phenotypic expression of the trait. Large half-sib families were simulated for 100 generations and 2% of the population was genotyped in the final generation. Simple ANOVA was applied and the marker with the greatest F-value was considered the most likely QTL position. For traits with continuous phenotypes, genotyping the most divergent pairs of half-sibs from all families was the best strategy in general, but standard selective genotyping was somewhat more precise when heritability was low. When the phenotype was distributed in ordered categories, discordant sib selection was the optimal approach for positioning QTL for traits with high heritability and concordant sib selection was the best approach when genetic effects were small. Genotyping of a few selected sibs from many families was generally more efficient than genotyping many individuals from a few highly selected sires.

Alleles↗
PubMed1994

High resolution fluorescence in situ hybridization to linearly extended DNA visually maps a tandem repeat associated with facioscapulohumeral muscular dystrophy immediately adjacent to the telomere of 4q.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder. The FSHD locus has been linked to the most distal genetic markers on the long arm of chromosome 4. An EcoRI fragment length polymorphism segregates with the disease in most FSHD families. Within the EcoRI fragment lies a tandem array of 3.2 kb repeats. Deletions of integral copies of this repeat have been associated with the disease. The 3.2 kbp repeat has recently been shown to cross-hybridize to several regions of heterochromatin in the human genome and DNA sequence analysis reveals strong homology to a class of heterochromatin repeats, LSau. In this report, we demonstrate that the 3.2 kbp tandem repeat lies adjacent to a subtelomeric sequence, which is within 5-14 kb of the telomeric repeat (TTAGGG)n. Direct visual fluorescence hybridization to linearly extended strands of DNA enabled the visualization of this subtelomeric sequence as a short string of signals at the end of a longer string of signals from the differentially labeled 3.2 kbp tandem repeat. Furthermore, in support of our data showing that the 3.2 kbp repeat lies in close proximity to the telomere of 4q, we demonstrated the lack of hybridization of total human DNA to this same region. Our results indicate that the tandem array of 3.2 kbp repeats, disrupted in FSHD, lies immediately adjacent to the telomere of 4q and that the gene responsible for FSHD is likely located proximal to the tandem repeat.

Animals↗
PubMedDate not supplied

Proteomic maps of the cancer-associated infectious agents.

The number of infectious agents associated with cancer is increasing. There is a need to develop approaches for the early detection of the infected host which might lead to tumor development. Recent advances in proteomic approaches provide that opportunity, and it is now possible to generate proteomic maps of cancer-associated infectious agents. Protein arrays, interaction maps, data archives, and biological assays are being developed to enable efficient and reliable protein identification and functional analysis. Herein, we discuss the current technologies and challenges in the field, and application of protein signatures in cancer detection and prevention.

Animals↗