Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Haplotype phasing”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 577 records · Page 32Linked to original sources
PubMed1983

Inbred mouse strains differ in resistance to lethal Coccidioides immitis infection.

Inbred strains of mice were infected intraperitoneally with Coccidioides immitis, and the mean lethal dose was determined after 28 days. DBA/2N mice had a mean lethal dose of greater than 10(5) arthroconidia, whereas BALB/cAnN, C57BL/6N, and C57L/J mice had a mean lethal dose of less than or equal to 10(3). Since both BALB/c and DBA/2 mice are the H-2d haplotype, resistance is not primarily determined by the major histocompatibility locus. Resistance was the dominant phenotype. The pattern of C. immitis-resistant strains does not correspond to the strain distribution of the lsh gene or to the pattern of resistance to Blastomyces dermatitidis or Cryptococcus neoformans. Both resistant and susceptible mice, however, could be successfully immunized with a killed spherule vaccine, and susceptible BALB/cAnN mice were protected from an otherwise lethal infection by prior immunization with an attenuated mutant of C. immitis. Despite the evidence that BALB/cAnN mice could respond to immunization, nonimmune mice did not control the later phase of intraabdominal infection as well as DBA/2N mice. Dissemination of C. immitis to the lung occurred frequently in BALB/cAnN but not in DBA/2N mice. This suggests that BALB/cAnN mice cannot mount an effective immune response to C. immitis during the course of infection.

Animals↗
PubMed2000

Two genes are responsible for Griscelli syndrome at the same 15q21 locus.

Griscelli syndrome is a rare autosomal recessive disease characterized by pigment dilution, variable cellular immunodeficiency, and an acute phase of uncontrolled T lymphocyte and macrophage activation. We previously mapped the disease locus to 15q21 and showed that a MyoVa gene (HGMW-approved symbol MYO5A) defect leads to Griscelli syndrome. We report a second MyoVa mutation in a new patient, confirming this first finding. However, in four other Griscelli syndrome patients analyzed, the MYOVA protein is expressed, and no mutation can be detected in the MyoVa gene coding sequence, even in the alternatively spliced region for which exon-intron boundaries were characterized. Linkage analysis performed in 15 Griscelli families thus far studied confirms the first localization. However, fine haplotype analysis in three families strongly suggests the existence of a second gene at the same locus for Griscelli syndrome less than 7.3 cM distant from the MyoVa gene.

Alternative Splicing↗
PubMed1979

Regulation of T-cell-mediated lympholysis by the murine major histocompatibility complex. I. Preferential in vitro responses to trinitrophenyl-modified self K- and D-coded gene products in parental and F1 hybrid mouse strains.

Spleen cells from H-2b,k,d C57Bl/10 congenic mice were sensitized in vitro to trinitrobenzenesulfonate (TNBS)-modified autologous spleen cells. Cold target competition studies at the lytic phase demonstrated three distinct patterns of cytotoxic responsiveness: (a) H-2b spleen cells generated approximately equivalent CTL responses against Kb and Db modified self products, (b) H-2d spleen cells generated preferential responses against Dd modified self products, and (c) H-2k spleen cells generated cytotoxic responses which could only be detected against Kk self products in association with TNP. F1 spleen cells were sensitized against autologous TNBS-treated cells. The results showed that, although H-2b parental cells generated approximately equivalent Kb-TNP- and Db-TNP-specific CTL, the presence of the H-2b haplotype did not result in the generation of (a) Dk-TNP CTL response by (H-2b x H-2k) spleen cells, nor (b) a Db CTL response by (H-2b x H-2a) F1 spleen cells. Additionally, (H-2d x H-2k) F1 cells failed to generate detectable Dd-TNP-specific CTL, although H-2d parental cells generated D-regional-specific CTL. The findings demonstrated that these F1 response patterns paralleled those of the H-2k and H-2a parents, i.e. weak or no D-region TNP-specific CTL were induced. Because (H-2d x H-2a) F1 responders stimulated with H-2d TNBS-treated cells did generate good Dd TNP responses, the results illustrated that the presence of responder genes was not sufficient to result in a D-region TNP CML. It is suggested that the absence of Kk alleles on the stimulating population is necessary for the generation of D-region TNP CTL in these F1's. Mechanisms which could account for these response patterns in parental F1 mice are discussed including immunodominance, suppression, T-cell response , and Ir-gene defects.

Animals↗
PubMed2003

Genotyping error detection through tightly linked markers.

The identification of genotyping errors is an important issue in mapping complex disease genes. Although it is common practice to genotype multiple markers in a candidate region in genetic studies, the potential benefit of jointly analyzing multiple markers to detect genotyping errors has not been investigated. In this article, we discuss genotyping error detections for a set of tightly linked markers in nuclear families, and the objective is to identify families likely to have genotyping errors at one or more markers. We make use of the fact that recombination is a very unlikely event among these markers. We first show that, with family trios, no extra information can be gained by jointly analyzing markers if no phase information is available, and error detection rates are usually low if Mendelian consistency is used as the only standard for checking errors. However, for nuclear families with more than one child, error detection rates can be greatly increased with the consideration of more markers. Error detection rates also increase with the number of children in each family. Because families displaying Mendelian consistency may still have genotyping errors, we calculate the probability that a family displaying Mendelian consistency has correct genotypes. These probabilities can help identify families that, although showing Mendelian consistency, may have genotyping errors. In addition, we examine the benefit of available haplotype frequencies in the general population on genotyping error detections. We show that both error detection rates and the probability that an observed family displaying Mendelian consistency has correct genotypes can be greatly increased when such additional information is available.

Family↗
PubMed2002

Inferences from a rapidly moving hybrid zone.

Anartia fatima and Anartia amathea (Lepidoptera: Nymphalidae) are sister taxa whose ranges abut in a narrow hybrid zone in eastern Panama. At the center of the zone, hybrids are abundant, although deviations from Hardy-Weinberg and linkage disequilibria are strong, due in part to assortative mating. We measured differences across the zone in four wing color-pattern characters, three allozyme loci, and mitochondrial haplotype. Wing pattern, allozyme, and mitochondrial clines were coincident (i.e., had the same positions) and concordant (i.e.. all markers had similar cline shapes, about 28 km wide). Repeated samples demonstrated that the hybrid zone has been moving eastwards at an average rate of 2.5 km/year over the past 20 years, accompanied by an equivalent movement of the mtDNA cline. No introgression of mtDNA haplotypes were found in the ''wake" of the moving cline, as might be expected for a neutral marker. The concordance of morphological and mtDNA clines between 1994 and 2000, in spite of hybrid zone movement, suggests strong epistasis between the mitochondrial genome and nuclear loci. Cline movement is achieved mainly by pure fatima immigrating into amathea populations; hybrids had little effect, and were presumably outcompeted by fitter pure fatima genotypes. This movement can be explained if random dispersal of 7-19 km x gen(1/2) is coupled with a competitive advantage to A. fatima genomes of 2-5%. Hybrid zone motion is equivalent to Phase III of Wright's shifting balance. Hybrid zone movement has rarely been considered likely in the past, but our results show that it may be more important in biogeography and evolution than generally realized.

Animals↗
PubMed1996

Marker-assisted introgression in backcross breeding programs.

The efficiency of marker-assisted introgression in backcross populations derived from inbred lines was investigated by simulation. Background genotypes were simulated assuming that a genetic model of many genes of small effects in coupling phase explains the observed breed difference and variance in backcross populations. Markers were efficient in introgression backcross programs for simultaneously introgressing an allele and selecting for the desired genomic background. Using a marker spacing of 10-20 cM gave an advantage of one to two backcross generations selection relative to random or phenotypic selection. When the position of the gene to be introgressed is uncertain, for example because its position was estimated from a trait gene mapping experiment, a chromosome segment should be introgressed that is likely to include the allele of interest. Even for relatively precisely mapped quantitative trait loci, flanking markers or marker haplotypes should cover approximately 10-20 cM around the estimated position of the gene, to ensure that the allele frequency does not decline in later backcross generations.

Alleles↗
PubMed1991

Mouse IL-1 receptor antagonist protein. Molecular characterization, gene mapping, and expression of mRNA in vitro and in vivo.

The IL-1R antagonist protein (IL-1RN/IL-1rn) is a member of the IL-1 family of inflammatory mediators. We have isolated and analyzed a mouse IL-1rn cDNA clone and established that the derived mouse IL-1rn protein sequence is highly homologous to the human counterpart molecule. Mouse IL-1rn mRNA may be induced in P388D1 monocytic cells with PMA and in mouse liver in vivo by development of an experimental inflammation via s.c. injection of azocasein. This latter observation implies the existence of an autocrine hepatic negative feedback loop that down-regulates the acute phase response and is itself induced at the same time as the major acute-phase proteins. The mouse Il 1rn gene was mapped to the proximal region of chromosome 2 between the centromere and Spna2; the other known members of the mouse IL-1 gene family, Il 1a and Il 1b, both map to the same chromosome, although not in close linkage.

Amino Acid Sequence↗
PubMed2005

Common VKORC1 and GGCX polymorphisms associated with warfarin dose.

We report a novel combination of factors that explains almost 60% of variable response to warfarin. Warfarin is a widely used anticoagulant, which acts through interference with vitamin K epoxide reductase that is encoded by VKORC1. In the next step of the vitamin K cycle, gamma-glutamyl carboxylase encoded by GGCX uses reduced vitamin K to activate clotting factors. We genotyped 201 warfarin-treated patients for common polymorphisms in VKORC1 and GGCX. All the five VKORC1 single-nucleotide polymorphisms covary significantly with warfarin dose, and explain 29-30% of variance in dose. Thus, VKORC1 has a larger impact than cytochrome P450 2C9, which explains 12% of variance in dose. In addition, one GGCX SNP showed a small but significant effect on warfarin dose. Incorrect dosage, especially during the initial phase of treatment, carries a high risk of either severe bleeding or failure to prevent thromboembolism. Genotype-based dose predictions may in future enable personalised drug treatment from the start of warfarin therapy.

Adult↗
PubMed2004

Latent autoimmune diabetes mellitus in children (LADC) with autoimmune thyroiditis and Celiac disease.

Latent autoimmune diabetes mellitus in adults (LADA) is characterized by clinical presentation as type 2 diabetes mellitus after 25 years of age, initial control achieved with oral hypoglycemic agents for at least 6 months, presence of autoantibodies and some immunogenetic features of type 1 diabetes mellitus. An 8.3 year-old girl was referred to our pediatric endocrinology department because of incidental glucosuria. She did not complain of polyuria, polydipsia, or weight loss. Her body mass index (BMI) was at the 80th percentile. Fasting glucose was 126 mg/dl, and OGTT glucose level at 120 min was 307 mg/dl. Although C-peptide levels were normal, her first phase insulin response (FIR) was lower than the 1st percentile. Anti-insulin antibody (AIA), islet cell antibody (ICA), and anti-glutamic acid decarboxylase (antiGAD) were negative. According to the clinical and laboratory findings, she was diagnosed as having type 2 diabetes mellitus. She was started with oral anti-diabetic treatment for a period of 1 year. Insulin had to be initiated for worsening of HbA1c levels. In the fourth year of follow-up, she was admitted to our hospital with diabetic ketoacidosis although she was on an intensive insulin regimen. At this time, C-peptide levels were low, antiGAD and AIA were positive with HLA DR3/DQ2 haplotype. In addition, her thyroid peroxidase antibody and endomysium antibody were found to be high at follow-up. Small intestinal biopsy revealed celiac disease. This patient may represent the first case of latent autoimmune diabetes mellitus in children (LADC) with autoimmune thyroiditis and celiac disease.

Blood Glucose↗
PubMed2000

Fabry disease: twenty-two novel mutations in the alpha-galactosidase A gene and genotype/phenotype correlations in severely and mildly affected hemizygotes and heterozygotes.

BACKGROUND: Fabry disease, an inborn error of glycosphingolipid catabolism, results from mutations in the X-chromosomal gene encoding the lysosomal exoglycosidase, alpha-galactosidase A (alpha-Gal A; EC 3.2.1.22). The nature of the molecular lesions in the alpha-Gal A gene in 36 unrelated families was determined in order to provide precise heterozygote detection, prenatal diagnosis, and to define genotype/phenotype correlations. METHODS: Genomic DNA was isolated from affected males and/or carrier females from 36 unrelated families with Fabry disease. The entire alpha-Gal A coding region and flanking intronic sequences were analyzed by PCR amplification and solid-phase or cycle sequencing. Markers closely linked to the alpha-Gal A gene were analyzed to determine if probands with the same mutations were related. RESULTS: Twenty-two novel mutations were identified including 10 missense (P40L, W95S, S148N, C172R, M187V, N224S, W226R, A230T, D266H, N320Y), three nonsense (Y134X, C142X, W204X in two families), three splice-site defects (IVS2(+1), IVS3(+1), IVS4(+1)) and six small deletions or insertions (26delA in two families, 672ins37, 774delAC, 833insA, 1139delC, 1188insT). Of the remaining 12 families (33.3%), each had a previously identified mutation, eight of which occurred at CpG dinucleotides including R112C (two families), R112H, R227Q, R227X (three families), and R301Q. Haplotype analysis of the mutant alleles that occurred in two or three presumably unrelated families revealed that the families with the rare novel alleles (W204X and 26delA) were probably related, whereas those with mutations involving CpG dinucleotides (R112C and R227X) were not, the latter being consistent with their origins as independent mutational events. Genotype/phenotype correlations revealed that certain mutations previously found in mild variant patients also were found in classic patients. In addition, the genotypes and spectrum of phenotypic severity were determined in five heterozygotes with no family history. CONCLUSIONS: These results illustrate the molecular heterogeneity of the lesions causing Fabry disease and emphasize the fact that CpG dinucleotides constitute important hot spots for mutation in the alpha-Gal A gene. These studies also permit precise heterozygote detection and prenatal diagnosis in these families, and delineate phenotype-genotype correlations in this disease.

Amino Acid Sequence↗
PubMed2006

Immunophenotypic characterization of peripheral blast cells in a leukemic miniature pig.

The health status of a 4-year-old female, dd-haplotype miniature pig deteriorated rapidly, so the animal finally had to be euthanized because of poor clinical condition. Necropsy revealed a massive leukocytic infiltration in the parenchymatous organs of the abdominal cavity. On hematologic cell counting, severe leukocytosis (69.3 x 10(9) cells/liter) and high-grade basophilia (6.9 x 10(9) cells/liter) were evident. Cytologic examination, as well as analysis of expression of leukocyte differentiation antigens by means of flow cytometry, classified blasts, which accounted for about 22% of leukocytes, as biphenotypic cells co-expressing the myeloid marker SWC3 (CD172a) and the lymphoid markers CD5 and CD25. Hematologic features resembled those seen in humans with chronic myeloid leukemia at blast phase.

Animals↗
PubMed1997

Tolerance induction to myelin basic protein by intravenous synthetic peptides containing epitope P85 VVHFFKNIVTP96 in chronic progressive multiple sclerosis.

Peptide-based tolerance induction may be useful for antigen-specific immunotherapy of human autoimmune diseases. Induction of tolerance to myelin basic protein (MBP) was examined in a Phase I clinical trial in multiple sclerosis (MS) patients with chronic progressive disease using a peptide that is immunodominant for MBP specific T cells and B cells. Tolerance induction was monitored by quantification of MBP specific autoantibodies in cerebrospinal fluid (CSF). The route of peptide administration was important since only intravenous but not intrathecal or subcutaneous injection induced tolerance to MBP. Following a single intravenous injection of a peptide containing epitope P85VVHFFKNIVTP96, MBP autoantibodies were undetectable for three to four months. Tolerance was more prolonged following a second injection since autoantibodies were low or undetectable after one year in the majority of patients. Duration of tolerance to MBP depended on MHC class II haplotypes of patients; tolerance was long-lived in all patients with disease associated HLA-DR2. No neurological or systemic side effects were observed, regardless of the route of peptide administration. These data demonstrate that intravenous administration of a soluble peptide can result in long-lasting tolerance to an autoantigen in humans.

Autoantibodies↗
PubMed1994

Mechanism of cyclosporin-induced tolerance to primarily vascularized allografts in miniature swine. Effect of administration of exogenous IL-2.

Indefinite tolerance to kidney allografts across a two-haplotype class I disparity can be induced in miniature swine in 100% of cases by a short course of cyclosporin A (CyA). Without CyA, all recipients reject kidney allografts within 2 wk. These animals therefore provide a unique opportunity to study the mechanisms of induction and maintenance of tolerance in a large animal model. Previous studies of cellular and humoral immunity suggested that a T cell help deficit at the time of the first exposure of the host's immune system to alloantigens was involved in tolerance induction. We have now studied the effect of exogenous T cell help in the form of an IL-2 infusion during both the induction and maintenance phases of tolerance. Lymphoid infiltrates were seen in class I mismatched renal allografts by day 8 in all animals whether treated with CyA or not. Administration of i.v. IL-2 on postoperative days 8, 9, and 10 to animals receiving the full CyA tolerizing regimen led to acute rejection in four of four animals. These rejecting animals showed induction of IL-2R expression on graft infiltrating cells in the kidney, suggesting that the infiltrates present before IL-2 administration were capable of causing rejection once T cell help was provided. Treatment with IL-2 did not abrogate long-term tolerance. Thus, limitation of T cell help at the time of first exposure to Ag in this model appears to be required to prevent rejection during the time required for active tolerance to develop. Once established, this tolerance does not appear to require continuous limitation of T cell help to be maintained, suggesting loss, inactivation, or suppression of the cells capable of causing rejection.

Animals↗
PubMed1987

Selective activation of helper and cytolytic T-cell functions of L3T4+ clones with either antireceptor antibody or phorbol ester and ionophore.

After activation with specific antigen and antigen presenting cells (APC) L3T4+ inducer T-cell clones can lyse Ia+ APC. The present study characterizes the mechanism of activation and specificity of L3T4+ inducer cell-mediated cytolytic function. Two methods that bypass the physiological stimulus of antigen presented on Ia+ APC were used to activate L3T4+ clones. The first method utilized an antireceptor monoclonal antibody (MAb), KJ16.133, to activate KJ16.133+ clones. The activated clones expressed nonspecific cytolytic activity, killing target cells irrespective of their H-2 haplotype or their ability to express cell surface Ia molecules. The crosslinking of bound KJ16.133 antibody greatly enhanced cytolytic activity. This activation is receptor specific because KJ16.133- clones were not activated under identical conditions. The second method of activation was provided by a synergistic action of phorbol-12-myristate-13-acetate (PMA) and ionophore A23187. These agents nonspecifically activated all L3T4+ clones tested. The simultaneous presence of the two agents is required for maximal activation. Again, the activated clones expressed potent nonspecific cytolytic activity. These observations demonstrated that L3T4+ inducer T-cell-mediated killing can be separated into two stages: an activation step, which can be specifically and nonspecifically triggered and an effector phase which causes nonspecific lysis of bystander targets. The induction of nonspecific cytolytic activity by antireceptor MAb was inhibited by anti-L3T4 MAb (GK1.5). In contrast, activation of nonspecific cytolytic activity by treatment with PMA plus A23187 was not inhibited by anti-L3T4 MAb. Under the above activation conditions, antireceptor MAb selectively induced the secretion of IL-3 and expression of nonspecific cytolytic activity. However, there was little or no concomitant proliferation and production of IL-2. In contrast, activation by PMA plus A23187 coordinately induces expression of nonspecific cytolytic activity, secretion of lymphokines (IL-3 and IL-2), and cell proliferation. Thus, the anticlonotypic activation preferentially induces certain functions whereas activation with PMA plus A23187 is not selective.

Animals↗
PubMed1995

A novel HLA-DR13 allele (DRB1*1314) identified by single-strand conformation polymorphism analysis and confirmed by direct sequencing.

A novel variant of the HLA-DR13 group is described. The new allele was found in a DR10, 13 heterozygous patient of Turkish origin, two HLA genotypically identical children of the patient typed as DR11,13, and one child typed as DR13,13. DR13 subtyping of the patient was initially performed by SSCP analysis of PCR-amplified DNA, using the 11th OHWS primers DRBAMP-3 and DRBAMP-B. Due to an unusual SSCP banding pattern, the PCR product was subjected to solid-phase sequencing. The sequence of the new allele, DRB1*1314, is different from that of DRB1*1307 by a single nucleotide substitution in codon 47, with T replacing consensus A. This results in a single amino acid change of tryptophan to phenylalanine in the first domain of the DR beta chain.

Anemia, Sickle Cell↗
PubMed1999

Impaired p53-mediated DNA damage response, cell-cycle disturbance and chromosome aberrations in Nijmegen breakage syndrome lymphoblastoid cell lines.

PURPOSE: To investigate the p53 ionizing radiation-induced response, G1/S cell-cycle block and cytogenetic damage in Nijmegen breakage syndrome (NBS) cells characterized by different haplotypes. MATERIAL AND METHODS: Lymphoblastoid cell lines derived from three normals, five NBS and two ataxia telangiectasia (AT) individuals were treated with moderate doses of X-rays and changes in the p53 response were studied by dose-response and time-course experiments. Multiparametric flow cytometry analysis of bromodesoxyuridine-incorporated cells was carried out to analyse G1/S checkpoint alterations. Cytogenetic damage induced by 2 Gy radiation was assessed in cells harvested 28 h later. RESULTS: Comparison of mean values of p53 accumulation in NBS, AT and control cells indicated that protein induction in NBS cells was between normal and AT cells. Cell-cycle experiments showed a markedly reduced S-phase fraction in irradiated samples of normal cell lines, while NBS, and particularly AT cells, showed less reduction in S-phase fraction. Irrespective of differences in p53 induction and G1/S block, chromatid-type aberrations were induced at a comparable level in both syndromes, while being almost absent in normal cells. CONCLUSIONS: The data suggested that failure of NBS cells to initiate cell-cycle delay cannot account alone for their extreme sensitivity to radiation.

Ataxia Telangiectasia↗
PubMed2000

Sequence variation in genes and genomic DNA: methods for large-scale analysis.

The large-scale typing of sequence variation in genes and genomic DNA presents new challenges for which it is not clear that current technologies are sufficiently sensitive, robust, or scalable. This review surveys the current platform technologies: separation-based approaches, which include mass spectrometry; homogeneous assays; and solid-phase/array-based assays. We assess techniques for discovering and typing variation on a large scale, especially that of single-nucleotide polymorphisms. The in-depth focus is the DNA chip/array platform, and some of the published large-scale studies are closely examined. The problem of large-scale amplification is addressed, and emerging technologies for present and future needs are indicated.

Base Sequence↗
PubMed2006

[Advances in the association analysis of complex diseases].

To identify the genetic factors influencing complex diseases is a challenging problem. With the development of several technologies, such as large-scale genome sequencing, gene chips and mass spectrometry, and the successful completion of the first phase of International HapMap Project, it is feasible to explore the associations between hundreds of polymorphisms in the human genome, even the whole genome, and complex diseases in populations with large number of samples. The present paper briefly describes the results of the International HapMap Project, the merging whole-genome association study, and some new methods applicable to data including multiple loci.

Bayes Theorem↗