SEARCH · PubMed Health

Results for “Haplotype structures”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

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

At least 1,261 records · Page 70Linked to original sources

PubMed1991

HLA class II sequences and genetic susceptibility to insulin dependent diabetes mellitus.

The analysis of HLA class II sequence variation in IDDM patients and controls, made possible by the PCR, has revealed that specific alleles are associated with IDDM. The HLA-DQ beta chain appears to play a role in determining genetic susceptibility and resistance, although polymorphisms in the DRB1, the DQ alpha, and the DP beta chain may also contribute. Although there is a correlation between susceptibility and the charge of DQ beta residue 57, the complex genetic epidemiology of IDDM cannot be accounted for by polymorphism at this position. As we have discussed previously (Horn et al, 1988a, 1988b; Erlich et al, 1990b), there are no unique class II sequences associated with IDDM, consistent with the view that 'normal' class II alleles confer susceptibility. Given the estimates of concordance of under 50% for monozygotic twins and approximately 15% (Tattersall and Pyke, 1972; Thomson, 1988) for HLA-identical sibs--it is not surprising that some unaffected individuals contain putative susceptibility alleles. Perhaps some environmental 'triggering' agent, such as viral infection, is required for the disease to develop in susceptible individuals. Other non-MHC-linked genes which contribute to susceptibility may account for the difference in concordance rates for monozygotic twins and for HLA-identical sibs. In the NOD (non-obese diabetic) mouse and the BB rat models for IDDM, non-MHC susceptibility loci have been identified and mapped (Colle et al, 1981; Hattori et al, 1986) but, in humans, the analysis of non-MHC candidate loci (i.e. the T cell receptor) has, thus far, failed to reveal any other susceptibility loci. In general, the HLA-linked genetic susceptibility to IDDM, as well as to other autoimmune diseases, appears to be associated with specific combinations of class II epitopes (e.g. alleles, haplotypes or genotypes) rather than with specific individual residues or epitopes. Understanding the role of these predisposing sequences will require structural analysis of the class II molecules as well as in vitro and in vivo functional studies of interactions with putative autoantigens and T cell receptors. In the meantime, DNA typing offers the potential for identifying individuals at high risk. These susceptible individuals could be monitored by immunological (e.g. anti-islet cell antibody) or by metabolic tests to detect the preclinical phase of IDDM.

Amino Acid Sequence↗

PubMedDate not supplied

Hybrid HLA-DC antigens provide molecular evidence for gene trans-complementation.

In the mouse there are hybrid determinants for the immune region (Ir) of the genome which contribute to the diversity of class II (Ia) antigens of the major histocompatibility complex (MHC) and provide a molecular basis for Ir gene complementation. In man, two prominent families of Ia molecule, HLA-DR and HLA-DC (or DS), have been identified which are respectively homologous to the murine I-E (E alpha, E beta) and I-A (A alpha, A beta) antigens. Whereas DR antigens consist of a constant alpha-chain and an extremely polymorphic beta-chain, both the alpha and beta subunits of DC antigens are structurally variable when different alleles are compared. The marked differences in the structure of the alpha- and beta-chains of HLA-DC molecules result in electrophoretic variants which allow the haplotype of origin of each subunit to be identified by two-dimensional gel electrophoresis. We report here that gene trans-complementation occurs in cells heterozygous for the HLA-D region, resulting in the expression of hybrid HLA-DC molecules in addition to the parental forms. Generation of new HLA-D region hybrid molecules contributes to the qualitative diversity of human MHC class II antigens and has important functional implications in immune regulation.

Animals↗

PubMed2002

Population genetic subdivision in the New Zealand greenshell mussel (Perna canaliculus) inferred from single-strand conformation polymorphism analysis of mitochondrial DNA.

Single-strand conformation polymorphism (SSCP) analysis of the NADH IV region of the mitochondrial DNA (mtDNA) molecule in greenshell mussels (Perna canaliculus) indicated strong population genetic structuring in this endemic New Zealand species. A northern and a southern group were differentiated by frequency shifts in common haplotypes and by the occurrence of a unique southern haplotype at approximately 20% frequency. This split occurred south of Cook Strait (the body of water between the North and the South Island) at approximately 42 degrees S latitude. Northern populations were less genetically diverse than southern populations and mussels from the west coast of the South Island were most distinct from northern mussels. We hypothesize that the unique haplotype VIII originated in the lower South Island, and that its spread northwards was obstructed by the opening of Cook Strait approximately 15 000-16 000 years ago and the subsequent establishment of present-day surface water circulation patterns in Greater Cook Strait. We suggest that present-day strong tidal flows and turbulent mixing of water masses in Cook Strait, and intense up-welling on the east and west coasts in this region, represent a barrier to gene flow between mussels located in the North Island and northern South Island vs. mussels in most of the South Island and Stewart Island.

Animals↗

PubMed2003

Refinement of the critical region for MCKD1 by detection of transcontinental haplotype sharing.

BACKGROUND: Autosomal-dominant medullary cystic kidney disease type 1 (MCKD1) [OMIM 174000] is a hereditary nephropathy that leads to renal salt wasting and end-stage renal failure at a median age of 62 years. In a Welsh MCKD1 kindred we have recently demonstrated linkage to the MCKD1 locus on chromosome 1q23.1 and refined the critical MCKD1 region to <3.3 Mb. METHODS: In order to refine the candidate gene region for MCKD1, high-resolution haplotype analysis in three large kindreds with MCKD1 was performed. RESULTS: We report here on high-resolution haplotype analysis in this Welsh kindred, as well as in the Arizona kindred, which was used for the first definition of MCKD as a disease entity, and in a kindred from the Dutch/German border. We detected extensive haplotype sharing among all affected individuals of all three kindreds. Scrutinization of the genealogy of the Arizona kindred revealed an origin from Germany in the 17th century, thereby providing historical data for haplotype sharing by descent at the MCKD1 locus. CONCLUSION: Under the hypothesis of haplotype sharing by descent, we refined the critical genetic interval to <650 kb, thus enabling candidate gene analysis.

Haplotypes↗

PubMed1977

H-2 restriction of cell-mediated immunity to an intracellular bacterium: effector T cells are specific for Listeria antigen in association with H-21 region-coded self-markers.

The protective activity of anti-Listeria-immune T cells assayed in an adoptive transfer system in H-2 restricted. As shown in the present studies, the demonstration of the restriction is directly dependent on the dose and the relative protective activity of spleen cells. In addition, some H-2-unrestricted protection is conferred predominantly by other than immunoglobulin-negative spleen cells. Thus, the activity of Listeria-immune T cells appears to be 'absolutely' restricted and is in this respect comparable to in vivo T-cell-mediated anti-viral protection. The predominant genetic region of H-2 coding for the structures which are mainly involved in this restriction in T-cell immunity to this prototype intracellular bacterium is the I region. The specificity of Listeria-immune T cells is determined by the H-2 haplotype of the donor. Thus, F1 hybrids seem to possess at least two separable sets of T cells, each specific for one parental haplotype. As is true in the virus model, the results cannot distinguish between an altered-self or a dual recognition model of T-cell recognition to explain H-2 restriction. They are, however, compatible with the idea and I-coded cell surface structures may serve as receptors for cell-specific differentiation signals, which trigger direct or lymphokin-mediated activation of macrophages to manifest increased bactericidal capacity. The interesting parallels in self-marker recognition of T cells in the virus and intracellular bacterium systems, respectively, appear to be reasonably explained by the different types of signals transmitted by T cells to various target cells via the distinctly different self-markers employed (i.e., K or D vs I).

Animals↗

PubMed2006

Multilocus association mapping using variable-length Markov chains.

I propose a new method for association-based gene mapping that makes powerful use of multilocus data, is computationally efficient, and is straightforward to apply over large genomic regions. The approach is based on the fitting of variable-length Markov chain models, which automatically adapt to the degree of linkage disequilibrium (LD) between markers to create a parsimonious model for the LD structure. Edges of the fitted graph are tested for association with trait status. This approach can be thought of as haplotype testing with sophisticated windowing that accounts for extent of LD to reduce degrees of freedom and number of tests while maximizing information. I present analyses of two published data sets that show that this approach can have better power than single-marker tests or sliding-window haplotypic tests.

Chromosome Mapping↗

PubMed2005

No association with hypertension of CLCNKB and TNFRSF1B polymorphisms at a hypertension locus on chromosome 1p36.

OBJECTIVE: Chromosome 1p36 has been linked to essential hypertension and systolic blood pressure. This locus contains the chloride channel-Kb gene (CLCNKB) and the tumour necrosis factor receptor 2 gene (TNFRSF1B). Polymorphisms of each of these have shown association with hypertension, and a CLCNKB T481S variant alters receptor function. Here we performed association studies in a well-characterized cohort of hypertensives and normotensives whose blood pressure status matched that of both their parents. METHODS: The study involved 196 essential hypertensives and 321 normotensives. These were genotyped for TNFRSF1B variants T-1710A upstream, A257G in exon 2, a CA-repeat polymorphism in intron 4, E232K and M196R in exon 6, and T1668G and T1690C in the 3'-untranslated region, and the T481S variant of CLCNKB. RESULTS: The CLCNKB T481S variant showed no association with hypertension. Thermodynamic modelling of the 3'-untranslated region of TNFRSF1B mRNA predicted that the T1668G variant alters the stem-loop structure and thus the mRNA stability and expression. However, neither this nor the other TNFRSF1B polymorphisms, either alone or after haplotype analysis, were associated with hypertension. Moreover, for each gene the blood pressure, body mass index, plasma sodium and plasma lipid concentrations were generally similar across genotypes. CONCLUSION: Our data fail to support previous association findings for TNFRSF1B and CLCNKB at the chromosome 1p36 locus implicated in hypertension.

3' Untranslated Regions↗

PubMed2003

Novel classical MHC class I alleles identified in horses by sequencing clones of reverse transcription-PCR products.

Improved typing of horse classical MHC class I is required to more accurately define these molecules and to extend the number identified further than current serological assays. Defining classical MHC class I alleleic polymorphism is important in evaluating cytotoxic T lymphocyte (CTL) responses in horses. In this study, horse classical MHC class I genes were analyzed based on reverse transcription (RT)-PCR amplification of sequences encoding the polymorphic peptide binding region and the more conserved alpha 3, transmembrane and cytoplasmic regions followed by cloning and sequencing. Primer sets included a horse classical MHC class I-specific reverse primer and a forward primer conserved in all known horse MHC class I genes. Sequencing at least 25 clones containing MHC class I sequences from each of 13 horses identified 25 novel sequences and three others which had been described. Of these, nine alleles were identified from different horses or different RT-PCR and 19 putative alleles were identified in multiple clones from the same RT-PCR. The primer pairs did not amplify putative non-classical MHC class I genes as only classical MHC class I and related pseudogenes were found in 462 clones. This method also identified classical MHC class I alleles shared between horses by descent, and defined differences in alleles between horses varying in equine leukocyte antigen (ELA)-A haplotype as determined by serology. However, horses sharing ELA-A haplotypes defined by serotyping did not always share cDNA sequences, suggesting subhaplotypic variations within serologically defined ELA-A haplotypes. The 13 horses in this study had two to five classical MHC class I sequences, indicating that multiple loci code for these genes. Sequencing clones from RT-PCR with classical MHC class I-specific primers should be useful for selection of haplotype matched and mismatched horses for CTL studies, and provides sequence information needed to develop easier and more discriminating typing procedures.

Alleles↗

PubMed2003

Comparative sequence analysis of equine and human MHC class II DQB genes.

The MHC class II DQB gene of horse was isolated and characterized. No obvious mutations causing frame shifts, or destruction of putative protein structure and splicing machinery were detected. Nucleotide sequence of exon 2 was consistent with an allelic sequence of the W23 haplotype. The cytoplasmic region of the equine DQB gene comprised two exons and an intron. A novel fragment of the gene was identified at the 3' intergenic region proximal to the ELA-DQB gene by sequence comparison between the human and horse DQB genes. This sequence showed the highest identity to exon 3 region of the DQB gene, however the 5' half of this exon was truncated as compared with the intact exon. This gene fragment was also identified in the same site of the HLA-DQB gene.

Amino Acid Sequence↗

PubMed2005

Protection against P. aeruginosa with an adenovirus vector containing an OprF epitope in the capsid.

Pseudomonas aeruginosa is an important opportunistic pathogen that can cause chronic and often life-threatening infections of the respiratory tract, particularly in individuals with cystic fibrosis (CF). Because infections with P. aeruginosa remain the major cause of the high morbidity and mortality of CF, a vaccine against P. aeruginosa would be very useful for preventing this disorder. The outer membrane protein F (OprF) of P. aeruginosa is a promising vaccine candidate and various B cell epitopes within OprF have been identified. Given that adenovirus (Ad) vectors have strong immunogenic potential and can function as adjuvants for genetic vaccines, the present study evaluates the immunogenic and protective properties of a novel replication-deficient Ad vector in which the Ad hexon protein was modified to include a 14-amino acid epitope of P. aeruginosa OprF (Epi8) in loop 1 of the hypervariable region 5 of the hexon (AdZ.Epi8). Immunization of C57BL/6 mice with AdZ.Epi8 resulted in detectable serum anti-P. aeruginosa and anti-OprF humoral responses. These responses were haplotype dependent, with higher serum anti-OprF titers in CBA mice than in BALB/c or C57BL/6 mice. AdZ.Epi8 induced Epi8-specific IFN-gamma-positive CD4 and CD8 T cell responses and resulted in protection against a lethal pulmonary challenge with agar-encapsulated P. aeruginosa. Importantly, repeated administration of AdZ.Epi8 resulted in boosting of the anti-OprF humoral and anti-Epi8 cellular response, whereas no boosting effect was present in the response against the transgene beta-galactosidase. These observations suggest that Ad vectors expressing pathogen epitopes in their capsid will protect against an extracellular pathogen and will allow boosting of the epitope-specific humoral response with repeated administration, a strategy that should prove useful in developing Ad vectors as vaccines where humoral immunity will be protective.

Adenoviridae↗

PubMed1990

Isolated human growth hormone deficiency due to the hGH-I gene deletion with (type IA) and without (the Israeli-type) hGH antibody formation during hGH therapy.

Three Japanese patients with isolated growth hormone deficiency from two different families were shown to be homozygous for deletion of the structural gene for human growth hormone (hGH-I gene). These three patients had the same restriction fragment length polymorphism haplotypes. In patient No. 1, the growth rate initially responded well to pituitary human growth hormone, but growth rapidly ceased concomitantly with the development of high levels of anti-hGH antibodies. He again responded well to recombinant methionyl hGH and recombinant hGH without the methionine residue, even though having high hGH antibodies. Two siblings (Patients No. 2 and 3) showed a rather good response to pituitary hGH treatment without hGH antibodies ever being detected (the Israeli-type). hGH-I gene deletions may not necessarily result in hGH antibody formation. Heterogeneity has been observed in isolated hGH deficiency due to hGH-I gene deletion. hGH-I gene analysis should not be limited to patients with hGH antibody formation and subnormal growth responses to hGH therapy.

Adolescent↗

PubMed2003

Phylogeography and population structure of the Japanese wild boar Sus scrofa leucomystax: mitochondrial DNA variation.

Phylogeographic characteristics and population structure of Japanese wild boar (Sus scrofa leucomystax) were investigated using mitochondrial DNA (mtDNA) sequence data. Sixteen Japanese wild boar haplotypes detected from partial sequences of the mtDNA control region (574-bp) from 180 Japanese wild boar specimens from 10 local populations on Honshu, Shikoku, and Kyushu islands and 41 haplotypes from other S. scrofa were analyzed using the neighbor-joining method. The Japanese wild boars were more closely related to Northeast Asian wild boars from Mongolia than to the other Asian continental S. scrofa. The Japanese and Northeast Asian wild boars were not significantly distinguished by corrected average pairwise difference analysis. The ancestors of Japanese wild boars are suggested to have been part of the continental S. scrofa population that spread from Southeast to Northeast Asia during the Middle to Late Pleistocene. The Japanese wild boar mtDNA haplotype cladogram shows 95% parsimoniously plausible branch connections supporting three sympatric clades. Nested clade analysis indicates that these three clades are the result of distinct historical events or gene flow. The present population of Japanese wild boars may have been formed by a few independent migrations of distinct clades from the continent with subsequent mixing on the Japanese Islands.

Analysis of Variance↗

PubMed1994

[Detection of amino acids on the agretopes of pigeon cytochrome c derived peptide p43-58 specifically bound to mouse MHC class II allelic products].

In our previous study it has been demonstrated that residues 46 and 54 on a pigeon cytochrome c derived peptide, 50V (AEGFSYTVANKNKGIT), work as agretopes (sites contact with MHC molecule) and residues 50 and 52 function as dominant epitopes (sites contact with TCR), when tri-molecular complexes are formed among 50V, I-Ab molecule and TCR. 50V was substituted from aspartic acid to valine at position 50 of p43-58 that was derived from residues 43 to 58 of pigeon cytochrome c. Substitution of agretopic residues on 50V altered this I-Ab binding peptide to an I-Ak binding peptide, suggesting that positions 46 and 54 also worked as agretopes in I-Ak restricted T cell responses. In the present report I examined whether residues 46 and 54 of the p43-58 related peptides worked as agretopes in binding to products of other I-A haplotypes and tried to determine which amino acids on agretopes bound strongly with each I-A molecule. The p43-58 related peptides with phenylalanine(F) at position 46 and alanine(A) at position 54 bound tightly to I-Ab, I-Aq and I-A(s) molecules and stimulated T cells most potently in mice bearing these I-A products. In contrast, p43-58 related peptides carrying aspartic acid(D) at position 46 and A at position 54 bound most potently to I-Ak molecules, and the peptides with arginine(R) at position 46 and A at position 54 bound most efficiently to I-Av molecules. These findings demonstrate that the agretopic positions on p43 -58 related peptides are preserved in T cell responses restricted to each I-A haplotype studied, but the specific amino acids on the agretopes exist a priori for each I-A allele specific structure.

Alleles↗

PubMed1994

Immunodominance correlates with T-cell receptor (alpha beta) gene usage in the class II-restricted response to influenza haemagglutinin.

Class II-restricted T-cell clones elicited by natural infection with influenza A virus (H3N2 subtype) exhibit extensive diversity in their recognition specificity for the envelope glycoprotein, haemagglutinin, and focus on hypervariable regions of the HA1 subunit that feature in antigenic drift. However, T-cell clones established from the same individual focus on a single antigenic site with differing fine specificity for mutant viruses. We wished to determine whether such diversity of the haplotype and contrasting immunodominance of the individual's repertoire was mirrored in T-cell receptor (TcR) gene usage. A structural analysis was undertaken of the alpha and beta chains of TcR from a panel of CD4+ T-cell memory clones established in vitro after natural infection with X31 virus and specific for eight distinct antigenic sites of the HA1 subunit: p48-67 (Ak), p58-73 (Ad), p120-139 (Ak), p177-199 (Ad), p186-200 (Ad), p226-245 (Ek), p246-265 (Ek) and p269-288 (Ak). Direct sequencing of the alpha and beta chains, using the polymerase chain reaction, revealed that T-cell clones derived from the same donor used identical V beta D beta J beta and V alpha J alpha elements. Moreover there was extensive diversity in usage of V beta (V beta 1 or V beta 4 or V beta 8) genes between individual mice, in association with diverse J beta and V alpha J alpha elements for the recognition of a common antigenic peptide. We conclude that the CD4+ T-cell memory repertoire of the individual, following primary exposure to infectious virus, is oligoclonal and recruited from a limited number of precursor cells.

Amino Acid Sequence↗

PubMed2005

DXS10079, DXS10074 and DXS10075 are STRs located within a 280-kb region of Xq12 and provide stable haplotypes useful for complex kinship cases.

The evaluation of the short tandem repeat (STR) markers DXS10079, DXS10074 and DXS10075 was amended to establish a STR cluster spanning a genetic distance<1 cM. These three STRs are located within a 280-kb region at Xq12 and provide stable haplotypes useful for solving complex kinship cases. Theoretically, this cluster could give rise to 2,548 different haplotypes in the German population and the genotyping of 781 men revealed the presence of 172 haplotypes. Since the three STRs were shown to be in strong linkage disequilibrium (LD), haplotype frequencies cannot be computed on the basis of a single locus allele frequency alone but have to be estimated directly. Here, we present data on linkage, haplotype frequencies and LD in a German population. Further clusters from other regions of the X chromosome will be published in the future to cover the chromosome with a well-structured network of highly informative sites.

Chromosomes, Human, X↗

PubMed1980

Evidence for mutation in an I-A gene.

Mutant mouse strains are important tools for immunogenetic studies of the regulation, structure and function of major histocompatibility (H-2) antigens1-3. Several inbred strains have been established which carry H-2-linked mutations that cause changes in cell surface antigens as recognized by cytotoxic T cells and sometimes antibodies. Using intra-H-2 recombinant haplotypes in skin graft complementation studies, lesions in several of these mutant strains have been genetically mapped to genes encoded in the K- or D-end of the H-2 complex3. More precise mapping has often not been possible as many of the available mutant strains possessed lesions in the K-end of the H-2b haplotype and a recombinant separating the Kb and I-Ab regions was not previously available. The genetic locations of the lesions in some of these mutant strains could therefore only be inferred when a serological and/or structural alteration was detected (see refs 1, 2). We describe here the use of a newly established recombinant strain, B10.MBR (ref. 4), for skin graft complementation studies to map K-end mutations. These studies provide the first genetic evidence that the B6.C-H-2bm12 mutation involves an I-Ab gene and also confirm that the lesions in two other mutants can be mapped to a gene in the Kb region.

Animals↗

PubMed2003

Novel variants of the IL-10 receptor 1 affect inhibition of monocyte TNF-alpha production.

IL-10-deficient mice exhibit spontaneous enterocolitis and other symptoms akin to Crohn's disease, indicating that IL-10 might regulate normal physiology in the gut. However, clinical trials with IL-10 in Crohn's disease were disappointing, although some patients showed healing of intestinal mucosa. This study searched for genetic polymorphisms within the IL-10 pathway. We decided to screen for mutations of the IL-10R1 cDNA in healthy volunteers and Crohn's disease patients and identified two novel variants: a serine 138-to-glycine (S138G) and a glycine 330-to-arginine (G330R) substitution. The allelic frequency in a European cohort was relatively high (16% for the S138G and 33% for the G330R), and S138G was in strong linkage disequilibrium with G330R. A similar allele frequency was found in a group of Crohn's patients. In IL-10R1 G330R-expressing monocytes, the inhibitory effect of IL-10 on TNF-alpha production was diminished, indicating that this variant may be a loss-of-function allele. No such difference was observed between haplotypes 4 (G330R only) and 7 (S138G and G330R). In addition, these IL-10R1 variants had no influence on the IL-10R1 expression density. Structural analysis of the S138G variant revealed that the substitution of S138G may interfere with binding of IL-10 to IL-10R1.

Amino Acid Substitution↗

PubMed2004

Evolutionary history of the northern leopard frog: reconstruction of phylogeny, phylogeography, and historical changes in population demography from mitochondrial DNA.

This study uses a combined methodological approach including phylogenetic, phylogeographic, and demographic analyses to understand the evolutionary history of the northern leopard frog, Rana pipiens. We tested hypotheses concerning how (or if) known geological events and key features of the species biology influenced the contemporary geographic and genetic distribution of R. pipiens. We assayed mitochondrial DNA variation from 389 individuals within 35 populations located throughout the species range. Our a priori expectations for patterns and processes influencing the current genetic structure of R. pipiens were supported by the data. However, our analyses revealed specific aspects of R. pipiens evolutionary history that were unexpected. The phylogenetic analysis indicated that R. pipiens is split into populations containing discrete eastern or western haplotypes, with the Mississippi River and Great Lakes region dividing the geographic ranges. Nested clade analysis indicated that the biological process most often invoked to explain the pattern of haplotype position is restricted gene flow with isolation by distance. Demographic analyses showed evidence of both historical bottlenecks and population expansions. Surprisingly, the genetic evidence indicated that the western haplotypes had significantly reduced levels of genetic diversity relative to the eastern haplotypes and that major range expansions occurred in both regions well before the most recent glacial retreat. This study provides a detailed history of how a widespread terrestrial vertebrate responded to episodic Pleistocene glacial events in North America. Moreover, this study illustrates how complementary methods of data analysis can be used to disentangle recent and ancient effects on the genetic structure of a species.

Animals↗