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 1,243 records · Page 69Linked to original sources

PubMed1993

Studies of the adjuvant-independent antibody response to immunotargeting. Target structure dependence, isotype distribution, and induction of long term memory.

Immunoconjugates composed of avidin linked to biotinylated antibodies specific for different surface determinants on cells of the immune system were evaluated for their ability to induce adjuvant-independent anti-avidin IgG responses in mice. Previously, we demonstrated that allele-specific murine anti-class II MHC-avidin immunoconjugates were immunogenic in mice bearing the appropriate haplotype. Herein we report the immunotargeting potential of heterologous anti-class II MHC antibodies specific for framework determinants, and extend the range of effective targets to include certain non-MHC structures present on APC (e.g., 33D1 on dendritic cells, 14.8 on B cells, and CD45--the leukocyte common antigen). However, antibodies with other specificities (e.g., leukocyte integrins and some macrophage markers) were not effective targeting vehicles. Surprisingly, immunoconjugates specific for CD3 and CD4 were immunogenic. The isotype distribution of the anti-avidin antibody response induced in mice by immunotargeting to class II MHC or 33D1 was similar to that induced by immunization with Ag emulsified in complete Freund's adjuvant. Most of the antibody induced was IgG1 (65-75%), but a significant proportion was IgG2a (20-30%). We also demonstrate that immunotargeting is able to prime for long-term immunologic memory in mice.

Animals↗

PubMed2006

Epistatic and pleiotropic effects of polymorphisms in the fibrinogen and coagulation factor XIII genes on plasma fibrinogen concentration, fibrin gel structure and risk of myocardial infarction.

An intricate interplay between the genes encoding fibrinogen gamma (FGG), alpha (FGA) and beta (FGB), coagulation factor XIII (F13A1) and interleukin 6 (IL6) and environmental factors is likely to influence plasma fibrinogen concentration, fibrin clot structure and risk of myocardial infarction (MI). In the present study, the potential contribution of SNPs harboured in the fibrinogen, IL6 and F13A1 genes to these biochemical and clinical phenotypes was examined. A database and biobank based on 387 survivors of a first MI and population-based controls were used. Sixty controls were selected according to FGG 9340T > C [rs1049636] genotype for studies on fibrin clot structure using the liquid permeation method. The multifactor dimensionality reduction method was used for interaction analyses. We here report that the FGA 2224G > A [rs2070011] SNP (9.2%), plasma fibrinogen concentration (13.1%) and age (8.1%) appeared as independent determinants of fibrin gel porosity. The FGA 2224G > A SNP modulated the relation between plasma fibrinogen concentration and fibrin clot porosity. The FGG-FGA*4 haplotype, composed of the minor FGG 9340C and FGA 2224A alleles, had similar effects, supporting its reported protective role in relation to MI. Significant epistasis on plasma fibrinogen concentration was detected between the FGA 2224G > A and F13A1 Val34Leu [rs5985] SNPs (p < 0.001). The FGG 9340T > C and FGB 1038G > A [rs1800791] SNPs appeared to interact on MI risk, explaining the association of FGG-FGB haplotypes with MI in the absence of effects of individual SNPs. Thus, epistatic and pleiotropic effects of polymorphisms contribute to the variation in plasma fibrinogen concentration, fibrin clot structure and risk of MI.

Environment↗

PubMed1998

Phylogeography of the freshwater fish, Mogurnda adspersa, in streams of northeastern Queensland, Australia: evidence for altered drainage patterns.

A phylogeographic survey was used to elucidate the relative roles of historical processes and contemporary gene flow in structuring the genetic pattern observed with Mogurnda adspersa. This species of freshwater fish is found in the rivers and streams of the northeastern highlands of Queensland, Australia. Specifically, this project focused on populations in the Tully and Herbert Rivers in the Atherton Tablelands. Sequence analysis indicated that three distinct clades exist in the headwaters of the Tully River. The population sampled from one of the Tully River streams (Cheetah Creek) contained haplotypes that displayed approximately 3.4% sequence divergence from other haplotypes detected in this river. Furthermore, these haplotypes formed part of the clade which exists throughout not only the Herbert River but other surrounding drainages in the area. These results support the hypothesis that the current genetic structure is strongly affected by changes in drainage patterns due to geomorphological processes that occurred in the recent past.

Animals↗

PubMed2006

Inferring the population structure and demographic history of the tick, Amblyomma americanum Linnaeus.

A hierarchial population genetic study was conducted on 703 individual Amblyomma americanum from nine populations in Georgia, U.S.A. Populations were sampled from the Coastal Plain, midland Piedmont region, and the upper Piedmont region. Twenty-nine distinct haplotypes were found. A minimum spanning tree was constructed that indicated these haplotypes comprised two lineages, the root of which was distinctly star-like. The majority of the variation found was among ticks within each population, indicating high amounts of gene flow and little genetic differentiation between the three regions. An overall F(ST) value of 0.006 supported the lack of genetic structuring between collection sites in Georgia. Mantel regression analysis revealed no isolation by distance. Signatures of population expansion were detected in the shapes of the mismatch distribution and tests of neutrality. The absence of genetic differentiation combined with the rejection of the null model of isolation by distance may indicate recent range expansion in Georgia or insufficient time to reach an equilibrium where genetic drift may have affected allele frequencies. Alternatively, the high degree of panmixia found within A. americanum in Georgia may be due to bird-mediated dispersal of ticks increasing the genetic similarity between geographically separated populations.

Animals↗

PubMed2004

Bottleneck effects on the sika deer Cervus nippon population in Hokkaido, revealed by ancient DNA analysis.

The population size of the sika deer Cervus nippon on Hokkaido Island of Japan had been remarkably reduced because of heavy hunting pressure since the beginning of Meiji Period and effects of heavy snow in 1879 and 1881. After that, the number of sika deer in Hokkaido has increased gradually due to the protection by the Hokkaido government. In the present study, in order to investigate the bottleneck effects, we analyzed ancient mitochondrial DNA (mtDNA) on sika deer bones excavated from archaeological sites just before Meiji Period. On 86 of 113 bones from 13 archaeological sites of Ainu Culture Period (17-19th centuries), 602 base-pair fragments of the mtDNA control region were successfully sequenced. Consequently, we found three new haplotypes (g-, h- and i-types) which had not been identified in modern sika deer. In addition, four haplotypes (a-, b-, c- and d-types) identified from modern sika deer were also found in the archaeological deer. The new haplotypes and previously reported hapoltypes from sika deer of Hokkaido were phylogenetically much closer to each other, compared with those of modern sika deer from Honshu, Kyushu and the Chinese continent. Geographical distribution patterns of haplotypes of the ancient population were different from those of the modern population in Hokkaido. Our findings indicated that their genetic diversity was reduced through the bottleneck and that population structures of sika deer were changed widely in Hokkaido due to genetic drift.

Animals↗

PubMed2005

Population differentiation decreases with depth in deep-sea bivalves.

The deep sea is the largest ecosystem on Earth. Recent exploration has revealed that it supports a highly diverse and endemic benthic invertebrate fauna, yet the evolutionary processes that generate this remarkable species richness are virtually unknown. Environmental heterogeneity, topographic complexity, and morphological divergence all tend to decrease with depth, suggesting that the potential for population differentiation may decrease with depth. To test this hypothesis, we use mitochondrial DNA (16S rRNA gene) to examine patterns of population differentiation in four species of protobranch bivalves (Nuculoma similis, Deminucula atacellana, Malletia abyssorum, and Ledella ultima) distributed along a depth gradient in the western North Atlantic. We sequenced 268 individuals from formalin-fixed samples and found 45 haplotypes. The level of sequence divergence among haplotypes within species was similar, but shifted from between populations at bathyal depths to within populations at abyssal depths. Levels of population structure as measured by phiST were considerably greater in the upper bathyal species (N. similis = 0.755 and D. atacellana = 0.931; 530-3834 m) than in the lower bathyal/abyssal species (M. abyssorum = 0.071 and L. ultima = 0.045; 2864-4970 m). Pairwise genetic distances among the samples within each species also decreased with depth. Population trees (UPGMA) based on modified coancestry coefficients and nested clade analysis both indicated strong population-level divergence in the two upper bathyal species but little for the deeper species. The population genetic structure in these protobranch bivalves parallels depth-related morphological divergence observed in deep-sea gastropods. The higher level of genetic and morphological divergence, coupled with the strong biotic and abiotic heterogeneity at bathyal depths, suggests this region may be an active area of species formation. We suggest that the steep, topographically complex, and dynamic bathyal zone, which stretches as a narrow band along continental margins, plays a more important role in the evolutionary radiation of the deep-sea fauna than the much more extensive abyss.

Analysis of Variance↗

PubMed2001

The phylogeography of Y chromosome binary haplotypes and the origins of modern human populations.

Although molecular genetic evidence continues to accumulate that is consistent with a recent common African ancestry of modern humans, its ability to illuminate regional histories remains incomplete. A set of unique event polymorphisms associated with the non-recombining portion of the Y-chromosome (NRY) addresses this issue by providing evidence concerning successful migrations originating from Africa, which can be interpreted as subsequent colonizations, differentiations and migrations overlaid upon previous population ranges. A total of 205 markers identified by denaturing high performance liquid chromatography (DHPLC), together with 13 taken from the literature, were used to construct a parsimonious genealogy. Ancestral allelic states were deduced from orthologous great ape sequences. A total of 131 unique haplotypes were defined which trace the microevolutionary trajectory of global modern human genetic diversification. The genealogy provides a detailed phylogeographic portrait of contemporary global population structure that is emblematic of human origins, divergence and population history that is consistent with climatic, paleoanthropological and other genetic knowledge.

Africa↗

PubMed2005

Multiple germline kappa light chains generate anti-insulin B cells in nonobese diabetic mice.

The highly selective nature of organ-specific autoimmune disease is consistent with a critical role for adaptive immune responses against specific autoantigens. In type 1 diabetes mellitus, autoantibodies to insulin are important markers of the disease process in humans and nonobese diabetic (NOD) mice; however, the Ag-specific receptors responsible for these autoantibodies are obscured by the polyclonal repertoire. NOD mice that harbor an anti-insulin transgene (Tg) (V(H)125Tg/NOD) circumvent this problem by generating a tractable population of insulin-binding B cells. The nucleotide structure and genetic origin of the endogenous kappa L chain (Vkappa or IgL) repertoire that pairs with the V(H)125Tg were analyzed. In contrast to oligoclonal expansion observed in systemic autoimmune disease models, insulin-binding B cells from V(H)125Tg/NOD mice use specific Vkappa genes that are clonally independent and germline encoded. When compared with homologous IgL genes from nonautoimmune strains, Vkappa genes from NOD mice are polymorphic. Analysis of the most frequently expressed Vkappa1 and Vkappa9 genes indicates these are shared with lupus-prone New Zealand Black/BINJ mice (e.g., Vkappa1-110*02 and 9-124) and suggests that NOD mice use the infrequent b haplotype. These findings show that a diverse repertoire of anti-insulin B cells is part of the autoimmune process in NOD mice and structural or regulatory elements within the kappa locus may be shared with a systemic autoimmune disease.

Animals↗

PubMed2005

A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.

Peeling skin syndrome is an autosomal recessive genodermatosis characterized by the shedding of the outer epidermis. In the acral form, the dorsa of the hands and feet are predominantly affected. Ultrastructural analysis has revealed tissue separation at the junction between the granular cells and the stratum corneum in the outer epidermis. Genomewide linkage analysis in a consanguineous Dutch kindred mapped the gene to 15q15.2 in the interval between markers D15S1040 and D15S1016. Two homozygous missense mutations, T109M and G113C, were found in TGM5, which encodes transglutaminase 5 (TG5), in all affected persons in two unrelated families. The mutation was present on the same haplotype in both kindreds, indicating a probable ancestral mutation. TG5 is strongly expressed in the epidermal granular cells, where it cross-links a variety of structural proteins in the terminal differentiation of the epidermis to form the cornified cell envelope. An established, in vitro, biochemical cross-linking assay revealed that, although T109M is not pathogenic, G113C completely abolishes TG5 activity. Three-dimensional modeling of TG5 showed that G113C lies close to the catalytic domain, and, furthermore, that this glycine residue is conserved in all known transglutaminases, which is consistent with pathogenicity. Other families with more-widespread peeling skin phenotypes lacked TGM5 mutations. This study identifies the first causative gene in this heterogeneous group of skin disorders and demonstrates that the protein cross-linking function performed by TG5 is vital for maintaining cell-cell adhesion between the outermost layers of the epidermis.

Binding Sites↗

PubMed2001

The role of introgressive hybridization in the evolution of the Gila robusta complex (Teleostei: Cyprinidae).

The extent and impact of introgressive hybridization was examined in the Gila robusta complex of cyprinid fishes using mitochondrial DNA (mtDNA) sequence variation. Lower Colorado River basin populations of G. robusta, G. elegans, and G. cypha exhibited distinct mtDNAs, with only limited introgression of G. elegans into G. cypha. The impact of hybridization was significant in upper Colorado River basin populations; most upper basin fishes sampled exhibited only G. cypha mtDNA haplotypes, with some individuals exhibiting mtDNA from G. elegans. The complete absence of G. robusta mtDNA, even in populations of morphologically pure G. robusta, indicates extensive introgression that predates human influence. Analysis of the geographic distribution of variation identified two distinctive G. elegans lineages; however, the small number of individuals and localities sampled precluded a comprehensive analysis. Analysis of haplotype and population networks for G. cypha mtDNAs from 15 localities revealed low divergence among haplotypes; however, significant frequency differences among populations within and among drainages were found, largely attributable to samples in the Little Colorado River region. This structure was not associated with G. cypha and G. robusta, as morphotypes from the same location are more similar than conspecific forms in other locations. This indicates that morphological and mtDNA variation are affected by different evolutionary forces in Colorado River Gila and illustrates how both hybridization and local adaptation can play important roles in evolution.

Animals↗

PubMed1989

Structural requirements for the interaction between peptide antigens and I-Ed molecules.

We have analyzed the structural characteristics of the interaction between I-Ed molecules and their peptide ligands. It was found that unrelated good I-Ed binders share structurally similar "core" regions that were experimentally demonstrated to be crucial for binding to I-Ed molecules. Single amino acid substitution analogues of one good I-Ed binder, hen egg lysozyme 107-116, were analyzed for their capacity to bind to I-Ed molecules and to activate two different I-Ed-restricted T cell hybridomas. The results illustrate the great permissiveness of I-Ed-peptide interaction and the great specificity of T cell recognition. It was concluded from these analyses that basic residues on the peptide molecule play a crucial role in binding to I-Ed. This contrasts with the structural requirements for binding to the other Iad isotype, I-Ad, the crucial hydrophobic residues. Thus, different class II molecules of the same MHC haplotype may have rather distinct peptide binding specificities, thereby expanding the repertoire of possible immunogenic peptides presented for T cell recognition.

Amino Acid Sequence↗

PubMed2002

Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus.

PSORS1, near HLA-C, is the major genetic determinant of psoriasis. We present genetic and structural evidence suggesting a major role for the HCR gene at the PSORS1 locus. Genotyping of 419 families from six populations revealed that coding single-nucleotide polymorphisms of HCR formed a conserved allele HCR*WWCC that associated highly significantly with psoriasis and with the HLA-Cw6 allele in all populations. Because of strong linkage disequilibrium between HLA-Cw6 and HCR*WWCC, the two genes could not be genetically distinguished by this sample size. However, the variant HCR allele was predicted to differ in secondary structure from the wild-type protein. HCR protein expression in lesional psoriatic skin differed considerably from that observed in normal skin. These results provide strong evidence for the HCR*WWCC allele as a major genetic determinant for psoriasis, probably by a mechanism impacting on keratinocyte proliferation.

Age of Onset↗

PubMed1993

H-2 gene complex and corticosteroid responsiveness: evidence that the corticosteroid hormone signal transduction pathway in the adult mouse lung is not associated with haplotype-specific responses to corticosteroids.

Differential responsiveness to corticosteroids (CORT) has been shown to be related to HLA haplotype. A strong association between the mouse homolog to the human HLA complex, the H-2 complex, and intrauterine responses to CORT have also been demonstrated; haplotype differences alter CORT-induced susceptibility to cleft palate and temporal differences in lung maturation. Since variation in the glucocorticoid receptor (GR) is associated with tissue specific responses to CORT, we hypothesize that haplotype-specific CORT responsiveness may be regulated by H-2 associated modification of GR expression and/or function. Given that H-2 congenic mice are genetically identical except at the H-2 complex on mouse chromosome 17 and the GR structural gene is encoded on chromosome 18, the GR gene is identical in these mice. However, any step in the GR signal transduction pathway may be regulated by gene(s) at or near the H-2 complex and result in haplotype-specific differences in CORT responsiveness. We have investigated differences in qualitative and quantitative characteristics of the adult B10 (H-2b) and B10.A (H-2a) pulmonary GR by Scatchard analysis, immunochemical and biochemical assays. No differences in the GR binding parameters (BMAX and Kd), receptor form and level, or ligand-GR complex binding to glucocorticoid response element (GR-GRE) were detected, leading us to conclude that H-2 associated factors do not regulate the relative intrauterine responses to CORT by modulating the adult GR.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗

PubMed1993

HLA-DR beta chain residue 86 controls DR alpha beta dimer stability.

Major histocompatibility complex class II molecules exist in two forms, which can be distinguished on the basis of their stability in sodium dodecyl sulfate (SDS) as SDS-stable and SDS-unstable alpha beta dimers. The ratio of stable vs. unstable alpha beta dimers varies between murine H-2 alleles and isotypes, but the molecular basis for this observation is unknown. Here we show that for the human HLA-DRB1 and HLA-DRB3 gene products this ratio is controlled by the valine/glycine dimorphism at position 86. Haplotypes coding for DR beta chains with a valine at position 86 express higher numbers of stable dimers compared to similar haplotypes expressing DR beta chains with a glycine at that position. Reverse-phase high-performance liquid chromatography analysis of iodinated peptides, which were eluted from DR dimers with either a DRB1*1101 or a DRB1*1104 beta chain which differ only at position 86, indicated that these DR dimers contain (partially) distinct sets of peptides. The valine/glycine dimorphism is highly conserved, present in most HLA-DR alleles and influences peptide-binding. Analysis of the occurrence of the Val86 and the Gly86 gene products revealed that these are not equally present in the population. Depending on the DR specificity either the Val86 of Gly86 allelic variant is favored. Thus, the natural, highly conserved dimorphism at HLA-DR beta chain position 86 influences peptide selection. The dimorphism is therefore likely to influence antigen presentation and forms the molecular basis for the observed differences in stability of Val86- and Gly86-containing DR dimers in the presence of SDS.

Alleles↗

PubMed2002

Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism.

Symphalangism (SYM or SYM1) is an autosomal dominant disorder characterized by multiple joint fusions. The disease is caused by mutations of the NOG gene, that maps to chromosome 17q22. So far, only six independent NOG mutations have been identified. We have analysed an Italian family in which father and son had bilateral symphalangism and detected a novel NOG mutation (P35S), originated in the father from a c.914C>T transition. A different mutation in the same codon (P35R) has been previously described. Comparison between different noggin gene hortologs shows that codon 35 is conserved. Therefore, this codon should play an important role in NOG gene function. This is the first mutation described for NOG after the initial report of NOG mutations being causative of SYM.

Amino Acid Sequence↗

PubMed1990

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

As we have discussed previously (Horn et al. 1988a; Erlich et al. 1989b; Horn et al. 1988b), there are no unique class II sequences associated with IDDM, which suggests that "normal" class II alleles confer susceptibility. Given the estimates of concordance--under 50% of monozygotic twins and approximately 15% (Tattersol, Pyle 1972 and 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 (Yoon, this volume), 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 nonobese diabetic mouse and the BB rat models for IDDM, non-MHC susceptibility loci have been identified and mapped (Hattori et al. 1986; Colle et al. 1981), 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 for IDDM.

Diabetes Mellitus, Type 1↗

PubMed2006

Contribution of the serotoninergic system to anxious and depressive traits that may be partially responsible for the phenotypical variability of bulimia nervosa.

Eating disorders (ED), such as anorexia nervosa (AN) and bulimia nervosa (BN), are complex psychiatric phenotypes influenced by both genetic and environmental factors. We investigated the genetic contribution of four single nucleotide polymorphisms (SNPs) within the serotonin receptor 5HT2C and two sequence variants within the serotonin transporter SLC6A4 to different ED-related psychopathological symptoms in a total sample of 82 ED patients. All patients were diagnosed according to DSM-IV criteria and underwent diagnostic and psychopathological assessments by means of structured clinical interviews and rating scales. We detected significant evidence of association between the -995A/-759T/-697C/Cys23 haplotype of the 5HT2C gene and different anxious and depressive subscales of the SCL90-R instrument, that included Somatization (p = 0.029), Obsessive-Compulsiveness (p = 0.021), Depression (p = 0.032), Anxiety (p = 0.004), Hostility (p = 0.028), Phobic Anxiety (p = 0.029) and Paranoid Ideation (p = 0.008), in BN patients. We also observed a strong association between the 5HTTLPR polymorphism of the SLC6A4 gene and Anxiety in the same group of BN patients (p = 0.004). However, no epistatic effects between the 5HT2C and SLC6A4 genes on the different anxious and depressive subscales were observed. Our preliminary data suggest that the serotoninergic system contributes to the different psychopathological symptoms that may be partially responsible for the phenotypical variability within the bulimic phenotype.

Adult↗

PubMed2026

Gene polymorphisms associated with progression of primary open-angle glaucoma: A systematic review.

Glaucoma is the leading global cause of irreversible blindness, with primary open-angle glaucoma (POAG) its most prevalent subtype. While elevated intraocular pressure is a major risk factor, glaucoma progression is multifactorial, influenced by genetic, environmental, vascular and mechanical factors. Genetic polymorphisms have been linked to both POAG susceptibility and progression, yet most studies focus on risk factors for disease onset rather than progression. We provide an overview of the current literature on gene polymorphisms associated with POAG progression. We conducted a systematic search following PRISMA guidelines in MEDLINE, EMBASE, Web of Science, Cochrane Library, Scopus and Public Health Genomics and Precision Health Knowledge Base. Eligible studies investigated associations between genetic variants and structural or functional markers of glaucoma progression in adult-onset POAG patients. Eighteen articles were included. HLA class I haplotypes (A1-B8 and A2-B40) and MYOC.mt1+ carriers showed faster progression of optic nerve head damage. The APOE ε4 allele was linked to faster macular thinning in normal tension glaucoma patients. BDNF rs6265 Val/Val homozygotes exhibited accelerated retinal nerve fiber layer loss, particularly in females. TGFBR3-CDC7 (rs1192415: G) and MYOC.mt1+ carriers experienced accelerated visual field deterioration. Carriers of GAS7 (rs9913911: AA), IL1B (rs1143627: CT and rs16944: CT) and OPTN (rs2234968) had a higher likelihood of requiring surgery. Variants in ABCA1, CDKN2B-AS, eNOS and Piezo1 showed inconclusive results. These findings support a role for genetic polymorphisms in POAG progression and highlight the potential of genetic screening to identify patients at increased risk for rapid disease progression.

Disease progression↗