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Results for “Haplotype structures”

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PubMed1996

Dominant type 1 von Willebrand disease caused by mutated cysteine residues in the D3 domain of von Willebrand factor.

No defects have been reported in moderately severe type 1 von Willebrand disease (vWD) with a clear autosomal dominant inheritance pattern, and the mechanism underlying this form of vWD remains obscure. We have studied a type 1 vWD family with such a dominant phenotype. The entire coding sequence of the von Willebrand factor (vWF) gene was analyzed by direct sequencing of DNA fragments amplified by polymerase chain reaction. Only one candidate mutation T(3445)-->C in exon 26 was detected that predicts a replacement of cysteine (C) at position 386 of the mature vWF subunit by arginine (R). Both mutant and normal vWF alleles were expressed as shown by analysis of platelet mRNA. This substitution segregates with vWD in the family and was not found in 100 unrelated individuals. The recombinant mutant vWF(C386R) was characterized by expression in 293T cells. The secretion of vWF(C386R) was greatly impaired due to retention in the endoplasmic reticulum. In cotransfections of normal and mutant vWF constructs, the vWF(C386R) subunits caused a dose-dependent decrease in the secretion of vWF. The multimer pattern remained nearly normal and consistent with a dominant vWD type 1 phenotype. The importance of the cysteine residues in the D3 domain of vWF in the pathogenesis of dominant type 1 vWD was further shown by the detection of another cysteine mutation, Cys367-->Phe, in two additional unrelated patients with a similar dominant type 1 vWD phenotype. We conclude that the loss of cysteine pairing in the D3 domain, leaving one free cysteine, can induce a purely quantitative deficiency of vWF by dominantly suppressing the secretion of normal vWF.

Alleles↗

PubMed2003

Haplotype mapping of the bronchiolitis susceptibility locus near IL8.

Susceptibility to viral bronchiolitis, the commonest cause of infant admissions to hospital in the industrialised world, is associated with polymorphism at the IL8 locus. Here we map the genomic boundaries of the disease association by case-control analysis and TDT in 580 affected UK infants. Markers for association mapping were chosen after determining patterns of linkage disequilibrium across the surrounding region of chromosome 4q, a 550-kb segment containing nine genes, extending from AFP to PPBP. The region has three major clusters of high linkage disequilibrium and is notable for its low haplotypic diversity. We exclude adjacent chemokine genes as the cause of the association, and identify a disease-associated haplotype that spans a 250-kb region from AFM to IL8. In between these two genes there is only one structural feature of interest, a novel gene RASSF6, which is predicted to encode a Ras effector protein.

Base Sequence↗

PubMed1990

Amino acid substitutions determining G3m(g5).

Amino acid substitutions specific for allotypic G3m(g5) marker were studied by sequence analysis of the C-terminal BrCN peptides of myeloma protein Ba [G3m(g5+)] and Bu [G3m(g5-)]. The results indicate that arginine and tyrosine at position 435 and 436 are responsible for the specificity. Two substitutions of IgG3 Bu [G3m(b1, b3)] and IgG3 Jir [G3m(b3,s,t)] [Matsumoto et al.: J. Immun. 131: 1865, 1983], in the same positions are arginine-phenylalanine and histidine-tyrosine, respectively. Affinity chromatographic data of modified IgG3 proteins show that the tyrosine residue at position 436 associated with phenylalanine at position 124 of protein A-B fragment plays a role in the interaction. The differences in the yields between IgG3s carrying various haplotypes on Protein A-Sepharose affinity chromatography [Ito et al.: Proc. Japan Acad. 56B: 226, 1980] are also explained through this chromatography and also by the configuration of the residues in tertiary structure [Deisenhofer: Biochemistry 20: 2361, 1980].

Amino Acid Sequence↗

PubMed2006

A novel mitochondrial intergenic spacer reflecting population structure of Pacific oyster.

Nucleotide sequence divergence in a novel major mitochondrial DNA intergenic spacer (IGS) of Pacific oyster Crassostrea gigas was analyzed for 29 cultured individuals within the Goseong population (Korea). A total of 7 variable sites were detected within the IGS, and the relative frequency of nucleotide alteration was determined to be 1.16%;. All alterations were due to a single nucleotide substitution, and 5 transitions and 2 transversions were observed. Among 29 specimens, only 8 haplotypes could be identified, and 6 of the haplotypes were unique to particular specimens. Pairwise genetic diversity of all 8 haplotypes was calculated to be 0.412+/-0.134 from multiple sequence substitutions based on the two-parameter model. The phylogenetic tree obtained for these haplotypes according to the neighbor-joining method illustrated a single cluster of linkages, which comprised 5 haplotypes associated with 23 specimens, while the other 3 haplotypes associated with 6 specimens were scattered. The results indicate that the IGS is higher polymorphic and thus more suitable as a genetic marker for population structure analysis of Pacific oyster than the mtDNA coding regions, such as cytochrome c oxidase I and 16S ribosomal RNA genes.

Animals↗

PubMed2006

Patterns of genetic connectivity among anchialine habitats: a case study of the endemic Hawaiian shrimp Halocaridina rubra on the island of Hawaii.

Anchialine habitats, landlocked bodies of mixohaline water that fluctuate with the tides but have no surface connection to the sea, are known from around the world. Many anchialine organisms have widespread distributions and it has been hypothesized that high levels of gene flow and low levels of genetic differentiation are characteristic of populations from these habitats. However, the generality of this hypothesis requires further assessment, particularly in light of the significant negative impact these habitats and their biota have experienced from anthropogenic causes. This study investigated the population structure and demography of an endemic Hawaiian anchialine species, the atyid shrimp Halocaridina rubra, using mitochondrial cytochrome c oxidase subunit I (COI) gene sequences. A survey of 305 individuals from 16 populations collected on the island of Hawaii revealed 135 haplotypes. These haplotypes belonged to one of two divergent (2.7-4.9%) lineages; notably, no haplotypes were shared between the two coasts of the island. Along each coast, strong subdivision and little to no gene flow occurs between populations separated by > 30 km. The population structure and demography of H. rubra on Hawaii are influenced by regional hydrology, geology, volcanism and two distinct colonization events of the island. Thus, H. rubra on Hawaii demonstrates that populations of endemic anchialine organisms may exhibit significant levels of genetic structure and restricted levels of gene flow over limited geographic scales. This report brings novel insight into the biology of anchialine organisms and has important implications for the future management of these habitats and their biota.

Animal Migration↗

PubMed1995

An anther-specific gene encoded by an S locus haplotype of Brassica produces complementary and differentially regulated transcripts.

The self-incompatibility locus of Brassica consists of a coadapted gene complex that contains at least two genes required for the recognition and inhibition of pollen by the stigma when self-pollinated. Here, we report the identification of a third S locus-linked gene from the S2 haplotype of Brassica oleracea. This gene, which we designated SLA (for S Locus Anther), is a novel gene with an unusual structure. SLA is transcribed from two promoters to produce two complementary anther-specific transcripts, one spliced and the other unspliced, that accumulate in an antiparallel manner in developing microspores and anthers. The sequence of the spliced transcript showed the presence of two open reading frames that predict proteins of 10 and 7.5 kD. Neither transcript was produced in a self-compatible B. napus strain carrying an S2-like haplotype, indicating that the SLA gene in this strain is nonfunctional. Interestingly, sequences related to SLA were not detected in DNA or RNA from plants carrying S haplotypes other than S2. The haplotype specificity of SLA, its anther-specific expression, and its physical linkage to the S locus are properties expected for a gene that encodes a determinant of S2 specificity in pollen.

Alternative Splicing↗

PubMed1995

The class I-b molecule Qa-1 forms heterodimers with H-2Ld and a novel 50-kD glycoprotein encoded centromeric to I-E beta.

Recent biochemical characterization of the T23-encoded Qa-1 molecule revealed an additional higher molecular mass species of 50 kD coprecipitated with the 48-kD Qa-1 molecule in H-2b and H-2d mouse strains. We now demonstrate that the 50-kD protein coprecipitated with Qa-1 is the class I-a antigen Ld in all H-2Ld-positive mouse strains examined. Furthers analyses of a panel of recombinants revealed that the 50-kD protein coprecipitated with Qa-1 in H-2b haplotype mouse strains is encoded or controlled by a gene centromeric to major histocompatibility complex class II I-E beta. We have designated this gene and corresponding protein product as Qsm, Qa-1 structure modifier. Both Ld and Qsm can interact with Qa-1 to form cell surface-expressed heterodimers in vivo. These Qa-1 heterodimers are not expressed in H-2k haplotype cells. The Qa-1/Ld and Qa-1/Qsm heterodimers are associated by noncovalent interactions and occur only between fully processed proteins. In addition, we show that the Qsm-encoded protein can form heterodimers with Ld as well, and that the Ld molecules participating in these interactions with Qa-1 and Qsm may be devoid of beta 2-microglobulin and/or peptide. These data represent the first demonstration that class I molecules can be expressed as heterodimers (Qa-1/Ld) on the cell surface, and map a gene (Qsm) that may potentially encode a novel class I molecule, or another protein, that associates with both Qa-1 and Ld. These interactions may enable increased levels of Qa-1 to reach the cell surface and may subsequently influence T cell recognition of Qa-1 and/or Ld molecules.

Animals↗

PubMed2003

Genetic structure and mtDNA diversity of Fundulus heteroclitus populations from polycyclic aromatic hydrocarbon-contaminated sites.

Genetic structure and diversity of mummichog (Fundulus heteroclitus) populations were investigated using mitochondrial DNA (mtDNA) sequences. Forty-six haplotypes were identified among 208 mummichog from the Elizabeth and York Rivers in Virginia, USA. No evidence of decreased gene or nucleotide diversity for mummichog from polycyclic aromatic hydrocarbon (PAH)-contaminated sites was observed. However, based on mtDNA data from 17 sites, a significant correlation (Mantel analysis, p = 0.035) was noted between genetic distance (F(ST)) and PAH concentration but not between genetic distance and geographic distance. Mummichog from the most heavily PAH-contaminated site, Atlantic Wood (AW), were genetically distinct from those of other Elizabeth River sites. At AW, high frequencies of several divergent haplotypes were observed that were more closely allied to the northern mummichog than to the more abundant southern form in the Chesapeake Bay. These data suggested that a locally stable population existed at the AW site. This conclusion is consistent with the observation that mummichog from the AW site display enhanced tolerance to PAH contamination relative to mummichog from noncontaminated sites. Conclusions about gene diversity and the correlation between genetic distance with site differences in PAH concentrations were also consistent with those from tandem genetic analyses based on allozymes.

Animals↗

PubMed1994

The three-dimensional structure of H-2Db at 2.4 A resolution: implications for antigen-determinant selection.

Solution at 2.4 A resolution of the structure of H-2Db with the influenza virus peptide NP366-374 (ASNEN-METM) and comparison with the H-2Kb-VSV (RGY-VYQGL) structure allow description of the molecular details of MHC class I peptide binding interactions for mice of the H-2b haplotype, revealing a strategy that maximizes the repertoire of peptides than can be presented. The H-2Db cleft has a mouse-specific hydrophobic ridge that causes a compensatory arch in the backbone of the peptide, exposing the arch residues to TCR contact and requiring the peptide to be at least 9 residues. This ridge occurs in about 40% of the known murine D and L allelic molecules, classifying them as a structural subgroup.

Amino Acid Sequence↗

PubMed2005

Genetic structure of Aedes aegypti populations in Thailand using mitochondrial DNA.

A hierarchical population genetic study was conducted among 19 Aedes aegypti populations in Thailand from Chiang Mai in the north to Songkhla province in the south. Single-strand conformation polymorphism analysis was used to examine variation in a 359-basepair region of the NADH dehydrogenase subunit 4 mitochondrial DNA gene (ND4). Seven haplotypes were detected in two lineages previously identified in ND4 haplotypes from North America. Gene flow estimates and highly significant variation among populations within 25 kilometers implicated genetic drift and vector control efforts as major factors in genetic structure. Mantel regression analysis demonstrated no isolation by distance. Urban areas were relatively panmictic, while suburban/rural sites exhibited more restricted gene flow. Significant genetic structure among groups of collections > 100 kilometers apart is consistent with recent (approximately 50 year) expansion of Ae. aegypti from highly populated areas accompanied by founder effects, but could also reflect the overall low genetic diversity in ND4 in Thailand.

Aedes↗

PubMed2025

Defining three dimensional chromatin structures of pediatric and adolescent B cells using primary B cell and EBV-immortalized B cell reference genomes.

BACKGROUND/PURPOSE: Knowledge of the 3D genome is essential to elucidate genetic mechanisms driving autoimmune diseases. The 3D genome is distinct for each cell type, and it is uncertain whether cell lines faithfully recapitulate the 3D architecture of primary human cells or whether developmental aspects of the pediatric immune system require use of pediatric samples. We undertook a systematic analysis of B cells and B cell lines to compare 3D genomic features encompassing risk loci for juvenile idiopathic arthritis (JIA), systemic lupus (SLE), and type 1 diabetes (T1D). METHODS: We isolated B cells from four healthy individuals, ages 9-17. HiChIP was performed using a CTCF antibody, and CTCF peaks were called within each sample separately. Peaks observed in all four samples were identified. CTCF loops were called within the pediatric samples using three CTCF peak datasets: 1) self-called CTCF consensus peaks called within the pediatric samples, 2) ENCODE's publicly available GM12878 CTCF ChIP-seq peaks, and 3) ENCODE's primary B cell CTCF ChIP-seq peaks from two adult females. Differential looping was assessed within the pediatric samples and each of the three peak datasets. RESULTS: The number of consensus peaks called in the pediatric samples was similar to that identified in ENCODE's GM12878 and primary B cell datasets. We observed < 1% of loops that demonstrated significantly differential looping between peaks called within the pediatric samples themselves and when called using ENCODE GM12878 peaks. Significant looping differences were even fewer when comparing loops of the pediatric called peaks to those of the ENCODE primary B cell peaks. When querying loops found in juvenile idiopathic arthritis, type 1 diabetes, or systemic lupus erythematosus risk haplotypes, we observed significant differences in only 2.2%, 1.0%, and 1.3% loops, respectively, when comparing peaks called within the pediatric samples and ENCODE GM12878 dataset. The differences were even less apparent when comparing loops called with the pediatric vs ENCODE adult primary B cell peak datasets. CONCLUSION: The 3D chromatin architecture in B cells is similar across pediatric, adult, and EBV-transformed cell lines. This conservation of 3D structure includes regions encompassing autoimmune risk haplotypes. Thus, even for pediatric autoimmune diseases, publicly available adult B cell and cell line datasets may be sufficient for assessing effects exerted in the 3D genomic space.

Humans↗

PubMed1996

Widespread geographical distribution of mitochondrial haplotypes in rock-dwelling cichlid fishes from Lake Tanganyika.

The spectacularly diverse cichlid fish species flocks of the East African Rift Lakes have elicited much debate on the potential evolutionary mechanisms responsible for the origin of these adaptive radiations. An historical perspective on population structure may offer insights into the processes driving population differentiation and possibly speciation. Here, we examine mitochondrial DNA (mtDNA) sequence variation in two endemic species of rock-dwelling cichlids, Simochromis babaulti and S. diagramma, from Lake Tanganyika. Phylogeographic analyses were used to infer what factors might have been important in the genetic structuring of Simochromis populations. Patterns of mtDNA differentiation in Simochromis were compared to those of other rock-dwelling cichlids to distinguish between competing hypotheses concerning the processes underlying their evolution. In striking contrast to previous findings, populations of Simochromis, even those separated by up to 300 km, were found to share mitochondrial DNA haplotypes. There is no correspondence between mtDNA genealogies and the geographical distribution of populations. Only S. babaulti, but not S. diagramma was found to have a significant association between genetic and geographic distance. These phylogeographic patterns suggest that the evolutionary effects of abiotic and biotic factors shaping population genetic structure may differ substantially even among closely related species of rock-dwelling cichlids. Physical events and barriers to gene flow that are believed to have had a major impact on the geographical distribution and intralacustrine speciation of Tropheus do not seem to have equally strongly affected its close relative Simochromis. These findings emphasize that no single mechanism can be responsible for the formation of population structure, speciation, and the adaptive radiation of all cichlid fishes.

Africa, Eastern↗

PubMed2002

Xenopus class II A genes: studies of genetics, polymorphism, and expression.

The amphibian Xenopus laevis has been a central model for the study of evolution of the major histocompatibility complex (MHC). Many of the counterparts of mammalian MHC genes have been identified in Xenopus, facilitating the understanding of MHC structure and function. Herein we characterize X. laevis MHC class II-alpha chain genes. There are three related class II A genes/haplotype in the four commonly used partially inbred strains, all of which linked to the functional MHC. At least two of these genes in the f haplotype encode full-length cDNA clones and a genomic fragment encoding the immunoglobulin-like domain of the third gene was also characterized. The protein structure and domain organization deduced from the two f/f cDNA clones are similar to mammalian MHC class II-alpha chains. Expression of class II A genes is highest in the spleen and intestine, similar to the previously examined tissue distribution of class II B genes. The two highly expressed genes display high sequence diversity among alleles, similar to what has been found in most other species. Surprisingly, transcript sizes of class II A alleles/isotypes are diverse, suggesting that Xenopus class II allelic lineages are very old.

Alleles↗

PubMed2000

Structural basis for the binding of an immunodominant peptide from myelin basic protein in different registers by two HLA-DR2 proteins.

Susceptibility to multiple sclerosis (MS) is associated with certain MHC class II haplotypes, in particular HLA-DR2. Two DR beta chains, DRB1*1501 and DRB5*0101, are co-expressed in the HLA-DR2 haplotype, resulting in the formation of two functional cell surface heterodimers, HLA-DR2a (DRA*0101, DRB5*0101) and HLA-DR2b (DRA*0101, DRB1*1501). Both isotypes can present an immunodominant peptide of myelin basic protein (MBP 84-102) to MBP-specific T cells from MS patients. We have determined the crystal structure of HLA-DR2a complexed with MBP 86-105 to 1.9 A resolution. A comparison of this structure with that of HLA-DR2b complexed with MBP 85-99, reported previously, reveals that the peptide register is shifted by three residues, such that the MBP peptide is bound in strikingly different conformations by the two MHC molecules. This shift in binding register is attributable to a large P1 pocket in DR2a, which accommodates Phe92, in conjunction with a relatively shallow P4 pocket, which is occupied by Ile95. In DR2b, by contrast, the small P1 pocket accommodates Val89, while the deep P4 pocket is filled by Phe92. In both complexes, however, the C-terminal half of the peptide is positioned higher in the binding groove than in other MHC class II/peptide structures. As a result of the register shift, different side-chains of the MBP peptide are displayed for interaction with T cell receptors in the DR2a and DR2b complexes. These results demonstrate that MHC molecules can impose different alignments and conformations on the same bound peptide as a consequence of topological differences in their peptide-binding sites, thereby creating distinct T cell epitopes.

Alleles↗

PubMed2001

Allele sequences of six new Y-STR loci and haplotypes in the Chinese Han population.

Human chromosome Y-specific short tandem repeat (Y-specific STR) markers have useful properties for forensic applications. However, there is a need to develop more Y-specific STR markers, because the discriminating power of each STR locus is limited. In the present study, we describe our results on six new Y-specific STR markers that were initially located using sequence database information by Ayub et al. and were named DYS434, DYS435, DYS436, DYS437, DYS438 and DYS439. Our studies focused on the analysis of the DNA sequence for each allele at all six Y-specific STR loci in order to understand their structures in the human genome and to construct human allelic ladders, which are necessary for forensic DNA typing. In addition, the haplotype distribution for all six analyzed loci was studied in a Chinese Han population sample. The results indicate that DYS434, DYS435, DYS436, DYS437, DYS438 and DYS439 are useful Y-specific STR markers for forensic sciences.

Alleles↗

PubMed1992

Structural and functional analysis of three D/L-like class I molecules from H-2v: indications of an ancestral family of D/L genes.

Three cDNA with D region gene features have been identified from the H-2v haplotype. Provisionally, the sequences have been designated as D/Lv1, D/Lv2, and D/Lv3. The coding segments for the antigen binding domain (ABD) of all three D/Lv genes were engineered into a class I genomic expression vector and expressed in L cells. FACS analysis of the three D/Lv-Ld gene transfectants revealed that the D/Lv1 molecules were recognized by both monoclonal antibodies (mAbs) 141 and 142, and the D/Lv2 molecules were recognized by mAb 143. In addition to the D/Lv1 molecules, the mAb 141 also recognized the D/Lv3 molecules. Both the D/Lv1-Ld and D/Lv2-Ld transfectants were killed efficiently by H-2Dv region-specific alloreactive CTL. The D/Lv3 gene is the first identified D region gene other than D and L that is transcribed abundantly in spleen and the D/Lv3 RNA is present as two alternatively spliced forms. Structural analysis of the D/Lv3 hybrid molecules showed that it was susceptible to proteolysis and thermolabile at 37 degrees C, suggesting D/Lv3 is a transcribed pseudogene. A parsimony tree analysis of three D/Lv sequences with a set of class I gene sequences revealed that the H-2v sequences clustered with D region genes. The presence of a third gene with D/L-like features in H-2v, yet structurally different from the known D/L alleles, raises the possibility that the current D/L genes evolved from a family of D/L-like genes, some of which are no longer represented among many of the mouse major histocompatibility complex haplotypes. The observation that D region alleles cluster into subgroups suggests that the alleles are not all related to each other by linear descent through a single locus. We propose that current alleles are derived from more than one ancestral locus in a manner similar to the origin of the gamma 2 a immunoglobulin constant region alleles.

Alleles↗

PubMed2002

Identification of T-cell epitopes in the structural and non-structural proteins of classical swine fever virus.

To identify new T-cell epitopes of classical swine fever virus (CSFV), 573 overlapping, synthetic pentadecapeptides spanning 82% of the CSFV (strain Glentorf) genome sequence were synthesized and screened. In proliferation assays, 26 peptides distributed throughout the CSFV viral protein sequences were able to induce specific T-cell responses in PBMCs from a CSFV-Glentorf-infected d/d haplotype pig. Of these 26 peptides, 18 were also recognized by PBMCs from a CSFV-Alfort/187-infected d/d haplotype pig. In further experiments, it could be shown that peptide 290 (KHKVRNEVMVHWFDD), which corresponds to amino acid residues 1446-1460 of the CSFV non-structural protein NS2-3 could induce interferon-gamma secretion after secondary in vitro restimulation. The major histocompatibility complex (MHC) restriction for stimulation of T-cells by this pentadecapeptide was identified as being mainly MHC class II and partially MHC class I. In cytolytic assays, CSFV-specific cytotoxic T-lymphocytes (CTLs) were able to lyse peptide 290-loaded target cells. These findings indicate the existence of a CSFV-specific helper T-cell epitope and a CTL epitope in this peptide.

Amino Acid Sequence↗

PubMed2002

Genomic profiles of clinical and environmental isolates of Vibrio cholerae O1 in cholera-endemic areas of Bangladesh.

Diversity, relatedness, and ecological interactions of toxigenic Vibrio cholerae O1 populations in two distinctive habitats, the human intestine and the aquatic environment, were analyzed. Twenty environmental isolates and 42 clinical isolates were selected for study by matching serotype, geographic location of isolation in Bangladesh, and season of isolation. Genetic profiling was done by enterobacterial repetitive intergenic consensus sequence-PCR, optimized for profiling by using the fully sequenced V. cholerae El Tor N16961 genome. Five significant clonal clusters of haplotypes were found from 57 electrophoretic types. Isolates from different areas or habitats intermingled in two of the five significant clusters. Frequencies of haplotypes differed significantly only between the environmental populations (exact test; P < 0.05). Analysis of molecular variance yielded a population genetic structure reflecting the differentiating effects of geographic area, habitat, and sampling time. Although a parameter confounding the latter differences explained 9% of the total molecular variance in the entire population (P < 0.01), the net effect of habitat and time could not be separated because of the small number of environmental isolates included in the study. Five subpopulations from a single area were determined, and from these we were able to estimate a relative differentiating effect of habitat, which was small compared with the effect of temporal change. In conclusion, the resulting population structure supports the hypothesis that spatial and temporal fluctuations in the composition of toxigenic V. cholerae populations in the aquatic environment can cause shifts in the dynamics of the disease.

Bangladesh↗