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PubMed2000

The frequency of heteroplasmy in the HVII region of mtDNA differs across tissue types and increases with age.

An immobilized sequence-specific oligonucleotide (SSO) probe system consisting of 16 SSO probes that detect sequence polymorphisms within five regions of the mtDNA control region was used to investigate the frequency of heteroplasmy in human mtDNA. Five regions of hypervariable region II (HVII) of the control region were studied in blood-, muscle-, heart-, and brain-tissue samples collected from 43 individuals during autopsy. An initial search for heteroplasmy was conducted by use of the SSO probe system. Samples in which multiple probe signals were detected within a region were sequenced for the HVII region, to verify the typing-strip results. The frequency of heteroplasmy was 5 of 43 individuals, or 11.6%. The frequency of heteroplasmy differed across tissue types, being higher in muscle tissue. The difference in the frequency of heteroplasmy across different age groups was statistically significant, which suggests that heteroplasmy increases with age. As a test for contamination and to confirm heteroplasmy, the samples were sequenced for the HVI region and were typed by use of a panel of five polymorphic nuclear markers. Portions of the tissues that appeared to be heteroplasmic were extracted at least one additional time; all gave identical results. The results from these tests indicate that the multiple sequences present in individual samples result from heteroplasmy and not from contamination.

Adolescent↗
PubMed1991

Characterization of the opa (class 5) gene family of Neisseria meningitidis.

Class 5 outer membrane proteins of Neisseria meningitidis show both phase- and antigenic variation of expression. The proteins are encoded by a family of opa genes that share a conserved framework interspersed with three variable regions, designated the semivariable (SV) region and hypervariable regions 1 (HV1) and 2 (HV2). In this study, we determined the number and DNA sequence of all of the opa genes of meningococcal strain FAM18, to assess the structural and antigenic variability in the family of proteins made by one strain. Pulsed field electrophoresis and Southern blotting showed that there are four opa genes in the FAM18 chromosome, and that they are not tightly clustered. DNA sequence analysis of the four cloned genes showed a modest degree of diversity in the SV region and more extensive differences in the HV1 and HV2 regions. There were four versions of HV1 and three versions of HV2 among the four genes. Each of the FAM18 opa loci contained a gene with a unique combination of SV, HV1, and HV2 sequences. We used lambda gt11 cloning and synthetic peptides to demonstrate that HV2 sequences completely encode the epitopes for two monoclonal antibodies specific for different class 5 proteins of FAM18.

Amino Acid Sequence↗
PubMed1997

Homology of E2 gene in 8 child-mother pairs infected with hepatitis C virus.

The frequency of genetic homology of hepatitis C virus (HCV) E2 gene in 8 child-mother pairs was investigated. The route of HCV infection of all children suggested mother-to-child infection by their past history. In this study, we analyzed at least 5 complementary DNA (cDNA) clones for each case. In 6 of the 8 (75%) child-mother pairs, for the region between hypervariable region (HVR)-1 and HVR-2, the similarity of the nucleotide sequence of all 5 cDNA clones between each child and the mother was higher than that between the child and the other children, the other mothers and the sequences from GenBank. One of the 8 (13%) child-mother pairs showed a great similarity in parts of all cDNA clones. This was also confirmed by phylogenetic analyses of the sequences of cDNA clones from families and that from GenBank. These results suggested that the homology search of nucleotide sequence of this region was useful to confirm mother-to-child transmission of HCV.

Amino Acid Sequence↗
PubMed2002

Novel cryptosporidium genotypes in sporadic cryptosporidiosis cases: first report of human infections with a cervine genotype.

In this study, we genotyped parasites from the fecal specimens of sporadic cryptosporidiosis cases in British Columbia from 1995 to 1999. Genotyping was conducted by polymerase chain amplification of the internal transcribed spacer region, a hypervariable region in the 18S rRNA gene and the Cryptosporidium oocyst wall protein gene. Subsequent analysis was by restriction fragment length polymorphism and DNA sequencing. We identified two new Cryptosporidium genotypes in humans. One of these genotypes has been found recently in deer in New York state. The other genotype has not been identified in humans or animals. These results have important implications for drinking water quality strategies, especially for communities that obtain drinking water supplies from surface sources located in forested regions with deer populations.

Animals↗
PubMed2001

Cryoglobulinemia in Japanese patients with chronic hepatitis C virus infection: host genetic and virological study.

Essential cryoglobulinemia is associated closely with hepatitis C virus (HCV) infection. The mechanism responsible for occurrence of the disease is unclear. The aim of this study was to investigate pathogenetic roles of HCV in cryoglobulinemia. One hundred sixty-seven consecutive patients with HCV were studied clinically by HCV grouping, HCV RNA levels, GBV-C/HGV, HCV quasispecies (target region was hypervariable region-1) and HLA polymorphism. The quasispecies in cryoprecipitate were compared with those in supernatant. The results of HLA polymorphism of patients with cryoglobulinemia were compared with those without cryoglobulinemia and healthy controls. The frequency of HCV-related cryoglobulinemia was 71 of 167 (42.5%). Patients with cirrhosis (36 of 63, 57.1%) had cryoglobulinemia more frequently than those with chronic hepatitis (35 of 104, 33.7%, P < 0.01). No significant differences were not found between the two groups (patients with and without cryoglobulinemia) in age, gender, HCV grouping, HCV RNA level and frequency of GBV-C/HGV. HCV was found quantitatively and clonally more frequently in the cryoprecipitate than in the supernatant. HLA polymorphism presented no significant differences among three groups. The stage of liver disease is one of pathogenetic factors. The greater the presence of HCV quasispecies in cryoprecipitate than in the supernatant indicates that various antigen presentations play an important role in the formation of cryoglobulin, whereas HLA typing dose not seem to contribute to the development of cryoglobulinemia.

Adult↗
PubMed1989

Monoclonal antibodies as catalysts and templates for organic chemical reactions.

The motives for mimicking enzymes are twofold: 1) to gain information and deeper understanding which will be relevant to biochemical catalysis, and 2) to extend the chemistry of living organisms in order to be able to invent new reactions--reactions that enzymes either cannot perform, or can perform only with difficulty. It has taken a long time for the bridge of catalytic antibodies to be erected and join organic chemistry and immunology. This is certainly in part because of differences in language, approach, and goals. Increasingly, many researchers in both disciplines are coming closer as a result of the unifying nature of molecular biology. The importance of the basic questions being addressed as well as the tremendous potential for application in diverse areas ensures that the recent initial results will be greatly expanded in the future. Concurrent developments in biology, chemistry, and physical techniques may also have great impact on the use of catalytic antibodies. Chimeric antibodies, where the binding site (variable region or hypervariable region) is derived from a mouse and chosen at will, while the majority of the antibody molecule is human-derived, may allow wide human application. Bifunctional antibodies with two different catalytic reactions taking place in each antibody molecule may be considered. The accurate depiction of the details of antigen-antibody interaction from x-ray crystallography and the prediction of structure will greatly assist those planning experiments. The future of "dial-a-property" catalytic antibodies looks promising and exciting.

Antibodies, Monoclonal↗
PubMed1990

Structural model for T-cell recognition of HLA class II-associated alloepitopes.

In an effort to investigate the structure-function relationship of HLA class II molecules vis-à-vis alloepitope expression, cloned T-cell reagents were used to define polymorphic epitopes associated with DR and DQ molecules. DNA sequences of genes encoding allelic or isotypic DR or DQ molecules that appear to express the same T-cell-defined epitopes were compared in an attempt to identify association of shared sequences with shared epitopes. When sequence sharing is associated with shared epitope expression, we suggest that it is the shared sequence that encodes the epitope in question. Based on the hypothetical three-dimensional structure of the class II molecule, an approximation is made as to which parts of the HLA class II molecule are involved in alloepitope expression. T-cell clones were generated from cells primed against HLA-DR2 haplotypes representing the cellularly defined subgroups Dw2 or Dw21 (previously designated MN2, FJ0, or Tb24). Those clones determined to be DR- or DQ-directed based on monoclonal antibody inhibition assays were tested by panel cell analysis utilizing DR2-positive and DR2-negative target cells. The data support the concept that amino acids 67, 70, 71, and 74 for DR molecules and amino acids 57, 70, and 71 for DQ molecules, which appear to comprise one face of the alpha helix, are of primary importance in T-cell recognition. In other cases, sharing of both the second hypervariable region (amino acids 25-33) and the third hypervariable region (amino acids 67-74) appears necessary to explain epitope sharing for DR molecules. We emphasize that the involvement of these two hypervariable regions may indicate that alloepitope expression involves the complex of class II molecule plus peptide, with the second HVR primarily involved in determining which peptides are bound and the third in T-cell receptor (TcR) recognition and/or peptide binding; we do not rule out that conformational changes of the second HVR can induce conformational changes in the third HVR. Finally, shared alloepitopes detected by some clones could not be explained based on shared primary sequences.

Amino Acid Sequence↗
PubMed1997

Reactivity of synthetic peptides representing selected sections of hepatitis C virus core and envelope proteins with a panel of hepatitis C virus-seropositive human plasma.

A series of 54 synthetic peptides, 15-20 residues long, that represented selected parts of the structural proteins of hepatitis C virus (HCV) were tested for immunoreactivity with a panel of 45 plasma samples from potential blood donors who were known to be seropositive for anti-HCV. Most of the ten peptides that represented the core protein showed reactivity with most of the panel samples. All except one of the 20 peptides that represented non-hypervariable regions of envelope proteins E1 and E2 showed little or no reactivity. In contrast, 18 of the the 24 peptides that represented variants of the hypervariable region 1 of the E2 protein reacted with at least one panel sample. Notably, 40% of the panel samples cross-reacted with two or more different peptides sequences some of which differed by more than 50%. Two panel samples each cross-reacted with seven different peptide sequences. The results suggest a broad anti-hypervariable region antibody specificity in many anti-HCV-seropositive samples and possible limits on the mutability of hypervariable region sequences. The work contributes to understanding the immunogenicity and persistence of HCV.

Amino Acid Sequence↗
PubMed2001

Form species Nostoc commune (Cyanobacteria).

The form species concept for the Cyanobacteria was evaluated using a comprehensive set of Nostoc samples that were collected during the past two centuries, from all continents, including regions from the Tropics to the Poles. Phylogenies were constructed based upon the conserved regions of tRNALeu (UAA) group I intron DNA sequences. Thirty-four forms contained a tRNALeu (UAA) intron of 284 nt. These 284-nt introns contained 200 nt of conserved sequence that, in most cases, shared 100% sequence identity, they had three variable regions (I, II and III) amounting to 84 nt, contained no hypervariable region and formed a discrete cluster in phylogenetic analysis. These forms represented 31 independent populations in both hemispheres and constitute examples of form species Nostoc commune. Multiple introns were obtained from several of the populations. Ten populations contained introns of 287-340 nt with a hypervariable region, 8 to 59 nt in length, located between variable regions I and II. Alignments identified 15 examples where 5'-AAAAUCC-3' occurred at the hypervariable region-variable region II boundary; this sequence is identical to the conserved sequence at the 3' intron-exon boundary (splice site) within the tRNALeu (UAA) gene. The possibility that hypervariable regions were removed from the primary intron through secondary splicing was tested in vitro but proved to be negative under the experimental conditions used. Shared morphologies of genetically different strains, dissimilar morphologies in strains that share identical genetic markers, incorrect naming of culture collection strains and genetic drift in cultured strains emphasize that the successful delineation of cyanobacterial species requires the application of multiple taxonomic criteria.

Base Sequence↗
PubMed1992

Structural repertoire of the human VH segments.

The VH gene segments produce the part of the VH domains of antibodies that contains the first two hypervariable regions. The sequences of 83 human VH segments with open reading frames, from several individuals, are currently known. It has been shown that these sequences are likely to form a high proportion of the total human repertoire and that an individual's gene repertoire produces about 50 VH segments with different protein sequences. In this paper we present a structural analysis of the amino acid sequences produced by the 83 segments. Particular residue patterns in the sequences of V domains imply particular main-chain conformations, canonical structures, for the hypervariable regions. We show that, in almost all cases, the residue patterns in the VH segments imply that the first hypervariable regions have one of three different canonical structures and that the second hypervariable regions have one of five different canonical structures. The different observed combinations of the canonical structures in the first and second regions means that almost all sequences have one of seven main-chain folds. We describe, in outline, structures of the antigen binding site loops produced by nearly all the VH segments. The exact specificity of the loops is produced by (1) sequence differences in their surface residues, particularly at sites near the centre of the combining site, and (2) sequence differences in the hypervariable and framework regions that modulate the relative positions of the loops.

Amino Acid Sequence↗
PubMed1981

Immunoglobulin heavy chains from anti-inulin myeloma proteins: evidence for a new heavy chain joining segment.

Immunoglobulin heavy chains have been shown to be encoded by at least 3 widely separated genetic elements, designated variable (V), diversity (D), and joining (J), which undergo rearrangement during somatic differentiation to produce the active gene form. The D segment codes for a portion of the 3rd hypervariable region and thus potentially contributes significantly to structural diversity in this portion of the molecule. Heavy chains from anti-inulin proteins are unusual in that they essentially lack a 3rd hypervariable region. Thus, if a D segment exists in these proteins, it is extremely short, possibly 1 to 2 amino acids, and more likely serves a framework function rather than introduces structural diversity in the 3rd hypervariable region. We have completed the heavy chain variable region amino acid sequence from proteins AMPC1 and T957 bringing to 6 the number of complete sequences from this group. All of these proteins lack a 3rd hypervariable region. In addition, substitutions are found within the J segments of AMPC1 and T957, which are unlikely to be generated by the recombination event. The occurrence of Pro at position 105 in both of these J segments in contrast to the Gln found in all other heavy chains using this J segment suggests the possible existence of a previously unidentified J segment gene.

Amino Acid Sequence↗
PubMed1991

Importance of purine and pyrimidine content of local nucleotide sequences (six bases long) for evolution of the human immunodeficiency virus type 1.

Human immunodeficiency virus type 1 evolves rapidly, and random base change is thought to act as a major factor in this evolution. However, segments of the viral genome differ in their variability: there is the highly variable env gene, particularly hypervariable regions located within env, and, in contrast, the conservative gag and pol genes. Computer analysis of the nucleotide sequences of human immunodeficiency virus type 1 isolates reveals that base substitution in this virus is nonrandom and affected by local nucleotide sequences. Certain local sequences 6 base pairs long are excessively frequent in the hypervariable regions. These sequences exhibit base-substitution hotspots at specific positions in their 6 bases. The hotspots tend to be nonsilent letters of codons in the hypervariable regions--thus leading to marked amino acid substitutions there. Conversely, in the conservative gag and pol genes the hotspots tend to be silent letters because of a difference in codon frame from the hypervariable regions. Furthermore, base substitutions in the local sequences that frequently appear in the conservative genes occurred at a low level, even within the variable env. Thus, despite the high variability of this virus, the conservative genes and their products could be conserved. These may be some of the strategies evolved in human immunodeficiency virus type 1 to allow for positive-selection pressures, such as the host immune system, and negative-selection pressures on the conservative gene products.

Acquired Immunodeficiency Syndrome↗
PubMed1975

Structural studies on induced antibodies with defined idiotypic specificities. I. The heavy chains of anti-p-azophenylarsonate antibodies from A/J mice bearing a cross-reactive idiotype.

Amino acid sequence analysis has been performed on three groups of heavy (H) chains of A/J mice. H chains derived from unimmunized animals were compared to anti-p-azophenylarsonate (anti-Ar) antibodies which were further subdivided into those possessing and those depleted of a cross-reacting idiotype (CRI). It was found that anti-Ar antibodies bearing the CRI are homogeneous through the first hypervariable region of the H chain. The same sequence was obtained for pooled antibody isolated from the ascites fluid of 18 A/J mice or from a single mouse. The H chains appear to belong to a minor V-H subgroup. In the first 30 positions Anti-Ar antibodies depleted of the CRI had the same sequence as those containing the CRI (with small amounts of heterogeneity at some positions), but contained a mixture of sequences in the first hypervariable region of the H chain. These studies indicate that antibodies with similar specificity and with identical framework sequences, but which differ in their hypervariable regions, contain different idiotypic determinants, and support the concept that the idiotypic determinants reside primarily within hypervariable regions.

Amino Acid Sequence↗
PubMed1987

Allelic variation in the DR subregion of the human major histocompatibility complex.

Allelic variation in the DR subregion of the human major histocompatibility complex has been analyzed by nucleic acid sequencing of cDNA clones obtained from cell lines homozygous by consanguinity for all the common serological types DR1-9. Two expressed loci were identified in the haplotypes DR2, -3, -4, -7, and -9; one locus being present at a much lower frequency (4-7%) than the other. The low-frequency allele was highly conserved between each of the DRw53 (DR4, -7, -9) and the DRw52 (DR3, -5, -6) haplotypes. Analysis of the variation between alleles confirms the presence of three allelic hypervariable regions. At each variable residue, a limited range of amino acid substitutions are found, distinguishing them from immunoglobulin hypervariable regions. Dinucleotide substitutions are extremely common. Individual hypervariable regions are often shared between haplotypes. Much of the variation in these alleles can be attributed to the shuffling of these regions between haplotypes, possibly by the mechanism of gene conversion.

Alleles↗
PubMed1999

Sequence variation within the capsid protein of Australian isolates of feline calicivirus.

The capsid protein of Australian feline calicivirus (FCV) isolates is demonstrably different from the prototype strain F9. Five Australian isolates of FCV, dating from 1970 to 1989, were analysed by western blotting and immunoprecipitation. Varying reactivity to a panel of F9 specific monoclonal antibodies (MAbs) was observed. DNA sequencing of RT-PCR generated clones supported the observation of variation between capsid proteins. Predicted amino acid sequences varied by 11 to 17.5% across the whole capsid when compared to the published F9 sequence. Differences in amino acid sequence were most apparent in previously described hypervariable regions (C and E). Within hypervariable region E differences of 22 to 34% were observed compared to F9. The observed lack of reactivity to F9 MAbs correlated with amino acid changes within previously characterized binding sites within region E.

Amino Acid Sequence↗
PubMed1992

The susceptibility sequence to rheumatoid arthritis is a cross-reactive B cell epitope shared by the Escherichia coli heat shock protein dnaJ and the histocompatibility leukocyte antigen DRB10401 molecule.

Immunological responses to bacterial heat shock proteins have been implicated in the pathogenesis of arthritis in animals and humans. The predicted amino acid sequence of dnaJ, a heat shock protein from Escherichia coli, contains an 11-amino acid segment that is homologous to the third hypervariable region of the human histocompatibility antigen (HLA) DRB10401 (formerly known as HLA Dw4), the part of the molecule that carries susceptibility to rheumatoid arthritis. To test the biological significance of this finding, we expressed and purified recombinant dnaJ (rdnaJ), and determined its immunologic cross-reactivity with HLA DRB10401. A rabbit antipeptide antiserum raised against the sequence of the third hypervariable region of HLA DRB10401 specifically bound to 'dnaJ, thus confirming that a similar sequence is expressed on the bacterial protein. Of greater consequence, an antiserum to the 'dnaJ protein recognized not only a peptide from the third hypervariable region of HLA DRB10401, but also the intact HLA DRB10401 polypeptide. Furthermore, the antibody to 'dnaJ reacted with HLA DRB10401 homozygous B lymphoblasts, but not with HLA DRB11501, DRB10101, DRB10301, and DRB10701 (formerly known as HLA Dw2, DR 1, DR 3, and DR 7, in the same order) homozygous cells. These results demonstrate that exposure to a bacterial heat shock protein can elicit antibodies against the rheumatoid arthritis susceptibility sequence in the third hypervariable region of HLA DRB10401.

Amino Acid Sequence↗
PubMed1998

Small subunit ribosomal RNA genes of tabanids and hippoboscids (Diptera: Brachycera): evolutionary relationships and comparison with other Diptera.

The small subunit ribosomal RNA (SSU rRNA) genes of hippoboscid (Ornithoica vicina Walker) and tabanid (Chrysops niger Macquart) Diptera were sequenced to determine their phylogenetic position within the order and to determine whether or not extensive hypervariable regions in this gene are widespread in the Diptera. A parsimony analysis of an alignment containing 8 dipteran sequences produced a single most parsimonious tree that placed O. vicina as sister group to Drosophila melanogaster Meigen. The tabanid Chrysops niger was sister group to the asilomorphan taxa, and the sister group to the Brachycera was a Tipula sp. although this relationship was not supported by bootstrap analysis. The hippoboscid and tabanid sequences contain extensive hypervariable regions in the V2, V4, V6, and V7 regions as do other Diptera. When these regions of the alignment were excluded from the phylogenetic analysis, a single most parsimonious tree was found. This tree had an identical overall topology to the tree obtained from the total data set. The hypervariable regions in parts of the dipteran SSU rRNA genes were more extensive in the nematocerous dipteran sequences used in this study than in the other dipteran representatives; these hypervariable regions may be of more utility in inferring relationship among species and subspecies than at the suprageneric level.

Animals↗
PubMed2002

Genetic variability and stability of Anaplasma phagocytophila msp2 (p44).

Anaplasma (Ehrlichia) phagocytophila's major immunodominant surface protein antigen, Msp2 (P44, 44-kDa antigen), is encoded by a family of paralogous genes characterized by conserved sequences flanking a hypervariable region. The antigenic profiles of most strains of A. phagocytophila are different, and the differences are principally related to Msp2 expression. To date, multiple unique msp2 gene paralogs have been found in A. phagocytophila isolates, but the overall number in the genome of a single strain is not yet known. Changes in msp2 expression may be related to antigenic variability; thus, we examined the minimal complement of msp2 genes or pseudogenes in two strains of A. phagocytophila and the number of transcriptionally active msp2 gene paralogs during low-passage, steady-state, in vitro propagation. Of 15 BDS strain clones, 1 had a hypervariable region identical to the region in a clone obtained from a BDS strain genomic library previously prepared from organisms after only two horse passages. When 124 Webster strain clones were examined, 18 unique hypervariable regions were identified. Of 64 Webster strain cDNA clones, 56 (87.5%) were derived from a single gene, and transcripts from six additional msp2 genes were also identified. The sequences of several hypervariable regions that were > or = 97% similar to regions present in other strains were identified by performing a BLAST analysis of sequences deposited in the GenBank database. These findings suggest that antigenic variability results from transcription of one or a few of the multiple paralogs and not from genetic instability that results in random accumulated mutations, although the possibility that gene recombination plays a role cannot be eliminated. The predominant Msp2 pattern in vitro is determined by transcription from a single gene.

Anaplasma↗