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Results for “hypervariable regions”

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PubMed1994

Adaptation of hepatitis C virus for persistent infection in patients with acute hepatitis.

Nucleotide sequencing was used to analyze amino acid substitutions in the putative envelope 1 (E1) and envelope 2/nonstructural 1 (E2/NS1) regions of hepatitis C virus (HCV) to clarify a viral mechanism of persistent infection in three patients with acute hepatitis C who developed chronic hepatitis and two patients with chronic hepatitis. The HCV RNA titer in serum decreased markedly after the onset of acute hepatitis and then re-elevated. During this period, the substitution rate in the E2/NS1 region (especially in the hypervariable region located in the N-terminus) was significantly higher in patients with acute hepatitis than in patients with chronic hepatitis (P < 0.05). When patients with acute hepatitis C became persistent HCV carriers, the substitution rate decreased to the level seen in patients with chronic hepatitis. The amino acid substitution rate in the E1 region in the acute phase was similar to that found in the chronic HCV carrier state. These observations suggest that rapid substitution of the amino acid sequence in the hypervariable region of the E2/NS1 region may be one of the mechanisms of persistent HCV infection.

Acute Disease↗

PubMed2005

Molecular analysis and physicochemical properties of electrophoretic variants of wild soybean Glycine soja storage proteins.

Cultivated soybeans (Glycine max) are derived from wild soybeans (Glycine soja) and can be crossed with them to produce fertile offspring. The latter exhibit greater genetic variation than the former, suggesting a possibility that wild soybeans contain storage proteins with properties different from and better than those of cultivated soybeans. To identify a wild soybean suitable for breeding a new soybean cultivar, we analyzed seed proteins from 390 lines of wild soybeans by electrophoresis. We found some lines containing electrophoretic variants of glycinin and beta-conglycinin subunits: one line containing a small alpha' subunit of beta-conglycinin and two and five lines containing small A3 and large A4 polypeptides of glycinin, respectively. Beta-Conglycinin and glycinin containing such variant subunits exhibited solubility and emulsifying ability similar to those of the predominant types of wild and cultivated soybeans. Glycinins containing small A3 and large A4 gave a shoulder derived from the start of denaturation at a temperature 4 degrees C lower than that of glycinin from the predominant types of wild and cultivated soybeans, although their thermal denaturation midpoint temperatures were very similar to each other. Cloning and sequencing of the predominant and variant subunit cDNAs revealed that the small alpha' and the small A3 lacked 24 amino acid residues in the extension region and four amino acid residues in the hypervariable region, respectively, and that the large A4 did not have an insert corresponding to the difference in the electrophoretic mobility but Arg279 and Gln305 were replaced by glutamine and histidine, respectively, in the hypervariable region. These suggest that small differences even in the hypervariable region can affect the thermal stability, as well as the electrophoretic mobilities, of the proteins.

Amino Acid Sequence↗

PubMed1975

Diversity of light chain variable region sequences among rabbit antibodies elicited by the same antigens.

We report the complete variable region sequences of three homogeneous rabbit antibody light chains and the partial sequences of five others. Wehn these are compared to other published rabbit light chain sequences, two regions of markedly increased variability are revealed, which are homologous in position to the first and third hypervariable regions of murine and human myeloma light chains. In addition, there is increased variability among the first three residues at the aminoterminal end. A hypervariable region homologous to that identified at positions 50 to 56 in myeloma light chains is not present in these rabbit antibody light chains. The available three-dimensional models of Fab fragments based on x-ray crystallography indicate that neither the amino-terminal portion of the light chain nor the region homologous to positions 50 to 56 forms a part of the combining site. Comparison of the hypervariable regions among six light chains from antibodies to Type III pneumococcal polysaccharide and among four from antibodies to Type VIII pneumococcal polysaccharide suggests that a large number of different sequences may be found in antibodies specific for these relatively simple antigens. Certain residues outside of the hypervariable regions are invariant in the rabbit light chains and correspond to residues that are required for proper chain folding in human and murine myeloma light chains, indicating that the general conformation of myeloma light chains is the same as that of light chains of elicited antibodies.

Amino Acid Sequence↗

PubMed2006

Population affinities of Neolithic Siberians: a snapshot from prehistoric Lake Baikal.

Archaeological evidence supports the inhabitation of the Lake Baikal region since the Paleolithic. Both metric and nonmetric osteological studies suggest that Neolithic Cis-Baikal populations are the ancestors of contemporary inhabitants of the region. To date, ancient DNA data have not been used to corroborate this biological continuity hypothesis. This study presents a temporal snapshot of the Cis-Baikal Neolithic by examining mtDNA diversity in two cemetery populations situated on the Angara River downstream of Lake Baikal. The 800 years separating the use of the two cemeteries is thought to represent a biocultural hiatus in the Cis-Baikal region, one that ended when a new group migrated into the area. To assess the likelihood that genetic continuity exists between these two Neolithic groups, we examined both mtDNA coding region and hypervariable region I (HVI) polymorphisms from skeletal remains excavated from both cemeteries (Lokomotiv and Ust'-Ida). The mtDNA haplogroup distributions of the two cemetery populations differ significantly, suggesting that they were biologically distinct groups. When the biological distance between these Neolithic groups is compared with modern Siberian and other East Eurasian groups, the posthiatus group (Serovo-Glazkovo) generally aligns with contemporary Siberians, while the prehiatus (Kitoi) individuals are significantly different from all but modern Kets and Shorians living in the Yenisey and Ob River basins to the west of Lake Baikal. These results suggest that the Lake Baikal region experienced a significant depopulation event during the sixth millennium BP, and was reoccupied by a new immigrant population some 800 years later.

Anthropology, Physical↗

PubMed2006

Individual human hair mitochondrial DNA control region heteroplasmy proportions in mothers and children.

Due to maternal inheritance, lack of recombination and a high polymorphic density, the mtDNA control region hypervariable (HV) regions are well suited for forensic identification using a maternal relative as the known sample. This analysis can be performed in hair, however, heteroplasmy in this tissue is not rare and can result in an apparent sequence mismatch that complicates this application. There is little data comparing mother and child mtDNA-CR heteroplasmic proportions in hair. In this study, we assayed four hairs per individual in 26 mother-child pairs by TTGE for heteroplasmy across HV1. Single nucleotide heteroplasmy was detected in seven families, and in four families at least two hairs were heteroplasmic. In each of the latter families, sequencing and PCR-RFLP confirmed single nucleotide heteroplasmy in proportions of the variant ranging from < or =10 to > or =90% in the mothers, with far less variability in their children. Sequencing alone would have revealed apparent homoplasmic differences at one nucleotide in these families, possibly resulting in an 'inconclusive' verdict for relatedness of child and mother. However, mother-child heteroplasmic variability did not exceed intra-individual variability in the mothers alone.

Adolescent↗

PubMed1999

Characterization of the structural-protein-coding region of SAT 2 type foot-and-mouth disease virus.

The South African Territories (SAT) types of foot-and-mouth disease (FMD) virus show marked genomic and antigenic variation in sub-Saharan Africa that is to a large extent geographically determined. This has implications for selection of appropriate vaccine strains as well as the accuracy of laboratory diagnosis. However, adaptation of field isolates as vaccine strains is cumbersome, time consuming and expensive. We propose the construction of recombinant viruses in which specific antigenic determinants can be manipulated. To achieve this goal, the structural-protein-coding region of a SAT 2 vaccine strain, ZIM 7/83/2, was determined and compared with two other known SAT 2 P1 regions. Five hypervariable regions were identified of which four are situated within VP1. The cleavage sites for proteolytic processing differs from serotype A, while the junction between P1/2A is variable within the SAT 2 serotype. These differences could influence the construction of recombinant vaccines.

Amino Acid Sequence↗

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↗

PubMed2005

Establishment of cloned Anaplasma phagocytophilum and analysis of p44 gene conversion within an infected horse and infected SCID mice.

Diverse p44 alleles at the p44 expression locus (p44Es) encoding surface-exposed major membrane proteins, P44s, of Anaplasma phagocytophilum were hypothesized to be garnered by recombination to enact antigenic variation. However, this hypothesis has not been proven so far, due to inability to clone this obligate intragranulocytic rickettsia. To define the p44E recombination, we developed a novel method to clone A. phagocytophilum. This isogenic cloned population containing a defined p44E was used to infect a naive horse and severe combined immunodeficiency (SCID) mice. During a 58-day infection period in the blood of the horse, p44E conversion was evident in a total of 11 new p44Es, 48% (115/242) of the sequenced p44E population. During a 50-day infection period in the blood of SCID mice, p44E conversion was manifested in a total of 13 new p44Es, 42% (192/460) of the p44E population. Thus, similar levels of p44E convertants were detected in either the presence or absence of an acquired immune system, suggesting that T- and B-cell immune pressure was not essential for recombination and/or selection of the p44E variants. Analysis of sequentially changed p44Es revealed that the entire central hypervariable region of donor p44 pseudogenes or of donor full-length p44s replaced the same region of the resident p44E as a cassette. Putative recombination points were detected within p44 conserved regions flanking the central hypervariable region by the TOPALi analysis. Our results unambiguously demonstrated p44E recombination. The cloning method developed would facilitate precise analysis of the recombination process and the extent of diversity which the recombination creates in the antigenic repertoire.

Anaplasma phagocytophilum↗

PubMed2005

Compartmentalization of hepatitis C virus quasispecies in blood mononuclear cells of patients with mixed cryoglobulinemic syndrome.

The aim of this study was to investigate the quasispecies heterogeneity of hepatitis C virus (HCV) in the plasma, cryoprecipitate, and peripheral lymphocytes of chronically infected HCV patients with mixed cryoglobulinemia (MC). We studied 360 clones from 10 HCV-positive patients with MC and 8 age-, gender- and HCV genotype-matched subjects with chronic HCV infection but without MC. A partial nucleotide sequence encompassing the E1/E2 region, including hypervariable region 1 (HVR1), was amplified and cloned from plasma, cryoprecipitates, and peripheral blood mononuclear cells (PBMC), and the genetic diversity and complexity and synonymous and nonsynonymous substitution rates were determined. Heterogeneous selection pressure at codon sites was evaluated. Compartmentalization was estimated by phylogenetic and phenetic (Mantel's test) approaches. The patients with MC had 3.3 times lower nonsynonymous substitution rates (1.7 versus 5.7 substitutions/100 sites). Among the subjects with HCV genotype 1, the MC patients had significantly less complexity than the controls, whereas the diversity and complexity were similar in the genotype 2 patients and controls. Site-specific selection analysis confirmed the low frequency of MC patients showing positive selection. There was a significant correlation between positive selection and the infecting HCV genotype. The quasispecies were less heterogeneous in PBMC than in plasma. Significant compartmentalization of HCV quasispecies was observed in the PBMC of four of nine subjects (three with MC) and seven of nine cryoprecipitates. In one subject with MC, we detected a 5-amino-acid insertion at codons 385 to 389 of HVR1. Our results suggest reduced quasispecies heterogeneity in MC patients that is related to a low selection pressure which is probably due to an impaired immune response, the HCV genotype, and/or the duration of the infection. The frequent HCV quasispecies compartmentalization in patients' PBMC suggests a possible pathogenetic significance.

Aged↗

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↗

PubMed2003

[Sequencing of adenovirus type 7 vaccine strain fragment and characterization of the hexon encoding gene].

OBJECTIVE: To complete the full-length sequencing of the human adenovirus type 7 vaccine strain (Ad7v) for novel vector constructing. METHODS: The Ad7v DNA was digested with SalI and the 17.5-68.0 map unit (mu) fragment was cloned and sequenced. The homology of encoding sequence of Ad7v hexon to those of group A,C,D,E,F and other numbers of group B was accomplished with the software CLUSTAL.V. The three-dimensional structure of the Ad7v hexon was predicted with the RasMo12.71. RESULTS: The fragment contains 17,596 bp, part of E2 and late gene L1, L2 and L3 were encoded by this region. Polypeptide encoded by hexon gene lies in L3 region, which is composed of 934 amino acids. Multiple sequence alignment with the other nine known hexon protein sequences suggested that the variable sequences are mainly concentrated on seven regions, namely hypervariable regions (HVRs). The seven HVRs are related to type-specificity and group-specificity. The three-dimensional structure of the Ad7v hexon revealed that the variable regions are located in the I1 and I2 loops of the molecule mostly on the tower of the hexon. CONCLUSION: The full-length genome sequencing of Ad7v was accomplished at last. Since the deduced amino acid sequence of Ad7v hexon was quite different from other adenoviral vectors such as Ad5 and Ad2, this virus can be potentially used for the construction of novel gene delivery vectors to counterpart the immunity to the vectors widely used at present.

Adenovirus E3 Proteins↗

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↗

PubMed2006

High allelic diversity in the methyltransferase gene of a phase variable type III restriction-modification system has implications for the fitness of Haemophilus influenzae.

Phase variable restriction-modification (R-M) systems are widespread in Eubacteria. Haemophilus influenzae encodes a phase variable homolog of Type III R-M systems. Sequence analysis of this system in 22 non-typeable H.influenzae isolates revealed a hypervariable region in the central portion of the mod gene whereas the res gene was conserved. Maximum likelihood (ML) analysis indicated that most sites outside this hypervariable region experienced strong negative selection but evidence of positive selection for a few sites in adjacent regions. A phylogenetic analysis of 61 Type III mod genes revealed clustering of these H.influenzae mod alleles with mod genes from pathogenic Neisseriae and, based on sequence analysis, horizontal transfer of the mod-res complex between these species. Neisserial mod alleles also contained a hypervariable region and all mod alleles exhibited variability in the repeat tract. We propose that this hypervariable region encodes the target recognition domain (TRD) of the Mod protein and that variability results in alterations to the recognition sequence of this R-M system. We argue that the high allelic diversity and phase variable nature of this R-M system have arisen due to selective pressures exerted by diversity in bacteriophage populations but also have implications for other fitness attributes of these bacterial species.

Alleles↗

PubMed2005

The cellulose synthase gene PrCESA10 is involved in cellulose biosynthesis in developing tracheids of the gymnosperm Pinus radiata.

One full length (PrCESA10) and seven other cDNA clones (PrCESA2, 3, 5-8, 11) encoding cellulose synthases (CESAs) were isolated from the coniferous gymnosperm Pinus radiata. PrCESA10 encodes a protein predicted to contain the same domains and regions as angiosperm CESA genes: a zinc finger domain, a hypervariable region 1 (HVR1), a plant-conserved region (CR-P), a class-specific region or hypervariable region 2 (HVR2), in addition to the four conserved domains U1-U4 that are characteristic of the family 2 processive beta-glycosyltransferases. The P. radiata protein is also predicted to contain eight transmembrane domains. The zinc finger domain, the CR-P and the C-terminal portion of the proteins, are highly conserved between P. radiata and the nearest angiosperm CESA protein from Solanum tuberosum. Reverse transcriptase-PCR showed that all the P. radiata genes were expressed in all organs tested, although to different extents. In situ hybridization studies with PrCESA10 in stems of 2- and 12-month-old seedlings showed that it was expressed in the secondary xylem in the two-to-three most recently developed tracheids, which were laying down secondary cell walls.

Amino Acid Sequence↗