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PubMed1990

Constant and hypervariable regions in conotoxin propeptides.

Conotoxins are small cysteine rich peptides found in the venom of the predatory cone snails (Conus) which have prove to be useful high affinity ligands for various receptors and ion channels. The first cloning data for conotoxins, reported here, were obtained for the King-Kong peptide, a 27 amino acid conotoxin found in the venom of the cloth-of-gold cone, Conus textile. Analysis of cDNA clones of the King-Kong peptide revealed a family of related toxin transcripts. Three different propeptide cDNA sequences were obtained; only one of these encoded sequence for the King-Kong peptide. The other cDNA sequences encoded two different peptides (KK-1 and KK-2). When the predicted propeptide sequences are compared, well defined conserved and hypervariable regions can be identified. The hypervariable regions comprise four regions between Cys residues in the final peptide toxins; the remainder of the propeptide sequences, i.e. the excised N-terminal regions and the disulfide bonded Cys residues, are highly conserved. We suggest that the conserved regions may direct the formation of a specific disulfide configuration in the King-Kong family of conotoxins.

Amino Acid Sequence↗
PubMed1991

Immune response to peptides from the third hypervariable region of the beta chain of MHC class II molecules. Implications for the immune response to foreign antigens.

To understand the biologic significance of amino acid sequence sharing between proteins from pathogens and hypervariable regions of HLA DR molecules, we studied the immunological status of a peptide from the third hypervariable region of IEb, the mouse equivalent of HLA DRb. We found that allo MHC peptides are recognized and self MHC peptide is tolerated. This suggests that MHC class II molecules may modulate the T cell repertoire not only by selective binding of antigenic peptides (determinant selection) but also by deleting or inactivating T cells specific for self MHC peptides. In the human, such a mechanism may explain why some HLA DR4 subjects have a deficient control of EBV infection.

Amino Acid Sequence↗
PubMed1974

Affinity labelling of the binding site of rabbit antibody. Evidence for the involvement of the hypervariable regions of the heavy chain.

The binding sites of rabbit antibodies with affinity for the haptenic group 4-azido-2-nitrophenyl-lysine have been specifically labelled by photolysis of the hapten-antibody complex. The extent of covalent labelling was 0.5-0.9mol of hapten bound/mol of antibody and, by using an immunoadsorbent, antibody with 1.3mol of hapten/mol was obtained. The antibody was specifically labelled in the binding site and the ratio of labelling of heavy and light chains was in the range 3.3-5.0. The labelled heavy chains were cleaved by CNBr treatment and after reduction and alkylation of the intrachain bonds, were digested with trypsin. Evidence is presented that two regions of the heavy chain, positions 29-34 and 95-114, together contain about 80% of the label on the heavy chain; these two regions respectively include two of the hypervariable regions of rabbit heavy chain.

Affinity Labels↗
PubMedDate not supplied

Conformations of immunoglobulin hypervariable regions.

On the basis of comparative studies of known antibody structures and sequences it has been argued that there is a small repertoire of main-chain conformations for at least five of the six hypervariable regions of antibodies, and that the particular conformation adopted is determined by a few key conserved residues. These hypotheses are now supported by reasonably successful predictions of the structures of most hypervariable regions of various antibodies, as revealed by comparison with their subsequently determined structures.

Amino Acid Sequence↗
PubMed1992

Complex intrapatient sequence variation in the V1 and V2 hypervariable regions of the HIV-1 gp 120 envelope sequence.

Human immunodeficiency virus (HIV) quasi-species fluctuate both in time and in space. In general intrapatient variation is less extensive than interpatient variation. The V1 and V2 hypervariable regions of the envelope gene were analyzed for patient samples harboring highly divergent genomes in other loci. Proviral sequences were amplified by PCR, cloned, and sequenced. It was concluded that intrapatient variation may exceed interpatient variation but the presence of two clearly distinct populations was not confirmed. The env hypervariable regions appeared to be evolving independently of one another, cautioning against extrapolation of data, particularly from the V3 region. Virus typing and the assessment of HIV superinfection by genetic methods will prove difficult and experimental approaches will have to be carefully designed.

Amino Acid Sequence↗
PubMed1976

Human and murine phosphorycholine-binding immunoglobulins: conserved subgroup and first hypervariable region of heavy chains.

The NH2-terminal 36 residues of the heavy chain and the NH2-terminal 40 residues of the light chain from a human Waldenström's IgM with binding activity for phosphorylcholine (phosphocholine) are compared with the published sequences of five mouse IgA myeloma proteins with the same activity. An extensive structural similarity; i.e., 3 amino acid interchanges within framework residues, and one in the hypervariable region, is noted between the heavy chains of both species. The light chains, however, show a considerable diversity and, in contrast to the heavy chain, no correlation between the primary structure of the first hypervariable region and the binding specificity is apparent. The finding of a very similar heavy chain variable region in two different species that are separated by about 75 million years in evolution favors the concept of stable transmission of variable region genes throughout evolution.

Amino Acid Sequence↗
PubMed1990

Resolution of hypervariable regions in T-cell receptor beta chains by a modified Wu-Kabat index of amino acid diversity.

The Wu-Kabat variability coefficient is a well-established descriptor of the susceptibility of an amino acid position to evolutionary replacements. It conveniently highlights stretches of accentuated amino acid variation that, for example, in an antibody molecule account for most of the antigen contacts (complementarity-determining regions). Diverse opinion are held as to why the index yields unclear results when applied instead to the polypeptide sequences of the T-cell antigen receptor. We show that a simple modification enhances the resolving power of the index by increasing the weight on the frequency distribution of the amino acids in the formula. Application of the improved index to T-cell receptor beta chains highlights four unambiguous hypervariable regions, three of which are positioned similar to immunoglobulin complementarity-determining regions along the chain. In a Fab-like three-dimensional model of the T-cell receptor, the four hypervariable regions coincide with the four loops on the surface of the domain and form a contiguous area available for binding.

Amino Acid Sequence↗
PubMed1988

Individual specific DNA fingerprints from a hypervariable region probe: alpha-globin 3'HVR.

A probe detecting a hypervariable region (HVR) 3' to the alpha globin locus on chromosome 16 has been used to produce DNA fingerprints. Segregation analysis has revealed multiple, randomly dispersed DNA fragments inherited in a Mendelian fashion with minimal allelism and linkage. The fingerprints are highly polymorphic (probability of chance association between random individuals much less than 10(-14]. The probe is, therefore, a powerful discriminating tool: it is envisaged that this probe will have forensic applications, including paternity cases, and will be informative in linkage analysis.

Alleles↗
PubMed1976

Purification, specificity, and hypervariable region sequence of anti-pneumococcal polysaccharide antibodies elicited in a single rabbit.

Four homogeneous antibodies to type VIII pneumococcal polysaccharide (S8) were isolated from the serum of a single rabbit (3322) by affinity chromatography on an S8 immunoadsoebent by utilizing gradient elution with cellobiose and NaCl. The binding properties of these antibodies were determined by a radioimmunoassay with 125I-bovine gamma-globulin-S8. Cellobiose (a disaccharide unit of S8) was the immunodominant group of each of the four antibodies, but each antibody bound to this disaccharide with different relative affinities. The amino acid sequences (positions 0-40) of three of the four antibody light chains were each different both in framework and first hypervariable region sequences. The fourth antibody light chain has a blocked amino terminus. These findings indicate that antibodies elicited by a relatively simple antigen and examined at one time during the course of immunization in a single rabbit may exhibit common specificities for an oligosaccharide determinant, yet have different binding affinities for that determinant as well as different primary structures in the complementarity (hypervariable) regions and framework regions.

Amino Acid Sequence↗
PubMed1987

Non-insulin-dependent diabetes mellitus and the 5' hypervariable region of the insulin gene in two South African Indian families.

The hypervariable region 5' to the human insulin gene has been characterised in two South African Indian families, each having two generations of individuals affected with non-insulin-dependent diabetes mellitus (NIDDM). Southern blot analysis, with the restriction endonuclease Pvu II and plasmid phins 310 as a probe, was used. In family 1, class 1 alleles (0.87, 0.79, 0.72 and 0.68 kilobase (kb)) were found at this locus but no linkage with NIDDM was shown. In family 2 a class 3 (2.51 kb) and two class 1 alleles (0.89, 0.76) were found. The 0.89 kb allele appears to be segregating with NIDDM in this family.

Adult↗
PubMed1989

Rapid typing of tandemly repeated hypervariable loci by the polymerase chain reaction: application to the apolipoprotein B 3' hypervariable region.

The 3' flanking region of the apolipoprotein B (apoB) gene contains a hypervariable region consisting of a variable number of tandemly repeated short A + T-rich DNA sequences (VNTRs). We present a general method that utilizes the polymerase chain reaction to rapidly and accurately type this and other VNTR loci. We use tailored oligonucleotides and thermostable Taq polymerase to amplify the targeted region. The amplification products are directly visualized after agarose gel electrophoresis. Twelve alleles were readily identified in a sample of 125 unrelated individuals. The alleles differ with respect to the length of the amplified gene region. This genetic variability is inherited in an autosomal codominant manner. DNA sequence data indicate that individual alleles differ in the number of repeat units and the sensitivity of the technique is such that alleles differing in length by only 32 base pairs are readily distinguishable. A system of nomenclature based on the number of repeat units is suggested; an allele containing 37 repeat units is designated 3' beta 37, one containing 35 units is 3' beta 35, and so on. The frequency distribution of the 12 apoB VNTR alleles is bimodal with peaks at 37 and 47 repeat units and a nadir near 43 repeat units. We estimate that the 3' apoB VNTR locus has a heterozygosity index of 0.75 and a polymorphic information content of 0.73. It is a highly informative marker for genetic linkage studies on chromosome 2 and clinical and epidemiological studies involving the apoB gene. The high sensitivity and inexpensive nature of this technique make it superior to traditional Southern blot analysis for typing the 3' apoB VNTR. The method described is also directly applicable for rapid typing of other VNTRs in the human genome.

Alleles↗
PubMed1992

Characterization of hypervariable regions in the putative envelope protein of hepatitis C virus.

We previously identified two hypervariable regions [HVR1 (27 amino acids) and HVR2 (7 amino acids)] in the putative envelope glycoprotein (gp70) by comparison of the amino acid sequences of many isolates of the HCV-II genotype. To understand the functional features of these HVRs, using the polymerase chain reaction we analyzed the rate of actual sequence variability in the region including HVR1 and HVR2 of HCV isolated successively at intervals of several months from two patients with chronic C-type hepatitis. In both patients, the amino acid sequence of HVR1, but not HVR2, was found to change dramatically during the observation period (about one amino acid per month). However, no alteration of the amino acid sequence of HVR1 of HCV was observed in a patient in the acute phase of chronic hepatitis. Restriction digestion analysis of sequence diversity showed that a HCV genome with a newly introduced mutation in HVR1 often became the predominant population at the next time of examination. Alterations of amino acids in HVR1 occurred sequentially in the two patients in the chronic phase. These findings suggest that mutations in HVR1 are involved in the mechanism of persistent chronic HCV infection.

Alanine Transaminase↗
PubMed1987

Restriction fragment length polymorphisms of the insulin gene hypervariable region in gestational onset diabetes mellitus.

Restriction fragment length polymorphisms in the insulin gene hypervariable region are compared among 93 women with gestational onset diabetes mellitus and 146 women with normal glucose tolerance during pregnancy. No significant differences in gene or genotype frequencies were observed in the overall sample (p greater than 0.50). However, an increased frequency of one allele (class 1) was observed among nonoverweight patients with gestational onset diabetes mellitus with elevated fasting plasma glucose levels compared with age-, race-, and parity-matched control subjects (p = 0.061). These data suggest that gestational onset diabetes mellitus is a heterogeneous disorder with respect to both genotypic and phenotypic characteristics, and that restriction fragment length polymorphisms near the insulin gene may serve as a molecular marker for susceptibility to gestational onset diabetes mellitus only in some women.

Alleles↗
PubMed1992

Analysis of the apolipoprotein B3' hypervariable region in patients with essential hypertension.

1. The typing of the apolipoprotein B 3' hypervariable region was investigated in hypertensive and normotensive subjects using rapid typing of a variable number of tandemly repeated short DNA sequences (VNTR) by the polymerase chain reaction. 2. In the DNA samples of 89 normotensive and 99 hypertensive patients, 13 different-sized alleles were detected. The most frequent allele has 35 repeat units in both groups with frequencies of 0.624 and 0.596 in normotensive and hypertensive patients, respectively. Frequency distribution of 13 alleles was similar in both groups. 3. These results demonstrate no association between the apolipoprotein B gene polymorphism and essential hypertension.

Aged↗
PubMed1990

Hypervariable regions of DNA for parentage testing and individual identification.

Four kinds of DNA probes that recognize hypervariable regions (HVR) were studied for parentage testing and individual identification. Allele frequencies and their confidence intervals among unrelated Japanese individuals were obtained. Codominant segregation of the polymorphism was confirmed in family studies. Two a priori probabilities were calculated for each HVR locus: the exclusion probabilities for an alleged father/mother/child trio and for an alleged parent/child duo, and the probabilities of matching of genotypes of two unrelated individuals or two siblings. The ease of availability of the probes and their highly discriminating polymorphic patterns mean they could be very useful for forensic purposes.

Alleles↗
PubMed1991

Application of single-locus hypervariable region DNA probes to deficiency cases in paternity testing.

Seven DNA probes which recognize single-locus hypervariable region (HVR) were applied to a paternity test in which the putative father and his wife were deceased. Three legitimate children, an illegitimate child and her mother were available for analysis. The cumulative paternity index of the illegitimate child derived from 15 conventional blood group markers was 18.71 and from 7 DNA probes 92,572.08, that is, 4,948 times higher than the former. Thus the DNA analyses gave nearly conclusive evidence that the putative father was the biological father of the child. The application of highly discriminating polymorphisms of DNA which recognize single HVR loci is considered to be extremely informative in cases of disputed parentage.

Child↗
PubMed1988

Restriction fragment length polymorphism in the interzeta hypervariable region for prenatal diagnosis of non-deletion alpha thalassemia.

A Bam HI restriction fragment length polymorphism in the interzeta hypervariable region (IZ HVR) of the zeta-alpha gene cluster was used for the prenatal diagnosis of a pregnancy at risk for Hb H hydrops fetalis. The parents had zeta-alpha thalassemia 1 and non-deletion alpha thalassemia, respectively, and a previous hydrops was missed using the conventional method of gene detection. In this prenatal diagnosis, linkage to IZ HVR was used to exclude non-deletion alpha thalassemia, and the numbers of zeta and alpha genes in the fetus were quantitated to predict the exact genotype. Confirmation was made by analysis of cord blood at delivery.

Amniocentesis↗
PubMed1989

Interzeta-globin gene hypervariable regions in Chinese: application to genetic diagnosis of adult polycystic kidney disease.

In order to investigate the interzeta-globin gene hypervariable regions (IZHVR) in Chinese, DNA samples from 114 unrelated normal individuals were analyzed using the restriction endonuclease BglII and hybridized with a 32P-labeled zeta-globin probe. Four polymorphic fragments containing IZHVR with different frequencies were found: 11.3 kb, 0.24; 10.8 kb, 0.50; 10.4 kb, 0.05, and 10.0 kb, 0.21. Using these polymorphic fragments as linkage markers, we were able to trace the affected siblings in a three-generation Chinese family with a history of adult polycystic kidney disease.

China↗