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PubMed1988

Genetic susceptibility to rheumatoid arthritis and human leukocyte antigen class II polymorphism. The role of shared conformational determinants.

Genetic susceptibility for rheumatoid arthritis has been associated with both human leukocyte antigen (HLA)-DR4 and HLA-DR1, depending on the ethnic origin of the population under study. Furthermore, various subtypes of DR4 exist, only some of which appear to be associated with rheumatoid arthritis. DNA sequence analysis of the DR-beta chain genes encoding the DR4 subtypes as well as DR1 has led to the observation that similar third hypervariable region sequences are found on rheumatoid arthritis-associated DR-beta chain alleles. The data indicate that third hypervariable region sequence polymorphisms strongly influence T cell recognition as well as risk for rheumatoid arthritis. This has led to the hypothesis that genetic susceptibility for rheumatoid arthritis is due to a group of similar third hypervariable region sequences that may share conformational determinants important in antigen presentation and/or immune regulation.

Alleles↗

PubMed2005

Differential membrane localization of ERas and Rheb, two Ras-related proteins involved in the phosphatidylinositol 3-kinase/mTOR pathway.

Two Ras-related proteins, ERas and Rheb, which are involved in the phosphatidylinositol 3-kinase pathway, display high GTP affinity and have atypical CAAX motifs. The factors governing the intracellular localization of ERas and Rheb are incompletely understood. In the current study, we show by confocal microscopy that ERas is localized to the plasma membrane, whereas Rheb is confined to the endomembranes. Membrane localization of the two proteins was abolished by mutation of the cysteine of the CAAX motif. Membrane targeting was also abolished by a farnesyltransferase inhibitor but not by a geranylgeranyltransferase inhibitor. In mouse fibroblasts deficient in either Rce1 (Ras converting enzyme 1) or Icmt (isoprenylcysteine carboxyl methyltransferase), ERas was mislocalized mainly to the Golgi apparatus, whereas Rheb showed diffuse localization. Mutation of cysteines in the hypervariable region of ERas prevented the plasma membrane localization of ERas, very strongly suggesting that palmitoylation of the cysteines is essential for membrane targeting. The hypervariable region of Rheb does not contain cysteines or polybasic residues, and when it was replaced with the hypervariable region of H-Ras, Rheb displayed plasma membrane localization. These data indicate that ERas shares the same posttranslational modifications with H-Ras and N-Ras and is localized at the plasma membrane. Rheb also shares the same membrane-targeting pathway but because of the absence of palmitoylation is located on endomembranes.

Alkyl and Aryl Transferases↗

PubMed2006

HvrBase++: a phylogenetic database for primate species.

HvrBase++ is the improved and extended version of HvrBase. Extensions are made by adding more population-based sequence samples from all primates including humans. The current collection comprises 13,873 hypervariable region I (HVRI) sequences and 4940 hypervariable region II (HVRII) sequences. In addition, we included 1376 complete mitochondrial genomes, 205 sequences from X-chromosomal loci and 202 sequences from autosomal chromosomes 1, 8, 11 and 16. In order to reduce the introduction of erroneous data into HvrBase++, we have developed a procedure that monitors GenBank for new versions of the current data in HvrBase++ and automatically updates the collection if necessary. For the stored sequences, supplementary information such as geographic origin, population affiliation and language of the sequence donor can be retrieved. HvrBase++ is Oracle based and easily accessible by a web interface (http://www.hvrbase.org). As a new key feature, HvrBase++ provides an interactive graphical tool to easily access data from dynamically created geographical maps.

Animals↗

PubMed1990

Structure of the Bordetella pertussis gene coding for the serotype 3 fimbrial subunit.

Bordetella pertussis strains contain at least three distinct genes coding for fimbrial subunits, designated fim2, fim3, and fimX. The sequences of the fim2 and fimX genes have been published. Here we present the sequence of the fim3 gene. Proximal and distal to the fim3 gene, regions were observed that could function as rho-independent terminators, suggesting that the gene is not part of a larger operon. Comparison of the putative promoter regions of the fim2 and fim3 genes revealed a conserved region containing a stretch of approximately 13 C's. This region may be involved in fimbrial phase variation. A comparison of the deduced amino acid sequences of the three fimbrial subunits revealed conserved, variable, and hypervariable regions. The hypervariable regions coincided with predicted antigenic determinants. Peptides derived from the conserved regions may be incorporated into a future pertussis vaccine to induce antibodies which confer protection against strains producing different fimbrial serotypes.

Amino Acid Sequence↗

PubMed2002

Phylogeography of the African buffalo based on mitochondrial and Y-chromosomal loci: Pleistocene origin and population expansion of the Cape buffalo subspecies.

Population genetics and phylogeography of the African buffalo (Syncerus caffer) are inferred from genetic diversity at mitochondrial D-loop hypervariable region I sequences and a Y-chromosomal microsatellite. Three buffalo subspecies from different parts of Africa are included. Nucleotide diversity of the subspecies Cape buffalo at hypervariable region I is high, with little differentiation between populations. A mutation rate of 13-18% substitutions/million years is estimated for hypervariable region I. The nucleotide diversity indicates an estimated female effective population size of 17 000-32 000 individuals. Both mitochondrial and Y-chromosomal diversity are considerably higher in buffalo from central and southwestern Africa than in Cape buffalo, for which several explanations are hypothesized. There are several indications that there was a late middle to late Pleistocene population expansion in Cape buffalo. This also seems to be the period in which Cape buffalo evolved as a separate subspecies, according to the net sequence divergence with the other subspecies. These two observations are in agreement with the hypothesis of a rapid evolution of Cape buffalo based on fossil data. Additionally, there appears to have been a population expansion from eastern to southern Africa, which may be related to vegetation changes. However, as alternative explanations are also possible, further analyses with autosomal loci are needed.

Africa↗

PubMed1999

Emergence of Anaplasma marginale antigenic variants during persistent rickettsemia.

Anaplasma marginale is an ehrlichial pathogen of cattle, in the order Rickettsiales, that establishes persistent cyclic rickettsemia in the infected host. Within each rickettsemic cycle, A. marginale expressing antigenically variant major surface protein 2 (MSP2) emerge. By cloning 17 full-length msp2 transcripts expressed during cyclic rickettsemia, we determined that emergent variants have a single, central hypervariable region encoding variant B-cell epitopes. The N- and C-terminal regions are highly conserved among the expressed A. marginale variants, and similar sequences define the MSP2 homologues in the agent of human granulocytic ehrlichiosis (HGE). This is in contrast to the MSP2 homologues in ehrlichial genogroup I pathogens, Ehrlichia chaffeensis, Ehrlichia canis, and Cowdria ruminantium, that have multiple hypervariable regions. By defining the variable and conserved regions, we were able to show that the single hypervariable region of A. marginale MSP2 encodes epitopes that are immunogenic and induce variant-specific antibody responses during persistent infection. These findings demonstrate that the MSP2 structural variants that emerge during each cycle of persistent rickettsemia are true antigenic variants, consistent with MSP2 antigenic variation as a mechanism of A. marginale persistence.

Amino Acid Sequence↗

PubMed1997

Striking sequence similarity in inter- and intra-specific comparisons of class I SLG alleles from Brassica oleracea and Brassica campestris: implications for the evolution and recognition mechanism.

Self-incompatibility in Brassica is controlled by a single multi-allelic locus (S locus), which contains at least two highly polymorphic genes expressed in the stigma: an S glycoprotein gene (SLG) and an S receptor kinase gene (SRK). The putative ligand-binding domain of SRK exhibits high homology to the secretory protein SLG, and it is believed that SLG and SRK form an active receptor kinase complex with a self-pollen ligand, which leads to the rejection of self-pollen. Here, we report 31 novel SLG sequences of Brassica oleracea and Brassica campestris. Sequence comparisons of a large number of SLG alleles and SLG-related genes revealed the following points. (i) The striking sequence similarity observed in an inter-specific comparison (95.6% identity between SLG14 of B. oleracea and SLG25 of B. campestris in deduced amino acid sequence) suggests that SLG diversification predates speciation. (ii) A perfect match of the sequences in hypervariable regions, which are thought to determine S specificity in an intra-specific comparison (SLG8 and SLG46 of B. campestris) and the observation that the hypervariable regions of SLG and SRK of the same S haplotype were not necessarily highly similar suggests that SLG and SRK bind different sites of the pollen ligand and that they together determine S specificity. (iii) Comparison of the hypervariable regions of SLG alleles suggests that intragenic recombination, together with point mutations, has contributed to the generation of the high level of sequence variation in SLG alleles. Models for the evolution of SLG/SRK are presented.

Alleles↗

PubMed1980

Nucleotide sequence of immunoglobulin heavy chain joining segments between translocated VH and mu constant regions genes.

To investigate the mechanism of recombination of immunoglobulin heavy chain variable and constant region genes, we have determined the nucleotide sequence of a large portion of the recombination region between an active C mu gene and its associated VH gene, isolated from an IgM-secreting mouse plasmacytoma, HPC76. By comparison with the sequence of the mu mRNA, we determined the exact boundaries of the intervening sequence between the VH76 and C mu genes. The rearranged VH76 gene encodes up to amino acid 116 without interruption, the 3' 39 nucleotides (the JH76 region) being derived from an embryonic JH segment (JH315) whose sequence was recently determined [Early, P., Huang, H., Davis, M., Calame, K. & Hood, L. (1980) Cell 195, 981-992]. The active JH76 does not use the first two codons of the embryonic JH315 from which it is derived. This indicates that V-J recombination is important in generating diversity within the third hypervariable region of heavy chains. We have identified another JH segment (JHA4), located 336 nucleotides 3' to the rearranged JH76 segment. This JH segment is expressed in the heavy chains of anti-levan myeloma proteins, which have truncated third hypervariable regions. We propose that the nucleotide sequence 5' to JHA4 is important for generating V region genes with shortened third hypervariable regions.

Animals↗

PubMed1995

Hepatitis C viral quasispecies in hepatitis C virus carriers with normal liver enzymes and patients with type C chronic liver disease.

Hepatitis C virus (HCV) has been reported to conform to a quasispecies nature, which is most evident in hypervariable regions of the putative envelope 2 domain. The aim of this study was to determine the relationship between the nucleotide complexity and diversity of hypervariable region 1 and various stages of the carrier states. The subjects studied were 20 HCV carriers with normal alanine aminotransferase (ALT) levels, 50 patients with chronic hepatitis who showed elevated ALT levels, 22 with cirrhosis, and 24 with hepatocellular carcinoma. The quasispecies complexity was analyzed by means of polymerase chain reaction-mediated single strand conformation polymorphism (PCR-SSCP). The value of nucleotide diversity was calculated by PCR cloning and sequencing. The number of SSCP bands ranged from 1 to 7, with no significant differences in the mean numbers among the stages of HCV infection. There was no correlation between the amounts of serum HCV RNA and the numbers of SSCP bands. No significant difference was found in the values of nucleotide diversity between carriers with normal ALT levels (mean, 6.6 x 10(-2) per site) and patients with chronic hepatitis (7.7 x 10(-2). These findings suggest that the quasispecies complexity of hypervariable region 1 is independent of the stage of chronic HCV infection.

Adolescent↗

PubMed1993

Sequence variation in the large envelope glycoprotein (E2/NS1) of hepatitis C virus during chronic infection.

Sequence variation in the putative large surface glycoprotein (E2/NS1) of hepatitis C virus (HCV) was analyzed over 18 months in 4 patients with chronic relapsing non-A, non-B liver disease, of whom 2 were treated with lymphoblastoid interferon-alpha. Sequence analysis showed marked heterogeneity between isolates from different patients at the hypervariable region mapping to the amino-terminus of E2/NS1 (amino acid position, 386-411) and the extended sequence analyzed again confirmed the existence of two types, HCV1 and HCV2. Sequential nucleotide analysis of the hypervariable region over 1 year for each patient showed 0-9 amino acid changes, more common in the untreated than in the interferon-alpha-treated patients (3 and 9 vs. 1 and 0). Peaks of raised serum transaminases in individual patients showed no consistent association with mutations within this region. However, results do not exclude the possibility that viral persistence may be due to the emergence of "escape mutants" in the hypervariable region.

Adult↗

PubMed1997

Prediction of effect of interferon on chronic hepatitis C.

Clinical, pathological, and virological analysis including hypervariable region-1 of hepatitis C virus (HCV) was performed to predict the effect of interferon (IFN) on 41 patients with chronic hepatitis type C. The low virus load, low frequency of the mutation in the hypervariable region-1 as the change of amino acid and high level of serum aminotransferase make one estimate the good effect of IFN on patients with HCV. Mutation in the hypervariable region-1 of HCV measured by fast assay fluorescence single-stranded conformational polymorphism was more frequent in nonresponders to IFN than responders. The most frequently mutated position was amino acid number 406. This indicates that the specific mutation site might affect the response of IFN.

Amino Acid Sequence↗

PubMed2000

Cell specificity of the transcription-factor repertoire used by a lentivirus: motifs important for expression of equine infectious anemia virus in nonmonocytic cells.

The equine infectious anemia virus (EIAV) long-terminal repeat (LTR) has been identified as highly variable, both in infected horses and in cell culture. This nucleotide hypervariation is localized to the LTR enhancer region. The EIAV LTR has been implicated in controlling both the cell tropism and virulence of the virus and it is postulated that the enhancer-region hypervariation may be responsible for the LTR effects. Our previous studies have demonstrated that the presence of DNA motifs bound by the ets transcription-factor family member PU.1 are critically important for EIAV expression in equine macrophages. Here we identify and characterize the EIAV LTR enhancer motifs PEA-2, Lvb, Oct, and CRE, that bind to fibroblast nuclear extracts. Three of these four motifs, PEA-2, Oct, and CRE, were determined to be important for expression of the LTR in a fibroblast cell line that supports productive infection of EIAV. These motifs that are important for expression of the LTR in fibroblasts were found to be interdigitated between the PU.1 sites. We hypothesize that the combination of motif interdigitation and cell-specific usage of these motifs may be responsible for the observed EIAV LTR enhancer-region hypervariation.

Animals↗

PubMedDate not supplied

Molecular characterization of seven Chinese isolates of infectious bursal disease virus: classical, very virulent, and variant strains.

Seven infectious bursal disease virus (IBDV) strains isolated from China have been characterized in this study, including a classical strain CJ801, an attenuated strain GZ911, a variant strain GZ902, and four very virulent strains G9201, G9302, F9502, and HK46. With the use of reverse transcription-polymerase chain reaction, the full-length VP2 genes were amplified and the hypervariable regions were sequenced. Protein sequences of the hypervariable region (a.a. 143-382) of the field isolates confirmed their identities. CJ801 has the highest identity to the classical strains STC and 52/70. GZ902 has the highest identity to the American variant strains A, E, and GLS, and they share unique amino acid residue at positions 249K and 254S, which are not present in standard serotype 1 strains. Attenuated strain GZ911, like other cell culture-adapted strains, has substitutions at positions 279(D to N) and 284 (A to T) as well as in the serine-rich heptapeptide region. Hence, these substitutions may take an important role in the reduced virulence of these strains. The four very virulent strains have the highest identity to the European very virulent strain UK661 and Japanese strain OKYM. These strains share unique amino acid residues at positions 222A, 256I, and 294I, which are not present in other less virulent strains. The very virulent strains isolated in Guangdong (G9201, G9303) and Fujian (F9502) Provinces have one to five amino acid substitutions at the two hydrophilic domains of VP2 comparing with UK661 and OKYM, indicating that new very virulent strains are evolving. Phylogenetic analysis suggests that Chinese very virulent IBDVs and European very virulent strains are derived from similar origin.

Amino Acid Sequence↗

PubMed1977

Primary structure of the variable regions of two canine immunoglobulin heavy chains.

The complete amino acid sequences of the variable regions of two canine immunoglobulin heavy chains have been determined by automated Edman degradation and found to be strongly homologous to the human VHIII subgroup. The canine sequences were identical with each other at 76 of 113 residue positions. Twenty-three of the 37 differences are located within the four hypervariable regions previously defined by the sequences of several human VHIII proteins. Forty-five of 77 framework residue positions are invariant in the seven human and two canine VHIII proteins which have been completely sequences. The canine proteins are 78% homologous to the framework of the human prototype. Phylogenetically associated residues before the first hypervariable region were confirmed and several potential phylogenetically associated residues were identified between the first and third hypervariable regions. This study represents the first complete amino acid sequences of VH regions of spontaneously occurring, nonhuman homogeneous immunoglobulins. The date demonstrate a high degree of preservation of VHIII structure in another species.

Amino Acid Sequence↗

PubMed1991

In vivo generation of hybrids between two Bacillus thuringiensis insect-toxin-encoding genes.

The parasporal crystal of Bacillus thuringiensis is composed of polypeptides highly toxic to a number of insect larvae. The structural genes (cryIA) encoding the Lepidoptera-specific toxin from different bacterial strains diverge primarily in a single hypervariable region, whereas the N-terminal and C-terminal parts of the proteins are highly conserved. In this report, we describe the generation of hybrid genes between two cryIA genes. Two truncated cryIA genes were cloned in a plasmid vector in such way as to have only the hypervariable region in common. The two truncated cryIA genes were separated by the tetracycline-resistance determinant (or part of it). In vivo recombination between the hypervariable regions of the cryIA genes reconstituted an entire hybrid cryIA gene. Direct sequence analysis of 17 recombinant plasmids identified eleven different crossover regions which did not alter the reading frame and allowed the production of eight different hybrid proteins. The recombination events were independent from the RecA function of Escherichia coli. Some of the hybrid gene products were more specific in their insecticidal action and one had acquired a new biological activity.

Amino Acid Sequence↗

PubMed1996

Hepatitis C in human immunodeficiency virus-coinfected patients: increased variability in the hypervariable envelope coding domain.

Patients coinfected with the hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) were studied with regard to nucleotide sequence variability in the E2/NS1 first hypervariable region of the HCV genome. The nucleotide variability within individual patients was compared to patients infected only with HCV. The proportion of predicted synonymous and nonsynonymous amino acid changes, and the relationship to putative high-antigenicity sites, were evaluated in the hypervariable envelope domain. Ninety-one clones from 10 patients with HCV/HIV coinfection were sequenced, following polymerase chain reaction (PCR) amplification of the hypervariable region. The control HCV group included 53 clones from 7 patients. Sequence analysis encompassed the region coding for amino acids 384 to 414. Consensus sequences from each patient were used as the internal standard for nonsynonymous amino acid codon variability. Cumulative proportional comparison at each amino acid site revealed increased variability in HCV RNA from patients with HCV/HIV coinfection versus HCV alone (P < .05). The greatest variability was observed at amino acids 386, 397, 400, 402, 405, 407, and 414, with >l0 percent clonal variation at these sites. Jameson-Wolf plots were used to predict putative high-antigenicity domains. Nonsynonymous clonal variation resulted in alteration of putative antigenic sites within the hypervariable region. All clones had at least one high-probability site. Clones with unique predicted antigenic domains were observed more frequently in HIV/HCV coinfected patients, and, independent of viral titer, were consistent with increased sequence variability. These data suggest an accumulation of envelope variants in the HCV/HIV coinfected patients, which could be related to ineffective viral clearance, and may help explain prior reports of interferon (IFN) resistance in this patient group.

Adult↗

PubMed1995

Variability analysis of the T-cell receptors using three variability indexes.

In the absence of a three-dimensional structure for TCR molecules, several attempts to identify their hypervariable regions by variability methods have been made; this subjects is still troublesome. In this paper three different variability indexes were used: (i) the Kabat index, which is the classical measure of sequence variability, (ii) the modified Kabat index, successfully used in the beta-chain of T-cell receptors and (iii) an information-theoretical entropy concept, recently proposed as an improved measure of the variability. In order to identify the hypervariable regions in the TCR sequences, a Fourier filtering was applied on each variability profile. Results show that the three variability indexes have distinct resolutions for different levels of variability. Thus, the simultaneous use of these indexes compensates for the deficiency of any one of them in estimating variability. Applying the Fourier filtering, it is found that the hypervariable regions here identified, roughly coincide with the defined CDR-2 and CDR-3 in TCR by analogy with Ig. However, no hypervariable in the CDR-1 of alpha- and beta-chains was found. The study on the influence of sample size in variability analysis, indicates that results are independent of the sample size. Considering current structural models of TCR-peptide-MHC interaction, one can suggest that the low-variability characteristics of these regions is inherently related to the interaction with relatively conserved region on the alpha-helices of MHC.

Amino Acid Sequence↗

PubMed2006

Dictyostelium RacH regulates endocytic vesicular trafficking and is required for localization of vacuolin.

Dictyostelium RacH localizes predominantly to membranes of the nuclear envelope, endoplasmic reticulum and Golgi apparatus. To investigate the role of this protein, we generated knockout and overexpressor strains. RacH-deficient cells displayed 50% reduced fluid-phase uptake and a moderate exocytosis defect, but phagocytosis was unaffected. Detailed examination of the endocytic pathway revealed defective acidification of early endosomes and reduced secretion of acid phosphatase in the presence of sucrose. The distribution of the post-lysosomal marker vacuolin was altered, with a high proportion of cells showing a diffuse vesicular pattern in contrast to the wild-type strain, where few intensely stained vacuoles predominate. Cytokinesis, cell motility, chemotaxis and development appeared largely unaffected. In a cell-free system, RacH stimulates actin polymerization, suggesting that this protein is involved in actin-based trafficking of vesicular compartments. We also investigated the determinants of subcellular localization of RacH by expression of green-fluorescent-protein-tagged chimeras in which the C-terminus of RacH and the plasma-membrane-targeted RacG were exchanged, the insert region was deleted or the net positive charge of the hypervariable region was increased. We show that several regions of the molecule, not only the hypervariable region, determine targeting of RacH. Overexpression of mistargeted RacH mutants did not recapitulate the phenotypes of a strain overexpressing nonmutated RacH, indicating that the function of this protein is in great part related to its subcellular localization.

Actins↗