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PubMed2006

Comparative genomic analysis of Campylobacter jejuni strains reveals diversity due to genomic elements similar to those present in C. jejuni strain RM1221.

Analysis of the complete genomic sequence of Campylobacter jejuni strain RM1221 identified four large genomic elements, Campylobacter jejuni-integrated elements (CJIEs), that were absent from C. jejuni strain NCTC 11168. To further investigate the genomic diversity of Campylobacter, we conducted a comparative genomic analysis from a collection of 67 C. jejuni and 12 Campylobacter coli strains isolated from various geographical locations and clinical and veterinary sources. Utilizing PCR, we demonstrated that 55% of the C. jejuni strains examined were positive for at least one RM1221-like genomic element and 27% were positive for two or more of these CJIEs. Furthermore, many C. coli strains were positive for either genomic element CJIE1 or CJIE3. To simultaneously assess for the presence or absence of several genes that comprise the various CJIEs, we developed a multistrain C. jejuni DNA microarray that contained most of the putative coding sequences for strains NCTC 11168 and RM1221. A comparative genomic hybridization (CGH) analysis of 35 of the 67 C. jejuni strains confirmed the presence of genomic elements similar to those in strain RM1221. Interestingly, the DNA microarray analysis demonstrated that these genomic elements in the other C. jejuni strains often exhibited modular patterns with some regions of the CJIEs present and other regions either absent or highly divergent compared to strain RM1221. Our CGH method also identified 18 other intraspecies hypervariable regions, such as the capsule and lipooligosaccharide biosynthesis regions. Thus, the inclusion of genes from these integrated genomic elements and the genes from the other intraspecies hypervariable regions contributes to a better assessment of the diversity in C. jejuni and may increase the usefulness of DNA microarrays as an epidemiological genotyping tool. Finally, we also showed that in CJIE1, a Campylobacter Mu-like phage, is located differentially in other strains of C. jejuni, suggesting that it may integrate essentially randomly.

Campylobacter jejuni↗
PubMed2007

Polymorphism of the L1 capsid gene and persistence of human papillomavirus type 52 infection in women at high risk or infected by HIV.

HIV-seropositive women are at increased risk for human papillomavirus (HPV) infection, which causes high-grade squamous intraepithelial lesions (HSILs). HPV-52 is a frequent HPV type in Canadian HIV-seropositive women. Because variations of the capsid gene, designated the L1 gene, could elicit immune responses that result in different efficiencies in eliminating HPV, we described HPV-52 polymorphism and assessed whether it was associated with HPV-52 persistence in 114 women at risk or infected by HIV. Nonsynonymous variations were more frequent in the 5 putative hypervariable regions (exposed loops of L1 protein) (10 [3.2%] variations over 311 nucleotides) than in nonvariable regions (4 [0.3%] variations over 1278 nucleotides; P < 0.0001). Synonymous variations were distributed evenly between hypervariable regions (10 [3.2%] variations over 311 nucleotides) and nonvariable regions (46 [3.6%] variations over 1278 nucleotides; P = 0.88). Nonprototype (nonreference) L1 variants were detected more frequently in women of African descent (24 [60.0%] of 40 women) than in white women (23 [37.1%] of 62 women, odds ratio = 2.54, 95% confidence interval: 1.11 to 5.81; P = 0.03). In contrast to previous findings that polymorphism in the long control region (LCR) was associated with HPV-52 persistence, L1 capsid variations were not associated with persistence (P = 0.45). L1 variations are unlikely to predispose to HPV-52 persistence and thus do not help to identify women at greater risk for HSILs.

Adult↗
PubMed1990

Analysis of the structural diversity of monoclonal antibodies to cyclosporine.

The immunosuppressive cyclic undecapeptide cyclosporine (Cs) represents a useful model for studying the molecular basis of antibody-antigen interactions. The three-dimensional structure of the Cs molecule is known and a large panel of monoclonal antibodies (mAbs) to Cs has been well characterized by cross-reactivity studies with numerous Cs analogs. In the present study, the sequences of the variable regions of seven mAbs to Cs were determined and a striking relationship was found between the expressed variable region genes and the Cs recognition pattern. An analysis of the length and hydrophobic content of the hypervariable regions and sequence similarities suggested that the heavy chain plays a major role in Cs recognition. Different fine specificities were observed for mAbs exhibiting identical light chains, while two antibodies differed by only a single amino acid located in the heavy chain. The presence of a duplication of 12 nucleotides within the heavy chain third hypervariable region of two antibodies suggests the existence of an additional mechanism for creating antibody diversity.

Amino Acid Sequence↗
PubMed1994

Evolution rate of hepatitis delta virus RNA isolated in Taiwan.

The complete RNA sequences of hepatitis delta viruses (HDV) isolated at 3 years apart from a chronic delta hepatitis patient in Taiwan were determined. The sequence analysis showed an overall evolution rate of 3.18 x 10(-3) substitutions/nucleotide/year. The evolution rates in different parts of HDV RNA varied. The hypervariable region evolved faster (4.55 x 10(-3) substitutions/nucleotide/year) than the hepatitis delta antigen (HDAg)-coding region (2.60 x 10(-3) substitutions/nucleotide/year) and the autocatalytic region (1.11 x 10(-3) substitutions/nucleotide/year). These data are compatible with the previous finding that the hypervariable region is more divergent than the HDAg-coding region and the autocatalytic regions among the HDV isolates from different geographic areas. No substitution was found in the four previously identified conserved domains of HDV RNA, further confirming their functional importance in viral replication. The evolution rate of this HDV RNA is higher than that determined from the partial RNA sequences of two Japanese HDV isolates and similar to that found in a Lebanon isolate. Further, it was found that this HDV RNA retained the same microheterogeneities at 15 nucleotide positions detected in the RNA 3 years earlier. It is concluded that HDV RNA in patients' serum is extremely heterogeneous, and that the nucleotide substitutions in certain nucleotide positions likely have conferred evolutionary advantages for HDV. Viral sequence evolution is a possible mechanism for chronic HDV infection.

Adult↗
PubMed1986

Molecular mapping of idiotopes of anti-arsonate antibodies.

As part of understanding molecular function in structural terms, we have been attempting to map the idiotypic topography of specific anti-arsonate (Ars) antibodies. A panel of anti-Ars hybridomas of which the complete primary sequences are known were used. These molecules show a varied reactivity profile with a panel of monoclonal anti-idiotypic antibodies. By judicious chain recombination experiments and chemical modifications that altered this reactivity profile, we were able to identify particular amino acid residues or discreet regions of anti-Ars antibodies as having crucial roles in the expression of idiotypic determinants. Idiotopes were mapped to the heavy chain second hypervariable region and D segment, and to the light chain first and third hypervariable regions.

Amino Acid Sequence↗
PubMed1998

Mytilus protamine-like sperm-specific protein genes are multicopy, dispersed, and closely associated with hypervariable RFLP regions.

Protamine-like sperm packaging proteins replace somatic histones during spermatogenesis, and although the proteins have been well-characterized in many marine invertebrate species, little is known of the arrangement of the genes. The research described here was designed to determine the sequence and structure of the protamine-like PL-III (or "phi 1") gene in marine mussels (Mytilus spp). The PL-III sequence was found to be extremely variable not only among the closely related Mytilus species, but also within species and populations. The variation observed among eight PL-III sequences from a single individual indicated that PL-III was probably multiple-copied. Southern analysis confirmed that PL-III, and another protamine-like gene, (PL-II), were multicopy and dispersed, as well as associated with a hypervariable element. Some PL-III genes are also arranged in nontandem clusters, and the spacer regions are probably the source of the hypervariable nature of the Southern blots. The arrangement of the protamine-like genes in Mytilus appears to be closer to that reported for histones than protamines; however, their association with a hypervariable element is novel.

Amino Acid Sequence↗
PubMedDate not supplied

Recognition of cell surface acceptors by two human alpha-2,6-sialyltransferases produced in CHO cells.

The action of sialyltransferases (STs) on cell surface glycoconjugates is a key process in shaping cell phenotype in a variety of cells mostly involved in migratory and adhesive pathways. The factors determining cell-specific pattern of glycosylation are so far poorly understood. Most STs are resident proteins of the Golgi apparatus, where acceptors are sialylated while they are in transit to the cell surface. To identify putative structural features that may account for their acceptor preference, we analyzed 53 cloned animal and human STs. We could identify conserved regions and peptide motifs representative of ST subfamilies, located at the C-terminal end of the hypervariable region upstream from the L-sialyl motif. Residues 93-100 in human ST6Gal I (hST6Gal I) were shown to be crucial for enzymatic activity when deleted and expressed in CHO cells. The Delta100 hST6Gal I mutant protein was fully recognized by polyclonal anti-hST6Gal I antibodies and followed the intracellular secretory pathway. This indicated that the conserved QVWxKDS sequence is essential for the whole catalytic domain to acquire a biologically active conformation. When full-length epitope-tagged hST6Gal I and hST6GalNAc I constructs were transfected in CHO cells, the alpha-2,6 sialylated glycotope was found to be largely restricted to intracellular resident acceptors and enzymatic activity based on fluorescent lectin staining. In contrast, both enzymes deprived of their membrane anchor and part of the hypervariable region but still possessing the conserved domains exhibited a very efficient transfer of sialic acid to cell surface glycoconjugates. Colocalization of the ST6Gal I mutant proteins with early and late Golgi markers such as giantin or rab6 proteins confirmed that soluble STs migrate forward in these subcompartments where they can act upon newly synthesized acceptors and follow the secretory pathway. It is thus concluded that downstream from the transmembrane domain, native STs possess peptide sequences that allow them to sialylate glycoprotein acceptors selectively along their transit within Golgi stacks.

Amino Acid Motifs↗
PubMed1991

The Staphylococcus aureus mec determinant comprises an unusual cluster of direct repeats and codes for a gene product similar to the Escherichia coli sn-glycerophosphoryl diester phosphodiesterase.

The DNA sequence located between mecA, the gene that codes for penicillin-binding protein PBP2', and insertion sequence-like element IS431mec has been termed hypervariable because of its length polymorphism among different staphylococcal isolates. We sequenced and characterized the hypervariable region of the methicillin resistance determinant (mec) isolated from Staphylococcus aureus BB270. Within the 2,040-bp hypervariable region, we identified an unusual accumulation of long direct repeats. Analysis of the DNA sequence revealed a minimal direct repeat unit (dru) of 40 bp which was repeated 10 times within 500 bp. The dru sequences are responsible for the length polymorphism of mec. Moreover, we identified an open reading frame that codes for 145 amino acids (ORF145), whose deduced amino acid sequence showed 57% amino acid sequence similarity to the N terminus of the glycerophosphoryl diester phosphodiesterase (UgpQ) of Escherichia coli.

Amino Acid Sequence↗
PubMed1997

Generation of coronavirus spike deletion variants by high-frequency recombination at regions of predicted RNA secondary structure.

Coronavirus RNA evolves in the central nervous systems (CNS) of mice during persistent infection. This evolution can be monitored by detection of a viral quasispecies of spike deletion variants (SDVs) (C. L. Rowe, S. C. Baker, M. J. Nathan, and J. O. Fleming, J. Virol. 71:2959-2969, 1997). We and others have found that the deletions cluster in the region from 1,200 to 1,800 nucleotides from the 5' end of the spike gene sequence, termed the "hypervariable" region. To address how SDVs might arise, we generated the predicted folding structures of the positive- and negative-strand senses of the entire 4,139-nt spike RNA sequence. We found that a prominent, isolated stem-loop structure is coincident with the hypervariable region in each structure. To determine if this predicted stem-loop is a "hot spot" for RNA recombination, we assessed whether this region of the spike is more frequently deleted than three other selected regions of the spike sequence in a population of viral sequences isolated from the CNS of acutely and persistently infected mice. Using differential colony hybridization of cloned spike reverse transcription-PCR products, we detected SDVs in which the hot spot was deleted but did not detect SDVs in which other regions of the spike sequence were exclusively deleted. Furthermore, sequence analysis and mapping of the crossover sites of 25 distinct patterns of SDVs showed that the majority of crossover sites clustered to two regions at the base of the isolated stem-loop, which we designated as high-frequency recombination sites 1 and 2. Interestingly, the majority of the left and right crossover sites of the SDVs were directly across from or proximal to one another, suggesting that these SDVs are likely generated by intramolecular recombination. Overall, our results are consistent with there being an important role for the spike RNA secondary structure as a contributing factor in the generation of SDVs during persistent infection.

Base Sequence↗
PubMed1989

Receptor specificity of the Escherichia coli T-even type phage Ox2. Mutational alterations in host range mutants.

The T-even type Escherichia coli phage Ox2 uses the outer membrane protein OmpA as a receptor. The protein is recognized with the ends of the virion's long tail fibers. The 266 residue protein 38 is located at this site and acts as an adhesin. Host-range mutants had previously been isolated from Ox2. Mutant Ox2h5 is able to infect cells possessing an altered OmpA protein, which renders the cell resistant to Ox2. Ox2h10 was selected from Ox2h5. This phage recognizes the OmpC protein in addition to the OmpA protein. Ox2h12, which stems from Ox2h10, binds to OmpC with high affinity, but has lost efficient binding to OmpA. The mutational alterations caused in genes 38 are: Asp231----Asn(h5) and His170----Arg(h10). The triple mutant Ox2h12 possesses an insertion of a Gly residue next to Gly121. The three mutants have additionally acquired mutations affecting their base plate, making them "trigger-happy". When protein 38 was compared with the same protein derived from other E. coli phages, it was found to contain two constant and one variable domains, the latter harboring four hypervariable regions flanked by a largely conserved glycine-rich sequence. The h5 and h10 mutations occurred within two hypervariable areas, while the additional Gly residue was present in one of the flanking conserved sequences. On the basis of these results, as well as those obtained from host-range mutants analyzed previously, a model for such adhesins is proposed. Receptor recognition is most likely performed via the hypervariable regions, which may form loops held together in close proximity by the oligoglycine sequences. The latter may achieve this by being part of highly compact omega loops.

Bacterial Outer Membrane Proteins↗
PubMed1977

Heavy-chain variable-region sequence from an inulin-binding myeloma protein.

The entire variable-region sequence of the heavy chain from ABE-47N, a BALB/c inulin-binding myeloma protein, has been determined. This protein is unusual in that the third complementarity region (H3) is extremely short, consisting of at the most three and probably only one amino acid. A comparison of the heavy-chain hypervariable regions from mouse, human, and rabbit proteins shows that the variability in length of H3 is greater than that seen in the first or second hypervariable regions. This variability in H3 length suggests a specialized function for this region.

Amino Acid Sequence↗
PubMed1977

Towards a chemical definition of idiotypy.

The idiotypic determinants have been precisely located to the variable regions of immunoglobulin polypeptide chains. Both chains are generally required to express the idiotype. The major idiotypic determinants are the result of the amino acid sequence of the hypervaiable regions, although some idiotypic determinants reside outside the antibody combining site and these so called "framework idiotypes" are important markers. In my view the hypervariable regions are spatially disposed so as to present adequate antigenic stimulation, and they display enough structural heterogeneity to account for the uniqueness of the idiotype in the general population of immunoglobulin molecules. Hypervariable regions, the antibody combining site, and the idiotypic determinants thus amalgamate three formerly diverse concepts into a unified theoretical construct.

Binding Sites, Antibody↗
PubMed1999

HvrBase: compilation of mtDNA control region sequences from primates.

HvrBase is a compilation of human and ape mtDNA control region sequences. Sequences and related information on individuals, such as from where the sequences were obtained, is stored in three ASCII files as described previously. Moreover, the collection is also available as Mac/PC database application with a graphical user interface. It can be accessed through the WWW at URL http://www.eva.mpg.de/hvrbase. The current collection comprises 5846 human sequences from hypervariable region I (HVRI) and 2302 human sequences from hypervariable region II (HVRII). From apes, 295 HVRI sequences and 13 HVRII sequences are available.

Animals↗
PubMed1994

Molecular basis for degenerate T-cell recognition of one peptide in the context of several DR molecules.

We report the study of one CD4+ T-cell clone that recognizes peptide HA306-320 in the context of autologous DR1101 molecules as well as of allogeneic DR1301, DR0402, DR1501, and DR1601 molecules. This degenerate T-cell recognition is mediated by a single T-cell receptor (TCR) as judged by both TCR-V beta sequencing and cold-target competition assays. Restriction analysis shows that substitutions of DR residues within the third hypervariable region result in a loss of T-cell reactivity, which is restored by additional substitutions in the first and/or second hypervariable regions. Thus, there is no correlation between antigen presentation abilities of the different allelic DR products and the degree of sequence homology between these products. DR residues whose substitution is compatible with T-cell recognition potentially interact with peptides rather than with TCRs by virtue of their location in the floor of the groove or as previously documented for residues of the alpha-helix. Furthermore, antigen presentation by allogeneic DR molecules occurs independently of their affinity for the peptide, as determined in cell surface-binding assays using biotinylated HA306-320. Altogether these data suggest that degenerate T-cell recognition mainly depends on an influence of polymorphic DR residues on the configuration adopted by the peptide in the DR groove so that the epitope is left intact.

Amino Acid Sequence↗
PubMed2001

Epitope mapping of the indirect T cell response to allogeneic class I MHC: sequences shared by donor and recipient MHC may prime T cells that provide help for alloantibody production.

Indirect allorecognition occurs when T cells recognize donor MHC presented as peptide epitopes by recipient APC, but the precise nature of the epitopes involved remains unclear. Rejection of rat MHC class I-disparate PVG.R8 (RT1.A(a)) grafts by PVG.RT1(u) (RT1.A(u)) recipients is mediated by indirectly restricted CD4 T cells that provide help for the generation of alloantibody. In this study, epitope mapping was performed using a functionally relevant readout (alloantibody production) to identify key peptides that prime an indirect alloimmune response, leading to graft rejection. PVG.RT1(u) rats were immunized with a series of overlapping 15-mer peptides (peptides 1-18) that spanned the alpha1 and alpha2 domains of the RT1.A(a) molecule. Several peptides were able to accelerate both the alloantibody response to the intact RT1.A(a) Ag and PVG.R8 heart graft rejection. An immunodominant epitope was identified within the hypervariable region of the alpha1 domain. Fine mapping of this region with a second series of peptides overlapping by single amino acids confirmed the presence of an eight-amino acid core determinant. Additional "subdominant" epitopes were identified, two of which were located within regions of amino acid homology between the RT1.A(a) and RT1.A(u) molecules and not, as had been expected, within other hypervariable regions. The contribution of self-epitopes to indirect allorecognition was emphasized by the demonstration that i.v. administration of a 15-mer peptide encompassing one of the subdominant self-determinants diminished the recipient's ability to mount an alloantibody response on challenge with intact A(a) alloantigen. Our findings suggest that cryptic self-epitopes recognized by autoreactive T cells may contribute to allograft rejection and should be considered when designing novel strategies for inducing tolerance to alloantigen.

Amino Acid Sequence↗
PubMed2002

Phylogeny of hydradephagan water beetles inferred from 18S rRNA sequences.

Several families in the beetle suborder Adephaga have an aquatic life style and are commonly grouped in the "Hydradephaga," but their monophyly is contentious and relationships between and within these families are poorly understood. Here we present full-length 18S rRNA sequence for 84 species of Hydradephaga, including representatives of most major groups down to the tribal level, and a total of 68 species of the largest family, Dytiscidae. Using a direct optimization method for the alignment of length-variable regions, the preferred tree topology was obtained when the cost of gaps and the cost of nucleotide changes were equal, and three hypervariable regions of 18S rRNA were downweighted by a factor of five. Confirming recent molecular studies, the Hydradephaga were found to be monophyletic, indicating a single colonization of the aquatic medium. The most basal group within Hydradephaga is Gyrinidae, followed in a comb-like arrangement by families Haliplidae, Noteridae, Amphizoidae, and Hygrobiidae plus Dytiscidae. Under most alignment parameters, Hygrobiidae is placed amid Dytiscidae in an unstable position, suggesting a possible data artifact. Basal relationships within Dytiscidae are not well established, nor is the monophyly of subfamilies Hydroporinae and Colymbetinae. In contrast, relationships at the genus level appear generally well supported. Despite the great differences in the rates of change and the significant incongruence of the phylogenetic signal in conserved vs hypervariable regions of the 18S rRNA gene, both contribute to establish relationships at all taxonomic levels.

Animals↗
PubMed1971

Heavy-chain variable regions in normal and pathological immunolobulins.

Aminoacid sequence analysis of immunoglobulin G heavy chains from each of 15 normal individuals showed the presence of VHIII subgroup sequences in all individuals, to an extent of about 15-25% of the total. Therefore, different subgroups of the heavy-chain variable region are not products of alleles of a single gene.N-terminal aminoacid sequences were determined for ten heavy chains of myeloma proteins that belonged to the VHIII subgroup. Our results demonstrate the existence of a "hypervariable" region of sequence between positions 30 and 35, homologous to one of the three hypervariable regions of light chains. At several positions, variants of the basic sequence are repeated in different proteins. It is likely that such variants are derived from several recently evolved genes that constitute the VHIII subgroup.

Amino Acid Sequence↗
PubMed1995

Variable region light chain genes encoding human antibodies to HIV-1.

In previous work, it was found that the heavy chain variable gene (VH) repertoire of human antibodies to HIV is markedly skewed and that the gp120 molecule is a ligand for VH3 gene products. Here, we have analysed the light chain (L-chain) variable region genes (VL) expressed by a panel of human monoclonal antibodies derived from an immunized volunteer, an AIDS patient and seropositive asymptomatic donors, and specific for HIV-1 p25, gp41 and gp120 proteins. We found that, in contrast to VH gene-family use, the VL repertoire does not exhibit a family-bias. We noticed however, a tendency to the use of VL genes that map to the downstream portion of the kappa locus. The VL genes expressed have mutated at lower rates than the corresponding VH genes and show no clustering of the replacement mutations in the hypervariable regions. We also found that the third hypervariable regions (CDR3) of the L-chains have undergone a marked diversification, with addition of untemplated nucleotides, frequent truncation at the 3' end of the VLs and somatic mutation. These molecular events result in a length heterogeneity of the CDR3s and an apparently positive selection of specific highly reactive amino acids. We conclude that the specificity of, at least some of the anti-HIV antibodies, is dictated by the L-chain CDR3 regions which bear the imprints of antigenic selection.

Amino Acid Sequence↗