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P D Ennis

Publications and source records attributed to P D Ennis.

15 recordsLinked to original sources
PubMed1993

Structural diversity in the HLA-A10 family of alleles: correlations with serology.

The HLA-A10 crossreacting group consists of the A25, A26, A34, A43 and A66 antigens. Here, we report allelic sequences for A43 and for 2 subtypes of both A26 and A34. Combining these results with previously determined sequences for A25, A26 and A66 enables molecular comparison of all the serologically defined A10 antigens. They form a closely related and well-defined group of alleles which may have originated with A*2601. Patterns of serological crossreactivity are correlated with sequence and a public epitope shared by A33 and members of the A10 family is localized to residues R62 and N63. The A*2501, A*4301 and A*6601 alleles appear to have derived from A*2601 by single gene conversion events with other HLA-A alleles. In the case of A*4301, the donor allele was probably an A29 allele as A*4301 has a small element of sequence in the alpha 1 helix (residues L62 and Q63) uniquely shared with A29. The chimaeric structure of A43 explains the reactivity of A43 molecules with both A10 and A29 alloantisera. The rare Oriental variant of A26 (A26v*) is encoded by an allele (A*2602) that differs from A*2601 by a unique nucleotide substitution which changes aspartate to asparagine at position 116 in the floor of the peptide binding groove. Thus A*2602 is a functionally distinct allele that originated by a point mutation. Alleles encoding A34 and A66 antigens are found to have very similar structures, explaining the difficulty in their serological definition.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1992

Distinctive HLA-A,B antigens of black populations formed by interallelic conversion.

Alleles encoding five HLA-A and B Ag characteristic of black populations have been isolated and their nucleotide sequences determined. In each case, the "black" allele is similar to a "related" allele found in caucasoid populations. The primary differences between these pairs of alleles are localized clusters of nucleotide substitutions that change two to five residues of the Ag recognition site. The pattern of differences indicates that the pairs of black and caucasoid alleles diverged primarily as a result of interallelic conversion events.

Africa↗
PubMed1991

Gene conversion in the evolution of the human and chimpanzee MHC class I loci.

Sixty-five DNA sequences from human and chimpanzee major histocompatibility complex class I loci were searched for statistical evidence of past gene conversion. Twenty-four potential conversions were detected; they were distributed across both variable and conserved portions of the gene, and involved both classical and non-classical loci. The majority spanned less than 100 bp, comparable in length to the conversions observed in spontaneous mutations in mice. Both within-locus and between-locus conversions were observed. Certain areas of the antigen recognition site appear to have been the target for multiple conversion events. The implications of these findings for the evolution of the class I multigene family are discussed.

Alleles↗
PubMed1990

HLA-AR, an inactivated antigen-presenting locus related to HLA-A. Implications for the evolution of the MHC.

The MHC contains many class I genes other than those known to present peptides to T lymphocytes. These additional class I genes vary between species and their functions are unknown. Genes involved in Ag presentation, HLA-A,B,C in humans, are highly diverse whereas other class I genes are of much more limited diversity. We have studied alleles of a gene, HLA-AR, that is closely linked and structurally related to HLA-A; properties consistent with these two loci having been formed by a gene duplication. Compared to HLA-A the diversity in HLA-AR is much less, and does not focus on residues of a putative Ag recognition site. However, the structure of HLA-AR alleles closely resembles those encoding Ag-presenting molecules, although the presence of one or two deleterious mutations prevents these alleles being active in Ag presentation. These results suggest HLA-AR derives from an Ag-presenting locus that became inactivated, possibly as a result of positive natural selection due to changing demands on T cell immunity. Thus absence of diversity may sometimes correlate with loss rather than preservation of function in class I MHC genes.

Alleles↗
PubMed1990

Rapid cloning of HLA-A,B cDNA by using the polymerase chain reaction: frequency and nature of errors produced in amplification.

A method for cloning full-length HLA-A,B cDNA (1.1 kilobases) by using the polymerase chain reaction (PCR) is described. Six HLA-A,B alleles (HLA-A2, -A25, -B7, -B37, -B51, and -B57) were cloned, and their structures were determined. Multiple PCR clones for each allele were sequenced to obtain both an accurate consensus sequence and an "authentic" clone having that sequence. Sequences from 50 clones encoding five different alleles permit assessment of the frequency and nature of PCR-produced errors. These include recombinations, deletions, and insertions in addition to point substitutions. Authentic clones were obtained at a frequency of between 30% and 70%, and analysis of three or four clones generally should be sufficient for characterization of an allele.

Alleles↗
PubMed1989

Diversity and diversification of HLA-A,B,C alleles.

The nucleotide sequences encoding 14 HLA-A,B,C and 5 ChLA-A,B,C molecules have been determined. Combining these sequences with published data has enabled the polymorphism in 40 HLA-A,B,C and 9 ChLA-A,B,C alleles to be analyzed. Diversity is generated through assortment of point mutations by recombinational mechanisms including gene and allelic conversions. The distribution and frequency of silent and replacement substitutions indicate that there has been positive selection for allelic diversity in the 5' part of the gene (exons 1 to 3) and for allelic homogenization and locus specificity in the 3' part of the gene (exons 4 to 8). These differences may correlate with the lengths of converted sequences in the two parts of the gene and frequency of the CpG dinucleotide. Locus-specific divergence of HLA-A,B, and C demonstrates that recombinational events involving alleles of a locus have been more important than conversion between loci. This contrasts with the predominance of gene conversion events in the evolution of mutants of the H-2Kb gene. However, a striking example of gene conversion involving HLA-B and C alleles of an oriental haplotype has been found. Comparison of human and chimpanzee alleles reveals extensive sharing of polymorphisms, confirming that diversification is a slow process, and that much of contemporary polymorphism originated in ancestral primate species before the emergence of Homo sapiens. There is less polymorphism at the HLA-A locus compared to HLA-B, with greater similarity also being seen between HLA-A and ChLA-A alleles than between HLA-B and ChLA-B alleles. Although greater diversity is seen in the 5' "variable" exons of HLA-B compared to HLA-A, there is increased heterogeneity in the 3' "conserved" exons of HLA-A compared to HLA-B.

Alleles↗
PubMed1989

HLA-B51 and HLA-Bw52 differ by only two amino acids which are in the helical region of the alpha 1 domain.

Genes encoding the serologically cross-reactive HLA-B51 and HLA-Bw52 molecules were isolated and the exons sequenced. HLA-B51 genes obtained from Caucasian and Oriental individuals were identical. HLA-Bw52 differs from HLA-B51 by four nucleotide substitutions in exon 2 encoding the alpha 1 domain. These comprise one isolated silent substitution in codon 23 and a cluster of three coding substitutions in codons 63 and 67. Amino acid substitutions of N----E at position 63 and F----S at position 67 are the only differences between HLA-B51 and HLA-Bw52 and these residues are postulated to form HLA-B51 specific epitopes. HLA-B51 could have been formed from HLA-Bw52 by the combination of a genetic exchange with HLA-B8 and a point mutation. Similarity of HLA-B51 and HLA-Bw52 with HLA-Bw58 suggest they also share a common ancestor.

Amino Acid Sequence↗
PubMed1988

HLA-A and B polymorphisms predate the divergence of humans and chimpanzees.

Major histocompatibility complex (MHC) glycoproteins bind processed fragments of proteins and present them to the receptors of T lymphocytes. The extraordinary polymorphism of class I MHC molecules in man (HLA-A, B and C) and mouse (H-2 K, D and L) poses many questions concerning their diversification and evolution. Comparison of allelic sequences within a species suggests diversity is generated by the assortment of point mutations into varied combinations by mechanisms of recombination and gene conversion. We have now compared class I MHC alleles in two closely related species: humans (Homo sapiens) and chimpanzees (Pan troglodytes). Chimpanzee homologues of HLA-A, HLA-B and a non-classical gene have been identified. No features distinguishing human and chimpanzee alleles could be found. Individual HLA-A or B alleles are more closely related to individual chimpanzee alleles than to other HLA-A or B alleles. These results show that a considerable proportion of contemporary HLA-A and B polymorphism existed before divergence of the chimpanzee and human lines. The stability of the polymorphism indicates that hyper-mutational mechanisms are not necessary to account for HLA-A, B and C diversity.

Alleles↗
PubMed1988

Molecular cloning of bovine class I MHC cDNA.

Two cDNA cloned from a Hereford cow B cell line (BL-3) have allowed the determination of the complete coding region for two class I molecules encoded by the bovine MHC (BoLA). The predicted protein sequences have all the features expected of expressed class I molecules that present peptide Ag to cytotoxic T cells. Comparison with class I molecules from other species strongly suggests these cDNA are derived from different genes and provides evidence for the existence of a second expressed class I BoLA locus. The BoLA proteins show greater similarity to HLA than to H-2 molecules, correlating with the cross-reactions of W6/32 and other murine anti-HLA-A,B,C mAb with BoLA molecules. The basis for the W6/32 epitope and the preferential association of H-2 class I H chains with bovine beta 2-m is examined.

Amino Acid Sequence↗
PubMed1988

Comparison of the structure of HLA-Bw47 to HLA-B13 and its relationship to 21-hydroxylase deficiency.

Adrenal 21-hydroxylase deficiency is strongly associated with HLA-Bw47. This rare HLA allele and the HLA-B13 allele are both found in positive genetic linkage disequilibrium with HLA-A3, -Cw6, -DR7 and also display serological cross-reactivity. To investigate the relationship between these two alleles at the structural level, the nucleotide sequences of the HLA-B13 and HLA-Bw47 genes have been determined. They differ by 28 nucleotides, resulting in 14 amino acid substitutions: 5 in the alpha 1 domain, 8 in the alpha 2 domain, and 1 in the transmembrane region. Comparison of HLA-Bw47 nucleotide sequence with other HLA-B sequences shows a segment of 228 bp identical with B44 in the alpha 1 domain and a segment of 218 bp identical with B27 in the alpha 2 domain, but only a 91 bp segment of identity with B13 in the alpha 1 domain. The complex pattern of substitutions and their degree of divergence indicate that HLA-B13 and HLA-Bw47 alleles are not related by a simple mutational event.

Adrenal Hyperplasia, Congenital↗
PubMed1988

Nature of polymorphism in HLA-A, -B, and -C molecules.

Diversity in 39 HLA-A, -B, and -C molecules is derived from 20 amino acid positions of high variability and 71 positions of low variability. Variation in the structurally homologous alpha 1 and alpha 2 domains is distinct and may correlate with partial segregation of peptide and T-cell receptor binding functions. Comparison of 15 HLA-A with 20 HLA-B molecules reveals considerable locus-specific character, due primarily to differences at polymorphic residues. The results indicate that genetic exchange between alleles of the same locus has been a more important mechanism in the generation of HLA-A, -B, and -C diversity than genetic exchange events between alleles of different loci.

Amino Acid Sequence↗
PubMed1983

Calcium-mediated changes in gap junction structure: evidence from the low angle X-ray pattern.

Rat liver gap junctions were isolated in Ca2+-free media and analyzed in controlled environments by x-ray diffraction of partially oriented pellets. Different treatments of the same preparations were compared. The ordered hexagonal lattices gave rise to detail that was sensitive to low Ca2+ concentrations (0.05 mM), but not to Mg2+ (up to 0.16 mM) or pH (between 6.0 and 8.0). The major Ca2+-mediated responses were reductions in the intensity of the (1, 0) peak and in the off-equatorial contributions to the (2, 1) peak, and changes of scale equivalent to a decrease (approximately 2%) in lattice dimension, but an increase (approximately 4%) in the dimension perpendicular to the lattice. A simple structural interpretation of these findings is that Ca2+ induces the subunits of the channel-forming assembly, the connexon, to align more nearly parallel to the channel, thereby causing the connexon to become slightly longer and more radially compact. The rearrangement is of the same nature as one found under less physiological circumstances by electron microscopy (Unwin, P. N. T., and G. Zampighi, 1980, Nature (Lond.)., 283:545-549), and may be part of a coordinated mechanism by which the channel closes.

Animals↗
PubMedDate not supplied

Two configurations of a channel-forming membrane protein.

The protein oligomer forming the gap junction channel has been analysed in two Ca2+-sensitive states by electron microscopy of membranes in frozen aqueous solutions. Switching between states occurs by a small cooperative rearrangement involving tilting of the subunits, which may be responsible for the effect of Ca2+ on channel permeability in vivo.

Animals↗