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  • 1
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract In most individuals two HLA-DR β genes are expressed from each chromosome. One of these genes encodes one of the classical DR specificities, while the other encodes either of the supertypic DRw52/DRw53 specificities. In addition to these genes usually one or two DR β pseudogenes are present. In contrast, the DRw8 chromosomal region only contains a single DR β gene. To determine the relationship of this single gene to the multiple DR β genes of other DR specificities, comparisons of Southern genomic blots were carried out. In this analysis genomic clones for each individual DR β chain locus were included. The DR β w8 gene was indistinguishable from the DR β III gene of DR3 cells (encoding DRw52), suggesting that it is closely related to the latter gene. The functional implications of this finding are discussed.
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  • 2
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
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  • 3
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Using locus- and allele-specific oligonucleotide probes, we have studied the polymorphism of the HLA-DR β III locus within the haplotypes of the DRw52 supertypic group. DNA from a number of homozygous typing cells typed for both Dw and DR was used. The DR β III polymorphisms, DRw52a and DRw52b, do not segregate with Dw typing, or with DR typing, indicating that the determinants responsible for Dw-defined T -cell response and for DR haplotypic recognition are not encoded by the DR β III locus. Hence, we can conclude that these DR specificities are encoded by the other functional DR locus, DR β I, while the DR β III locus encodes only the supertypic product.
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  • 4
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The nature of the DR β II pseudogene in a haplo-type of the DRw52 supertypic group was investigated by nucleotide sequence analysis. It revealed several deleterious mutations in the signal sequence and second domain regions in addition to the complete absence of the first domain and adjacent sequences. No expression of DR βII pseudogene mRNA can be detected. The same DR βII pseudogene is probably present in other members of the DRw52 supertypic group. The pattern of mutations in this DR βII pseudogene is different from that observed in the DR β pseudogene of the DRw53 supertypic group, indicating a distinct evolutionary pathway for these two groups of DR haplotypes.
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  • 5
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The organization and sequence of the HLA-DR β chain genes are compared in the two supertypic groups, DRw52 and DRw53, which together account for more than 80% of HLA-DR alleles. From the structural data, we conclude that these two groups represent distinct lineages which have followed different patterns of evolution. The fine structure of the β chain locus encoding the DRw53 specificity corresponds most closely to the DR βII pseudogene in the DRw52 haplotypes. Concomitantly, the DR βI locus in DRw53 haplotypes is more closely related to both of the two expressed DR β loci of theDRw5 haplotypes (DR βI and DR β III). These two loci are the result of a recent duplication. This leads to the proposal that both expressed DR β chain genes in the DRw52 haplotypes (DR βI and DR βIII) are derived from a single precursor locus, while the two loci expressed in the DRw53 haplotypes are derived from distinct ancestral loci. The genes encoding DRw52 and DRw53 are therefore not true alleles of the same original locus. A scheme is proposed that accounts for the evolution of DR specificities within the DRw52 and DRw53 groups of haplotypes. It is evident that the differentHLA-DR alleles are not structurally equidistant and that one must take into consideration different degrees of heterozygosity or mismatch among the DR alleles.
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  • 6
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The human HLA-DR3 haplotype consists of two functional genes (DRB1*03 and DRB3*01) and one pseudogene (DRB2), arranged in the order DRB1... DRB2... DRB3 on the chromosome. To shed light on the origin of the haplotype, we sequenced 1480 nucleotides of the HLA-DRB2 gene and aong stretches of two other genes, Gogo-DRB2 from a gorilla, “Sylvia” and Patr-DRB2 from a chimpanzee, “Hugo”. All three sequences (HLA-DRB2, Gogo-DRB2, Patr-DRB2) are pseudogenes. The HLA-DRB2 and Gogo-DRB2 pseudogenes lack exon 2 and contain a twenty-nucleotide deletion in exon 3, which destroys the correct translational reading frame and obliterates the highly conserved cysteine residue at position 173. The Patr-DRB2 pseudogene lacks exons 1 and 2; it does not contain the twenty-nucleotide deletion, but does contain a characteristic duplication of that part of exon 6 which codes for the last four amino acid residues of the cytoplasmic region. When the nucleotide sequences of these three genes are compared to those of all other known DRB genes, the HLA-DRB2 is seen as most closely related to Gogo-DRB2, indicating orthologous relationship between the two sequences. The Patr-DRB2 gene is more distantly related to these two DRB2 genes and whether it is orthologous to them is uncertain. The three genes are in turn most closely related to HLA-DRBVI (the pseudogene of the DR2 haplotype) and Patr-DRB6 (another pseudogene of the Hugo haplotype), followed by HLA-DRB4 (the functional but nonpolymorphic gene of the DR4 haplotype). These relationships suggest that these six genes evolved from a common ancestor which existed before the separation of the human, gorilla, and chimpanzee lineages. The DRB2 and DRB6 have apparently been pseudogenes for at least six million years (myr). In the human and the gorilla haplotype, the DRB2 pseudogene is flanked on each side by what appear to be related genes. Apparently, the DR3 haplotype has existed in its present form for more than six myr.
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  • 7
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The Daudi cell line is characterized by an absence of HLA antigen on its surface. This has been attributed to a lack of β2-microglobulin (β2M) while the heavy chain of HLA is present intracellularly. Karyotype analysis of Daudi cells has shown a deletion involving one of the β2-microglobulin alleles. It was generally believed that the absence of β2-microglobulin in that cell line resulted from an absence of expression of the remaining gene. We report here the unexpected finding of a normal amount of β2-microglobulin messenger RNA in Daudi cells. This was demonstrated by “Northern blot” hybridization with cDNA plasmid clones as a probe. This mRNA, however, when purified by hybridization-selection with β2-microglobulin plasmid DNA., is unable to function as messenger in protein synthesis and is therefore an inactive mRNA. The finding of a translationally inactive β2-microglobulin mRNA. provides a new explanation for the absence of β2-microglobulin and therefore of HLA antigens in Daudi cells.
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  • 8
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract HLA class 11 molecules were isolated from mouse L cells transfected with a DR α gene and an allele, 52a, of locus DR β III from an HLA-homozygous cell line, AVL, of the DR3 haplotype. The isolated molecules were found to possess a new allospecificity, named TR81. This specificity behaved allelic to the previously described DR β III locus. The TR81 specificity was also present on the DR β I gene product of the DR3 haplotype. The nucleotide sequence of the gene encoding TR81 differs from TR81-negative DR β genes of the DRw52 family in only two codons, both located in the regions known to be involved in a gene conversion event. Consequently, the following conclusions can be formulated. (a) TR81 is a bi-locus specificity and allelic to TR22 only in its DR β III locus localization. (b) The TR81 specificity is the phenotypic counterpart of the gene conversion event which led to the generation of the DR β I gene of the DR3 haplotype. (c) One or both individual amino acid substitutions in the first domain of the DR β chain are responsible for the TR81 allospecificity. (d) Since TR81 is expressed on the DR β I chain of the DR3 haplotype, it is possible that TR81 and DR3 represent the same serological specificity.
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  • 9
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract TheHLA-D region of the major histocompatibility complex (MHC) is characterized by a remarkable diversity. Most of theHLA class II genes are highly polymorphic, and in addition, the number and organization of individual loci in that region varies in different haplotypes. This extensive allelic polymorphism of immune response genes has well-known functional implications. Within theHLA-D region, two loci,DQA2 andDQB2 (formerly calledDXα andDXβ), represent a very special case: the detailed structure of these two genes is entirely compatible with expression, yet their expression has never been demonstrated in any tissue. Consequently, there exists no known corresponding protein product. Pseudogenes are known to accumulate mutations, as observed for instance in the case ofHLA-DPA2,-DPB2, or-DRB2 genes. We have therefore investigated the extent of DQ2 genes' polymorphism by DNA sequence comparison and by oligonucleotide hybridization across a large number of different haplotypes, and compared it with other genes in theHLA-D region. We show here that, contrary to the adjacentDQ1 genes,DQ2 genes exhibit little and possibly no polymorphism. This conservation ofDQ2 genes in many haplotypes indicates that the DQ 1-DQ2 duplication event must have preceeded the extensive diversification ofDQ1 genes and raises the puzzling question of whyDQ2 genes have remained nonpolymorphic. This suggests that either these genes correspond to an unusually invariant region of the MHC or they are under a strong selective pressure for the conservation of the amino acid sequence of a putative DQ2 gene product. The latter would imply that theHLA-DQ2 genes are expressed into a protein product endowed with essential functional properties.
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  • 10
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] A stretch of 200 kilobases (kb) of DNA from the I region of the mouse major histocompatibility complex has been cloned and characterized. It contains the genes for the biochemically defined class II proteins Eα, Eβ and Aβ. DNA blot analyses suggest ...
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