Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The DRB region of the human and great-ape major histocompatibility complex displays not only gene but also haplotype polymorphism. The number of genes in the human DRB region can vary from one to four, and even greater variability exists among the DRB haplotypes of chimpanzees, gorillas, and orangutans. Accumulating evidence indicates that, like gene polymorphism, part of the haplotype polymorphism predates speciation. In an effort to determine when the gene haplotype polymorphisms emerged in the primate lineage, we sequenced three cDNA clones of the New-World monkey, the cottontop tamarin (Saguinus oedipus). We could identify two DRB loci in this species, one (Saoe-DRB1) occupied by apparently functional alleles (*0101 and *0102) which differ by only two nucleotide substitutions and the other (Saoe-DRB2) occupied by an apparent pseudogene. The Saoe-DRB2 gene contains an extra sequence derived from the 3' portion of exon 2 and placed 5' to this exon. This sequence contains a stop codon which makes the translation of the bulk of the Saoe-DRB2 gene unlikely. Preliminary Southern blot hybridization analysis with probes derived from these two genes suggests that both the DRB gene polymorphism and the haplotype polymorphism in the cottontop tamarin may be low. In most individuals the DRB region of this species probably consists of three genes. Comparisons of the Saoe-DRB sequences with those of other primates suggest that probably all of the DRB genes found until now in the Catarrhini were derived from a common ancestor after the separation of the Catarrhini and Platyrrhini lineages. The extant DRB gene and haplotype polymorphism may therefore have been founded in the mid-Oligocene some 33 Mya.
Mol Biol Evol 1992 May
PMID:Major-histocompatibility-complex DRB genes of a New-World monkey, the cottontop tamarin (Saguinus oedipus). 158 11

The DRB family of human class II major histocompatibility complex (Mhc) loci is unusual in that individuals differ in the number and combination of genes (haplotypes) they carry. Indications are that both the allelic and haplotype polymorphisms of the DRB loci predate speciation. Searching for the evolutionary origins of these polymorphisms, we have sequenced five DRB clones isolated from a cDNA library of a pigtail macaque (Macaca nemestrina) B lymphocyte line. The clones represent five different genes which we designate Mane-DRB*01-Mane-DRB*05. The genes appears to be approximately equidistant from each other, so that allelic relationships between them cannot be established on the basis of the sequence data alone. If positions coding for the peptide-binding region of the class II beta chains are eliminated from sequence comparisons, the Mane-DRB genes appear to be most closely related to the human (HLA) DRB1 genes of the DRw52 group. We interpret this finding to indicate that the ancestral gene of the DRw52 group of human DRB1 alleles separated from the rest of the HLA-DRB1 alleles before the separation of the Old World monkeys (Cercopithecoidea) from the apes (Hominoidea) in the early Oligocene. After this separation, the ancestral DRB1 gene of the DRw52 group duplicated in the Old World monkey lineage to give rise to genes at three loci at least, while in the ape lineage this gene may have remained single and diverged into a number of alleles instead. These findings suggest that some of the polymorphism currently present at the DRB1 locus is greater than 35 Myr old.
Mol Biol Evol 1991 Sep
PMID:Mhc-DRB genes of the pigtail macaque (Macaca nemestrina): implications for the evolution of human DRB genes. 176 59

In placental mammals, the class II region of the major histocompatibility complex (Mhc) consists of several gene families which show orthologous relationships in the different species. As these families are not orthologous with the Mhc class II beta-chain-encoding gene families of birds, the different mammalian families must have diverged after the separation of birds and mammals approximately 250 Mya but before the radiation of placental mammals (60-80 Mya). To obtain further information about the origin of the class II genes in mammals, we studied the beta-chain-encoding genes of the wallaby as a representative of marsupials, which split from placental mammals approximately 125 Mya. Three beta-chain-encoding genes were isolated from a red-necked wallaby (Macropus rufogriseus) cDNA library by using a chimpanzee DRB probe, and their nucleotide sequences were determined. The genes are not orthologous to any of the genes in mammals studied thus far but belong to two new families which we designated Maru-DAB and Maru-DBB. One of the three sequences (DAB2) seems to be derived from a transcribed pseudogene; it lacks the codons specifying the first 51 amino acid residues of the beta 2 domain. The fact that the DAB and DBB families have thus far not been found in placental mammals and that none of the DOB, DPB, DQB, or DRB genes seems to be expressed in the one representative marsupial species can be interpreted as suggesting that class II gene families of eutherian and metatherian mammals evolved from different ancestral genes.
Mol Biol Evol 1991 Nov
PMID:MHC class II genes of a marsupial, the red-necked wallaby (Macropus rufogriseus): identification of new gene families. 177 63

Study of the MHC class II region is complicated by strong linkage disequilibrium between DR and DQ. Comparison of DR-DQ haplotypes between different races partly resolves this problem. We present the results of an analysis of DRB, DQA and DQB restriction fragment length polymorphisms in serologically DR-typed subjects of Negroid origin. Clearly distinguishable DRB RFLPs were observed for DR1,2,5,7 and w8. DR4,9 and w10 were uncommon in this group. DR3 was associated with two extended haplotypes, one characterised by the DQw4 allele, the other by the DQw2 allele. A recently recognised DQB RFLP (DQB 2c) was associated with DR7 and also occurred on DR5 and DR9 haplotypes. Both DR5 and DRw6 were heterogeneous in their DR-DQ relationships. Negroid subjects exhibit DR-DQ relationships distinct from other races. These provide scope for further study of MHC class II associations with disease.
Mol Immunol 1990 Mar
PMID:Analysis of MHC class II DNA polymorphisms in Negroid subjects. 197 22

Two new allelic exon-2 HLA-DRB sequences have been identified by using universal and also specific DRB primers. They may correspond to a previously unidentified DRB gene (DRB sigma) and define a new supratypic group ("DRw54") which includes DR1, DR"Br", DR2 and DRw10 bearing HLA haplotypes. This is probably the last HLA-DRB gene to be described in the standard DR haplotypes on the bases of the number of TaqI RFLPs obtained. Sequence comparison with their respective DP and DQ sequences shows that DRB sigma is unequivocally placed within the DRB family and also a constructed "neighbouring homology tree" indicates that DRB sigma gene is probably the eldest in the DRB family, thus the first to diverge from the ancestral DRB gene. An hypothetically deduced DRB sigma beta 1 protein domain was found to be quite different from the corresponding DRB1, DRB3, DRB4 and DRB5 products, since residues 40-55 would bear a longer alpha-helical conformation and would also exist a loss of both the extended conformation at residues 50-54 and the alpha-helix at residues 64-71. Thus, the putative DRB sigma protein would be remarkably different to other DRB ones. Also, a DRB sigma partial transcript (exon-2) has been obtained by PCR of cDNA by using specific DRB sigma oligonucleotides, but a specific Northern blot hybridization has not been achieved.
Mol Immunol
PMID:Exon-2 nucleotide sequences, polymorphism and haplotype distribution of a new HLA-DRB gene: HLA-DRB sigma. 206 26

To determine the role of DRB in transcription, we isolated a resistant (DRBR) HeLa cell mutant. After mutagenesis with N-methyl-N'-nitro-nitrosoguanidine, cell colonies able to grow at 20 micrograms DRB/ml (63 microM) were selected. One of these colonies, DRBR-1, was stable and able to grow at concentrations of DRB three to five times higher than tolerated by normal HeLa cells. The DNA of DRBR-1 was able to confer resistance to DRB to other HeLa cells by transfection. Uridine uptake was reduced by DRB to a similar extent in both wild-type and mutant cells. In contrast, transcription in the mutant cells, as measured by [3H]uridine incorporation into RNA in short pulses, was resistant to DRB. Cell-free extracts prepared from DRBR-1 cells are able to transcribe the epsilon-globin or the adenovirus 2 major late promoter genes at DRB concentrations that eliminate the transcriptional activity of HeLa cell extracts. Thus the transcriptional machinery of the mutant is altered. The presence of both DRB-resistant and DRB-sensitive transcriptional activities in extracts from DRBR-1 cells, grown in the presence of the drug, suggests constitutive expression of this cellular component. Efficient somatic cell hybridization with an alpha-amanitin-resistant RNA polymerase II mouse mutant indicates cross-complementation in vivo. This DRBR mutant provides a useful tool for the biochemical analysis of the mechanism of action of DRB on transcription. It also serves as a genetic handle for selection of the gene responsible for DRB resistance.
J Mol Biol 1983 Apr 15
PMID:Mechanism of action of 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole. II. A resistant human cell mutant with an altered transcriptional machinery. 618 48

5,6-Dichloro-1-beta-D-ribofuranosylbenzimidazole, an adenosine analogue, has been used previously as an inhibitor of heterogeneous nuclear and messenger RNA synthesis. In an in vitro transcriptional system, we have detected inhibition of synthesis of full-length runoff RNAs at concentrations at which in vivo mRNA synthesis is inhibited. By hybridization of RNA synthesized in vitro to single-stranded DNA and gel analysis, we were able to reduce the background of the transcription reaction, detect DRB-induced inhibition of full-length runoff RNAs and DRB-insensitive transcription of short RNAs. To establish further the effect of DRB on initiation of transcription, preincubation experiments with template, whole cell extract and two initial nucleotides of the transcript were performed. Elongation was then measured as discrete-sized RNAs transcribed from the truncated template after addition of the other triphosphates (one of them labeled), in the presence or absence of DRB. An effect on initiation but not on elongation or termination was detected. Fingerprint analysis of these runoff RNAs indicates that the labeling of U in the presence of DRB is uniform throughout the molecule. A model to explain a novel interpretation of the action of DRB is presented.
J Mol Biol 1983 Jul 05
PMID:Mechanism of action of DRB. III. Effect on specific in vitro initiation of transcription. 687 57

Exon 2 sequences of an expressed MHC-DRB locus from sheep were examined for polymorphisms in both the antigen-binding regions and the adjacent intronic mixed simple tandem repeat. Twenty-one novel exon 2 Ovar-DRB alleles were identified. Short nucleotide motifs are extensively shared between certain exon 2 regions of Ovar-DRB alleles. The simple repeat variations, the number of different amino acids at usually polymorphic sites, and the number of silent substitutions were reduced in the intraspecies analyses of sheep DRB sequences, compared with those of cattle and goats. It was paradoxical that the abundance of different sheep alleles was similar to that of cattle and goats. This paradox may be explained by postulating a relatively small number of "ancient" alleles, with the present-day Ovar-DRB alleles being generated by reciprocal exchange of nucleotide motifs. At the antigen-binding sites, new combinations of amino acids were maintained in Ovar-DRB alleles by strong positive selection. In sheep--and less pronounced in goats and cattle--the DRB alleles can be divided into two groups. In one group, silent substitutions are increased when compared with the other. This suggests separate evolutionary pathways for certain groups of DRB alleles within a species. The simple repetitive sequences are also discussed with respect to the evolution of DRB alleles.
Mol Biol Evol 1994 Mar
PMID:Interdependent MHC-DRB exon-plus-intron evolution in artiodactyls. 817 Mar 65

An efficient oligonucleotide typing method for the highly polymorphic MHC-DRB genes is described for artiodactyls like cattle, sheep and goat. By means of the polymerase chain reaction, the second exon of MHC-DRB is amplified as well as part of the adjacent intron containing a mixed simple repeat sequence. Using this primer combination we were able to amplify the MHC-DRB exons 2 and adjacent introns from all of the investigated 10 species of the family of Bovidae and giraffes. Therefore, the DRB genes of novel artiodactyl species can also be readily studied. Oligonucleotide probes specific for the polymorphisms of ungulate DRB genes are used with which sequences differing in at least one single base can be distinguished. Exonic polymorphism was found to be correlated with the allele lengths and the patterns of the repeat structures. Hence oligonucleotide probes specific for different simple repeats and polymorphic positions serve also for typing across species barriers. The strict correlation of sequence length and exonic polymorphism permits a preselection of specific oligonucleotides for hybridization. Thus more than 20 alleles can already be differentiated from each of the three species.
Mol Ecol 1993 Feb
PMID:Typing of artiodactyl MHC-DRB genes with the help of intronic simple repeated DNA sequences. 818 Jul 32

Twenty-one different caprine and 13 ovine MHC-DRB exon 2 sequences were determined including part of the adjacent introns containing simple repetitive (gt)n(ga)m elements. The positions for highly polymorphic DRB amino acids vary slightly among ungulates and other mammals. From man and mouse to ungulates the basic (gt)n(ga)m structure is fixed in evolution for 7 x 10(7) years whereas ample variations exist in the tandem (gt)n and (ga)m dinucleotides and especially their "degenerated" derivatives. Phylogenetic trees for the alpha-helices and beta-pleated sheets of the ungulate DRB sequences suggest different evolutionary histories. In hoofed animals as well as in humans DRB beta-sheet encoding sequences and adjacent intronic repeats can be assembled into virtually identical groups suggesting coevolution of noncoding as well as coding DNA. In contrast alpha-helices and C-terminal parts of the first DRB domain evolve distinctly. In the absence of a defined mechanism causing specific, site-directed mutations, double-recombination or gene-conversion-like events would readily explain this fact. The role of the intronic simple (gt)n(ga)m repeat is discussed with respect to these genetic exchange mechanisms during evolution.
J Mol Evol 1993 Sep
PMID:The paradox of MHC-DRB exon/intron evolution: alpha-helix and beta-sheet encoding regions diverge while hypervariable intronic simple repeats coevolve with beta-sheet codons. 823 Feb 50


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