33 results on '"HLA-DR beta-Chains"'
Search Results
2. Antinuclear antibodies and HLA class II alleles in Jamaican patients with systemic lupus erythematosus.
- Author
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Christian N, Smikle MF, DeCeulaer K, Daniels L, Walravens MJ, and Barton EN
- Subjects
- Adolescent, Adult, Aged, Case-Control Studies, Counterimmunoelectrophoresis, Female, HLA-DR beta-Chains, HLA-DRB3 Chains, Humans, Jamaica epidemiology, Lupus Erythematosus, Systemic epidemiology, Male, Middle Aged, Prevalence, Risk Factors, Antibodies, Antinuclear analysis, Genes, MHC Class II genetics, HLA-DR Antigens genetics, Lupus Erythematosus, Systemic genetics
- Abstract
Objective: The relationship between human leukocyte antigens class II (HLA) and antinuclear antibodies was investigated in Jamaican patients with Systemic Lupus Erythematosus (SLE)., Methods: Samples of blood of 82 patients with SLE and 75 healthy controls were tested for antinuclear antibodies using the fluorescent antinuclear antibody (FANA) test, counterimmunoelectrophoresis (CIEP) and the Crithidia luciliae immunofluorescence test (CL-IFT). A DNA-based HLA typing method was used to determine the frequencies of alleles of HLA-DRB1, DRB3, DRB4 and DRB5 in patients and healthy controls., Results: The FANA test was positive in all of the sera from patients with SLE. Anti-dsDNA antibodies were present in 49% (40/82), anti-Sm/RNP 44% (36/82) and anti-Ro/La 43% (35/82) of the sera from SLE patients. The frequency of HLA-DR4 was significantly lower in SLE patients than in healthy controls (2/82, 2% vs 15/75, 20%; RR = 0.12; p = 0.0004; CP = 0.005) but no other HLA-DRB1 SLE associations were found. A positive HLA-DR3 anti-Ro/La antibody association was found in the patients with SLE (9/21, 43% vs 5/55, 9%; odds ratio (OR) = 7.5; CP = 0.01). In contrast, possession of HLA-DR6 was negatively associated with the absence of anti-dsDNA antibodies (9/32, 28% vs 27/44, 61%; OR = 0.2; CP = 0.05)., Conclusion: The HLA-DR6 allele is associated with the absence of antinuclear antibodies and HLA-DR3 with the presence of anti-Ro/La antibodies in Jamaican patients with SLE. However, these results and those of previous studies of Jamaican patients suggest that the HLA-DR3 association with the development of SLE reported in other populations might in fact reflect the association of HLA-DR3 with anti-Ro/La antibodies. Further investigations are needed to determine whether HLA-DRB antinuclear antibody associations define clinical subsets of SLE in Jamaican patients.
- Published
- 2007
- Full Text
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3. HLA class II DRB high resolution genotyping by pyrosequencing: comparison of group specific PCR and pyrosequencing primers.
- Author
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Ringquist S, Alexander AM, Styche A, Pecoraro C, Rudert WA, and Trucco M
- Subjects
- Base Sequence, Cell Line, Cloning, Molecular, DNA chemistry, DNA genetics, DNA isolation & purification, DNA Primers genetics, Genotype, HLA-DR beta-Chains, HLA-DRB1 Chains, HLA-DRB3 Chains, HLA-DRB4 Chains, HLA-DRB5 Chains, Heterozygote, Histocompatibility Antigens Class II genetics, Humans, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Linear Models, Molecular Sequence Data, Polymerase Chain Reaction, Polymorphism, Genetic genetics, Sequence Homology, Nucleic Acid, HLA-DR Antigens genetics, Sequence Analysis, DNA methods
- Abstract
Sequencing of alleles of the highly polymorphic, multiple loci HLA-DRB gene family was performed by pyrosequencing using purified DNA from the 11(th) International Histocompatibility Workshop human lymphoblastiod cell lines as well as genomic DNA isolated from blood samples obtained from healthy adult volunteers. Genomic DNA was prepared from donors whose blood had been stored either frozen or as dried blood spots. Pyrosequence-based typing was optimized for identifying alleles of the HLA-DRB1, -3, -4, and -5 genes. The procedure should be applicable to other HLA loci including the class I genes HLA-A and -B that, along with HLA-DRB, are crucial for histocompatibility matching of tissue antigens during transplantation. Computer simulation of pyrosequencing data suggest that alleles of HLA-DRB1, -3, -4, and -5 were readily identifiable by pyrosequencing as were their heterozygous allelic combinations. Pyrosequencing primers were designed to specifically sequence HLA loci of interest even in a background of other amplified, closely related sequences such as alleles of the pseudogene HLA-DRB6, -7, -8, and -9. Polymorphic residues of HLA-DRB genes were identified within each pyrosequencing reaction, obtained by 50 to 70 nucleotide read lengths. Heterozygous allelic combinations of HLA genes were analyzed and compared successfully to genotyping of alleles by sequence-specific oligonucleotide probe hybridization as well as allele specific polymerase chain reaction protocols. Pyrosequence-based typing is compatible with genotyping of allelic combinations expected from heterozygous individuals, resulting in nucleotide resolution of the highly polymorphic HLA system. Using a single pyrosequence instrument, complete typing of HLA-DRB genes can be performed daily on hundreds of individuals for high resolution histocompatibility genotyping studies.
- Published
- 2004
- Full Text
- View/download PDF
4. Complete cDNA sequences of the DRB6 gene from humans and chimpanzees: a possible model of a stop codon readingthrough mechanism in primates.
- Author
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Moreno-Pelayo MA, Fernández-Soria VM, Paz-Artal E, Ferre-López S, Rosal M, Morales P, Varela P, and Arnaiz-Villena A
- Subjects
- 3' Untranslated Regions, Alleles, Amino Acid Sequence, Animals, Base Sequence, Cell Line, Computer Simulation, DNA Primers genetics, DNA, Complementary chemistry, HLA-DR beta-Chains, Humans, Models, Molecular, Molecular Sequence Data, Nucleic Acid Conformation, Primates genetics, Primates immunology, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Species Specificity, Codon, Terminator genetics, DNA, Complementary genetics, HLA-DR Antigens genetics, Models, Genetic, Pan troglodytes genetics, Pan troglodytes immunology
- Abstract
The defective major histocompatibility complex (MHC) DRB6 gene is transcribed into mRNA in human [peripheral blood lymphocytes, transfected and Epstein-Barr virus (EBV)] and chimpanzee EBV cell lines. MHC-DRB6 presents several anomalies, which include stop codons in exon 2, lack of the usual polyadenilation signal of other MHC-DRB genes, and a promoter region and exon 1 taken from a locally inserted retrovirus. The complete cDNA sequences from human DRB6*0201 and three common chimpanzee alleles (Patr-DRB6*0108, Patr-DRB6*0109, Patr-DRB6*0111) have been obtained; two exon 1-exon 2 cDNA sequences from bonobos (Papa-DRB6*0101 and Papa-DRB6*0102) are also shown. In contrast to chimpanzee DRB6 transcripts, the human ones: (1) present an exon 1-exon 2 splicing site that includes the transcription of the first 141 nucleotides of intron 1, rendering a longer exon 1, and (2) show a duplication of exon 6, which would render a longer cytoplasmic tail in a putative DRB6 protein. These two characteristics are found in all the human sequences obtained, regardless of the cellular type tested, and they are not present in any of the chimpanzee alleles reported; consequently, they are human-specific. All the alleles reported here bear stop codons in the three possible reading frames; however, a certain level of expression of DRB6 has been observed by cytofluorometry. This could be due to the presence of a selenocysteine insertion sequence (SECIS) stem-loop structure located at the 3 untranslated region of the DRB6 mRNA, which directs selenocysteine incorporation at UGA codons. DRB6 transcription and translation would be the first gene model of a readingthrough stop codon mechanism in primate MHC. It is also feasible that the DRB6 gene might generate a population of short polypeptides, bound to plasmatic membranes, having non-antigen-presenting functions or which are presented by other MHC molecules as HLA-E presents HLA-G and -B leader sequence-derived peptides.
- Published
- 1999
- Full Text
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5. Transcription and weak expression of HLA-DRB6: a gene with anomalies in exon 1 and other regions.
- Author
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Fernandez-Soria VM, Morales P, Castro MJ, Suarez B, Recio MJ, Moreno MA, Paz-Artal E, and Arnaiz-Villena A
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, DNA, Complementary, Exons, Gene Expression, HLA-DR beta-Chains, Humans, L Cells, Mice, Molecular Sequence Data, RNA Processing, Post-Transcriptional, RNA, Messenger metabolism, Transfection, HLA-DR Antigens genetics, Transcription, Genetic
- Abstract
HLA-DRB6 is one of the human major histocompatibility complex (MHC) genes present in DR1, DR2, and DR10 haplotypes (approximately 26% of individuals). It shows several anomalies in human and non-human primates, including exon 2 stop codons (non-randomly grouped between codons 74 and 94) and a promoter region, and an exon 1 coming from an inserted retrovirus. It has been shown that not only chimpanzee but also human Mhc-DRB6 lack the usual 3' untranslated (UT) polyadenylation signal, and in the present work it was found that the human DRB6 gene coming from an HLA-DR2 haplotype is effectively transcribed after transfection in mouse L cells, and that HLA-DRB6 molecules may be expressed on the cell surface. DRB6 transcription level is remarkably lower in human than in chimpanzee. Moreover, their exons 1 (both taken from the 3'LTR region of a mammary tumor retrovirus) are also different; this shows that these viral insertions may be an important mechanism for different evolutionary changes in orthologous genes of different species. The pathways by which DRB6 molecules may be expressed on the membrane are unclear but other examples of truncated protein expression have also been described, even within the human major histocompatibility complex (i. e., in HLA-G). Finally, the presence of mature HLA-DRB6 mRNA molecules supports the notion that splicing may take place even in the absence of a canonical 3'UT polyadenylation signal.
- Published
- 1998
- Full Text
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6. Complex origin of the HLA-DR10 haplotype.
- Author
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Gongora R, Figueroa F, and Klein J
- Subjects
- Base Sequence, Cell Line, Transformed, Cloning, Molecular, HLA-DR beta-Chains, HLA-DRB1 Chains, HLA-DRB3 Chains, HLA-DRB4 Chains, HLA-DRB5 Chains, Humans, Introns, Molecular Sequence Data, Phylogeny, Genes, MHC Class II, HLA-DR Antigens genetics, Haplotypes
- Abstract
The region of the HLA complex occupied by the DRB genes has undergone many rearrangements in the course of primate evolution. The rearrangements have produced a number of haplotypes differing from one another in the number and composition of the DRB genes. Some of the rearrangements also affected the DRB genes themselves. Selective intron sequencing has revealed the DR10 haplotype to be composed of at least three segments, each of different origin. The haplotype carries three DRB genes (gene fragments): DRB1*10, DRB6, and DRB9. The 5' end of the DRB1*10 gene, from the promoter region to a site in intron 1 approximately 500 bp from the beginning of exon 2, is derived from a DRB1*03-like gene. The segment of the DR10 haplotype encompassing the rest of the DRB1*10 gene and extending to the region between the DRB1 and DRB6 genes is of independent origin; it diverged from other DRB genes (DRB1*01 and DRB1*03) approximately 30 million years ago. Finally, the third segment encompassing the remainder of the DR10 haplotype is derived from a DR1-like haplotype. Since the functional part of the DR10 haplotype is of independent origin, there is little justification for the currently common practice of placing the haplotype together with DR1 in the group of DR1 haplotypes. The rearrangements in the DR haplotypes may constitute one of several mechanisms for increasing diversity at the DRB loci. The region of high instability seems to be flanked by conservatively evolving regions.
- Published
- 1997
7. New HLA-DR haplotypes containing the DRB6 pseudogene.
- Author
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Salazar M, Granja CB, Selvakumar A, Fresia B, Alosco S, Dupont B, and Yunis EJ
- Subjects
- HLA-DR beta-Chains, Humans, Polymerase Chain Reaction, HLA-DR Antigens genetics, Haplotypes, Pseudogenes
- Abstract
An unexpected probe reaction pattern was observed in two samples during HLA-DR typing by PCR-Sequence Specific Oligonucleotide Probes. In order to confirm the unusual typings, samples were analyzed by PCR-Sequence Specific Primers, cloning, and nucleotide sequencing of the second exon of the HLA-DRB-genes. The confirmed DR, DQ phenotype for one sample was DRB1*0701, DRB4*01, DRB5*0101, DRB6*0201, DQB*0602, DQB1*0202. The phenotype of other sample was DRB1*1602, DRB1*1302, DRB3*0301, DRB6*0101, DQB1*0501, DQB1*0502. The first sample has the novel combination of DRB1*0701 with DRB5*0101 and DRB6*0201. The second sample has either DRB6*0101 together with DRB1*1602 in absence of any DRB5 allele or DRB6*0101 together with DRB1*1302, DRB3*0301. We postulate that the most likely haplotype in sample #1 is DRB1*0701; DRB5*0101, DRB1*0602 which could have arisen from gene conversion. The most likely haplotype in sample #2, DRB1*1602, DRB6*0101, DQB1*0502 would have arisen from an homologous recombination event.
- Published
- 1996
- Full Text
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8. Ancestral major histocompatibility complex DRB genes beget conserved patterns of localized polymorphisms.
- Author
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Gaur LK and Nepom GT
- Subjects
- Animals, Base Sequence, Conserved Sequence, DNA Primers, Exons, Galago, Genetic Variation, HLA-DR beta-Chains, HLA-DRB1 Chains, Humans, Lemur, Macaca, Molecular Sequence Data, Papio, Polymerase Chain Reaction, Primates, Sequence Deletion, Sequence Homology, Nucleic Acid, Biological Evolution, HLA-DR Antigens genetics, Polymorphism, Genetic
- Abstract
Genes within the major histocompatibility complex (MHC) are characterized by extensive polymorphism within species and also by a remarkable conservation of contemporary human allelic sequences in evolutionarily distant primates. Mechanisms proposed to account for strict nucleotide conservation in the context of highly variable genes include the suggestion that intergenic exchange generates repeated sets of MHC DRB polymorphisms [Gyllensten, U. B., Sundvall, M. & Erlich, H. A. (1991) Proc. Natl. Acad. Sci. USA 88, 3686-3690; Lundberg, A. S. & McDevitt, H. 0. (1992) Proc. Natl. Acad. Sci. USA 89, 6545-6549]. We analyzed over 50 primate MHC DRB sequences, and identified nucleotide elements within macaque and baboon DRB6-like sequences with deletions corresponding to specific exon 2 hypervariable regions, which encode a discrete alpha helical segment of the MHC antigen combining site. This precisely localized deletion provides direct evidence implicating segmental exchange of MHC-encoded DRB gene fragments as one of the evolutionary mechanisms both generating and maintaining MHC diversity. Intergenic exchange at this site may be fundamental to the diversification of immune protection in populations by permitting alteration in the specificity of the MHC that determines the repertoire of antigens bound.
- Published
- 1996
- Full Text
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9. Primate DRB6 gene expression and evolution: a study in Macaca mulatta and Cercopithecus aethiops.
- Author
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Paz-Artal E, Corell A, Varela P, Martinez-Laso J, Gomez-Casado E, Fernandez-Soria VM, Moreno MA, and Arnaiz-Villena A
- Subjects
- Animals, Base Sequence, Cell Line, Chlorocebus aethiops, Gorilla gorilla, HLA-DR Antigens biosynthesis, HLA-DR beta-Chains, Humans, Macaca mulatta, Molecular Sequence Data, Pan troglodytes, Pongo pygmaeus, Evolution, Molecular, Gene Expression immunology, Genes, MHC Class II immunology, HLA-DR Antigens genetics
- Abstract
DRB6 has been found to be transcribed in human and apes. Promoter region and exon 1 come from a 5' LTR from a mammary tumour retrovirus. However, the putative protein structure would be very different to other DR molecules and it is doubtful that it may function as an antigen presenting molecule. Primate DRB6 alleles previously published together with the two new macaque sequences reported here support the existence of a strong selective pressure working on exon 2 to generate stop codons at the end of the exon (between codons 74 and 94) during at least 23 million years. The topology of dendrograms constructed with different primate DRB6 alleles supports the "trans-species" evolution proposed for MHC class I, class II and possibly C4 genes. Finally, DRB6, which is one of the oldest DRB genes, has been lost in the HLA-DRB3 (or DR52) group of haplotypes (DR3, DR5, DR6 and DR8) and a small DRB6 sequence is present at the exon 2 first hypervariable region of DRB4 (or DR53) gene, which is present in DR4, DR7 and DR9 haplotypes.
- Published
- 1996
- Full Text
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10. Resolution of the HLA-DRB6 puzzle: a case of grafting a de novo-generated exon on an existing gene.
- Author
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Mayer WE, O'hUigin C, and Klein J
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Biological Evolution, Exons, Gene Expression Regulation, HLA-DR beta-Chains, Humans, Macaca mulatta genetics, Molecular Sequence Data, Open Reading Frames, Pan troglodytes genetics, Polymerase Chain Reaction, Promoter Regions, Genetic, Proviruses genetics, RNA, Messenger genetics, Repetitive Sequences, Nucleic Acid, Retroviridae genetics, Sequence Alignment, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Transcription, Genetic, Genes, MHC Class II, HLA-DR Antigens genetics
- Abstract
HLA-DRB6, one of the human major histocompatibility complex genes, lacks exon 1, which normally codes for the leader and the first four amino acid residues of the mature protein. Because it also lacks the HLA promoter, it was surprising to find that the gene is transcribed at a low level in a chimpanzee B-lymphoblastoma cell line, in which the DRB6 homolog is truncated as in humans. The study designed to resolve the paradox has revealed that a retrovirus related to the mouse mammary tumor viruses was inserted into intron 1 of DRB6 > 23 million years ago. The insertion was either accompanied or followed by the deletion of exon 1 and the promoter region of DRB6. In the 3' long terminal repeat of the retrovirus, however, an open reading frame for a new exon arose, which codes for a sequence of mostly hydrophobic amino acid residues; the sequence could function as a leader for the truncated DRB6 gene. This new exon has a functional donor splice site at its 3' end, which enables it to be spliced in register with DRB6 exon 2. Upstream from the new exon is a promoter enabling transcription of the DRB6 gene. Besides providing an example of a de novo generation of an exon, the study suggests a potential mechanism for generating new genes through the replacement of old exons with newly generated ones.
- Published
- 1993
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11. The HLA-DRB6*0201 allele of a pseudogene commonly associated with HLA-DR2 specificities is present in an HLA-DRB1*0101-DRB5*0101 haplotype.
- Author
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Fischer GF, Fae I, and Pickl WF
- Subjects
- Adult, Base Sequence, Child, Female, HLA-DR beta-Chains, HLA-DRB1 Chains, Humans, Male, Molecular Sequence Data, Oligodeoxyribonucleotides, Polymorphism, Restriction Fragment Length, HLA-DR Antigens genetics, HLA-DR2 Antigen genetics, Haplotypes, Histocompatibility Antigens Class II genetics, Pseudogenes
- Published
- 1993
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12. A study of DR2-LUM haplotype generation and the DRB6*0202 linkage to DRB1*1601.
- Author
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Corell A, Varela P, Morales P, Paz-Artal E, Martínez-Laso J, Martín-Villa JM, du Toit E, and Arnaiz-Villena A
- Subjects
- Cell Line, Cell Transformation, Viral, Cloning, Molecular, Genetic Linkage, HLA-DR beta-Chains, HLA-DRB1 Chains, Histocompatibility Antigens Class II genetics, Humans, Leukocytes, Molecular Sequence Data, Polymerase Chain Reaction, Recombination, Genetic, Sequence Analysis, DNA, Exons genetics, HLA-DR Antigens genetics, HLA-DR2 Antigen genetics, Haplotypes genetics
- Published
- 1993
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13. Allelic diversity at the primate major histocompatibility complex DRB6 locus.
- Author
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Corell A, Morales P, Varela P, Paz-Artal E, Martin-Villa JM, Martinez-Laso J, and Arnaiz-Villena A
- Subjects
- Alleles, Animals, Base Sequence, Biological Evolution, HLA-DR beta-Chains, Humans, Molecular Sequence Data, Polymorphism, Genetic, Genes, MHC Class II, HLA-DR Antigens genetics, Major Histocompatibility Complex, Primates genetics
- Abstract
The HLA-DRB6 gene (also called DRB sigma/V1) has been found only in about 26% of human HLA haplotypes, i.e.; DR1, DRw10, and DR2-bearing ones (Corell et al. 1991). In contrast, exon-2 DRB6 sequences have been obtained from all tested primates: nine chimpanzees (Pan troglodytes), three gorillas (Gorilla gorilla) and three orangutans (Pongo pygmaeus); other apes which had already been sequenced (one gorilla and one chimpanzee) also had the DRB6 gene. Thus, all apes tested from three different species, some of them evolutionary separated by at least 14-16 million years, bear the DRB6 gene. In addition, more than one gene copy per haplotype has been found in one chimpanzee; this, together with the apparent loss of this gene in some of the human DR haplotypes, may indicate that the DR genome has undergone evolutionary changes more recently and more actively than class I or III genes. In addition, ten different and presumably allelic DRB6 exon-2 sequences have been obtained, and some of them coming from different species are more similar to each other than the one from the same species; this finding goes in favor of the trans-species theory of major histocompatibility complex polymorphism generation. Also, data are presented supporting that DRB6 may be one of the eldest genes of the DRB family, thus one of the first to diverge from the ancestral DRB gene.
- Published
- 1992
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14. Gorilla major histocompatibility complex-DRB pseudogene orthologous to HLA-DRBVIII.
- Author
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Klein D, Vincek V, Kasahara M, Schönbach C, O'hUigin C, and Klein J
- Subjects
- Animals, Base Sequence, Biological Evolution, Cell Line, Cosmids, DNA analysis, DNA isolation & purification, Exons genetics, Gorilla gorilla, HLA-DR beta-Chains, Molecular Sequence Data, Oligonucleotide Probes, Pan troglodytes, Sequence Homology, Nucleic Acid, HLA-DR Antigens genetics, HLA-DR4 Antigen genetics, Histocompatibility Antigens genetics, Pseudogenes
- Abstract
The HLA-DR4 haplotype consists of four DRB genes: DRB1*04, DRBVII, DRBVIII, and DRB4*01, arranged in this order on the chromosome. The DRB1 and DRB4 genes code for beta chains of the alpha beta heterodimers expressed on the cell surface and bearing the HLA-DR4 and HLA-DRw53 determinants, respectively; the DRBVII and DRBVIII are pseudogenes. We found and sequenced a gene closely related to HLA-DRBVIII in the genome of the lowland gorilla "Sylvia." We designate this gene Gogo-DRB8. The close relationship between the two genes is indicated by the overall sequence similarity, the absence of recognizable exons 1 and 2 in both genes, the presence of two Alu repeats at corresponding positions, and high sequence similarity between corresponding repeats. The comparison with an outgroup (tamarin) gene and the functional counterparts of the DRB8 gene indicate that DRB8 emerged between 18 and 26 million years ago and became inactivated at the same time as or shortly after its creation. Hence DRB8 has probably existed as a pseudogene since the divergence of apes from Old World monkeys more than 20 million years ago.
- Published
- 1991
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15. The HLA-DRB6 locus defines an evolutionary supratypic group within the DRB family of genes.
- Author
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Corell A, Martin-Villa JM, Morales P, de Juan MD, Vicario JL, Martínez-Laso J, Varela P, and Arnaiz-Villena A
- Subjects
- Base Sequence, DNA blood, DNA genetics, HLA-DR beta-Chains, Haplotypes, Homozygote, Humans, Molecular Sequence Data, Polymerase Chain Reaction methods, Polymorphism, Restriction Fragment Length, Sequence Homology, Nucleic Acid, Biological Evolution, Genes, MHC Class II, HLA-DR Antigens genetics, Multigene Family
- Abstract
A novel DRB gene member has recently been identified (DRB6). It defines a new supratypic group of HLA-DR alleles comprising the DR1-, DR2-, and DRw10-carrying haplotypes. The comparison of this gene either at the nucleotide or at the protein level with other HLA-DRB genes supports its inclusion in the DRB gene family and not in DPB or DQB gene families. Moreover, the construction of an evolutionary gene-tree shows that this gene is probably the eldest member of the DRB gene family. Contradictory expression results do not clarify whether or not DRB6 is a pseudogene.
- Published
- 1991
- Full Text
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16. Co-regulated expression of alpha and beta mRNAs encoding HLA-DR surface heterodimers is mediated by the MHCII RNA operon
- Author
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Giovanna Del Pozzo, Donatella Malanga, Laura Pisapia, Antonella Maffei, Russell S. Hamilton, Pasquale Barba, and Valeria Cicatiello
- Subjects
DNA, Complementary ,Transcription, Genetic ,Operon ,HLA-DR beta-Chains ,HLA-DR alpha-Chains ,RNA-binding protein ,Biology ,Biochemistry ,Endocrinology ,Transcription (biology) ,Cell Line, Tumor ,HLA-DRA ,Genetics ,Humans ,RNA, Messenger ,Nucleotide Motifs ,RNA Processing, Post-Transcriptional ,Nuclear Factor 90 Proteins ,HLA-DR Antigen ,Adaptor Proteins, Signal Transducing ,Ribonucleoprotein ,Regulation of gene expression ,Models, Genetic ,RNA-Binding Proteins ,RNA ,HLA-DR Antigens ,Molecular biology ,Gene Expression Regulation ,Ribonucleoproteins ,FOS: Biological sciences ,Protein Multimerization ,5' Untranslated Regions - Abstract
Major histocompatibility complex class II (MHCII) molecules are heterodimeric surface proteins involved in the presentation of exogenous antigens during the adaptive immune response. We demonstrate the existence of a fine level of regulation, coupling the transcription and processing of mRNAs encoding α and β chains of MHCII molecules, mediated through binding of their Untraslated Regions (UTRs) to the same ribonucleoproteic complex (RNP). We propose a dynamic model, in the context of the ‘MHCII RNA operon’ in which the increasing levels of DRA and DRB mRNAs are docked by the RNP acting as a bridge between 5′- and 3′-UTR of the same messenger, building a loop structure and, at the same time, joining the two chains, thanks to shared common predicted secondary structure motifs. According to cell needs, as during immune surveillance, this RNP machinery guarantees a balanced synthesis of DRA and DRB mRNAs and a consequent balanced surface expression of the heterodimer.
- Published
- 2013
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17. Complete cDNA sequences of the DRB6 gene from humans and chimpanzees: a possible model of a stop codon readingthrough mechanism in primates
- Author
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V Fernández-Soria, Antonio Arnaiz-Villena, Manuel Cobo del Rosal, Pablo Morales, S. Ferre-Lopez, Pilar Varela, M A Moreno-Pelayo, and Estela Paz-Artal
- Subjects
Models, Molecular ,Primates ,DNA, Complementary ,Pan troglodytes ,HLA-DR beta-Chains ,Molecular Sequence Data ,Immunology ,Reading frame ,Biology ,Exon shuffling ,Cell Line ,Exon ,Species Specificity ,Sequence Homology, Nucleic Acid ,Genetics ,Animals ,Humans ,Computer Simulation ,Amino Acid Sequence ,3' Untranslated Regions ,Gene ,Alleles ,DNA Primers ,Base Sequence ,Models, Genetic ,Sequence Homology, Amino Acid ,Three prime untranslated region ,Intron ,HLA-DR Antigens ,Molecular biology ,Stop codon ,Codon, Terminator ,Nucleic Acid Conformation ,Selenocysteine incorporation - Abstract
The defective major histocompatibility complex (MHC) DRB6 gene is transcribed into mRNA in human [peripheral blood lymphocytes, transfected and Epstein-Barr virus (EBV)] and chimpanzee EBV cell lines. MHC-DRB6 presents several anomalies, which include stop codons in exon 2, lack of the usual polyadenilation signal of other MHC-DRB genes, and a promoter region and exon 1 taken from a locally inserted retrovirus. The complete cDNA sequences from human DRB6*0201 and three common chimpanzee alleles (Patr-DRB6*0108, Patr-DRB6*0109, Patr-DRB6*0111) have been obtained; two exon 1-exon 2 cDNA sequences from bonobos (Papa-DRB6*0101 and Papa-DRB6*0102) are also shown. In contrast to chimpanzee DRB6 transcripts, the human ones: (1) present an exon 1-exon 2 splicing site that includes the transcription of the first 141 nucleotides of intron 1, rendering a longer exon 1, and (2) show a duplication of exon 6, which would render a longer cytoplasmic tail in a putative DRB6 protein. These two characteristics are found in all the human sequences obtained, regardless of the cellular type tested, and they are not present in any of the chimpanzee alleles reported; consequently, they are human-specific. All the alleles reported here bear stop codons in the three possible reading frames; however, a certain level of expression of DRB6 has been observed by cytofluorometry. This could be due to the presence of a selenocysteine insertion sequence (SECIS) stem-loop structure located at the 3 untranslated region of the DRB6 mRNA, which directs selenocysteine incorporation at UGA codons. DRB6 transcription and translation would be the first gene model of a readingthrough stop codon mechanism in primate MHC. It is also feasible that the DRB6 gene might generate a population of short polypeptides, bound to plasmatic membranes, having non-antigen-presenting functions or which are presented by other MHC molecules as HLA-E presents HLA-G and -B leader sequence-derived peptides.
- Published
- 1999
- Full Text
- View/download PDF
18. Evolution of Mhc-DRB introns: Implications for the origin of primates
- Author
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Naoyuki Takahata, Heike Kupfermann, Herbert Tichy, Jan Klein, and Yoko Satta
- Subjects
Primates ,HLA-DR beta-Chains ,Molecular Sequence Data ,Biology ,Archonta ,Evolution, Molecular ,Phylogenetics ,Genetics ,Animals ,Humans ,Molecular Biology ,Gene ,Phylogeny ,Ecology, Evolution, Behavior and Systematics ,Base Sequence ,Phylogenetic tree ,Histocompatibility Antigens Class II ,Intron ,HLA-DR Antigens ,biology.organism_classification ,Introns ,HLA-DRB5 Chains ,Scandentia ,genomic DNA ,Sister group ,HLA-DRB1 Chains - Abstract
Introns are generally believed to evolve too rapidly and too erratically to be of much use in phylogenetic reconstructions. Few phylogenetically informative intron sequences are available, however, to ascertain the validity of this supposition. In the present study the supposition was tested on the example of the mammalian class II major histocompatibility complex (Mhc) genes of the DRB family. Since the Mhc genes evolve under balancing selection and are believed to recombine or rearrange frequently, the evolution of their introns could be expected to be particularly rapid and subject to scrambling. Sequences of intron 4 and 5 DRB genes were obtained from polymerase chain reaction-amplified fragments of genomic DNA from representatives of six eutherian orders—Primates, Scandentia, Chiroptera, Dermoptera, Lagomorpha, and Insectivora. Although short stretches of the introns have indeed proved to be unalignable, the bulk of the intron sequences from all six orders, spanning >85 million years (my) of evolution, could be aligned and used in a study of the tempo and mode of intron evolution. The analysis has revealed the Mhc introns to evolve at a rate similar to that of other genes and of synonymous sites of non-Mhc genes. No evidence of homogenization or large-scale scrambling of the intron sequences could be found. The Mhc introns apparently evolve largely by point mutations and insertions/deletions. The phylogenetic signals contained in the intron sequences could be used to identify Scandentia as the sister group of Primates, to support the existence of the Archonta superorder, and to confirm the monophyly of the Chiroptera.
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- 1999
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19. Transcription and weak expression of HLA-DRB6 : a gene with anomalies in exon 1 and other regions
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Estela Paz-Artal, V Fernández-Soria, Maria J. Recio, Miguel A. Moreno, Belen Suarez, María Jesús Pena Castro, Antonio Arnaiz-Villena, and Pablo Morales
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DNA, Complementary ,Transcription, Genetic ,Polyadenylation ,HLA-DR beta-Chains ,Molecular Sequence Data ,Immunology ,Gene Expression ,Human leukocyte antigen ,Biology ,Transfection ,Major histocompatibility complex ,Mice ,Exon ,L Cells ,Genetics ,Animals ,Humans ,Amino Acid Sequence ,RNA, Messenger ,RNA Processing, Post-Transcriptional ,Gene ,Base Sequence ,Promoter ,Exons ,HLA-DR Antigens ,Stop codon ,RNA splicing ,biology.protein - Abstract
HLA-DRB6 is one of the human major histocompatibility complex (MHC) genes present in DR1, DR2, and DR10 haplotypes (approximately 26% of individuals). It shows several anomalies in human and non-human primates, including exon 2 stop codons (non-randomly grouped between codons 74 and 94) and a promoter region, and an exon 1 coming from an inserted retrovirus. It has been shown that not only chimpanzee but also human Mhc-DRB6 lack the usual 3' untranslated (UT) polyadenylation signal, and in the present work it was found that the human DRB6 gene coming from an HLA-DR2 haplotype is effectively transcribed after transfection in mouse L cells, and that HLA-DRB6 molecules may be expressed on the cell surface. DRB6 transcription level is remarkably lower in human than in chimpanzee. Moreover, their exons 1 (both taken from the 3'LTR region of a mammary tumor retrovirus) are also different; this shows that these viral insertions may be an important mechanism for different evolutionary changes in orthologous genes of different species. The pathways by which DRB6 molecules may be expressed on the membrane are unclear but other examples of truncated protein expression have also been described, even within the human major histocompatibility complex (i. e., in HLA-G). Finally, the presence of mature HLA-DRB6 mRNA molecules supports the notion that splicing may take place even in the absence of a canonical 3'UT polyadenylation signal.
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- 1998
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20. Complex origin of the HLA-DR10 haplotype
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R, Gongora, F, Figueroa, and J, Klein
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Base Sequence ,Genes, MHC Class II ,HLA-DR beta-Chains ,Molecular Sequence Data ,Immunology ,HLA-DR Antigens ,Introns ,HLA-DRB5 Chains ,Haplotypes ,Humans ,Immunology and Allergy ,Cloning, Molecular ,HLA-DRB3 Chains ,HLA-DRB4 Chains ,Phylogeny ,Cell Line, Transformed ,HLA-DRB1 Chains - Abstract
The region of the HLA complex occupied by the DRB genes has undergone many rearrangements in the course of primate evolution. The rearrangements have produced a number of haplotypes differing from one another in the number and composition of the DRB genes. Some of the rearrangements also affected the DRB genes themselves. Selective intron sequencing has revealed the DR10 haplotype to be composed of at least three segments, each of different origin. The haplotype carries three DRB genes (gene fragments): DRB1*10, DRB6, and DRB9. The 5' end of the DRB1*10 gene, from the promoter region to a site in intron 1 approximately 500 bp from the beginning of exon 2, is derived from a DRB1*03-like gene. The segment of the DR10 haplotype encompassing the rest of the DRB1*10 gene and extending to the region between the DRB1 and DRB6 genes is of independent origin; it diverged from other DRB genes (DRB1*01 and DRB1*03) approximately 30 million years ago. Finally, the third segment encompassing the remainder of the DR10 haplotype is derived from a DR1-like haplotype. Since the functional part of the DR10 haplotype is of independent origin, there is little justification for the currently common practice of placing the haplotype together with DR1 in the group of DR1 haplotypes. The rearrangements in the DR haplotypes may constitute one of several mechanisms for increasing diversity at the DRB loci. The region of high instability seems to be flanked by conservatively evolving regions.
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- 1997
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21. New HLA-DR haplotypes containing the DRB6 pseudogene
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B. Fresia, S. M. Alosco, Clarissa Granja, Annamalai Selvakumar, M. Salazar, Bo Dupont, and Edmond J. Yunis
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musculoskeletal diseases ,Genetics ,Pseudogene ,HLA-DR beta-Chains ,Immunology ,Haplotype ,HLA-DR Antigens ,General Medicine ,Biology ,Polymerase Chain Reaction ,Biochemistry ,Molecular biology ,Exon ,Haplotypes ,immune system diseases ,HLA-DR ,Humans ,Immunology and Allergy ,Typing ,Gene conversion ,Allele ,skin and connective tissue diseases ,Homologous recombination ,Pseudogenes - Abstract
An unexpected probe reaction pattern was observed in two samples during HLA-DR typing by PCR-Sequence Specific Oligonucleotide Probes. In order to confirm the unusual typings, samples were analyzed by PCR-Sequence Specific Primers, cloning, and nucleotide sequencing of the second exon of the HLA-DRB-genes. The confirmed DR, DQ phenotype for one sample was DRB1*0701, DRB4*01, DRB5*0101, DRB6*0201, DQB*0602, DQB1*0202. The phenotype of other sample was DRB1*1602, DRB1*1302, DRB3*0301, DRB6*0101, DQB1*0501, DQB1*0502. The first sample has the novel combination of DRB1*0701 with DRB5*0101 and DRB6*0201. The second sample has either DRB6*0101 together with DRB 1*1602 in absence of any DRB5 allele or DRB6*0101 together with DRB1*1302, DRB 3*0301. We postulate that the most likely haplotype in sample #1 is DRB1*0701, DRB5*0101, DRB1*0602 which could have arisen from gene conversion. The most likely haplotype in sample #2, DRB 1*1602, DRB6*0101, DQB1*0502 would have arisen from an homologous recombination event.
- Published
- 1996
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22. Ancestral major histocompatibility complex DRB genes beget conserved patterns of localized polymorphisms
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Gerald T. Nepom and Lakshmi K. Gaur
- Subjects
Primates ,HLA-DR beta-Chains ,Molecular Sequence Data ,Context (language use) ,Biology ,Major histocompatibility complex ,Polymerase Chain Reaction ,Conserved sequence ,Exon ,Intergenic region ,Sequence Homology, Nucleic Acid ,Animals ,Humans ,Gene ,Conserved Sequence ,HLA-DR Antigen ,DNA Primers ,Sequence Deletion ,Genetics ,Polymorphism, Genetic ,Multidisciplinary ,Base Sequence ,Lemur ,Galago ,Genetic Variation ,Exons ,HLA-DR Antigens ,Biological Evolution ,Hypervariable region ,biology.protein ,Macaca ,HLA-DRB1 Chains ,Papio ,Research Article - Abstract
Genes within the major histocompatibility complex (MHC) are characterized by extensive polymorphism within species and also by a remarkable conservation of contemporary human allelic sequences in evolutionarily distant primates. Mechanisms proposed to account for strict nucleotide conservation in the context of highly variable genes include the suggestion that intergenic exchange generates repeated sets of MHC DRB polymorphisms [Gyllensten, U. B., Sundvall, M. & Erlich, H. A. (1991) Proc. Natl. Acad. Sci. USA 88, 3686-3690; Lundberg, A. S. & McDevitt, H. 0. (1992) Proc. Natl. Acad. Sci. USA 89, 6545-6549]. We analyzed over 50 primate MHC DRB sequences, and identified nucleotide elements within macaque and baboon DRB6-like sequences with deletions corresponding to specific exon 2 hypervariable regions, which encode a discrete alpha helical segment of the MHC antigen combining site. This precisely localized deletion provides direct evidence implicating segmental exchange of MHC-encoded DRB gene fragments as one of the evolutionary mechanisms both generating and maintaining MHC diversity. Intergenic exchange at this site may be fundamental to the diversification of immune protection in populations by permitting alteration in the specificity of the MHC that determines the repertoire of antigens bound.
- Published
- 1996
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23. Primate DRB6 gene expression and evolution: a study inMacaca mulattaandCercopithecus aethiops
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Eduardo Gomez-Casado, Miguel A. Moreno, V Fernández-Soria, Antonio Arnaiz-Villena, Pilar Varela, Jorge Martinez-Laso, Alfredo Corell, and Estela Paz-Artal
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Pan troglodytes ,Genes, MHC Class II ,HLA-DR beta-Chains ,Molecular Sequence Data ,Immunology ,Gene Expression ,Biochemistry ,Macaque ,Cell Line ,Evolution, Molecular ,Exon ,Pongo pygmaeus ,biology.animal ,Chlorocebus aethiops ,MHC class I ,Genetics ,Animals ,Humans ,Immunology and Allergy ,Gene ,Gorilla gorilla ,Base Sequence ,biology ,Haplotype ,Promoter ,HLA-DR Antigens ,General Medicine ,Macaca mulatta ,Stop codon ,Hypervariable region ,biology.protein - Abstract
DRB6 has been found to be transcribed in human and apes. Promoter region and exon 1 come from a 5' LTR from a mammary tumour retrovirus. However, the putative protein structure would be very different to other DR molecules and it is doubtful that it may function as an antigen presenting molecule. Primate DRB6 alleles previously published together with the two new macaque sequences reported here support the existence of a strong selective pressure working on exon 2 to generate stop codons at the end of the exon (between codons 74 and 94) during at least 23 million years. The topology of dendrograms constructed with different primate DRB6 alleles supports the "trans-species" evolution proposed for MHC class I, class II and possibly C4 genes. Finally, DRB6, which is one of the oldest DRB genes, has been lost in the HLA-DRB3 (or DR52) group of haplotypes (DR3, DR5, DR6 and DR8) and a small DRB6 sequence is present at the exon 2 first hypervariable region of DRB4 (or DR53) gene, which is present in DR4, DR7 and DR9 haplotypes.
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- 1996
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24. Resolution of the HLA-DRB6 puzzle: a case of grafting a de novo-generated exon on an existing gene
- Author
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Werner E. Mayer, Jan Klein, and Colm O'hUigin
- Subjects
Pan troglodytes ,Transcription, Genetic ,Genes, MHC Class II ,HLA-DR beta-Chains ,Molecular Sequence Data ,Biology ,Exon shuffling ,Polymerase Chain Reaction ,Open Reading Frames ,Exon ,Exon trapping ,Proviruses ,Sequence Homology, Nucleic Acid ,Animals ,Humans ,Amino Acid Sequence ,RNA, Messenger ,Promoter Regions, Genetic ,Gene ,Peptide sequence ,Repetitive Sequences, Nucleic Acid ,Genetics ,Multidisciplinary ,Splice site mutation ,Base Sequence ,Sequence Homology, Amino Acid ,Exons ,HLA-DR Antigens ,Gene rearrangement ,Biological Evolution ,Macaca mulatta ,Retroviridae ,Gene Expression Regulation ,Tandem exon duplication ,Sequence Alignment ,Research Article - Abstract
HLA-DRB6, one of the human major histocompatibility complex genes, lacks exon 1, which normally codes for the leader and the first four amino acid residues of the mature protein. Because it also lacks the HLA promoter, it was surprising to find that the gene is transcribed at a low level in a chimpanzee B-lymphoblastoma cell line, in which the DRB6 homolog is truncated as in humans. The study designed to resolve the paradox has revealed that a retrovirus related to the mouse mammary tumor viruses was inserted into intron 1 of DRB6 > 23 million years ago. The insertion was either accompanied or followed by the deletion of exon 1 and the promoter region of DRB6. In the 3' long terminal repeat of the retrovirus, however, an open reading frame for a new exon arose, which codes for a sequence of mostly hydrophobic amino acid residues; the sequence could function as a leader for the truncated DRB6 gene. This new exon has a functional donor splice site at its 3' end, which enables it to be spliced in register with DRB6 exon 2. Upstream from the new exon is a promoter enabling transcription of the DRB6 gene. Besides providing an example of a de novo generation of an exon, the study suggests a potential mechanism for generating new genes through the replacement of old exons with newly generated ones.
- Published
- 1993
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25. Gorilla major histocompatibility complex-DRB pseudogene orthologous to HLA-DRBVIII
- Author
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Vladimir Vincek, Masanori Kasahara, Dagmar Klein, Colm O'hUigin, Christian Schönbach, and Jan Klein
- Subjects
Pan troglodytes ,Pseudogene ,HLA-DR beta-Chains ,Molecular Sequence Data ,Immunology ,Alu element ,Human leukocyte antigen ,Biology ,Genome ,Homology (biology) ,Cell Line ,Exon ,Histocompatibility Antigens ,Sequence Homology, Nucleic Acid ,HLA-DR4 Antigen ,Animals ,Immunology and Allergy ,Gene ,Genetics ,Gorilla gorilla ,Base Sequence ,Haplotype ,DNA ,Exons ,HLA-DR Antigens ,General Medicine ,Cosmids ,Biological Evolution ,Oligonucleotide Probes ,Pseudogenes - Abstract
The HLA-DR4 haplotype consists of four DRB genes: DRB1 ∗ 04, DRBVII, DRBVIII, and DRB4 ∗ 01, arranged in this order on the chromosome. The DRB1 and DRB4 genes code for β chains of the αβ heterodimers expressed on the cell surface and bearing the HLA-DR4 and HLA DRw53 determinants, respectively; the DRBVII and DRBVIII are pseudogenes. We found and sequenced a gene closely related to HLA-DRBVIII in the genome of the lowland gorilla “Sylvia”. We designate this gene Gogo-DRB8. The close relationship between the two genes is indicated by the overall sequence similarity, the absence of recognizable exons 1 and 2 in both genes, the presence if two Alu repeats at corresponding positions, and high sequence similarity between corresponding repeats. The comparison with an outgroup (tamarin) gene and the functional counterparts of the DRB8 gene indicate that DRB8 emerged between 18 and 26 million years ago and became inactivated at the same time as or shortly after its creation. Hence DRB8 has probably existed as a pseudogene since the divergence of apes from Old World monkeys more than 20 million years ago. Human Immunology 32, 211–220 (1991)
- Published
- 1991
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26. The HLA-DRB6 locus defines an evolutionary supratypic group within the DRB family of genes
- Author
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M D de Juan, P. Morales, José Manuel Martín-Villa, Antonio Arnaiz-Villena, Jorge Martinez-Laso, Alfredo Corell, Pilar Varela, and Jose L. Vicario
- Subjects
Cancer Research ,Pseudogene ,Genes, MHC Class II ,HLA-DR beta-Chains ,Molecular Sequence Data ,Locus (genetics) ,Human leukocyte antigen ,Biology ,Polymerase Chain Reaction ,Sequence Homology, Nucleic Acid ,Humans ,Gene family ,Allele ,Gene ,Genetics ,Base Sequence ,Homozygote ,Haplotype ,Nucleic acid sequence ,DNA ,HLA-DR Antigens ,Biological Evolution ,Haplotypes ,Oncology ,Multigene Family ,Polymorphism, Restriction Fragment Length - Abstract
A novel DRB gene member has recently been identified (DRB6). It defines a new supratypic group of HLA-DR alleles comprising the DR1-, DR2-, and DRw 10-carrying haplotypes. The comparison of this gene either at the nucleotide or at the protein level with other HLA-DRB genes supports its inclusion in the DRB gene family and not in DPB or DQB gene families. Moreover, the construction of an evolutionary gene-tree shows that this gene is probably the eldest member of the DRB gene family. Contradictory expression results do not clarify whether or not DRB6 is a pseudogene.
- Published
- 1991
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27. Correlated evolution of nucleotide substitution rates and allelic variation in Mhc-DRB lineages of primates
- Author
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László Zsolt Garamszegi, Natasja G. de Groot, and Ronald E. Bontrop
- Subjects
Primates ,Evolution ,Lineage (evolution) ,Population ,Genes, MHC Class II ,HLA-DR beta-Chains ,Locus (genetics) ,Biology ,Major histocompatibility complex ,Evolution, Molecular ,Gene Frequency ,Species Specificity ,Polymorphism (computer science) ,QH359-425 ,Animals ,Humans ,Allele ,Selection, Genetic ,education ,Codon ,Ecology, Evolution, Behavior and Systematics ,Phylogeny ,Genetics ,education.field_of_study ,Binding Sites ,Polymorphism, Genetic ,Phylogenetic tree ,Models, Genetic ,Exons ,HLA-DR Antigens ,Sequence Analysis, DNA ,Amino Acid Substitution ,Evolutionary biology ,biology.protein ,Synonymous substitution ,Research Article - Abstract
Background The major histocompatibility complex (MHC) is a key model of genetic polymorphism. Selection pressure by pathogens or other microevolutionary forces may result in a high rate of non-synonymous substitutions at the codons specifying the contact residues of the antigen binding sites (ABS), and the maintenance of extreme MHC allelic variation at the population/species level. Therefore, selection forces favouring MHC variability for any reason should cause a correlated evolution between substitution rates and allelic polymorphism. To investigate this prediction, we characterised nucleotide substitution rates and allelic polymorphism (i.e. the number of alleles detected in relation to the number of animals screened) of several Mhc class II DRB lineages in 46 primate species, and tested for a correlation between them. Results First, we demonstrate that species-specific and lineage-specific evolutionary constraints favour species- and lineage-dependent substitution rate at the codons specifying the ABS contact residues (i.e. certain species and lineages can be characterised by high substitution rate, while others have low rate). Second, we show that although the degree of the non-synonymous substitution rate at the ABS contact residues was systematically higher than the degree of the synonymous substitution rate, these estimates were strongly correlated when we controlled for species-specific and lineage-specific effects, and also for the fact that different studies relied on different sample size. Such relationships between substitution rates of different types could even be extended to the non-contact residues of the molecule. Third, we provide statistical evidence that increased substitution rate along a MHC gene may lead to allelic variation, as a high substitution rate can be observed in those lineages in which many alleles are maintained. Fourth, we show that the detected patterns were independent of phylogenetic constraints. When we used phylogenetic models that control for similarity between species, due to common descent, and focused on variations within a single lineage (DRB1*03), the positive relationship between different substitution rates and allelic polymorphisms was still robust. Finally, we found the same effects to emerge in the analyses that eliminated within-species variation in MHC traits by using strictly single population-level studies. However, in a set of contrasting analyses, in which we focused on the non-functional DRB6 locus, the correlation between substitution rates and allelic variation was not prevalent. Conclusion Our results indicate that positive selection for the generation of allelic polymorphism acting on the functional part of the protein has consequences for the nucleotide substitution rate along the whole exon 2 sequence of the Mhc-DRB gene. Additionally, we proved that an increased substitution rate can promote allelic variation within lineages. Consequently, the evolution of different characteristics of genetic polymorphism is not independent.
- Published
- 2008
28. A novel HLA-DRB1 allele, DRB1*0832, identified by sequence-based typing method
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T. Y.-C. Liu, Yann-Jinn Lee, Ching-Wen Dang, Cheng-Hsin Chu, and Marie Lin
- Subjects
musculoskeletal diseases ,Immunology ,HLA-DR beta-Chains ,Molecular Sequence Data ,Biology ,Biochemistry ,immune system diseases ,Genetics ,Immunology and Allergy ,Humans ,Gene conversion ,Amino Acid Sequence ,Sequence-based Typing ,Allele ,skin and connective tissue diseases ,HLA-DRB1 ,Alleles ,chemistry.chemical_classification ,General Medicine ,HLA-DR Antigens ,Amino acid ,chemistry ,Amino Acid Substitution ,Sequence Alignment ,HLA-DRB1 Chains - Abstract
Human leukocyte antigen-DRB1*0832 may have arisen by gene conversion from a DRB1*080302 backbone, leading to amino acid changes at codons 26, 28, 30, 32, 37, and 38.
- Published
- 2007
29. HLA and RA revisited: citrullinated food for the SE hypothesis, the DR6 effect, and NIMA
- Author
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Tom W J Huizinga, René E. M. Toes, and René R. P. de Vries
- Subjects
Immunology ,HLA-DR beta-Chains ,Human leukocyte antigen ,Pathogenesis ,Arthritis, Rheumatoid ,Epitopes ,HLA Antigens ,medicine ,Immunology and Allergy ,Humans ,Genetic Predisposition to Disease ,Allele ,Prospective cohort study ,Autoantibodies ,Genetics ,biology ,business.industry ,Haplotype ,Models, Immunological ,General Medicine ,HLA-DR Antigens ,medicine.disease ,Hypervariable region ,Rheumatoid arthritis ,biology.protein ,Citrulline ,Antibody ,business ,Immunity, Maternally-Acquired ,HLA-DRB1 Chains - Abstract
An obvious way to unravel the apparently complex association between human leukocyte antigen (HLA) and rheumatoid arthritis (RA) is to reduce the heterogeneity of this multifactorial disease. Recently we have discovered that shared epitope (SE)-positive HLA-DRB1 alleles are exclusively associated with a subgroup of RA patients that test positive for auto-antibodies against cyclic citrullinated peptides. Further studies suggested that SE-positive alleles are classical immune response genes for the development of these antibodies. On the basis of these and other data we formulated a two-hit model for the pathogenesis of RA which incorporates a novel “citrullinated” SE hypothesis. About 5 years ago Zanelli et al. reported that HLA-DR6 (*1301 and *1302) and some other DR alleles that share the DERAA-sequence on amino acids 70–74 of their third hypervariable region are associated with protection from (severe) RA. Recently we corroborated these data in a large prospective cohort study and demonstrated that protection was observed both in the presence and in the absence of a SE susceptibility allele on the other haplotype. Finally we review the state of the art of the association of noninherited maternal HLA antigens with both susceptibility to and protection from RA.
- Published
- 2006
30. HLA class II DRB high resolution genotyping by pyrosequencing: comparison of group specific PCR and pyrosequencing primers
- Author
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Christopher Pecoraro, Andrew L. Alexander, Massimo Trucco, Alexis Styche, Steven Ringquist, and William A. Rudert
- Subjects
Heterozygote ,Genotype ,Immunology ,HLA-DR beta-Chains ,Molecular Sequence Data ,Human leukocyte antigen ,Biology ,Polymerase Chain Reaction ,law.invention ,Cell Line ,law ,Sequence Homology, Nucleic Acid ,Immunology and Allergy ,Humans ,Cloning, Molecular ,Genotyping ,Polymerase chain reaction ,DNA Primers ,Genetics ,Polymorphism, Genetic ,Base Sequence ,Histocompatibility Antigens Class II ,General Medicine ,DNA ,HLA-DR Antigens ,Sequence Analysis, DNA ,Histocompatibility ,Transplantation ,HLA-DRB5 Chains ,genomic DNA ,Leukocytes, Mononuclear ,Linear Models ,Pyrosequencing ,Oligomer restriction ,HLA-DRB3 Chains ,HLA-DRB4 Chains ,HLA-DRB1 Chains - Abstract
Sequencing of alleles of the highly polymorphic, multiple loci HLA-DRB gene family was performed by pyrosequencing using purified DNA from the 11th International Histocompatibility Workshop human lymphoblastiod cell lines as well as genomic DNA isolated from blood samples obtained from healthy adult volunteers. Genomic DNA was prepared from donors whose blood had been stored either frozen or as dried blood spots. Pyrosequence-based typing was optimized for identifying alleles of the HLA-DRB1, -3, -4, and -5 genes. The procedure should be applicable to other HLA loci including the class I genes HLA-A and -B that, along with HLA-DRB, are crucial for histocompatibility matching of tissue antigens during transplantation. Computer simulation of pyrosequencing data suggest that alleles of HLA-DRB1, -3, -4, and -5 were readily identifiable by pyrosequencing as were their heterozygous allelic combinations. Pyrosequencing primers were designed to specifically sequence HLA loci of interest even in a background of other amplified, closely related sequences such as alleles of the pseudogene HLA-DRB6, -7, -8, and -9. Polymorphic residues of HLA-DRB genes were identified within each pyrosequencing reaction, obtained by 50 to 70 nucleotide read lengths. Heterozygous allelic combinations of HLA genes were analyzed and compared successfully to genotyping of alleles by sequence-specific oligonucleotide probe hybridization as well as allele specific polymerase chain reaction protocols. Pyrosequence-based typing is compatible with genotyping of allelic combinations expected from heterozygous individuals, resulting in nucleotide resolution of the highly polymorphic HLA system. Using a single pyrosequence instrument, complete typing of HLA-DRB genes can be performed daily on hundreds of individuals for high resolution histocompatibility genotyping studies.
- Published
- 2003
31. A study of DR2-LUM haplotype generation and the DRB6*0202 linkage to DRB1*1601
- Author
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Pillar Varela, Estela Pas-Artal, J. Manuel Martin-Villa, Jorgr Martínez-Laso, Alfredo Corell, Antonio Arnaiz-Villena, Pablo Morales, and Ernette du Toit
- Subjects
Genetic Linkage ,HLA-DR beta ,Immunology ,HLA-DR beta-Chains ,Molecular Sequence Data ,Biology ,Polymerase Chain Reaction ,Cell Line ,Modal haplotype ,Genetic linkage ,Hla dr2 antigen ,Genetics ,Leukocytes ,Humans ,HLA-DR2 Antigen ,Cloning, Molecular ,Linkage (software) ,Recombination, Genetic ,Haplotype ,Histocompatibility Antigens Class II ,Exons ,HLA-DR Antigens ,Sequence Analysis, DNA ,Tag SNP ,Cell Transformation, Viral ,HLA-DR locus ,Haplotypes ,HLA-DRB1 Chains - Published
- 1993
32. The HLA-DRB6*0201 allele of a pseudogene commonly associated with HLA-DR2 specificities is present in an HLA-DRB1*0101-DRB5*0101 haplotype
- Author
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Winfried F. Pickl, Gottfried Fischer, and Ingrid Fae
- Subjects
Adult ,Male ,Pseudogene ,HLA-DR beta-Chains ,Molecular Sequence Data ,Immunology ,Human leukocyte antigen ,Biology ,Genetics ,Humans ,HLA-DR2 Antigen ,Allele ,Child ,HLA-DRB1 ,Base Sequence ,Haplotype ,Histocompatibility Antigens Class II ,HLA-DR Antigens ,Human genetics ,HLA-DR locus ,Haplotypes ,Oligodeoxyribonucleotides ,Female ,Polymorphism, Restriction Fragment Length ,Pseudogenes ,HLA-DRB1 Chains - Published
- 1993
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33. Allelic diversity at the primate major histocompatibility complex DRB6 locus
- Author
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Antonio Arnaiz-Villena, José Manuel Martín-Villa, Estela Paz-Artal, P. Morales, Jorge Martinez-Laso, Alfredo Corell, and Pilar Varela
- Subjects
Primates ,Genes, MHC Class II ,HLA-DR beta-Chains ,Molecular Sequence Data ,Immunology ,Gorilla ,Locus (genetics) ,Major histocompatibility complex ,Major Histocompatibility Complex ,Molecular evolution ,biology.animal ,Genetics ,Animals ,Humans ,Primate ,Allele ,Gene ,Alleles ,Polymorphism, Genetic ,Base Sequence ,biology ,Haplotype ,HLA-DR Antigens ,Biological Evolution ,biology.protein - Abstract
The HLA-DRB6 gene (also called DRB sigma/V1) has been found only in about 26% of human HLA haplotypes, i.e.; DR1, DRw10, and DR2-bearing ones (Corell et al. 1991). In contrast, exon-2 DRB6 sequences have been obtained from all tested primates: nine chimpanzees (Pan troglodytes), three gorillas (Gorilla gorilla) and three orangutans (Pongo pygmaeus); other apes which had already been sequenced (one gorilla and one chimpanzee) also had the DRB6 gene. Thus, all apes tested from three different species, some of them evolutionary separated by at least 14-16 million years, bear the DRB6 gene. In addition, more than one gene copy per haplotype has been found in one chimpanzee; this, together with the apparent loss of this gene in some of the human DR haplotypes, may indicate that the DR genome has undergone evolutionary changes more recently and more actively than class I or III genes. In addition, ten different and presumably allelic DRB6 exon-2 sequences have been obtained, and some of them coming from different species are more similar to each other than the one from the same species; this finding goes in favor of the trans-species theory of major histocompatibility complex polymorphism generation. Also, data are presented supporting that DRB6 may be one of the eldest genes of the DRB family, thus one of the first to diverge from the ancestral DRB gene.
- Published
- 1992
- Full Text
- View/download PDF
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