RESUMO
Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system. Evidence from family studies indicates a strong genetic component. Despite many studies of candidate genes, only an association with the HLA-DRB1*1501-DQB1*0602 haplotype has been generally detected, and HLA linkage established by transmission disequilibrium testing. A genome-wide scan revealed suggestive linkage of MS with markers on chromosome 7p15 in HLA-DR15-nonsharing British families, in a region syntenic to a locus predisposing to experimental autoimmune encephalomyelitis in the rat. We therefore tested the 7p15 region as a candidate region for genetic susceptibility to MS in 104 French families with at least two affected siblings. We found evidence suggestive of a predisposing locus in families in which only one affected sibling or none of them carry the HLA-DR15 allele. Comparison of the results of the British and French groups suggests that the region of interest can be narrowed to a 2.45-cM interval.
Assuntos
Encefalomielite Autoimune Experimental/genética , Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Esclerose Múltipla/genética , Alelos , Animais , Cromossomos , Feminino , França , Marcadores Genéticos , Cadeias beta de HLA-DQ , Subtipos Sorológicos de HLA-DR , Humanos , Masculino , Repetições de Microssatélites , Esclerose Múltipla/etiologia , Ratos , Reino UnidoRESUMO
The myelin basic protein (MBP) gene is a candidate locus for susceptibility to multiple sclerosis. Several groups have tested a complex (TGGA)n repeat in the 5' region of this gene for association/linkage with multiple sclerosis, with divergent results. This region of tandem repetitive sequence has been subjected to complex rearrangements, and there is a possibility that alleles of the same size have different internal structures, which reduces the interest of this marker for linkage disequilibrium studies and may at least partly explain the conflicting results obtained so far. To overcome this problem, we isolated a new polymorphic (CA)n repeat within the Golli-MBP locus. The limited number of alleles identified makes this other marker suitable for transmission disequilibrium studies. We tested this marker for linkage with multiple sclerosis, using the transmission-disequilibrium test (TDT) on a sample of 196 nuclear families in which the genotypes of both parents could be unambiguously defined. We found no evidence of transmission disequilibrium between multiple sclerosis and any of the three alleles of this marker, even when the patients were subdivided according to their HLA-DRB1*1501 status. The present data thus provide no evidence for a contribution of the MBP gene to multiple sclerosis susceptibility in French patients.
Assuntos
Desequilíbrio de Ligação , Esclerose Múltipla/genética , Proteína Básica da Mielina/genética , Sequência de Bases , França , Humanos , Repetições de Microssatélites , Dados de Sequência MolecularRESUMO
We present the cloning, structural analysis, and mapping of new members belonging to two multigenic families, the B30-RING finger family and the B7.1-B7.2 family, as well as two genes derived by exon shuffling from members of these families. Eight new members were found and three of them map to the human major histocompatibilitiy complex (MHC) region. Phylogenic and physical mapping analysis allowed us to decipher the evolutionary story of these two multigenic families and to shed light on the evolution of the MHC region. We also show that a deductive analysis can be used to predict the existence of a given gene.
Assuntos
Antígeno HLA-B7/genética , Antígenos de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/genética , Família Multigênica , Sequência de Aminoácidos , Sequência de Bases , Butirofilinas , Mapeamento Cromossômico , Cromossomos Artificiais de Levedura , Cromossomos Humanos Par 6 , Evolução Molecular , Éxons , Biblioteca Genômica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Glicoproteínas de Membrana/genética , Modelos Genéticos , Dados de Sequência Molecular , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Proteínas com Motivo TripartidoRESUMO
The B30.2 domain is a conserved domain of around 170 amino acids. It is found associated with different protein domains: immunoglobulin domain in the case of butyrophilin and Ring Finger domain in the case of Ret Finger Protein. B30.2 should therefore be considered a migratory domain. We here report new members of these families as well as new protein families having the B30.2 domain, and we tentatively propose a general function for this domain.
Assuntos
Proteínas/química , Sequência de Aminoácidos , Butirofilinas , Sequência Conservada/genética , Venenos de Peixe/química , Humanos , Imunoglobulina G/química , Sistemas de Informação , Ligantes , Glicoproteínas de Membrana/química , Dados de Sequência Molecular , Alinhamento de SequênciaRESUMO
We have refined and extended the map of the distal half of the human major histocompatibility complex. The map is continuous from HLA-E to 1000 kb telomeric of HLA-F and includes six new markers and genes. In addition, the corresponding sequences that were not previously mapped in the mouse genome have been located. The human and the mouse organizations have therefore been compared. This comparison allows us to demonstrate that the structure of the distal part of the MHC is similar in the two species. In addition, this comparison shows the presence of a breakpoint of synteny telomeric of the distal part of the H-2 region. Indeed, the region telomeric of HLA in human is found on a chromosome different from that carrying H-2 in mouse. The mapping analysis of paralogous genes (structurally related genes) around the breakpoint shows that the human organization probably represents the putative human/mouse ancestral one. This evolutionary breakpoint was precisely mapped in human, and the surrounding region was cloned into yeast artificial chromosomes. Finally, we show that the region found around the breakpoint was involved several times in chromosome recombinations in the mouse lineage, as it seems to correspond also to the t-complex distal inversion point.
Assuntos
Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 6/genética , Genes MHC Classe I , Animais , Sequência de Bases , Evolução Biológica , Southern Blotting , Cromossomos Artificiais de Levedura , Cruzamentos Genéticos , Eletroforese em Gel de Campo Pulsado , Marcadores Genéticos , Humanos , Hibridização In Situ , Camundongos , Dados de Sequência Molecular , Translocação GenéticaRESUMO
The P5-1 cDNA clone maps to the human MHC class I region (Vernet et al. 1993a). In this paper, we show that the P5-1 cDNA represents a chimeric transcript in which the first exon of an MHC class I gene has been spliced to an unrelated sequence. The corresponding gene P5-1 is composed of the 5' sequence of an MHC class I gene including the promoter region, the first exon, and the half of the first intron fused to an unrelated intron, followed by a large exon. Furthermore, the non-class I part of P5-1 is present within the MHC class I region in multiple copies, defining the P5 family. Another member of the P5 family is fused to a class I gene, although by a type of rearrangement different from P5-1. These two fusion events between members of HLA class I and P5 families reflect the existence of a duplication unit including two class I genes and a P5 sequence. These data shed light on the MHC class I evolution and on the creation and evolution of new genes.
Assuntos
Genes MHC Classe I/genética , Proteínas/genética , Proteínas Recombinantes de Fusão/genética , Recombinação Genética , Sequência de Bases , Clonagem Molecular , DNA Complementar , Éxons , Expressão Gênica , Humanos , Íntrons , Complexo Principal de Histocompatibilidade , Dados de Sequência Molecular , Família Multigênica , Regiões Promotoras Genéticas , RNA Longo não Codificante , RNA não TraduzidoRESUMO
OTF3 (octamer transcription factor 3) is a transcription factor containing a POU-specific domain and a homeodomain that could play a role in early development. In situ hybridization and pairwise linkage analysis showed that OTF3 gene maps close to the human MHC (major histocompatibility complex). In this paper, we define its localization within the MHC, around 100 kb telomeric to HLA-C, using a combination of physical and genetic analyses.
Assuntos
Proteínas de Ligação a DNA/genética , Complexo Principal de Histocompatibilidade , Fatores de Transcrição/genética , Alelos , Mapeamento Cromossômico/métodos , Cromossomos Artificiais de Levedura , Troca Genética , Desenvolvimento Embrionário e Fetal/genética , Genes , Haplótipos/genética , Humanos , Hibridização In Situ , Meiose , Fator 3 de Transcrição de OctâmeroRESUMO
A gene coding for a putative GTP-binding protein, MMR1, has been localized on band C of the murine Chr 17 within or close to the MHC (Denizot et al. 1992). Its human homolog, HSR1, localized to the human MHC class I region, is described in this paper. Its sequence, compared with MMR1, shows that the conceptual proteins encoded by these genes are highly homologous and have thus been subjected to high constraints during evolution. Furthermore, a detailed databank search with HSR1 leads to the characterization of a new subfamily of GTP-binding proteins, of which HSR1 and MMR1 are the only eukaryotic members. The precise localization of HSR1 within the human MHC class I region is also presented.
Assuntos
Evolução Biológica , Proteínas de Ligação ao GTP/genética , Genes MHC Classe I , Sequência de Aminoácidos , Linhagem Celular , Mapeamento Cromossômico , DNA Complementar , Humanos , Dados de Sequência Molecular , Análise de Sequência de DNA , Homologia de Sequência de AminoácidosRESUMO
The human major histocompatibility complex (MHC) region is a genomic region spanning about 4000 kilobases (kb) including the class I, class II, and class III subregions. The class I subregion is larger than the two others but with fewer genes described to date. It includes a) classical human leucocyte antigen (HLA) class I genes (HLA-A, HLA-B, HLA-C) which are highly polymorphic and encode products presenting the endogenous antigenic peptides to the T-cell receptors, and b) non-classical class I genes (HLA-E, HLA-F, HLA-G) whose function is still unknown. In this study, we describe the first coding sequence which is not structurally related to the class I genes, although it is localized within the MHC class I region. This novel gene, P5-1, belongs to a multiple copy family, all members of which map within the MHC. Although the P5-1 sequence showed no similarity to sequences in different databanks, its transcription, which is restricted to lymphoid tissues, argues for an immunological function of its product.
Assuntos
Genes , Complexo Principal de Histocompatibilidade , Proteínas/genética , Sequência de Aminoácidos , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 6 , Clonagem Molecular , Humanos , Dados de Sequência Molecular , Família Multigênica , RNA Longo não Codificante , RNA não Traduzido , Mapeamento por RestriçãoRESUMO
The thyroxin-binding globulin (TBG) polymorphism was investigated in three African groups: two belonged to the Bwa villages of Mali, and the third was a Dogon group living in the same area. The Bwa groups were characterized by the occurrence of nodular goitres, whereas the Dogon population did not show similar pathological symptoms. Females were more affected by goitre than males in the affected villages. The TBG polymorphism enabled us to demonstrate the presence of an undescribed allele (TBG C1) in these populations. The frequency of the TBG S allele was also higher than previously published in other African groups. We observed a disequilibrium in the distribution of the C and S alleles in the population, with an excess of homozygous TBG S individuals. No clear relationship between the TBG polymorphism and the number of nodules can be drawn.
