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PubMed2005

Association of proopiomelanocortin gene polymorphisms with obesity in the IRAS family study.

Proopiomelanocortin (POMC) has been found to be associated with rare Mendelian forms of obesity in children, and, in linkage studies, genomic regions containing the POMC locus have been linked to leptin levels, a predictor of obesity, in white, Mexican-American, and African-American families. POMC polymorphisms have not been investigated in detail for association with obesity in the general population. Five single nucleotide polymorphisms (SNPs) (G-3460C, C17T, G3473A, C3755T, and A7069G) were genotyped on 811 Hispanic individuals in the Insulin Resistance Atherosclerosis Family Study and tested for association with multiple obesity quantitative traits. General and family-based association analyses for each individual SNP and for haplotypes were performed using the generalized estimating equation and quantitative pedigree disequilibrium test (QPDT), respectively. Modest but consistent associations were observed for SNP C3755T, with p values ranging from 0.011 to 0.045 for association with BMI, waist, visceral adipose tissue, and subcutaneous adipose tissue. G-3460C, G3473A, and A7069G were also found to be associated with additional obesity measurements (p value 0.025 to 0.04), with comparable levels of evidence observed for linkage disequilibrium between these traits and these SNPs. Results of the haplotype analyses were also consistent with the single SNP analysis, with haplotypes containing C3755T showing the greatest evidence of association (p values ranging 0.004 to 0.048). Monte Carlo simulations (gene dropping) that account for the number of comparisons and the correlation structure indicate that the multivariate significance for these obesity traits with these polymorphisms was p = 0.0091. Collectively, the POMC polymorphisms showed consistent evidence for association with obesity traits in Hispanic Americans across several analytical approaches using SNP and haplotype analysis. These results support the hypothesis that POMC contributes genetically to the development of obesity.

Adult↗

PubMed1984

Multiple Ia-like molecules characterize HLA-DR2-associated haplotypes which differ in HLA-D.

Two-dimensional gel electrophoresis of immunoprecipitated human Ia-like molecules was used to investigate the structural relationship between HLA-D and HLA-DR2. Eight different lymphoblastoid lines derived from HLA-DR2-associated homozygous typing cells, representing five distinct HLA-D clusters, were compared. Two or three distinct beta chain molecules from DR-like loci were identified in the DR2 homozygous cell lines studied. Furthermore, one of these molecules was present in all lines tested, while the others were highly variable. The electrophoretic mobility of these variable DR-like molecules correlated very well with HLA-D typing studies, suggesting that the HLA-DR specificity and the HLA-D specificity on these DR2 cells may be present on separate, but related, molecules.

Alleles↗

PubMed2006

Origin, genetic diversity, and population structure of Chinese domestic sheep.

To characterize the origin, genetic diversity, and phylogeographic structure of Chinese domestic sheep, we here analyzed a 531-bp fragment of mtDNA control region of 449 Chinese autochthonous sheep from 19 breeds/populations from 13 geographic regions, together with previously reported 44 sequences from Chinese indigenous sheep. Phylogenetic analysis showed that all three previously defined lineages A, B, and C were found in all sampled Chinese sheep populations, except for the absence of lineage C in four populations. Network profiles revealed that the lineages B and C displayed a star-like phylogeny with the founder haplotype in the centre, and that two star-like subclades with two founder haplotypes were identified in lineage A. The pattern of genetic variation in lineage A, together with the divergence time between the two central founder haplotypes suggested that two independent domestication events have occurred in sheep lineage A. Considerable mitochondrial diversity was observed in Chinese sheep. Weak structuring was observed either among Chinese indigenous sheep populations or between Asian and European sheep and this can be attributable to long-term strong gene flow induced by historical human movements. The high levels of intra-population diversity in Chinese sheep and the weak phylogeographic structuring indicated three geographically independent domestication events have occurred and the domestication place was not only confined to the Near East, but also occurred in other regions.

Animal Migration↗

PubMed1991

Nonrandom selection of T cell specificities in anti-HLA-DR responses. Sequence motifs of the responder HLA-DR allele influence T cell recruitment.

The self-restriction of Ag-specific T cell responses is interpreted as the result of a positive selection of the individual's T cell specificities for their compatibility with self-MHC molecules. If the T cell receptor (TCR) specificities in any given individual have an affinity for syngeneic MHC molecules, it is unclear how they interact with allogeneic MHC structures. To approach this question, we analyzed 123 alloreactive HLA-DR4 Dw4 or Dw14 specific T cell clones that were generated from responder/stimulator combinations with defined disparities in the HLA-DR beta 1-chain. Sets of T cell clones were established from three different HLA-Dw4+ responders and compared for their fine specificities. The majority of HLA-DR4 Dw14 specific T cell clones co-recognized HLA-DR1 Dw1+ (33 to 36% of all T cell clones) or HLA-DRw14 Dw16+ (26 to 33%) stimulators, both of which share very similar sequences in the third hypervariable region of the HLA-DR beta 1-chain with the HLA-DR4 alleles Dw4 and Dw14. These data suggest that sequence and structural similarities in the alpha-helical portions of the HLA-DR molecule impose a strong bias on the recognition of allotargets. The second haplotype of the responder did not appear to affect the typical fingerprint of T cell recognition except for the deletion of self-reactive TCR specificities. Nonrandom usage of TCR specificities in anti-HLA-DR responses was also found for HLA-DRw11/DRw13+ and HLA-DRw11/DR7+ T cell donors who did not share any obvious polymorphic sequence stretches with the allostimulators HLA-DR4 Dw4 or Dw14. T cell clones from an HLA-DRw11/DRw13+ responder functionally resembled the TCR specificities derived from the HLA-DR4 Dw4+ donors. T cell clones derived from an HLA-DRw11/DR7+ individual were characterized by a distinct cross-reactivity pattern preferring HLA-DRw13 Dw19+ (50 to 60%) and HLA-DR3+ (43 to 57%) stimulator cells. These findings suggest that the responder HLA-DR alleles influence the structural constraints in the recognition of allo-HLA-DR molecules in closely related and in completely disparate responder/stimulator combinations.

Amino Acid Sequence↗

PubMed2001

Genetic, structural and functional diversities of human complement components C4A and C4B and their mouse homologues, Slp and C4.

The complement protein C4 is a non-enzymatic component of the C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. The covalent binding of C4 to immunoglobulins and immune complexes (IC) also enhances the solubilization of immune aggregates, and the clearance of IC through complement receptor one (CR1) on erythrocytes. Human C4 is the most polymorphic protein of the complement system. In this review, we summarize the current concepts on the 1-2-3 loci model of C4A and C4B genes in the population, factors affecting the expression levels of C4 transcripts and proteins, and the structural, functional and serological diversities of the C4A and C4B proteins. The diversities and polymorphisms of the mouse homologues Slp and C4 proteins are described and contrasted with their human homologues. The human C4 genes are located in the MHC class III region on chromosome 6. Each human C4 gene consists of 41 exons coding for a 5.4-kb transcript. The long gene is 20.6 kb and the short gene is 14.2 kb. In the Caucasian population 55% of the MHC haplotypes have the 2-locus, C4A-C4B configurations and 45% have an unequal number of C4A and C4B genes. Moreover, three-quarters of C4 genes harbor the 6.4 kb endogenous retrovirus HERV-K(C4) in the intron 9 of the long genes. Duplication of a C4 gene always concurs with its adjacent genes RP, CYP21 and TNX, which together form a genetic unit termed an RCCX module. Monomodular, bimodular and trimodular RCCX structures with 1, 2 and 3 complement C4 genes have frequencies of 17%, 69% and 14%, respectively. Partial deficiencies of C4A and C4B, primarily due to the presence of monomodular haplotypes and homo-expression of C4A proteins from bimodular structures, have a combined frequency of 31.6%. Multiple structural isoforms of each C4A and C4B allotype exist in the circulation because of the imperfect and incomplete proteolytic processing of the precursor protein to form the beta-alpha-gamma structures. Immunofixation experiments of C4A and C4B demonstrate > 41 allotypes in the two classes of proteins. A compilation of polymorphic sites from limited C4 sequences revealed the presence of 24 polymophic residues, mostly clustered C-terminal to the thioester bond within the C4d region of the alpha-chain. The covalent binding affinities of the thioester carbonyl group of C4A and C4B appear to be modulated by four isotypic residues at positions 1101, 1102, 1105 and 1106. Site directed mutagenesis experiments revealed that D1106 is responsible for the effective binding of C4A to form amide bonds with immune aggregates or protein antigens, and H1106 of C4B catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens. The expression of C4 is inducible or enhanced by gamma-interferon. The liver is the main organ that synthesizes and secretes C4A and C4B to the circulation but there are many extra-hepatic sites producing moderate quantities of C4 for local defense. The plasma protein levels of C4A and C4B are mainly determined by the corresponding gene dosage. However, C4B proteins encoded by monomodular short genes may have relatively higher concentrations than those from long C4A genes. The 5' regulatory sequence of a C4 gene contains a Spl site, three E-boxes but no TATA box. The sequences beyond--1524 nt may be completely different as the C4 genes at RCCX module I have RPI-specific sequences, while those at Modules II, III and IV have TNXA-specific sequences. The remarkable genetic diversity of human C4A and C4B probably promotes the exchange of genetic information to create and maintain the quantitative and qualitative variations of C4A and C4B proteins in the population, as driven by the selection pressure against a great variety of microbes. An undesirable accompanying byproduct of this phenomenon is the inherent deleterious recombinations among the RCCX constituents leading to autoimmune and genetic disorders.

Amino Acid Sequence↗

PubMed1989

Immunogenic capacity of macrophage hybridomas.

Two clones, E2-7.7 and E2-10.50, derived from two macrophage(M phi)hybridomas, E2-7 and E2-10, have been studied. The first clone, E2-7.7, is Ia+ and Fc receptor (FcR) negative and manifests a strong antigen-presenting capacity. When we pulsed its cells in vitro with keyhole limpet hemocyanin (KLH) antigen and injected them into syngeneic animals, we found that as small a dose as 10(3) cells initiated an immune response in vivo. On the other hand, antigen-pulsed cells of the E2-10.50 clone, which are Ia- and FcR+, were almost incapable of triggering immunity, even when injected at a dose of 10(5) cells. Thus, the two clones differ in their immunogenic capacity (both cellular and humoral immunity). In experiments aimed at testing the stimulation in vitro of primed lymph node (LN) cells by antigen-pulsed cells of these two hybridoma clones, we observed that E2-7.7 stimulated the unfractionated population of LN cells and the LN-derived population of T cells. The E2-10.50 cells stimulated only the unfractionated population of LN cells, but not the T cell population. Subsequent tests indicated that the E2-10.50 cells require an intermediate Ia+ accessory cell to present the antigen to the T lymphocytes. Analyzing the molecular structure of the M phi hybridomas, we discovered that major histocompatibility complex (MHC) genes of the myeloma haplotype (H-2d), and of the splenic M phi used for fusion (H-2k), which were not expressed in the parental myeloma or in the E2-10.50, were expressed in the E2-7.7. Thus, somatic cell fusion of M phi resulted in the activation of suppressed genes of the myeloma partner. It appears that these antigens participate in controlling the immunogenic properties of the E2-7.7 clone. Testing the effects of interferons on the M phi hybridomas, we observed that interferon-gamma activated, at both the mRNA and the cell surface-antigen levels, the expression of H-2Dk, H-2Kd and H-2Dd in the E2-10.50 cells, but not in the E2-7.7. Consequently, interferon-gamma augmented significantly antigen presentation by E2-10.50 but not by E2-7.7 cells. These two hybridoma clones might represent two distinct subsets of normal M phi, manifesting two different sets of functional properties.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

Allelic differences affecting invariant chain dependency of MHC class II subunit assembly.

The conserved invariant chain associates with highly polymorphic alpha and beta subunits guiding class II transport through the secretory pathway. Early associations of these three polypeptides inside antigen-presenting cells are poorly understood. The present experiments provide a detailed picture of the structure and fate of class II alpha and beta subunits in invariant chain mutants possessing different MHC haplotypes. In the absence of invariant chain, A alpha bA beta b is predominantly expressed as free A alpha b and A beta b chains by both splenocytes and activated LPS/IL-4 blasts, confirming that A alpha bA beta b assembly is strongly dependent on invariant chain coexpression. A quite different situation exists with respect to other allelic products. In the absence of invariant chain, A alpha kA beta k, E alpha kE beta k, and A alpha dA beta d molecules assemble efficiently and are conformationally similar to mature wild-type heterodimers. The contribution of invariant chain to subunit assembly thus differs for allelic variants, suggesting that sequential associations of alpha, beta, and invariant chain may be affected by polymorphic differences.

Alleles↗

PubMed2004

Isolates and their potential use in complex gene mapping efforts.

Linkage disequilibrium (LD), detectable with microsatellites in disease alleles over wide genetic intervals in population isolates, has facilitated mapping and positional cloning of numerous disease genes. We, among others, have shown that the LD intervals reach up to 1 Mb in general alleles of young subisolates, and that this feature most probably offers an avenue for the initial locus positioning for complex traits. Development of efficient SNP genotyping and characterization of haploblock structure of the human genome have introduced new prospects to LD-based fine mapping and haplotype-association studies. Encouraging associations have been reported for several complex diseases. Final breakthroughs in mapping of complex disease loci have emerged on large pedigrees in population isolates. Conversely, ignoring genealogical makeup of the study population seems to disclose false negative and false positive associations, directing resources down the drain.

Chromosome Mapping↗

PubMed2003

Phylogeography of the rock partridge (Alectoris graeca).

We used mitochondrial DNA control-region and microsatellite data to infer the evolutionary history and past demographic changes in 332 rock partridges (Alectoris graeca) sampled from throughout the species' distribution range, with the exception of the central Balkans region. Maternal and biparental DNA markers indicated concordantly that rock partridge populations are structured geographically (mtDNA phiST = 0.86, microsatellite FST = 0.35; RST = 0.31; P < 0.001). Phylogenetic analyses of 22 mtDNA haplotypes identified two major phylogroups (supported by bootstrap values = 93%), splitting partridges from Sicily vs. all the other sampled populations at an average Tamura-Nei genetic distance of 0.035, which corresponds to 65% of the average distance between closely related species of Alectoris. Coalescent estimates of divergence times suggested that rock partridges in Sicily were isolated for more than 200000 years. This deep subdivision was confirmed by multivariate, Bayesian clustering and population assignment analyses of microsatellite genotypes, which supported also a subdivision of partridges from the Alps vs. populations in the Apennines, Albania and Greece. Partridges in the Apennines and Albania-Greece were probably connected by gene flow since recently through a late Pleistocene Adriatic landbridge. Deglaciated Alps were probably colonized by distinct and, perhaps, not yet sampled source populations. Bottleneck and mismatch analyses indicate that rock partridges have lost variability through past population declines, and did not expand recently. Deglaciated areas could have been recolonized without any strong demographic expansion. Genetic data partially supported subspecies subdivisions, and allowed delimiting distinct conservation units. Rock partridges in Sicily, formally recognized as A. g. whitakeri, met the criteria for a distinct evolutionary significant unit.

Animals↗

PubMed1989

Prediction of major histocompatibility complex binding regions of protein antigens by sequence pattern analysis.

We have previously experimentally analyzed the structural requirements for interaction between peptide antigens and mouse major histocompatibility complex (MHC) molecules of the d haplotype. We describe here two procedures devised to predict specifically the capacity of peptide molecules to interact with these MHC class II molecules (IAd and IEd). The accuracy of these procedures has been tested on a large panel of synthetic peptides of eukaryotic, prokaryotic, and viral origin, and also on a set of overlapping peptides encompassing the entire staphylococcal nuclease molecule. For both sets of peptides, IAd and IEd binding was successfully predicted in approximately 75% of the cases. This suggests that definition of such sequence "motifs" could be of general use in predicting potentially immunogenic peptide regions within proteins.

Amino Acid Sequence↗

PubMed2004

Population structure and genetic variability within isolates of Grapevine fanleaf virus from a naturally infected vineyard in France: evidence for mixed infection and recombination.

The nematode-borne Grapevine fanleaf virus, from the genus Nepovirus in the family Comoviridae, causes severe degeneration of grapevines in most vineyards worldwide. We characterized 347 isolates from transgenic and conventional grapevines from two vineyard sites in the Champagne region of France for their molecular variant composition. The population structure and genetic diversity were examined in the coat protein gene by IC-RT-PCR-RFLP analysis with EcoRI and StyI, and nucleotide sequencing, respectively. RFLP data suggested that 55 % (191 of 347) of the isolates had a population structure consisting of one predominant variant. Sequencing data of 51 isolates representing the different restrictotypes confirmed the existence of mixed infection with a frequency of 33 % (17 of 51) and showed two major predominant haplotypes representing 71 % (60 of 85) of the sequence variants. Comparative nucleotide diversity among population subsets implied a lack of genetic differentiation according to host (transgenic vs conventional) or field site for most restrictotypes (17 of 18 and 13 of 18) and for haplotypes in most phylogenetic groups (seven of eight and six of eight), respectively. Interestingly, five of the 85 haplotypes sequenced had an intermediate divergence (0.036-0.066) between the lower (0.005-0.028) and upper range (0.083-0.138) of nucleotide variability, suggesting the occurrence of homologous RNA recombination. Sequence alignments clearly indicated a mosaic structure for four of these five variants, for which recombination sites were identified and parental lineages proposed. This is the first in-depth characterization of the population structure and genetic diversity in a nepovirus.

Base Sequence↗

PubMed2025

Genome-wide diversity of chromosomal inversions and their disease relationships.

Chromosomal inversions shape evolution and are implicated in human disease, yet their effects on genomic variation and health outcomes remain poorly understood. We analyze genome-wide human inversion polymorphisms, contrasting single-event and recurrent loci. Inversion recurrence is validated using structured-coalescent simulations. We show that single-event inversions evolve in near-complete isolation: inverted haplotypes show ~16-fold lower diversity and strong differentiation from direct haplotypes (median FST = 0.33). By contrast, recurrent inversions maintain gene flow, resulting in similar diversity across orientations and ~4-fold lower differentiation. We further find marked differences in coding sequence conservation between single-event and recurrent inversions. Using the NIH All of Us biobank, we impute inversions and identify four inversions with significant disease associations. Notably, the 17q21 inversion is associated with reduced risk of cognitive decline (OR=0.919) and breast cancer (OR=0.910) but with increased obesity risk (OR=1.097), consistent with pleiotropic selection. These findings establish inversions as major drivers of human genetic diversity and disease, with evolutionary outcomes critically dependent on recurrence.

Evolution↗

PubMed1977

Reactivity of anti-HLA sera against mouse lymphocytes.

The reactivity of anti-HLA hyper-immune sera was tested by the microlymphocytotoxicity technique (LCT) against a panel of mouse lymphocytes. Three levels of reactivity were observed: negative (immune sera titre 1:20 or less), weak (titre 1:40 to 1:80 with a percentage of dead cells less than 50%) or strong (titre 1:60 or more with 100% killing). Thirteen normal human sera were non-reactive. Eleven out of 60 hyper-immune sera were strongly reactive. Tests using congenic lines showed that the reactivity was controlled at the H-2 complex. One serum (CODRON) was studied in detail. When tested against a panel of strains carrying 10 different H-2 haplotypes, it reacted strongly against lymphocytes H-2d, ja, k, p and r; and did not react, or at least only weakly, against lymphocytes H-2b, f, q, s and v. Tests using mouse strains carrying the recombinant H-2 haplotypes h4, i5, i, y2, g, g2 and t1, suggested that the observed reactivity was directed against structures controlled at the K end of the H-2 complex (H-2.47?). Absorption-elution experiments with human and murine lymphocytes and platelets confirmed that the structures recognised by serum CODRON were determined at the major histocompatibility complex.

Animals↗

PubMed2005

Selecting additional tag SNPs for tolerating missing data in genotyping.

BACKGROUND: Recent studies have shown that the patterns of linkage disequilibrium observed in human populations have a block-like structure, and a small subset of SNPs (called tag SNPs) is sufficient to distinguish each pair of haplotype patterns in the block. In reality, some tag SNPs may be missing, and we may fail to distinguish two distinct haplotypes due to the ambiguity caused by missing data. RESULTS: We show there exists a subset of SNPs (referred to as robust tag SNPs) which can still distinguish all distinct haplotypes even when some SNPs are missing. The problem of finding minimum robust tag SNPs is shown to be NP-hard. To find robust tag SNPs efficiently, we propose two greedy algorithms and one linear programming relaxation algorithm. The experimental results indicate that (1) the solutions found by these algorithms are quite close to the optimal solution; (2) the genotyping cost saved by using tag SNPs can be as high as 80%; and (3) genotyping additional tag SNPs for tolerating missing data is still cost-effective. CONCLUSION: Genotyping robust tag SNPs is more practical than just genotyping the minimum tag SNPs if we can not avoid the occurrence of missing data. Our theoretical analysis and experimental results show that the performance of our algorithms is not only efficient but the solution found is also close to the optimal solution.

Algorithms↗

PubMedDate not supplied

Immunopathogenesis of celiac disease.

The immunopathogenesis of celiac disease requires interactions between genetic, environmental and immunologic factors. Genes within the class II region of the major histocompatibility complex (HLA-D region) represent a major component contributing to disease susceptibility. Structural studies of genes within the HLA-D region have shown that the class II HLA haplotype associated with celiac disease is extended, and includes not only the HLA-DR and DQ subregions, but also the HLA-DP subregion. The celiac disease-associated haplotype is marked in the HLA-DP subregion by a polymorphic 4 kilobase Rsa I genomic fragment derived from a DP beta chain. Other studies suggest that, in addition to dietary gliadins, a viral protein may play a role in the pathogenesis of celiac disease, perhaps by virtue of immunologic cross reactivity between antigenic determinant shared by the viral protein and alpha gliadins.

Antibody Formation↗

PubMed2025

Dissecting adult plant resistance to stem rust through multi-model GWAS in a diverse barley germplasm panel.

INTRODUCTION: Stem rust (SR), caused by Puccinia graminis f. sp. tritici (Pgt), remains a major threat to global barley production, particularly in regions with conducive environments and evolving pathogen populations. Despite progress in understanding seedling resistance, adult plant resistance (APR) to SR remains underexplored in diverse barley germplasm. This study aimed to dissect the genetic architecture of APR to SR in a panel of diverse origins of two-row spring barley using a genome-wide association study (GWAS). METHODS: A total of 273 barley accessions were evaluated for APR to SR in two distinct environments in Kazakhstan. Phenotypic data were combined with high-density SNP genotyping to perform GWAS using five statistical models (GLM, MLM, MLMM, FarmCPU, and BLINK). Population structure and kinship were accounted for to identify robust marker-trait associations (MTAs), followed by haplotype-based QTL delineation. Transcriptomic data from 16 barley tissues were used to identify candidate genes within major QTL regions. Substantial phenotypic variation in SR severity was observed across environments. RESULTS: A total of 204 MTAs were identified, among which 96 were stable across models, resulting in 19 model-stable QTLs spanning all seven barley chromosomes. Six QTLs co-localized with known SR-resistance QTLs and genes, including Rpg1 and Rpg6. Q_rpg_7H.1 (coinciding with Rpg1) was one of the strongest and most consistent QTL, harboring 42 highly expressed candidate genes. A novel major-effect QTL on chromosome 5H, Q_rpg_5H.1 (3.5 - 9.9 Mb), not previously associated with known resistance loci, contained 10 highly expressed genes grouped into three co-expression clusters, including WRKY transcription factors and PR-5 proteins. CONCLUSION: This study provides new insights into the complex, multilayered genetic control of SR resistance in barley. The discovery of both known and novel QTLs offers valuable targets for marker-assisted selection and lays the foundation for breeding durable SR-resistant barley adapted to diverse agroecological conditions.

Hordeum vulgare L.↗

PubMed1995

Exon-intron organization of Xenopus MHC class II beta chain genes.

The amphibian Xenopus laevis is the most primitive vertebrate in which the major histocompatibility complex (MHC) has been defined at the biochemical, functional, and molecular genetic levels. We previously described the isolation and characterization of cDNA clones encoding X. laevis MHC class II beta chains. In the present study, genomic clones encoding class II beta chains were isolated from X. laevis homozygous for the MHC f haplotype. Three class II beta chain genes, designated Xela-DAB, Xela-DBB, and Xela-DCB, were identified. Sequence analysis of these genes showed that Xela-DBB and Xela-DCB correspond to the previously characterized cDNA clones F3 and F8, respectively, whereas Xela-DAB encodes a third, hitherto unidentified class II beta chain of the MHC f haplotype. As a representative of X. laevis class II beta chain genes, the Xela-DAB gene underwent detailed structural analysis. In addition, the nucleotide sequence of Xela-DABf cDNA clones was determined. The Xela-DAB gene is made up of at least six exons, with an exon-intron organization similar to that of a typical mammalian class II beta chain gene. The 5'-flanking region of the Xela-DAB gene contains transcriptional control elements known as X1, X2, and Y, but lacks typical TATA or CCAAT boxes. A notable feature of the X. laevis class II beta chain genes is that the sizes of the introns are larger than those of their mammalian counterparts. As assessed by northern blot analysis, the three class II beta chain genes had similar expression patterns, with the highest level of transcription detected in the intestine. Identification of the Xela-DAB, -DBB, and -DCB genes is consistent with our previous observations, which suggested that the MHC of the tetraploid frog X. laevis is diploidized at the genomic level and contains three class II beta chain genes per haplotype that cross-hybridize to one another under reduced stringency conditions.

Amino Acid Sequence↗

PubMed1998

Diversity of sequence haplotypes associated with beta-thalassaemia mutations in Algeria: implications for their origin.

We report the allelic sequence polymorphism associated with seven beta-thalassaemia mutations. Thirty-two DNAs originating from Algeria and 12 DNAs from Sardinia and Sicily were investigated. Their analysis revealed an association with a unique haplotype for three beta-thalassaemia mutations (-29, IVS-I-2 and IVS-I-1). It seems clear that these mutations have a unicentric origin. The presence of the -29 mutation could be explained by migration and founding effect. However, the local origin of IVS-I-2 seems clear. The four other mutations, FS6, IVS-I-6, IVS-I-110 and stop39 were found to be associated with at least two different sequence haplotypes. The likelihood of so many recurrent nucleotide dimorphisms in different lineages as a consequence of random mutation is very low; it is supported neither by the analysis of equivalent regions in other primates, nor by the presence of highly mutable sites such as CpG dinucleotides. The fact that these mutations are found exclusively in the Mediterranean area is not in favour of a recurrent origin of the mutation. The diversity is far more important for the preponderant thalassaemia mutations of the Mediterranean area and is higher in the 5' part of the beta-globin gene. Hence, the IVS-I-110, the preponderant beta-thalassaemia in the Eastern Mediterranean, probably emerged in the extension of the fertile crescent. For the stop39, all the data support the hypothesis of a West-Mediterranean origin. The diversity of haplotypes would then be generated by recombination events (crossing-over or gene conversions) between the original beta-thalassaemia chromosome and the other chomosomal structures present in the normal population.

Algeria↗