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Stephan Beck

Publications and source records attributed to Stephan Beck.

14 recordsLinked to original sources
PubMed2004

Comparative genomic analysis of two avian (quail and chicken) MHC regions.

We mapped two different quail Mhc haplotypes and sequenced one of them (haplotype A) for comparative genomic analysis with a previously sequenced haplotype of the chicken Mhc. The quail haplotype A spans 180 kb of genomic sequence, encoding a total of 41 genes compared with only 19 genes within the 92-kb chicken Mhc. Except for two gene families (B30 and tRNA), both species have the same basic set of gene family members that were previously described in the chicken "minimal essential" Mhc. The two Mhc regions have a similar overall organization but differ markedly in that the quail has an expanded number of duplicated genes with 7 class I, 10 class IIB, 4 NK, 6 lectin, and 8 B-G genes. Comparisons between the quail and chicken Mhc class I and class II gene sequences by phylogenetic analysis showed that they were more closely related within species than between species, suggesting that the quail Mhc genes were duplicated after the separation of these two species from their common ancestor. The proteins encoded by the NK and class I genes are known to interact as ligands and receptors, but unlike in the quail and the chicken, the genes encoding these proteins in mammals are found on different chromosomes. The finding of NK-like genes in the quail Mhc strongly suggests an evolutionary connection between the NK C-type lectin-like superfamily and the Mhc, providing support for future studies on the NK, lectin, class I, and class II interaction in birds.

Animals↗
PubMed2004

Complete MHC haplotype sequencing for common disease gene mapping.

The future systematic mapping of variants that confer susceptibility to common diseases requires the construction of a fully informative polymorphism map. Ideally, every base pair of the genome would be sequenced in many individuals. Here, we report 4.75 Mb of contiguous sequence for each of two common haplotypes of the major histocompatibility complex (MHC), to which susceptibility to >100 diseases has been mapped. The autoimmune disease-associated-haplotypes HLA-A3-B7-Cw7-DR15 and HLA-A1-B8-Cw7-DR3 were sequenced in their entirety through a bacterial artificial chromosome (BAC) cloning strategy using the consanguineous cell lines PGF and COX, respectively. The two sequences were annotated to encompass all described splice variants of expressed genes. We defined the complete variation content of the two haplotypes, revealing >18,000 variations between them. Average SNP densities ranged from less than one SNP per kilobase to >60. Acquisition of complete and accurate sequence data over polymorphic regions such as the MHC from large-insert cloned DNA provides a definitive resource for the construction of informative genetic maps, and avoids the limitation of chromosome regions that are refractory to PCR amplification.

Autoimmune Diseases↗
PubMed2003

Co-duplication of olfactory receptor and MHC class I genes in the mouse major histocompatibility complex.

We report the 897 kb sequence of a cluster of olfactory receptor (OR) genes located at the distal end of the major histocompatibility complex (MHC) class I region on mouse chromosome 17 of strain 129/SvJ (H2bc). With additional information from the mouse genome draft sequence, we identified 59 OR loci (approximately 20% pseudogenes) in contrast to only 25 OR loci (approximately 50% pseudogenes) in the corresponding centromeric OR cluster that is part of the 'extended MHC class I region' on human chromosome 6. Comparative analysis leads to three major observations: (i) most of the OR subfamilies have evolved independently in the two species, expanding more in the mouse, and resulting in co-orthologs--subfamilies of highly similar paralogs that keep orthologous relationships with their human counterparts; (ii) three of the mouse OR subfamilies have no orthologs in humans; and (iii) MHC class I loci are interspersed in the OR cluster in mouse but not in human, and were subjected to co-duplication with OR genes. Screening of our sequence against the available sequences of other strains/haplotypes revealed that most of the OR loci are polymorphic and that the number of OR loci may vary among strains/haplotypes. Our findings that MHC-linked OR loci share duplication with MHC class I loci, have duplicated extensively and are polymorphic revives questions about potential reciprocal influences acting on the dynamics and evolution of the H2 region and the H2-linked OR loci.

Alleles↗
PubMed2003

Complex transcription and splicing of odorant receptor genes.

Human major histocompatibility (human leucocyte antigen (HLA)) complex-linked odorant receptor (OR) genes are among the best characterized OR genes in the human genome. In addition to their functions as odorant receptors in olfactory epithelium, they have been suggested to play a role in the fertilization process. Here, we report the first in-depth analysis of their expression and regulation within testicular tissue. Sixteen HLA-linked OR and three non-HLA-linked OR were analyzed. One OR gene (hs6M1-16, in positive transcriptional orientation) exhibited six different transcriptional start sites combined with extensive alternative splicing within the 5'-untranslated region, the coding exon, and the 3'-untranslated region. Long distance splicing, exon sharing, and premature polyadenylation were features of another three OR loci (hs6M1-18, -21, and -27, all upstream of hs6M1-16, but in negative transcriptional orientation). Determination of the transcriptional start sites of these OR genes identified a region of 81 bp with potential bi-directional transcriptional activity. The results demonstrate that HLA-linked OR genes are subject to unusually complex transcriptional regulatory mechanisms.

Base Sequence↗
PubMed2003

The human TREM gene cluster at 6p21.1 encodes both activating and inhibitory single IgV domain receptors and includes NKp44.

We have characterized a cluster of single immunoglobulin variable (IgV) domain receptors centromeric of the major histocompatibility complex (MHC) on human chromosome 6. In addition to triggering receptor expressed on myeloid cells (TREM)-1 and TREM2, the cluster contains NKp44, a triggering receptor whose expression is limited to NK cells. We identified three new related genes and two gene fragments within a cluster of approximately 200 kb. Two of the three new genes lack charged residues in their transmembrane domain tails. Further, one of the genes contains two potential immunotyrosine Inhibitory motifs in its cytoplasmic tail, suggesting that it delivers inhibitory signals. The human and mouse TREM clusters appear to have diverged such that there are unique sequences in each species. Finally, each gene in the TREM cluster was expressed in a different range of cell types.

Amino Acid Motifs↗
PubMed2003

Immunogenomics: towards a digital immune system.

One of the major differences that set apart vertebrates from non-vertebrates is the presence of a complex immune system. Over the past 400-500 million years, many novel immune genes and gene families have emerged and their products form sophisticated pathways providing protection against most pathogens. The Human Genome Project has laid the foundation to study these genes and pathways in unprecedented detail. Members of the immunoglobulin (Ig) superfamily alone were found to make up over 2% of human genes possibly constituting the largest gene family in the human genome. A subgroup of these human immune genes, those (among others) involved in antigen processing and presentation, are encoded in a single region, the major histocompatibility complex (MHC) on the short arm of chromosome 6. My laboratory has a long-standing interest in understanding the molecular organization and evolution of the MHC. To this end, we have been generating a range of MHC genomic resources that we make available in the form of maps and databases. Much of the complex data of the immune system can be reduced to binary (on/off) information that can easily be made available and analysed by bioinformatics approaches, thus contributing to better understand immune function via a 'digital immune system'.

Animals↗
PubMed2002

Initial sequencing and comparative analysis of the mouse genome.

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

Animals↗
PubMed2002

Recruitment of heterogeneous nuclear ribonucleoprotein A1 in vivo to the LMP/TAP region of the major histocompatibility complex.

Sequences containing the matrix recognition signature were identified adjacent to the LMP/TAP gene cluster in the human and mouse major histocompatibility complex class II region. These sequences were shown to function as nuclear matrix attachment regions (MARs). Three of the five human MARs and the single mouse MAR recruit heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) in vivo during transcriptional up-regulation of the major histocompatibility complex class II genes. The timing of this recruitment correlates with a rise in mature TAP1 mRNA. Two of the human MARs bind hnRNP-A1 in vitro directly within a 35-bp sequence that shows over 90% similarity to certain Alu repeat sequences. This study shows that MARs recruit and bind hnRNP-A1 upon transcriptional up-regulation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

The human homologue of unc-93 maps to chromosome 6q27 - characterisation and analysis in sporadic epithelial ovarian cancer.

BACKGROUND: In sporadic ovarian cancer, we have previously reported allele loss at D6S193 (62%) on chromosome 6q27, which suggested the presence of a putative tumour suppressor gene. Based on our data and that from another group, the minimal region of allele loss was between D6S264 and D6S149 (7.4 cM). To identify the putative tumour suppressor gene, we established a physical map initially with YACs and subsequently with PACs/BACs from D6S264 to D6S149. To accelerate the identification of genes, we sequenced the entire contig of approximately 1.1 Mb. Seven genes were identified within the region of allele loss between D6S264 and D6S149. RESULTS: The human homologue of unc-93 (UNC93A) in C. elegans was identified to be within the interval of allele loss centromeric to D6S149. This gene is 24.5 kb and comprises of 8 exons. There are two transcripts with the shorter one due to splicing out of exon 4. It is expressed in testis, small intestine, spleen, prostate, and ovary. In a panel of 8 ovarian cancer cell lines, UNC93A expression was detected by RT-PCR which identified the two transcripts in 2/8 cell lines. The entire coding sequence was examined for mutations in a panel of ovarian tumours and ovarian cancer cell lines. Mutations were identified in exons 1, 3, 4, 5, 6 and 8. Only 3 mutations were identified specifically in the tumour. These included a c.452G>A (W151X) mutation in exon 3, c.676C>T (R226X) in exon 5 and c.1225G>A(V409I) mutation in exon 8. However, the mutations in exon 3 and 5 were also present in 6% and 2% of the normal population respectively. The UNC93A cDNA was shown to express at the cell membrane and encodes for a protein of 60 kDa. CONCLUSIONS: These results suggest that no evidence for UNC93A as a tumour suppressor gene in sporadic ovarian cancer has been identified and further research is required to evaluate its normal function and role in the pathogenesis of ovarian cancer.

Amino Acid Sequence↗
PubMed2002

Physical and transcript map of the region between D6S264 and D6S149 on chromosome 6q27, the minimal region of allele loss in sporadic epithelial ovarian cancer.

We have previously shown a high frequency of allele loss at D6S193 (62%) on chromosomal arm 6q27 in ovarian tumours and mapped the minimal region of allele loss between D6S297 and D6S264 (3 cM). We isolated and mapped a single non-chimaeric YAC (17IA12, 260-280 kb) containing D6S193 and D6S297. A further extended bacterial contig (between D6S264 and D6S149) has been established using PACs and BACs and a transcript map has been established. We have mapped six new markers to the YAC; three of them are ESTs (WI-15078, WI-8751, and TCP10). We have isolated three cDNA clones of EST WI-15078 and one clone contains a complete open reading frame. The sequence shows homology to a new member of the ribonuclease family. The other two clones are splice variants of this new gene. The gene is expressed ubiquitously in normal tissues. It is expressed in 4/8 ovarian cancer cell lines by Northern analysis. The gene encodes for a 40 kDa protein. Direct sequencing of the gene in all the eight ovarian cancer cell lines did not identify any mutations. Clonogenic assays were performed by transfecting the full-length gene in to ovarian cancer cell lines and no suppression of growth was observed.

Amino Acid Sequence↗
PubMed2002

A cluster of ten novel MHC class I related genes on human chromosome 6q24.2-q25.3.

We have identified a novel family of human major histocompatibility complex (MHC) class I genes. This MHC class I related gene family is defined by 10 members, among which 6 encode potentially functional glycoproteins. The 180-kb cluster containing them has been generated by serial duplication and minimal diversification of an ancestral prototype. They are not located within the MHC on 6p21.3, but near the tip of its long arm at q24.2-q25.3, close to the human equivalent of the mouse H2-linked t-complex, a subchromosomal region syntenic to a segment of mouse chromosome 10 harboring the orthologous MHC class I related retinoic acid early transcript loci, Raet1a-d. Hence we have named the identified loci RAET1E-N. Human RAET1 products are all devoid of the membrane-proximal immunoglobulin-like alpha3 domain and most, but not all, are predicted to remain membrane-anchored via glycosylphosphatidylinositol linkage and are shown to display an atypical pattern of polymorphism. RAET1 transcripts are absent from hematopoietic tissues, but largely expressed in tumors. The involvement of orthologous mouse RAET1A-D/H60 in natural killer and T-cell activation through NKG2D engagement augurs a similar function for the human RAET1 proteins.

Animals↗