Gene Ludwig - Podcast Details

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Plugged In - A Banking PodcastEp 13: Balancing Smart Regulation and Innovation // Gene LudwigIn today's episode, Steve and Al talk with Gene Ludwig, former Comptroller of the Currency and a banking regulation, risk management, and fiscal policy expert. Gene shares some powerful insights into modernizing the banking industry. They discuss the importance of smart regulation that helps to balance banking activities and technological advancements, the need for regulators to have the tools to manage tail risks quickly and avoid being caught off guard, and the need to have a mechanism that gives regulators and the public time to act in a crisis.2023-04-1929 min

New Books in FinanceGene Ludwig, "The Vanishing American Dream" (Disruption Books, 2020)Gene Ludwig cares. The former banker, government regulator, and serial entrepreneur cares deeply about the hollowing out of the American middle class over the past several decades, not least of all in his hometown of York, PA. So he gathered the country's best and brightest in 2019 for a conference at Yale Law School to come up with specific policy proposals that can reverse that process.The details of what has happened make for difficult but necessary reading. In The Vanishing American Dream: A Frank Look at the Economic Realities Facing Middle- and Lower-Income Americans (Disruption Books) the...2020-09-2852 min

Fakultät für Mathematik, Informatik und Statistik - Digitale Hochschulschriften der LMU - Teil 02/02Network-based analysis of gene expression dataThe methods of molecular biology for the quantitative measurement of gene expression have undergone a rapid development in the past two decades. High-throughput assays with the microarray and RNA-seq technology now enable whole-genome studies in which several thousands of genes can be measured at a time. However, this has also imposed serious challenges on data storage and analysis, which are subject of the young, but rapidly developing field of computational biology. To explain observations made on such a large scale requires suitable and accordingly scaled models of gene regulation. Detailed models, as available for single genes, need to be extended...2016-04-2900 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 05/06Role and regulation of TET-mediated DNA modifications in gene expressionIn the mammalian genome, cytosine methylation (5mC) plays a central role in the epigenetic regulation of gene expression and has been implicated in a variety of biological processes, including genome stability, imprinting or differentiation. Compared to other epigenetic marks, DNA methylation has been thought to be relatively stable. However, genome-wide loss of 5mC, or DNA demethylation, has been observed in specific developmental stages and in various types of cancer. The discovery of the TET family of enzymes in 2009 was a watershed moment in comprehending the mechanisms of DNA demethylation. TET proteins oxidize 5mC to 5- hydroxymethylcytosine (5hmC), 5-formlycytosine (5fC) and 5...2014-12-1900 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 05/06Local adaptation of gene regulation in natural populations of Drosophila melanogasterThe central goal of this dissertation is to understand the genetic and functional aspects of how populations adapt to new or changing environments. Genetic variation within a population, either at protein coding genes or at regulatory elements, provides the substrate upon which natural selection can act to drive adaptation. There is considerable evidence that changes in gene expression account for a large proportion of morphological, physiological and behavioral variation between and within species that can contribute to adaptation and speciation. Due to the major role that gene expression changes can have in shaping phenotypes, the first three chapters of this...2014-07-0200 min

Medizin - Open Access LMU - Teil 22/22A large kindred of pulmonary fibrosis associated with a novel ABCA3 gene variantBackground: Interstitial lung disease occurring in children is a condition characterized by high frequency of cases due to genetic aberrations of pulmonary surfactant homeostasis, that are also believed to be responsible of a fraction of familial pulmonary fibrosis. To our knowledge, ABCA3 gene was not previously reported as causative agent of fibrosis affecting both children and adults in the same kindred. Methods: We investigated a large kindred in which two members, a girl whose interstitial lung disease was first recognized at age of 13, and an adult, showed a diffuse pulmonary fibrosis with marked differences in terms of morphology and imaging...2014-01-0100 min

Tierärztliche Fakultät - Digitale Hochschulschriften der LMU - Teil 06/07Identifizierung Interferon-regulierter Gene beim HaushuhnTyp I Interferon stellt einen essentiellen Teil der angeborenen Immunantwort dar und besitzt antivirale und immunmodulatorische Eigenschaften. Diese Funktionen werden durch die Induktion sogenannter Interferon-regulierter Gene (IRGs) vermittelt, deren Expression in der Zelle nach Bindung von IFN an seinen Rezeptor reguliert wird. Im Rahmen dieser Arbeit gelang es mit Hilfe verschiedener Ansätze erstmals, eine umfassende Anzahl Typ I Interferon-regulierte Gene beim Huhn zu identifizieren. Hierzu wurden umfangreiche Datenbankrecherchen und Transkriptomanalysen von Milz und Lunge sowohl nach Applikation von rekombinanten Hühner Interferon alpha, als auch einer Infektion mit Newcastle Disease Virus, einem starken IFN Induktor, durchgeführt. Etwa 30% der hie...2013-07-2000 min

Medizin - Open Access LMU - Teil 20/22Gene set of nuclear-encoded mitochondrial regulators is enriched for common inherited variation in obesityThere are hints of an altered mitochondrial function in obesity. Nuclear-encoded genes are relevant for mitochondrial function (3 gene sets of known relevant pathways: (1) 16 nuclear regulators of mitochondrial genes, (2) 91 genes for oxidative phosphorylation and (3) 966 nuclear-encoded mitochondrial genes). Gene set enrichment analysis (GSEA) showed no association with type 2 diabetes mellitus in these gene sets. Here we performed a GSEA for the same gene sets for obesity. Genome wide association study (GWAS) data from a case-control approach on 453 extremely obese children and adolescents and 435 lean adult controls were used for GSEA. For independent confirmation, we analyzed 705 obesity GWAS trios (extremely obese child and...2013-01-0100 min

Medizin - Open Access LMU - Teil 20/22Suv4-20h Histone Methyltransferases Promote Neuroectodermal Differentiation by Silencing the Pluripotency-Associated Oct-25 GenePost-translational modifications (PTMs) of histones exert fundamental roles in regulating gene expression. During development, groups of PTMs are constrained by unknown mechanisms into combinatorial patterns, which facilitate transitions from uncommitted embryonic cells into differentiated somatic cell lineages. Repressive histone modifications such as H3K9me3 or H3K27me3 have been investigated in detail, but the role of H4K20me3 in development is currently unknown. Here we show that Xenopus laevis Suv4-20h1 and h2 histone methyltransferases (HMTases) are essential for induction and differentiation of the neuroectoderm. Morpholino-mediated knockdown of the two HMTases leads to a selective and...2013-01-0100 min

Medizin - Open Access LMU - Teil 20/22Repair of large segmental bone defects: BMP-2 gene activated muscle grafts vs. autologous bone graftingBackground: Common cell based strategies for the treatment of osseous defects require the isolation and expansion of autologous cells. Since this makes such approaches time-consuming and expensive, we developed a novel expedited technology creating gene activated muscle grafts. We have previously shown that large segmental bone defects in rats can be regenerated by implantation of muscle tissue fragments activated by BMP-2 gene transfer. Results: In the present study, we compared the bone healing capacities of such gene activated muscle grafts with bone isografts, mimicking autologous bone grafting, the clinical gold standard for treatment of bone defects in patients. Two of 14...2013-01-0100 min

Medizin - Open Access LMU - Teil 20/22A commonly used rumen-protected conjugated linoleic acid supplement marginally affects fatty acid distribution of body tissues and gene expression of mammary gland in heifers during early lactationBackground: Conjugated linoleic acids (CLA) in general, and in particular the trans-10, cis-12 (t10, c12-CLA) isomer are potent modulators of milk fat synthesis in dairy cows. Studies in rodents, such as mice, have revealed that t10, c12-CLA is responsible for hepatic lipodystrophy and decreased adipose tissue with subsequent changes in the fatty acid distribution. The present study aimed to investigate the fatty acid distribution of lipids in several body tissues compared to their distribution in milk fat in early lactating cows in response to CLA treatment. Effects in mammary gland are further analyzed at gene expression level. Methods...2013-01-0100 min

Medizin - Open Access LMU - Teil 20/22A new reporter mouse cytomegalovirus reveals maintained immediate-early gene expression but poor virus replication in cycling liver sinusoidal endothelial cellsBackground: The MCMV major immediate early promoter/enhancer (MIEP) is a bidirectional promoter that drives the expression of the three immediate early viral genes, namely ie1, ie2 and ie3. The regulation of their expression is intensively studied, but still incompletely understood. Methods: We constructed a reporter MCMV, (MCMV-MIEPr) expressing YFP and tdTomato under the control of the MIEP as proxies of ie1 and ie2, respectively. Moreover, we generated a liver sinusoidal endothelial cell line (LSEC-uniLT) where cycling is dependent on doxycycline. We used these novel tools to study the kinetics of MIEP-driven gene expression in the context of infection and...2013-01-0100 min

Fakultät für Physik - Digitale Hochschulschriften der LMU - Teil 04/05Experiment and quantitative modeling of cell-free gene expression dynamicsGenexpression that is the cellular synthesis of proteins is comprised of the sub-steps tran- scription (mRNA synthesis based on the DNA master), translation (protein synthesis based on the mRNA) and protein folding. Owing to the large number of interactions between individual components this process is very complex in vivo and therefore mathematical modeling is extremely laborious. By means of simpli�ed in vitro model systems individual aspects of cellular gene expression can be studied in detail. Cell-free gene expression denotes the biochemical synthesis of proteins in vitro. Cell-free systems are comprised of the predominant components of the cellular transcription and tr...2012-12-0500 min

Medizin - Open Access LMU - Teil 20/22Real-time transcriptional profiling of cellular and viral gene expression during lytic cytomegalovirus infection.During viral infections cellular gene expression is subject to rapid alterations induced by both viral and antiviral mechanisms. In this study, we applied metabolic labeling of newly transcribed RNA with 4-thiouridine (4sU-tagging) to dissect the real-time kinetics of cellular and viral transcriptional activity during lytic murine cytomegalovirus (MCMV) infection. Microarray profiling on newly transcribed RNA obtained at different times during the first six hours of MCMV infection revealed discrete functional clusters of cellular genes regulated with distinct kinetics at surprising temporal resolution. Immediately upon virus entry, a cluster of NF-κB- and interferon-regulated genes was induced. Rapid viral counter-regulation of t...2012-09-0100 min

Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 14/19Adenovirus-based gene therapy approaches for hemophilia BGene therapy can be used to treat devastating inherited diseases, especially diseases and patients that are not suitable for a conventional cure. The blood clotting disorder hemophilia is one of the most extensively studied monogenetic diseases in gene therapeutic approaches. Several viral vectors were tested for the treatment of hemophilia B. The administration of an episomal adenoviral vector at non-toxic dose showed effective phenotypic correction, but the therapeutic effect was only transient. Therefore, the combination of non-viral integration machineries for somatic integration with adenoviral vectors for efficient delivery offers a promising alternative for achieving persistent transgene expression. Towards this end...2012-06-1200 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 04/06The influence of sex on gene expression and protein evolution in Drosophila melanogasterA long-standing question in evolutionary biology concerns the molecular causes underlying adaptive evolution. These can either stem from structural changes in proteins or from changes in the expression patterns of proteins or mature RNAs. Over the last decade, many studies have shown that gene expression changes can have a huge impact on the phenotype of an organism and play an important role in adaptive evolution. A major prerequisite for adaptive evolution to occur at the gene expression level is the presence of expression variation among members of a population. This variation serves as the raw material for adaptive evolution. The...2012-04-0200 min

Fakultät für Mathematik, Informatik und Statistik - Digitale Hochschulschriften der LMU - Teil 01/02Activity of microRNAs and transcription factors in Gene Regulatory NetworksIn biological research, diverse high-throughput techniques enable the investigation of whole systems at the molecular level. The development of new methods and algorithms is necessary to analyze and interpret measurements of gene and protein expression and of interactions between genes and proteins. One of the challenges is the integrated analysis of gene expression and the associated regulation mechanisms. The two most important types of regulators, transcription factors (TFs) and microRNAs (miRNAs), often cooperate in complex networks at the transcriptional and post-transcriptional level and, thus, enable a combinatorial and highly complex regulation of cellular processes. For instance, TFs activate and inhibit...2012-02-1000 min

Medizin - Open Access LMU - Teil 18/22Expression of a neuroendocrine gene signature in gastric tumor cells from CEA 424-SV40 large T antigen-transgenic mice depends on SV40 large T antigen.A large fraction of murine tumors induced by transgenic expression of SV40 large T antigen (SV40 TAg) exhibits a neuroendocrine phenotype. It is unclear whether SV40 TAg induces the neuroendocrine phenotype by preferential transformation of progenitor cells committed to the neuroendocrine lineage or by transcriptional activation of neuroendocrine genes. To address this question we analyzed CEA424-SV40 TAg-transgenic mice that develop spontaneous tumors in the antral stomach region. Immunohistology revealed expression of the neuroendocrine marker chromogranin A in tumor cells. By ELISA an 18-fold higher level of serotonin could be detected in the blood of tumor-bearing mice in comparison to...2012-01-0100 min

Medizin - Open Access LMU - Teil 18/22Characterization of Ku70(2)-NLS as bipartite nuclear localization sequence for non-viral gene delivery.Several barriers have to be overcome in order to achieve gene expression in target cells, e.g. cellular uptake, endosomal release and translocation to the nucleus. Nuclear localization sequences (NLS) enhance gene delivery by increasing the uptake of plasmid DNA (pDNA) to the nucleus. So far, only monopartite NLS were analysed for non-viral gene delivery. In this study, we examined the characteristics of a novel bipartite NLS like construct, namely NLS Ku70. We synthesized a dimeric structure of a modified NLS from the Ku70 protein (Ku70(2)-NLS), a nuclear transport active mutant of Ku70(2)-NLS (s1Ku70(2)-NLS) and a...2012-01-0100 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 04/06Analysis of paternal plastid inheritance in Arabidopsis thaliana and its impact on biosafety of gene-modified plantsGenetically modified plants for the use of transgene containment are a central concern. Nuclear gene flow is one of the most discussed topics in our days; therefore, plastid genetic engineering is a promising tool to reduce the risk of transgene flow, because in most angiosperm species plastids are inherited maternally. In addition, plastid transformation has the advantage that the site of gene insertion can be controlled, high rates of transgene expression and protein accumulation can be achieved and epigenetic effects are absent. In Arabidopsis pollen, plastids are inherited also maternally and not created de novo, but arise from pre-existing plastids...2011-03-2800 min

Medizin - Open Access LMU - Teil 17/22Gene-disease network analysis reveals functional modules in mendelian, complex and environmental diseasesScientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge...2011-01-0100 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 04/06Gene Expression Profiling of Encephalitogenic CD4+ T cells: Identification of Genes Controlling Migration of Effector T cells into the CNST cells directed against brain antigens are generally held to play a crucial role in the initiation of multiple sclerosis (MS). This was deduced from experimental autoimmune encephalomyelitis (EAE). In this model for MS, T cells reactive for myelin antigens induced a severe paralytic disease upon transfer to healthy syngeneic recipients. Intriguingly, the disease does not start immediately upon transfer of the pathogenic effector T cells. Instead, as earlier studies have shown, the effector T cells attack their target organ only after having migrated in the periphery through secondary lymphoid organs. The aim of the project was to characterize the...2010-10-2500 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 04/06Identifikation zellulärer Ziel-Gene KSHV-kodierter miRNAsHerpesviren exprimieren Micro-(mi)RNAs, welche die Expression von zellulären und viralen Genen beeinflussen. Das Genom des Kaposi Sarkom Assoziierten Herpesvirus (KSHV) kodiert ein Cluster von insgesamt 12 miRNAs, welche sowohl während der latenten, als auch während der lytischen Infektion exprimiert werden. Da bisher nur sehr wenige zelluläre Zielgene für KSHV miRNAs bekannt sind, war es das Ziel dieser Studie, Gene zu identifizieren, deren Expression durch virale miRNAs von KSHV beeinflusst wird. Zu diesem Zweck wurden KSHV miRNAs mit Hilfe eines lentiviralen Transduktionssystems in B-Zellen und in Endothelzellen exprimiert. Diese sind beide natürliche Wirtszellen für KSHV...2010-07-0700 min

Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 11/19Fluorescence labeled PEI-based gene delivery systems for near infrared imaging in nude miceGene therapy is a research area where nucleic acids are transferred into cells to treat neoplastic, metabolic and hereditary diseases. Delivery of genetic material into living organisms can be achieved with viral or non-viral vectors. Viral gene carriers are very efficient but present some major disadvantages due to their pathogenicity and immunogenicity. Nonviral carriers are based on synthetic molecules binding and condensing nucleic acids into small, virus-like particles. The aim of this thesis was to study the biodistribution and tumor targeting properties of non-viral gene vectors based on polyethylenimine (PEI) after systemic injection into mice. The gene vectors were labeled...2010-03-0400 min

Medizin - Open Access LMU - Teil 17/22Mutations in the WTX - gene are found in some high-grade microsatellite instable (MSI-H) colorectal cancersBackground: Genetically, colorectal cancers (CRCs) can be subdivided into tumors with chromosomal instability (CIN) or microsatellite instability (MSI). In both types of CRCs genes that are involved in the degradation of beta-CATENIN are frequently mutated. Whereas in CIN CRCs APC (Adenomatous Polyposis Coli) is affected in most cases, high grade MSI (MSI-H) CRCs frequently display mutations in various genes, like the APC-, AXIN2- or CTNNBI (beta-CATENIN) gene itself. Recently in Wilms tumors, WTX (Wilms tumor gene on the X-chromosome) was discovered as another gene involved in the destruction of beta-CATENIN. As the WTX-gene harbors a short T(6)-microsatellite in...2010-01-0100 min

Medizin - Open Access LMU - Teil 16/22Systematic analysis of a novel human renal glomerulus-enriched gene expression dataset.Glomerular diseases account for the majority of cases with chronic renal failure. Several genes have been identified with key relevance for glomerular function. Quite a few of these genes show a specific or preferential mRNA expression in the renal glomerulus. To identify additional candidate genes involved in glomerular function in humans we generated a human renal glomerulus-enriched gene expression dataset (REGGED) by comparing gene expression profiles from human glomeruli and tubulointerstitium obtained from six transplant living donors using Affymetrix HG-U133A arrays. This analysis resulted in 677 genes with prominent overrepresentation in the glomerulus. Genes with 'a priori' known prominent glomerular...2010-01-0100 min

Medizin - Open Access LMU - Teil 16/22Variants of the FADS1 FADS2 gene cluster, blood levels of polyunsaturated fatty acids and eczema in children within the first 2 years of life.Association of genetic-variants in the FADS1-FADS2-gene-cluster with fatty-acid-composition in blood of adult-populations is well established. We analyze this genetic-association in two children-cohort-studies. In addition, the association between variants in the FADS-gene-cluster and blood-fatty-acid-composition with eczema was studied. Data of two population-based-birth-cohorts in The Netherlands and Germany (KOALA, LISA) were pooled (n = 879) and analyzed by (logistic) regression regarding the mutual influence of single-nucleotide-polymorphisms (SNPs) in the FADS-gene-cluster (rs174545, rs174546, rs174556, rs174561, rs3834458), on polyunsaturated fatty acids (PUFA) in blood and parent-reported eczema until the age of 2 years. All SNPs were highly significantly associated with all PUFAs except for alpha-linolenic-acid and...2010-01-0100 min

Medizin - Open Access LMU - Teil 16/22Evidence for STAT4 as a common autoimmune gene: rs7574865 is associated with colonic Crohn's disease and early disease onset.Recent studies demonstrated an association of STAT4 variants with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), indicating that multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 variants on the susceptibility and phenotype of inflammatory bowel diseases (IBD) in a large patient and control cohort. Genomic DNA from 2704 individuals of Caucasian origin including 857 patients with Crohn's disease (CD), 464 patients with ulcerative colitis (UC), and 1383 healthy, unrelated controls was analyzed for seven SNPs in the STAT4 gene (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694, rs10174238). In addition, a detailed genotype-phenotype analysis was performed. Our analysis revealed...2010-01-0100 min

Podcast Archives - The Jazz SessionThe Jazz Session #72: Gene Ludwig Jason Crane interviews organist Gene Ludwig. He tossed a coin to decide whether to be an engineer or a musician. With that out of the way, Ludwig came on the scene in the late 1950s and has made a living playing the organ ever since. He’s been in the bands of Sonny Stitt and Arthur Prysock, and has played opposite everyone from Dizzy Gillespie to Cannonball Adderley. The musical samples in this interview are from Ludwig’s recording Hands On (Blue Leaf Records, 2003). Learn more at GeneLudwig.com. If you’d like t...2009-08-1700 min

The Jazz SessionThe Jazz Session #72: Gene Ludwig Jason Crane interviews organist Gene Ludwig. He tossed a coin to decide whether to be an engineer or a musician. With that out of the way, Ludwig came on the scene in the late 1950s and has made a living playing the organ ever since. He’s been in the bands of Sonny Stitt and Arthur Prysock, and has played opposite everyone from Dizzy Gillespie to Cannonball Adderley. The musical samples in this interview are from Ludwig’s recording Hands On (Blue Leaf Records, 2003). Learn more at GeneLudwig.com. If you’d like t...2009-08-1700 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 03/06Impact of glyphosate application to transgenic Roundup Ready® soybean on horizontal gene transfer of the EPSPS gene to Bradyrhizobium japonicum and on the root-associated bacterial communityAbstract In this study, two topics causing major public concern related to transgenic plants were investigated: The possibility of a horizontal gene transfer from plant to bacteria and the impact of transgenic plants after herbicide treatment on root associated bacteria. The transgenic plant chosen for this study was Roundup Ready® (RR) soybean, which is tolerant to the herbicide glyphosate and is the most commonly used genetically modified crop worldwide. Glyphosate, the active ingredient of Roundup Ready®, inhibits the EPSPS enzyme (5-enolpyruvylshikimate-3-phosphate synthase). EPSPS is an enzyme involved in the shikimic acid pathway leading to the aromatic amino acid biosynthesis an...2009-07-1400 min

Medizin - Open Access LMU - Teil 16/22Gene-Gene Interaction between APOA5 and USF1: Two Candidate Genes for the Metabolic SyndromeObjective: The metabolic syndrome, a major cluster of risk factors for cardiovascular diseases, shows increasing prevalence worldwide. Several studies have established associations of both apolipoprotein A5 (APOA5) gene variants and upstream stimulatory factor 1 (USF1) gene variants with blood lipid levels and metabolic syndrome. USF1 is a transcription factor for APOA5. Methods: We investigated a possible interaction between these two genes on the risk for the metabolic syndrome, using data from the German population-based KORA survey 4 (1,622 men and women aged 55-74 years). Seven APOA5 single nucleotide polymorphisms (SNPs) were analyzed in combination with six USF1 SNPs, applying logistic regression in an...2009-01-0100 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 03/06Evolution of gene expression and gene-regulatory sequences in Drosophila melanogasterIn this work, I investigate the role of gene regulatory changes in the evolution of Drosophila melanogaster. As a first step, I performed a survey of gene expression variation in the species using whole-genome microarrays. I surveyed eight strains from an ancestral African population and eight strains from a derived European population using an experimental design that allowed for the detection of expression differences within and between populations. Levels of gene expression variation were nearly equal within the two populations, but a higher amount of variation was detected in comparisons between the two populations. Most gene expression variation within populations...2008-12-0500 min

Fakultät für Mathematik, Informatik und Statistik - Digitale Hochschulschriften der LMU - Teil 01/02Text Mining and Gene Expression Analysis Towards Combined Interpretation of High Throughput DataMicroarrays can capture gene expression activity for thousands of genes simultaneously and thus make it possible to analyze cell physiology and disease processes on molecular level. The interpretation of microarray gene expression experiments profits from knowledge on the analyzed genes and proteins and the biochemical networks in which they play a role. The trend is towards the development of data analysis methods that integrate diverse data types. Currently, the most comprehensive biomedical knowledge source is a large repository of free text articles. Text mining makes it possible to automatically extract and use information from texts. This thesis addresses two key...2007-09-1300 min

Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 07/19Investigation of murine cytomegalovirus US22 gene family members m139 and m142Human cytomegalovirus is a ubiquitous human pathogen, causing disease in the immunocompromised host. Most of its ORFs have not been well studied due to a limited host range and slow growth of HCMV in cultured cells. MCMV, a natural pathogen isolated from mice, constitutes the most amenable animal model for human β-herpesviruses. To date most of its approximately 200 genes have an unknown function. For the analysis of these genes straightforward mutagenesis methods are necessary. With the cloning of herpesviruses as an infectious bacterial artificial chromosome a novel approach of mutagenesis has been established. Herpesviruses are now accessible to the tools o...2007-06-2800 min

Medizin - Open Access LMU - Teil 14/22SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome.Background: Heterozygous gain-of-function mutations in various genes encoding proteins of the Ras-MAPK signalling cascade have been identified as the genetic basis of Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS). Mutations of SOS1, the gene encoding a guanine nucleotide exchange factor for Ras, have been the most recent discoveries in patients with NS, but this gene has not been studied in patients with CFCS. Methods and results: We investigated SOS1 in a large cohort of patients with disorders of the NS–CFCS spectrum, who had previously tested negative for mutations in PTPN11, KRAS, BRAF, MEK1 and MEK2. Missense mutations of SOS1 we...2007-01-0100 min

Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 06/19Ectopic expression of the homeobox gene Cdx2 is the key transforming event in a mouse model of t(12;13)(p13;q12) acute myeloid leukemia; a novel mechanism in AMLThis thesis demonstrates for the first time that activation of a proto-oncogene by a chromosomal translocation can be the key step in myeloid leukemogenesis, even if a fusion gene is generated and expressed in parallel. This mechanism of AML leukemogenesis was proven in a murine model of t(12;13)(p13;q12) AML, showing that myeloid leukemogenesis is induced by the ectopic expression of Cdx2 and not by the ETV6/CDX2 chimeric gene. Mice transplanted with bone marrow cells retrovirally engineered to express Cdx2 rapidly succumbed to fatal and transplantable AML. In contrast, mice which were transplanted with BM cells expressing the...2006-11-0600 min

Fakultät für Mathematik, Informatik und Statistik - Digitale Hochschulschriften der LMU - Teil 01/02Contextual Analysis of Gene Expression DataAs measurement of gene expression using microarrays has become a standard high throughput method in molecular biology, the analysis of gene expression data is still a very active area of research in bioinformatics and statistics. Despite some issues in quality and reproducibility of microarray and derived data, they are still considered as one of the most promising experimental techniques for the understanding of complex molecular mechanisms. This work approaches the problem of expression data analysis using contextual information. While all analyses must be based on sound statistical data processing, it is also important to include biological knowledge to arrive at...2006-07-2000 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06Identification and functional characterization of the human and murine OSTL gene, which encodes a RING-DRIL-RING domain protein possibly involved in B cell differentiation and leukemogenesisThe OSTL gene is localized at the band q23 in the chromosome 6. Its localization corresponds to a translocation breakpoint between chromosomes 6 and 12, the t(6;12)(q23;p13), that was characterized in our group in an acute lymphoblastic leukemia cell line. This translocation involves the ETV6 (translocation ETs leukemia) gene localized in chromosome 12 with the STL (six twelve leukemia gene) gene localized in chromosome 6. The STL gene shares the first exon with a novel gene, that we named OSTL (opposite STL), but they are transcribed in opposite directions. Since the fusion gene ETV6/STL encodes only for a very small protein which...2006-05-2900 min

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06Cell culture models and novel gene therapeutic strategies for colorectal cancerThe development of relevant cellular model systems for colorectal cancer is of utmost importance for an improved in vitro assessment of therapeutic strategies against colorectal cancer. Recently published low passage colon cancer cell lines that closely reflect the characteristics of the respective parental in vivo tumor cells represent very promising cell culture models and were therefore used for the investigations in the present thesis. To provide an in vitro model system that also recapitulates the three-dimensional structure of in vivo tumors, these low passage cell lines were cultivated as multicellular spheroids. Compared to monolayer cultures the multicellular spheroids exhibited a...2006-02-1500 min

Tierärztliche Fakultät - Digitale Hochschulschriften der LMU - Teil 02/07Analysis of the Leukemogenic Potential of the CALM/AF10 Fusion Gene in Patients, Transgenic Mice and Cell Culture ModelsThe t(10;11)(p13;q14) is a recurring translocation resulting in the fusion of the CALM and AF10 genes. The leukemogenic CALM/AF10 fusion genes codes for a 1595 amino acids protein. This translocation was first identified in a patient with hystiocytic lymphoma and was subsequently found in patients with AML, T-ALL and malignant lymphoma. This translocation is found in younger patients and is associated with a poor prognosis. The CALM/AF10-associated leukemias can exhibit myeloid, lymphoid or mixed lymphoid-meyloid features, indicating a stem cell or an early commited progenitor as the target cell of leukemic transformation. At the present time...2006-02-1000 min

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06Novel biodegradable gene carriers based on oligomerized polyaminesGene therapy is a very promising approach to treat or to prevent diseases. However, progress in this field is hindered by lack of suitable vectors. Current research focuses on the development of novel nonviral biodegradable gene carriers with improved gene transfer activity and low toxicity. In the course of this thesis, a library of degradable DNA compacting domains based on oligomerized polyamines was synthesized and analyzed. Degradation of the originated polymers was either based on site-specific reductive cleavage of disulfide bonds or on time-dependent ester/amide hydrolysis. DNA binding activity, polyplex stability, transfection efficiency, toxicity, and hemocompatibility studies were performed...2006-01-2400 min

Medizin - Open Access LMU - Teil 14/22The sepiapterin reductase gene region reveals association in the PARK3 locus: analysis of familial and sporadic Parkinson's disease in European populationsBackground: Parkinson's disease is a genetically complex disease with mixed mode of inheritance. Recently, a haplotype across the sepiapterin reductase (SPR) gene, which is located in the PARK3 linkage region, was shown to modulate age of onset of Parkinson's disease in sibships from North America.Objective: To make a thorough assessment of the SPR gene region in sporadic Parkinson's disease.Methods: A linkage study in 122 European sibship families with five microsatellite and 17 single nucleotide polymorphism (SNP) markers in and around the SPR gene region, and an association analysis in 340 sporadic cases of Parkinson's disease and 680 control subjects from Germany with 40...2006-01-0100 min

Medizin - Open Access LMU - Teil 14/22Gene and protein nomenclature in public databasesBackground: Frequently, several alternative names are in use for biological objects such as genes and proteins. Applications like manual literature search, automated text-mining, named entity identification, gene/protein annotation, and linking of knowledge from different information sources require the knowledge of all used names referring to a given gene or protein. Various organism-specific or general public databases aim at organizing knowledge about genes and proteins. These databases can be used for deriving gene and protein name dictionaries. So far, little is known about the differences between databases in terms of size, ambiguities and overlap. Results: We compiled five gene and...2006-01-0100 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06Endothellzellproliferation und die Identifizierung neuer pro-angiogener Gene durch ein neuartiges Hochdurchsatz-Screen-SystemDas Blutgefäßsystem eines Organismus stellt eines der größten Organe des menschlichen Körpers dar. Den Grundbaustein der Gefäße bilden Endothelzellen, die durch eine einfache Zellschicht das gesamte System von innen auskleiden. Bei einer Vielzahl an physiologischen und pathophysiologischen Prozessen, wie beispielsweise dem weiblichen Menstruationszyk¬lus, der Wundheilung, den Entzündungsreaktionen oder aber der Ischämie und der Tumorpro¬gression, spielt das Endothel eine wesentliche Rolle. Die Aktivierung der Endothelzellen wird durch zahlreiche verschiedene Faktoren reguliert, die entweder im Blut zirkulieren, von be¬nachbarten Zellen oder aber auch von Tumorzellen sezerniert werden können. Im Rahmen der vorliegenden Arbeit wurde...2005-12-1500 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06Gene expression profiling in acute leukemias: New insights into biology and a global approach to the diagnosis of leukemia using microarray technologyThe application of global gene expression profiling allows to obtain detailed molecular fingerprints of underlying gene expression in any cell of interest. In this work gene expression profiles were generated from a comprehensive cohort of leukemia patients and healthy donors referred to and diagnosed in the Laboratory for Leukemia Diagnostics, Munich, Germany, which is a nation-wide reference center for the diagnosis of hematologic malignancies. Thoroughly characterized clinical samples were analyzed by high-density microarrays interrogating the expression status of more than 33,000 transcripts. In one specific aspect of this work the potential application of gene expression signatures for the prediction and classification...2005-10-2600 min

Tierärztliche Fakultät - Digitale Hochschulschriften der LMU - Teil 02/07Identification of the nucleotide sequence of the lipoprotein lipase gene as well as its role in the development of hyperlipidemia and pancreatitis in the Miniature SchnauzerLipoprotein Lipase (LPL) is a key enzyme in lipid transport. It catalyses the hydrolysis of the triacylglycerol component of chylomicrons and very low-density lipoproteins (VLDL), providing non-esterified fatty acids for tissue utilization. The gene encoding for LPL has already been identified in several species except the dog. Mutations of the human LPL-gene have been shown to cause partial or complete malfunction of the enzyme, resulting in accumulation of lipoproteins in the blood. This condition is called familial LPL deficiency. LPL malfunction results in hyperlipoproteinemia, recurrent acute pancreatitis, and ultimately pancreatic insufficiency. Several authors have postulated a genetic cause for pancreatitis...2005-07-1500 min

Tierärztliche Fakultät - Digitale Hochschulschriften der LMU - Teil 02/07Klonieren der felinen Zytokin-Gene IL-2, GM-CSF und IFNγ zum adjuvanten, nonviralen gentherapeutischen Einsatz beim Fibrosarkom der KatzeThe feline fibrosarcoma is a spontaneous malignant soft tissue sarcoma. Due to the high recurrence rate of approximatelly 70 % even after radical surgical excision the prognosis is very poor. There have been carried out different gene-therapy protocolls adjuvant to tumour excision, yet. In the following study a local, nonviral gene-transfer with the feline cytokine-genes Interleukin 2, Granulocyte-macrophage colony-stimulating factor and Interferon γ is conducted. As local gene delivery system serves a collagen-sponge loaded with a plasmid-DNA-PEI-PEG-formulation. The immunomodulating cytokines are expected to improve the antigen presentation, to activate immune effector cells and to generate memory cells against specific tumour antigens. The goal is t...2005-07-1500 min

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06Improved nonviral gene vectors: Efficient and non-toxic polyplexes with enhanced endosomolytic activityFor the development of improved polyethylenimine (PEI) polyplexes towards ‘artificial viruses’ two key issues are i) to improve the toxicity profile of the applied vectors and ii) to enhance endosomal release, one of the major barriers to efficient gene transfer with PEI polyplexes. Nonviral vectors based on PEI usually contain an excess of PEI that is not complexed to DNA. Since free PEI contributes to cellular and systemic toxicity purification of polyplexes from unbound PEI is highly desirable. In this thesis an easy and efficient method based on size exclusion chromatography (SEC) was developed, which for the first time allowed comp...2005-02-2300 min

Medizin - Open Access LMU - Teil 14/22Structure and evolution of the mouse pregnancy-specific glycoprotein (Psg) gene locusBackground: The pregnancy-specific glycoprotein (Psg) genes encode proteins of unknown function, and are members of the carcinoembryonic antigen (Cea) gene family, which is a member of the immunoglobulin gene (Ig) superfamily. In rodents and primates, but not in artiodactyls (even-toed ungulates/hoofed mammals), there have been independent expansions of the Psg gene family, with all members expressed exclusively in placental trophoblast cells. For the mouse Psg genes, we sought to determine the genomic organisation of the locus, the expression profiles of the various family members, and the evolution of exon structure, to attempt to reconstruct the evolutionary history of this...2005-01-0100 min

Medizin - Open Access LMU - Teil 14/22ProMiner: rule-based protein and gene entity recognitionBackground: Identification of gene and protein names in biomedical text is a challenging task as the corresponding nomenclature has evolved over time. This has led to multiple synonyms for individual genes and proteins, as well as names that may be ambiguous with other gene names or with general English words. The Gene List Task of the BioCreAtIvE challenge evaluation enables comparison of systems addressing the problem of protein and gene name identification on common benchmark data. Methods: The ProMiner system uses a pre-processed synonym dictionary to identify potential name occurrences in the biomedical text and associate protein and gene database...2005-01-0100 min

Medizin - Open Access LMU - Teil 14/22Inter- and intra-specific gene-density-correlated radial chromosome territory arrangements are conserved in Old World monkeysRecently it has been shown that the gene-density correlated radial distribution of human 18 and 19 homologous chromosome territories (CTs) is conserved in higher primates in spite of chromosomal rearrangements that occurred during evolution. However, these observations were limited to apes and New World monkey species. In order to provide further evidence for the evolutionary conservation of gene-density-correlated CT arrangements, we extended our previous study to Old World monkeys. They comprise the remaining species group to be analyzed in order to obtain a comprehensive overview of the nuclear topology of human 18 and 19 homologous CTs in higher primates. In the present study we...2005-01-0100 min

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06NoRC, a novel chromatin remodeling complex involved in ribosomal RNA gene silencingRegulation of gene expression takes place in the nucleus in a highly structured and condensed nucleoprotein environment, called chromatin (Felsenfeld and Groudine, 2003; Khorasanizadeh, 2004; Vaquero et al., 2003). A broad group of factors regulates the properties of chromatin; e.g. by covalently modifying histones and / or by ATP-dependent chromatin remodeling, thereby allowing or preventing gene expression. The mammalian genome contains hundreds of gene copies encoding precursor ribosomal RNA and the transcription of these genes is highly regulated with respect to cellular metabolism (Grummt, 2003). However, even in actively growing cells, only a subset of the rRNA genes are actively transcribed, exhibiting an accessible...2004-11-1900 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 01/06Oxidativer Stress- assoziierter neuronaler Zelltod und die Identifikation neuroprotektiver Gene durch ein neuartiges Screening-SystemIn dieser Arbeit wurden mit Hilfe einer neuartigen Screening-Methode im Hochdurchsatz-Maßstab Gene identifiziert, welche einen Schutz vor dem bei Morbus Alzheimer assoziierten oxidativen Nervenzelltod vermitteln können. Dazu wurde jeder Klon einer cDNA Kollektion einzeln in klonale hippokampale Mausneuronen der Zelllinie HT-22 transient transfiziert und die Zellen anschließend mit einer toxischen Konzentration Wasserstoffperoxid stimuliert. Nach Inkubation wurde der Anteil lebender Zellen als Grad für den durch das transfizierte Gen vermittelten Schutz bestimmt. Auf diese Weise konnten sechs Gene identifiziert werden, welche HT-22 Zellen signifikant vor toxischen Konzentrationen von Wasserstoffperoxid schützten. Vier der sechs Gene: Glutathion Peroxidase-1, Perox...2004-07-2600 min

Tierärztliche Fakultät - Digitale Hochschulschriften der LMU - Teil 01/07Analysis and characterisation of the mouse Hic2 gene5.1 Analysis and characterization of the mouse Hic2 gene Like Hic1 and γFBP (chicken), Hic2 cDNA coded five Krüppel-type C2H2 zinc finger domain. Through the sequencing and comparation with different protein sequences from the homolog proteins from different species (HIC1, Hic1, HIC2, γFBP, and Hypothetical protein), Hic2 protein shares more than 80% homology with HIC1 through the BTB/POZ and zinc finger domains, and both proteins have identical GLDLSKK/R motifs. A new part of Hic2 gene coding, exon two, and new exon one deduced full-length Hic2 protein contains 601 amino acids. Hic2 gene has two Exons (240 and 1842 bp), with one Int...2004-02-1300 min

Medizin - Open Access LMU - Teil 13/22Topical colchicine selection of keratinocytes transduced with the multidrug resistance gene (MDR1) can sustain and enhance transgene expression in vivoIn gene therapy, a clinically relevant therapeutic effect requires long-term expression of the desired gene at a level sufficient to correct or at least alleviate the underlying gene defect. One approach to achieve persistent as well as high-level transgene expression in a significant percentage of target cells would be to select cells expressing both the desired transgene and a linked selectable gene such as the human multi-drug resistance (MDR1) gene-in a bicistronic vector. Because of its accessibility, the skin is a very attractive target tissue to select genetically modified cells, allowing topical application of a selecting agent, thus minimizing potential...2004-01-0100 min

Medizin - Open Access LMU - Teil 13/22Progress in the use of adeno-associated viral vectors for gene therapyThe development of safe and efficient gene transfer vectors is crucial for the success of gene therapy trials. A viral vector system promising to meet these requirements is based on the apathogenic adeno-associated virus (AAV-2), a member of the parvovirus family. The advantages of this vector system is the stability of the viral capsid, the low immunogenicity, the ability to transduce both dividing and non-dividing cells, the potential to integrate site specifically and to achieve long-term gene expression even in vivo, and its broad tropism allowing the efficient transduction of diverse organs including the skin. All this makes AAV-2 attractive...2004-01-0100 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 01/06Transcriptional Regulation of the Xenopus MyoD GeneMyoD is one of the MRFs (Muscle Regulatory Factors) and it functions to determine the muscle cell fate. The mechanism by which MyoD regulates the muscle development program is very well understood. However, the transcriptional regulation of the MyoD gene itself has not studied in Xenopus. In this thesis, I have analyzed the transcriptional regulatory mechanism of the MyoD gene in Xenopus by different approaches, which include transgenic reporter analysis of its cis-regulatory elements of MyoD transcription and gain-of-function and loss-of-function tests of several potential regulaters. Here I showed that the expression of the XmyoD gene is controlled by a...2003-07-2500 min

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 01/06Adeno-associated virus type 2 as vector for human gene therapy: Characterization of virus-host interactionsVectors based on adeno-associated virus type 2 (AAV) offer considerable promise for somatic gene therapy of various diseases (e.g. cystic fibrosis, hemophilia B, cancer). Limitations, however, still exist and require further improvement. The study presented here addresses two major problems that hamper a widespread use of AAV in human gene therapy: First, the loss of site-specific integration of recombinant AAV vectors (rAAV) due to the deletion of the rep gene, and secondly, the potential neutralization of AAV gene therapy vectors by preexisting antibodies. It could be demonstrated that site-specific integration of a transgene encoding rAAV vector can be efficiently restored...2003-06-2300 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 01/06Gene expression in plastids of higher plants: evolutionary and functional aspects of different RNA polymerases - coordinated assembly of multiprotein-complexesPlastid gene organisation maintains characteristics typical of its prokaryotic ancestry. The regulation of plastid gene expression however strongly deviates from that one its free-living cyanobacteria relatives. This intriguing complication of plastid gene expression characteristics is the result of an integration process of the cellular subgenomes that introduced eukaryotic traits into the formerly prokaryotic compartment (Herrmann et al. 1997). An interesting example for this process is the transcription system, which consists of both prokaryotic (PEP) and eukaryotic (NEP) RNA polymerases. In order to understand, how far the transcriptional apparatus within plastids was adapted to nuclear needs, three approaches have been undertaken. Firstly...2003-04-0800 min

Medizin - Open Access LMU - Teil 13/22Modeling gene expression measurement error: a quasi-likelihood approachBackground: Using suitable error models for gene expression measurements is essential in the statistical analysis of microarray data. However, the true probabilistic model underlying gene expression intensity readings is generally not known. Instead, in currently used approaches some simple parametric model is assumed (usually a transformed normal distribution) or the empirical distribution is estimated. However, both these strategies may not be optimal for gene expression data, as the non-parametric approach ignores known structural information whereas the fully parametric models run the risk of misspecification. A further related problem is the choice of a suitable scale for the model (e. g...2003-01-0100 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 01/06Development of a gene therapy approach for the treatment of human mammary carcinoma using tissue specific retroviral vectorsMetastatic breast cancer is commonly thought to be incurable, but gene therapy strategies with suicide genes are emerging as a potential treatment for metastatic breast cancer. Retroviral vectors are attractive candidates for such in vivo gene therapy applications. Most of these vectors contain viral promoters that are not tissue specific. In order to specifically target malignant cells while at the same time sparing normal tissue, cancer gene therapy will need to combine highly selective delivery with highly specific gene expression, specific gene product activity and, possibly, specific drug activation. Use of cell type or tissue specific promoters would allow specificity...2002-10-1800 min

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 01/06Etablierung und Anwendung von Hochdurchsatz-Verfahren zur Identifizierung strahleninduzierbarer Gene in der HefeDie Microarray-Technik stellt eine sehr neue Technologie dar, die zwei wesentliche Vorteile gegenüber herkömmlichen Techniken besitzt. Zum einen ist durch Fluoreszenzmarkierung eine kompetitive Hybridisierung möglich, so daß die behandelte Probe und die zugehörige Kontrolle in einem Experiment unter exakt gleichen Bedingungen untersucht werden können. Der noch größere Vorteil dieser Technik liegt in der Möglichkeit, die Expression mehrerer tausend Gene gleichzeitig untersuchen zu können. In diesem Kapitel wurde der Einfluß verschiedener Strahlenarten (UV-C, γ-, Protonen- und C6+-Ionen-Strahlung) auf die Expression von Hefegenen getestet. In einem ersten Schritt wurden für die verschiedenen Noxen die äqu...2000-10-1000 min

Medizin - Open Access LMU - Teil 12/22Gene rearrangements in bone marrow cells of patients with acute myelogenous leukemiaAt diagnosis, clonal gene rearrangement probes {[}retinoic acid receptor (RAR)-alpha, major breakpoint cluster region (M-bcr), immunoglobulin (Ig)-JH, T cell receptor (TcR)-beta, myeloid lymphoid leukemia (MLL) or cytokine genes (GM-CSF, G-CSF, IL-3)] were detected in bone marrow samples from 71 of 153 patients with acute myelogenous leukemia (AML) (46%): in 41 patients with primary AML (pAML) (58%) and in 30 patients with secondary AML (42%). In all cases with promyelocytic leukemia (AML-M3) RAR-alpha gene rearrangements were detected (n = 9). Gene rearrangements in the Ig-JH or the TcR-beta or GM-CSF or IL-3 or MLL gene were detected in 12, 10, 16 and 12% of the cases, respectively, whereas only few cases...2000-01-0100 min

Medizin - Open Access LMU - Teil 11/22XDJ1, a gene encoding a novel non-essential DnaJ homologue from Saccharomyces cerevisiaeThe gene encoding a novel DnaJ-like protein, termed Xdj1, has been identified by amplification of Saccharomyces cerevisiae genomic DNA. An open reading frame of 1380 bp was detected. Disruption of XDJ1 did not yield any detectable new phenotype. A double-deletion strain containing a disruption of both XDJ1 and YDJ1, another gene coding for a DnaJ-like protein, was still viable. Under a variety of growth conditions, no XDJ1 transcripts could be detected by Northern blot analysis and no translation product was found by immunoblotting with antibody against Xdj1 produced in Escherichia coli. Thus, XDJ1 is either expressed only under very specific conditions...1994-12-3100 min

Medizin - Open Access LMU - Teil 11/22Gene Structure, cDNA Sequence, and mRNA DistributionThe rat HNF-3 (hepatocyte nuclear factor 3) gene family encodes three transcription factors known to be important in the regulation of gene expression in liver and lung. We have cloned and characterized the mouse genes and cDNAs for HNF-3α, β, and γ and analyzed their expression patterns in various adult tissues and mouse embryonic stages. The HNF-3 proteins are highly conserved between mouse and rat, with the exception of the amino terminus of HNF-3γ, which in mouse is more similar to those of HNF-3α and β than to the amino termini of the rat HNF-3γ protein. The mouse HNF-3 genes are small and contain only tw...1994-01-0100 min

Medizin - Open Access LMU - Teil 11/22Identification and expression of a murine cytomegalovirus early gene coding for an Fc receptorSeveral herpesviruses, including cytomegalovirus, induce receptors for the Fc domain of murine immunoglobulin G (IgG) molecules. Viral genes coding for these receptors have been characterized only for alphaherpesviruses. In this report, we describe a new approach that led to the identification of an Fc receptor (FcR) of murine cytomegalovirus (MCMV). The Fc fragment of IgG precipitated glycoproteins (gp) of 86 to 88 and 105 kDa from MCMV-infected cells. Deglycosylation by endoglycosidase F resulted in a protein with a molecular mass of 64 kDa. Injection of complete MCMV DNA or of DNA fragments, and the subsequent testing of cytoplasmic binding of IgG by immunofluorescence microscopy...1994-01-0100 min

Chemie und Pharmazie - Open Access LMU - Teil 02/02Efficient Foreign Gene Expression in Epstein-Barr Virus-Transformed Human B-CellsEpstein-Barr virus (EBV) is a herpesvirus that transforms B-cells (B-LCL) and has undergone intense scrutiny owing to its association with Burkitt's lymphoma, nasopharyngeal carcinoma, and immunoblastic lymphomas. B-LCL have also proven useful in the study of human immunology. We describe a novel system for inducing efficient foreign gene expression in B-LCL using biotinylated adenovirus as an endosome-disrupting agent. Plasmid DNA is coupled to the exterior of viral particles by streptavidin-polylysine chimeric proteins. Up to 67% of B-LCL may be induced to express foreign genes in vitro in transient expression systems, and gene expression lasts for at least 17 days. We have expressed...1994-01-0100 min

Medizin - Open Access LMU - Teil 11/22Inactivation of the Neurospora crassa Gene Encoding the Mitochondrial Protein Import Receptor MOM19 by the Technique of ''Sheltered RIP''We have used a technique referred to as ``sheltered RIP'' (repeat induced point mutation) to create mutants of the mom-19 gene of Neurospora crassa, which encodes an import receptor for nuclear encoded mitochondrial precursor proteins. Sheltered RIP permits the isolation of a mutant gene in one nucleus, even if that gene is essential for the survival of the organism, by sheltering the nucleus carrying the mutant gene in a heterokaryon with an unaffected nucleus. Furthermore, the nucleus harboring the RIPed gene contains a selectable marker so that it is possible to shift nuclear ratios in the heterokaryons to a state...1994-01-0100 min

Biologie - Open Access LMU - Teil 02/02Extinction of tyrosine aminotransferase gene activity in somatic cell hybrids involves modification and loss of several essential transcription factorsExtinction is defined as the loss of cell type-specific gene expression that occurs in somatic cell hybrids derived by fusion of cells with dissimilar phenotypes. To explore the basis of this dominant-negative regulation, we have studied the activities of the control elements of the liver-specific gene encoding tyrosine aminotransferase (TAT) in hepatoma/fibroblast hybrid crosses. We show that extinction in complete somatic cell hybrids is accompanied by the loss of activity of all known cell type-specific control elements of the TAT gene. This inactivity is the result of first, lack of expression of genes coding for the transcriptional activators HNF4...1993-01-0100 min

Biologie - Open Access LMU - Teil 02/02Activation of the tyrosine aminotransferase gene is dependent on synergy between liver-specific and hormone-responsive elementsTyrosine aminotransferase (TAT; L-tyrosine: 2-oxoglutarate aminotransferase, EC 2.6.1.5) gene activity is stimulated by glucocorticoids and glucagon and is repressed by insulin. Expression and responsiveness to the different signal transduction pathways are restricted to the liver, in which the gene is activated shortly after birth. Here we provide a model for the basis of this tissue specificity of the hormonal control. In the two enhancers mediating hormone induction of TAT gene activity we find the hormone response elements in combination with binding sites for constitutive liver-enriched transcription factors: proteins of the hepatocyte nuclear factor 3 family bind in the vicinity of the glucocorticoid ...1993-01-0100 min

Medizin - Open Access LMU - Teil 10/22Point mutations of the P53 gene, human hepatocellular carcinoma and aflatoxinsThe tumor suppressor p53 exerts important protective functions towards DNA-damaging agents. Its inactivation by allelic deletions or point mutations within the P53 gene as well as complex formation of wildtype p53 with cellular or viral proteins is a common and crucial event in carcinogenesis. Mutations increase the half-life of the p53 protein allowing the immunohistochemical detection and anti-p53 antibody formation. Distinct G to T point mutations in codon 249 leading to a substitution of the basic amino acid arginine by the neutral amino acid serin are responsible for the altered functionality of the mutant gene product and were originally identified in 8...1993-01-0100 min

Medizin - Open Access LMU - Teil 10/22Organization and sequence of the gene encoding the human acrosin-trypsin inhibitor (HUSI-II)A complete cDNA encoding the acrosin-trypsin inhibitor, HUSI-II, was used as a probe to isolate genomic clones from a human placenta library. Three clones which cover the entire HUSI-II gene were isolated and characterized. The exon-intron organization of the gene was determined and found to be identical to other known Kazal-type inhibitor-encoding genes. The striking similarity in the amino acid sequences which was found previously in HUSI-II and glycoprotein hormone β-subunits, is neither reflected in codon usage nor in the exon-intron arrangement of the genes. A 1.8-kb segment 5′ of the gene was sequenced. The analysis of this sequence showed that HUS...1993-01-0100 min

Medizin - Open Access LMU - Teil 09/22Characterization of Murine Carcinoembryonic Antigen Gene Family MembersThe carcinoembryonic antigen (CEA) is a human tumor marker whose gene belongs to a family with more than 20 members. This gene family codes for a group of proteins with in vitro cell adhesion properties and for a group of abundantly expressed pregnancy-specific glycoproteins (PSG) with unknown functions. As a basis for in vivo functional studies, we have started to analyze the murine CEA gene family and have identified five new members (Cea-2 to Cea-6). cDNA clones were isolated for Cea-2, Cea-3, and Cea-6. The deduced amino acid sequences of Cea-2 and Cea-6 indicate three IgV-like (N), followed by one IgC-like...1992-01-0100 min

Chemie und Pharmazie - Open Access LMU - Teil 02/02Coupling of adenovirus to transferrin-polylysine/DNA complexes greatly enhances receptor-mediated gene delivery and expression of transfected genes.We are developing efficient methods for gene transfer into tissue culture cells. We have previously shown that coupling of a chimeric adenovirus with polylysine allowed the construction of an adenovirus-polylysine-reporter-gene complex that transferred the transporter gene with great efficiency into HeLa cells. We have now explored simpler, biochemical means for coupling adenovirus to DNA/polylysine complexes and show that such complexes yield virtually 100% transfection in tissue culture cell lines. In these methods adenovirus is coupled to polylysine, either enzymatically through the action of transglutaminase or biochemically by biotinylating adenovirus and streptavidinylating the polylysine moiety. Combination complexes containing DNA, adenovirus-polylysine, and...1992-01-0100 min

Medizin - Open Access LMU - Teil 09/22Cortically evoked motor responses in patients with Xp22.3-linked Kallmann's syndrome and in female gene carriersPatients with Kallmann's syndrome show hypothalamic hypogonadism, hyposmia, and congenital mirror movements. As a correlate, a defect of gonadotropic neuron migration into the brain was recently detected. Considering abnormal outgrowth of neurons also as a possible substrate underlying mirror movements, we studied 3 patients and 2 asymptomatic female gene carriers from a kindred with proven linkage to Xp22.3, using focal transcranial magnetic stimulation of motor cortex hand areas with a figure-eight coil. In all 3 affected brothers, bilateral responses could be evoked almost simultaneously in their thenar muscles (slight latency differences were statistically insignificant). In contrast, the mother and the maternal aunt showed...1992-01-0100 min

Medizin - Open Access LMU - Teil 09/22Assembly and Analysis of Cosmid Contigs in the CEA-gene Family Region of Human Chromosome 19The carcinoembryonic antigen (CEA)-like genes are members of a large gene family which Is part of the immunoglobulln superfamily. The CEA family is divided into two major subgroups, the CEA-subgroup and the pregnancy-specific glycoprotein (PSG)-subgroup. In the course of an effort to develop a set of overlapping cosmlds spanning human chromosome 19, we identified 245 cosmids In a human chromosome 19 cosmid library (6 – 7X redundant) by hybridization with an IgC-like domain fragment of the CEA gene. A fluorescence-based restriction enzyme digest fingerprinting strategy was used to assemble 212 probe-positive cosmids, along with 115 additional cosmids from a collection of ~ 8, 000 randomly selected cosmids, into fi...1992-01-0100 min

Medizin - Open Access LMU - Teil 09/22Long-Range Chromosomal Mapping of the Carcinoembryonic Antigen (CEA) Gene Family ClusterA long-range physical map of the carcinoembryonic antigen (CEA) gene family cluster, which is located on the long arm of chromosome 19, has been constructed. This was achieved by hybridization analysis of large DNA fragments separated by pulse-field gel electrophoresis and of DNA from human/rodent somatic cell hybrids, as well as the assembly of ordered sets of cosmids for this gene region into contigs. The different approaches yielded very similar results and indicate that the entire gene family is contained within a region located at position 19q13.1–q13.2 between the CYP2A and the D19S15/D19S8 markers. The ph...1992-01-0100 min

Medizin - Open Access LMU - Teil 09/22Structural organization, expression, and functional characterization of the murine cytomegalovirus immediate-early gene 3.We have previously defined ie3 as a coding region located downstream of the ie1 gene which gives rise to a 2.75-kb immediate-early (IE) transcript. Here we describe the structural organization of the ie3 gene, the amino acid sequence of the gene product, and some of the functional properties of the protein. The 2.75-kb ie3 mRNA is generated by splicing and is composed of four exons. The first three exons, of 300, 111, and 191 nucleotides (nt), are shared with the ie1 mRNA and are spliced to exon 5, which is located downstream of the fourth exon used by the ie1 mRNA. Exon 5 starts 28 nt...1992-01-0100 min

Medizin - Open Access LMU - Teil 09/22Identification of the murine cytomegalovirus glycoprotein B gene and its expression by recombinant vaccinia virusThe gene encoding glycoprotein B (gB) of murine cytomegalovirus (MCMV) strain Smith was identified, sequenced, and expressed by recombinant vaccinia virus. The gB gene was found adjacent to the polymerase gene, as it is in the genome of human cytomegalovirus (HCMV). The open reading frame consists of 2,784 nucleotides capable of encoding a protein of 928 amino acids. Comparison with gB homologs of other herpesviruses revealed a high degree of homology. The similarity between the MCMV gB and the HCMV gB is most prominent, since 45% of the amino acids are identical. In addition, all cysteine residues are at homologous positions, indicating a...1992-01-0100 min

Chemie und Pharmazie - Open Access LMU - Teil 02/02DNA-binding transferrin conjugates as functional gene-delivery agents: synthesis by linkage of polylysine or ethidium homodimer to the transferrin carbohydrate moietyWe have previously demonstrated that transferrin-polycation conjugates are efficient carrier molecules for the introduction of genes into eucariotic cells. We describe here a more specific method for conjugation of transferrin with DNA-binding compounds involving attachment at the transferrin carbohydrate moiety. We used the polycation poly(L-lysine) or the DNA intercalator, ethidium homodimer as DNAbinding domains. Successful transferrin-receptor-mediatedd elivery and expression of the Photinus pyralis luciferase gene in K562 cells has been shown with these new transferrin conjugates. The activity of the transferrin-ethidium homodimer (TfEtD) conjugates is low relative to transferrin-polylysine conjugates; probably because of incomplete condensation of the DNA. However...1991-01-0100 min

Medizin - Open Access LMU - Teil 08/22Carcinoembryonic Antigen Gene FamilyThe carcinoembryonic antigen (CEA) gene family belongs to the immunoglobulin supergene family and can be divided into two main subgroups based on sequence comparisons. In humans it is clustered on the long arm of chromosome 19 and consists of approximately 20 genes. The CEA subgroup genes code for CEA and its classical crossreacting antigens, which are mainly membrane-bound, whereas the other subgroup genes encode the pregnancy-specific glycoproteins (PSG), which are secreted. Splice variants of individual genes and differential post-translational modifications of the resulting proteins, e.g., by glycosylation, indicate a high complexity in the number of putative CEA-related molecules. So far, only...1991-01-0100 min

Biologie - Open Access LMU - Teil 02/02Developmental and tissue-specific expression of the Q5k geneExpression of the Q5k gene was examined by northern blot analysis and polymerase chain reaction (PCR) in the AKR mouse and various cell lines, each of the H-2k haplotype. Our results show that Q5k mRNA is present during the whole postimplantational development of the AKR embryo/fetus (gestation day 6 to 15). In the juvenile mouse (week 2 to 4) transcription of the Q5k gene persisted in all organs examined. In contrast, in the adult animal expression of the Q5k gene was limited to the thymus and uterus of the pregnant mouse. Upon malignant transformation, the amount of Q5...1991-01-0100 min

Medizin - Open Access LMU - Teil 08/22Cloning of a Carcinoembryonic Antigen Gene Family Member Expressed in Leukocytes of Chronic Myeloid Leukemia Patients and Bone MarrowThe carcinoembryonic antigen (CEA) gene family belongs to the immunoglobulin superfamily and can be subdivided into the CEA and pregnancy-specific glycoprotein subgroups. The basic structure of the encoded proteins consists of, in addition to a leader, one IgV-like and 2, 3, or 6 IgC-like domains. These domains are followed by varying COOH-terminal regions responsible for secretion, transmembrane anchoring, or insertion into the membrane by a glycosyl phosphatidylinositol tail. Here we report on the characterization of CGM6, a new member of the CEA gene subgroup, by complementary DNA cloning. The deduced coding region comprises 349 amino acids and consists of a leader, one IgV-like, two...1990-10-1500 min

Biologie - Open Access LMU - Teil 02/02Chromatin Structures of the Rat Tyrosine Aminotransferase Gene Relate to the Function of Its cis-Acting ElementsThe relationship between DNase I-hypersensitive sites (HSs) and transcriptional enhancers of the rat tyrosine aminotransferase (TAT) gene was examined by comparing HSs in and around the TAT gene with the activity of the corresponding DNA sequences in transient transfection assays. In this manner, we identified two HSs as liver-specific enhancers. Of three hepatoma cell lines examined, only one sustained TAT mRNA levels comparable to those of liver. In this cell line, both enhancers were strongly active, and strong hypersensitivity in chromatin over the enhancers was evident. The other two hepatoma cell lines had reduced levels of TAT mRNA and no...1990-01-0100 min

Medizin - Open Access LMU - Teil 07/22cDNA and Gene Analyses Imply a Novel Structure for a Rat Carcinoembryonic Antigen-related ProteinThe gene encoding the human tumor marker carcinoembryonic antigen (CEA) belongs to a gene family which can be subdivided into the CEA and the pregnancy-specific glycoprotein subgroups. The corresponding proteins are members of the immunoglobulin superfamily, characterized through the presence of one IgV-like domain and a varying number of IgC-like domains. Since the function of the CEA family is not well understood, we decided to establish an animal model in the rat to study its tissue- specific and developmental stage-dependent expression. To this end, we have screened an 18-day rat placenta cDNA library with a recently isolated fragment of a...1990-01-0100 min

Medizin - Open Access LMU - Teil 07/22Cloning of the Complete Gene for Carcinoembryonic AntigenCarcinoembryonic antigen (CEA) is a widely used tumor marker, especially in the surveillance of colonic cancer patients. Although CEA is also present in some normal tissues, it is apparently expressed at higher levels in tumorous tissues than in corresponding normal tissues. As a first step toward analyzing the regulation of expression of CEA at the transcriptional level, we have isolated and characterized a cosmid clone (cosCEA1), which contains the entire coding region of the CEA gene. A close correlation exists between the exon and deduced immunoglobulin-like domain borders. We have determined a cluster of transcriptional starts for CEA and the...1990-01-0100 min

Medizin - Open Access LMU - Teil 07/22Identification of a Carcinoembryonic Antigen Gene Family in the RatThe existence of a carcinoembryonic antigen (CEA)-like gene family in rat has been demonstrated through isolation and sequencing of the N- terminal domain exons of presumably five discrete genes (rnCGM1-5). This finding will allow for the first time the study of functional and clinical aspects of the tumor marker CEA and related antigens in an animal model. Sequence comparison with the corresponding regions of members of the human CEA gene family revealed a relatively low similarity at the amino acid level, which indicates rapid divergence of the CEA gene family during evolution and explains the lack of cross...1989-01-0100 min

Medizin - Open Access LMU - Teil 07/22Cell-type specificity of regulatory elements identified by linker scanning mutagenesis in the promoter of the chicken lysozyme geneThe chicken lysozyme gene is constitutively expressed in macrophages, in oviduct cells its expression is controlled by steroid hormones, and in fibroblasts the gene is not expressed. A fusion gene consisting of promoter sequences of the lysozyme gene from –208 to +15 in front of the chloramphenicol acetyltransferase (CAT) coding region was more than 50 times less active in non-expressing cells as compared to expressing cells. In order to identify the element(s) responsible for this cell-type specificity 31 different linker scanning mutations were generated within this promoter fragment and analyzed by transient transfections in the three types of chicken cells mentioned above. Three mu...1989-01-0100 min

Medizin - Open Access LMU - Teil 07/22cDNA Cloning Demonstrates the Expression of Pregnancy-Specific Glycoprotein Genes, a Subgroup of the Carcinoembryonic Antigen Gene Family, in Fetal LiverThe pregnancy-specific glycoprotein (PSG) genes constitute a subgroup of the carcinoembryonic antigen (CEA) gene family. Here we report the cloning of four cDNAs coding for different members of the PSG family from a human fetal liver cDNA library. They are derived from three closely related genes (PSG1, PSG4 and PSG6). Two of the cDNA clones represent splice variants of PSG1 (PSG1a, PSG1d) differing in their C-terminal domain and 3′-untranslated regions. All encoded proteins show the same domain arrangement (N-RA1-RA2-RB2-C). Transcripts of the genes PSG1 and PSG4 could be detected in placenta by hybridization with gene-specific ol...1989-01-0100 min

Medizin - Open Access LMU - Teil 07/22Intra- and Interspecies Analyses of the Carcinoembryonic Antigen (CEA) Gene Family Reveal Independent Evolution in Primates and RodentsVarious rodent and primate DNAs exhibit a stronger intra- than interspecies cross-hybridization with probes derived from the N-terminal domain exons of human and rat carcinoembryonic antigen (CEA)-like genes. Southern analyses also reveal that the human and rat CEA gene families are of similar complexity. We counted at least 10 different genes per human haploid genome. In the rat, approximately seven to nine different N-terminal domain exons that presumably represent different genes appear to be present. We were able to assign the corresponding genomic restriction endonuclease fragments to already isolated CEA gene family members of both human and rat. Highly similar...1989-01-0100 min

Medizin - Open Access LMU - Teil 07/22Analysis of the Size of the Carcinoembryonic Antigen (CEA) Gene FamilyFive members of the human CEA gene family [human pregnancy-specific β1-glycoprotein (PSβG), hsCGM1, 2, 3 and 4] have been isolated and identified through sequencing the exons containing their N-terminal domains. Sequence comparisons with published data for CEA and related molecules reveal the existence of highly-conserved gene subgroups within the CEA family. Together with published data eleven CEA family members have so far been determined. Apart from the highly conserved coding sequences, these genes also show strong sequence conservation in their introns, indicating a duplication of whole gene units during the evolution of the CEA gene family.1989-01-0100 min

Biologie - Open Access LMU - Teil 01/02Sequence of the mouse Q4 class I gene and characterization of the gene productThe Q4 class I gene has been shown to participate in gene conversion events within the mouse major histocompatibility complex. Its complete genomic nucleotide sequence has been determined. The 5' half of Q4 resembles H-2 genes more strongly than other Q genes. Its 3' end, in contrast, is Q-like and contains a translational stop signal in exon 5 which predicts a polypeptide with an incomplete membrane spanning segment. The presence of two inverted B1 repeats suggests that part of the Q4 gene may be mobile within the genome. Gene transfer experiments have shown that the Q4 gene encodes a ß2-microglobulin associated p...1988-01-0100 min

Medizin - Open Access LMU - Teil 05/22Sequence and structural organization of murine cytomegalovirus immediate-early gene 1In murine cytomegalovirus, abundant immediate-early transcription originates from 0.769 to 0.815 map units of the genome. This region contains the immediate-early gene (gene ieI) which encodes pp89, a phosphoprotein active in transcriptional regulation. In this paper we report on the precise location, structural organization, and sequence of gene ieI. The predominant ieI transcript, a 2.75-kilobase mRNA, is generated by splicing and composed of four exons. The precise termini of the 2.75-kilobase mRNA and the positions of the exons were determined by nuclease digestion experiments with either 5' or 3' end-labeled DNA fragments or in vitro transcribed cRNA probes. Exons of 300, 111, 191, and 1,703 nucleotides...1987-01-0100 min

Biologie - Open Access LMU - Teil 01/02Interaction Between Kb and Q4 Gene Sequences Generates the Kbm6 MutationGenetic interaction as a mechanism for the generation of mutations is suggested by recurrent, multiple nucleotide substitutions that are identical to nucleotide sequences elsewhere in the genome. We have sequenced the mutant K gene from the bm6 mouse, which is one of a series of eight closely related, yet independently occuring mutants known collectively as the "bg series." Two changes from the Kb gene are found, positioned 15 nucleotides apart: an A-to-T change and a T-to-C change in the codons corresponding to amino acids 116 and 121, resulting in Tyr-to-Phe and Cys-to-Arg substitutions, respectively. Hybridization analysis with an oligonucleotide specific for the altered...1986-01-0100 min

Medizin - Open Access LMU - Teil 05/22The 89,000-Mr murine cytomegalovirus immediate-early protein activates gene transcriptionTo study trans-activation of gene expression by murine cytomegalovirus (MCMV) immediate-early (IE) proteins, the IE coding region 1 (ie1), which encodes the 89,000-Mr IE phosphoprotein (pp89), was stably introduced into L cells. A cell line was selected and characterized that efficiently expressed the authentic viral protein. The pp89 that was constitutively expressed in L cells stimulated the expression of transfected recombinant constructs containing the bacterial chloramphenicol acetyltransferase (CAT) gene under the control of viral promoters. The regulatory function of the ie1 product was confirmed by transient expression assays in which MCMV IE genes were cotransfected into L cells together with recombinant...1986-01-0100 min

Biologie - Open Access LMU - Teil 01/02Duplicated gene pairs and alleles of class I genes in the Qa2 region of the murine major histocompatibility complex. a comparisonDNA restriction maps of the major histocompatibility complex and hybridization with low copy probes have previously revealed strong homology between the Q6-Q7 and the Q8-Q9 class I gene pairs in the Qa2 region of the C57BL/10 mouse. After DNA sequence analysis of the Q7, Q8 and Q9 genes, we have compared the Q7 gene with its apparent allele, 27.1, from the BALB/c mouse; the 99% homology between Q7 and 27.1 indicates that this is a non-polymorphic gene. Comparison of Q7 with Q9, its homologue in the Q8-Q9 gene pair, revealed > 99% homology, thus supporting our proposal that the Qa2...1985-01-0100 min

Biologie - Open Access LMU - Teil 01/02A Nonpolymorphic Class I Gene in the Murine Major Histocompatibility ComplexDNA sequence analysis of a class I gene (QlO), which maps to the Qa2,3 locus in the C57BL/lO (H- 2b haplotype) mouse, reveals that it is almost identical to a cDNA clone (pH16) isolated from a SWR/J (H-2q haplotype) mouse liver cDNA library. Exon 5, in particular, has an unusual structure such that a polypeptide product is unlikely to be anchored in the cell membrane. Our findings suggest that the two sequences are derived from allelic class I genes, which are nonpolymorphic, in contrast to H-2K allelic sequences from the same mice, and they may encode ...1984-01-0100 min

Biologie - Open Access LMU - Teil 01/02The DNA sequence of the H-2Kb gene. Evidence for gene conversion as a mechanism for the generation of polymorphism in histocompatibilty antigensWe have determined the DNA sequence of the H-2Kb gene of the C57B1/10 mouse. Comparison of this sequence with that of the allelic H-2Kd shows surprisingly that the exons have accumulated more mutations than their introns. Moreover, many of these changes in the exons are clustered in short regions or hot spots. Additional comparison of these sequences with the H-2Ld and H-2Db sequences shows that, in several cases, the altered sequence generated at the hot spot is identical to the corresponding region of a non-allelic H-2 gene. The clustered changes are responsible for 60wo of...1983-01-0100 min