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PubMed2000

Nucleotide excision repair/TFIIH helicases RAD3 and SSL2 inhibit short-sequence recombination and Ty1 retrotransposition by similar mechanisms.

Eukaryotic genomes contain potentially unstable sequences whose rearrangement threatens genome structure and function. Here we show that certain mutant alleles of the nucleotide excision repair (NER)/TFIIH helicase genes RAD3 and SSL2 (RAD25) confer synthetic lethality and destabilize the Saccharomyces cerevisiae genome by increasing both short-sequence recombination and Ty1 retrotransposition. The rad3-G595R and ssl2-rtt mutations do not markedly alter Ty1 RNA or protein levels or target site specificity. However, these mutations cause an increase in the physical stability of broken DNA molecules and unincorporated Ty1 cDNA, which leads to higher levels of short-sequence recombination and Ty1 retrotransposition. Our results link components of the core NER/TFIIH complex with genome stability, homologous recombination, and host defense against Ty1 retrotransposition via a mechanism that involves DNA degradation.

Adenosine Triphosphatases↗
PubMed2002

Fine mapping of a putative tuberculosis-susceptibility locus on chromosome 15q11-13 in African families.

Host genetics plays an important role in individual susceptibility and resistance to infectious diseases, but no genes have yet been identified using genome-wide screens. Twin studies have indicated that tuberculosis susceptibility has a significant host genetic component, and several genes appear to be involved. Recently, a genome-wide linkage analysis of 136 African families identified chromosome 15q11-13 as a region with suggestive evidence of linkage, with a LOD score of 2.0. We tested 10 microsatellite markers and 5 positional candidate genes in this chromosomal region for deviation from random transmission from parents to affected offspring. The polymorphisms, lying in a region of 14 cM, were initially typed in the same 79 Gambian families used in the genome screen. A borderline significant association with a 7 bp deletion in UBE3A (P = 0.01) was found. This polymorphism was then evaluated further in a larger series of families with tuberculosis, including 44 Guinean families and 57 families from South Africa. Testing for association between the deletion and tuberculosis across all the families using the exact symmetry test further supported the association (overall P = 0.002). These fine-mapping data suggest that UBE3A or a closely flanking gene may be a tuberculosis-susceptibility locus.

Black People↗
PubMed2006

Neuroendocrinology of protochordates: insights from Ciona genomics.

The genome for two species of Ciona is available making these tunicates excellent models for studies on the evolution of the chordates. In this review most of the data is from Ciona intestinalis, as the annotation of the C. savignyi genome is not yet available. The phylogenetic position of tunicates at the origin of the chordates and the nature of the genome before expansion in vertebrates allows tunicates to be used as a touchstone for understanding genes that either preceded or arose in vertebrates. A comparison of Ciona, a sea squirt, to other model organisms such as a nematode, fruit fly, zebrafish, frog, chicken and mouse shows that Ciona has many useful traits including accessibility for embryological, lineage tracing, forward genetics, and loss- or gain-of-function experiments. For neuroendocrine studies, these traits are important for determining gene function, whereas the availability of the genome is critical for identification of ligands, receptors, transcription factors and signaling pathways. Four major neurohormones and their receptors have been identified by cloning and to some extent by function in Ciona: gonadotropin-releasing hormone, insulin, insulin-like growth factor, and cionin, a member of the CCK/gastrin family. The simplicity of tunicates should be an advantage in searching for novel functions for these hormones. Other neuroendocrine components that have been annotated in the genome are a multitude of receptors, which are available for cloning, expression and functional studies.

Animals↗
PubMed2004

Roles of MAP kinase cascades in Caenorhabditis elegans.

Mitogen-activated protein kinases (MAPKs) are serine/threonine protein kinases that are activated by diverse stimuli such as growth factors, cytokines, neurotransmitters and various cellular stresses. MAPK cascades are generally present as three-component modules, consisting of MAPKKK, MAPKK and MAPK. The precise molecular mechanisms by which these MAPK cascades transmit signals is an area of intense research, and our evolving understanding of these signal cascades has been facilitated in great part by genetic analyses in model organisms. One organism that has been commonly used for genetic manipulation and physiological characterization is the nematode Caenorhabditis elegans. Genes sequenced in the C. elegans genome project have furthered the identification of components involved in several MAPK pathways. Genetic and biochemical studies on these components have shed light on the physiological roles of MAPK cascades in the control of cell fate decision, neuronal function and immunity in C. elegans.

Animals↗
PubMedDate not supplied

[G-protein coupled peptide receptors and their ligands in human genome].

The G-protein coupled peptide receptors as well as their ligands, endogenous peptides, are involved in regulation of many important physiological processes in the organism and therefore represent attractive targets for pharmaceutical investigation and drug design. With the completion of the human draft genome sequencing, it has become possible to take a comprehensive picture of all genes encoding both peptide receptors and peptides themselves. In the present study a first attempt has been made to carry out a comprehensive analysis of G-protein coupled peptide receptors and their respective endogenous peptide ligands in the human genome. We searched the genome sequence by means of sequential application of standard bioinformatical methods (such as homology search, hierarchical cluster analysis, building of hmm-profiles etc.) with the goal of identifying all the components of peptide ligand/receptor system in the human genome. As a result of this search it was concluded that the probable number of functional peptide receptors in the human genome is 218, and the probable peptide precursors' number is 126 amino acid sequences. These two groups include, respectively, 12 novel G-protein coupled peptide receptors and 10 novel peptide precursors, discovered in the present study. The probable biological functions of newly discovered candidates were determined based on the sequence similarity to the earlier known proteins. Classification of all peptide GPCRs and their ligands based on the ligand specificity was performed for all probable G-protein coupled peptide receptors. The issue of ligand-receptor specificity in the human genome is also discussed.

Amino Acid Sequence↗
PubMed2004

Human genomics and its impact on arrhythmias.

Investigation of families with monogenic arrhythmia syndromes has identified genes whose further study has proven extraordinarily valuable in further understanding variability in cardiac electrophysiology and its response to exogenous stressors. One lesson being learned from this work is that individuals from the same kindred with the same disease-associated DNA variant may nevertheless display strikingly different phenotypes. Further, common function-altering polymorphisms are being identified in these and other genes controlling cardiac excitability. These findings, combined with the recognition that very common arrhythmia syndromes (such as atrial fibrillation or sudden arrhythmic death) include a genetic component, raise the prospect that analysis of genomic variability among individuals and populations may in the future be used to manage patients

Arrhythmias, Cardiac↗
PubMedDate not supplied

Comparative genomics and host resistance against infectious diseases.

The large size and complexity of the human genome have limited the identification and functional characterization of components of the innate immune system that play a critical role in front-line defense against invading microorganisms. However, advances in genome analysis (including the development of comprehensive sets of informative genetic markers, improved physical mapping methods, and novel techniques for transcript identification) have reduced the obstacles to discovery of novel host resistance genes. Study of the genomic organization and content of widely divergent vertebrate species has shown a remarkable degree of evolutionary conservation and enables meaningful cross-species comparison and analysis of newly discovered genes. Application of comparative genomics to host resistance will rapidly expand our understanding of human immune defense by facilitating the translation of knowledge acquired through the study of model organisms. We review the rationale and resources for comparative genomic analysis and describe three examples of host resistance genes successfully identified by this approach.

Agammaglobulinemia↗
PubMed1998

Genetic analysis of dioxin dioxygenase of Sphingomonas sp. Strain RW1: catabolic genes dispersed on the genome.

The dioxin dioxygenase of Sphingomonas sp. strain RW1 activates dibenzo-p-dioxin and dibenzofuran for further metabolism by introducing two atoms of oxygen at a pair of vicinal carbon atoms, one of which is involved in one of the bridges between the two aromatic rings, i.e., an angular dioxygenation. The dxnA1 and dxnA2 cistrons encoding this dioxygenase have been cloned and shown to be located just upstream of a hydrolase gene which specifies an enzyme involved in the subsequent step of the dibenzofuran biodegradative pathway. Genes encoding the electron supply system of the dioxygenase are not clustered with the dioxygenase gene but rather are located on two other distinct and separate genome segments. Moreover, whereas expression of dxnA1A2 is modulated according to the available carbon source, expression of the dbfB gene encoding the ring cleavage enzyme of the dibenzofuran pathway, which is located in the neighborhood of dxnA1A2 but oriented in the opposite direction, is constitutive. The scattering of genes for the component proteins of dioxin dioxygenase system around the genome of Sphingomonas sp. strain RW1, and the differential expression of dioxin pathway genes, is unusual and contrasts with the typical genetic organization of catabolic pathways where component cistrons tend to be clustered in multicistronic transcriptional units. The sequences of the alpha and beta subunits of the dioxin dioxygenase exhibit only weak similarity to other three component dioxygenases, but some motifs such as the Fe(II) binding site and the [2Fe-2S] cluster ligands are conserved. Dioxin dioxygenase activity in Escherichia coli cells containing the cloned dxnA1A2 gene was achieved only through coexpression of the cognate electron supply system from RW1. Under these conditions, exclusively angular dioxygenation of dibenzofuran and dibenzo-p-dioxin was obtained. The dioxin dioxygenase was not active in E. coli cells coexpressing a class IIB electron supply system. In the course of the isolation of the dxnA1 and dxnA2 cistrons, a number of other catabolic genes dispersed over different genome segments were identified, which may indicate greater catabolic potential than was previously suspected. This finding is consistent with the catabolic versatility of members of the genus Sphingomonas, which is becoming increasingly evident, and may indicate a less well evolved and regulated but more dynamic genetic organization in this organism than is the case for better-studied pathways in organisms such as Pseudomonas species.

Amino Acid Sequence↗
PubMed2003

Induction of specific T-cell responses, opsonizing antibodies, and protection against Plasmodium chabaudi adami infection in mice vaccinated with genomic expression libraries expressed in targeted and secretory DNA vectors.

It has been proposed that a multivalent malaria vaccine is necessary to mimic the naturally acquired resistance to this disease observed in humans. A major experimental challenge is to identify the optimal components to be used in such a multivalent vaccine. Expression library immunization (ELI) is a method for screening genomes of a pathogen to identify novel combinations of vaccine sequences. Here we describe immune responses associated with, and the protective efficacy of, genomic Plasmodium chabaudi adami DS expression libraries constructed in VR1020 (secretory), monocyte chemotactic protein-3 (chemoattractant), and cytotoxic T lymphocyte antigen 4 (lymph node-targeting) DNA vaccine vectors. With splenocytes from vaccinated mice, specific T-cell responses, as well as gamma interferon and interleukin-4 production, were observed after stimulation with P. chabaudi adami-infected erythrocytes, demonstrating the specificity of genomic library vaccination for two of the three libraries constructed. Sera obtained from mice vaccinated with genomic libraries promoted the opsonization of P. chabaudi adami-infected erythrocytes by murine macrophages in vitro, further demonstrating the induction of malaria-specific immune responses following ELI. Over three vaccine trials using biolistic delivery of the three libraries, protection after lethal challenge with P. chabaudi adami DS ranged from 33 to 50%. These results show that protective epitopes or antigens are expressed within the libraries and that ELI induces responses specific to P. chabaudi adami malaria. This study further demonstrates that ELI is a suitable approach for screening the malaria genome to identify the components of multivalent vaccines.

Abatacept↗
PubMed2006

Rapid genetic grouping of factor h-binding protein (genome-derived neisserial antigen 1870), a promising group B meningococcal vaccine candidate.

The most important antigen component of a promising multicomponent group B meningococcal recombinant protein vaccine is based on genome-derived neisserial antigen 1870, which recently was renamed factor H-binding protein (FHBP) to reflect one of its critical functions as a complement regulatory protein. Neisseria meningitidis strains can be subdivided into three FHBP variant groups based on divergence of FHBP amino acid sequences. Within each variant group, amino acid sequences are >90% conserved. To develop an FHBP-based group B vaccine, it is important to know the distribution of FHBP variant 1, 2, and 3 strains in different geographic regions, since antibodies against FHBP are bactericidal against strains within the homologous group but show minimal activity against strains from other groups. We have devised a high-throughput, quantitative PCR-based method that allows rapid and precise assignment of FHBP genes into each of the three major variant lineages. Among 48 group B isolates from patients hospitalized in California in 2003 to 2004, 83%, 13%, and 4%, respectively, had variant 1, 2, and 3 genes. Thus, a vaccine based on the variant 1 protein has the potential to prevent the majority of cases of group B disease. The quantitative PCR-based method will be useful for determining and monitoring the prevalence of meningococcal isolates with genes encoding different FHBP variant proteins. The technique also is suitable for monitoring variation of genes encoding other protein antigens targeted for vaccination.

Antigens, Bacterial↗
PubMed1999

Functional analysis of human FEN1 in Saccharomyces cerevisiae and its role in genome stability.

The flap endonuclease, FEN1, is an evolutionarily conserved component of DNA replication from archaebacteria to humans. Based on in vitro results, it processes Okazaki fragments during replication and is involved in base excision repair. FEN1 removes the last primer ribonucleotide on the lagging strand and it cleaves a 5' flap that may result from strand displacement during replication or during base excision repair. Its biological importance has been revealed largely through studies in the yeast Saccharomyces cerevisiae where deletion of the homologous gene RAD27 results in genome instability and mutagen sensitivity. While the in vivo function of Rad27 has been well characterized through genetic and biochemical approaches, little is understood about the in vivo functions of human FEN1. Guided by our recent results with yeast RAD27, we explored the function of human FEN1 in yeast. We found that the human FEN1 protein complements a yeast rad27 null mutant for a variety of defects including mutagen sensitivity, genetic instability and the synthetic lethal interactions of a rad27 rad51 and a rad27 pol3-01 mutant. Furthermore, a mutant form of FEN1 lacking nuclease function exhibits dominant-negative effects on cell growth and genome instability similar to those seen with the homologous yeast rad27 mutation. This genetic impact is stronger when the human and yeast PCNA-binding domains are exchanged. These data indicate that the human FEN1 and yeast Rad27 proteins act on the same substrate in vivo. Our study defines a sensitive yeast system for the identification and characterization of mutations in FEN1.

Amino Acid Sequence↗
PubMed2004

After the genome--the phenome?

What next? The Human Genome Project signifies complexity rather than simplification in the relationship between genotype and phenotype. Genotypes are embedded in genomes. Individuality in phenotypes is embedded in components of the phenome (transcriptome, metabolome, proteome, etc.). The phenome, its layers, and its nodes, links and networks, require elucidation; there is a need for a Human Phenome Project (Freimer and Sabatti 2003). Biology has largely been a reductive science in the recent past; integrative biology lies ahead. Clinician-scientists (including human biochemical geneticists) will be recognized as key participants in the 'medical' Phenome Project as it reveals components of individuality, and their contributions, in simple or combinatorial fashion, to Mendelian and complex traits; better ways to treat 'genetic disease' will be by-products of the project. Although the Word is common to all, most men live as if each had a private wisdom of his own.Herakleitos

Genomics↗
PubMed1988

Expression of cytoskeleton components in various Epstein-Barr virus infected cell lines.

It has been shown that viruses can induce alterations in the content and distribution of cytoskeleton structures, particularly actin microfilaments and microtubules. An immunomorphologic study of the cytoskeleton components of various EBV-infected cell lines with expression of different functions of EBV genome has been performed using antibodies to each of its three major components. Intermediate filaments and microtubules were similarly represented in all examined lymphoblastoid cell lines. The distribution of actin microfilaments, on the contrary, differed significantly from cell line to cell line. It is concluded that the morphologic expression of actin might depend on the expression of EBV genome. Furthermore, some of these cell lines might represent a useful substrate for the identification of anticytoskeleton antibodies, mainly anti-actin antibodies, in human sera.

Actins↗
PubMed1984

Amphotropic retrovirus vector system for human cell gene transfer.

Retroviral vectors have been constructed for gene transfer in mammalian and avian cells, however most retroviral vector systems are complicated by the spread of a replication-competent helper virus. This problem has been circumvented by segregating the viral genome into cis- and trans-acting components. By establishing helper cell lines that produce the trans-acting viral gene products, one can propagate the cis-acting component in them and harvest defective viral particles that contain only the cis-acting component. The cis-acting component can provide a useful vehicle for the highly efficient transfer of genes into target cells. The defective vector systems described to date, however, are restricted in host range to murine, avian, rat, and dog cells. We describe a helper-free vector system based entirely on an amphotropic murine virus with a wide mammalian host range, including the ability to carry out efficient gene transfer into human cells. We also describe a double mutation constructed in the trans-acting genome which reduces the frequency of replication-competent recombinant viruses to undetectable levels.

Animals↗
PubMed1989

Intraviral homology and subgenomic RNAs of pepper ringspot virus.

The Tobraviruses constitute a group of rod-shaped, bipartite, plus-stranded RNA viruses. We report on homologies between the two viral genomic RNA molecules of pepper ringspot virus (PRV) and on the subgenomic components generated from them during infection. It has previously been shown that the 3'-terminal 459 nucleotides of PRV RNA-1 and RNA-2 are identical. Here it is shown that there is a second homology between RNA-1 and a region of RNA-2, located at least 240 nucleotides downstream from its 5' terminus. In agreement with strains in another Tobravirus group, we observe three subgenomic components in extracts of plants infected with PRV. Two of these, RNAs-1a (1.6 kb) and -1b (0.8 kb), are derived from RNA-1 (the larger genomic RNA). They are probably mRNAs for 29- and 16-kDa nonstructural virus proteins. The smaller genomic RNA, RNA-2, generates the subgenomic component RNA-2a (1.3-1.45 kb) which is probably an efficient capsid protein mRNA. Previously reported subgenomic components of 2.8 and 1.1 kb are shown to be electrophoretic artifacts. RNA-2a, but not 1a or 1b, is present in virion RNA preparations, indicating that it is the only subgenomic species to be encapsidated.

DNA↗
PubMed2000

Walking into the unknown: a 'step down' PCR-based technique leading to the direct sequence analysis of flanking genomic DNA.

We describe a novel and efficient PCR-based technique for walking into unknown flanking genomic DNA without recourse to protracted laborious library screening for overlapping sequences. This two component 'hot start' and 'step down' PCR method uses 6x1 microg of genomic DNA (ca 20kb in length) restricted with six different endonucleases and ligated to adaptors with the inclusion of two further restriction enzymes to prevent self-ligation. This allowed us to walk, in a single step, up to 6kb into flanking DNA and gave sufficient PCR products for up to 200 different walking experiments. This technology enabled us to clone and characterize the previously elusive 5' sequence of the barley powdery mildew chitin synthase gene, BgChs2, which includes a myosin motor-like sequence fused to a type V chitin synthase gene.

Amino Acid Sequence↗
PubMed1981

[Absorption of radioactive iodine by cells of the follicular and interfollicular epithelia of the thyroid gland].

Autoradiography was used in experiments on male rats to measure the accumulation of a single dose of 131I (1 microCi) injected intraperitoneally by cells of the thyroid parenchyma proper. A calculation was made of the number of tracks above the cytoplasm of thyrocytes, follicular buds, interfollicular thyrocytes and microfollicular thyrocytes 3, 6, 9, 12, 24, 48 and 96 h after the isotope injection. It was ascertained that cell components of the thyroid gland undergoing different stages of proliferation do not lose their genome specificity. In spite of the decrease in the function of these components, one can observe an intensification of this function as microfollicles are formed.

Absorption↗
PubMed2026

Shared genetic architecture and therapeutic targets across paediatric immune-mediated diseases.

OBJECTIVES: Paediatric-onset immune-mediated inflammatory diseases (IMIDs), including juvenile idiopathic arthritis and related rheumatic diseases, remain genetically undercharacterised. We aimed to define shared and category-specific genetic architecture across paediatric IMIDs, compare signals with adult IMIDs, and identify therapeutic opportunities. METHODS: We analysed 24 paediatric IMIDs classified as autoimmune, polygenic-autoinflammatory, mixed-pattern, or allergic. Genome-wide association analyses included 18,086 cases and 131,019 controls of European ancestry. We estimated single nucleotide polymorphism (SNP)-based heritability, genetic correlations, and polygenic overlap; performed subset-based meta-analysis; and conducted functional annotation, gene prioritisation, pathway and protein network analyses, adult-IMID comparison, and drug-target prioritisation. RESULTS: SNP-based heritability ranged from 28.9% for allergic IMIDs to 61.9% for autoimmune IMIDs. Genetic correlation and polygenic modelling supported partial sharing across categories with category-specific components. Meta-analysis identified 39 genome-wide significant loci outside the Major Histocompatibility Complex (MHC) region, including 15 previously unreported loci; 19 loci were shared between categories. Gene-prioritisation and protein interaction analyses identified a core MHC-centred antigen-presentation network, with category-enriched modules involving complement, innate/barrier pathways, epithelial biology, and type 2 immunity. Enriched pathways included nuclear factor κB signalling, T helper 17 related pathways, Janus kinase-signal transducer and activator of transcription signalling, programmed cell death protein 1/programmed death‑ligand 1, cytotoxic T‑lymphocyte associated protein 4 regulation, and osteoclast differentiation, several of which are relevant to rheumatic diseases. Paediatric IMIDs shared broad polygenic architecture with adult IMIDs, whereas top-ranked genes converged strongly with adult rheumatic diseases. Priority Index analysis identified 178 high-scoring genes, including 43 approved or investigational IMID drug targets. CONCLUSIONS: Paediatric-onset IMIDs share core pathways with adult forms but exhibit distinct genetic architecture shaped by age-specific immune and neurodevelopmental biology. These findings provide a genomic framework for paediatric precision medicine, guiding classification, risk prediction, and therapeutic development.

Humans↗