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PubMed2000

Transgenic gene knock-outs: functional genomics and therapeutic target selection.

The completion of the first draft of the human genome presents both a tremendous opportunity and enormous challenge to the pharmaceutical industry since the whole community, with few exceptions, will soon have access to the same pool of candidate gene sequences from which to select future therapeutic targets. The commercial imperative to select and pursue therapeutically relevant genes from within the overall content of the genome will be particularly intense for those gene families that currently represent the chemically tractable or 'drugable' gene targets. As a consequence the emphasis within exploratory research has shifted towards the evaluation and adoption of technology platforms that can add additional value to the gene selection process, either through functional studies or direct/indirect measures of disease alignment e.g., genetics, differential gene expression, proteomics, tissue distribution, comparative species data etc. The selection of biological targets for the development of potential new medicines relies, in part, on the quality of the in vivo biological data that correlates a particular molecular target with the underlying pathophysiology of a disease. Within the pharmaceutical industry, studies employing transgenic animals and, in particular, animals with specific gene deletions are playing an increasingly important role in the therapeutic target gene selection, drug candidate selection and product development phases of the overall drug discovery process. The potential of phenotypic information from gene knock-outs to contribute to a high-throughput target selection/validation strategy has hitherto been limited by the resources required to rapidly generate and characterise a large number of knock-out transgenics in a timely fashion. The offerings of several companies that provide an opportunity to overcome these hurdles, albeit at a cost, are assessed with respect to the strategic business needs of the pharmaceutical industry.

Animals↗

PubMed2006

Comparative and functional genomics of closteroviruses.

The largest extant RNA genomes are found in two diverse families of positive-strand RNA viruses, the animal Coronaviridae and the plant Closteroviridae. Comparative analysis of the viruses from the latter family reveals three levels of gene conservation. The most conserved gene module defines RNA replication and is shared with plant and animal viruses in the alphavirus-like superfamily. A module of five genes that function in particle assembly and transport is a hallmark of the family Closteroviridae and was likely present in the ancestor of all three closterovirus genera. This module includes a homologue of Hsp70 molecular chaperones and three diverged copies of the capsid protein gene. The remaining genes show dramatic variation in their numbers, functions, and origins among closteroviruses within and between the genera. Proteins encoded by these genes include suppressors of RNA silencing, RNAse III, papain-like proteases, the AlkB domain implicated in RNA repair, Zn-ribbon-containing protein, and a variety of proteins with no detectable homologues in the current databases. The evolutionary processes that have shaped the complex and fluid genomes of the large RNA viruses might be similar to those that have been involved in evolution of genomic complexity in other divisions of life.

Amino Acid Sequence↗

PubMed2001

Generation of full-length cDNA libraries enriched for differentially expressed genes for functional genomics.

Here, we describe the application of a RecA-based cloning technology to generate full-length cDNA libraries enriched for genes that are differentially expressed between tumor and normal tissue samples. First, we show that the RecA-based method can be used to enrich cDNA libraries for several target genes in a single reaction. Then, we demonstrate that this method can be extended to enrich a cDNA library for many full-length cDNA clones using fragments derived from a subtracted cDNA population. The results of these studies show that this RecA-mediated cloning technology can be used to convert subtracted cDNAs or a mixture of several cDNA fragments corresponding to differentially expressed genes into a full-length library in a single reaction. This procedure yields a population of expression-ready clones that can be used for further high-throughput functional screening.

DNA, Complementary↗

PubMed2026

Unravelling the biological nexus of smoking and postpartum depression: a meta-analysis and functional genomics approach.

PURPOSE: Postpartum depression (PPD) is a prevalent psychological condition among birthing women. While several psycho-socio-economic and neurobiological factors influence its development, its relationship with smoking behavior and nicotine addiction remains largely inconclusive. METHODS: In this combinatorial study, we first evaluate the relationship between smoking and depressive behaviors in postpartum women using data extracted from pertinent primary epidemiological studies. Additionally, to discern the molecular and cellular mechanisms underlying this association, we identified common genetic elements and evaluated their functional attributes using in silico analyses. RESULTS: Meta-analytical assessment of systematically collected data from 38 studies indicated that smoking women are twice as likely to develop PPD, compared to their non-smoking counterparts. While geocultural attributes did not affect this relationship, timing of smoking was a significant moderator, with current and gestational smoking statuses being more strongly linked with PPD outcome, compared to the past smoking habit. Further, depression scores in smoking postpartum women were higher than those in non-smoking controls. Analysis of the common protein-encoding genes underlying the pathophysiology of nicotine addiction and PPD revealed several critical hub proteins (viz., AKT1, JUN, CTNNB1, PTEN, EGFR, ESR1, SRC, STAT3, FN1, IL1B, IL6, TNF, TP53, GAPDH, INS, MYC, and ALB) which were predicted to alter multiple pathophysiological pathways associated with transcriptional expression, intra- and intercellular signaling transduction, metabolism, and immune functions. CONCLUSION: Our results indicate that smoking is strongly associated with depressive behavior in postpartum women, although this association involve mediation of additional environmental and psychosocial elements. Moreover, network analysis of common genetic elements identified several potentially disrupted neurophysiological pathways in postpartum women with smoking and depressive behaviors which may aid in characterizing the underlying relationship between the two conditions.

Humans↗

PubMed1999

Functional genomics and DNA array techniques in atherosclerosis research.

DNA arrays are revolutionizing the analysis of gene expression and single nucleotide polymorphisms of genomic DNA. Currently, the expression of 10-15% of human genes can be analysed simultaneously in a single experiment using cDNA or oligonucleotide-based format of DNA array. Alternatively, smaller DNA arrays with a limited number of selected genes, such as cytokines, growth factors or transcription factors, can be used. In concordance with Human Genome Project, after a few years, the DNA arrays will allow the analysis of expression of the whole human genome and will have a great impact on basic research, drug development and diagnostics. It is important to characterise mechanisms of atherosclerosis-related diseases at the level of gene expression so that new therapeutic strategies can be identified. With the aid of DNA array it is possible to identify multiple, simultaneous, transcriptional events that ameliorate or contribute to atherogenesis. The results are non-physical maps of the function, hierarchy and interactions of genetic programs. In this review we focus on DNA array technology and its applications in atherosclerosis research.

Arteriosclerosis↗

PubMed2004

Functional genomics tools for the analysis of zebrafish pigment.

Genetic model organisms are increasingly valuable in the post-genomics era to provide a basis for comparative analysis of the human genome. For higher order processes of vertebrate pigment cell biology and development, the mouse has historically been the model of choice. A complementary organism, the zebrafish (Danio rerio), shares many of the signaling and biological processes of vertebrates, e.g. neural crest development. The zebrafish has a number of characteristics that make it an especially valuable model for the study of pigment cell biology and disease. Large-scale genetic screens have identified a collection of pigmentation mutants that have already made valuable contributions to pigment research. An increasing repertoire of genomic resources such as an expressed sequence tag-based Gene Index (The Institute for Genomic Research) and improving methods of mutagenesis, transgenesis, and gene targeting make zebrafish a particularly attractive model. Morpholino phosphorodiamidate oligonucleotide (MO) 'knockdown' of pigment gene expression provides a non-conventional antisense tool for the analysis of genes involved in pigment cell biology and disease. In addition, an ongoing, reverse-genetic, MO-based screen for the rapid identification of gene function promises to be a valuable complement to other high-throughput microarray and proteomic approaches for understanding pigment cell biology. Novel reagents for zebrafish transgenesis, such as the Sleeping Beauty transposon system, continue to improve the capacity for genetic analysis in this system and ensure that the zebrafish will be a valuable genetic model for understanding a variety of biological processes and human diseases for years to come.

Animals↗

PubMed2005

Functional genomic analysis of global regulator NolR in Sinorhizobium meliloti.

NolR is a regulator of nodulation genes present in species belonging to the genera Rhizobium and Sinorhizobium. The expression of the nolR gene in Sinorhizobium meliloti AK631 was investigated in relation to stage of growth, availability of nutrients, and different environmental stimuli using the nolR::lacZ fusion report system. It has been shown that the nolR gene is regulated in a population-density-dependent fashion and influenced by a number of environmental stimuli, including nutrients, pH, and oxygen. Exploration of the physiological functions of NolR under various laboratory conditions has shown that NolR is required for the optimal growth of the bacteria on solid media, optimal survival of the bacteria in carbon-starved minimal medium, and after heat shock challenge. NolR also is involved in recipient-induced conjugative transfer of a plasmid. Proteome analysis of strain AK631 and its Tn5-induced nolR-deficient mutant EK698 revealed that a functional NolR induced significant differences in the accumulation of 20 polypeptides in peptide mass fingerprinting early-log-phase cultures and 48 polypeptides in stationary-phase cultures. NolR acted mainly as a repressor in the early-log-phase cultures, whereas it acted as both repressor and activator in the stationary-phase cultures. The NolR protein and 59 NolR-associated proteins have been identified by peptide mass fingerprinting. The NolR protein was differentially expressed only in the NolR+ wild-type strain AK631 but not in its NolR- derivative EK698, confirming that no functional NolR was produced in the mutant. The NolR-associated proteins have diverse functions in amino acid metabolism, carbohydrate metabolism, lipid metabolism, nucleotide metabolism, energy metabolism, metabolism of Co-factors, and cellular adaptation and transportation. These results further support our previous proposal that the NolR is a global regulatory protein which is required for the optimization of nodulation, bacterial growth and survival, and conjugative transfer of a plasmid.

Bacterial Proteins↗

PubMed2003

Human estrogen sulfotransferase (SULT1E1) pharmacogenomics: gene resequencing and functional genomics.

1. Estrogens are used as drugs and estrogen exposure is a risk factor for hormone-dependent diseases such as breast cancer. Sulfate conjugation is an important pathway for estrogen metabolism. The sulfotransferase (SULT) enzyme SULT1E1 has the lowest K(m) values for estrogens and catecholestrogens of the 10 known human SULT isoforms. 2. We previously cloned and characterized the human SULT1E1 cDNA and gene as steps toward pharmacogenetic studies. In the present experiments, we set out to determine whether common, functionally significant genetic polymorphisms might exist for SULT1E1. As a first step, we 'resequenced' the eight SULT1E1 exons and exon-intron splice junctions as well as portions of the 5'-flanking region using DNA from 60 African-American and 60 Caucasian-American subjects. 3. In all, 23 polymorphisms, 22 single nucleotide polymorphisms (SNPs) and one insertion deletion were observed. There were three nonsynonymous coding SNPs (cSNPs) that altered the following encoded amino acids: Asp22Tyr, Ala32Val and Pro253His. Among these, 12 pairs of SNPs were tightly linked. In addition, 12 unambiguous SULT1E1 haplotypes were identified, including six that were common to both populations studied. 4. Transient expression in COS-1 cells of constructs containing the three nonsynonymous cSNPs showed significant decreases in SULT1E1 activity for the Tyr22 and Val32 allozymes, with corresponding decreases in levels of immunoreactive protein. There were no changes in levels of either activity or immunoreactive protein for the His253 allozyme. Apparent K(m) values of the Val32 allozyme for the two cosubstrates for the reaction, 17beta-estradiol and 3'-phosphoadenosine 5'-phosphosulfate, were not significantly different from those of the wild-type enzyme, but there was a two- to three-fold increase in K(m) values for the His253 allozyme and a greater than five-fold increase for the Tyr22 allozyme. 5. These observations raise the possibility that genetically determined variation in SULT1E1-catalyzed estrogen sulfation might contribute to the pathophysiology of estrogen-dependent diseases as well as variation in the biotransformation of exogenously administered estrogens.

Black or African American↗

PubMed2004

Functional genomics analysis of Singapore grouper iridovirus: complete sequence determination and proteomic analysis.

Here we report the complete genome sequence of Singapore grouper iridovirus (SGIV). Sequencing of the random shotgun and restriction endonuclease genomic libraries showed that the entire SGIV genome consists of 140,131 nucleotide bp. One hundred sixty-two open reading frames (ORFs) from the sense and antisense DNA strands, coding for lengths varying from 41 to 1,268 amino acids, were identified. Computer-assisted analyses of the deduced amino acid sequences revealed that 77 of the ORFs exhibited homologies to known virus genes, 23 of which matched functional iridovirus proteins. Forty-two putative conserved domains or signatures were detected in the National Center for Biotechnology Information CD-Search database and PROSITE database. An assortment of enzyme activities involved in DNA replication, transcription, nucleotide metabolism, cell signaling, etc., were identified. Viruses were cultured on a cell line derived from the embryonated egg of the grouper Epinephelus tauvina, isolated, and purified by sucrose gradient ultracentrifugation. The protein extract from the purified virions was analyzed by polyacrylamide gel electrophoresis followed by in-gel digestion of protein bands. Matrix-assisted laser desorption ionization-time of flight mass spectrometry and database searching led to identification of 26 proteins. Twenty of these represented novel or previously unidentified genes, which were further confirmed by reverse transcription-PCR (RT-PCR) and DNA sequencing of their respective RT-PCR products.

Animals↗

PubMed2001

Reprogramming of genome function through epigenetic inheritance.

Most cells contain the same set of genes and yet they are extremely diverse in appearance and functions. It is the selective expression and repression of genes that determines the specific properties of individual cells. Nevertheless, even when fully differentiated, any cell can potentially be reprogrammed back to totipotency, which in turn results in re-differentiation of the full repertoire of adult cells from a single original cell of any kind. Mechanisms that regulate this exceptional genomic plasticity and the state of totipotency are being unravelled, and will enhance our ability to manipulate stem cells for therapeutic purposes.

Animals↗

PubMed2005

Reverse genetic approaches for functional genomics of rice.

T-DNA and transposable elements e.g., Ds and Tos17, are used to generate a large number of insertional mutant lines in rice. Some carry the GUS or GFP reporter for gene trap or enhancer trap. These reporter systems are valuable for identifying tissue- or organ-preferential genes. Activation tagging lines have also been generated for screening mutants and isolating mutagenized genes. To utilize these resources more efficiently, tagged lines have been produced for reverse genetic approaches. DNA pools of the T-DNA tagged lines and Tos17 lines have been prepared for PCR screening of insertional mutants in a given gene. Tag end sequences (TES) of the inserts have also been produced. TES databases are beneficial for analyzing the function of a large number of rice genes.

Binding Sites↗

PubMed1979

Inactivation by u.v.-irradiation of interfering herpes simplex virus particles: interference requires a functional genome.

The sensitivity of interfering herpes simplex virus (HSV) particles to u.v.-irradiation was studied in a virus stock of HSV-1 strain ANG that contained an excess of interfering over infectious particles. Following u.v.-irradiation, samples of this virus stock were assayed for their plaque-forming capacity and their capacity to interfere with the replication of unirradiated standard virus. Depending on the assay conditions, interfering particles appeared to be less, equally, or more sensitive to u.v. light than infectious particles. It is concluded that interference is a gene function of interfering particles rather than being exerted directly by structural constituents of these particles.

Animals↗

PubMed2006

Developmental control of nuclear morphogenesis and anchoring by charleston, identified in a functional genomic screen of Drosophila cellularisation.

Morphogenesis of epithelial tissues relies on the precise developmental control of cell polarity and architecture. In the early Drosophila embryo, the primary epithelium forms during cellularisation, following a tightly controlled genetic programme where specific sets of genes are upregulated. Some of them, for example, control membrane invagination between the nuclei anchored at the apical surface of the syncytium. We used microarrays to describe the global programme of gene expression underlying cellularisation and identified distinct classes of upregulated genes during this process. Fifty-seven genes were then tested functionally by RNAi. We found six genes affecting various aspects of cellular architecture: membrane growth, organelle transport or organisation and junction assembly. We focus here on charleston (char), a new regulator of nuclear morphogenesis and of apical nuclear anchoring. In char-depleted embryos, the nuclei fail to maintain their elongated shape and, instead, become rounded. In addition, together with a disruption of the centrosome-nuclear envelope interaction, the nuclei lose their regular apical anchoring. These nuclear defects perturb the regular columnar organisation of epithelial cells in the embryo. Although microtubules are required for both nuclear morphogenesis and anchoring, char does not control microtubule organisation and association to the nuclear envelope. We show that Char is lipid anchored at the nuclear envelope by a farnesylation group, and localises at the inner nuclear membrane together with Lamin. Our data suggest that Char forms a scaffold that regulates nuclear architecture to constrain nuclei in tight columnar epithelial cells. The upregulation of Char during cellularisation and gastrulation reveals the existence of an as yet unknown developmental control of nuclear morphology and anchoring in embryonic epithelia.

Alkyl and Aryl Transferases↗

PubMed2003

A need for a 'whole-istic functional genomics' approach in complex human diseases: arthritis.

'Genomic tools', such as gene/protein chips, single nucleotide polymorphism and haplotype analyses, are empowering us to generate staggering amounts of correlative data, from human/animal genetics and from normal and disease-affected tissues obtained from complex diseases such as arthritis. These tools are transforming molecular biology into a 'data rich' science, with subjects with an '-omic' suffix. These disciplines have to converge and integrate at a systemic level to examine the structure and dynamics of cellular and organismal function ('functionomics') simultaneously, using a multidimensional approach for cells, tissues, organs, rodents and Zebra fish models, which intertwines various approaches and readouts to study the development and homeostasis of a system. In summary, the postgenomic era of functionomics will facilitate narrowing the bridge between correlative data and causative data, thus integrating 'intercoms' of interacting and interdependent disciplines and forming a unified whole.

Arthritis↗

PubMed2005

Functional genomic analysis of three nitrogenase isozymes in the photosynthetic bacterium Rhodopseudomonas palustris.

The photosynthetic bacterium Rhodopseudomonas palustris is one of just a few prokaryotes described so far that has vnf and anf genes for alternative vanadium cofactor (V) and iron cofactor (Fe) nitrogenases in addition to nif genes for a molybdenum cofactor (Mo) nitrogenase. Transcriptome data indicated that the 32 genes in the nif gene cluster, but not the anf or vnf genes, were induced in wild-type and Mo nitrogenase-expressing strains grown under nitrogen-fixing conditions in Mo-containing medium. Strains that were unable to express a functional Mo nitrogenase due to mutations in Mo nitrogenase structural genes synthesized functional V and Fe nitrogenases and expressed vnf and anf genes in nitrogen-fixing growth media that contained Mo and V at concentrations far in excess of those that repress alternative nitrogenase gene expression in other bacteria. Thus, not only does R. palustris have multiple enzymatic options for nitrogen fixation, but in contrast to reports on other nitrogen-fixing bacteria, the expression of its alternative nitrogenases is not repressed by transition metals. Between 95 and 295 genes that are not directly associated with nitrogenase synthesis and assembly were induced under nitrogen-fixing conditions, depending on which nitrogenase was being used by R. palustris. Genes for nitrogen acquisition were expressed at particularly high levels during alternative nitrogenase-dependent growth. This suggests that alternative nitrogenase-expressing cells are relatively starved for nitrogen and raises the possibility that fixed nitrogen availability may be the primary signal that controls the synthesis of the V and Fe nitrogenases.

Adaptation, Physiological↗

PubMed2004

Functional genomic hypothesis generation and experimentation by a robot scientist.

The question of whether it is possible to automate the scientific process is of both great theoretical interest and increasing practical importance because, in many scientific areas, data are being generated much faster than they can be effectively analysed. We describe a physically implemented robotic system that applies techniques from artificial intelligence to carry out cycles of scientific experimentation. The system automatically originates hypotheses to explain observations, devises experiments to test these hypotheses, physically runs the experiments using a laboratory robot, interprets the results to falsify hypotheses inconsistent with the data, and then repeats the cycle. Here we apply the system to the determination of gene function using deletion mutants of yeast (Saccharomyces cerevisiae) and auxotrophic growth experiments. We built and tested a detailed logical model (involving genes, proteins and metabolites) of the aromatic amino acid synthesis pathway. In biological experiments that automatically reconstruct parts of this model, we show that an intelligent experiment selection strategy is competitive with human performance and significantly outperforms, with a cost decrease of 3-fold and 100-fold (respectively), both cheapest and random-experiment selection.

Algorithms↗

PubMed2005

Functional genomics and expression analysis of the Corynebacterium glutamicum fpr2-cysIXHDNYZ gene cluster involved in assimilatory sulphate reduction.

BACKGROUND: Corynebacterium glutamicum is a high-GC Gram-positive soil bacterium of great biotechnological importance for the production of amino acids. To facilitate the rational design of sulphur amino acid-producing strains, the pathway for assimilatory sulphate reduction providing the necessary reduced sulfur moieties has to be known. Although this pathway has been well studied in Gram-negative bacteria like Escherichia coli and low-GC Gram-positives like Bacillus subtilis, little is known for the Actinomycetales and other high-GC Gram-positive bacteria. RESULTS: The genome sequence of C. glutamicum was searched for genes involved in the assimilatory reduction of inorganic sulphur compounds. A cluster of eight candidate genes could be identified by combining sequence similarity searches with a subsequent synteny analysis between C. glutamicum and the closely related C. efficiens. Using mutational analysis, seven of the eight candidate genes, namely cysZ, cysY, cysN, cysD, cysH, cysX, and cysI, were demonstrated to be involved in the reduction of inorganic sulphur compounds. For three of the up to now unknown genes possible functions could be proposed: CysZ is likely to be the sulphate permease, while CysX and CysY are possibly involved in electron transfer and cofactor biosynthesis, respectively. Finally, the candidate gene designated fpr2 influences sulphur utilisation only weakly and might be involved in electron transport for the reduction of sulphite. Real-time RT-PCR experiments revealed that cysIXHDNYZ form an operon and that transcription of the extended cluster fpr2 cysIXHDNYZ is strongly influenced by the availability of inorganic sulphur, as well as L-cysteine. Mapping of the fpr2 and cysIXHDNYZ promoters using RACE-PCR indicated that both promoters overlap with binding-sites of the transcriptional repressor McbR, suggesting an involvement of McbR in the observed regulation. Comparative genomics revealed that large parts of the extended cluster are conserved in 11 of 17 completely sequenced members of the Actinomycetales. CONCLUSION: The set of C. glutamicum genes involved in assimilatory sulphate reduction was identified and four novel genes involved in this pathway were found. The high degree of conservation of this cluster among the Actinomycetales supports the hypothesis that a different metabolic pathway for the reduction of inorganic sulphur compounds than that known from the well-studied model organisms E. coli and B. subtilis is used by members of this order, providing the basis for further biochemical studies.

Actinobacteria↗

PubMed2004

Nuclear architecture and genome functioning in plants and animals: what can we learn from both?

In this short review, we combine information about large-scale chromosome and chromatin structure in the interphase nucleus from animals and plants in relation to transcription. We propose a rosette-like structure for interphase chromosomes in higher eukaryotes in which condensed heterochromatin domains act as organizing centers from which euchromatic loops sprout that contain the transcription units available to that particular cell. In the same context, we address the apparent discrepancy between the spatial distribution of transcriptionally active sites in the nucleus and our understanding of the linear organization of genes on the linear genome. It is likely that this paradox can be solved by taking into account the probably large number of genes for nonprotein-coding RNAs.

Animals↗