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PubMed2004

TILLING. Traditional mutagenesis meets functional genomics.

Most of the genes of an organism are known from sequence, but most of the phenotypes are obscure. Thus, reverse genetics has become an important goal for many biologists. However, reverse-genetic methodologies are not similarly applicable to all organisms. In the general strategy for reverse genetics that we call TILLING (for Targeting Induced Local Lesions in Genomes), traditional chemical mutagenesis is followed by high-throughput screening for point mutations. TILLING promises to be generally applicable. Furthermore, because TILLING does not involve transgenic modifications, it is attractive not only for functional genomics but also for agricultural applications. Here, we present an overview of the status of TILLING methodology, including Ecotilling, which entails detection of natural variation. We describe public TILLING efforts in Arabidopsis and other organisms, including maize (Zea mays) and zebrafish. We conclude that TILLING, a technology developed in plants, is rapidly being adopted in other systems.

Agriculture↗

PubMed2006

Functional genomics of sex hormone-dependent neuroendocrine systems: specific and generalized actions in the CNS.

Sex hormone effects on hypothalamic neurons have been worked out to a point where receptor mechanisms are relatively well understood, a neural circuit for a sex steroid-dependent behavior has been determined, and several functional genomic regulations have been discovered and conceptualized. With that knowledge in hand, we approach deeper problems of explaining sexual arousal and generalized CNS arousal. After a brief summary of arousal mechanisms, we focus on three chemical systems which signal generalized arousal and impact hormone-dependent hypothalamic neurons of behavioral importance: histamine, norepinephrine and enkephalin.

Animals↗

PubMed2000

Rice transformation for crop improvement and functional genomics.

Although several japonica and some indica varieties of rice have already been transformed, there is significant scope for improvement in the technology for transformation of economically important indica varieties. Successful transformation of rice employing Agrobacterium and recent advances in direct gene transfer by biolistics, evidenced by transfer of multiple genes, have removed some of the serious impediments in the area of gene engineering. The transfer of genes for nutritionally important biosynthetic pathway has provided many opportunities for performing metabolic engineering. Other useful genes for resistance against pests, diseases and abiotic stresses have also been transferred to rice. But the limited knowledge about important target genes requires rapid progress in the field of functional genomics. Transgenic rice system can be applied to isolate new genes, promoters, and enhancers and their functions could be unravelled. The combination of novel regulatory systems for targeted expression and useful new genes should pave the way for improvement of rice and other cereals.

Journal Article↗

PubMed2006

Plant cell wall biosynthesis: genetic, biochemical and functional genomics approaches to the identification of key genes.

Cell walls are dynamic structures that represent key determinants of overall plant form, plant growth and development, and the responses of plants to environmental and pathogen-induced stresses. Walls play centrally important roles in the quality and processing of plant-based foods for both human and animal consumption, and in the production of fibres during pulp and paper manufacture. In the future, wall material that constitutes the major proportion of cereal straws and other crop residues will find increasing application as a source of renewable fuel and composite manufacture. Although the chemical structures of most wall constituents have been defined in detail, the enzymes involved in their synthesis and remodelling remain largely undefined, particularly those involved in polysaccharide biosynthesis. There have been real recent advances in our understanding of cellulose biosynthesis in plants, but, with few exceptions, the identities and modes of action of polysaccharide synthases and other glycosyltransferases that mediate the biosynthesis of the major non-cellulosic wall polysaccharides are not known. Nevertheless, emerging functional genomics and molecular genetics technologies are now allowing us to re-examine the central questions related to wall biosynthesis. The availability of the rice, Populus trichocarpa and Arabidopsis genome sequences, a variety of mutant populations, high-density genetic maps for cereals and other industrially important plants, high-throughput genome and transcript analysis systems, extensive publicly available genomics resources and an increasing armoury of analysis systems for the definition of candidate gene function will together allow us to take a systems approach to the description of wall biosynthesis in plants.

Biotechnology↗

PubMed2005

The functional genomics of noncoding RNA.

Large numbers of noncoding RNA transcripts (ncRNAs) are being revealed by complementary DNA cloning and genome tiling array studies in animals. The big and as yet largely unanswered question is whether these transcripts are relevant. A paper by Willingham et al. shows the way forward by developing a strategy for large-scale functional screening of ncRNAs, involving small interfering RNA knockdowns in cell-based screens, which identified a previously unidentified ncRNA repressor of the transcription factor NFAT. It appears likely that ncRNAs constitute a critical hidden layer of gene regulation in complex organisms, the understanding of which requires new approaches in functional genomics.

Animals↗

PubMed2004

High-throughput functional genomics identifies genes that ameliorate toxicity due to oxidative stress in neuronal HT-22 cells: GFPT2 protects cells against peroxide.

We describe a novel genetic screen that is performed by transfecting every individual clone of an expression clone collection into a separate population of cells in a high-throughput mode. We combined high-throughput functional genomics with experimental validation to discover human genes that ameliorate cytotoxic responses of neuronal HT-22 cells upon exposure to oxidative stress. A collection of 5,000 human cDNAs in mammalian expression vectors were individually transfected into HT-22 cells, which were then exposed to H(2)O(2). Five genes were found that are known to be involved in pathways of detoxification of peroxide (catalase, glutathione peroxidase-1, peroxiredoxin-1, peroxiredoxin-5, and nuclear factor erythroid-derived 2-like 2). The presence of those genes in our "hit list" validates our screening platform. In addition, a set of candidate genes was found that has not been previously described as involved in detoxification of peroxide. One of these genes, which was consistently found to reduce H(2)O(2) -induced toxicity in HT-22, was GFPT2. This gene is expressed at significant levels in the central nervous system (CNS) and encodes glutamine-fructose-6-phosphate transaminase (GFPT) 2, a rate-limiting enzyme in hexosamine biosynthesis. GFPT has recently also been shown to ameliorate the toxicity of methylmercury in Saccharomyces cerevisiae. Methylmercury causes neuronal cell death in part by protein modification as well as enhancing the production of reactive oxygen species (ROS). The protective effect of GFPT2 against H(2)O(2) toxicity in neuronal HT-22 cells may be similar to its protection against methylmercury in yeast. Thus, GFPT appears to be conserved among yeast and men as a critical target of methylmercury and ROS-induced cytotoxicity.

Animals↗

PubMed2000

On the optimization of classes for the assignment of unidentified reading frames in functional genomics programmes: the need for machine learning.

At present, the assignment of function to novel genes uncovered by the systematic genome-sequencing programmes is a problem. Many studies anticipate that this can be achieved by analysing patterns of gene expression via the transcriptome, proteome and metabolome. Thus, functional genomics is, in part, an exercise in pattern classification. Because many genes have known functional classes, the problem of predicting their functional class is a supervised learning problem. However, most pattern classification methods that have been applied to the problem have been unsupervised clustering methods. Consequently, the best classification tools have not always been used. Furthermore, the present functional classes are suboptimal and new unsupervised clustering methods are needed to improve them. Better-structured functional classes will facilitate the prediction of biochemically testable functions.

Animals↗

PubMed2005

MicroTom--a high-throughput model transformation system for functional genomics.

We have developed a high-throughput Agrobacterium-mediated transformation model system using both nptII and the 5-enolpyruvylshikimate-3-phosphate synthase gene from Agrobacterium tumefaciens strain CP4 (cp4) based selections in MicroTom, a miniature rapid-cycling cherry tomato variety. With the NPTII selection system, transformation frequency calculated as independent transgenic events per inoculated explant ranged from 24 to 80% with an average of 56%, in industrial production scale transformation experiments. For CP4, with glyphosate selection, the average transformation frequency was 57%. Stable transformation frequency was positively correlated with transient expression (R=0.85), and variable with the genes of interest. DNA integration and germline transformation were confirmed by biological assay, Southern Blot analysis, and R(1) phenotype segregation. Transgene expression was observed in leaf, root, stem, flower, and fruit tissues of the transgenic plants. Ninety-five percent of transgenic events coexpressed two introduced genes based on beta-glucuronidase (GUS) and neonmycin phosphotransferase II (NPTII) expression. Seventy-five percent of transgenic events contained one to two copies of the introduced uidA (GUS) gene based on Southern analysis. Transgenic plants from the cotyledon explants to the transgenic plants transferred to soil were produced within about 2-3 months depending on the genes of interest. The utility of this MicroTom model transformation system for functional genomic studies, such as identification of genes related to important agricultural traits and gene function, is discussed.

3-Phosphoshikimate 1-Carboxyvinyltransferase↗

PubMed1999

Functional genomic analysis reveals the utility of the I/LWEQ module as a predictor of protein:actin interaction.

The I/LWEQ module is a conserved sequence that we have identified as an actin-binding motif in the metazoan focal adhesion protein talin and the yeast protein Sla2p. Both of these proteins are associated with the actin cytoskeleton in cells. To better establish the value of the I/LWEQ module for prediction of actin-binding function, we have applied a functional genomics approach. Analysis of the 23 available I/LWEQ module sequences supports the division of I/LWEQ protein superfamily into four groups: (1) metazoan talin, (2) Dictyostelium discoideum talin homologs TalA/B, (3) metazoan Hip1p, and (4) yeast Sla2p. We show here that I/LWEQ modules from each major group bind to F-actin in vitro and that GFP-fusion proteins of the I/LWEQ modules of talin and Sla2p bind to F-actin in vivo. Therefore, the presence of an I/LWEQ module is strongly predictive of protein-actin interactions. The structural and functional conservation of the I/LWEQ module across the phylogenetic distance between cellular slime molds and mammals implies that the role of the I/LWEQ module is to connect diverse proteins involved in distinct cellular processes, including cell adhesion, cytoskeletal organization, and cell differentiation, to the actin cytoskeleton.

Actins↗

PubMed2005

Understanding bovine trypanosomiasis and trypanotolerance: the promise of functional genomics.

African bovine trypanosomiasis, caused by the protozoan parasite Trypanosoma congolense, is endemic throughout sub-Saharan Africa and is a major constraint on livestock production. A promising approach to disease control is to understand and exploit naturally evolved trypanotolerance. We describe the first attempt to investigate the transcriptional response of susceptible Boran (Bos indicus) cattle to trypanosome infection via a functional genomics approach using a bovine total leukocyte (BOTL) cDNA microarray platform. Four male Boran cattle were experimentally infected with T. congolense and peripheral blood mononuclear cells (PBMC) were collected before infection and 13, 17, 23 and 30 days post-infection (dpi). A reference experimental design was employed using a universal bovine reference RNA pool. Data were normalised to the median of a set of invariant genes (GAPDH) and BRB-Array tools was used to search for statistically significant differentially expressed genes between each time-point. Using a set of 20 microarray hybridisations, we have made a significant contribution to understand the temporal transcriptional response of bovine PBMC in vivo to a controlled trypanosome infection. The greatest changes were evident 13 dpi after parasites were first detected in the blood. Significant differences were observed in clusters of protein kinase C subunits and MHC class I/II related molecules.

Animals↗

PubMed2005

Blast2GO: a universal tool for annotation, visualization and analysis in functional genomics research.

SUMMARY: We present here Blast2GO (B2G), a research tool designed with the main purpose of enabling Gene Ontology (GO) based data mining on sequence data for which no GO annotation is yet available. B2G joints in one application GO annotation based on similarity searches with statistical analysis and highlighted visualization on directed acyclic graphs. This tool offers a suitable platform for functional genomics research in non-model species. B2G is an intuitive and interactive desktop application that allows monitoring and comprehension of the whole annotation and analysis process. AVAILABILITY: Blast2GO is freely available via Java Web Start at http://www.blast2go.de. SUPPLEMENTARY MATERIAL: http://www.blast2go.de -> Evaluation.

Algorithms↗

PubMed2003

Validation of a more sensitive method for using spotted oligonucleotide DNA microarrays for functional genomics studies on bacterial communities.

Spotted oligonucleotide microarrays potentially offer a wide scope of applications for microbial ecology, especially as they improve the flexibility of design and the specificity of detection compared to PCR product based microarrays. Sensitivity, however, was expected to be problematic, as studies with the more sensitive PCR-based cDNA microarrays indicate that only genes from populations contributing to more than 5% of the community DNA can be detected. We evaluated several parameters to increase sensitivity and then tested applicability for bacterial functional genomics. The optimal parameters were the use of 5'-C6-amino-modified 70-mers printed on CMT-GAPS II substrates at a 40 micro M concentration combined with the use of Tyramide Signal Amplification labelling. This protocol allowed detection of single copy genes belonging to an organism contributing to 1% or more of the total community. To demonstrate its application, we detected the specific aromatic oxygenase genes in a soil community degrading polychlorinated biphenyls (PCBs). This increase in sensitivity is important if oligonucleotide microarrays are to be used for simultaneous monitoring of a range of functions performed by different microorganisms in the environment.

Bacteria↗

PubMed2002

Functional genomics and the breast cancer problem.

The clinical treatment of primary breast cancers has been greatly complicated by the inability to accurately predict which tumors will eventually become invasive and metastatic and which will remain localized and indolent. Lacking the ability to discriminate between these two classes of breast cancer patients, oncologists often apply aggressive adjuvant therapy to women in both groups. However, the use of functional genomics analysis has now made it possible to assemble a set of gene markers, the expression of which enables one to predict, with reasonably high accuracy, whether or not the patient will relapse or remain tumor-free five years after initial diagnosis and treatment.

Biomarkers, Tumor↗

PubMed2004

FGDP: functional genomics data pipeline for automated, multiple microarray data analyses.

UNLABELLED: Gene expression microarrays and oligonucleotide GeneChips have provided biologists with a means of measuring, in a single experiment, the expression levels of entire genomes under a variety of conditions. As with any nascent field, there is no single accepted method for analyzing the new data types, with new methods appearing monthly. Investigators using the new technology must constantly seek access to the latest tools and explore their data in multiple ways. The functional genomics data pipeline provides an integrated, extendable analysis environment permitting multiple, simultaneous analyses to be automatically performed and provides a web server and interface for presenting results. AVAILABILITY: Source code and executables are available under the GNU public license at http://bioinformatics.fccc.edu/

Computing Methodologies↗

PubMed2001

Structure and functional genomics of lipopolysaccharide expression in Haemophilus influenzae.

The involvement of genes in the lic loci in H. influenzae LPS expression has been known for some time. However, it was not until recently that it was shown that the lic1 locus contains genes required for phase variable expression of phosphocholine substituents, while genes in the lic2 locus and lgtC are required for expression of the globoside trisaccharide, alpha-D-Galp-(1 --> 4)-beta-D-Galp-(1 --> 4)-beta-D-Glcp (i.e., the pK blood group epitope). The availability of the complete sequence of the H. influenzae strain Rd genome has facilitated significant progress in understanding the role of these and other genes in the expression and biosynthesis of LPS. We have employed a comparative structural fingerprinting strategy to establish the structural relationships among LPS from H. influenzae mutant strains in which putative biosynthesis genes were inactivated. Using this functional genomics approach, we have gained considerable insight into the genetic basis for intra-strain and strain-to-strain variation in epitope expression.

Base Sequence↗

PubMed2001

Functional genomics and the study of development, variation and evolution.

It has rarely been possible to connect the developmental and evolutionary branches of genetics, particularly with regard to the precise changes in the molecular control of development that are responsible for phenotypic variation and evolution. Making such connections will require a high-resolution molecular description of the genetic networks that underlie development and an understanding of their responses to genetic and environmental variation. Functional genomics approaches to development and evolution promise to accelerate the research necessary to accomplish these goals.

Animals↗

PubMed2002

Functional genomic analysis of the Bacillus subtilis Tat pathway for protein secretion.

Protein secretion from Bacillus species is a major industrial production tool with a market of over $1 billion per year. However, standard export technologies, based on the well-characterised general secretory (Sec) pathway, are frequently inapplicable for the production of proteins. The recently discovered twin-arginine translocation (Tat) pathway offers additional potential to transport proteins. Here we review the use of functional genomic and proteomic approaches to explore the Tat pathway of Bacillus subtilis. The properties of Tat pathway components and the twin-arginine signal peptides that direct proteins into this pathway are discussed. Where appropriate, a comparison is made with Tat systems from other organism, such as Escherichia coli. Recent findings with the latter organism in particular provide proof-of-principle that the Tat pathway can be exploited for the production of Sec-incompatible proteins.

Amino Acid Sequence↗

PubMed2005

An analysis of extensible modelling for functional genomics data.

BACKGROUND: Several data formats have been developed for large scale biological experiments, using a variety of methodologies. Most data formats contain a mechanism for allowing extensions to encode unanticipated data types. Extensions to data formats are important because the experimental methodologies tend to be fairly diverse and rapidly evolving, which hinders the creation of formats that will be stable over time. RESULTS: In this paper we review the data formats that exist in functional genomics, some of which have become de facto or de jure standards, with a particular focus on how each domain has been modelled, and how each format allows extensions. We describe the tasks that are frequently performed over data formats and analyse how well each task is supported by a particular modelling structure. CONCLUSION: From our analysis, we make recommendations as to the types of modelling structure that are most suitable for particular types of experimental annotation. There are several standards currently under development that we believe could benefit from systematically following a set of guidelines.

Chemistry Techniques, Analytical↗