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PubMed2000

The role of the pathologist as tissue refiner and data miner: the impact of functional genomics on the modern pathology laboratory and the critical roles of pathology informatics and bioinformatics.

This article provides an overview of how functional genomics is likely to impact on the pathology laboratory and highlights how informatics and tissue banking will greatly facilitate the molecular age of medicine. Important aspects of functional genomics in the post-genome era, including the roles of laser capture microdissection, DNA- and complementary DNA-based microarrays, proteomic methods, collaborative human tissue banking, tissue microarrays, and pathobioinformatics in the modern pathology laboratory are discussed. The role of mass spectroscopy in the analysis of RNA, DNA, and protein and its impact on the clinical laboratory, particularly in cost-effectiveness and time savings, are evaluated. This article explores how laboratory information systems (LISs) and the devices that feed them information may need to be modified to adapt to greater volumes of data for the new testing modalities that require understanding sophisticated fluorescence detection methods and image processing. Emerging genomic testing methods and their impact on pathology laboratory testing, especially in the area of molecular classification of neoplasms, are examined. The role of the tissue bank in the modern pathology laboratory as an archive of control normal tissues, as well as subsamples of the spectrum of progressive neoplastic states, is discussed in light of its critical importance to the molecular classification of cancer. Establishing a database that combines structured reports in pathology LISs and construction of tissue banking information systems will provide a rich resource for pathology departments. The article discusses a hypothetical resource, such as the Shared Tumor Expression Profiler, that would provide access to well-characterized tissue-based research resources for clinicians and researchers. Last, the article emphasizes how LISs can prepare for these changes, and how training pathologists in pathology informatics and bioinformatics (pathobioinformatics) is critical to ensure pathology's overall leadership role in the post-genome era.

Clinical Laboratory Techniques↗

PubMed2001

Arabidopsis genome sequence as a tool for functional genomics in tomato.

Tomato is a well-established model organism for studying many biological processes including resistance and susceptibility to pathogens and the development and ripening of fleshy fruits. The availability of the complete Arabidopsis genome sequence will expedite map-based cloning in tomato on the basis of chromosomal synteny between the two species, and will facilitate the functional analysis of tomato genes.

Arabidopsis↗

PubMed2005

High-efficiency transformation of the diploid strawberry (Fragaria vesca) for functional genomics.

Fragaria vesca L., a diploid (2n = 2x = 14) relative of the commercial octoploid strawberry, is an attractive model for functional genomics research in Rosaceae. Its small genome size, short reproductive cycle, and facile vegetative and seed propagation make F. vesca a promising candidate for forward and reverse genetics experiments. However, the lack of a high-efficiency transformation protocol required for systematic production of thousands of T-DNA insertional mutant lines and high-throughput gene validation is a major bottleneck. We describe a new transformation procedure that uses leaf explants from newly unfolded trifoliate leaves obtained from stock plants 6-7 weeks after seed germination, co-cultivation with Agrobacterium strain GV3101, and stringent selection on MS medium containing 4 mg l(-1) hygromycin. Using this protocol we achieved 100% transformation efficiency for 6 of 14 F. vesca accessions tested. Accession PI 551572 was determined to be the best candidate for a model in F. vesca functional genomics research, as it showed the greatest propensity for callus formation, transformation, shoot regeneration, ex vitro establishment, and plant growth, requiring only 14-15 weeks to complete its life cycle in different seasons in the greenhouse.

Cinnamates↗

PubMed2000

Genome-wide mutant collections: toolboxes for functional genomics.

The sequencing of entire genomes has led to the identification of many genes. A future challenge will be to determine the function of all of the genes of an organism. One of the best ways to ascertain function is to disrupt genes and determine the phenotype of the resulting organism. Novel large-scale approaches for generating gene disruptions and analyzing the resulting phenotype are underway in the budding yeast Saccharomyces cerevisiae and other organisms including flies, Mycoplasma, worms, plants and mice. These approaches and mutant collections will be extremely valuable to the scientific community and will dramatically alter the manner in which science is performed in the future.

Animals↗

PubMed2002

Functional genomics in neuropsychiatric disorders and in neuropharmacology.

The rapidly accumulating amount of information concerning gene and protein expression patterns produced by functional genomics, proteomics and bioinformatics is presently providing new targets for drug development. Furthermore, the analysis of gene expression in cells and tissues affected by a disease may reveal the underlying metabolic pathways and cellular processes affected. Finally, changes in gene expression may be used in either diagnostics or the monitoring of drug responses. This review focuses on advances in the use of functional genomics in neurological and neuropsychiatric diseases and neuropsychopharmacology. Although the number of published studies in this field is still limited, it already appears that this strategy may become a fruitful means in the analysis of the aetiology of neuropsychiatric disorders and the search for novel neuropharmacological drugs.

Central Nervous System Agents↗

PubMed2006

Glia maturation factor gamma (GMFG): a cytokine-responsive protein during hematopoietic lineage development and its functional genomics analysis.

Human hematopoiesis was evaluated using the techniques of controlled stem cell differentiation, two-dimensional gel electrophoresis-based proteomics, and functional genomics. We provide the first report that glia maturation factor gamma (GMFG) is a cytokine-responsive protein in erythropoietin-induced and granulocyte-colony stimulating factor-induced hematopoietic lineage development. Results from global functional genomics analysis indicate that GMFG possesses several other features: hematopoietic tissue-specific gene expression, a promoter concentrated with high-score hematopoiesis-specific transcription factors, and possible molecular coevolution with a rudimentary blood/immune system. On the basis of our findings, we hypothesize that GMFG is a hematopoietic-specific protein that may mediate the pluripotentiality and lineage commitment of human hematopoietic stem cells.

Amino Acid Sequence↗

PubMed2004

Genome-wide high-throughput screens in functional genomics.

The availability of complete genome sequences from many organisms has yielded the ability to perform high-throughput, genome-wide screens of gene function. Within the past year, rapid advances have been made towards this goal in many major model systems, including yeast, worms, flies, and mammals. Yeast genome-wide screens have taken advantage of libraries of deletion strains, but RNA-interference has been used in other organisms to knockdown gene function. Examples of recent large-scale functional genetic screens include drug-target identification in yeast, regulators of fat accumulation in worms, growth and viability in flies, and proteasome-mediated degradation in mammalian cells. Within the next five years, such screens are likely to lead to annotation of function of most genes across multiple organisms. Integration of such data with other genomic approaches will extend our understanding of cellular networks.

Animals↗

PubMed2001

Brachypodium distachyon. A new model system for functional genomics in grasses.

A new model for grass functional genomics is described based on Brachypodium distachyon, which in the evolution of the Pooideae diverged just prior to the clade of "core pooid" genera that contain the majority of important temperate cereals and forage grasses. Diploid ecotypes of B. distachyon (2n = 10) have five easily distinguishable chromosomes that display high levels of chiasma formation at meiosis. The B. distachyon nuclear genome was indistinguishable in size from that of Arabidopsis, making it the simplest genome described in grasses to date. B. distachyon is a self-fertile, inbreeding annual with a life cycle of less than 4 months. These features, coupled with its small size (approximately 20 cm at maturity), lack of seed-head shatter, and undemanding growth requirements should make it amenable to high-throughput genetics and mutant screens. Immature embryos exhibited a high capacity for plant regeneration via somatic embryogenesis. Regenerated plants display very low levels of albinism and have normal fertility. A simple transformation system has been developed based on microprojectile bombardment of embryogenic callus and hygromycin selection. Selected B. distachyon ecotypes were resistant to all tested cereal-adapted Blumeria graminis species and cereal brown rusts (Puccinia reconditia). In contrast, different ecotypes displayed resistance or disease symptoms following challenge with the rice blast pathogen (Magnaporthe grisea) and wheat/barley yellow stripe rusts (Puccinia striformis). Despite its small stature, B. distachyon has large seeds that should prove useful for studies on grain filling. Such biological characteristics represent important traits for study in temperate cereals.

Anti-Bacterial Agents↗

PubMed1999

Functional genomics: from genes to new therapies.

The application of genomics in pharmaceutical R&D is presently one of the central issues in the industry. The evolution of functional genomics approaches and their integration into a technology platform for therapeutic discovery is a challenging and complex process. In this review, the authors describe how functional genomics will offer significant opportunities in the search for causal and disease-modifying therapies for better treatment of society's most outstanding medical needs.

Journal Article↗

PubMed2003

Identifying novel helix-loop-helix genes in Caenorhabditis elegans through a classroom demonstration of functional genomics.

A 14-week, undergraduate-level Genetics and Population Biology course at Morgan State University was modified to include a demonstration of functional genomics in the research laboratory. Students performed a rudimentary sequence analysis of the Caenorhabditis elegans genome and further characterized three sequences that were predicted to encode helix-loop-helix proteins. Students then used reverse transcription-polymerase chain reaction to determine which of the three genes is normally expressed in C. elegans. At the end of this laboratory activity, students were 1) to demonstrate a rudimentary knowledge of bioinformatics, including the ability to differentiate between "having" a gene and "expressing" a gene, and 2) to understand basic approaches to functional genomics, including one specific technique for assaying for gene expression. It was also anticipated that students would increase their skills at effectively communicating their research activities through written and/or oral presentation. This article describes the laboratory activity and the assessment of the effectiveness of the activity.

Animals↗

PubMed2002

Physiological variation in metabolic phenotyping and functional genomic studies: use of orthogonal signal correction and PLS-DA.

Metabolic phenotyping, or metabotyping, is increasingly being used as a probe in functional genomics studies. However, such profiling is subject to intrinsic physiological variation found in all animal populations. Using a nuclear magnetic resonance-based metabonomic approach, we show that diurnal variations in metabolism can obscure the interpretation of strain-related metabolic differences in two phenotypically normal mouse strains (C57BL10J and Alpk:ApfCD). To overcome this problem, diurnal-related metabolic variation was removed from these spectral data by application of orthogonal signal correction (OSC), a data filtering method. Interpretation of the removed orthogonal variation indicated that diurnal-related variation had been removed and that the AM samples contained higher levels of creatine, hippurate, trimethylamine, succinate, citrate and 2-oxo-glutarate and lower levels of taurine, trimethylamine-N-oxide, spermine and 3-hydroxy-iso-valerate relative to the PM samples. We propose OSC will have great potential removing confounding variation obscuring subtle changes in metabolism in functional genomic studies and will be of benefit to optimising interpretation of proteomic and genomic datasets.

Animals↗

PubMed2006

Functional genomics of Plasmodium falciparum through transposon-mediated mutagenesis.

Plasmodium falciparum is the causative agent for the most lethal form of human malaria, killing millions annually. Genetic analyses of P. falciparum have been relatively limited due to the lack of robust techniques to manipulate this parasite. Development of transfection technologies and whole genome analyses have helped in understanding the complex biology of this parasite. Even with this wealth of information functional genomics approaches are still very limited in P. falciparum due to the cumbersome and inefficient methods of genetic manipulation. This review focuses on a recently developed, highly efficient method for transposon-based mutagenesis and transgene expression in P. falciparum that will allow functional genomics studies to be performed proficiently on this deadly malaria parasite. By using a piggyBac-based transposition system, multiple random integrations have been obtained into the genome of the parasite. This technique could hence be employed to set up several biological screens in this lethal protozoan parasite that may lead to identification of novel drug targets and vaccine candidates.

Animals↗

PubMed2005

Transgene-induced RNA interference as a tool for plant functional genomics.

RNA interference (RNAi) is a powerful tool for functional genomics in a number of species. The logistics and procedures for doing high-throughput RNAi to investigate the functions of large numbers of genes in Arabidopsis thaliana and in Zea mays are described. Publicly available plasmid vectors that facilitate the stable chromosomal integration of inverted repeat transgenes that trigger RNAi have been used to generate more than 50 independent transgenic lines each in Arabidopsis and maize. Analysis of mRNA abundance of the targeted genes in independent lines transformed with distinct constructs indicates that the success of RNAi-induced silencing is gene dependent. mRNA levels were not detectably reduced for some genes, but were dramatically reduced for a number of genes targeted. A common pattern was that multiple independent lines transgenic for the same construct showed the same extent of silencing. This chapter describes the procedures used to generate and test transgenic lines mediating RNAi in Arabidopsis and maize.

Arabidopsis↗

PubMed2003

The application of functional genomics to Alzheimer's disease.

Alzheimer's disease (AD) is a polygenic/complex disorder in which more than 50 genetic loci are involved. Primary and secondary loci are potentially responsible for the phenotypic expression of the disease under the influence of both environmental factors and epigenetic phenomena. The construction of haplotypes as genomic clusters integrating the different genotype combinations of AD-related genes is a suitable strategy to investigate functional genomics in AD. It appears that AD patients show about 3-5 times higher genetic variation than the control population. The analysis of genotype-phenotype correlations has revealed that the presence of the APOE-4 allele in AD, in conjunction with other loci distributed across the genome, influence disease onset, brain atrophy, cerebrovascular perfusion, blood pressure, beta-amyloid deposition, ApoE secretion, lipid metabolism, brain bioelectrical activity, cognition, apoptosis and treatment outcome. Pharmacogenomics studies also indicate that the therapeutic response in AD is genotype-specific and that approximately 15% of the cases with efficacy and/or safety problems are associated with a defective CYP2D6 gene. Consequently, the understanding of functional genomics in AD will foster productive pharmacogenomic studies in the search for effective medications and preventive strategies in AD.

Alzheimer Disease↗

PubMed2026

CRISPR-Enabled functional genomics in hPSCs-derived neural models for autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a genetically heterogeneous neurodevelopmental condition in which hundreds of individually rare risk variants converge on a small number of shared biological pathways, including synaptic scaffolding, chromatin remodeling, excitation-inhibition balance, and cellular energy metabolism. Translating this genetic heterogeneity into mechanistic insight requires experimental systems capable of interrogating individual gene functions in human-relevant neural contexts at scale. CRISPR-enabled functional genomics in human pluripotent stem cell (hPSC)-derived neural models, spanning neural progenitors, cortical and inhibitory neurons, astrocytes, microglia, and brain organoids, provides precisely this capability. By integrating pooled perturbation screens with multimodal readouts including single-cell and spatial transcriptomics, chromatin accessibility profiling, proximity labeling proteomics, multi-electrode array electrophysiology, and metabolic flux analysis, these platforms enable systematic, causal mapping of ASD gene function at system resolution. Early applications have already revealed convergent mechanisms: BAF complex disruption expands the ventral progenitor pool and biases its fate toward oligodendrocyte and interneuron lineages; ADNP loss impairs microglial synaptic pruning through altered endocytic trafficking; and mTOR pathway dysregulation in PTEN- and TSC2-perturbed models links genetic risk directly to metabolic and mitochondrial dysfunction. Computational frameworks including MIMOSCA and SCEPTRE enable causal network reconstruction and pseudotime inference from these datasets, moving the field from gene lists toward pathway-level models of ASD pathobiology. Translational applications leverage isogenic iPSC panels and variant-level base and prime editing to stratify ASD variants by functional impact, informing gene therapy design for haploinsufficient targets such as CHD8 and SCN2A via AAV or antisense oligonucleotide delivery. Remaining challenges, including model developmental immaturity, batch variability, and the difficulty of modeling polygenic risk, are addressed by a roadmap integrating spatial perturbomics, AI-driven causal inference, and population-scale standardized biobanks. This review synthesizes the current state of CRISPR-based functional genomics in human stem cell neural models as a coherent experimental framework for converting ASD genetic associations into mechanistic understanding and therapeutic opportunity.

Humans↗

PubMed2006

Transformation of Actinidia eriantha: a potential species for functional genomics studies in Actinidia.

Protocols were developed for regeneration and Agrobacterium-mediated transformation of Actinidia eriantha Benth. A. eriantha has a number of features that make it a useful tool for functional genomics in Actinidia: the vines are relatively small and non-vigorous in nature, flowers form all over the vine including on lower axillary branches and the species flowers prolifically in greenhouse conditions. Flowering and fruiting of transgenic A. eriantha plants was obtained within 2 years of transformation in a containment greenhouse. GUS (beta-glucuronidase) activity indicating stable expression of the uidA gene was observed in leaf, stem, root, petal and fruit tissues. Molecular evidence for incorporation of transgenes into the A. eriantha genome was obtained by PCR and DNA gel blot analysis. Inheritance of transgenic phenotypes was demonstrated in seedling progeny. Functional genomic studies in kiwifruit have been initiated using transgenic A. eriantha plants.

Actinidia↗

PubMed2000

A transgenic perspective on plant functional genomics.

Transgenic crops are very much in the news due to the increasing public debate on their acceptance. In the scientific community though, transgenic plants are proving to be powerful tools to study various aspects of plant sciences. The emerging scientific revolution sparked by genomics based technologies is producing enormous amounts of DNA sequence information that, together with plant transformation methodology, is opening up new experimental opportunities for functional genomics analysis. An overview is provided here on the use of transgenic technology for the functional analysis of plant genes in model plants and a link made to their utilization in transgenic crops. In transgenic plants, insertional mutagenesis using heterologous maize transposons or Agrobacterium mediated T-DNA insertions, have been valuable tools for the identification and isolation of genes that display a mutant phenotype. To discover functions of genes that do not display phenotypes when mutated, insertion sequences have been engineered to monitor or change the expression pattern of adjacent genes. These gene detector insertions can detect adjacent promoters, enhancers or gene exons and precisely reflect the expression pattern of the tagged gene. Activation tag insertions can mis-express the adjacent gene and confer dominant phenotypes that help bridge the phenotype gap. Employment of various forms of gene silencing technology broadens the scope of recovering knockout phenotypes for genes with redundant function. All these transgenic strategies describing gene-phenotype relationships can be addressed by high throughput reverse genetics methods that will help provide functions to the genes discovered by genome sequencing. The gene functions discovered by insertional mutagenesis and silencing strategies along with expression pattern analysis will provide an integrated functional genomics perspective and offer unique applications in transgenic crops.

Crops, Agricultural↗

PubMed2003

Functional genomics reveals relationships between the retrovirus-like Ty1 element and its host Saccharomyces cerevisiae.

Retroviruses and their relatives, the long terminal repeat (LTR) retrotransposons, carry out complex life cycles within the cells of their hosts. We have exploited a collection of gene deletion mutants developed by the Saccharomyces Genome Deletion Project to perform a functional genomics screen for host factors that influence the retrovirus-like Ty1 element in yeast. A total of 101 genes that presumably influence many different aspects of the Ty1 retrotransposition cycle were identified from our analysis of 4483 homozygous diploid deletion strains. Of the 101 identified mutants, 46 had significantly altered levels of Ty1 cDNA, whereas the remaining 55 mutants had normal levels of Ty1 cDNA. Thus, approximately half of the mutants apparently affected the early stages of retrotransposition leading up to the assembly of virus-like particles and cDNA replication, whereas the remaining half affected steps that occur after cDNA replication. Although most of the mutants retained the ability to target Ty1 integration to tRNA genes, 2 mutants had reduced levels of tRNA gene targeting. Over 25% of the gene products identified in this study were conserved in other organisms, suggesting that this collection of host factors can serve as a starting point for identifying host factors that influence LTR retroelements and retroviruses in other organisms. Overall, our data indicate that Ty1 requires a large number of cellular host factors to complete its retrotransposition cycle efficiently.

Blotting, Southern↗