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PubMed1996

A screen for genes that function downstream of Ras1 during Drosophila eye development.

Cell-fate specification of the R7 photoreceptor cell is controlled by the sevenless receptor tyrosine kinase (SevRTK) and Ras1, the Drosophila homologue of mammalian H-ras, K-ras and N-ras oncogenes. An activated form of Ras1 expressed under control of the sevenless enhancer/promoter (sev-Ras1V12) induces production of supernumerary R7 photoreceptor cells, which causes the eye to become rough in appearance. To isolate mutations in genes functioning downstream of Ras1, we carried out a screen for dominant suppressors and enhancers of this rough eye phenotype. Approximately 850,000 mutagenized flies were screened, and 282 dominant suppressors and 577 dominant enhancers were isolated. Mutations in the Drosophila homologues of Raf, MEK, MAPK, type I Geranylgeranyl Transferase and Protein Phosphatase 2A were isolated, as were mutations in several novel signaling genes. Some of these mutant genes appear to be general signaling factors that function in other Ras1 pathways, while one seems to be more specific for photoreceptor development. At least two suppressors appear to function either between Ras1 and Raf or in parallel to Raf.

Animals↗
PubMed2002

A maximum likelihood method for analyzing pseudogene evolution: implications for silent site evolution in humans and rodents.

We present a new likelihood method for detecting constrained evolution at synonymous sites and other forms of nonneutral evolution in putative pseudogenes. The model is applicable whenever the DNA sequence is available from a protein-coding functional gene, a pseudogene derived from the protein-coding gene, and an orthologous functional copy of the gene. Two nested likelihood ratio tests are developed to test the hypotheses that (1) the putative pseudogene has equal rates of silent and replacement substitutions; and (2) the rate of synonymous substitution in the functional gene equals the rate of substitution in the pseudogene. The method is applied to a data set containing 74 human processed-pseudogene loci, 25 mouse processed-pseudogene loci, and 22 rat processed-pseudogene loci. Using the informatics resources of the Human Genome Project, we localized 67 of the human-pseudogene pairs in the genome and estimated the GC content of a large surrounding genomic region for each. We find that, for pseudogenes deposited in GC regions similar to those of their paralogs, the assumption of equal rates of silent and replacement site evolution in the pseudogene is upheld; in these cases, the rate of silent site evolution in the functional genes is approximately 70% the rate of evolution in the pseudogene. On the other hand, for pseudogenes located in genomic regions of much lower GC than their functional gene, we see a sharp increase in the rate of silent site substitutions, leading to a large rate of rejection for the pseudogene equality likelihood ratio test.

Animals↗
PubMed2003

MeKE: discovering the functions of gene products from biomedical literature via sentence alignment.

MOTIVATION: Research on roles of gene products in cells is accumulating and changing rapidly, but most of the results are still reported in text form and are not directly accessible by computers. To expedite the progress of functional bioinformatics, it is, therefore, important to efficiently process large amounts of biomedical literature and transform the knowledge extracted into a structured format usable by biologists and medical researchers. Our aim was to develop an intelligent text-mining system that will extract from biomedical documents knowledge about the functions of gene products and thus facilitate computing with function. RESULTS: We have developed an ontology-based text-mining system to efficiently extract from biomedical literature knowledge about the functions of gene products. We also propose methods of sentence alignment and sentence classification to discover the functions of gene products discussed in digital texts. AVAILABILITY: http://ismp.csie.ncku.edu.tw/~yuhc/meke/

Biomedical Research↗
PubMed2006

High-efficiency gene transfer into cultured embryonic motoneurons using recombinant lentiviruses.

Primary neurons are a common tool for investigating gene function for survival and morphological and functional differentiation. Gene transfer techniques play an important role in this context. However, the efficacy of conventional gene transfer techniques, in particular for primary motoneurons is low so that it is not possible to distinguish whether the observed effects are representative for all neurons or only for the small subpopulation that expresses the transfected cDNA. In order to develop techniques that allow high gene transfer rates, we have optimized lentiviral-based gene transfer for cultured motoneurons by using a replication-defective viral vector system. These techniques result in transduction efficacies higher than 50%, as judged by EGFP expression under the control of SFFV or CMV promoters. Under the same conditions, survival and morphology of the cultured motoneurons was not altered, at least not when virus titers did not exceed a multiplicity of infection of 100. Under the same cell culture conditions, electroporation resulted in less than 5% transfected motoneurons and reduced survival. Therefore we consider this lentivirus-based gene transfer protocol as a suitable tool to study the effects of gene transfer on motoneuron survival, differentiation and function.

Animals↗
PubMed1998

Predicting function: from genes to genomes and back.

Predicting function from sequence using computational tools is a highly complicated procedure that is generally done for each gene individually. This review focuses on the added value that is provided by completely sequenced genomes in function prediction. Various levels of sequence annotation and function prediction are discussed, ranging from genomic sequence to that of complex cellular processes. Protein function is currently best described in the context of molecular interactions. In the near future it will be possible to predict protein function in the context of higher order processes such as the regulation of gene expression, metabolic pathways and signalling cascades. The analysis of such higher levels of function description uses, besides the information from completely sequenced genomes, also the additional information from proteomics and expression data. The final goal will be to elucidate the mapping between genotype and phenotype.

Bacterial Proteins↗
PubMed1991

Multiple human D5 dopamine receptor genes: a functional receptor and two pseudogenes.

Three genes closely related to the D1 dopamine receptor were identified in the human genome. One of the genes lacks introns and encodes a functional human dopamine receptor, D5, whose deduced amino acid sequence is 49% identical to that of the human D1 receptor. Compared with the human D1 dopamine receptor, the D5 receptor displayed a higher affinity for dopamine and was able to stimulate a biphasic rather than a monophasic intracellular accumulation of cAMP. Neither of the other two genes was able to direct the synthesis of a receptor. Nucleotide sequence analysis revealed that these two genes are 98% identical to each other and 95% identical to the D5 sequence. Relative to the D5 sequence, both contain insertions and deletions that result in several in-frame termination codons. Premature termination of translation is the most likely explanation for the failure of these genes to produce receptors in COS-7 and 293 cells even though their messages are transcribed. We conclude that the two are pseudogenes. Blot hybridization experiments performed on rat genomic DNA suggest that there is one D5 gene in this species and that the pseudogenes may be the result of a relatively recent evolutionary event.

Amino Acid Sequence↗
PubMed1995

The hepatitis B virus X gene: analysis of functional domain variation and gene phylogeny using multiple sequences.

The hepatitis B virus (HBV) X gene shares sequences with both the polymerase and precore genes, carries several regulatory signals critical to the replicative cycle, and its product has a transactivating function. In this study, the X gene sequences of 29 HBV strains from 14 different countries were characterized and compared to all corresponding databank sequences where the origin of the strain was stated. The X gene and its product are relatively well conserved. However, several rare or unique point mutations in the predicted X protein are described which further define regions on the primary sequence which may be of structural and/or functional significance. Phylogenetic analysis of the 29 X genes and their predicted proteins in this study using unrooted trees indicates that a common ancestral sequence gave rise to two main groups of X genes, represented by HBV strains found predominantly either in the Western or Eastern Hemisphere. In turn, each of these two main groups of sequences appear to have branched into two main lineages. Introduction of 33 additional DNA sequences from the databank has further verified these inferences and confirmed the groupings as previously described subgroups A to D. Whilst the split of X gene lineages into subgroups A and D seems feasible on geographical/anthropological grounds, the corresponding split of Eastern Hemisphere lineages into B and C may require an alternative hypothesis. Additionally, there was a correlation between the HBeAg/anti-HBeAg status of our patients and nucleotide identity at two positions in the core promoter, 52 and 50 bases upstream from the precore start codon. This finding, also shown recently by others, suggests that control of HBeAg secretion may involve mutations affecting transcription and not only precore/core translation.

Amino Acid Sequence↗
PubMed1997

Generation of radiation-induced deletion complexes in the mouse genome using embryonic stem cells.

As the genetic and physical mapping stage of the Human Genome Project nears completion, the focus is shifting toward the development of technologies for high-throughput analysis of gene function. Whereas DNA sequencing will enable the assignment of presumed function to a large number of genes in mice and humans, it is clear that the great majority of genes will have to be evaluated in vivo to accurately assess their role in a complex organism. While gene targeting in mouse embryonic stem (ES) cells is the current method of choice for the characterization of gene function in mice, it remains relatively labor intensive and lacks the throughput required for analysis of genome function on a large scale. Alternative methods of efficient mutagenesis will clearly be required for this task. Chromosomal deletions are powerful tools in the genetic analysis of complex genomes, enabling the systematic identification and localization of functional units along defined chromosomal regions. Not only are deletions useful for the identification of genetic functions, but they serve as mapping reagents for existing mutations or traits. While their use has been an essential tool in Drosophila genetics, classical mutagenesis in mice has been logistically impractical for generating deletions. We have previously described an efficient method for generating radiation-induced deletion complexes at defined regions in the genome using ES cells. In this article, we detail the methodological aspects of this technology and describe the applications of chromosomal deletions for characterizing gene function in ways that make optimal use of the information generated by the first stage of the Genome Project.

Animals↗
PubMed1992

Tobamovirus-plant interactions.

It is clear that the genetic information responsible for the phenomenon we think of as TMV not only consists of the genes carried in the viral genome, but that numerous plant genes are equally important in viral gene functions. These gene products not only allow the virus to replicate, but may effect functions of evolution that determine what the virus is. Even the processes of pathogenesis and resistance appear to involve similarly precise plant interactions. The challenge of the future is to identify the plant genes involved in these precise interactions and to understand both components of genetic information that comprise plant viruses.

Biological Evolution↗
PubMed2006

Combining gene annotations and gene expression data in model-based clustering: weighted method.

It has been increasingly recognized that incorporating prior knowledge into cluster analysis can result in more reliable and meaningful clusters. In contrast to the standard modelbased clustering with a global mixture model, which does not use any prior information, a stratified mixture model was recently proposed to incorporate gene functions or biological pathways as priors in model-based clustering of gene expression profiles: various gene functional groups form the strata in a stratified mixture model. Albeit useful, the stratified method may be less efficient than the global analysis if the strata are non-informative to clustering. We propose a weighted method that aims to strike a balance between a stratified analysis and a global analysis: it weights between the clustering results of the stratified analysis and that of the global analysis; the weight is determined by data. More generally, the weighted method can take advantage of the hierarchical structure of most existing gene functional annotation systems, such as MIPS and Gene Ontology (GO), and facilitate choosing appropriate gene functional groups as priors. We use simulated data and real data to demonstrate the feasibility and advantages of the proposed method.

Algorithms↗
PubMed2002

Engineering polydactyl zinc-finger transcription factors.

The availability of rapid and robust methods for controlling gene function is of prime importance not only for assigning functions to newly discovered genes, but also for therapeutic intervention. Traditionally, gene function has been probed by often-laborious methods that either increase the level of a gene product or decrease it. Advances now make it possible to rapidly produce zinc-finger proteins capable of recognizing virtually any 18 bp stretch of DNA--a sequence long enough to specify a unique address in any genome. The attachment of functional domains also allows the design of tailor-made transcription factors for specific genes. Recent studies demonstrate that artificial transcription factors are capable of controlling the expression of endogenous genes in their native chromosomal context with a high degree of specificity in both animals and plants. Dominant regulatory control of expression of any endogenous gene can be achieved rapidly and can be also placed under chemical control. A wide range of potential applications is now within reach.

Animals↗
PubMed2003

Phenotype- and gene-driven approaches to discovering the functions of mammalian genes.

All of us are involved in discovery science as we pursue the genes, networks, cellular processes and biophysical principles that govern our chosen biological question. For those of us who choose to proceed using plant or animal models to dissect the elements of our favorite biological system, there are many classical and newer approaches available for our use, including two complementary strategies by which the discovery process is proceeding at the Oak Ridge National Laboratory (ORNL). The ORNL has been known for six decades for its investigations of the effects of radiation and chemicals in inducing heritable mutations in mouse germ cells, and for using mouse mutations as tools for the cloning and characterization of mammalian genes. Our history and experience in making mouse models are being applied via these two complementary strategies: 1), a phenotype-driven approach, in which mice carrying random chemically-induced mutations are screened for abnormal phenotypes; and 2) a gene-driven approach in which heritable single nucleotide polymorphisms (SNP) in preselected genes already thought likely to influence a biological system of choice can be recovered in live mice. The SNP-carrying mice can then be phenotyped for alterations in one's target biology. Both approaches have value and are necessary; while we can use mutations in genes that we already know to be of interest in our favorite biology to discover gene function, we also know that biology is full of surprise genes whose effects on our favorite biology would not be predicted and which will be identified only through phenotype screening.

Animals↗
PubMed2002

Functional second genes generated by retrotransposition of the X-linked ribosomal protein genes.

We have identified a new class of ribosomal protein (RP) genes that appear to have been retrotransposed from X-linked RP genes. Mammalian ribosomes are composed of four RNA species and 79 different proteins. Unlike RNA constituents, each protein is typically encoded by a single intron- containing gene. Here we describe functional autosomal copies of the X-linked human RP genes, which we designated RPL10L (ribosomal protein L10-like gene), RPL36AL and RPL39L after their progenitors. Because these genes lack introns in their coding regions, they were likely retrotransposed from X-linked genes. The identities between the retrotransposed genes and the original X-linked genes are 89-95% in their nucleotide sequences and 92-99% in their amino acid sequences, respectively. Northern blot and PCR analyses revealed that RPL10L and RPL39L are expressed only in testis, whereas RPL36AL is ubiquitously expressed. Although the role of the autosomal RP genes remains unclear, they may have evolved to compensate for the reduced dosage of X-linked RP genes.

5' Flanking Region↗
PubMed2002

Predicting gene ontology functions from ProDom and CDD protein domains.

A heuristic algorithm for associating Gene Ontology (GO) defined molecular functions to protein domains as listed in the ProDom and CDD databases is described. The algorithm generates rules for function-domain associations based on the intersection of functions assigned to gene products by the GO consortium that contain ProDom and/or CDD domains at varying levels of sequence similarity. The hierarchical nature of GO molecular functions is incorporated into rule generation. Manual review of a subset of the rules generated indicates an accuracy rate of 87% for ProDom rules and 84% for CDD rules. The utility of these associations is that novel sequences can be assigned a putative function if sufficient similarity exists to a ProDom or CDD domain for which one or more GO functions has been associated. Although functional assignments are increasingly being made for gene products from model organisms, it is likely that the needs of investigators will continue to outpace the efforts of curators, particularly for nonmodel organisms. A comparison with other methods in terms of coverage and agreement was performed, indicating the utility of the approach. The domain-function associations and function assignments are available from our website http://www.cbil.upenn.edu/GO.

Algorithms↗
PubMed2006

Levels of interpopulation differentiation among different functional classes of immunologically important genes.

It has been postulated that gene function may influence the degree to which allele frequencies differ among populations. In order to evaluate this effect, genotypic data from resequencing studies of genes classified as cytokines, cytokine receptors, cell adhesion molecules, Toll-like receptors and coagulation proteins were analysed for genetic differentiation (FST) between population samples of European and African descent. FST values did not differ statistically among functional groups when all polymorphic sites were included in the analyses. However, analysis based on nonsynonymous SNPs alone suggested weak heterogeneity among functional classes (P=0.0424). Particularly high levels of differentiation were shown by individual nonsynonymous SNPs at some genes, most notably ICAM1 and some Toll-like receptors. These genes interact directly with pathogens, and may therefore have been subject to geographically localised natural selection. Such loci warrant particular attention in studies of genetic disease risk and local adaptation to environmental conditions.

Black People↗
PubMed2005

Disease gene discovery through integrative genomics.

The availability of complete genome sequences and the wealth of large-scale biological data sets now provide an unprecedented opportunity to elucidate the genetic basis of rare and common human diseases. Here we review some of the emerging genomics technologies and data resources that can be used to infer gene function to prioritize candidate genes. We then describe some computational strategies for integrating these large-scale data sets to provide more faithful descriptions of gene function, and how such approaches have recently been applied to discover genes underlying Mendelian disorders. Finally, we discuss future prospects and challenges for using integrative genomics to systematically discover not only single genes but also entire gene networks that underlie and modify human disease.

Databases, Genetic↗
PubMed2005

Exploring trafficking GTPase function by mRNA expression profiling: use of the SymAtlas web-application and the Membrome datasets.

Despite complete sequencing of the human and mouse genomes, functional annotation of novel gene function still remains a major challenge in mammalian biology. Emerging strategies to help elucidate unknown gene function include the analysis of tissue-specific patterns of mRNA expression. A recent study investigated the steady-state mRNA expression profiling of the vast majority of protein-encoding human and mouse genes across a panel of 79 human and 61 mouse nonredundant tissues. The microarray data from this study constitutes the Genomics Institute of Novartis Foundation (GNF) Human and Mouse Gene Atlases and is publicly available for exploration through the SymAtlas web-application (http://symatlas.gnf.org/). We have recently reported the use of these data and hierarchical clustering algorithms to generate a global overview of the distribution of Rabs, SNAREs, and coat machinery components, as well as their respective adaptors, effectors, and regulators. This systems biology approach led us to propose Rab-centric protein activity hubs as a framework for an integrated coding system, the membrome network, which orchestrates the dynamics of specialized membrane architecture of differentiated cells. Here, we describe the use of the SymAtlas web-application and the Membrome datasets to help explore trafficking GTPase function. The human and mouse membrome datasets are available through the Membrome homepage (http://www.membrome.org/) and correspond to subsets of the SymAtlas content restricted to known membrane trafficking components. Considering the fragmentary nature of the current reductionist approaches in elucidating trafficking component functions, the membrome datasets provide a more focused systems biology perspective that not only complements our current understanding of transport in complex tissues but also provides an integrated perspective of Rab activity in controlling membrane architecture.

Animals↗
PubMed1996

Efficient modification of human chromosomal alleles using recombination-proficient chicken/human microcell hybrids.

Targeted modification of human chromosomal alleles by homologous recombination is a powerful approach to study gene function, but gene targeting in mammalian cells is an inefficient process. In contrast, gene targeting in a chicken pre-B cell line, DT40, is highly efficient. We have transferred human chromosome 11 into DT40 cells by microcell fusion, and find that the resulting hybrids are recombination-proficient. In these cells, targeting efficiencies into the chicken ovalbumin locus were > 90% and into the human beta-globin and Ha-ras loci were 10-15%. These modified human chromosomes can be transferred subsequently to mammalian cells for functional tests. This chromosome shuttle system allows for the efficient homologous modification of human chromosomal genes, and for subsequent phenotypic analyses of the modified alleles in different mammalian cell types.

Alleles↗