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At least 1,045 records · Page 58Linked to original sources
PubMed1994

Gene conversion between unlinked sequences in the germline of mice.

Gene conversion between homologous sequences on non-homologous chromosomes (ectopic gene conversion) is remarkably frequent in fungi. It is thought to be a consequence of genome-wide homology scanning required to form synapses between homologous chromosomes. This activity provides a mechanism for concerted evolution of dispersed genes. Technical obstacles associated with mammalian systems have hitherto precluded investigations into ectopic gene conversion in the mammals. Here, we describe a binary transgenic mouse system to detect ectopic gene conversion in mice. Conversion events are visualized by histochemical staining of spermatids, and corroborated by polymerase chain reaction amplification of transgenes in spermatozoa. The results show that conversion between unliked, hemizygous lacZ transgenes is frequent in the male germline, ranging from 0.1 to 0.7% of spermatids. Genomic location may affect the susceptibility to recombination, since the frequency varied between lines. The results suggest that homologous genes can undergo concerted evolution despite being genomically dispersed. However, mechanisms may exist to modulate this activity, enabling the divergence of duplicated genes.

Animals↗
PubMed2005

Vestige: maximum likelihood phylogenetic footprinting.

BACKGROUND: Phylogenetic footprinting is the identification of functional regions of DNA by their evolutionary conservation. This is achieved by comparing orthologous regions from multiple species and identifying the DNA regions that have diverged less than neutral DNA. Vestige is a phylogenetic footprinting package built on the PyEvolve toolkit that uses probabilistic molecular evolutionary modelling to represent aspects of sequence evolution, including the conventional divergence measure employed by other footprinting approaches. In addition to measuring the divergence, Vestige allows the expansion of the definition of a phylogenetic footprint to include variation in the distribution of any molecular evolutionary processes. This is achieved by displaying the distribution of model parameters that represent partitions of molecular evolutionary substitutions. Examination of the spatial incidence of these effects across regions of the genome can identify DNA segments that differ in the nature of the evolutionary process. RESULTS: Vestige was applied to a reference dataset of the SCL locus from four species and provided clear identification of the known conserved regions in this dataset. To demonstrate the flexibility to use diverse models of molecular evolution and dissect the nature of the evolutionary process Vestige was used to footprint the Ka/Ks ratio in primate BRCA1 with a codon model of evolution. Two regions of putative adaptive evolution were identified illustrating the ability of Vestige to represent the spatial distribution of distinct molecular evolutionary processes. CONCLUSION: Vestige provides a flexible, open platform for phylogenetic footprinting. Underpinned by the PyEvolve toolkit, Vestige provides a framework for visualising the signatures of evolutionary processes across the genome of numerous organisms simultaneously. By exploiting the maximum-likelihood statistical framework, the complex interplay between mutational processes, DNA repair and selection can be evaluated both spatially (along a sequence alignment) and temporally (for each branch of the tree) providing visual indicators to the attributes and functions of DNA sequences.

Algorithms↗
PubMed2006

A plaidoyer for 'systems immunology'.

A complete understanding of the immune system will ultimately require an integrated perspective on how genetic and epigenetic entities work together to produce the range of physiologic and pathologic behaviors characteristic of immune function. The immune network encompasses all of the connections and regulatory associations between individual cells and the sum of interactions between gene products within a cell. With 30,000+ protein-coding genes in a mammalian genome, further compounded by microRNAs and yet unrecognized layers of genetic controls, connecting the dots of this network is a monumental task. Over the past few years, high-throughput techniques have allowed a genome-scale view on cell states and cell- or system-level responses to perturbations. Here, we observe that after an early burst of enthusiasm, there has developed a distinct resistance to placing a high value on global genomic or proteomic analyses. Such reluctance has affected both the practice and the publication of immunological science, resulting in a substantial impediment to the advances in our understanding that such large-scale studies could potentially provide. We propose that distinct standards are needed for validation, evaluation, and visualization of global analyses, such that in-depth descriptions of cellular responses may complement the gene/factor-centric approaches currently in favor.

Allergy and Immunology↗
PubMed1999

Mapping and genomic characterization of the gene encoding diacylglycerol kinase gamma (DAGK3): assessment of its role in dominant optic atrophy (OPA1).

The family of diacylglycerol kinases (DAGKs) is known to play an important role in signal transduction linked to phospholipid turnover. In the fruitfly Drosophila melanogaster, a human DAGK ortholog, DGK2, was shown to underlie the phenotype of the visual mutant retinal degeneration A (rdgA). Previously, the gene encoding a novel member of the human DAGK family, termed DAGK3, was cloned and demonstrated to be abundantly expressed in the human retina. Based on these findings we reasoned that DAGK3 might be an excellent candidate gene for a human eye disease. In the present study, we report the genomic organization of the human DAGK3 gene, which spans over 30 kb of genomic DNA interrupted by 23 introns. In addition, we have mapped the gene locus by fluorescence in situ hybridization to 3q27-28, overlapping the chromosomal region known to contain the gene underlying dominant optic atrophy (OPA1), the most common form of hereditary atrophy of the optic nerve. Mutational analysis of the entire coding region of DAGK3 in 19 unrelated German OPA1 patients has not revealed any disease-causing mutations, therefore excluding DAGK3 as a major cause underlying OPA1.

Adolescent↗
PubMed2005

Gene proximity analysis across whole genomes via PQ trees.

Permutations on strings representing gene clusters on genomes have been studied earlier by Uno and Yagiura (2000), Heber and Stoye (2001), Bergeron et al. (2002), Eres et al. (2003), and Schmidt and Stoye (2004) and the idea of a maximal permutation pattern was introduced by Eres et al. (2003). In this paper, we present a new tool for representation and detection of gene clusters in multiple genomes, using PQ trees (Booth and Leuker, 1976): this describes the inner structure and the relations between clusters succinctly, aids in filtering meaningful from apparently meaningless clusters, and also gives a natural and meaningful way of visualizing complex clusters. We identify a minimal consensus PQ tree and prove that it is equivalent to a maximal pi pattern (Eres et al., 2003) and each subgraph of the PQ tree corresponds to a nonmaximal permutation pattern. We present a general scheme to handle multiplicity in permutations and also give a linear time algorithm to construct the minimal consensus PQ tree. Further, we demonstrate the results on whole genome datasets. In our analysis of the whole genomes of human and rat, we found about 1.5 million common gene clusters but only about 500 minimal consensus PQ trees, with E. Coli K-12 and B. Subtilis genomes, we found only about 450 minimal consensus PQ trees out of about 15,000 gene clusters, and when comparing eight different Chloroplast genomes, we found only 77 minimal consensus PQ trees out of about 6,700 gene clusters. Further, we show specific instances of functionally related genes in two of the cases.

Algorithms↗
PubMed2001

Optimal classification of protein sequences and selection of representative sets from multiple alignments: application to homologous families and lessons for structural genomics.

Hierarchical classification is probably the most popular approach to group related proteins. However, there are a number of problems associated with its use for this purpose. One is that the resulting tree showing a nested sequence of groups may not be the most suitable representation of the data. Another is that visual inspection is the most common method to decide the most appropriate number of subsets from a tree. In fact, classification of proteins in general is bedevilled with the need for subjective thresholds to define group membership (e.g., 'significant' sequence identity for homologous families). Such arbitrariness is not only intellectually unsatisfying but also has important practical consequences. For instance, it hinders meaningful identification of protein targets for structural genomics. I describe an alternative approach to cluster related proteins without the need for an a priori threshold: one, through its use of dynamic programming, which is guaranteed to produce globally optimal solutions at all levels of partition granularity. Grouping proteins according to weights assigned to their aligned sequences makes it possible to delineate dynamically a 'core-periphery' structure within families. The 'core' of a protein family comprises the most typical sequences while the 'periphery' consists of the atypical ones. Further, a new sequence weighting scheme that combines the information in all the multiply aligned positions of an alignment in a novel way is put forward. Instead of averaging over all positions, this procedure takes into account directly the distribution of sequence variability along an alignment. The relationships between sequence weights and sequence identity are investigated for 168 families taken from HOMSTRAD, a database of protein structure alignments for homologous families. An exact solution is presented for the problem of how to select the most representative pair of sequences for a protein family. Extension of this approach by a greedy algorithm allows automatic identification of a minimal set of aligned sequences. The results of this analysis are available on the Web at http://mathbio.nimr.mrc.ac.uk/~amay.

Algorithms↗
PubMed1998

Rearrangements in minisatellite sequences induced by aflatoxin B1 in a metabolically competent strain of Saccharomyces cerevisiae.

The role of aflatoxin B1 (AFB1) in the induction of rearrangements affecting minisatellite sequences was studied in an in vitro yeast model. The Saccharomyces cerevisiae strain used expresses human cytochrome P450 1A2 and NADPH-cytochrome P450 oxidoreductase and has previously been used to study genetic recombination events induced by AFB1. DNA multilocus fingerprinting was performed using probe M13 core hybridizing to a set of hypervariable minisatellite sequences in S. cerevisiae. Frequent spontaneous genomic alterations that affect the minisatellite fingerprint pattern were observed. Control cultures showed 15.8% rearrangements in minisatellites, and this frequency increased to 40.0% in cultures exposed to AFB1 (80 microg/ml). A total of approximately 29 minisatellite loci were visualized for each culture. Given the number of cultures examined (40 AFB1-treated and 38 controls) the rearrangement frequency per detectable minisatellite was 2.59% in the AFB1-treated group and 0.73% in the control group, which represents a statistically significant (P = 0.001) difference. Thus, our data strongly suggest that AFB1 can promote the genetic events responsible for minisatellite rearrangements in the yeast genome. Such genetic rearrangements may be important events during the etiology of liver carcinogenesis in people chronically exposed to dietary aflatoxins.

Aflatoxin B1↗
PubMed2004

Automated whole-genome multiple alignment of rat, mouse, and human.

We have built a whole-genome multiple alignment of the three currently available mammalian genomes using a fully automated pipeline that combines the local/global approach of the Berkeley Genome Pipeline and the LAGAN program. The strategy is based on progressive alignment and consists of two main steps: (1) alignment of the mouse and rat genomes, and (2) alignment of human to either the mouse-rat alignments from step 1, or the remaining unaligned mouse and rat sequences. The resulting alignments demonstrate high sensitivity, with 87% of all human gene-coding areas aligned in both mouse and rat. The specificity is also high: <7% of the rat contigs are aligned to multiple places in human, and 97% of all alignments with human sequence >100 kb agree with a three-way synteny map built independently, using predicted exons in the three genomes. At the nucleotide level <1% of the rat nucleotides are mapped to multiple places in the human sequence in the alignment, and 96.5% of human nucleotides within all alignments agree with the synteny map. The alignments are publicly available online, with visualization through the novel Multi-VISTA browser that we also present.

Animals↗
PubMed1999

Lateral genomics.

More than 20 complete prokaryotic genome sequences are now publicly available, each by itself an unparalleled resource for understanding organismal biology. Collectively, these data are even more powerful: they could force a dramatic reworking of the framework in which we understand biological evolution. It is possible that a single universal phylogenetic tree is not the best way to depict relationships between all living and extinct species. Instead a web- or net-like pattern, reflecting the importance of horizontal or lateral gene transfer between lineages of organisms, might provide a more appropriate visual metaphor. Here, I ask whether this way of thinking is really justified, and explore its implications.

Evolution, Molecular↗
PubMed2005

Reconstructing the metabolic network of a bacterium from its genome.

The prospect of understanding the relationship between the genome and the physiology of an organism is an important incentive to reconstruct metabolic networks. The first steps in the process can be automated and it does not take much effort to obtain an initial metabolic reconstruction from a genome sequence. However, such a reconstruction is certainly not flawless and correction of the many imperfections is laborious. It requires the combined analysis of the available information on protein sequence, phylogeny, gene-context and co-occurrence but is also aided by high-throughput experimental data. Simultaneously, the reconstructed network provides the opportunity to visualize the "omics" data within a relevant biological functional context and thus aids the interpretation of those data.

Bacteria↗
PubMed2002

Alkylation of guanine in DNA by S23906-1, a novel potent antitumor compound derived from the plant alkaloid acronycine.

The discovery of a new DNA-targeted antitumor agent is a challenging enterprise, and the elucidation of its mechanism of action is an essential first step in investigating the structural and biological consequences of DNA modification and to guide the rational design of analogues. Here, we have dissected the mode of action of the newly discovered antitumor agent S23906-1. Gel retardation experiments reveal that the diacetate compound S23906-1 and its monoacetate analogue S28687 form highly stable covalent adducts with DNA. The covalent adducts formed between S23906-1 and a 7-bp hairpin oligonucleotide duplex were identified by spectrometry. In contrast, the inactive compound S23907, lacking the two acetate groups of S23906-1, fails to yield covalent DNA adducts, indicating that the C1-C2 functionality is the DNA reactive moiety. DNase I footprinting and DNA alkylation experiments indicate that S23906-1 reacts primarily with guanine residues. A 30-mer oligonucleotide containing only G.C bp forms highly stable complexes with S23906-1 and S28687, whereas the equivalent A.T oligonucleotide is not a good substrate for these two drugs. The use of an oligonucleotide duplex containing inosines instead of guanosines identifies the guanine 2-amino group exposed in the minor groove of DNA as the potential reactive site. The reactivity of S23906-1 toward the guanine-N2 group was independently confirmed by fluorescence spectroscopy. Covalent DNA adducts were also identified in the genomic DNA of B16 melanoma cells exposed to S23906-1, and the specific accumulation of the drug in the nucleus of the cells was visualized by confocal microscopy. The elucidation of the mechanism of action of this highly potent anticancer agent opens a new field for future drug design.

Acronine↗
PubMed1996

High-resolution physical mapping in Arabidopsis thaliana and tomato by fluorescence in situ hybridization to extended DNA fibres.

A technique to detect DNA sequences on extended DNA fibres (EDF) prepared from interphase nuclei from tomato (Lycopersicon esculentum) and Arabidopsis thaliana leaves by fluorescence in situ hybridization (FISH) is described. Three nuclear lysis procedures have been tested for their ability to decondense chromatin and to generate highly extended intact DNA fibres on microscopic slides. DNA probes of various sizes have been used in FISH experiments to EDFs to establish the resolution and sensitivity of the technique. The fluorescent signals of a 5S rDNA probe hybridized to tomato EDFs revealed continuous strings of about 200 microns, that corresponded to a molecular size of about 660 kb. In A. thaliana, a contig of three cosmids spanning a genomic region with a total length of about 89 kb was analysed. By means of multicolour hybridization the physical positions of the cosmids were visualized as red and green fluorescence strings with overlapping regions in yellow. Comparison of the length of the fluorescent signals with the molecular data revealed a stretching degree of the DNA fibres at 3.27 kb microns-1, which is close to the Watson-Crick DNA length estimate of 2.9 kb microns-1. Other experiments on small size molecular probes with both lambda clones (13.5-17 kb insert sizes) and plasmids (4.2 and 5 kb) in a contig of A. thaliana, and the 5S rDNA region in tomato showed close agreement with molecular data. The lower limit of the detection, which was established in a hybridization experiment with two DNA probes from the 45S ribosomal gene on extended fibres of tomato, was about 0.7 kb. Consistent patterns of alternating fluorescent red and green spots were obtained reflecting the tandemly repeated arrangement of the 18S and 25S ribosomal sequences. On the basis of the microscopic distance between these hybridization spots the size of the ribosomal unit was estimated at 8.2 kb. This implies a drastic improvement of high-resolution physical mapping of DNA sequences by FISH on plant DNA.

Arabidopsis↗
PubMed2002

Large-scale analysis of the human and mouse transcriptomes.

High-throughput gene expression profiling has become an important tool for investigating transcriptional activity in a variety of biological samples. To date, the vast majority of these experiments have focused on specific biological processes and perturbations. Here, we have generated and analyzed gene expression from a set of samples spanning a broad range of biological conditions. Specifically, we profiled gene expression from 91 human and mouse samples across a diverse array of tissues, organs, and cell lines. Because these samples predominantly come from the normal physiological state in the human and mouse, this dataset represents a preliminary, but substantial, description of the normal mammalian transcriptome. We have used this dataset to illustrate methods of mining these data, and to reveal insights into molecular and physiological gene function, mechanisms of transcriptional regulation, disease etiology, and comparative genomics. Finally, to allow the scientific community to use this resource, we have built a free and publicly accessible website (http://expression.gnf.org) that integrates data visualization and curation of current gene annotations.

Animals↗
PubMed1987

Molecular karyotype of Plasmodium falciparum: conserved linkage groups and expendable histidine-rich protein genes.

We describe fractionation of the Plasmodium falciparum genome into 14 chromosomal DNA molecules by pulsed-field gel electrophoresis. This number agrees with the number of chromosomes observed by electron microscopic visualization of kinetochores. The assignment of 25 markers to 12 of the 14 chromosomes in three cloned parasite lines demonstrates that chromosomal size variation can greatly change the relative migration of genetically equivalent chromosomes. Deletions that include genes for three different histidine-rich proteins, located on chromosomes 2, 8, and 13, contribute to size differences in some clones. Other karyotypic differences result from chromosome segregation and/or recombination during meiosis.

Animals↗
PubMed2003

PAINT: a promoter analysis and interaction network generation tool for gene regulatory network identification.

We have developed a bioinformatics tool named PAINT that automates the promoter analysis of a given set of genes for the presence of transcription factor binding sites. Based on coincidence of regulatory sites, this tool produces an interaction matrix that represents a candidate transcriptional regulatory network. This tool currently consists of (1) a database of promoter sequences of known or predicted genes in the Ensembl annotated mouse genome database, (2) various modules that can retrieve and process the promoter sequences for binding sites of known transcription factors, and (3) modules for visualization and analysis of the resulting set of candidate network connections. This information provides a substantially pruned list of genes and transcription factors that can be examined in detail in further experimental studies on gene regulation. Also, the candidate network can be incorporated into network identification methods in the form of constraints on feasible structures in order to render the algorithms tractable for large-scale systems. The tool can also produce output in various formats suitable for use in external visualization and analysis software. In this manuscript, PAINT is demonstrated in two case studies involving analysis of differentially regulated genes chosen from two microarray data sets. The first set is from a neuroblastoma N1E-115 cell differentiation experiment, and the second set is from neuroblastoma N1E-115 cells at different time intervals following exposure to neuropeptide angiotensin II. PAINT is available for use as an agent in BioSPICE simulation and analysis framework (www.biospice.org), and can also be accessed via a WWW interface at www.dbi.tju.edu/dbi/tools/paint/.

Angiotensin II↗
PubMed1992

Determination of the chromosomal size of three different strains of Enterococcus faecalis and one strain of Enterococcus faecium.

Pulsed-field gel electrophoresis was used to determine the chromosomal size of three different strains of Enterococcus faecalis and one strain of Enterococcus faecium. The size determinations of OG1X, a strain of E. faecalis widely used in many laboratories for genetic studies, using Sma I, Not I, and Sfi I alone or in combination, ranged from 2,750 to 2,761 kb. Using the same enzymes as with OG1X, the size of HH-67, a plasmid-free clinical isolate of E. faecalis, was determined to be 2,170-2,288 kb and the size of JH2-2, an E. faecalis recipient strain, ranged from 2,008 to 2,135 kb. The size range generated for GE-1, a plasmid-free E. faecium strain, with the use of Sma I, Not I, and Apa I was 2,045-2,155 kb. Although OG1X differed in size from the other three enterococci, each individual enterococcal strain generated reproducible results in different experiments. However, for both E. faecalis OG1X and E. faecium GE-1, one of the enzymes used generated a considerably smaller molecular size than that generated by the other two enzymes. The discrepancy was due to visually undiscernible comigrating fragments, and serves to point out a potential source of error if fewer than two enzymes are used to size a genome. The size discrepancies were resolved by digesting individual fragments with a second enzyme. The molecular sizes of these enterococcal strains are larger than that recently reported for Campylobacter, smaller than that of Escherichia coli and Pseudomonas aeruginosa, and similar (OG1X) or smaller (JH2-2, HH67, and GE-1) than the 2,819-kb reported for Streptococcus mutans.

Chromosomes, Bacterial↗
PubMed1998

A distributed environment for physical map construction.

MOTIVATION: With the main focus of the Human Genome Project shifting to sequencing, bioinformatics support for constructing large-scale genomic maps of other organisms is still required. We attempt to provide for this with our work, aimed at the delivery of robust and user-friendly contig-building software on the WWW. RESULTS: We present a prototype distributed analytical environment for molecular biologists working in the area of genomic mapping. It consists of the WWW server for constructing contigs from users' data with a hypertext output connected to Java-based map visualization software. AVAILABILITY: Freely available on http://www.mpimg-berlin-dahlem.mpg. de/ approximately andy/server/ CONTACT: andy@rag3.rz-berlin.mpg.de

Algorithms↗
PubMed1997

Assignment of Chinese hamster p53 gene (TP53) to chromosome band 2p31, a region not involved in the karyotypic changes of a tumorigenic cell line.

The Chinese hamster tumor-derived cell line 835T2 exhibits specific karyotypic changes, including the loss and/or translocation of genetic material. To investigate whether the p53 tumor suppressor gene was involved in the exchanges, cDNA from primary Chinese hamster cells was isolated by using sense and antisense primers of the human p53 gene. The cDNA was sequenced, and the sequence was compared with the Syrian and human p53 cDNA reported sequences. The sequence homology was very elevated, demonstrating that the cloned fragment contained part of the Chinese hamster p53 gene. The corresponding genomic fragment was also cloned and used as a biotin-labeled probe for in situ hybridization on Chinese hamster chromosome spreads. Hybridization was visualized by avidin-FITC, and the assignment was done comparing the banding obtained with BamHI restriction enzyme and the location of the fluorescent signals pattern of the same metaphase. The signals revealed that the p53 gene (TP53) is localized on Chinese hamster chromosome band 2p31, which is not involved in the karyotypic changes specific to the 835T2 cell line.

Animals↗