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PubMed2002

GAZE: a generic framework for the integration of gene-prediction data by dynamic programming.

We describe a method (implemented in a program, GAZE) for assembling arbitrary evidence for individual gene components (features) into predictions of complete gene structures. Our system is generic in that both the features themselves, and the model of gene structure against which potential assemblies are validated and scored, are external to the system and supplied by the user. GAZE uses a dynamic programming algorithm to obtain the highest scoring gene structure according to the model and posterior probabilities that each input feature is part of a gene. A novel pruning strategy ensures that the algorithm has a run-time effectively linear in sequence length. To demonstrate the flexibility of our system in the incorporation of additional evidence into the gene prediction process, we show how it can be used to both represent nonstandard gene structures (in the form of trans-spliced genes in Caenorhabditis elegans), and make use of similarity information (in the form of Expressed Sequence Tag alignments), while requiring no change to the underlying software. GAZE is available at http://www.sanger.ac.uk/Software/analysis/GAZE.

Algorithms↗
PubMed1995

Molecular cloning and characterization of the dpy-20 gene of Caenorhabditis elegans.

We describe the molecular analysis of the dpy-20 gene in Caenorhabditis elegans. Isolation of genomic sequences was facilitated by the availability of a mutation that resulted from insertion of a Tc1 transposable element into the dpy-20 gene. The Tc1 insertion site in the m474::Tc1 allele was identified and was found to lie within the coding region of dpy-20. Three revertants (two wild-type and one partial revertant) resulted from the excision of this Tc1 element. Genomic dpy-20 clones' were isolated from a library of wild-type DNA and were found to lie just to the left of the unc-22 locus on the physical map, compatible with the position of dpy-20 on the genetic map. Cosmid DNA containing the dpy-20 gene was successfully used to rescue the mutant phenotype of animals homozygous for another dpy-20 allele, e1282ts. Sequence analysis of the putative dpy-20 homologue in Caenorhabditis briggsae was performed to confirm identification of the coding regions of the C. elegans gene and to identify conserved regulatory regions. Sequence analysis of dpy-20 revealed that it was not similar to other genes encoding known cuticle components such as collagen or cuticulin. The dpy-20 gene product, therefore, identifies a previously unknown type of protein that may be directly or indirectly involved in cuticle function. Northern blot analysis showed that dpy-20 is expressed predominantly in the second larval stage and that the mRNA is not at all abundant. Data from temperature shift studies using the temperature-sensitive allele e1282ts showed that the sensitive period also occurs at approximately the second larval stage. Therefore, expression of dpy-20 mRNA and function of the DPY-20 protein are closely linked temporally.

Amino Acid Sequence↗
PubMed1995

Meiotic recombination, noncoding DNA and genomic organization in Caenorhabditis elegans.

The genetic map of each Caenorhabditis elegans chromosome has a central gene cluster (less pronounced on the X chromosome) that contains most of the mutationally defined genes. Many linkage group termini also have clusters, though involving fewer loci. We examine the factors shaping the genetic map by analyzing the rate of recombination and gene density across the genome using the positions of cloned genes and random cDNA clones from the physical map. Each chromosome has a central gene-dense region (more diffuse on the X) with discrete boundaries, flanked by gene-poor regions. Only autosomes have reduced rates of recombination in these gene-dense regions. Cluster boundaries appear discrete also by recombination rate, and the boundaries defined by recombination rate and gene density mostly, but not always, coincide. Terminal clusters have greater gene densities than the adjoining arm but similar recombination rates. Thus, unlike in other species, most exchange in C. elegans occurs in gene-poor regions. The recombination rate across each cluster is constant and similar; and cluster size and gene number per chromosome are independent of the physical size of chromosomes. We propose a model of how this genome organization arose.

Animals↗
PubMed2000

Functional genomic analysis of C. elegans chromosome I by systematic RNA interference.

Complete genomic sequence is known for two multicellular eukaryotes, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster, and it will soon be known for humans. However, biological function has been assigned to only a small proportion of the predicted genes in any animal. Here we have used RNA-mediated interference (RNAi) to target nearly 90% of predicted genes on C. elegans chromosome I by feeding worms with bacteria that express double-stranded RNA. We have assigned function to 13.9% of the genes analysed, increasing the number of sequenced genes with known phenotypes on chromosome I from 70 to 378. Although most genes with sterile or embryonic lethal RNAi phenotypes are involved in basal cell metabolism, many genes giving post-embryonic phenotypes have conserved sequences but unknown function. In addition, conserved genes are significantly more likely to have an RNAi phenotype than are genes with no conservation. We have constructed a reusable library of bacterial clones that will permit unlimited RNAi screens in the future; this should help develop a more complete view of the relationships between the genome, gene function and the environment.

Animals↗
PubMed2004

A genome sequence survey of the filarial nematode Brugia malayi: repeats, gene discovery, and comparative genomics.

Comparative nematode genomics has thus far been largely constrained to the genus Caenorhabditis, but a huge diversity of other nematode species, and genomes, exist. The Brugia malayi genome is approximately 100 Mb in size, and distributed across five chromosome pairs. Previous genomic investigations have included definition of major repeat classes and sequencing of selected genes. We have generated over 18,000 sequences from the ends of large-insert clones from bacterial artificial chromosome libraries. These end sequences, totalling over 10 Mb of sequence, contain just under 8 Mb of unique sequence. We identified the known Mbo I and Hha I repeat families in the sequence data, and also identified several new repeats based on their abundance. Genomic copies of 17% of B. malayi genes defined by expressed sequence tags have been identified. Nearly one quarter of end sequences can encode peptides with significant similarity to protein sequences in the public databases, and we estimate that we have identified more than 2700 new B. malayi genes. Importantly, 459 end sequences had homologues in other organisms, but lacked a match in the completely sequenced genomes of Caenorhabditis briggsae and Caenorhabditis elegans, emphasising the role of gene loss in genome evolution. B. malayi is estimated to have over 18,500 protein-coding genes.

Animals↗
PubMed1996

Cuticular collagen genes from the parasitic nematode Ostertagia circumcincta.

The nematode cuticle is a multifunctional structure whose roles include exoskeleton and barrier between the animal and its environment. It is an extracellular matrix which consists predominantly of small collagen-like proteins. For those species studied, these cuticular collagens are encoded by a multigene family. In the free living nematode Caenorhabditis elegans, this family has approximately 100 members. Our data indicate a gene family of similar size in the parasitic nematode Ostertagia circumcincta. We have characterised a pair of tandemly duplicated collagen genes from O. circumcincta, colost-1 and colost-2, which we believe to be the direct homologues of col-12 and col-13, a tandemly duplicated pair previously identified in C. elegans. The interspecies comparison of these homologues indicates regions of extreme conservation. We conclude that the gene duplication event that resulted in the creation of col-12 and col-13 in C. elegans is most likely the same duplication that generated colost-1 and colost-2 in O. circumcincta, and thus this particular gene duplication precedes the divergence of the two species. These two nematode species are deeply diverged, O. circumcincta belonging to the order Strongylata and C. elegans to Rhabditata. The ability to identify direct homologues of individual cuticular collagen genes between deeply diverged species provides a powerful method for determining regions of structural importance in these small collagens. Characteristics that are conserved between homologues in divergent species, but not conserved with other members of the multigene family within one species, must relate to the specific function of that particular cuticular collagen.

Amino Acid Sequence↗
PubMed1998

Caenorhabditis elegans as a model for parasitic nematodes.

Caenorhabditis elegans has become a popular model system for genetic and molecular research, since it is easy to maintain and has a very fast life-cycle. Its genome is small and a virtually complete physical map in the form of cosmids and YAC clones exists. Thus it was chosen as a model system by the Genome Project for sequencing, and it is expected that by 1998 the complete sequence (100 million bp) will be available. The accumulated wealth of information about C. elegans should be a boon for nematode parasitologists, as many aspects of gene regulation and function can be studied in this simple model system. A large array of techniques is available to study many aspects of C. elegans biology. In combination with genome projects for parasitic nematodes, conserved genes can be identified rapidly. We expect many new areas of fertile research that will lead to new insights in helminth parasitology, which are based not only on the information gained from C. elegans per se, but also from its use as a heterologous system to study parasitic genes.

Animals↗
PubMed2004

Genomics of parasitic flatworms.

Although we live in what is often touted as the 'post-genomic era', this term is hardly appropriate when we consider the paucity of knowledge of the genomic biology of parasitic flatworms. The situation is, however, changing-at least for two species of Schistosoma. Recent transcriptome analysis of Schistosoma mansoni and of Schistosoma japonicum has identified novel genes and genes not previously reported for schistosomes, as well as the identification of the molecular mechanisms for host-dependent maturation, immune evasion, development, signalling and sexual dimorphism. The analyses also identify potential vaccine candidates and drug targets. Here, the current state of knowledge is reviewed for mitochondrial and nuclear genomes of parasitic flatworms. We highlight the remarkable recent progress in gene discovery for schistosomes and the goal of sequencing complete schistosome genomes.

Animals↗
PubMed2003

The structure and early evolution of recently arisen gene duplicates in the Caenorhabditis elegans genome.

The significance of gene duplication in provisioning raw materials for the evolution of genomic diversity is widely recognized, but the early evolutionary dynamics of duplicate genes remain obscure. To elucidate the structural characteristics of newly arisen gene duplicates at infancy and their subsequent evolutionary properties, we analyzed gene pairs with < or =10% divergence at synonymous sites within the genome of Caenorhabditis elegans. Structural heterogeneity between duplicate copies is present very early in their evolutionary history and is maintained over longer evolutionary timescales, suggesting that duplications across gene boundaries in conjunction with shuffling events have at least as much potential to contribute to long-term evolution as do fully redundant (complete) duplicates. The median duplication span of 1.4 kb falls short of the average gene length in C. elegans (2.5 kb), suggesting that partial gene duplications are frequent. Most gene duplicates reside close to the parent copy at inception, often as tandem inverted loci, and appear to disperse in the genome as they age, as a result of reduced survivorship of duplicates located in proximity to the ancestral copy. We propose that illegitimate recombination events leading to inverted duplications play a disproportionately large role in gene duplication within this genome in comparison with other mechanisms.

Animals↗
PubMed2003

CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing.

To maintain genome stability, DNA replication is strictly regulated to occur only once per cell cycle. In eukaryotes, the presence of 'licensing proteins' at replication origins during the G1 cell-cycle phase allows the formation of the pre-replicative complex. The removal of licensing proteins from chromatin during the S phase ensures that origins fire only once per cell cycle. Here we show that the CUL-4 ubiquitin ligase temporally restricts DNA-replication licensing in Caenorhabditis elegans. Inactivation of CUL-4 causes massive DNA re-replication, producing cells with up to 100C DNA content. The C. elegans orthologue of the replication-licensing factor Cdt1 (refs 2, 3) is required for DNA replication. C. elegans CDT-1 is present in G1-phase nuclei but disappears as cells enter S phase. In cells lacking CUL-4, CDT-1 levels fail to decrease during S phase and instead remain constant in the re-replicating cells. Removal of one genomic copy of cdt-1 suppresses the cul-4 re-replication phenotype. We propose that CUL-4 prevents aberrant re-initiation of DNA replication, at least in part, by facilitating the degradation of CDT-1.

Animals↗
PubMed1999

Pattern of selective constraint in C. elegans and C. briggsae genomes.

Similarity between related genomes may carry information on selective constraint in each of them. We analysed patterns of similarity between several homologous regions of Caenorhabditis elegans and C. briggsae genomes. All homologous exons are quite similar. Alignments of introns and of intergenic sequences contain long gaps, segments where similarity is low and close to that between random sequences aligned using the same parameters, and segments of high similarity. Conservative estimates of the fractions of selectively constrained nucleotides are 72%, 17% and 18% for exons, introns and intergenic sequences, respectively. This implies that the total number of constrained nucleotides within non-coding sequences is comparable to that within coding sequences, so that at least one-third of nucleotides in C. elegans and C. briggsae genomes are under strong stabilizing selection.

Animals↗
PubMed2002

Functional exploration of the C. elegans genome using DNA microarrays.

Global changes in gene expression underlie developmental processes such as organogenesis, embryogenesis and aging in Caenorhabditis elegans. Recently developed methods allow gene expression profiles to be determined selectively for individual tissues and cell types. Results from both whole-animal and tissue-specific expression profiling have provided an unprecedented view into genome organization and gene function. Integration of these results with other types of functional genomics data gathered from RNA-mediated interference and yeast two-hybrid analyses will allow rapid identification and exploration of the complex functional gene networks that govern C. elegans development.

Animals↗
PubMed1999

Deep within the filarial genome: progress of the filarial genome project.

Four years ago, a WHO/United Nations Development Programme/World Bank-sponsored genome project to study the filarial lymphatic nematode parasite Brugia malayi was initiated. The project took as its aims gene discovery for drug target and vaccine candidate identification, genome mapping, dissemination of genomic data to the world community and training of endemic country partners in genomic research. In this article, the principal investigators in the laboratories behind the project describe the background to the project, the data now emerging and goals for the future. Open access to filarial genome data is emphasized.

Animals↗