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PubMed2003

ProSplicer: a database of putative alternative splicing information derived from protein, mRNA and expressed sequence tag sequence data.

ProSplicer is a database of putative alternative splicing information derived from the alignment of proteins, mRNA sequences and expressed sequence tags (ESTs) against human genomic DNA sequences. Proteins, mRNA and ESTs provide valuable evidence that can reveal splice variants of genes. The alternative splicing information in the database can help users investigate the alternative splicing and tissue-specific expression of genes.

Alternative Splicing↗

PubMed1999

Genomic detection of new yeast pre-mRNA 3'-end-processing signals.

To investigate Saccharomyces cerevisiae 3'-end-processing signals, a set of 1352 unique pre-mRNA 3'-end-processing sites, corresponding to 861 different genes, was identified by alignment of expressed sequence tag sequences with the complete yeast genome. Nucleotide word frequencies in the vicinity of the cleavage sites were analyzed to reveal the signal element features. In addition to previously recognized processing signals, two previously uncharacterized components of the 3'-end-processing signal sequence were discovered, specifically a predominance of U-rich sequences located on either side of the cleavage site. One of these, the downstream U-rich signal, provides a further link between the 3'-end-processing mechanisms of yeast and higher eukaryotes. Analysis of the complete set of 3'-end-processing sites by means of a discrimination function supports a 'contextual' model in which the sum total effectiveness of the signals in all four elements determines whether or not processing occurs.

Expressed Sequence Tags↗

PubMed2004

Regulation of virulence determinants in vitro and in vivo in Staphylococcus aureus.

Staphylococcus aureus is an opportunistic pathogen. In response to changing host environments, this bacterium has the capability to switch on selective sets of genes to enhance its chances for survival. This switching process is precisely controlled by global regulatory elements. There are two major groups of global regulatory elements in S. aureus, including two-component regulatory systems (TCRSs) and the SarA protein family. Presumably, the sensor proteins of the 16 TCRSs in S. aureus provide external sensing, while the response regulators, in conjunction with alternative transcription factors and the SarA protein family, function as effectors within the intricate regulatory network to respond to environmental stimuli. Sequence alignment and structural data indicate that the SarA protein family could be subdivided into three subfamilies: (1) single-domain proteins; (2) double-domain proteins; and (3) proteins homologous to the MarR protein family. Recent data using reporter gene fusions in animal models, have confirmed distinct expression profiles of selected regulatory and target genes in vitro vs. in vivo.

Artificial Gene Fusion↗

PubMed2003

Using motif-based methods in multiple genome analyses: a case study comparing orthologous mesophilic and thermophilic proteins.

Protein motifs represent highly conserved regions within protein families and are generally accepted to describe critical regions required for protein stability and/or function. In this comprehensive analysis, we present a robust, unique approach to identify and compare corresponding mesophilic and thermophilic sequence motifs between all orthologous proteins within 44 microbial genomes. Motif similarity is determined through global sequence alignment of mesophilic and thermophilic motif pairs, which are identified by a greedy algorithm. Our results reveal only modest correlation between motif and overall sequence similarity, highlighting the rationale of motif-based approaches in comprehensive multigenome comparisons. Conserved mutations reflect previously suggested physiochemical principles for conferring thermostability. Additionally, comparisons between corresponding mesophilic and thermophilic motif pairs provide key biochemical insights related to thermostability and can be used to test the evolutionary robustness of individual structural comparisons. We demonstrate the ability of our unique approach to provide key insights in two examples: the TATA-box binding protein and glutamate dehydrogenase families. In the latter example, conserved mutations hint at novel origins leading to structural stability differences within the hexamer structures. Additionally, we present amino acid composition data and average protein length comparisons for all 44 microbial genomes.

Amino Acid Motifs↗

PubMed2005

PriFi: using a multiple alignment of related sequences to find primers for amplification of homologs.

Using a comparative approach, the web program PriFi (http://cgi-www.daimi.au.dk/cgi-chili/PriFi/main) designs pairs of primers useful for PCR amplification of genomic DNA in species where prior sequence information is not available. The program works with an alignment of DNA sequences from phylogenetically related species and outputs a list of possibly degenerate primer pairs fulfilling a number of criteria, such that the primers have a maximal probability of amplifying orthologous sequences in other phylogenetically related species. Operating on a genome-wide scale, PriFi automates the first steps of a procedure for developing general markers serving as common anchor loci across species. To accommodate users with special preferences, configuration settings and criteria can be customized.

DNA Primers↗

PubMed1999

Significance testing for direct identity-by-descent mapping.

Direct identity-by-descent mapping is a technique for narrowing down the location of the gene or genes responsible for a given genetic disease to small segments of the genome. The technique involves DNA comparisons between pairs of affected individuals. The data generated are in the form of matching segments of the genome, representing regions likely to be identical-by-descent (IBD). Regions in the genome over which there are significantly more segments aligned than is expected by chance are taken as candidate regions for the disease gene or genes. Due to the complex geometric nature of the data, significance testing involves certain mathematical difficulties. We present here a new method for measuring this significance. This method introduces a novel statistic and is appropriate whether or not the relationships between the paired individuals are known. We give examples that we have calculated by implementing this method, including an application to real data.

Chromosome Mapping↗

PubMed2003

Retroposed copies of the HMG genes: a window to genome dynamics.

Retroposed copies (RPCs) of genes are functional (intronless paralogs) or nonfunctional (processed pseudogenes) copies derived from mRNA through a process of retrotransposition. Previous studies found that gene families involved in mRNA translation or nuclear function were more likely to have large numbers of RPCs. Here we characterize RPCs of the few families coding for the abundant high-mobility-group (HMG) proteins in humans. Using an algorithm we developed, we identified and studied 219 HMG RPCs. For slightly more than 10% of these RPCs, we found evidence indicating expression. Furthermore, eight of these are potentially new members of the HMG families of proteins. For three RPCs, the evidence indicated expression as part of other transcripts; in all of these, we found the presence of alternative splicing or multiple polyadenylation signals. RPC distribution among the HMGs was not even, with 33-65 each for HMGB1, HMGB3, HMGN1, and HMGN2, and 0-6 each for HMGA1, HMGA2, HMGB2, and HMGN3. Analysis of the sequences flanking the RPCs revealed that the junction between the target site duplications and the 5'-flanking sequences exhibited the same TT/AAAA consensus found for the L1 endonuclease, supporting an L1-mediated retrotransposition mechanism. Finally, because our algorithm included aligning RPC flanking sequences with the corresponding HMG genomic sequence, we were able to identify transcribed regions of HMG genes that were not part of the published mRNA sequences.

Chromosome Mapping↗

PubMed1998

Phylogenetic Invariants for Metazoan Mitochondrial Genome Evolution.

The method of phylogenetic invariants was developed to apply to aligned sequence data generated, according to a stochastic substitution model, for N species related through an unknown phylogenetic tree. The invariants are functions of the probabilities of the observable N-tuples, which are identically zero, over all choices of branch length, for some trees. Evaluating the invariants associated with all possible trees, using observed N-tuple frequencies over all sequence positions, enables us to rapidly infer the generating tree. An aspect of evolution at the genomic level much studied recently is the rearrangements of gene order along the chromosome from one species to another. Instead of the substitutions responsible for sequence evolution, we examine the non-local processes responsible for genome rearrangements such as inversion of arbitrarily long segments of chromosomes. By treating the potential adjacency of each possible pair of genes as a position", an appropriate substitution" model can be recognized as governing the rearrangement process, and a probabilistically principled phylogenetic inference can be set up. We calculate the invariants for this process for N=5, and apply them to mitochondrial genome data from coelomate metazoans, showing how they resolve key aspects of branching order.

Journal Article↗

PubMed2002

Potential multiple endonuclease functions and a ribonuclease H encoded in retroposon genomes.

Among the retroposons, the source of the endonuclease activity is known to be variable and can be provided as either a retroviral-like integrase or a protein similar to the cellular apurinic-apyrimidinic endonuclease. It has also been reported that other retroposon and retrointron sequences have limited similarity to various eubacterial endonucleases. We investigated whether any retroposon genomes possibly encode multiple endonuclease functions. Amino acid alignments were generated and analyzed for the presence of the characterized ordered-series-of-motifs (OSM) representative of four different endonuclease functions. The results indicate that SLACS, CZAR, CRE1, CRE2, and some Trypanosoma brucei retroposon sequences encode multiple putative endonuclease functions. Interestingly, one of the endonuclease functions is embedded within the potential ribonuclease H sequence found in SLACS, CZAR, CRE1, CRE2, and R2BM retroposons.

Amino Acid Sequence↗

PubMed1999

Optical mapping and its potential for large-scale sequencing projects.

Physical mapping has been rediscovered as an important component of large-scale sequencing projects. Restriction maps provide landmark sequences at defined intervals, and high-resolution restriction maps can be assembled from ensembles of single molecules by optical means. Such optical maps can be constructed from both large-insert clones and genomic DNA, and are used as a scaffold for accurately aligning sequence contigs generated by shotgun sequencing.

Base Sequence↗

PubMed2006

Mapping genes for resistance to Leptosphaeria maculans in Brassica juncea.

Blackleg disease of crucifers, caused by the fungus Leptosphaeria maculans, is a major concern to oilseed rape producers worldwide. Brassica species containing the B genome have high levels of resistance to blackleg. Brassica juncea F2 and first-backcross (B1) populations segregating for resistance to a PG2 isolate of L. maculans were created. Segregation for resistance to L. maculans in these populations suggested that resistance was controlled by two independent genes, one dominant and one recessive in nature. A map of the B. juncea genome was constructed using segregation in the F2 population of a combination of restriction fragment length polymorphism (RFLP) and microsatel lite markers. The B. juncea map consisted of 325 loci and was aligned with previous maps of the Brassica A and B genomes. The gene controlling dominant resistance to L. maculans was positioned on linkage group J13 based on segregation for resistance in the F2 population. This position was confirmed in the B1 population in which the resistance gene was definitively mapped in the interval flanked by pN199RV and sB31143F. The provisional location of the recessive gene controlling resistance to L. maculans on linkage group J18 was identified using a subset of informative F2 individuals.

Ascomycota↗

PubMed2004

Information for the Coordinates of Exons (ICE): a human splice sites database.

We present a comprehensive database, Information for the Coordinates of Exons (ICE), of genomic splice sites (SSs) for 10,803 human genes. ICE contains 91,846 pairs of donor acceptor sites, supported by the alignment of "full-length" human mRNAs (including transcript variants) on human genomic sequences. ICE represents the largest collection of human SSs known to date and provides a significant resource to both molecular biologists and bioinformaticians alike. A user can visualize and extract genomic sequences around SSs of the donor acceptor pairs and can also visualize the primary structure of individual genes. We list in this article the 22 most frequently found canonical and noncanonical splice sites. The top four most represented donor acceptor pairs (GT-AG, GC-AG, AT-AC, and GT-GG) accounted for 99.16% of our data set. In addition, we calculated the SS matrix models for the three most common donor acceptor pairs. The database is focused on providing SSs and surrounding sequence information, associated SS and sequence characteristics, and relation to overall transcript structure. It allows targeted search and presents evidence for the gene structure.

Computational Biology↗

PubMed2004

BLAST: at the core of a powerful and diverse set of sequence analysis tools.

Basic Local Alignment Search Tool (BLAST) is one of the most heavily used sequence analysis tools available in the public domain. There is now a wide choice of BLAST algorithms that can be used to search many different sequence databases via the BLAST web pages (http://www.ncbi.nlm.nih.gov/BLAST/). All the algorithm-database combinations can be executed with default parameters or with customized settings, and the results can be viewed in a variety of ways. A new online resource, the BLAST Program Selection Guide, has been created to assist in the definition of search strategies. This article discusses optimal search strategies and highlights some BLAST features that can make your searches more powerful.

Databases, Genetic↗

PubMed1976

A partial denaturation map of herpes simplex virus type 1 DNA: evidence for inversions of the unique DNA regions.

Partial denaturation maps of 30 HSV-I DNA molecules have been obtained using a procedure designed to avoid possible hydrolysis of the DNA at alkalilabile bonds. From the denaturation pattern of the long unique DNA region these molecules were divided into two groups comprised of 16 and 14 molecules. Histogram plots relating the precentage denaturation to position on the DNA for these two groups were aligned in a manner appropriate to the HSV-I genome model. It was apparent that these groups had the orientation of the long region inverted with respect to each other. Similarly, from the denaturation maps of the short unique region, the molecules were divided into two groups each comprising 15 molecules. Alignment of the histogram plots of these groups indicated that the orientation of the short region was inverted in one group relative to the other. These partial denaturation data confirm the presence of four HSV-I genome arrangements resulting from the possible combinations of inversions of the two unique DNA regions.

DNA, Viral↗

PubMed2026

nf-core/magmap: Map metatranscriptomes to large collections of genomes.

SUMMARY: The lack of publicly available reference genomes has forced annotation of metatranscriptomes to either use direct alignment of sequence reads to reference databases or de novo assembly. As more and more natural environments are covered by metagenomic surveys, this is rapidly changing. This opens up the possibility of genome-resolved studies of prokaryotic metatranscriptomes by mapping to genomes from public repositories or metagenome-assembled genomes derived from the same environment. Here, we present the nf-core/magmap pipeline that provides a reproducible, easy-to-access, and well-documented workflow for selecting reference genomes, mapping to them, and quantifying features. Genomes can be drawn from public sources or originate from private collections. The pipeline is primarily aimed at prokaryotic communities but can, together with collections of reference mature gene sequences, also be applied to eukaryotes. AVAILABILITY AND IMPLEMENTATION: The nf-core/magmap pipeline is implemented in Nextflow and part of the nf-core collaboration. The pipeline is available at the nf-core website (https://nf-co.re/magmap) and GitHub (https://github.com/nf-core/magmap).

Software↗

PubMed1993

Detecting subtle sequence signals: a Gibbs sampling strategy for multiple alignment.

A wealth of protein and DNA sequence data is being generated by genome projects and other sequencing efforts. A crucial barrier to deciphering these sequences and understanding the relations among them is the difficulty of detecting subtle local residue patterns common to multiple sequences. Such patterns frequently reflect similar molecular structures and biological properties. A mathematical definition of this "local multiple alignment" problem suitable for full computer automation has been used to develop a new and sensitive algorithm, based on the statistical method of iterative sampling. This algorithm finds an optimized local alignment model for N sequences in N-linear time, requiring only seconds on current workstations, and allows the simultaneous detection and optimization of multiple patterns and pattern repeats. The method is illustrated as applied to helix-turn-helix proteins, lipocalins, and prenyltransferases.

Algorithms↗

PubMed1987

Two related viral genes are located on a single superhelical DNA segment of the multipartite Campoletis sonorensis virus genome.

Campoletis sonorensis virus (CsV) (Polydnaviridae) is a large eucaryotic DNA virus with a structurally complex genome consisting of 28 or more superhelical (SH) DNA segments. Little is known of the relationship between different SH DNAs, but some SH DNAs do cross hybridize, indicating a relatedness between certain SH DNAs. In a previous study of viral expression in parasitized Heliothis virescens larvae, several partially homologous viral mRNAs were also identified (G. W. Blissard, S. B. Vinson, and M. D. Summers, 1986, J. Virol. 57, 318-327). To study the organization of the viral genome and the relationship between two partially homologous viral mRNAs, we analyzed cDNA clones and a cloned SH DNA segment of the CsV genome. Of the two CsV mRNAs examined (1.6 and 1.0 kb), both mRNAs were abundant at 48 hr after parasitization and the 1.6-kb mRNA was detected as early as 2 hr after parasitization. Nucleotide sequence analyses of cDNA clones representing the two partially homologous CsV mRNAs (1.6 and 1.0 kb) show that the two CsV mRNAs share five regions of imperfect homology (68 to 88%) which include a large part of each mRNA. These data indicate that the two mRNAs are transcribed from two separate but closely related CsV genes. Comparison of predicted amino acid sequences shows that the two related viral genes encode proteins with divergent amino acid sequences. Northern and Southern hybridization analyses using cloned cDNAs as probes showed that one CsV mRNA (1.6 kb) is homologous to CsV SH DNAs W, R, and M, while the other mRNA (1.0 kb) shows strong homology only to SH DNA W. By cloning and Southern hybridization mapping of the 15.8-kbp SH DNA W, we demonstrate that the genes for the related 1.6- and 1.0-kb mRNAs are located on different regions of this single 15.8-kbp SH DNA. Alignment of nucleotide sequences from a cloned viral genomic DNA and a cDNA demonstrates that the CsV gene encoding the 1.6-kb mRNA is a spliced gene containing at least two introns. Conservation of splice junctions between the two mRNAs suggests that the 1.0-kb mRNA is also spliced. These data represent the detailed analysis of two closely related CsV mRNAs abundantly expressed in parasitized H. virescens larvae, the first observation of related viral genes in a eucaryotic DNA virus, the demonstration of splicing in the Polydnaviridae, and the cloning and mapping of one of the largest SH DNA segments of the CsV genome.

Base Sequence↗

PubMed1999

Genomic organization of the human fibroblast growth factor receptor 2 (FGFR2) gene and comparative analysis of the human FGFR gene family.

The human fibroblast growth factor receptor (FGFR) genes play important roles in normal vertebrate development. Mutations in the human FGFR2 gene have been associated with many craniosynostotic syndromes and malformations, including Crouzon, Pfeiffer, Apert, Jackson-Weiss, Beare-Stevenson cutis gyrata, and Antley-Bixler syndromes, and Kleeblaatschadel (cloverleaf skull) deformity. The mutations identified to date are concentrated in the previously characterized region of FGFR2 that codes for the extracellular IgIII domain of the receptor protein. The search for mutations in other regions of the gene, however, has been hindered by lack of knowledge of the genomic structure. Using a combination of genomic library screening, long-range PCR, and genomic walking, we have characterized the genomic structure of nearly the entire human FGFR2 gene, including a delineation of the organization and size of all introns and exons and determination of the DNA sequences at the intron/exon boundaries. Comparative analysis of the human FGFR gene family reveals that the genomic organization of the FGFRs is relatively conserved. Moreover, alignment of the amino acid sequences shows that the four corresponding proteins share 46% identity overall, with up to 70% identity between individual pairs of FGFR proteins. However, the FGFR2 gene contains an additional exon not found in other members of the family, and it also has much larger intronic sequences throughout the gene. Remarkable similarities in genomic organization, intron/exon boundaries, and intron sizes are found between the human and mouse FGFR2 genes. Knowledge gained from this study of the human FGFR2 gene structure may prove useful in future screening studies designed to find additional mutations associated with craniosynostotic syndromes, and in understanding the molecular and cell biology of this receptor family.

Alternative Splicing↗