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Results for “Genome alignment”

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PubMed2004

Speeding up whole-genome alignment by indexing frequency vectors.

MOTIVATION: Many biological applications require the comparison of large genome strings. Current techniques suffer from high computational and I/O costs. RESULTS: We propose an efficient technique for local alignment of large genome strings. A space-efficient index is computed for one string, and the second string is compared with this index in order to prune substring pairs that do not contain similar regions. The remaining substring pairs are handed to a hash-table-based tool, such as BLAST, for alignment. A dynamic strategy is employed to optimize the number of disk seeks needed to access the hash table. Additionally, our technique provides the user with a coarse-grained visualization of the similarity pattern, quickly and before the actual search. The experimental results show that our technique aligns genome strings up to two orders of magnitude faster than BLAST. Our technique can be used to accelerate other search tools as well. AVAILABILITY: A web-based demo can be found at http://bioserver.cs.ucsb.edu/. Source code is available from the authors on request.

Databases, Genetic↗
PubMed2003

Strategies and tools for whole-genome alignments.

The availability of the assembled mouse genome makes possible, for the first time, an alignment and comparison of two large vertebrate genomes. We investigated different strategies of alignment for the subsequent analysis of conservation of genomes that are effective for assemblies of different quality. These strategies were applied to the comparison of the working draft of the human genome with the Mouse Genome Sequencing Consortium assembly, as well as other intermediate mouse assemblies. Our methods are fast and the resulting alignments exhibit a high degree of sensitivity, covering more than 90% of known coding exons in the human genome. We obtained such coverage while preserving specificity. With a view towards the end user, we developed a suite of tools and Web sites for automatically aligning and subsequently browsing and working with whole-genome comparisons. We describe the use of these tools to identify conserved non-coding regions between the human and mouse genomes, some of which have not been identified by other methods.

Algorithms↗
PubMed2000

UTR reconstruction and analysis using genomically aligned EST sequences.

Untranslated regions (UTR) play important roles in the posttranscriptional regulation of mRNA processing. There is a wealth of UTR-related information to be mined from the rapidly accumulating EST collections. A computational tool, UTR-extender, has been developed to infer UTR sequences from genomically aligned ESTs. It can completely and accurately reconstruct 72% of the 3' UTRs and 15% of the 5' UTRs when tested using 908 functionally cloned transcripts. In addition, it predicts extensions for 11% of the 5' UTRs and 28% of the 3' UTRs. These extension regions are validated by examining splicing frequencies and conservation levels. We also developed a method called polyadenylation site scan (PASS) to precisely map polyadenylation sites in human genomic sequences. A PASS analysis of 908 genic regions estimates that 40-50% of human genes undergo alternative polyadenylation. Using EST redundancy to assess expression levels, we also find that genes with short 3' UTRs tend to be highly expressed.

Algorithms↗
PubMed1994

Genomic alignment.

As sequencing techniques become increasingly efficient, the average length of a sequence is bound to grow. Traditional sequence-comparison algorithms can either compare DNA or protein, but not a mixture, which is actually a common situation. Most obtained DNA sequences contain coding regions, and it is more reliable to compare the coding regions as protein than just as DNA. A heuristic algorithm is presented that can compare DNA with both coding and noncoding regions, but that also can compare multiple reading frames and determine which exons are homologous. A program, GenA1 (Genomic Alignment), was developed that implements the algorithm. Its use is demonstrated on two retroviruses.

Algorithms↗
PubMed2004

An SNP resource for rice genetics and breeding based on subspecies indica and japonica genome alignments.

Dense coverage of the rice genome with polymorphic DNA markers is an invaluable tool for DNA marker-assisted breeding, positional cloning, and a wide range of evolutionary studies. We have aligned drafts of two rice subspecies, indica and japonica, and analyzed levels and patterns of genetic diversity. After filtering multiple copy and low quality sequence, 408,898 candidate DNA polymorphisms (SNPs/INDELs) were discerned between the two subspecies. These filters have the consequence that our data set includes only a subset of the available SNPs (in particular excluding large numbers of SNPs that may occur between repetitive DNA alleles) but increase the likelihood that this subset is useful: Direct sequencing suggests that 79.8% +/- 7.5% of the in silico SNPs are real. The SNP sample in our database is not randomly distributed across the genome. In fact, 566 rice genomic regions had unusually high (328 contigs/48.6 Mb/13.6% of genome) or low (237 contigs/64.7 Mb/18.1% of genome) polymorphism rates. Many SNP-poor regions were substantially longer than most SNP-rich regions, covering up to 4 Mb, and possibly reflecting introgression between the respective gene pools that may have occurred hundreds of years ago. Although 46.2% +/- 8.3% of the SNPs differentiate other pairs of japonica and indica genotypes, SNP rates in rice were not predictive of evolutionary rates for corresponding genes in another grass species, sorghum. The data set is freely available at http://www.plantgenome.uga.edu/snp.

Breeding↗
PubMed2000

Web-based visualization tools for bacterial genome alignments.

With the increase in the flow of sequence data, both in contigs and whole genomes, visual aids for comparison and analysis studies are becoming imperative. We describe three web-based tools for visualizing alignments of bacterial genomes. The first, called Enteric, produces a graphical, hypertext view of pairwise alignments between a reference genome and sequences from each of several related organisms, covering 20 kb around a user-specified position. Insertions, deletions and rearrangements relative to the reference genome are color-coded, which reveals many intriguing differences among genomes. The second, Menteric, computes and displays nucleotide-level multiple alignments of the same sequences, together with annotations of ORFs and regulatory sites, in a 1 kb region surrounding a given address. The third, a Java-based viewer called Maj, combines some features of the previous tools, and adds a zoom-in mechanism. We compare the Escherichia coli K-12 genome with the partially sequenced genomes of Klebsiella pneumoniae, Yersinia pestis, Vibrio cholerae, and the Salmonella enterica serovars Typhimurium, Typhi and Paratyphi A. Examination of the pairwise and multiple alignments in a region allows one to draw inferences about regulatory patterns and functional assignments. For example, these tools revealed that rffH, a gene involved in enterobacterial common antigen (ECA) biosynthesis, is partly deleted in one of the genomes. We used PCR to show that this deletion occurs sporadically in some strains of some serovars of S.enterica subspecies I but not in any strains tested from six other subspecies. The resulting cell surface diversity may be associated with selection by the host immune response.

DNA, Bacterial↗
PubMed2003

EnteriX 2003: Visualization tools for genome alignments of Enterobacteriaceae.

We describe EnteriX, a suite of three web-based visualization tools for graphically portraying alignment information from comparisons among several fixed and user-supplied sequences from related enterobacterial species, anchored on a reference genome (http://bio.cse.psu.edu/). The first visualization, Enteric, displays stacked pairwise alignments between a reference genome and each of the related bacteria, represented schematically as PIPs (Percent Identity Plots). Encoded in the views are large-scale genomic rearrangement events and functional landmarks. The second visualization, Menteric, computes and displays 1 Kb views of nucleotide-level multiple alignments of the sequences, together with annotations of genes, regulatory sites and conserved regions. The third, a Java-based tool named Maj, displays alignment information in two formats, corresponding roughly to the Enteric and Menteric views, and adds zoom-in capabilities. The uses of such tools are diverse, from examining the multiple sequence alignment to infer conserved sites with potential regulatory roles, to scrutinizing the commonalities and differences between the genomes for pathogenicity or phylogenetic studies. The EnteriX suite currently includes >15 enterobacterial genomes, generates views centered on four different anchor genomes and provides support for including user sequences in the alignments.

Computer Graphics↗
PubMed1994

Aligning genomes with inversions and swaps.

The decision about what operators to allow and how to charge for these operations when aligning strings that arise in a biological context is the decision about what model of evolution to assume. Frequently the operators used to construct an alignment between biological sequences are limited to deletion, insertion, or replacement of a character or block of characters, but there is biological evidence for the evolutionary operations of exchanging the positions of two segments in a sequence and the replacement of a segment by its reversed complement. In this paper we describe a family of heuristics designed to compute alignments of biological sequences assuming a model of evolution with swaps and inversions. The heuristics will necessarily be approximate since the appropriate way to charge for the evolutionary events (delete, insert, substitute, swap, and invert) is not known. The paper concludes with a pairwise comparison of 20 Picornavirus genomes, and a detailed comparison of the hepatitis delta virus with the citrus exocortis viroid.

Amino Acid Sequence↗
PubMed2004

The CHAOS/DIALIGN WWW server for multiple alignment of genomic sequences.

Cross-species sequence comparison is a powerful approach to analyze functional sites in genomic sequences and many discoveries have been made based on genomic alignments. Herein, we present a WWW-based software system for multiple alignment of large genomic sequences. Our server utilizes the previously developed combination of CHAOS and DIALIGN to achieve both speed and alignment accuracy. CHAOS is a fast database search tool that creates a list of local sequence similarities. These are used by DIALIGN as anchor points to speed up the final alignment procedure. The resulting alignment is returned to the user in different formats together with a list of anchor points found by CHAOS. The CHAOS/DIALIGN software is freely available at http://dialign.gobics.de/chaos-dialign-submission.

Genomics↗
PubMed2005

Evaluation of regulatory potential and conservation scores for detecting cis-regulatory modules in aligned mammalian genome sequences.

Techniques of comparative genomics are being used to identify candidate functional DNA sequences, and objective evaluations are needed to assess their effectiveness. Different analytical methods score distinctive features of whole-genome alignments among human, mouse, and rat to predict functional regions. We evaluated three of these methods for their ability to identify the positions of known regulatory regions in the well-studied HBB gene complex. Two methods, multispecies conserved sequences and phastCons, quantify levels of conservation to estimate a likelihood that aligned DNA sequences are under purifying selection. A third function, regulatory potential (RP), measures the similarity of patterns in the alignments to those in known regulatory regions. The methods can correctly identify 50%-60% of noncoding positions in the HBB gene complex as regulatory or nonregulatory, with RP performing better than do other methods. When evaluated by the ability to discriminate genomic intervals, RP reaches a sensitivity of 0.78 and a true discovery rate of approximately 0.6. The performance is better on other reference sets; both phastCons and RP scores can capture almost all regulatory elements in those sets along with approximately 7% of the human genome.

Algorithms↗
PubMed2005

Identification of transposable elements using multiple alignments of related genomes.

Accurate genome-wide cataloging of transposable elements (TEs) will facilitate our understanding of mobile DNA evolution, expose the genomic effects of TEs on the host genome, and improve the quality of assembled genomes. Using the availability of several nearly complete Drosophila genomes and developments in whole genome alignment methods, we introduce a large-scale comparative method for identifying repetitive mobile DNA regions. These regions are highly enriched for transposable elements. Our method has two main features distinguishing it from other repeat-finding methods. First, rather than relying on sequence similarity to determine the location of repeats, the genomic artifacts of the transposition mechanism itself are systematically tracked in the context of multiple alignments. Second, we can derive bounds on the age of each repeat instance based on the phylogenetic species tree. We report results obtained using both complete and draft sequences of four closely related Drosophila genomes and validate our results with manually curated TE annotations in the Drosophila melanogaster euchromatin. We show the utility of our findings in exploring both transposable elements and their host genomes: In the study of TEs, we offer predictions for novel families, annotate new insertions of known families, and show data that support the hypothesis that all known TE families in D. melanogaster were recently active; in the study of the host, we show how our findings can be used to determine shifts in the eu-heterochromatin junction in the pericentric chromosome regions.

Animals↗
PubMed2005

COMPAM :visualization of combining pairwise alignments for multiple genomes.

UNLABELLED: COMPAM is a tool for visualizing relationships among multiple whole genomes by combining all pairwise genome alignments. It displays shared conserved regions (blocks) and where these blocks occur (edges) as block relation graphs which can be explored interactively. An unannotated genome, e.g. can then be explored using information from well-annotated genomes, COG-based genome annotation and genes. COMPAM can run either as a stand-alone application or through an applet that is provided as service to PLATCOM, a toolset for whole genome comparative analysis, where a wide variety of genomes can be easily selected. Features provided by COMPAM include the ability to export genome relationship information into file formats that can be used by other existing tools. AVAILABILITY: http://bio.informatics.indiana.edu/projects/compam/

Algorithms↗
PubMed2004

Aligning multiple genomic sequences with the threaded blockset aligner.

We define a "threaded blockset," which is a novel generalization of the classic notion of a multiple alignment. A new computer program called TBA (for "threaded blockset aligner") builds a threaded blockset under the assumption that all matching segments occur in the same order and orientation in the given sequences; inversions and duplications are not addressed. TBA is designed to be appropriate for aligning many, but by no means all, megabase-sized regions of multiple mammalian genomes. The output of TBA can be projected onto any genome chosen as a reference, thus guaranteeing that different projections present consistent predictions of which genomic positions are orthologous. This capability is illustrated using a new visualization tool to view TBA-generated alignments of vertebrate Hox clusters from both the mammalian and fish perspectives. Experimental evaluation of alignment quality, using a program that simulates evolutionary change in genomic sequences, indicates that TBA is more accurate than earlier programs. To perform the dynamic-programming alignment step, TBA runs a stand-alone program called MULTIZ, which can be used to align highly rearranged or incompletely sequenced genomes. We describe our use of MULTIZ to produce the whole-genome multiple alignments at the Santa Cruz Genome Browser.

Animals↗
PubMedDate not supplied

Genomic divergence between human and chimpanzee estimated from large-scale alignments of genomic sequences.

To study the genomic divergence between human and chimpanzee, large-scale genomic sequence alignments were performed. The genomic sequences of human and chimpanzee were first masked with the RepeatMasker and the repeats were excluded before alignments. The repeats were then reinserted into the alignments of nonrepetitive segments and entire sequences were aligned again. A total of 2.3 million base pairs (Mb) of genomic sequences, including repeats, were aligned and the average nucleotide divergence was estimated to be 1.22%. The Jukes-Cantor (JC) distances (nucleotide divergences) in nonrepetitive (1.44 Mb) and repetitive sequences (0.86 Mb) are 1.14% and 1.34%, respectively, suggesting a slightly higher average rate in repetitive sequences. Annotated coding and noncoding regions of homologous chimpanzee genes were also retrieved from GenBank and compared. The average synonymous and nonsynonymous divergences in 88 coding genes are 1.48% and 0.55%, respectively. The JC distances in intron, 5' flanking, 3' flanking, promoter, and pseudogene regions are 1.47%, 1.41%, 1.68%, 0.75%, and 1.39%, respectively. It is not clear why the genetic distances in most of these regions are somewhat higher than those in genomic sequences. One possible explanation is that some of the genes may be located in regions with higher mutation rates.

Animals↗
PubMed2005

Improvements to GALA and dbERGE II: databases featuring genomic sequence alignment, annotation and experimental results.

We describe improvements to two databases that give access to information on genomic sequence similarities, functional elements in DNA and experimental results that demonstrate those functions. GALA, the database of Genome ALignments and Annotations, is now a set of interlinked relational databases for five vertebrate species, human, chimpanzee, mouse, rat and chicken. For each species, GALA records pairwise and multiple sequence alignments, scores derived from those alignments that reflect the likelihood of being under purifying selection or being a regulatory element, and extensive annotations such as genes, gene expression patterns and transcription factor binding sites. The user interface supports simple and complex queries, including operations such as subtraction and intersections as well as clustering and finding elements in proximity to features. dbERGE II, the database of Experimental Results on Gene Expression, contains experimental data from a variety of functional assays. Both databases are now run on the DB2 database management system. Improved hardware and tuning has reduced response times and increased querying capacity, while simplified query interfaces will help direct new users through the querying process. Links are available at http://www.bx.psu.edu/.

Animals↗
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↗
PubMed2004

SITEBLAST--rapid and sensitive local alignment of genomic sequences employing motif anchors.

MOTIVATION: Comparative sequence analysis is the essence of many approaches to genome annotation. Heuristic alignment algorithms utilize similar seed pairs to anchor an alignment. Some applications of local alignment algorithms (e.g. phylogenetic footprinting) would benefit from including prior knowledge (e.g. binding site motifs) in the alignment building process. RESULTS: We introduce predefined sequence patterns as anchor points into a heuristic local alignment strategy. We extended the BLASTZ program for this purpose. A set of seed patterns is either given as consensus sequences in IUPAC code or position-weight-matrices. Phylogenetic footprinting of promoter regions is one of many potential applications for the SITEBLAST software. AVAILABILITY: The source code is freely available to the academic community from http://corg.molgen.mpg.de/software

Algorithms↗