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PubMed2002

Microsatellite evolution inferred from human-chimpanzee genomic sequence alignments.

Most studies of microsatellite evolution utilize long, highly mutable loci, which are unrepresentative of the majority of simple repeats in the human genome. Here we use an unbiased sample of 2,467 microsatellite loci derived from alignments of 5.1 Mb of genomic sequence from human and chimpanzee to investigate the mutation process of tandemly repetitive DNA. The results indicate that the process of microsatellite evolution is highly heterogeneous, exhibiting differences between loci of different lengths and motif sizes and between species. We find a highly significant tendency for human dinucleotide repeats to be longer than their orthologues in chimpanzees, whereas the opposite trend is observed in mononucleotide repeat arrays. Furthermore, the rate of divergence between orthologues is significantly higher at longer loci, which also show significantly greater mutability per repeat number. These observations have important consequences for understanding the molecular mechanisms of microsatellite mutation and for the development of improved measures of genetic distance.

Animals↗
PubMed2003

The human SPANX multigene family: genomic organization, alignment and expression in male germ cells and tumor cell lines.

Multigenicity is one of the features of cancer/testis-associated genes. In the present study we analyzed the number and expression of genes of the SPANX(CTp11) family of cancer/testis-associated genes. Genomic database analysis, next to the four previously described SPANX genes, revealed the presence of a novel gene: SPANXE. Moreover, we detected an allelic variant of SPANXB resulting in one amino acid substitution in the encoded protein: SPANXB'. Most SPANX genes are present on contig NT_011574 located at Xq26.3-Xq27.1. Based on expressed sequence tag databases and RT-PCR analysis three additional novel SPANX sequences were identified, though not represented so far in the human genome sequence. Sequence alignments justify a subdivision of this gene family based on the absence (SPANXA-likes) or presence (SPANXB) of an 18 base pair sequence stretch in the open reading frame. The alignments also reveal an unusually high level (99%) of intron homology. Furthermore, the nucleotide variations in the open reading frame almost all lead to amino acid substitutions. Southern blot and database analyses indicate that SPANX sequences are exclusively present in primates. With RT-PCR analysis on human sperm cell precursors and tumor cell lines most family members could be detected. SPANXB was only found in sperm cell precursors and could not be detected in the tumor cell lines tested. Overall SPANXA was the most frequently expressed SPANX variant in melanoma and glioblastoma cell lines.

Amino Acid Sequence↗
PubMed2002

SUPERFAMILY: HMMs representing all proteins of known structure. SCOP sequence searches, alignments and genome assignments.

The SUPERFAMILY database contains a library of hidden Markov models representing all proteins of known structure. The database is based on the SCOP 'superfamily' level of protein domain classification which groups together the most distantly related proteins which have a common evolutionary ancestor. There is a public server at http://supfam.org which provides three services: sequence searching, multiple alignments to sequences of known structure, and structural assignments to all complete genomes. Given an amino acid or nucleotide query sequence the server will return the domain architecture and SCOP classification. The server produces alignments of the query sequences with sequences of known structure, and includes multiple alignments of genome and PDB sequences. The structural assignments are carried out on all complete genomes (currently 59) covering approximately half of the soluble protein domains. The assignments, superfamily breakdown and statistics on them are available from the server. The database is currently used by this group and others for genome annotation, structural genomics, gene prediction and domain-based genomic studies.

Amino Acid Sequence↗
PubMed2006

Combo: a whole genome comparative browser.

SUMMARY: Combo is a comparative genome browser that provides a dynamic view of whole genome alignments along with their associated annotations. Combo provides two different visualization perspectives. The perpendicular (dot plot) view provides a dot plot of genome alignments synchronized with a display of genome annotations along each axis. The parallel view displays two genome annotations horizontally, synchronized through a panel displaying local alignments as trapezoids. Users can zoom to any resolution, from whole chromosomes to individual bases. They can select, highlight and view detailed information from specific alignments and annotations. Combo is an organism agnostic and can import data from a variety of file formats. AVAILABILITY: Combo is integrated as part of the Argo Genome Browser which also provides single-genome browsing and editing capabilities. Argo is written in Java, runs on multiple platforms and is freely available for download at http://www.broad.mit.edu/annotation/argo/.

Algorithms↗
PubMed2004

Analysis of multiple genomic sequence alignments: a web resource, online tools, and lessons learned from analysis of mammalian SCL loci.

Comparative analysis of genomic sequences is becoming a standard technique for studying gene regulation. However, only a limited number of tools are currently available for the analysis of multiple genomic sequences. An extensive data set for the testing and training of such tools is provided by the SCL gene locus. Here we have expanded the data set to eight vertebrate species by sequencing the dog SCL locus and by annotating the dog and rat SCL loci. To provide a resource for the bioinformatics community, all SCL sequences and functional annotations, comprising a collation of the extensive experimental evidence pertaining to SCL regulation, have been made available via a Web server. A Web interface to new tools specifically designed for the display and analysis of multiple sequence alignments was also implemented. The unique SCL data set and new sequence comparison tools allowed us to perform a rigorous examination of the true benefits of multiple sequence comparisons. We demonstrate that multiple sequence alignments are, overall, superior to pairwise alignments for identification of mammalian regulatory regions. In the search for individual transcription factor binding sites, multiple alignments markedly increase the signal-to-noise ratio compared to pairwise alignments.

Animals↗
PubMed2005

Phylogeny of prokaryotes and chloroplasts revealed by a simple composition approach on all protein sequences from complete genomes without sequence alignment.

The complete genomes of living organisms have provided much information on their phylogenetic relationships. Similarly, the complete genomes of chloroplasts have helped to resolve the evolution of this organelle in photosynthetic eukaryotes. In this paper we propose an alternative method of phylogenetic analysis using compositional statistics for all protein sequences from complete genomes. This new method is conceptually simpler than and computationally as fast as the one proposed by Qi et al. (2004b) and Chu et al. (2004). The same data sets used in Qi et al. (2004b) and Chu et al. (2004) are analyzed using the new method. Our distance-based phylogenic tree of the 109 prokaryotes and eukaryotes agrees with the biologists "tree of life" based on 16S rRNA comparison in a predominant majority of basic branching and most lower taxa. Our phylogenetic analysis also shows that the chloroplast genomes are separated to two major clades corresponding to chlorophytes s.l. and rhodophytes s.l. The interrelationships among the chloroplasts are largely in agreement with the current understanding on chloroplast evolution.

Chloroplasts↗
PubMed2026

Assessing Hardy-Weinberg equilibrium in T2T-aligned 1000 genomes project.

Quality control of markers in genome-wide association studies often includes testing for Hardy-Weinberg equilibrium (HWE). However, this is usually implemented in a homogeneous population without stratifying by sex. Previous work indicates sex-based selection at numerous autosomal loci in cohorts with active recruitment. Sex chromosome sequences can also interfere with autosomal SNPs. These motivate a re-examination of HWE in sex-aware analyses. Using the telomere-to-telomere (T2Tv2)-aligned high-coverage whole genome sequencing data from 2,490 individuals in the 1000 Genomes Project, we examined genome-wide sex-specific deviations from HWE across five super-populations. Our analyses were restricted to bi-allelic SNPs with non-missing genotypes and minor allele frequency (MAF) &#x2265;5% in both sexes of the five super-populations. We applied an allele-based framework to quantify both the magnitude and direction of Hardy-Weinberg disequilibrium (HWD), followed by a second-order omnibus meta-analysis that combined HWD results across populations and sexes. At a genome-wide significance threshold of p&#x2009;<&#x2009;5e-8, 0.9% of autosomal SNPs exhibited significant deviations from HWE. The majority of these deviations were associated with genomic features indicative of poor sequence quality. Restricting the analysis to reliable genomic regions substantially reduced the number of signals, yielding 255 autosomal SNPs and one non-pseudoautosomal chromosome X SNP. Among these, 140 autosomal SNPs displayed significant heterogeneity across populations but not across sexes. Notably, eight SNPs within a 15-bp region on chromosome 14q31.3 showed excess heterozygosity in both sexes of the African super-population (AFR). Finally, we developed a multivariate predictor of HWD based on sequence features, providing a practical tool that can be integrated into existing quality control pipelines for whole genome sequencing studies.

Journal Article↗
PubMed2004

ECR Browser: a tool for visualizing and accessing data from comparisons of multiple vertebrate genomes.

With an increasing number of vertebrate genomes being sequenced in draft or finished form, unique opportunities for decoding the language of DNA sequence through comparative genome alignments have arisen. However, novel tools and strategies are required to accommodate this large volume of genomic information and to facilitate the transfer of predictions generated by comparative sequence alignment to researchers focused on experimental annotation of genome function. Here, we present the ECR Browser, a tool that provides easy and dynamic access to whole genome alignments of human, mouse, rat and fish sequences. This web-based tool (http://ecrbrowser.dcode.org) provides the starting point for discovery of novel genes, identification of distant gene regulatory elements and prediction of transcription factor binding sites. The genome alignment portal of the ECR Browser also permits fast and automated alignments of any user-submitted sequence to the genome of choice. The interconnection of the ECR Browser with other DNA sequence analysis tools creates a unique portal for studying and exploring vertebrate genomes.

Animals↗
PubMed2000

PipMaker--a web server for aligning two genomic DNA sequences.

PipMaker (http://bio.cse.psu.edu) is a World-Wide Web site for comparing two long DNA sequences to identify conserved segments and for producing informative, high-resolution displays of the resulting alignments. One display is a percent identity plot (pip), which shows both the position in one sequence and the degree of similarity for each aligning segment between the two sequences in a compact and easily understandable form. Positions along the horizontal axis can be labeled with features such as exons of genes and repetitive elements, and colors can be used to clarify and enhance the display. The web site also provides a plot of the locations of those segments in both species (similar to a dot plot). PipMaker is appropriate for comparing genomic sequences from any two related species, although the types of information that can be inferred (e.g., protein-coding regions and cis-regulatory elements) depend on the level of conservation and the time and divergence rate since the separation of the species. Gene regulatory elements are often detectable as similar, noncoding sequences in species that diverged as much as 100-300 million years ago, such as humans and mice, Caenorhabditis elegans and C. briggsae, or Escherichia coli and Salmonella spp. PipMaker supports analysis of unfinished or "working draft" sequences by permitting one of the two sequences to be in unoriented and unordered contigs.

Animals↗
PubMed2026

A-liner: linear alignment visualizer for genome comparisons.

SUMMARY: A-liner is a flexible command-line tool for linear visualization of genome-scale sequence alignments, supporting outputs from multiple aligners and integrated visualization of annotations, highlights, quantitative tracks, and coordinate scales. It is applicable to a wide range of organisms, from bacteria to large eukaryotic genomes, and facilitates efficient generation of publication-ready comparative genome visualizations. AVAILABILITY AND IMPLEMENTATION: The source code and example output files for a-liner are available in the GitHub repository: https://github.com/mokuno3430/a-liner. A-liner v1.1.0 has been archived on Zenodo at https://doi.org/10.5281/zenodo.19702001.

Software↗
PubMed2006

Intronic alternative splicing regulators identified by comparative genomics in nematodes.

Many alternative splicing events are regulated by pentameric and hexameric intronic sequences that serve as binding sites for splicing regulatory factors. We hypothesized that intronic elements that regulate alternative splicing are under selective pressure for evolutionary conservation. Using a Wobble Aware Bulk Aligner genomic alignment of Caenorhabditis elegans and Caenorhabditis briggsae, we identified 147 alternatively spliced cassette exons that exhibit short regions of high nucleotide conservation in the introns flanking the alternative exon. In vivo experiments on the alternatively spliced let-2 gene confirm that these conserved regions can be important for alternative splicing regulation. Conserved intronic element sequences were collected into a dataset and the occurrence of each pentamer and hexamer motif was counted. We compared the frequency of pentamers and hexamers in the conserved intronic elements to a dataset of all C. elegans intron sequences in order to identify short intronic motifs that are more likely to be associated with alternative splicing. High-scoring motifs were examined for upstream or downstream preferences in introns surrounding alternative exons. Many of the high-scoring nematode pentamer and hexamer motifs correspond to known mammalian splicing regulatory sequences, such as (T)GCATG, indicating that the mechanism of alternative splicing regulation is well conserved in metazoans. A comparison of the analysis of the conserved intronic elements, and analysis of the entire introns flanking these same exons, reveals that focusing on intronic conservation can increase the sensitivity of detecting putative splicing regulatory motifs. This approach also identified novel sequences whose role in splicing is under investigation and has allowed us to take a step forward in defining a catalog of splicing regulatory elements for an organism. In vivo experiments confirm that one novel high-scoring sequence from our analysis, (T)CTATC, is important for alternative splicing regulation of the unc-52 gene.

Alternative Splicing↗
PubMed2006

A full-genome phylogenetic analysis of varicella-zoster virus reveals a novel origin of replication-based genotyping scheme and evidence of recombination between major circulating clades.

Varicella-zoster virus (VZV) is a remarkably stable virus that until recently was thought to exhibit near-universal genetic homogeneity among circulating wild-type strains. In recent years, the expanding knowledge of VZV genetics has led to a number of groups proposing sequence-based typing schemes, but no study has yet examined the relationships between VZV genotypes at a full-genome level. A central hypothesis of this study is that VZV has coevolved with humankind. In this study, 11 additional full VZV genomic sequences are presented, bringing the current number of complete genomic sequences publicly available to 18. The full-genome alignment contained strains representing four distinct clades, but the possibility exists that a fifth clade comprised of African and Asian-like isolates was not represented. A consolidated VZV genotyping scheme employing the origin-associated region between reiteration region R4 and open reading frames (ORFs) 63 and 70 is described, one which accurately categorizes strains into one of four clades related to the geographic origin of the isolates. The full-genome alignment also provided evidence for recombination having occurred between the major circulating VZV clades. One Canadian clinical isolate was primarily Asian-like in origin, with most of the genome showing strong sequence identity to the Japanese-like clade B, with the exceptions being two putative recombination regions, located in ORFs 14 to 17 and ORFs 22 to 26, which showed clear similarity to the European/North American clade A. The very low rate of single-nucleotide polymorphisms scattered across the genome made full-genome sequencing the only definitive method for identifying specific VZV recombination events.

Base Sequence↗
PubMed2006

Parametric alignment of Drosophila genomes.

The classic algorithms of Needleman-Wunsch and Smith-Waterman find a maximum a posteriori probability alignment for a pair hidden Markov model (PHMM). To process large genomes that have undergone complex genome rearrangements, almost all existing whole genome alignment methods apply fast heuristics to divide genomes into small pieces that are suitable for Needleman-Wunsch alignment. In these alignment methods, it is standard practice to fix the parameters and to produce a single alignment for subsequent analysis by biologists. As the number of alignment programs applied on a whole genome scale continues to increase, so does the disagreement in their results. The alignments produced by different programs vary greatly, especially in non-coding regions of eukaryotic genomes where the biologically correct alignment is hard to find. Parametric alignment is one possible remedy. This methodology resolves the issue of robustness to changes in parameters by finding all optimal alignments for all possible parameters in a PHMM. Our main result is the construction of a whole genome parametric alignment of Drosophila melanogaster and Drosophila pseudoobscura. This alignment draws on existing heuristics for dividing whole genomes into small pieces for alignment, and it relies on advances we have made in computing convex polytopes that allow us to parametrically align non-coding regions using biologically realistic models. We demonstrate the utility of our parametric alignment for biological inference by showing that cis-regulatory elements are more conserved between Drosophila melanogaster and Drosophila pseudoobscura than previously thought. We also show how whole genome parametric alignment can be used to quantitatively assess the dependence of branch length estimates on alignment parameters.

Algorithms↗
PubMed1999

Alignment of whole genomes.

A new system for aligning whole genome sequences is described. Using an efficient data structure called a suffix tree, the system is able to rapidly align sequences containing millions of nucleotides. Its use is demonstrated on two strains of Mycoplasma tuberculosis, on two less similar species of Mycoplasma bacteria and on two syntenic sequences from human chromosome 12 and mouse chromosome 6. In each case it found an alignment of the input sequences, using between 30 s and 2 min of computation time. From the system output, information on single nucleotide changes, translocations and homologous genes can easily be extracted. Use of the algorithm should facilitate analysis of syntenic chromosomal regions, strain-to-strain comparisons, evolutionary comparisons and genomic duplications.

Algorithms↗
PubMed2004

Visualization of multiple genome annotations and alignments with the K-BROWSER.

We introduce a novel genome browser application, the K-BROWSER, that allows intuitive visualization of biological information across an arbitrary number of multiply aligned genomes. In particular, the K-BROWSER simultaneously displays an arbitrary number of genomes both through overlaid annotations and predictions that describe their respective characteristics, and through the multiple alignment that describes their global relationship to one another. The browsing environment has been designed to allow users seamless access to information available in every genome and, furthermore, to allow easy navigation within and between genomes. As of the date of publication, the K-BROWSER has been set up on the human, mouse, and rat genomes.

Animals↗
PubMed2005

Ancestral sequence alignment under optimal conditions.

BACKGROUND: Multiple genome alignment is an important problem in bioinformatics. An important subproblem used by many multiple alignment approaches is that of aligning two multiple alignments. Many popular alignment algorithms for DNA use the sum-of-pairs heuristic, where the score of a multiple alignment is the sum of its induced pairwise alignment scores. However, the biological meaning of the sum-of-pairs of pairs heuristic is not obvious. Additionally, many algorithms based on the sum-of-pairs heuristic are complicated and slow, compared to pairwise alignment algorithms. An alternative approach to aligning alignments is to first infer ancestral sequences for each alignment, and then align the two ancestral sequences. In addition to being fast, this method has a clear biological basis that takes into account the evolution implied by an underlying phylogenetic tree. In this study we explore the accuracy of aligning alignments by ancestral sequence alignment. We examine the use of both maximum likelihood and parsimony to infer ancestral sequences. Additionally, we investigate the effect on accuracy of allowing ambiguity in our ancestral sequences. RESULTS: We use synthetic sequence data that we generate by simulating evolution on a phylogenetic tree. We use two different types of phylogenetic trees: trees with a period of rapid growth followed by a period of slow growth, and trees with a period of slow growth followed by a period of rapid growth. We examine the alignment accuracy of four ancestral sequence reconstruction and alignment methods: parsimony, maximum likelihood, ambiguous parsimony, and ambiguous maximum likelihood. Additionally, we compare against the alignment accuracy of two sum-of-pairs algorithms: ClustalW and the heuristic of Ma, Zhang, and Wang. CONCLUSION: We find that allowing ambiguity in ancestral sequences does not lead to better multiple alignments. Regardless of whether we use parsimony or maximum likelihood, the success of aligning ancestral sequences containing ambiguity is very sensitive to the choice of gap open cost. Surprisingly, we find that using maximum likelihood to infer ancestral sequences results in less accurate alignments than when using parsimony to infer ancestral sequences. Finally, we find that the sum-of-pairs methods produce better alignments than all of the ancestral alignment methods.

Data Interpretation, Statistical↗
PubMed2005

Genomic multiple sequence alignments: refinement using a genetic algorithm.

BACKGROUND: Genomic sequence data cannot be fully appreciated in isolation. Comparative genomics--the practice of comparing genomic sequences from different species--plays an increasingly important role in understanding the genotypic differences between species that result in phenotypic differences as well as in revealing patterns of evolutionary relationships. One of the major challenges in comparative genomics is producing a high-quality alignment between two or more related genomic sequences. In recent years, a number of tools have been developed for aligning large genomic sequences. Most utilize heuristic strategies to identify a series of strong sequence similarities, which are then used as anchors to align the regions between the anchor points. The resulting alignment is globally correct, but in many cases is suboptimal locally. We describe a new program, GenAlignRefine, which improves the overall quality of global multiple alignments by using a genetic algorithm to improve local regions of alignment. Regions of low quality are identified, realigned using the program T-Coffee, and then refined using a genetic algorithm. Because a better COFFEE (Consistency based Objective Function For alignmEnt Evaluation) score generally reflects greater alignment quality, the algorithm searches for an alignment that yields a better COFFEE score. To improve the intrinsic slowness of the genetic algorithm, GenAlignRefine was implemented as a parallel, cluster-based program. RESULTS: We tested the GenAlignRefine algorithm by running it on a Linux cluster to refine sequences from a simulation, as well as refine a multiple alignment of 15 Orthopoxvirus genomic sequences approximately 260,000 nucleotides in length that initially had been aligned by Multi-LAGAN. It took approximately 150 minutes for a 40-processor Linux cluster to optimize some 200 fuzzy (poorly aligned) regions of the orthopoxvirus alignment. Overall sequence identity increased only slightly; but significantly, this occurred at the same time that the overall alignment length decreased--through the removal of gaps--by approximately 200 gapped regions representing roughly 1,300 gaps. CONCLUSION: We have implemented a genetic algorithm in parallel mode to optimize multiple genomic sequence alignments initially generated by various alignment tools. Benchmarking experiments showed that the refinement algorithm improved genomic sequence alignments within a reasonable period of time.

Algorithms↗