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PubMed2004

Mammalian genomes ease location of human DNA functional segments but not their description.

Under the assumption that a significant motivation for sequencing the genomes of mammals is the resulting ability to help us locate and characterize functional DNA segments shared with humans, we have developed a statistical analysis to quantify the expected advantage. Examining uncertainty in terms of the width of a confidence interval, we show that uncertainty in the rate of nucleotide mutation can be shrunk by a factor of nearly four when nine mammals; human, chimpanzee, baboon, cat, dog, cow, pig, rat, mouse; are used instead of just two; human and mouse. Contrastingly, we show confidence interval shrinkage by a factor of only 1.5 for measurements of the distribution of nucleotides at an aligned sequence site. These additional genomes should greatly help in identifying conserved DNA sites, but would be much less effective at precisely describing the expected pattern of nucleotides at those sites.

Journal Article↗
PubMed1989

Probabilistic models of genome shuffling.

The comparison of entire genomes in evolutionary studies gives rise to alignments characterized by many intersections, or inversions in the order of two fragments in different genomes. To model this, we suggest a random migration process for fragments, and discuss its equilibrium distribution in the case of linear and circular genomes. Simulations are carried out to explore "cut-off" behavior as the process approaches equilibrium. We define a new process to take into account the indistinguishability of two fragments which are adjacent in both genomes being compared. Questions of applicability of these models are discussed.

Biological Evolution↗
PubMed2005

TruMatch--a BLAST post-processor that identifies bona fide sequence matches to genome assemblies.

SUMMARY: BLAST is a widely used alignment tool for detecting matches between a query sequence and entries in nucleotide sequence databases. Matches (high-scoring pairs, HSPs) are assigned a score based on alignment length and quality and, by default, are reported with the top-scoring matches listed first. For certain types of searches, however, this method of reporting is not optimal. This is particularly true when searching a genome sequence with a query that was derived from the same genome, or a closely related one. If the genome is complex and the assembly is far from complete, correct matches are often relegated to low positions in the results, where they may be easily overlooked. To rectify this problem, we developed TruMatch--a program that parses standard BLAST outputs and identifies HSPs that involve query segments with unique matches to the assembly. Candidates for bona fide matches between a query sequence and a genome assembly are listed at the top of the TruMatch output. AVAILABILITY: TruMatch is written in Perl and is freely available to non-commercial users via web download at the URL: http://genome.kbrin.uky.edu/fungi_tel/TruMatch/

Algorithms↗
PubMed2006

A fungal phylogeny based on 42 complete genomes derived from supertree and combined gene analysis.

BACKGROUND: To date, most fungal phylogenies have been derived from single gene comparisons, or from concatenated alignments of a small number of genes. The increase in fungal genome sequencing presents an opportunity to reconstruct evolutionary events using entire genomes. As a tool for future comparative, phylogenomic and phylogenetic studies, we used both supertrees and concatenated alignments to infer relationships between 42 species of fungi for which complete genome sequences are available. RESULTS: A dataset of 345,829 genes was extracted from 42 publicly available fungal genomes. Supertree methods were employed to derive phylogenies from 4,805 single gene families. We found that the average consensus supertree method may suffer from long-branch attraction artifacts, while matrix representation with parsimony (MRP) appears to be immune from these. A genome phylogeny was also reconstructed from a concatenated alignment of 153 universally distributed orthologs. Our MRP supertree and concatenated phylogeny are highly congruent. Within the Ascomycota, the sub-phyla Pezizomycotina and Saccharomycotina were resolved. Both phylogenies infer that the Leotiomycetes are the closest sister group to the Sordariomycetes. There is some ambiguity regarding the placement of Stagonospora nodurum, the sole member of the class Dothideomycetes present in the dataset. Within the Saccharomycotina, a monophyletic clade containing organisms that translate CTG as serine instead of leucine is evident. There is also strong support for two groups within the CTG clade, one containing the fully sexual species Candida lusitaniae, Candida guilliermondii and Debaryomyces hansenii, and the second group containing Candida albicans, Candida dubliniensis, Candida tropicalis, Candida parapsilosis and Lodderomyces elongisporus. The second major clade within the Saccharomycotina contains species whose genomes have undergone a whole genome duplication (WGD), and their close relatives. We could not confidently resolve whether Candida glabrata or Saccharomyces castellii lies at the base of the WGD clade. CONCLUSION: We have constructed robust phylogenies for fungi based on whole genome analysis. Overall, our phylogenies provide strong support for the classification of phyla, sub-phyla, classes and orders. We have resolved the relationship of the classes Leotiomyctes and Sordariomycetes, and have identified two classes within the CTG clade of the Saccharomycotina that may correlate with sexual status.

Ascomycota↗
PubMed2002

Achieving congruency of phylogenetic trees generated by W-curves of genomic sequences.

Comparative genomic analysis at its most fundamental level involves alignment and analysis of linear strings of DNA. Many useful and powerful tools, such as BlastN and ClustalW are able to respectively, search for, and align similar strings of DNA from a variety of species. However, interesting genomic patterns cannot be immediately visualized within the information contact embedded in long genomic strings without extensive a priori knowledge. More problematic is the question of whether we will be able to crystallize long genomic sequences and analyze their true secondary and tertiary structures. It is, of course, these putative motifs that are binding to the three-dimensional structures of proteins and inducing replication and transcription events. The W-curve is a numerical mapping algorithm that allows one to geometrically visualize the information content of genomic motifs. Patterns of ALU, LINES, SINEs, and duplication sequences may be easily visualized with the W-curve. It is our hope that this pattern recognition algorithm will lead to visualization tools to track the evolutionary history of motif patterns. The combinatorics of DNA motif crossover-recombination events will be more easily followed as we continue to sequence more and more genomes. In our laboratory we are currently collaborating with mathematicians and computer scientists to develop and test tools, such as the W-curve, for analyzing patterns of long genomic sequences. In this paper, we examine the limitations of using the W-curve to infer the phylogenetic history of species.

Bacteria↗
PubMed1999

Hepatitis B virus core promoter mutations in children with multiple anti-HBe/HBeAg reactivations result in enhanced promoter activity.

Sera of two children were examined to determine whether specific hepatitis B virus (HBV) mutants may contribute to anti-hepatitis B e/hepatitis B e antigen (anti-HBe/HBeAg) reactivations during the course of chronic hepatitis B. The full-length HBV genome isolated from sera of patient 1 and the basic core promoter (BCP) from patient 2 were amplified and sequenced before and after several reactivations. The functional significance of the mutant BCP from patient 1 was studied using the luciferase assay. In both patients, rare mutations were found in the BCP at nucleotides 1764(G-->T)/1766(C-->G) and 1766(C-->T)/1768(T-->A) in case 1 and 2, respectively. In the BCP from patient 1, a putative new binding site for the transcription factor hepatocyte nuclear factor 3 (HNF3) was generated. The functional analyses of the mutant showed a 2.8-fold increase of core promoter activity, whereas the BCP variant of patient 2 was also identified to result in enhanced promoter activity. The alignment of full-length genomes from child 1 to the reference sequence showed 61 nucleotide substitutions. Furthermore, the time of reactivations from child 1 was always accompanied by selection of a precore mutation at nucleotide position 1899. In liver tissue of patient 1 before development of hepatocellular carcinoma only free viral sequences were found, whereas a single site integration of HBV was detected in hepatocytes after activation of carcinogenesis. Specific mutations in the HBV BCP of the two patients that are rarely present in chronic carriers were identified to increase the core promoter activity possibly by altering transcription factor binding, suggesting that these variants may be involved in the pathogenesis of frequent HBV reactivations.

Adolescent↗
PubMed1999

Calign: aligning sequences with restricted affine gap penalties.

MOTIVATION: Given a genomic DNA sequence, it is still an open problem to determine its coding regions, i.e. the region consisting of exons and introns. The comparison of cDNA and genomic DNA helps the understanding of coding regions. For such an application, it might be adequate to use the restricted affine gap penalties which penalize long gaps with a constant penalty. RESULTS: Several techniques developed for solving the approximate string-matching problem are employed to yield efficient algorithms for computing the optimal alignment with restricted affine gap penalties. In particular, efficient algorithms can be derived based on the suffix automaton with failure transitions and on the diagonalwise monotonicity of the cost tables. We have implemented the above methods in C on Sun workstations running SunOS Unix. Preliminary experiments show that these approaches are very promising for aligning a cDNA sequence with a genomic DNA sequence. AVAILABILITY: Calign is available free of charge by anonymous ftp at: iubio.bio. indiana.edu, directory: molbio/align, files: calign.driver.c calign. c. Another URL reference for the files is http://iubio.bio.indiana.edu/soft/molbio/align/+ ++calign.c.

Algorithms↗
PubMed2006

Conservation patterns in different functional sequence categories of divergent Drosophila species.

We have explored the distributions of fully conserved ungapped blocks in genome-wide pair-wise alignments of recently completed species of Drosophila: D. melanogaster, D. yakuba, D. ananassae, D. pseudoobscura, D. virilis, and D. mojavensis. Based on these distributions we have found that nearly every functional sequence category possesses its own distinctive conservation pattern, sometimes independent of the overall sequence conservation level. In the coding and regulatory regions, the ungapped blocks were longer than in introns, UTRs, and nonfunctional sequences. At the same time, the blocks in the coding regions carried a 3N + 2 signature characteristic of synonymous substitutions in the third-codon position. Larger block sizes in transcription regulatory regions can be explained by the presence of conserved arrays of binding sites for transcription factors. We also have shown that the longest ungapped blocks, or "ultraconserved" sequences, are associated with specific gene groups, including those encoding ion channels and components of the cytoskeleton. We discuss how restraining conservation patterns may help in mapping functional sequence categories and improve genome annotation.

Animals↗
PubMed2002

A comparison of whole-genome shotgun-derived mouse chromosome 16 and the human genome.

The high degree of similarity between the mouse and human genomes is demonstrated through analysis of the sequence of mouse chromosome 16 (Mmu 16), which was obtained as part of a whole-genome shotgun assembly of the mouse genome. The mouse genome is about 10% smaller than the human genome, owing to a lower repetitive DNA content. Comparison of the structure and protein-coding potential of Mmu 16 with that of the homologous segments of the human genome identifies regions of conserved synteny with human chromosomes (Hsa) 3, 8, 12, 16, 21, and 22. Gene content and order are highly conserved between Mmu 16 and the syntenic blocks of the human genome. Of the 731 predicted genes on Mmu 16, 509 align with orthologs on the corresponding portions of the human genome, 44 are likely paralogous to these genes, and 164 genes have homologs elsewhere in the human genome; there are 14 genes for which we could find no human counterpart.

Animals↗
PubMed2002

Integrated gene and species phylogenies from unaligned whole genome protein sequences.

MOTIVATION: Most molecular phylogenies are based on sequence alignments. Consequently, they fail to account for modes of sequence evolution that involve frequent insertions or deletions. Here we present a method for generating accurate gene and species phylogenies from whole genome sequence that makes use of short character string matches not placed within explicit alignments. In this work, the singular value decomposition of a sparse tetrapeptide frequency matrix is used to represent the proteins of organisms uniquely and precisely as vectors in a high-dimensional space. Vectors of this kind can be used to calculate pairwise distance values based on the angle separating the vectors, and the resulting distance values can be used to generate phylogenetic trees. Protein trees so derived can be examined directly for homologous sequences. Alternatively, vectors defining each of the proteins within an organism can be summed to provide a vector representation of the organism, which is then used to generate species trees. RESULTS: Using a large mitochondrial genome dataset, we have produced species trees that are largely in agreement with previously published trees based on the analysis of identical datasets using different methods. These trees also agree well with currently accepted phylogenetic theory. In principle, our method could be used to compare much larger bacterial or nuclear genomes in full molecular detail, ultimately allowing accurate gene and species relationships to be derived from a comprehensive comparison of complete genomes. In contrast to phylogenetic methods based on alignments, sequences that evolve by relative insertion or deletion would tend to remain recognizably similar.

Algorithms↗
PubMed2001

Enrichment of regulatory signals in conserved non-coding genomic sequence.

MOTIVATION: Whole genome shotgun sequencing strategies generate sequence data prior to the application of assembly methodologies that result in contiguous sequence. Sequence reads can be employed to indicate regions of conservation between closely related species for which only one genome has been assembled. Consequently, by using pairwise sequence alignments methods it is possible to identify novel, non-repetitive, conserved segments in non-coding sequence that exist between the assembled human genome and mouse whole genome shotgun sequencing fragments. Conserved non-coding regions identify potentially functional DNA that could be involved in transcriptional regulation. RESULTS: Local sequence alignment methods were applied employing mouse fragments and the assembled human genome. In addition, transcription factor binding sites were detected by aligning their corresponding positional weight matrices to the sequence regions. These methods were applied to a set of transcripts corresponding to 502 genes associated with a variety of different human diseases taken from the Online Mendelian Inheritance in Man database. Using statistical arguments we have shown that conserved non-coding segments contain an enrichment of transcription factor binding sites when compared to the sequence background in which the conserved segments are located. This enrichment of binding sites was not observed in coding sequence. Conserved non-coding segments are not extensively repeated in the genome and therefore their identification provides a rapid means of finding genes with related conserved regions, and consequently potentially related regulatory mechanism. Conserved segments in upstream regions are found to contain binding sites that are co-localized in a manner consistent with experimentally known transcription factor pairwise co-occurrences and afford the identification of novel co-occurring Transcription Factor (TF) pairs. This study provides a methodology and more evidence to suggest that conserved non-coding regions are biologically significant since they contain a statistical enrichment of regulatory signals and pairs of signals that enable the construction of regulatory models for human genes. CONTACT: samuel.levy@celera.com.

Algorithms↗
PubMed2003

A complexity reduction algorithm for analysis and annotation of large genomic sequences.

DNA is a universal language encrypted with biological instruction for life. In higher organisms, the genetic information is preserved predominantly in an organized exon/intron structure. When a gene is expressed, the exons are spliced together to form the transcript for protein synthesis. We have developed a complexity reduction algorithm for sequence analysis (CRASA) that enables direct alignment of cDNA sequences to the genome. This method features a progressive data structure in hierarchical orders to facilitate a fast and efficient search mechanism. CRASA implementation was tested with already annotated genomic sequences in two benchmark data sets and compared with 15 annotation programs (10 ab initio and 5 homology-based approaches) against the EST database. By the use of layered noise filters, the complexity of CRASA-matched data was reduced exponentially. The results from the benchmark tests showed that CRASA annotation excelled in both the sensitivity and specificity categories. When CRASA was applied to the analysis of human Chromosomes 21 and 22, an additional 83 potential genes were identified. With its large-scale processing capability, CRASA can be used as a robust tool for genome annotation with high accuracy by matching the EST sequences precisely to the genomic sequences.

Algorithms↗
PubMed2002

PASS2: a semi-automated database of protein alignments organised as structural superfamilies.

PASS2 is a nearly automated version of CAMPASS and contains sequence alignments of proteins grouped at the level of superfamilies. This database has been created to fall in correspondence with SCOP database (1.53 release) and currently consists of 110 multi-member superfamilies and 613 superfamilies corresponding to single members. In multi-member superfamilies, protein chains with no more than 25% sequence identity have been considered for the alignment and hence the database aims to address sequence alignments which represent 26 219 protein domains under the SCOP 1.53 release. Structure-based sequence alignments have been obtained by COMPARER and the initial equivalences are provided automatically from a MALIGN alignment and subsequently augmented using STAMP4.0. The final sequence alignments have been annotated for the structural features using JOY4.0. Several interesting links are provided to other related databases and genome sequence relatives. Availability of reliable sequence alignments of distantly related proteins, despite poor sequence identity and single-member superfamilies, permit better sampling of structures in libraries for fold recognition of new sequences and for the understanding of protein structure-function relationships of individual superfamilies. The database can be queried by keywords and also by sequence search, interfaced by PSI-BLAST methods. Structure-annotated sequence alignments and several structural accessory files can be retrieved for all the superfamilies including the user-input sequence. The database can be accessed from http://www.ncbs.res.in/%7Efaculty/mini/campass/pass.html.

Amino Acid Sequence↗
PubMed2005

Classifying genomic sequences by sequence feature analysis.

Traditional sequence analysis depends on sequence alignment. In this study, we analyzed various functional regions of the human genome based on sequence features, including word frequency, dinucleotide relative abundance, and base-base correlation. We analyzed the human chromosome 22 and classified the upstream, exon, intron, downstream, and intergenic regions by principal component analysis and discriminant analysis of these features. The results show that we could classify the functional regions of genome based on sequence feature and discriminant analysis.

Algorithms↗
PubMed1999

Genome signature comparisons among prokaryote, plasmid, and mitochondrial DNA.

Our basic observation is that each genome has a characteristic "signature" defined as the ratios between the observed dinucleotide frequencies and the frequencies expected if neighbors were chosen at random (dinucleotide relative abundances). The remarkable fact is that the signature is relatively constant throughout the genome; i.e. , the patterns and levels of dinucleotide relative abundances of every 50-kb segment of the genome are about the same. Comparison of the signatures of different genomes provides a measure of similarity which has the advantage that it looks at all the DNA of an organism and does not depend on the ability to align homologous sequences of specific genes. Genome signature comparisons show that plasmids, both specialized and broad-range, and their hosts have substantially compatible (similar) genome signatures. Mammalian mitochondrial (Mt) genomes are very similar, and animal and fungal Mt are generally moderately similar, but they diverge significantly from plant and protist Mt sets. Moreover, Mt genome signature differences between species parallel the corresponding nuclear genome signature differences, despite large differences between Mt and host nuclear signatures. In signature terms, we find that the archaea are not a coherent clade. For example, Sulfolobus and Halobacterium are extremely divergent. There is no consistent pattern of signature differences among thermophiles. More generally, grouping prokaryotes by environmental criteria (e.g., habitat propensities, osmolarity tolerance, chemical conditions) reveals no correlations in genome signature.

Animals↗
PubMed2004

Integration of the rat recombination and EST maps in the rat genomic sequence and comparative mapping analysis with the mouse genome.

Inbred strains of the laboratory rat are widely used for identifying genetic regions involved in the control of complex quantitative phenotypes of biomedical importance. The draft genomic sequence of the rat now provides essential information for annotating rat quantitative trait locus (QTL) maps. Following the survey of unique rat microsatellite (11,585 including 1648 new markers) and EST (10,067) markers currently available, we have incorporated a selection of 7952 rat EST sequences in an improved version of the integrated linkage-radiation hybrid map of the rat containing 2058 microsatellite markers which provided over 10,000 potential anchor points between rat QTL and the genomic sequence of the rat. A total of 996 genetic positions were resolved (avg. spacing 1.77 cM) in a single large intercross and anchored in the rat genomic sequence (avg. spacing 1.62 Mb). Comparative genome maps between rat and mouse were constructed by successful computational alignment of 6108 mapped rat ESTs in the mouse genome. The integration of rat linkage maps in the draft genomic sequence of the rat and that of other species represents an essential step for translating rat QTL intervals into human chromosomal targets.

Animals↗
PubMed2005

Human-zebrafish non-coding conserved elements act in vivo to regulate transcription.

Whole genome comparisons of distantly related species effectively predict biologically important sequences--core genes and cis-acting regulatory elements (REs)--but require experimentation to verify biological activity. To examine the efficacy of comparative genomics in identification of active REs from anonymous, non-coding (NC) sequences, we generated a novel alignment of the human and draft zebrafish genomes, and contrasted this set to existing human and fugu datasets. We tested the transcriptional regulatory potential of candidate sequences using two in vivo assays. Strict selection of non-genic elements which are deeply conserved in vertebrate evolution identifies 1744 core vertebrate REs in human and two fish genomes. We tested 16 elements in vivo for cis-acting gene regulatory properties using zebrafish transient transgenesis and found that 10 (63%) strongly modulate tissue-specific expression of a green fluorescent protein reporter vector. We also report a novel quantitative enhancer assay with potential for increased throughput based on normalized luciferase activity in vivo. This complementary system identified 11 (69%; including 9 of 10 GFP-confirmed elements) with cis-acting function. Together, these data support the utility of comparative genomics of distantly related vertebrate species to identify REs and provide a scaleable, in vivo quantitative assay to define functional activity of candidate REs.

Animals↗
PubMed2000

Conservation of DNA regulatory motifs and discovery of new motifs in microbial genomes.

Regulatory motifs can be found by local multiple alignment of upstream regions from coregulated sets of genes, or regulons. We searched for regulatory motifs using the program AlignACE together with a set of filters that helped us choose the motifs most likely to be biologically relevant in 17 complete microbial genomes. We searched the upstream regions of potentially coregulated genes grouped by three methods: (1) genes that make up functional pathways; (2) genes homologous to regulons from a well-studied species (Escherichia coli); and (3) groups of genes derived from conserved operons. This last group is based on the observation that genes making up homologous regulons in different species are often assorted into coregulated operons in different combinations. This allows partial reconstruction of regulons by looking at operon structure across several species. Unlike other methods for predicting regulons, this method does not depend on the availability of experimental data other than the genome sequence and the locations of genes. New, statistically significant motifs were found in the genome sequence of each organism using each grouping method. The most significant new motif was found upstream of genes in the methane-metabolism functional group in Methanobacterium thermoautotrophicum. We found that at least 27% of the known E. coli DNA-regulatory motifs are conserved in one or more distantly related eubacteria. We also observed significant motifs that differed from the E. coli motif in other organisms upstream of sets of genes homologous to known E. coli regulons, including Crp, LexA, and ArcA in Bacillus subtilis; four anaerobic regulons in Archaeoglobus fulgidus (NarL, NarP, Fnr, and ModE); and the PhoB, PurR, RpoH, and FhlA regulons in other archaebacterial species. We also used motif conservation to aid in finding new motifs by grouping upstream regions from closely related bacteria, thus increasing the number of instances of the motif in the sequence to be aligned. For example, by grouping upstream sequences from three archaebacterial species, we found a conserved motif that may regulate ferrous ion transport that was not found in individual genomes. Discovery of conserved motifs becomes easier as the number of closely related genome sequences increases.

Computational Biology↗