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David Landsman

Publications and source records attributed to David Landsman.

16 recordsLinked to original sources
PubMed2006

Database resources of the National Center for Biotechnology Information.

In addition to maintaining the GenBank nucleic acid sequence database, the National Center for Biotechnology Information (NCBI) provides analysis and retrieval resources for the data in GenBank and other biological data made available through NCBI's Web site. NCBI resources include Entrez, the Entrez Programming Utilities, My NCBI, PubMed, PubMed Central, Entrez Gene, the NCBI Taxonomy Browser, BLAST, BLAST Link(BLink), Electronic PCR, OrfFinder, Spidey, Splign, RefSeq, UniGene, HomoloGene, ProtEST, dbMHC, dbSNP, Cancer Chromosomes, Entrez Genome, Genome Project and related tools, the Trace and Assembly Archives, the Map Viewer, Model Maker, Evidence Viewer, Clusters of Orthologous Groups (COGs), Viral Genotyping Tools, Influenza Viral Resources, HIV-1/Human Protein Interaction Database, Gene Expression Omnibus (GEO), Entrez Probe, GENSAT, Online Mendelian Inheritance in Man (OMIM), Online Mendelian Inheritance in Animals (OMIA), the Molecular Modeling Database (MMDB), the Conserved Domain Database (CDD), the Conserved Domain Architecture Retrieval Tool (CDART) and the PubChem suite of small molecule databases. Augmenting many of the Web applications are custom implementations of the BLAST program optimized to search specialized data sets. These resources can be accessed through the NCBI home page at www.ncbi.nlm.nih.gov.

Animals↗
PubMed2006

Scanning sequences after Gibbs sampling to find multiple occurrences of functional elements.

BACKGROUND: Many DNA regulatory elements occur as multiple instances within a target promoter. Gibbs sampling programs for finding DNA regulatory elements de novo can be prohibitively slow in locating all instances of such an element in a sequence set. RESULTS: We describe an improvement to the A-GLAM computer program, which predicts regulatory elements within DNA sequences with Gibbs sampling. The improvement adds an optional "scanning step" after Gibbs sampling. Gibbs sampling produces a position specific scoring matrix (PSSM). The new scanning step resembles an iterative PSI-BLAST search based on the PSSM. First, it assigns an "individual score" to each subsequence of appropriate length within the input sequences using the initial PSSM. Second, it computes an E-value from each individual score, to assess the agreement between the corresponding subsequence and the PSSM. Third, it permits subsequences with E-values falling below a threshold to contribute to the underlying PSSM, which is then updated using the Bayesian calculus. A-GLAM iterates its scanning step to convergence, at which point no new subsequences contribute to the PSSM. After convergence, A-GLAM reports predicted regulatory elements within each sequence in order of increasing E-values, so users have a statistical evaluation of the predicted elements in a convenient presentation. Thus, although the Gibbs sampling step in A-GLAM finds at most one regulatory element per input sequence, the scanning step can now rapidly locate further instances of the element in each sequence. CONCLUSION: Datasets from experiments determining the binding sites of transcription factors were used to evaluate the improvement to A-GLAM. Typically, the datasets included several sequences containing multiple instances of a regulatory motif. The improvements to A-GLAM permitted it to predict the multiple instances.

Animals↗
PubMed2006

The Histone Database: a comprehensive resource for histones and histone fold-containing proteins.

The Histone Database is a curated and searchable collection of full-length sequences and structures of histones and nonhistone proteins containing histone-like folds, compiled from major public databases. Several new histone fold-containing proteins have been identified, including the huntingtin-interacting protein HYPM. Additionally, based on the recent crystal structure of the Son of Sevenless protein, an interpretation of the sequence analysis of the histone fold domain is presented. The database contains an updated collection of multiple sequence alignments for the four core histones (H2A, H2B, H3, and H4) and the linker histones (H1/H5) from a total of 975 organisms. The database also contains information on the human histone gene complement and provides links to three-dimensional structures of histone and histone fold-containing proteins. The Histone Database is a comprehensive bioinformatics resource for the study of structure and function of histones and histone fold-containing proteins. The database is available at http://research.nhgri.nih.gov/histones/.

Amino Acid Sequence↗
PubMed2006

Multiple independent evolutionary solutions to core histone gene regulation.

BACKGROUND: Core histone genes are periodically expressed along the cell cycle and peak during S phase. Core histone gene expression is deeply evolutionarily conserved from the yeast Saccharomyces cerevisiae to human. RESULTS: We evaluated the evolutionary dynamics of the specific regulatory mechanisms that give rise to the conserved histone regulatory phenotype. In contrast to the conservation of core histone gene expression patterns, the core histone regulatory machinery is highly divergent between species. There has been substantial evolutionary turnover of cis-regulatory sequence motifs along with the transcription factors that bind them. The regulatory mechanisms employed by members of the four core histone families are more similar within species than within gene families. The presence of species-specific histone regulatory mechanisms is opposite to what is seen at the protein sequence level. Core histone proteins are more similar within families, irrespective of their species of origin, than between families, which is consistent with the shared common ancestry of the members of individual histone families. Structure and sequence comparisons between histone families reveal that H2A and H2B form one related group whereas H3 and H4 form a distinct group, which is consistent with the nucleosome assembly dynamics. CONCLUSION: The dissonance between the evolutionary conservation of the core histone gene regulatory phenotypes and the divergence of their regulatory mechanisms indicates a highly dynamic mode of regulatory evolution. This distinct mode of regulatory evolution is probably facilitated by a solution space for promoter sequences, in terms of functionally viable cis-regulatory sites, that is substantially greater than that of protein sequences.

Base Sequence↗
PubMed2005

Alignments anchored on genomic landmarks can aid in the identification of regulatory elements.

MOTIVATION: The transcription start site (TSS) has been located for an increasing number of genes across several organisms. Statistical tests have shown that some cis-acting regulatory elements have positional preferences with respect to the TSS, but few strategies have emerged for locating elements by their positional preferences. This paper elaborates such a strategy. First, we align promoter regions without gaps, anchoring the alignment on each promoter's TSS. Second, we apply a novel word-specific mask. Third, we apply a clustering test related to gapless BLAST statistics. The test examines whether any specific word is placed unusually consistently with respect to the TSS. Finally, our program A-GLAM, an extension of the GLAM program, uses significant word positions as new 'anchors' to realign the sequences. A Gibbs sampling algorithm then locates putative cis-acting regulatory elements. Usually, Gibbs sampling requires a preliminary masking step, to avoid convergence onto a dominant but uninteresting signal from a DNA repeat. However, since the positional anchors focus A-GLAM on the motif of interest, masking DNA repeats during Gibbs sampling becomes unnecessary. RESULTS: In a set of human DNA sequences with experimentally characterized TSSs, the placement of 791 octonucleotide words was unusually consistent (multiple test corrected P < 0.05). Alignments anchored on these words sometimes located statistically significant motifs inaccessible to GLAM or AlignACE. AVAILABILITY: The A-GLAM program and a list of statistically significant words are available at ftp://ftp.ncbi.nih.gov/pub/spouge/papers/archive/AGLAM/.

Amino Acid Motifs↗
PubMed2005

Global regulation by the yeast Spt10 protein is mediated through chromatin structure and the histone upstream activating sequence elements.

The yeast SPT10 gene encodes a putative histone acetyltransferase (HAT) implicated as a global transcription regulator acting through basal promoters. Here we address the mechanism of this global regulation. Although microarray analysis confirmed that Spt10p is a global regulator, Spt10p was not detected at any of the most strongly affected genes in vivo. In contrast, the presence of Spt10p at the core histone gene promoters in vivo was confirmed. Since Spt10p activates the core histone genes, a shortage of histones could occur in spt10Delta cells, resulting in defective chromatin structure and a consequent activation of basal promoters. Consistent with this hypothesis, the spt10Delta phenotype can be rescued by extra copies of the histone genes and chromatin is poorly assembled in spt10Delta cells, as shown by irregular nucleosome spacing and reduced negative supercoiling of the endogenous 2mum plasmid. Furthermore, Spt10p binds specifically and highly cooperatively to pairs of upstream activating sequence elements in the core histone promoters [consensus sequence, (G/A)TTCCN(6)TTCNC], consistent with a direct role in histone gene regulation. No other high-affinity sites are predicted in the yeast genome. Thus, Spt10p is a sequence-specific activator of the histone genes, possessing a DNA-binding domain fused to a likely HAT domain.

Base Sequence↗
PubMed2005

Histone structure and nucleosome stability.

Histone proteins play essential structural and functional roles in the transition between active and inactive chromatin states. Although histones have a high degree of conservation due to constraints to maintain the overall structure of the nucleosomal octameric core, variants have evolved to assume diverse roles in gene regulation and epigenetic silencing. Histone variants, post-translational modifications and interactions with chromatin remodeling complexes influence DNA replication, transcription, repair and recombination. The authors review recent findings on the structure of chromatin that confirm previous interparticle interactions observed in crystal structures.

Animals↗
PubMed2004

High-resolution genome-wide mapping of histone modifications.

The expression patterns of eukaryotic genomes are controlled by their chromatin structure, consisting of nucleosome subunits in which DNA of approximately 146 bp is wrapped around a core of 8 histone molecules. Post-translational histone modifications play an essential role in modifying chromatin structure. Here we apply a combination of SAGE and chromatin immunoprecipitation (ChIP) protocols to determine the distribution of hyperacetylated histones H3 and H4 in the Saccharomyces cerevisiae genome. We call this approach genome-wide mapping technique (GMAT). Using GMAT, we find that the highest acetylation levels are detected in the 5' end of a gene's coding region, but not in the promoter. Furthermore, we show that the histone acetyltransferase, GCN5p, regulates H3 acetylation in the promoter and 5' end of the coding regions. These findings indicate that GMAT should find valuable applications in mapping target sites of chromatin-modifying enzymes.

Chromatin↗
PubMed2004

Statistical analysis of over-represented words in human promoter sequences.

The identification and characterization of regulatory sequence elements in the proximal promoter region of a gene can be facilitated by knowing the precise location of the transcriptional start site (TSS). Using known TSSs from over 5700 different human full-length cDNAs, this study extracted a set of 4737 distinct putative promoter regions (PPRs) from the human genome. Each PPR consisted of nucleotides from -2000 to +1000 bp, relative to the corresponding TSS. Since many regulatory regions contain short, highly conserved strings of less than 10 nucleotides, we counted eight-letter words within the PPRs, using z-scores and other related statistics to evaluate their over- and under-representation. Several over-represented eight-letter words have known biological functions described in the eukaryotic transcription factor database TRANSFAC; however, many did not. Besides calculating a P-value with the standard normal approximation associated with z-scores, we used two extra statistical controls to evaluate the significance of over-represented words. These controls have important implications for evaluating over- and under-represented words with z-scores.

Base Sequence↗
PubMed2003

Characterization of sequence variability in nucleosome core histone folds.

The three-helix, approximately 65-residue histone fold domain is the most structurally conserved part of the core histones H2A, H2B, H3, and H4. However, it evinces a notable degree of sequence variation within and between histone classes. We used two approaches to characterize sequence variation in these histone folds, toward elucidating their structure/function relationships and evolution. On the one hand we asked how much of the sequence variation seen in structure-based alignments of the folds maintains physicochemical properties at a position, and on the other, whether conservation correlates to structural importance, as measured by the number of residue-to-residue contacts a position makes. Strong physicochemical conservation or correlation of conservation to contacts would support the idea that functional constraints, rather than genetic drift, determines the observed range of variants at a given position. We used an 11-state table of physicochemical properties to classify each position in the core histone fold (CHF) alignments, and a public website (http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/valdar/scorecons_server.pl) to score conservation. We found that, depending on histone class, from 38 to 77% of CHF positions are maximally conserved physicochemically, and that for H2B, H3, and H4 the degree to which a position is conserved correlates positively to the number of contacts made by the residue at that position in the crystal structure of the nucleosome core particle. We also examined the correlation between conservation and the type of contact (e.g., inter- or intrachain, histone-histone, or histone-DNA, etc.). For H2B, H3, and H4 we found a positive correlation between conservation and number of interchain protein contacts. No such correlation or statistical significance was found for DNA or intrachain contacts. This suggests that variations in the CHF sequences could be functionally constrained by requirements to make sufficient interchain histone contacts. We also suggest that inventory of histone residue variants can augment functional studies of histones. An example is presented for histone H3.

Binding Sites↗
PubMed2003

Identifying related L1 retrotransposons by analyzing 3' transduced sequences.

BACKGROUND: A large fraction of the human genome is attributable to L1 retrotransposon sequences. Not only do L1s themselves make up a significant portion of the genome, but L1-encoded proteins are thought to be responsible for the transposition of other repetitive elements and processed pseudogenes. In addition, L1s can mobilize non-L1, 3'-flanking DNA in a process called 3' transduction. Using computational methods, we collected DNA sequences from the human genome for which we have high confidence of their mobilization through L1-mediated 3' transduction. RESULTS: The precursors of L1s with transduced sequence can often be identified, allowing us to reconstruct L1 element families in which a single parent L1 element begot many progeny L1s. Of the L1s exhibiting a sequence structure consistent with 3' transduction (L1 with transduction-derived sequence, L1-TD), the vast majority were located in duplicated regions of the genome and thus did not necessarily represent unique insertion events. Of the remaining L1-TDs, some lack a clear polyadenylation signal, but the alignment between the parent-progeny sequences nevertheless ends in an A-rich tract of DNA. CONCLUSIONS: Sequence data suggest that during the integration into the genome of RNA representing an L1-TD, reverse transcription may be primed internally at A-rich sequences that lie downstream of the L1 3' untranslated region. The occurrence of L1-mediated transduction in the human genome may be less frequent than previously thought, and an accurate estimate is confounded by the frequent occurrence of segmental genomic duplications.

Base Sequence↗
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↗
PubMed2002

Molecular archeology of L1 insertions in the human genome.

BACKGROUND: As the rough draft of the human genome sequence nears a finished product and other genome-sequencing projects accumulate sequence data exponentially, bioinformatics is emerging as an important tool for studies of transposon biology. In particular, L1 elements exhibit a variety of sequence structures after insertion into the human genome that are amenable to computational analysis. We carried out a detailed analysis of the anatomy and distribution of L1 elements in the human genome using a new computer program, TSDfinder, designed to identify transposon boundaries precisely. RESULTS: Structural variants of L1 elements shared similar trends in the length and quality of their target site duplications (TSDs) and poly(A) tails. Furthermore, we found no correlation between the composition and genomic location of the pre-insertion locus and the resulting anatomy of the L1 insertion. We verified that L1 insertions with TSDs have the 5'-TTAAAA-3' cleavage site associated with L1 endonuclease activity. In addition, the second target DNA cut required for L1 insertion weakly matches the consensus pattern TTAAAA. On the other hand, the L1-internal breakpoints of deleted and inverted L1 elements do not resemble L1 endonuclease cleavage sites. Finally, the genome sequence data indicate that whereas singly inverted elements are common, doubly inverted elements are almost never found. CONCLUSIONS: The sequence data give no indication that the creation of L1 structural variants depends on characteristics of the insertion locus. In addition, the formation of 5' truncated and 5' inverted L1s are probably not due to the action of the L1 endonuclease.

Algorithms↗
PubMed2002

The Histone Database.

Histone proteins are often noted for their high degree of sequence conservation. It is less often recognized that the histones are a heterogeneous protein family. Furthermore, several classes of non-histone proteins containing the histone fold motif exist. Novel histone and histone fold protein sequences continue to be added to public databases every year. The Histone Database (http://genome.nhgri.nih.gov/histones/) is a searchable, periodically updated collection of histone fold-containing sequences derived from sequence-similarity searches of public databases. Sequence sets are presented in redundant and non-redundant FASTA form, hotlinked to GenBank sequence files. Partial sequences are also now included in the database, which has considerably augmented its taxonomic coverage. Annotated alignments of full-length non-redundant sets of sequences are now available in both web-viewable (HTML) and downloadable (PDF) formats. The database also provides summaries of current information on solved histone fold structures, post-translational modifications of histones, and the human histone gene complement.

Amino Acid Motifs↗
PubMed2002

B-ZIP proteins encoded by the Drosophila genome: evaluation of potential dimerization partners.

The basic region-leucine zipper (B-ZIP) (bZIP) protein motif dimerizes to bind specific DNA sequences. We have identified 27 B-ZIP proteins in the recently sequenced Drosophila melanogaster genome. The dimerization specificity of these 27 B-ZIP proteins was evaluated using two structural criteria: (1) the presence of attractive or repulsive interhelical g<-->e' electrostatic interactions and (2) the presence of polar or charged amino acids in the 'a' and 'd' positions of the hydrophobic interface. None of the B-ZIP proteins contain only aliphatic amino acids in the'a' and 'd' position. Only six of the Drosophila B-ZIP proteins contain a "canonical" hydrophobic interface like the yeast GCN4, and the mammalian JUN, ATF2, CREB, C/EBP, and PAR leucine zippers, characterized by asparagine in the second 'a' position. Twelve leucine zippers contain polar amino acids in the first, third, and fourth 'a' positions. Circular dichroism spectroscopy, used to monitor thermal denaturations of a heterodimerizing leucine zipper system containing either valine (V) or asparagine (N) in the 'a' position, indicates that the V-N interaction is 2.3 kcal/mole less stable than an N-N interaction and 5.3 kcal/mole less stable than a V-V interaction. Thus, we propose that the presence of polar amino acids in novel positions of the 'a' position of Drosophila B-ZIP proteins has led to leucine zippers that homodimerize rather than heterodimerize.

Amino Acid Sequence↗