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PubMed2006

Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals.

The recent hapmap effort has placed focus on the application of genome-wide SNP analysis to assess the contribution of genetic variability, particularly SNPs, to traits such as disease. Here, we describe the utility of genome-wide SNP analysis in the direct detection of extended homozygosity and structural genomic variation. We use this approach to assess the frequency of genomic alterations resulting from the lymphoblast immortalization and culture processes commonly used in cell repositories. We have assayed 408 804 SNPs in 276 DNA samples extracted from Epstein-Barr virus immortalized cell lines, which were derived from lymphocytes of elderly neurologically normal subjects. These data reveal extended homozygosity (contiguous tracts >5 Mb) in 9.5% (26/272) and 340 structural genomic alterations in 182 (66.9%) DNA samples assessed, 66% of which did not overlap with previously described structural variations. Examination of DNA extracted directly from the blood of 30 of these subjects confirmed all examined instances of extended homozygosity (6/6), 75% of structural genomic alteration <5 Mb in size (12/16) and 13% (1/8) of structural genomic alteration >5 Mb in size. These data suggest that structural genomic variation is a common phenomenon in the general population. While a proportion of this variability may be caused or its relative abundance altered by the immortalization and clonal process this will have only a minor effect on genotype and allele frequencies in a large cohort. It is likely that this powerful methodology will augment existing techniques in the identification of chromosomal abnormalities.

Aged↗
PubMed2001

Genomic structure of the gene for mouse germ-cell nuclear factor (GCNF). II. Comparison with the genomic structure of the human GCNF gene.

BACKGROUND: Germ-cell nuclear factor (GCNF, NR6AI) is an orphan nuclear receptor. Its expression pattern suggests it functions during embryogenesis, in the placenta and in germ-cell development. Mouse GCNF cDNA codes for a protein of 495 amino acids, whereas the four reported human cDNA variants code for proteins of 454 to 480 amino acids. Apart from this size difference, there is sequence conservation of up to 98.7%. To elucidate the genomic structure that gives rise to the different human GCNF mRNAs, the sequence information of the human GCNF locus is compared to the previously reported structure of the mouse locus. RESULTS: The genomic structures of the mouse and human GCNF genes are highly conserved. The comparison reveals that the shorter human protein results from skipping the 45 base-pair third exon. Three different human isoforms - GCNF-1, GCNF-2a and GCNF-2b - are generated by differential usage of alternative splice acceptor sites of the fourth and the seventh exon. CONCLUSION: By homology with the mouse gene, 11 GCNF coding exons can be defined on human chromosome 9. All human GCNF cDNAs identified so far are, however, derived from mRNAs generated by splicing the fourth to the second exon. Although the genomic sequence is highly conserved, the analysis suggests that alternative splicing generates a higher complexity of human GCNF isoforms compared with the situation in the mouse.

Alternative Splicing↗
PubMed2006

RAPD analysis of jasmine rice-specific genomic structure.

Total genomic DNA was extracted from 29 samples of rice seed, including jasmine rice Oryza sativa L. subsp indica 'KDML105', 'KDML105'-derived varieties, nonaromatic Thailand rice, and japonica rice. Polymorphism in RAPD profiles was analyzed to explore the genomic structure specific to jasmine rice. The degree of band sharing was used to evaluate genetic distance between varieties and to construct a phylogenetic tree. RD15, CNTLR85033, and CNT87040 were found to be closest to 'KDML105', which was consistent with the true relation among them. Four RAPD fragments that cooperatively distinguished jasmine rice from others were cloned and sequenced. PCR amplification using pairs of primers designed specifically further confirmed the credibility of the RAPD result. Comparison through Genbank revealed that a 454 bp RAPD band was similar to the first intron of a putative Cf2/Cf5 disease resistance gene and a 1,107 bp RAPD band similar to a wall-associated kinase (wak) gene sequence.

Crosses, Genetic↗
PubMed1999

Making High-level Queries on Diverse Genome Data: A Structured Genome Document Database System Based on GXML and GQL.

Complete DNA sequences (genomes) and associated data are being made available worldwide at an astonishing rate. Through computer analysis of such data, molecular biologists hope to gain an overall understanding of the genome, such as by predicting large-scale gene networks. However, this is difficult because diverse genome data are scattered across many highly heterogeneous databases, and because existing database systems lack the facilities to expose and analyze functional relationships among the data. To address these problems, we propose a new type of genome database system. Since a genome can be thought of intuitively as a kind of 'document', our system uses a structured document language based on XML to effectively represent genomes and associated data. The information-rich structures of the genome documents help cope with data diversity and heterogeneity. A powerful query language is introduced that exposes important biological relationships among the genome data. We have obtained favorable results from several experiments, demonstrating the usefulness of our method in building a top-down view of genome functionality.

Journal Article↗
PubMedDate not supplied

The Paris-Sud yeast structural genomics pilot-project: from structure to function.

We present here the outlines and results from our yeast structural genomics (YSG) pilot-project. A lab-scale platform for the systematic production and structure determination is presented. In order to validate this approach, 250 non-membrane proteins of unknown structure were targeted. Strategies and final statistics are evaluated. We finally discuss the opportunity of structural genomics programs to contribute to functional biochemical annotation.

Genomics↗
PubMed2005

Progress of structural genomics initiatives: an analysis of solved target structures.

The explosion in gene sequence data and technological breakthroughs in protein structure determination inspired the launch of structural genomics (SG) initiatives. An often stated goal of structural genomics is the high-throughput structural characterisation of all protein sequence families, with the long-term hope of significantly impacting on the life sciences, biotechnology and drug discovery. Here, we present a comprehensive analysis of solved SG targets to assess progress of these initiatives. Eleven consortia have contributed 316 non-redundant entries and 323 protein chains to the Protein Data Bank (PDB), and 459 and 393 domains to the CATH and SCOP structure classifications, respectively. The quality and size of these proteins are comparable to those solved in traditional structural biology and, despite huge scope for duplicated efforts, only 14% of targets have a close homologue (>/=30% sequence identity) solved by another consortium. Analysis of CATH and SCOP revealed the significant contribution that structural genomics is making to the coverage of superfamilies and folds. A total of 67% of SG domains in CATH are unique, lacking an already characterised close homologue in the PDB, whereas only 21% of non-SG domains are unique. For 29% of domains, structure determination revealed a remote evolutionary relationship not apparent from sequence, and 19% and 11% contributed new superfamilies and folds. The secondary structure class, fold and superfamily distributions of this dataset reflect those of the genomes. The domains fall into 172 different folds and 259 superfamilies in CATH but the distribution is highly skewed. The most populous of these are those that recur most frequently in the genomes. Whilst 11% of superfamilies are bacteria-specific, most are common to all three superkingdoms of life and together the 316 PDB entries have provided new and reliable homology models for 9287 non-redundant gene sequences in 206 completely sequenced genomes. From the perspective of this analysis, it appears that structural genomics is on track to be a success, and it is hoped that this work will inform future directions of the field.

Animals↗
PubMed2005

Protein production and crystallization at the joint center for structural genomics.

By definition, structural genomics centers must be able to address a large number of diverse protein targets. The methods developed should permit parallel and cost-effective processing while allowing for the diverse nature of proteins. Our approach to this problem is a multi-tiered effort where targets are characterized and categorized by behavior and processed in parallel by appropriate methods. The Joint Center for Structural Genomics (JCSG) has applied this tactic to create a fully integrated and scaleable structure determination pipeline. Highlights of the development of the current pipeline for protein production and crystallization are presented here.

Crystallization↗
PubMed2026

Uchimata: a toolkit for visualization of 3D genome structures on the web and in computational notebooks.

SUMMARY: Uchimata is a toolkit for visualization of 3D structures of genomes. It consists of two packages: a Javascript library facilitating the rendering of 3D models of genomes, and a Python widget for visualization in Jupyter Notebooks. Main features include an expressive way to specify visual encodings, and filtering of 3D genome structures based on genomic semantics and spatial aspects. Uchimata is designed to be highly integratable with biological tooling available in Python. AVAILABILITY AND IMPLEMENTATION: Uchimata is released under the MIT License. The Javascript library is available on NPM, while the widget is available as a Python package hosted on PyPI. The source code for both is available publicly on Github (https://github.com/hms-dbmi/uchimata and https://github.com/hms-dbmi/uchimata-py) and Zenodo (https://doi.org/10.5281/zenodo.17831959 and https://doi.org/10.5281/zenodo.17832045). The documentation with examples is hosted at https://hms-dbmi.github.io/uchimata/.

Software↗
PubMed2025

Uchimata: a toolkit for visualization of 3D genome structures on the web and in computational notebooks.

SUMMARY: Uchimata is a toolkit for visualization of 3D structures of genomes. It consists of two packages: a Javascript library facilitating the rendering of 3D models of genomes, and a Python widget for visualization in Jupyter Notebooks. Main features include an expressive way to specify visual encodings, and filtering of 3D genome structures based on genomic semantics and spatial aspects. Uchimata is designed to be highly integratable with biological tooling available in Python. AVAILABILITY AND IMPLEMENTATION: Uchimata is released under the MIT License. The Javascript library is available on NPM, while the widget is available as a Python package hosted on PyPI. The source code for both is available publicly on Github (https://github.com/hms-dbmi/uchimata and https://github.com/hms-dbmi/uchimata-py). The documentation with examples is hosted at https://hms-dbmi.github.io/uchimata/. CONTACT: david_kouril@hms.harvard.edu or nils@hms.harvard.edu.

Journal Article↗
PubMed2004

Predicted role for the archease protein family based on structural and sequence analysis of TM1083 and MTH1598, two proteins structurally characterized through structural genomics efforts.

Recently, the structures of two proteins belonging to the archease family, TM1083 from Thermotoga maritima and MTH1598 from Methanobacterium thermoautotrophicum, have been solved independently by two Protein Structure Initiative structural genomics pilot centers using X-ray crystallography and NMR, respectively. The archease protein family is a good example of one of the paradoxes of structural genomics: Approximately one third of protein structures produced by structural genomics centers have no known function and are still annotated as "hypothetical proteins" in the Protein Data Bank. In the case of archeases, despite the existence of two protein structures and abundant sequence information, there is still no function assigned to this protein family. Here, our group predicts, based on structural similarity, sequence conservation, and gene context analyses, that members of this protein family might function as chaperones or modulators of proteins involved in DNA/RNA processing. The conservation of genomic context for this protein family is constant from Archaea and Bacteria to humans, and suggests that unannotated open reading frames contiguous to them could be novel RNA/DNA binding proteins.

Amino Acid Motifs↗
PubMed2004

Automation of protein purification for structural genomics.

A critical issue in structural genomics, and in structural biology in general, is the availability of high-quality samples. The additional challenge in structural genomics is the need to produce high numbers of proteins with low sequence similarities and poorly characterized or unknown properties. 'Structural-biology-grade' proteins must be generated in a quantity and quality suitable for structure determination experiments using X-ray crystallography or nuclear magnetic resonance (NMR). The choice of protein purification and handling procedures plays a critical role in obtaining high-quality protein samples. The purification procedure must yield a homogeneous protein and must be highly reproducible in order to supply milligram quantities of protein and/or its derivative containing marker atom(s). At the Midwest Center for Structural Genomics we have developed protocols for high-throughput protein purification. These protocols have been implemented on AKTA EXPLORER 3D and AKTA FPLC 3D workstations capable of performing multidimensional chromatography. The automated chromatography has been successfully applied to many soluble proteins of microbial origin. Various MCSG purification strategies, their implementation, and their success rates are discussed in this paper.

Automation↗
PubMed2004

The status of structural genomics defined through the analysis of current targets and structures.

Structural genomics--large-scale macromolecular 3-dimenional structure determination--is unique in that major participants report scientific progress on a weekly basis. The target database (TargetDB) maintained by the Protein Data Bank (http://targetdb.pdb.org) reports this progress through the status of each protein sequence (target) under consideration by the major structural genomics centers worldwide. Hence, TargetDB provides a unique opportunity to analyze the potential impact that this major initiative provides to scientists interested in the sequence-structure-function-disease paradigm. Here we report such an analysis with a focus on: (i) temporal characteristics--how is the project doing and what can we expect in the future? (ii) target characteristics--what are the predicted functions of the proteins targeted by structural genomics and how biased is the target set when compared to the PDB and to predictions across complete genomes? (iii) structures solved--what are the characteristics of structures solved thus far and what do they contribute? The analysis required a more extensive database of structure predictions using different methods integrated with data from other sources. This database, associated tools and related data sources are available from http://spam.sdsc.edu.

Computational Biology↗
PubMed2001

Global efforts in structural genomics.

A worldwide initiative in structural genomics aims to capitalize on the recent successes of the genome projects. Substantial new investments in structural genomics in the past 2 years indicate the high level of support for these international efforts. Already, enormous progress has been made on high-throughput methodologies and technologies that will speed up macromolecular structure determinations. Recent international meetings have resulted in the formation of an International Structural Genomics Organization to formulate policy and foster cooperation between the public and private efforts.

Animals↗
PubMed2005

Implications of structural genomics target selection strategies: Pfam5000, whole genome, and random approaches.

Structural genomics is an international effort to determine the three-dimensional shapes of all important biological macromolecules, with a primary focus on proteins. Target proteins should be selected according to a strategy that is medically and biologically relevant, of good value, and tractable. As an option to consider, we present the "Pfam5000" strategy, which involves selecting the 5000 most important families from the Pfam database as sources for targets. We compare the Pfam5000 strategy to several other proposed strategies that would require similar numbers of targets. These strategies include complete solution of several small to moderately sized bacterial proteomes, partial coverage of the human proteome, and random selection of approximately 5000 targets from sequenced genomes. We measure the impact that successful implementation of these strategies would have upon structural interpretation of the proteins in Swiss-Prot, TrEMBL, and 131 complete proteomes (including 10 of eukaryotes) from the Proteome Analysis database at the European Bioinformatics Institute (EBI). Solving the structures of proteins from the 5000 largest Pfam families would allow accurate fold assignment for approximately 68% of all prokaryotic proteins (covering 59% of residues) and 61% of eukaryotic proteins (40% of residues). More fine-grained coverage that would allow accurate modeling of these proteins would require an order of magnitude more targets. The Pfam5000 strategy may be modified in several ways, for example, to focus on larger families, bacterial sequences, or eukaryotic sequences; as long as secondary consideration is given to large families within Pfam, coverage results vary only slightly. In contrast, focusing structural genomics on a single tractable genome would have only a limited impact in structural knowledge of other proteomes: A significant fraction (about 30-40% of the proteins and 40-60% of the residues) of each proteome is classified in small families, which may have little overlap with other species of interest. Random selection of targets from one or more genomes is similar to the Pfam5000 strategy in that proteins from larger families are more likely to be chosen, but substantial effort would be spent on small families.

Animals↗
PubMed2006

Iterative ACORN as a high throughput tool in structural genomics.

High throughput macromolecular structure determination is very essential in structural genomics as the available number of sequence information far exceeds the number of available 3D structures. ACORN, a freely available resource in the CCP4 suite of programs is a comprehensive and efficient program for phasing in the determination of protein structures, when atomic resolution data are available. ACORN with the automatic model-building program ARP/wARP and refinement program REFMAC is a suitable combination for the high throughput structural genomics. ACORN can also be run with secondary structural elements like helices and sheets as inputs with high resolution data. In situations, where ACORN phasing is not sufficient for building the protein model, the fragments (incomplete model/dummy atoms) can again be used as a starting input. Iterative ACORN is proved to work efficiently in the subsequent model building stages in congerin (PDB-ID: lis3) and catalase (PDB-ID: 1gwe) for which models are available.

Animals↗
PubMed2002

SCOP database in 2002: refinements accommodate structural genomics.

The SCOP (Structural Classification of Proteins) database is a comprehensive ordering of all proteins of known structure, according to their evolutionary and structural relationships. Protein domains in SCOP are grouped into species and hierarchically classified into families, superfamilies, folds and classes. Recently, we introduced a new set of features with the aim of standardizing access to the database, and providing a solid basis to manage the increasing number of experimental structures expected from structural genomics projects. These features include: a new set of identifiers, which uniquely identify each entry in the hierarchy; a compact representation of protein domain classification; a new set of parseable files, which fully describe all domains in SCOP and the hierarchy itself. These new features are reflected in the ASTRAL compendium. The SCOP search engine has also been updated, and a set of links to external resources added at the level of domain entries. SCOP can be accessed at http://scop.mrc-lmb.cam.ac.uk/scop.

Animals↗
PubMedDate not supplied

Genome structure of spirochetes.

The genome structures of several pathogenic spirochetes have recently been determined. The genomes of Borrelia species consist of a linear chromosome of approximately one million base pairs (Mb) and various linear and circular plasmids. Analysis of restriction fragment length polymorphisms and 16S ribosomal RNA sequence data indicate the division of Borrelia burgdorferi into at least three distinct genetic groups. Leptospira interrogans has a circular chromosome 5 Mb in size and a 0.35 Mb extrachromosomal element. Repetitive sequence elements similar to insertion sequences have been identified in the Leptospira interrogans genome. The chromosome of Treponema pallidum subsp. pallidum is circular and has a size of approximately one Mb. Genetic studies conducted to date indicate that B. burgdorferi and L. interrogans have a high degree of genetic diversity, whereas remarkably few genetic differences have been observed among the pathogenic Treponema. Knowledge of the genomic structure of these organisms will serve as a basis for future genetic studies.

Borrelia burgdorferi Group↗