Biomedical subjects

Genomics

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PubMed2005

Marine genomics: a clearing-house for genomic and transcriptomic data of marine organisms.

BACKGROUND: The Marine Genomics project is a functional genomics initiative developed to provide a pipeline for the curation of Expressed Sequence Tags (ESTs) and gene expression microarray data for marine organisms. It provides a unique clearing-house for marine specific EST and microarray data and is currently available at http://www.marinegenomics.org. DESCRIPTION: The Marine Genomics pipeline automates the processing, maintenance, storage and analysis of EST and microarray data for an increasing number of marine species. It currently contains 19 species databases (over 46,000 EST sequences) that are maintained by registered users from local and remote locations in Europe and South America in addition to the USA. A collection of analysis tools are implemented. These include a pipeline upload tool for EST FASTA file, sequence trace file and microarray data, an annotative text search, automated sequence trimming, sequence quality control (QA/QC) editing, sequence BLAST capabilities and a tool for interactive submission to GenBank. Another feature of this resource is the integration with a scientific computing analysis environment implemented by MATLAB. CONCLUSION: The conglomeration of multiple marine organisms with integrated analysis tools enables users to focus on the comprehensive descriptions of transcriptomic responses to typical marine stresses. This cross species data comparison and integration enables users to contain their research within a marine-oriented data management and analysis environment.

Animals↗

PubMed2006

Genome-wide identification of peroxisome proliferator response elements using integrated computational genomics.

Peroxisome proliferator-activated receptor (PPAR) agonists are currently used therapeutically in humans, even though many of their direct gene targets are unknown. Because PPARs can directly regulate gene expression through peroxisome proliferator response elements (PPREs), we pursued the computational prediction of PPREs on a genome-wide scale. Contrary to current hypotheses, PPREs are not isotype-specific, nor do flanking nucleotides confer additional information. However, a position weight matrix-based search for PPREs within upstream conserved elements yielded sufficient selectivity for a genome-wide search. Additionally, a novel motif occurring with greater prevalence than PPREs was revealed. Microarray and gene ontology analyses further validated our search technique and provided new functional clusters of genes that were not previously known to be directly regulated by PPARs (e.g., chromatin remodeling, DNA damage response, Wnt, and mitogen-activated protein kinase signaling). This first genome-wide library of high-confidence predicted PPAR target genes will be a valuable resource to PPAR biologists.

Animals↗

PubMed2003

The human genome and comparative genomics: understanding human evolution, biology, and medicine.

The entire 2.9-billion-letter sequence (nucleotide base pairs) of the human genome is available as a resource for scientific discovery. Some of the findings from the completion of the human genome were expected, confirming knowledge anticipated by many years of research and analysis in both human and comparative genetics. Other findings were not expected. In either case, the availability of the human genome is likely to have significant implications on basic research, clinical investigation, and ultimately the practice of medicine.

Biological Evolution↗

PubMed2002

A whole-genome linkage scan suggests several genomic regions potentially containing QTLs underlying the variation of stature.

Human height is a complex trait under the control of both genetic and environment factors. In order to identify genomic regions underlying the variation of stature, we performed a whole-genome linkage analysis on a sample of 53 human pedigrees containing 1,249 sib pairs, 1,098 grandparent-grandchildren pairs, 1,993 avuncular pairs, and 1,172 first-cousin pairs. Several genomic regions were suggested by our study to be linked with human height variation. These regions include 5q31 at 144 cM from pter on chromosome 5 (with a maximum LOD score of 2.14 in multipoint linkage analyses), Xp22 at the marker DXS1060, and Xq25 at DXS1001 on the X chromosome (with LOD scores of 1.95 and 1.91, respectively, in two-point linkage analyses). Noticeably, Xp22 happens to be the very region where a newly identified gene underlying idiopathic short stature, SHOX, maps. Based on our findings, further confirmation and fine-mapping studies are to be pursued on expanded samples and/or with denser markers for eventual identification of major functional genes involved in human height variation.

Body Height↗

PubMed2005

Construction and application of a full-coverage, high-resolution, human chromosome 8q genomic microarray for comparative genomic hybridization.

BACKGROUND: Array-based comparative genomic hybridization (aCGH) enables genome-wide quantitative delineation of genomic imbalances. A high-resolution contig array was developed specifically for chromosome 8q because this chromosome arm is frequently altered in many human cancers. METHODS: A minimal tiling path contig of 702 8q-specific bacterial artificial chromosome (BAC) clones was generated with a novel computational tool (BAC Contig Assembler). BAC clones were amplified by degenerative oligonucleotide primer (DOP) polymerase chain reaction and subsequently printed onto glass slides. For validation of the array DNA samples of gastroesophageal and prostate cancer cell lines, and chronic myeloid leukemia specimens were used, which were previously characterized by multicolor fluorescence in situ hybridization and conventional CGH. RESULTS: Single and double copy gains were confidently demonstrated with the 8q array. Single copy loss and high-level amplifications were accurately detected and confirmed by bicolor fluorescence in situ hybridization experiments. The 8q array was further tested with paraffin-embedded prostate cancer specimens. In these archival specimens, the copy number changes were confirmed. In fresh and archival samples, additional alterations were disclosed. In comparison with conventional CGH, the resolution of the detected changes was much improved, which was demonstrated by an amplicon of 0.7 Mb and a deletion of 0.6 Mb, both spanned by only six BAC clones. CONCLUSIONS: A comprehensive array is presented, which provides a high-resolution method for mapping copy number alterations on chromosome 8q.

Adenocarcinoma↗

PubMed2026

Pleomorphic Liposarcoma: Comprehensive Genomic Analysis of 39 Cases With Comparison to Other Genomically Complex Sarcomas.

Pleomorphic liposarcoma (PLPS) is an aggressive high-grade sarcoma that often shows diverse morphological features and can mimic high-grade undifferentiated pleomorphic sarcoma (UPS)/spindle cell sarcoma or myxofibrosarcoma (MFS), especially when pleomorphic lipoblasts are sparse. The molecular profile of PLPS is distinct from well differentiated/dedifferentiated liposarcoma and myxoid liposarcoma. In this study, we investigate 39 cases of PLPS by comprehensive genomic profiling, occurring in 32 patients with available molecular data. Cases were reviewed and morphologic parameters-lipoblastic component, UPS-like, and MFS-like areas were estimated. The genomic findings were collected and compared to UPS and MFS groups studied using the same platform. The cohort included 15 females and 17 males, with a median age of 56.5 (range, 34-78). The lower extremity (n = 17) was the most common site involved, followed by upper extremity (n = 5) and pelvis (n = 5). UPS-like and MFS-like patterns were the most common morphologic variants, ranging from 15% to 95% and 20% to 90%, respectively. TP53 (87%) and RB1 (51%) mutations and copy number alterations were the most common alterations seen, followed by ATRX (36%). Compared to UPS and MFS, TP53 and RB1 gene alterations were significantly more common in PLPS. Conversely, CDKN2A/B deletions were infrequent in PLPS. Survival analysis showed that MYC amplification was associated with significantly shorter overall survival in PLPS. Among histologic variants, CYSLTR2 alterations were found to be highest in cases with predominantly pleomorphic lipoblasts; additionally, strong correlations were found between gene alteration frequencies of MFS and MFS-like PLPS, and between UPS and UPS-like PLPS. RB1 allele-specific copy number analysis showed loss of heterozygosity in 82% of cases. Our cohort of PLPS showed a complex molecular landscape with distinct genetic alterations, histologic correlations, and clinical outcomes, highlighting its unique position among genomically complex sarcomas and providing insights that may inform future diagnostic and therapeutic approaches.

Humans↗

PubMed1998

Sampling the genomic pool of protein tyrosine kinase genes using the polymerase chain reaction with genomic DNA.

The polymerase chain reaction (PCR), with cDNA as template, has been widely used to identify members of protein families from many species. A major limitation of using cDNA in PCR is that detection of a family member is dependent on temporal and spatial patterns of gene expression. To circumvent this restriction, and in order to develop a technique that is broadly applicable we have tested the use of genomic DNA as PCR template to identify members of protein families in an expression-independent manner. This test involved amplification of DNA encoding protein tyrosine kinase (PTK) genes from the genomes of three animal species that are well known development models; namely, the mouse Mus musculus, the fruit fly Drosophila melanogaster, and the nematode worm Caenorhabditis elegans. Ten PTK genes were identified from the mouse, 13 from the fruit fly, and 13 from the nematode worm. Among these kinases were 13 members of the PTK family that had not been reported previously. Selected PTKs from this screen were shown to be expressed during development, demonstrating that the amplified fragments did not arise from pseudogenes. This approach will be useful for the identification of many novel members of gene families in organisms of agricultural, medical, developmental and evolutionary significance and for analysis of gene families from any species, or biological sample whose habitat precludes the isolation of mRNA. Furthermore, as a tool to hasten the discovery of members of gene families that are of particular interest, this method offers an opportunity to sample the genome for new members irrespective of their expression pattern.

Amino Acid Sequence↗

PubMed1998

Enrichment for loci identical-by-descent between pairs of mouse or human genomes by genomic mismatch scanning.

Mapping genes that underlie complex genetic traits, including genes that determine susceptibility to common diseases, requires an efficient method for high-resolution genotyping. Single-nucleotide differences between pairs of allelic sequences from unrelated individuals occur approximately once in every kilobase. Genomic mismatch scanning (GMS), by analyzing numerous single-nucleotide polymorphisms in a single genome-wide step, offers a potentially powerful and efficient approach to linkage analysis. GMS, originally developed in a yeast system, is shown here to be applicable to the more complex mouse and human genomes.

Adenosine Triphosphatases↗

PubMed1998

A whole-genome radiation hybrid map of the dog genome.

A whole genome radiation hybrid (RH) map of the canine genome was constructed by typing 400 markers, including 218 genes and 182 microsatellites, on a panel of 126 radiation hybrid cell lines. Fifty-seven RH groups have been determined with lod scores greater than 6, and 180 framework landmarks were ordered with odds greater than 1000:1. Average spacing between adjacent markers is 23 cR5000, an estimated physical distance of 3.8 Mb. Fourteen groups have been assigned to 9 of the canine chromosomes, and a comparison of RH and genetic groups allowed the successful bridging of both types of data on one map composed of 31 RH and 13 syntenic RH groups. Comparison of canine, human, mouse, and pig maps underlined regions of conserved synteny. This integrated map, covering an estimated 80% of the dog genome, should prove a powerful tool for localizing and identifiying genes implicated in pathological and phenotypical traits.

Animals↗

PubMed1996

The probability of occurrence of oligomer motifs in the human genome and genomic microheterogeneity.

A previously published method for predicting the frequency of random occurrence of a completely specified DNA oligomer in a longer sequence dataset has been generalized to allow degeneracy in the oligomer sequence. With this enhancement, several datasets consisting of sequences from the human genome were searched for the occurrence of consensus binding sites for a set of 13 transcription factors. Although because of the biological significance of these sequences one might predict that they would occur more often than the random frequency, many of the consensus oligomers were found at lower than expected frequencies. Several (G+C)-rich oligomers were found to be moderately over-represented, but this could be accounted for, in part, by the occurrence of (G+C)-rich tracts in the human sequences. Regions very high in (G+C) were found to occur at much higher frequencies than expected in the human genome, and this severely limits the usefulness of this approach for predicting the frequency of (G+C)-rich oligomers. Unexpectedly, more than 1% of the human genome consists of tracts at least 28 bp in length with a (G+C) content greater than 85%.

Base Sequence↗

PubMed2001

From chromosomal alterations to target genes for therapy: integrating cytogenetic and functional genomic views of the breast cancer genome.

A vast number of recurrent chromosomal alterations have been implicated in cancer development and progression. However, most of the genes involved in recurrent chromosomal alterations in solid tumors remain unknown, despite the recent substantial progress in genomic research and availability of high-throughput technologies. For example, it is now possible to quickly identify large numbers of differentially expressed genes in cancer specimens using cDNA microarrays. Integration of this "functional genomic view" of the cancer genome with the "cytogenetic view" could lead to the identification of genes playing a critical role in cancer development and progression. In this review, we illustrate how the combination of three different microarray technologies, cDNA, CGH, and tissue microarrays, makes it possible to directly identify genes involved in chromosomal rearrangements in cell line model systems and then rapidly explore their significance as potential diagnostic and therapeutic targets in human primary breast cancer progression.

Breast Neoplasms↗

PubMed2001

The genome of the archaeal virus SIRV1 has features in common with genomes of eukaryal viruses.

The virus SIRV1 of the extremely thermophilic archaeon Sulfolobus has a double-stranded DNA genome similar in architecture to the genomes of eukaryal viruses of the families Poxviridae, Pycodnaviridae, and Asfarviridae: the two strands of the 32,301 bp long linear genome are covalently connected forming a continuous polynucleotide chain and 2029 kb long inverted repeats are present at the termini. Very likely it also shares with these viruses mechanisms of initiation of replication and resolution of replicative intermediates.

Base Sequence↗

PubMed2007

[The National Genome Research Network. Genome research in Germany].

In 2001 Germany's Federal Ministry of Education and Research (BMFM) initiated the National Genome Research Network (NGFN). The goals of the NGFN are the investigation of the molecular basis of common diseases to improve new methods for prevention, diagnosis and therapy. The disease-oriented genome networks investigate cardiovascular diseases, cancer, diseases of the nervous system, diseases due to environmental factors and infection, and inflammation. They are supported by technological platforms and a component for technology transfer. The explicit aims include better integration of public health research and economy in order to gain an efficient economical and technological utilisation and application in community health. This article describes the creation of the NGFN in the context of international and national genome research, shows the structure and content of the NGFN and gives examples for NGFN research in networks on a highly, internationally recognised level.

Academies and Institutes↗

PubMed2006

The relationship between the rate of molecular evolution and the rate of genome rearrangement in animal mitochondrial genomes.

Evolution of mitochondrial genes is far from clock-like. The substitution rate varies considerably between species, and there are many species that have a significantly increased rate with respect to their close relatives. There is also considerable variation among species in the rate of gene order rearrangement. Using a set of 55 complete arthropod mitochondrial genomes, we estimate the evolutionary distance from the common ancestor to each species using protein sequences, tRNA sequences, and breakpoint distances (a measure of the degree of genome rearrangement). All these distance measures are correlated. We use relative rate tests to compare pairs of related species in several animal phyla. In the majority of cases, the species with the more highly rearranged genome also has a significantly higher rate of sequence evolution. Species with higher amino acid substitution rates in mitochondria also have more variable amino acid composition in response to mutation pressure. We discuss the possible causes of variation in rates of sequence evolution and gene rearrangement among species and the possible reasons for the observed correlation between the two rates.

Amino Acids↗

PubMed1998

Pulsed-field gel electrophoresis analysis of the genome of Rhodococcus fascians: genome size and linear and circular replicon composition in virulent and avirulent strains.

Total DNA of virulent and avirulent strains of Rhodococcus fascians was resolved by pulsed-field gel electrophoresis (PFGE) into a discrete number of fragments by digestion with the endonucleases AseI and DraI. Restriction endonucleases PacI, PmeI, and SwaI yielded no fragments upon digestion of R. fascians genome, and all the other tested endonucleases recognizing 6 bp released too many fragments. The genome size was 5.6 megabases for the type strain R. fascians DSM 20669, and 5.8 megabases for the virulent R. fascians D188 strain. However the genome size of R. fascians CECT 3001 (NRRL B15096) was 8.0 megabases. No linear chromosome in the megabase range was observed under pulse conditions in which Saccharomyces cerevisiae and Schizosaccharomyces pombe chromosomes were perfectly resolved, suggesting that the R. fascians chromosome is circular. A new linear plasmid pIRN640 of 640 kb was found in the avirulent R. fascians CECT 3001 that did not hybridize with a probe internal to the fas region of pFiD188 known to be involved in plant pathogenicity in the virulent strain R. fascians D188. Virulence was correlated in all strains tested with the presence of the fas region. The AseI and DraI bands corresponding to the extrachromosomal elements were identified providing the basis for a physical map of this organism.

DNA, Circular↗

PubMed2006

Sequencing of the bicistronic genome segments S7 and S9 of Mal de Río Cuarto virus (Fijivirus, Reoviridae) completes the genome of this virus.

The nucleotide sequences of genomic segments S7 and S9 of Mal de Río Cuarto virus (MRCV, Fijivirus group II) have been determined, thus completing the entire genome sequence of the virus. These segments showed a non-overlapping bicistronic structure, as in other members of the genus. MRCV S7 ORF-1 had a length of 1086 bp and encoded a 41.5 kDa putative polypeptide, whereas MRCV S7 ORF-2 had a length of 930 bp and encoded a 36.8 kDa putative polypeptide. Proteins of 39 and 20.5 kDa were predicted for the 1014 bp long MRCV S9 ORF-1 and the 537 bp long MRCV S9 ORF-2, respectively. The terminal 5' and 3' sequences of both segments were 5'AAGUUUUU3' and 5'CAGCUnnnGUC3', respectively. Specific imperfect inverted repeats of each segment were identified. Comparison of the predicted proteins with those of related virus genome segments counterparts in maize rough dwarf virus (MRDV) and rice black streaked dwarf virus (RBSDV), showed 64.5-44.3% identities. These values are lower than those resulting from comparisons between MRDV and RBSDV. The topology of the trees obtained using the complete nucleotide and amino acid sequences of MRCV S7 and MRCV S9 was consistent with the analysis of the other MRCV segments previously published.

3' Untranslated Regions↗

PubMed2002

Genomic sequencing reveals gene content, genomic organization, and recombination relationships in barley.

Barley (Hordeum vulgare L.) is one of the most important large-genome cereals with extensive genetic resources available in the public sector. Studies of genome organization in barley have been limited primarily to genetic markers and sparse sequence data. Here we report sequence analysis of 417.5 kb DNA from four BAC clones from different genomic locations. Sequences were analyzed with respect to gene content, the arrangement of repetitive sequences and the relationship of gene density to recombination frequencies. Gene densities ranged from 1 gene per 12 kb to 1 gene per 103 kb with an average of 1 gene per 21 kb. In general, genes were organized into islands separated by large blocks of nested retrotransposons. Single genes in apparent isolation were also found. Genes occupied 11% of the total sequence, LTR retrotransposons and other repeated elements accounted for 51.9% and the remaining 37.1% could not be annotated.

Chromosomes, Artificial, Bacterial↗

PubMed2005

Whole genome amplification strategy for forensic genetic analysis using single or few cell equivalents of genomic DNA.

Evidentiary items sometimes contain an insufficient quantity of DNA for routine forensic genetic analysis. These so-called low copy number DNA samples (< 100 pg of genomic DNA) often fall below the sensitivity limitations of routine DNA analysis methods. Theoretically, one way of making such intractable samples amenable to analysis would be to increase the number of starting genomes available for subsequent STR (short tandem repeat) analysis by a whole genome amplification strategy (WGA). Although numerous studies employing WGA have focused primarily on clinical applications, few in-depth studies have been conducted to evaluate the potential usefulness of these methods in forensic casework. After an initial evaluation of existing methods, a modified WGA strategy was developed that appears to have utility for low copy number forensic casework specimens. The method employs a slight, but important, modification of the "improved primer extension preamplification PCR" method (I-PEP-PCR), which we term mIPEP (modified-I-PEP-PCR). Complete autosomal STR and Y-STR (Y chromosome short tandem repeat) profiles were routinely obtained with 5 pg of template DNA, which is equivalent to 1-2 diploid cells. Remarkably, partial Y- and autosomal STR profiles were obtained from mIPEP-treated DNA recovered from bloodstains exposed to the outside environment for 1 year whereas non-mIPEP-treated samples did not produce profiles. STR profiles were obtained from contact DNA from single dermal ridge fingerprints when the DNA was subjected to prior mIPEP amplification but not when the mIPEP step was omitted.

Blood Stains↗