Biomedical subjects

Genomics

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PubMed2003

[Ethical, legal, and social issues of genome research--new phase of genome research desperately requires social understanding and safeguards on the use of medical records and other personal information].

This article provides an overview of the use of human materials and information (human subject) in the new phase of pharmacological research and development in the current context, especially as it relates to the progress of the human genome project. In a sense, humanity has been drastically reduced to an array of DNA sequences that can be universally used in comparing living things. Pharmacological studies now acquire a unique status in bridging chemical substances to human body function. To perform the full activity of the nature of pharmacology, it requires both genotype and personal information, i.e. medical records and life style information, as research resources. In the UK, the Medical Research Council, the Wellcome Trust, and the Department of Health had started to plan UK Biobank for promoting and supporting the new stage of medical and pharmacological research and development. UK Biobank will collect DNA samples, medical records, and life style information of 500,000 people between the age range of 45 to 69 years old. It will follow the changes in health status of the participants for more than 10 years. The Biobank will provide researchers chances to correlate the genotypic traits to phenotypic ones, i.e. common diseases. In relation to the secondary use of medical records in health research, National Health Service (NHS) initiated a new strategy on the governance of patient information. These movements clearly demonstrated the indispensable nature of infrastructures for promoting and supporting pharmacological and medical research. We discuss on the necessary policies in constructing the Japanese infrastructure.

Cohort Studies↗

PubMed1998

Single-read sequence tags of a limited number of genomic DNA fragments provide an inexpensive tool for comparative genome analysis.

Single-read sequences from both ends of 415 3-kb average size genomic DNA fragments of Candida albicans were compared with the complete sequence data of Saccharomyces cerevisiae. Comparison at the protein level, translated DNA against protein sequences, revealed 138 sequence tags with clear similarity to S. cerevisiae proteins or open reading frames. One case of synteny was found for the open reading frames of RAD16 and LYS2, which are adjacent to each other in S. cerevisiae and C. albicans.

Adenosine Triphosphatases↗

PubMed2001

Genome-wide analysis of sixteen chordomas by comparative genomic hybridization and cytogenetics of the first human chordoma cell line, U-CH1.

Cytogenetic information on chordomas is rudimentary and restricted to GTG-banding analysis of 26 cases worldwide. In this study, we present the chromosomal imbalances detected in a series of 16 chordomas (10 sacrococcyeal, five sphenooccipital, and one spinal) from 13 patients using comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). On average, 3.2 losses and 4.2 gains were detected per tumor. The most common DNA copy number alterations were losses on chromosomal arms 3p (50%) and 1p (44%). Losses of 3p were detected in five of seven primary chordomas. Therefore, the loss of 3p might be an early event in chordoma genesis. The most common gains involved 7q (69%), 20 (50%), 5q (38%), and 12q (38%). Additionally, we raised the first human chordoma cell line, U-CH1, from a recurrence of a sacral chordoma. U-CH1 and its parent tumor had almost the same CGH profile. According to GTG-banding and multicolor FISH, U-CH1 has the following clonal chromosomal abnormalities: der(1)t(1;22), del(4), +del(5), +del(6), +7, del(9), del(10), +der(20)t(10;20), +21. Thus, the novel permanent human chordoma cell line U-CH1 has chordoma-typical cytogenetic aberrations. Our data suggest that tumor suppressor genes or mismatch repair genes (located at 1p31 and 3p14) and oncogenes (located in 7q36) might be involved in chordoma genesis.

Adult↗

PubMed1996

Very fast identification of RNA motifs in genomic DNA. Application to tRNA search in the yeast genome.

A common strategy characterises the various methods independently defined to identify almost unambiguously different types of RNA molecules in DNA fragments. So far, the good quality of detection of RNA motif has been the prior motivation and effectively delayed the optimisation of programs. As an illustration of possible improvements, a modified version of tRNAscan is described. The previous algorithm was altered to run 500 times faster and to lower both rates of false positives and false negatives. The newly sequenced genome of Saccharomyces cerevisiae is scanned both ways in less than three minutes and results match annotations found in databanks with three exceptions, two of which being arguably not real tRNAs.

Algorithms↗

PubMed1996

Genomic rearrangement in genome segment 12 of rice dwarf phytoreovirus.

The genome segment 12 (S12) of rice dwarf phytoreovirus (RDV) isolated from the Philippines (RDV-P) and of a variant (RDV-S-6) of RDV severe strain (RDV-S) migrated abnormally slower during polyacrylamide gel electrophoresis than that of the isolate maintained at Hokkaido University (RDV-H). Nucleotide sequence analysis revealed that rearrangement had occurred in these segments, affecting the open reading frame. A polypeptide encoded by S12 (Pns12) of RDV-P had a duplication of 28 amino acids while 1/3 of the carboxyl terminus of Pns12 was deleted in RDV-S-6 by premature termination due to a frameshift. RDV-S is always present in plants infected with the RDV-S-6 variant, suggesting that Pns12 of RDV-S-6 is defective. On the other hand, Pns12 of RDV-P was expressed and appeared to be functional in infected cells in spite of the duplication, as demonstrated by immunoblot analyses using antibody raised against Pns12 expressed in Escherichia coli.

Base Sequence↗

PubMed1992

Genomic organization and nucleotide sequence of a long mosaic repetitive DNA in the mouse genome.

A long mosaic repetitive sequence (LMRS) was isolated from a mouse liver genome library using a mouse repetitive DNA as a probe. LMRS exhibits the following features: (1) it is almost 15 kb in length; (2) it is partly organized in tandem array and frequently interrupted by other repeated sequences; and (3) it is located predominantly on the A3 band of the mouse X Chromosome (Chr). One fragment of LMRS (B6) shows restriction fragment length polymorphism (RFLP) between different mouse strains, and is thus potentially useful for mapping studies. The nucleotide sequence confirms a mosaic organization of LMRS which includes three repeats in the 5' part, showing similarity with the 5' end of L1Md-A2, and seven long A + T rich segments in the central part of the element. Our findings suggest that this sequence may have arisen from the duplication of an ancestral motif and has expanded by successive waves of amplification and invasion by foreign sequences.

Animals↗

PubMed2000

Whole-genome analysis of human astrocytic tumors by comparative genomic hybridization.

Frozen sections of 35 astrocytic tumors of various histologic malignancies were analyzed by comparative genomic hybridization in an attempt to characterize the profile of genetic aberrations. Over 94% of the samples revealed DNA copy number aberrations, which increased with higher histological malignancy grades, and also involvement of more than one chromosome was seen in 85% of instances. The aberrations observed were mainly deletions and most frequently incorporated chromosomes 1p, 10, 19q, and 22q. On the other hand, gains or amplifications were detected only in glioblastomas. Additionally, such gains or amplifications were present in all tumor samples where the initial histopathological diagnosis was glioblastoma and immunohistochemical study disclosed p53 tumor suppressor protein negative and epidermal growth factor receptor positive immunoreactivity; such glioblastomas possessing p53 tumor suppressor protein positive and epidermal growth factor receptor negative immunoreactivity seldom displayed any gain. Thus, glioblastomas exhibiting two different profiles of genetic aberrations were recognized--one with and the other without any gains/ amplifications. We speculate that the former variety is de novo glioblastoma.

Adult↗

PubMed2002

An orphan gyrB in the Mycobacterium smegmatis genome uncovered by comparative genomics.

DNA gyrase is an essential topoisomerase found in all bacteria. It is encoded by gyrB and gyrA genes. These genes are organized differently in different bacteria. Direct comparison of Mycobacterium tuberculosis and Mycobacterium smegmatis genomes reveals presence of an additional gyrB in M. smegmatis flanked by novel genes. Analysis of the amino acid sequence of GyrB from different organisms suggests that the orphan GyrB in M. smegmatis may have an important cellular role.

Amino Acid Sequence↗

PubMed2004

Recombination in primeval genomes: a step forward but still a long leap from maintaining a sizable genome.

A stubborn question in early molecular evolution is how to sustain the "minimum" informational length required for the basic features of life with a putative low-copying fidelity RNA polymerase ribozyme. Proposals to circumvent the information crisis have primarily focused on networks of cooperative molecules or compartmentalization of non-cooperative unlinked templates, but success has been very limited so far. Lehman (2003) has recently suggested that recombination--a frequently ignored player in early evolution--could have been crucial to building up primeval genomes of sizable length. Here we investigate this claim by assuming (without loss of generality) that genes were already enclosed in a compartment (vesicle, protocell). The numerical results show a quite intricate interplay among mutation, recombination, and gene redundancy. Provided that the minimum number of gene copies per protocell was enough for recombination to recreate wildtype templates--but not too high to impose an unbearable burden of mutants--informational content could have increased by at least 25% by keeping the same mutational load as that for a population without recombination. However, the upper bound of informational length would still be far from the "minimal life" provisions.

Chromosome Positioning↗

PubMed1996

Pig genome analysis: differential distribution of SINE and LINE sequences is less pronounced than in the human and mouse genomes.

The distribution of SINE and LINE sequences in the pig genome was examined by fluorescence in situ hybridization (FISH), interspersed repeat PCR, and restriction analysis of high molecular weight DNA. FISH revealed a largely uniform hybridization to the euchromatic chromosome regions with both interspersed repeats, although a bias toward the G-bands was observed for the LINE probe. Southern blots of inter-SINE and inter-LINE PCR products showed strong hybridization to LINE and SINE probes, respectively. High molecular weight DNA derived from a pig x hamster hybrid cell line was cut with a panel of G + C and A + T rich rare cutter restriction enzymes, then run on a pulsed field gel and Southern blotted. Sequential hybridization with SINE and LINE probes showed that SINE hybridization was to relatively low molecular weight fragments with the G + C rich enzymes, whereas the LINE probe gave hybridization to significantly larger fragments produced by these enzymes. DNA samples digested with A + T rich enzymes gave essentially similar patterns with SINE and LINE probes. We conclude that the pattern of differential distribution of SINEs and LINEs, which has been described in man and mouse, does exist in the pig but is much less pronounced.

Animals↗

PubMed2003

Genomic sequence of Wild potato mosaic virus as compared to the genomes of other potyviruses.

The complete nucleotide sequence of Wild potato mosaic virus (WPMV) was determined, showing that it is a distinct member of the genus Potyvirus (family Potyviridae). The genome consists of 9853 nucleotides and encodes a single polyprotein of 3065 amino acids. The 5'- and 3'-non translated regions (NTR) were 182 and 472 nucleotides, respectively. Alignment of the predicted WPMV polyprotein sequence with other members of the genus Potyvirus revealed nine putative cleavage sites resulting in ten mature proteins. Amino acid and nucleotide sequence identities and the exceptionally long 3'-NTR indicated a close relationship between WPMV and Potato virus V (PVV). Phylogenetic analysis based on the polyprotein and coat protein amino acid sequences grouped WPMV, PVV, Pepper mottle virus and Potato virus Y in one cluster distinct from other potyviruses.

Amino Acid Sequence↗

PubMed2005

The genome of the virulent phage Lc-Nu of probiotic Lactobacillus rhamnosus, and comparative genomics with Lactobacillus casei phages.

The complete 36,466-bp genome sequence of the virulent phage Lc-Nu of probiotic Lactobacillus rhamnosus was determined. The linear dsDNA with a GC-content of 44.2% contained 3' single-stranded cohesive ends of 12 nucleotides. A total of 51 putative open reading frames (orfs) were predicted. Lc-Nu showed to be evolutionary closely related to the temperate Lactobacillus casei phages phi AT3 and A2. High DNA homology with phi AT3 was shared over the late transcribed genes, and the highest homology with A2 was within the genetic switch region. The truncated cI-like repressor was the only lysogeny related gene left, which strongly suggested Lc-Nu to be recently evolved from a temperate origin. Three putative methylases and endonucleases were detected from the region of early-transcribed genes. The putative origin of replication within the putative gene orf34 homologous to replisome organizers resembled to that of lambdoid phages. The present study suggested Lc-Nu to be a new candidate for the proposed Sfi21-like species.

Base Composition↗

PubMed1993

Sequence analysis of the Ebola virus genome: organization, genetic elements, and comparison with the genome of Marburg virus.

Sequence analysis of the second through the sixth genes of the Ebola virus (EBO) genome indicates that it is organized similarly to rhabdoviruses and paramyxoviruses and is virtually the same as Marburg virus (MBG). In vitro translation experiments and predicted amino acid sequence comparisons showed that the order of the EBO genes is: 3'-NP-VP35-VP40-GP-VP30-VP24-L. The transcriptional start and stop (polyadenylation) signals are conserved and all contain the sequence 3'-UAAUU. Three base intergenic sequences are present between the NP and VP35 genes (3'-GAU) and VP40 and GP genes (3'-AGC), and a large intergenic sequence of 142 bases separates the VP30 and VP24 genes. Novel gene overlaps were found between the VP35 and VP40, the GP and VP30, and the VP24 and L genes. Overlaps are 20 or 18 bases in length and are limited to the conserved sequences determined for the transcriptional signals. Stem-and-loop structures were identified in the putative (+) leader RNA and at the 5' end of each mRNA. Hybridization studies showed that a small second mRNA is transcribed from the glycoprotein gene, and is produced by termination of transcription at an atypical polyadenylation signal located in the middle of the coding region. The predicted amino acid sequence of the glycoprotein contains an N-terminal signal peptide sequence, a hydrophobic anchor sequence, and 17 potential N-linked glycosylation sites. Alignment of predicted amino acid sequences showed that the structural proteins of EBO and MBG contain large regions of homology despite the absence of serologic cross-reactivity.

Amino Acid Sequence↗

PubMed2005

DNA shuttling between plasmid vectors and a genome vector: systematic conversion and preservation of DNA libraries using the Bacillus subtilis genome (BGM) vector.

The combined use of the contemporary vector systems, the bacterial artificial chromosome (BAC) vector and the Bacillus subtilis genome (BGM) vector, makes possible the handling of giant-length DNA (above 100 kb). Our newly constructed BGM vector efficiently integrated DNA prepared in the BAC vector. A BAC library comprised of 18 independent clones prepared from mitochondrial DNA (mtDNA) of Arabidopsis thaliana was converted to a parallel BGM library using the new BGM vector. The effectiveness of the combined use of the vector systems was confirmed by the stable recovery of all 18 DNAs as BAC clones from the respective BGM clones. We show that DNA in BGM was stably preserved at room temperature after spore formation of the host B.subtilis. Rapid and stable shuttling between Escherichiacoli and the B. subtilis host, combined with spore-mediated DNA storage, may facilitate the long-term and low-cost preservation and the transportation of DNA resources.

Arabidopsis↗

PubMed2006

A biased detection of the flexible genome content: missing large restriction fragments in comparative genomics.

Gene content variation between closely related bacteria is largely due to mobile elements and gene erosion. Various techniques are available to assess this variation, yet biased pools of restriction fragments have been used in several comparative genomics studies. Excluding important large restriction fragments from the actual hybridisation or from post-hybridisation amplification reactions compromise the comprehensiveness of these studies.

Bacteria↗

PubMed2004

Flying through the genome: a comprehensive study of functional genomics using RNAi in Drosophila.

Sequencing the DNA of an entire mammalian genome now seems routine. The human sequence along with the mouse--the model for mammalian genetics--and the rat--the model for mammalian physiology--are now part of the data archive. However, the real challenges for the 21st century are what to do with this information and how to test the function of so many different genes in so many different cellular contexts. The potential payoffs are enormous. Examples include a better understanding of disease pathologies with effective strategies for therapeutic interventions that cause few, if any, side effects.

Animals↗

PubMed1998

Functional genomics in the post-genome era.

As the biomedical research community enters the post-genome era, studying gene expression patterns and phenotypes in model organisms will be an important part of analyzing the role of genes in human health and disease. New technologies involving DNA chips will improve the ability to evaluate the differential expression of a large number of genes simultaneously. Also, new approaches for generating mutations in mice will significantly decrease the cost and increase the rate of generating mutant lines that model human disease.

Alleles↗

PubMed1999

Evidence that the mitochondrial genome is the thrifty genome.

Although mitochondrial DNA (mtDNA) abnormalities are known to cause insulin deficiency, insulin resistance and diabetes mellitus, it's quantitative aspect was not addressed well. In this review, mitochondrial genome hypothesis of thrifty phenomenon is proposed, based on the data and review of literatures. From a population based epidemiologic study, it was found that mtDNA quantity was decreased in the peripheral blood of diabetic subjects, and also in those subjects who will convert to diabetes mellitus within 2 years. In this population, low mtDNA subjects were found to have higher blood pressure and high waist hip ratio. These findings suggested mtDNA status might be quantitatively linked to the insulin resistance syndrome. As quantitative relationships between peripheral blood mtDNA levels and insulin requirement, and energy utilization pattern (fat and carbohydrate oxidation during hyperinsulinemic clamp studies) were observed in a group of male students; and maternal mtDNA content (peripheral blood) correlated with birth weight and peripheral blood mtDNA content of the offspring in another study, possibility of thrifty phenotype phenomena might be due to the low mitochondrial status arose. As thrifty phenotype phenomenon shows the quantitatively continuous relationship between involved parameters and characteristics of 'imprinting', a possible mechanism is suggested.

Animals↗