Biomedical subjects

Genomics

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PubMed2003

Synergism between genomic and non genomic estrogen action mechanisms.

The 17beta-estradiol (E2) action mechanism for inducing target gene expression can be attributed to both the direct binding of its receptor (ER) to specific sequences, the estrogen response element (ERE), and to the interaction between ER and other DNA-binding transcription factors. At the present meagre information is available for the role played by the rapid hormone action mechanism(s) (i.e., activation of ERK, PI(3)K, PKC-alpha) in modulating E2-induced gene promoter activity. Here the involvement of the rapid non genomic mechanism in triggering the transcriptional activity of two E2-regulated target genes in human hepatoma HepG2 cells has been studied, taking into consideration the cyclin D1 (ERE-devoid) and the complement protein 3 (ERE-containing) promoter-luciferase report constructs. The results indicate that the activation of the ERK pathway is essential for the E2-induced activity of both promoters, whereas the other rapid E2-induced membrane-starting signal transduction pathways (i.e., PI(3)K and PKC-alpha) were differently required. These results permit the amplification of the E2 action mechanism by the addition of synergy between the non genomic and genomic molecular actions of the E2-induced gene transcription.

Enzyme Activation↗

PubMed1995

Mitochondrial ribosomal protein L11 gene of Dictyostelium discoideum resides not in the nuclear genome but in the mitochondrial genome.

During the course of analysis of the mitochondrial genome of the cellular slime mold, Dictyostelium discoideum, we found a gene (rpl11) for mitochondrial ribosomal protein (RPL11), having 172 amino acid residues. Southern blot analysis revealed that the gene resided in the mitochondrial DNA as a single-copy but not in the nuclear DNA. From Northern blot experiments, one major mRNA (about 27 kb) and two minor mRNAs (about 4 and 5 kb) for the gene were detected in the mitochondria. This is the first report showing that the active gene for RPL11 still resides in the mitochondrial genome and has not been transferred to the nuclear genome in D. discoideum.

Amino Acid Sequence↗

PubMed1991

Fine structural features of the chloroplast genome: comparison of the sequenced chloroplast genomes.

The entire nucleotide sequences of the rice, tobacco and liverwort chloroplast genomes have been determined. We compared all the chloroplast genes, open reading frames and spacer regions in the plastid genomes of these three species in order to elucidate general structural features of the chloroplast genome. Analyses of homology, GC content and codon usage of the genes enabled us to classify them into two groups: photosynthesis genes and genetic system genes. Based on comparisons of homology, GC content and codon usage, unidentified ORFs can also be assigned to each of these groups such that it is possible to speculate about the functions of products which may be produced by these ORFs. The spacer regions and intron sequences were compared and found to have no obvious homology between rice and liverwort or between tobacco and liverwort.

Base Composition↗

PubMed1993

Methylation profiles of genomic DNA of mouse developmental brain detected by restriction landmark genomic scanning (RLGS) method.

Restriction landmark genomic scanning using methylation-sensitive endonucleases (RLGS-M) is a newly developed powerful method for systematic detection of DNA methylation. Using this method, we scanned mouse brain genomic DNAs from various developmental stages to detect the transcriptionally active regions. This approach is based on the assumption that CpG methylation, particularly of CpG islands, might be associated with gene transcriptional regulation. Genomic DNAs were prepared from telencephalons of 9.5-, 13.5- and 16.5-day embryos, 1- and 10-day neonates and adults, followed by subjecting them to RLGS-M and comparing their patterns with each other or with that of the adult liver. We used NotI as a methylation-sensitive restriction enzyme and surveyed the methylation states of 2,600 NotI sites, almost of which should correspond to gene loci. Although almost all RLGS spots (98%) were present constantly at every developmental stages, only a few percent of spots reproducibly appeared and disappeared at different developmental stages of the brain (44 spots, 1.7%) and some were tissue-specific (10 spots, 0.7%). These data suggest that DNA methylation associated with gene transcription is a well-programmed event during the central nervous system (CNS) development. Thus, RLGS-M can offer a means for detecting systematically the genes in which the state of DNA methylation changes during development of the higher organism.

Animals↗

PubMed1999

Detailed chromosomal and molecular genetic analysis of single cells by whole genome amplification and comparative genomic hybridisation.

Molecular genetic analysis of isolated single cells and other minute DNA samples is limited because there is insufficient DNA to perform more than one independent PCR amplification. One solution to this problem is to first amplify the entire genome, thus providing enough DNA for numerous subsequent PCRs. In this study we have investigated four different methods of whole genome amplification performed on single cells, and have identified a protocol that generates sufficient quantities of DNA for comparative genomic hybridisation (CGH) as well as more than 90 independent amplification reactions. Thus, numerous specific loci and the copy number of every chromosome can be assessed in a single cell. We report here the first reliable application of CGH to single cells from human preimplantation embryos (blastomeres) and to single fibroblasts, buccal cells and amniocytes.

Humans↗

PubMed1999

Historical overview of research on the tobacco mosaic virus genome: genome organization, infectivity and gene manipulation.

Early in the development of molecular biology, TMV RNA was widely used as a mRNA [corrected] that could be purified easily, and it contributed much to research on protein synthesis. Also, in the early stages of elucidation of the genetic code, artificially produced TMV mutants were widely used and provided the first proof that the genetic code was non-overlapping. In 1982, Goelet et al. determined the complete TMV RNA base sequence of 6395 nucleotides. The four genes (130K, 180K, 30K and coat protein) could then be mapped at precise locations in the TMV genome. Furthermore it had become clear, a little earlier, that genes located internally in the genome were expressed via subgenomic mRNAs. The initiation site for assembly of TMV particles was also determined. However, although TMV contributed so much at the beginning of the development of molecular biology, its influence was replaced by that of Escherichia coli and its phages in the next phase. As recombinant DNA technology developed in the 1980s, RNA virus research became more detached from the frontier of molecular biology. To recover from this setback, a gene-manipulation system was needed for RNA viruses. In 1986, two such systems were developed for TMV, using full-length cDNA clones, by Dawson's group and by Okada's group. Thus, reverse genetics could be used to elucidate the basic functions of all proteins encoded by the TMV genome. Identification of the function of the 30K protein was especially important because it was the first evidence that a plant virus possesses a cell-to-cell movement function. Many other plant viruses have since been found to encode comparable 'movement proteins'. TMV thus became the first plant virus for which structures and functions were known for all its genes. At the birth of molecular plant pathology, TMV became a leader again. TMV has also played pioneering roles in many other fields. TMV was the first virus for which the amino acid sequence of the coat protein was determined and first virus for which cotranslational disassembly was demonstrated both in vivo and in vitro. It was the first virus for which activation of a resistance gene in a host plant was related to the molecular specificity of a product of a viral gene. Also, in the field of plant biotechnology, TMV vectors are among the most promising. Thus, for the 100 years since Beijerinck's work, TMV research has consistently played a leading role in opening up new areas of study, not only in plant pathology, but also in virology, biochemistry, molecular biology, RNA genetics and biotechnology.

Capsid↗

PubMed1986

Nucleotide sequence of a cloned hepatitis B virus genome, subtype ayr: comparison with genomes of the other three subtypes.

The entire nucleotide sequence of genomic DNA was determined for hepatitis B virus (HBV) of subtype ayr, which had been derived from the blood of a Japanese asymptomatic carrier. The genome was 3215 nucleotides long, and differed in DNA sequence by 10% from that of subtypes adw or ayw, but by only 2% from that of subtype adr. Amino acid sequences coded for by the S, C, P and X genes, as well as by the pre-S region, closely resembled those of subtype adr, indicating that the evolution of HBV/ayr from HBV/adr was more recent than the differentiation of the other three subtypes. In the product of the S gene, the mutually exclusive subtypic determinants of the surface antigen, d and y, were associated with variation of amino acid residues at only the 68th and 122nd positions from the N terminus, in contrast to the variation at as many as seven positions for the other set of subtypic determinants, w and r. Sequences representing high local hydrophilicity in the product of the S gene were involved in subtypic variation, although such sequences in the pre-S region were shared by HBV genomes of the various subtypes. In particular, a hydrophilic sequence of 19 amino acid residues, coded for by the pre-S(2) region and implicated in the presumed hepatotropism of HBV, was possessed in common by HBV/adr, HBV/ayr and HBV/ayw, and differed in HBV/adw by only one residue at the 9th position. This amino acid sequence appears to be a promising candidate for a synthetic peptide vaccine.

Amino Acid Sequence↗

PubMed1992

Physical map of the Cryptophlebia leucotreta granulosis virus genome and its relationship to the genome of Cydia pomonella granulosis virus.

A physical map of the genome of Cryptophlebia leucotreta granulosis virus (CIGV) was constructed for the restriction enzymes BamHI, EcoRI, KpnI, NdeI, NruI, SacI and XhoI using hybridization techniques. The size of the viral genome was determined to be 112.4 kbp. A restriction fragment library covering almost the entire genome of CIGV was constructed, and the position of the granulin gene was identified by cross-hybridization with granulin coding fragments of Cydia pomonella granulosis virus (CpGV). Two further regions of intergenomic similarity between CIGV and CpGV were mapped. These regions were aligned and show a collinear arrangement.

Baculoviridae↗

PubMed1999

Novel phosphotransferase system genes revealed by genome analysis - the complete complement of PTS proteins encoded within the genome of Bacillus subtilis.

Bacillus subtilis can utilize several sugars as single sources of carbon and energy. Many of these sugars are transported and concomitantly phosphorylated by the phosphoenolpyruvate:sugar phosphotransferase system (PTS). In addition to its role in sugar uptake, the PTS is one of the major signal transduction systems in B. subtilis. In this study, an analysis of the complete set of PTS proteins encoded within the B. subtilis genome is presented. Fifteen sugar-specific PTS permeases were found to be present and the functions of novel PTS permeases were studied based on homology to previously characterized permeases, analysis of the structure of the gene clusters in which the permease encoding genes are located and biochemical analysis of relevant mutants. Members of the glucose, sucrose, lactose, mannose and fructose/mannitol families of PTS permeases were identified. Interestingly, nine pairs of IIB and IIC domains belonging to the glucose and sucrose permease families are present in B. subtilis; by contrast only five Enzyme IIA(Glc)-like proteins or domains are encoded within the B. subtilis genome. Consequently, some of the EIIA(Glc)-like proteins must function in phosphoryl transfer to more than one IIB domain of the glucose and sucrose families. In addition, 13 PTS-associated proteins are encoded within the B. subtilis genome. These proteins include metabolic enzymes, a bifunctional protein kinase/phosphatase, a transcriptional cofactor and transcriptional regulators that are involved in PTS-dependent signal transduction. The PTS proteins and the auxiliary PTS proteins represent a highly integrated network that catalyses and simultaneously modulates carbohydrate utilization in this bacterium.

Bacillus subtilis↗

PubMed2025

Insights from farming Macrocystis pyrifera offshore: phenotypic analysis, genome-wide association studies, genomic selection.

Seaweed farming, as a part of aquaculture, offers a sustainable alternative to modern agricultural practices; however, genetic enhancement and breeding programs for most species are underdeveloped. We aimed to advance seaweed domestication by focusing on giant kelp (Macrocystis pyrifera), the fastest-growing haplodiplontic brown alga, which has significant ecological and commercial importance. We analyzed phenotypic data from two offshore experimental farms conducted in 2019 and 2020, which involved hundreds of outplanted genetically diverse sporophytes. We found that outplanting season and farm design had significant effects on giant kelp biomass. Broad-sense heritability estimates showed moderate (0.27-0.50) genetic contributions to two phenotypes, carbon content and total biomass. Genome-wide association studies for these phenotypes resulted in three statistically significant SNPs, located near or within genes involved in carbohydrate metabolism and cytoskeletal functions. In addition, we applied genomic selection models that integrated sporophyte phenotypes and parental gametophyte genotypes. These models utilized reduced sets of GWAS-ranked SNPs obtained by a procedure based on linkage disequilibrium estimations. Model testing yielded cross-validation accuracy values of up to 0.84 and predictive accuracy values of up to 0.40, demonstrating the potential of marker-assisted breeding for phenotype improvement. Our results provide foundational genomic resources and tools for domesticating and breeding M. pyrifera, offering a basis for developing giant kelp varieties with desirable traits.

Journal Article↗

PubMed2004

The functional genomic distribution of protein divergence in two animal phyla: coevolution, genomic conflict, and constraint.

We compare the functional spectrum of protein evolution in two separate animal lineages with respect to two hypotheses: (1) rates of divergence are distributed similarly among functional classes within both lineages, indicating that selective pressure on the proteome is largely independent of organismic-level biological requirements; and (2) rates of divergence are distributed differently among functional classes within each lineage, indicating species-specific selective regimes impact genome-wide substitutional patterns. Integrating comparative genome sequence with data from tissue-specific expressed-sequence-tag (EST) libraries and detailed database annotations, we find a functional genomic signature of rapid evolution and selective constraint shared between mammalian and nematode lineages despite their extensive morphological and ecological differences and distant common ancestry. In both phyla, we find evidence of accelerated evolution among components of molecular systems involved in coevolutionary change. In mammals, lineage-specific fast evolving genes include those involved in reproduction, immunity, and possibly, maternal-fetal conflict. Likelihood ratio tests provide evidence for positive selection in these rapidly evolving functional categories in mammals. In contrast, slowly evolving genes, in terms of amino acid or insertion/deletion (indel) change, in both phyla are involved in core molecular processes such as transcription, translation, and protein transport. Thus, strong purifying selection appears to act on the same core cellular processes in both mammalian and nematode lineages, whereas positive and/or relaxed selection acts on different biological processes in each lineage.

Amino Acid Substitution↗

PubMed1997

A first-generation whole genome-radiation hybrid map spanning the mouse genome.

We have assembled a first-generation anchor map of the mouse genome using a panel of 94 whole-genome-radiation hybrids (WG-RHs) and 271 sequence-tagged sites (STSs). This is the first genome-wide RH anchor map of a model organism. All of the STSs have been previously localized on the genetic map and are located 8.8 Mb apart on average. This mouse WG-RH panel, known as T31, has an average retention frequency of 27.6% and an estimated potential resolution of 145 kb, making it a powerful resource for efficient large-scale expressed sequence tag mapping. [All of the mapping data for the maps presented here have been deposited at the Research Genetics, Inc., web site and can be freely accessed and downloaded at http://www.resgen.com/.]

Animals↗

PubMed1982

DNA sequence relationship of the baboon endogenous virus genome to the genomes of other type C and type D retroviruses.

Baboon endogenous virus (BaEV) is a type C retrovirus present in multiple proviral copies in the DNA of baboons. Although interspecies antigenic determinants present on reverse transcriptase and gag proteins are shared among all mammalian type C viruses, no nucleic acid homology between BaEV and other type C viruses (except RD-114) has been found in conventional liquid hybridization experiments. In this study, we used restriction fragments of cloned BaEV DNA immobilized on nitrocellulose to test for relatedness with [(32)P]cDNA's of various type C and type D viruses. We detected the following distant relationships previously found only through immunological and protein sequencing techniques: (i) eight type C viral cDNA's (the endogenous virus of rhesus monkeys, feline leukemia virus, simian sarcoma virus, gibbon ape leukemia virus, Rauscher murine leukemia virus, BALB-2, NZB, and RD-114) and two type D viral cDNA's (Mason-Pfizer monkey virus and squirrel monkey retrovirus) were able to hybridize with cloned BaEV DNA; (ii) the eight type C probes hybridized to restriction fragments spanning most of the BaEV genome, but only RD-114 hybridized to fragments within the 1.9 kilobases at the 3' end of the genome; (iii) the two type D probes hybridized primarily to fragments within the 1.9 kilobases at the 3' terminus and weakly or not at all elsewhere; and (iv) [(32)P]cDNA's of several other oncornaviruses (mouse mammary tumor virus, equine infectious anemia virus, bovine leukemia virus, and reticuloendotheliosis virus) exhibited no homology with BaEV DNA. DNA sequence analysis has allowed us to orient the BaEV restriction map with the genetic map at both ends of the genome. Homologies between retroviral cDNA's and BaEV clone restriction fragments could thus be related to specific BaEV genes. Whereas type C cDNA's hybridized to fragments from gag, pol, and the pol-env junction, squirrel monkey retrovirus cDNA hybridized only to a fragment coding for the p15E portion of env. Mason-Pfizer monkey virus cDNA also hybridized within the p15E region, but exhibited homology to the 3' half of gp70 as well. These results are discussed relative to previously reported antigenic relatedness of retroviral proteins. The data suggest that BaEV represents an important link in oncornavirus evolution.

Base Sequence↗

PubMed1983

Alignment of the genome of monkey B-lymphotropic papovavirus to the genomes of simian virus 40 and BK virus.

We located the origin of DNA replication of African green monkey B-lymphotropic papovavirus DNA by analyzing pulse-labeled form I DNA. With the replication origin used as a reference point, the B-lymphotropic papovavirus genome was aligned with the genomes of simian virus 40 and BK virus from DNA homology between specific fragments hybridized under low-stringency conditions. From the results of these experiments, it was possible to deduce the correlation between the physical and functional maps of the B-lymphotropic papovavirus genome.

BK Virus↗

PubMed1985

A noninverting genome of a viable herpes simplex virus 1: presence of head-to-tail linkages in packaged genomes and requirements for circularization after infection.

The wild-type herpes simplex virus 1 genome consists of two components, L and S, which invert relative to each other, giving rise to four isomers. Previously we reported the construction of a herpes simplex virus 1 genome, HSV-1(F)I358, from which 15 kilobase pairs of DNA spanning the junction between L and S components were deleted and which no longer inverted (Poffenberger et al., Proc. Natl. Acad. Sci. U.S.A. 80:2690-2694, 1983). Further studies on the structure of HSV-1(F)I358 revealed the presence of two submolar populations among packaged DNA. The first, comprising no more than 10% of total packaged DNA, consisted of defective genomes with a subunit size of 36 kilobase pairs. The results suggest that this population arose by recombination through a directly repeated sequence inserted in place of the deleted L-S junction. The second minor population consisted of HSV-1(F)I358 DNA linked head-to-tail. Analyses of the structure of HSV-1(F)I358 DNA after infection indicated that the fraction of total DNA linked head-to-tail increased to approximately 40 to 50% within 30 min after exposure of cells to virus. The formation of head-to-tail linkages did not require de novo protein synthesis. Our interpretation of the results is that the termini of full-length DNA molecules are held together during packaging, that a small fraction of the termini is covalently linked during or after packaging, and that the remainder is covalently joined after the release of viral DNA from the infecting virus by either host or viral factors introduced into the cell during infection.

Cell Line↗

PubMed1986

Nucleotide sequence of human endogenous retrovirus genome related to the mouse mammary tumor virus genome.

We determined the complete nucleotide sequence of the human endogenous retrovirus genome HERV-K10 isolated as the sequence homologous to the Syrian hamster intracisternal A-particle (type A retrovirus) genome. HERV-K10 is 9,179 base pairs long with long terminal repeats of 968 base pairs at both ends; a sequence 290 base pairs long, however, was found to be deleted. It was concluded that a composite genome having the 290-base-pair fragment is the prototype HERV-K provirus gag (666 codons), protease (334 codons), pol (937 codons), and env (618 codons) genes. The size of the protease gene product of HERV-K is essentially the same as that of A- and D-type oncoviruses but nearly twice that of other retroviruses. A comparison of the deduced amino acid sequences encoded by the pol region showed HERV-K to be closely related to types A and D retroviruses and even more so to type B retrovirus. It was noted that the env gene product of HERV-K structurally resembles the mouse mammary tumor virus (type B retrovirus) env protein, and the possible expression of the HERV-K env gene in human breast cancer cells is discussed.

Amino Acid Sequence↗

PubMed1985

gamma 2-Thymidine kinase chimeras are identically transcribed but regulated a gamma 2 genes in herpes simplex virus genomes and as beta genes in cell genomes.

True gamma or gamma 2 genes, unlike alpha, beta, and gamma 1 (beta gamma) genes of herpes simplex virus 1 (HSV-1), stringently require viral DNA synthesis for their expression. We report that gamma 2 genes resident in cells were induced in trans by infection with HSV-1 but that the induction did not require amplification of either the resident gene or the infecting viral genome. Specifically, to test the hypothesis that expression of these genes is amplification dependent, we constructed two sets of gamma 2-thymidine kinase (TK) chimeric genes. The first (pRB3038) consisted of the promoter-regulatory region and a portion of 5'-transcribed noncoding region of the domain of a gamma 2 gene identified by Hall et al. (J. Virol. 43:594-607) in the HSV-1(F) BamHI fragment D' to the 5'-transcribed noncoding and coding regions of the TK gene. The second (pRB3048) contained, in addition, an origin of HSV-1 DNA replication. Cells transfected with either the first or second construct and selected for the TK+ phenotype were then tested for TK induction after superinfection with HSV-1(F) delta 305, containing a deletion in the coding sequences of the TK gene, and viruses containing, in addition, a ts lesion in the alpha 4 regulatory protein (ts502 delta 305) or in the beta 8 major DNA-binding protein (tsHA1 delta 305). The results were as follows: induction by infection with TK- virus of chimeric TK genes with or without an origin of DNA replication was dependent on functional alpha 4 protein but not on viral DNA synthesis; the resident chimeric gene in cells selected for G418 (neomycin) resistance was regulated in the same fashion; the chimeric gene recombined into the viral DNA was regulated as a gamma 2 gene in that its expression in infected cells was dependent on viral DNA synthesis; the gamma 2-chimeric genes resident in the host and in viral genomes were transcribed from the donor BamHI fragment D' containing the promoter-regulatory domain of the gamma 2 gene. The significance of the differential regulation of gamma 2 genes in the environments of host and viral genomes by viral trans-acting factors is discussed.

Animals↗

PubMed1999

THE CAENORHABDITIS ELEGANS GENOME: A Guide in The Post Genomics Age.

The completion of the entire genome sequence of the free-living nematode, Caenorhabditis elegans is a tremendous milestone in modern biology. Not only will scientists be poring over data mined from this resource, but techniques and methodologies developed along the way have changed the way we can approach biological questions. The completion of the C. elegans genomic sequence will be of particular importance to scientists working on parasitic nematodes. In many cases, these nematode species present intractable challenges to those interested in their biology and genetics. The data already compared from parasites to the C. elegans database reveals a wealth of opportunities for parasite biologists. It is likely that many of the same genes will be present in parasites and that these genes will have similar functions. Additional information regarding differences between free-living and parasitic species will provide insight into the evolution and nature of parasitism. Finally, genetic and genomic approaches to the study of parasitic nematodes now have a clearly marked path to follow.

Journal Article↗