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PubMed2000

Comparative genome mapping in the sequence-based era: early experience with human chromosome 7.

The success of the ongoing Human Genome Project has resulted in accelerated plans for completing the human genome sequence and the earlier-than-anticipated initiation of efforts to sequence the mouse genome. As a complement to these efforts, we are utilizing the available human sequence to refine human-mouse comparative maps and to assemble sequence-ready mouse physical maps. Here we describe how the first glimpses of genomic sequence from human chromosome 7 are directly facilitating these activities. Specifically, we are actively enhancing the available human-mouse comparative map by analyzing human chromosome 7 sequence for the presence of orthologs of mapped mouse genes. Such orthologs can then be precisely positioned relative to mapped human STSs and other genes. The chromosome 7 sequence generated to date has allowed us to more than double the number of genes that can be placed on the comparative map. The latter effort reveals that human chromosome 7 is represented by at least 20 orthologous segments of DNA in the mouse genome. A second component of our program involves systematically analyzing the evolving human chromosome 7 sequence for the presence of matching mouse genes and expressed-sequence tags (ESTs). Mouse-specific hybridization probes are designed from such sequences and used to screen a mouse bacterial artificial chromosome (BAC) library, with the resulting data used to assemble BAC contigs based on probe-content data. Nascent contigs are then expanded using probes derived from newly generated BAC-end sequences. This approach produces BAC-based sequence-ready maps that are known to contain a gene(s) and are homologous to segments of the human genome for which sequence is already available. Our ongoing efforts have thus far resulted in the isolation and mapping of >3,800 mouse BACs, which have been assembled into >100 contigs. These contigs include >250 genes and represent approximately 40% of the mouse genome that is homologous to human chromosome 7. Together, these approaches illustrate how the availability of genomic sequence directly facilitates studies in comparative genomics and genome evolution.

Animals↗

PubMed1986

Mapping and sequencing of RNAs without recourse to molecular cloning: application to RNAs of the Sabin 1 strain of poliovirus and its defective interfering particles.

Complementary DNA to the genome of the Sabin 1 strain of poliovirus was prepared by reverse transcription with oligo(dT)10 as a primer and separated into six classes of DNA by their size. Each class of the DNA, after digestion with restriction endonuclease HaeIII, was analyzed by two-dimensional polyacrylamide gel electrophoresis. Comparison of the patterns of the restriction fragments led us to compose a possible arrangement of the restriction fragments on the viral genome. Sequence analysis of these fragments indicated that the arrangement was consistent with the known total nucleotide sequence of the genome. In the determined sequences, two bases were observed to differ from those of a cloned complementary DNA of the Sabin 1 genome. This suggested that the sequence of the cloned DNA reflected that of a mutated virus genome that was a minor component in the virus inoculation stock. The genomes of defective interfering particles generated from the Sabin 1 strain were also analyzed by this technique. The results suggested that the RNAs lacked an internal region of the Sabin 1 RNA encoding viral capsid proteins. The location of the deletion was further confirmed by determination of the nucleotide sequence of a cloned complementary DNA copy of the defective interfering particle RNA. Thus, the method described here is useful for mapping and sequencing of RNAs and for knowing whether cloned cDNAs represent the major population of RNA molecules or not.

Base Sequence↗

PubMed2005

Linkage to 10q22 for maximum intraocular pressure and 1p32 for maximum cup-to-disc ratio in an extended primary open-angle glaucoma pedigree.

PURPOSE: The purpose of this study was to identify genetic contributions to primary open-angle glaucoma (POAG) through investigations of two quantitative components of the POAG phenotype. METHODS: Genome-wide multipoint variance-components linkage analyses of maximum recorded intraocular pressure (IOP) and maximum vertical cup-to-disc ratio were conducted on data from a single, large Australian POAG pedigree that has been found to segregate the myocilin Q368X mutation in some individuals. RESULTS: Multipoint linkage analysis of maximum recorded IOP produced a peak LOD score of 3.3 (P = 0.00015) near marker D10S537 on 10q22, whereas the maximum cup-to-disc ratio produced a peak LOD score of 2.3 (P = 0.00056) near markers D1S197 to D1S220 on 1p32. Inclusion of the myocilin Q368X mutation as a covariate provided evidence of an interaction between this mutation and the IOP and cup-to-disc ratio loci. CONCLUSIONS: Significant linkage has been identified for maximum IOP and suggestive linkage for vertical cup-to-disc ratio. Identification of genes contributing to the variance of these traits will enhance understanding of the pathophysiology of POAG as a whole.

Chromosomes, Human, Pair 1↗

PubMed2001

Tumor invasion as dysregulated cell motility.

Investigations across a range of disciplines over the past decade have brought the study of cell motility and its role in invasion to an exciting threshold. The biophysical forces proximally involved in generating cell locomotion, as well as the underlying signaling and genomic regulatory processes, are gradually becoming elucidated. We now appreciate the intricacies of the many cellular and extracellular events that modulate cell migration. This has enabled the demonstration of a causal role of cell motility in tumor progression, with various points of 'dysregulation' of motility being responsible for promoting invasion. In this paper, we describe key fundamental principles governing cell motility and branch out to describe the essence of the data that describe these principles. It has become evident that many proposed models may indeed be converging into a tightly-woven tapestry of coordinated events which employ various growth factors and their receptors, adhesion receptors (integrins), downstream molecules, cytoskeletal components, and altered genomic regulation to accomplish cell motility. Tumor invasion occurs in response to dysregulation of many of these modulatory points; specific examples include increased signaling from the EGF receptor and through PLC gamma, altered localization and expression of integrins, changes in actin modifying proteins and increased transcription from specific promoter sites. This diversity of alterations all leading to tumor invasion point to the difficulty of correcting causal events leading to tumor invasion and rather suggest that the underlying common processes required for motility be targeted for therapeutic intervention.

Cell Adhesion↗

PubMed1999

New applications of low-C0tDNA as a DNA fingerprint probe.

New applications of low-C0t DNA are reported as probes for genetic identification and genome characterization. These fast and intermediately reannealing fractions have sometimes either been discarded in genomic library construction to enhance the probability of finding single copy genes, or they are used as resources for identifying individual repetitive sequences. In addition, they are used as blockers to enhance hybridization signals. C0t-1 DNA serves as a probe for DNA fingerprinting of human yeast artificial chromosomes. We have isolated low-C0t DNA from bacteria, fungus, plant, mussel, chicken, rat and fish from the sheared genomic DNA of the respective species. Low-C0t DNA is labeled to generate DNA fingerprints and for in situ hybridization. Individual specific DNA fingerprint profiles are observed and species-specific DNA fragments can be identified in bacteria, fungus, plants (Ginseng and Amaranthus) and mussel. When low-C0t DNA probes from rat, chicken and fish were employed, only smear profiles and no distinct DNA banding patterns were evident. In these species, individual clones can be used as a probe for DNA fingerprinting containing repetitive sequences after subcloning. The advantage of this approach is to quickly develop a useful probe for DNA fingerprinting for genetic identification and analysis without sequencing knowledge a priori. This represents an innovative approach to the use of these repetitive components of the genome.

Animals↗

PubMed1992

copia-like retrotransposons are ubiquitous among plants.

Transposable genetic elements are assumed to be a feature of all eukaryotic genomes. Their identification, however, has largely been haphazard, limited principally to organisms subjected to molecular or genetic scrutiny. We assessed the phylogenetic distribution of copia-like retrotransposons, a class of transposable element that proliferates by reverse transcription, using a polymerase chain reaction assay designed to detect copia-like element reverse transcriptase sequences. copia-like retrotransposons were identified in 64 plant species as well as the photosynthetic protist Volvox carteri. The plant species included representatives from 9 of 10 plant divisions, including bryophytes, lycopods, ferns, gymnosperms, and angiosperms. DNA sequence analysis of 29 cloned PCR products and of a maize retrotransposon cDNA confirmed the identity of these sequences as copia-like reverse transcriptase sequences, thereby demonstrating that this class of retrotransposons is a ubiquitous component of plant genomes.

Amino Acid Sequence↗

PubMed2002

Methylation and the genome: the power of a small amendment.

Methylation is a major regulator of mammalian genome function in vivo. The methylation of DNA on cytosine residues is a critical component of the host genome defense pathway against the expansion of repetitive DNA and is central to such epigenetic phenomena as monoallelic expression of genes regulated by imprinting and dosage compensation. Deregulation of the DNA methylation pathway leads to aberrant gene repression in cancer and contributes to cell cycle misregulation. Transcriptional repression of methylated DNA loci results from a poorly understood interplay between various chromatin-based regulatory machines, such as histone deacetylases, and auxiliary pathways. Intranuclear protein methylation also has considerable regulatory impact: this includes the function of histone methyltransferases in establishing regions of transcriptionally inert heterochromatin and of protein methyltransferases in mediating transcriptional activation by the nuclear hormone receptors. An important thermodynamic distinction between methylation and many other covalent modifications of intracellular components-e.g., phosphorylation or acetylation-is the relative chemical stability of the methylated form of an amino acid (typically, lysine or arginine) compared with its cognate acetylated form. Thus, a protein, once methylated, may persist in that state. Together with the well characterized role of DNA methylation in long-term ("epigenetic") modes of gene expression, this points to methylation in general as a chemical modification that is associated with enabling stable patterns of genome behavior. Considering the ubiquity of methylation in genome control pathways, it is possible that dietary imbalance affecting methyl-generating pathways may contribute to genome misregulation and disease etiology by affecting the ability of the nucleus to maintain methylation of its components at physiological levels.

Chromatin↗

PubMed1999

Comparative genomics of the Archaea (Euryarchaeota): evolution of conserved protein families, the stable core, and the variable shell.

Comparative analysis of the protein sequences encoded in the four euryarchaeal species whose genomes have been sequenced completely (Methanococcus jannaschii, Methanobacterium thermoautotrophicum, Archaeoglobus fulgidus, and Pyrococcus horikoshii) revealed 1326 orthologous sets, of which 543 are represented in all four species. The proteins that belong to these conserved euryarchaeal families comprise 31%-35% of the gene complement and may be considered the evolutionarily stable core of the archaeal genomes. The core gene set includes the great majority of genes coding for proteins involved in genome replication and expression, but only a relatively small subset of metabolic functions. For many gene families that are conserved in all euryarchaea, previously undetected orthologs in bacteria and eukaryotes were identified. A number of euryarchaeal synapomorphies (unique shared characters) were identified; these are protein families that possess sequence signatures or domain architectures that are conserved in all euryarchaea but are not found in bacteria or eukaryotes. In addition, euryarchaea-specific expansions of several protein and domain families were detected. In terms of their apparent phylogenetic affinities, the archaeal protein families split into bacterial and eukaryotic families. The majority of the proteins that have only eukaryotic orthologs or show the greatest similarity to their eukaryotic counterparts belong to the core set. The families of euryarchaeal genes that are conserved in only two or three species constitute a relatively mobile component of the genomes whose evolution should have involved multiple events of lineage-specific gene loss and horizontal gene transfer. Frequently these proteins have detectable orthologs only in bacteria or show the greatest similarity to the bacterial homologs, which might suggest a significant role of horizontal gene transfer from bacteria in the evolution of the euryarchaeota.

Amino Acid Sequence↗

PubMed1986

Infectious mutants of cassava latent virus generated in vivo from intact recombinant DNA clones containing single copies of the genome.

Intact recombinant DNAs containing single copies of either component of the cassava latent virus genome can elicit infection when mechanically inoculated to host plants in the presence of the appropriate second component. Characterisation of infectious mutant progeny viruses, by analysis of virus-specific supercoiled DNA intermediates, indicates that most if not all of the cloning vector has been deleted, achieved at least in some cases by intermolecular recombination in vivo between DNAs 1 and 2. Significant rearrangements within the intergenic region of DNA 2, predominantly external to the common region, can be tolerated without loss of infectivity suggesting a somewhat passive role in virus multiplication for the sequences in question. Although packaging constraints might impose limits on the amount of DNA within geminate particles, isolation of an infectious coat protein mutant defective in virion production suggests that packaging is not essential for systemic spread of the viral DNA.

DNA Viruses↗

PubMed2004

How viruses enter animal cells.

Viruses replicate within living cells and use the cellular machinery for the synthesis of their genome and other components. To gain access, they have evolved a variety of elegant mechanisms to deliver their genes and accessory proteins into the host cell. Many animal viruses take advantage of endocytic pathways and rely on the cell to guide them through a complex entry and uncoating program. In the dialogue between the cell and the intruder, the cell provides critical cues that allow the virus to undergo molecular transformations that lead to successful internalization, intra-cellular transport, and uncoating.

Active Transport, Cell Nucleus↗

PubMed2006

Multiple QTL influence the serum Lp(a) concentration: a genome-wide linkage screen in the PROCARDIS study.

The serum concentration of lipoprotein Lp (a) is known to be highly heritable and associated with cardiovascular risk. A genome-wide variance component linkage analysis was performed to localise quantitative trait loci (QTLs) influencing Lp(a) levels in a large cohort collected in the PROCARDIS coronary heart disease study. Highly significant linkage was detected at the previously described LP(a) locus on chromosome 6q27 (LOD 108). Taking into account the effect of the locus detected on chromosome 6, a highly significant LOD score was detected on chromosome 13q22-31 (LOD 7.0). Another significant region of linkage was observed on chromosomes 11p14-15 (LOD 3.5). The significant peak at 13q22-31 shows an essential overlap with a locus modulating cholesterol in familial hypercholesterolemia. If the gene underlying these loci is the same, it will be a promising candidate target for manipulating LDL-cholesterol and Lp(a). We also detected linkage at a previously identified locus influencing Lp(a) on chromosome 1q23 (LOD 1.5). Our findings provide new and confirmatory information about genomic regions involved in the quantitative variation of Lp(a) and serve as a basis for further studies of candidate genes in these regions.

Aged↗

PubMed2004

The mouse genome: experimental examination of gene predictions and transcriptional start sites.

The completion of the mouse and other mammalian genome sequences will provide necessary, but not sufficient, knowledge for an understanding of much of mouse biology at the molecular level. As a requisite next step in this process, the genes in mouse and their structure must be elucidated. In particular, knowledge of the transcriptional start site of these genes will be necessary for further study of their regulatory regions. To assess the current state of mouse genome annotation to support this activity, we identified several hundred gene predictions in mouse with varying levels of supporting evidence and tested them using RACE-PCR. Modifications were made to the procedure allowing pooling of RNA samples, resulting in a scaleable procedure. The results illustrate potential errors or omissions in the current 5' end annotations in 58% of the genes detected. In testing experimentally unsupported gene predictions, we were able to identify 58 that are not usually annotated as genes but produced spliced transcripts (approximately 25% success rate). In addition, in many genes we were able to detect novel exons not predicted by any gene prediction algorithms. In 19.8% of the genes detected in this study, multiple transcript species were observed. These data show an urgent need to provide direct experimental validation of gene annotations. Moreover, these results show that direct validation using RACE-PCR can be an important component of genome-wide validation. This approach can be a useful tool in the ongoing efforts to increase the quality of gene annotations, especially transcriptional start sites, in complex genomes.

Animals↗

PubMed2002

Integration of Cot analysis, DNA cloning, and high-throughput sequencing facilitates genome characterization and gene discovery.

Cot-based sequence discovery represents a powerful means by which both low-copy and repetitive sequences can be selectively and efficiently fractionated, cloned, and characterized. Based upon the results of a Cot analysis, hydroxyapatite chromatography was used to fractionate sorghum (Sorghum bicolor) genomic DNA into highly repetitive (HR), moderately repetitive (MR), and single/low-copy (SL) sequence components that were consequently cloned to produce HRCot, MRCot, and SLCot genomic libraries. Filter hybridization (blotting) and sequence analysis both show that the HRCot library is enriched in sequences traditionally found in high-copy number (e.g., retroelements, rDNA, centromeric repeats), the SLCot library is enriched in low-copy sequences (e.g., genes and "nonrepetitive ESTs"), and the MRCot library contains sequences of moderate redundancy. The Cot analysis suggests that the sorghum genome is approximately 700 Mb (in agreement with previous estimates) and that HR, MR, and SL components comprise 15%, 41%, and 24% of sorghum DNA, respectively. Unlike previously described techniques to sequence the low-copy components of genomes, sequencing of Cot components is independent of expression and methylation patterns that vary widely among DNA elements, developmental stages, and taxa. High-throughput sequencing of Cot clones may be a means of "capturing" the sequence complexity of eukaryotic genomes at unprecedented efficiency.

Base Composition↗

PubMed2004

Evolutionary history of Oryza sativa LTR retrotransposons: a preliminary survey of the rice genome sequences.

BACKGROUND: LTR Retrotransposons transpose through reverse transcription of an RNA intermediate and are ubiquitous components of all eukaryotic genomes thus far examined. Plant genomes, in particular, have been found to be comprised of a remarkably high number of LTR retrotransposons. There is a significant body of direct and indirect evidence that LTR retrotransposons have contributed to gene and genome evolution in plants. RESULTS: To explore the evolutionary history of long terminal repeat (LTR) retrotransposons and their impact on the genome of Oryza sativa, we have extended an earlier computer-based survey to include all identifiable full-length, fragmented and solo LTR elements in the rice genome database as of April 2002. A total of 1,219 retroelement sequences were identified, including 217 full-length elements, 822 fragmented elements, and 180 solo LTRs. In order to gain insight into the chromosomal distribution of LTR-retrotransposons in the rice genome, a detailed examination of LTR-retrotransposon sequences on Chromosome 10 was carried out. An average of 22.3 LTR-retrotransposons per Mb were detected in Chromosome 10. CONCLUSIONS: Gypsy-like elements were found to be >4 x more abundant than copia-like elements. Eleven of the thirty-eight investigated LTR-retrotransposon families displayed significant subfamily structure. We estimate that at least 46.5% of LTR-retrotransposons in the rice genome are older than the age of the species (< 680,000 years). LTR-retrotransposons present in the rice genome range in age from those just recently inserted up to nearly 10 million years old. Approximately 20% of LTR retrotransposon sequences lie within putative genes. The distribution of elements across chromosome 10 is non-random with the highest density (48 elements per Mb) being present in the pericentric region.

Chromosomes, Plant↗

PubMed1995

Minisatellites corresponding to the human polycore probes 33.6 and 33.15 in the genome of the most 'primitive' known eukaryote Giardia lamblia.

DNA fingerprinting has been widely used for genetic characterization and individual recognition in a range of species, from man and other mammals down the evolutionary scale to some lower eukaryotic parasites. These techniques utilise repetitive elements first characterised in the human genome, known as minisatellites, which display extensive allelic variability. Few biological or biochemical characteristics have been found that distinguish isolates of Giardia lamblia (Gl), or their apparent variations in virulence. We have characterized 21 Gl isolates in axenic culture using DNA fingerprinting with the human minisatellite probes, 33.6 and 33.15. Up to 12 variable bands per isolate were recognized in the size range of 2.5 to 15 kb by Southern blot hybridization of restriction endonuclease-digested Gl DNA. Most isolates demonstrated a distinct banding pattern or DNA fingerprint. The results suggest that this method may provide a basis for the detailed genotypic characterization of Gl which will be amenable to computer and statistical analysis for use in studies of virulence and epidemiology. Also, as Gl occupies a unique phylogenetic position as a member of the earliest known divergence from the eukaryotic line of descent, this study may provide a useful model for the study of other important eukaryotic pathogens, as it is rapidly becoming apparent that minisatellites are ubiquitous components of eukaryotic genomes.

Animals↗

PubMed1984

Molecular aspects of sperm-egg fusion.

Fertilization, as one of the few well-studied physiological cell fusion systems, provides a glimpse of hierarchies of control that may exist in other membrane fusions as well. Sperm become fusogenic only after undergoing exocytosis from an apical vesicle; this acrosome reaction, induced by an egg surface component, confers upon the sperm the capacity to bind to and fuse with an egg. The acrosome reaction requires Ca2+ and Na+ and is mediated by a complex series of ionic alterations in sperm, including plasma membrane potential depolarization, Ca2+ influx, and increased intracellular pH. These changes take their toll of the sperm, which dies soon thereafter if it does not fertilize an egg. Sperm-egg fusion itself is rapid, with a negligible requirement for extracellular Ca2+, and is inhibited by depolarization of the egg plasma membrane potential. Gamete membrane fusion is followed by dramatic changes in egg physiology, including those that inhibit subsequent sperm-egg fusions. These blocks to polyspermy include a partial decrease in egg surface receptivity caused by egg membrane depolarization immediately after gamete fusion, followed by a complete inhibition of sperm entry due to a massive exocytosis from vesicles beneath the egg plasma membrane, with a concomitant change in the egg plasma membrane and cell coat. The sperm that has successfully fused with an egg contributes not only its genome, but cytoplasmic components as well. Some cytoplasmic constituents from the sperm, including several proteins, persist without degradation throughout early development; several remain localized in a single region. Whether these cytoplasmic components transferred from the sperm play a role in subsequent morphogenesis of the embryo is not clear.

Acrosome↗

PubMed2026

Genomic analysis of breed composition and population structure in Montana composite cattle.

The Montana composite was developed in Brazil from crosses between Bos indicus and Bos taurus and structured into four biological types: Zebu (N), adapted taurine (A), British taurine (B), and continental taurine (C). This study aimed to characterize the genetic diversity and population structure of the Montana composite using genomic data through principal component analysis (PCA), admixture analysis, and Wright's FST statistic. The PCA revealed a clear separation between Bos indicus and Bos taurus groups, with Montana animals distributed in an intermediate position. The first two principal components explained 69.48% and 3.45% of the total variation, respectively. Supervised admixture estimates indicated a predominance of taurine contribution, with type A accounting for 34.47%, 52.64%, and 51.71% at K = 4, 9, and 11, respectively. Increasing the ancestry resolution refined the contribution of individual founder breeds without changing the overall predominance of taurine ancestry. Comparisons between breed proportions obtained from pedigree and genomic data revealed significant differences, for most biological types and ancestry models (P < 0.001), indicating that realized breed composition deviates from theoretical expectations. Estimates of genetic differentiation confirmed greater divergence between Zebu and taurine groups, as well as reduced distances among populations sharing common ancestry. Specific relationships were identified between the composite and some of its founder breeds, particularly Belmont Red, Senepol, and Tuli. Overall, the results demonstrate that the Montana composite has a complex genomic structure, with genomic ancestry varying according to the resolution adopted and differing from pedigree-based expectations.

Animals↗

PubMed1994

The genomic instability associated with integrated simian virus 40 DNA is dependent on the origin of replication and early control region.

DNA rearrangements in the form of deletions and duplications are found within and near integrated simian virus 40 (SV40) DNA in nonpermissive cell lines. We have found that rearrangements also occur frequently with integrated pSV2neo plasmid DNA. pSV2neo contains the entire SV40 control region, including the origin of replication, both promoters, and the enhancer sequences. Linearized plasmid DNA was electroporated into X1, an SV40-transformed mouse cell line that expresses SV40 large T antigen (T Ag) and shows very frequent rearrangements at the SV40 locus, and into LMtk-, a spontaneously transformed mouse cell line that contains no SV40 DNA. Stability was analyzed by subcloning G-418-resistant clones and examining specific DNA fragments for alterations in size. Five independent X1 clones containing pSV2neo DNA were unstable at both the neo locus and the T Ag locus. By contrast, four X1 clones containing mutants of pSV2neo with small deletions in the SV40 core origin and three X1 clones containing a different neo plasmid lacking SV40 sequences were stable at the neo locus, although they were still unstable at the T Ag locus. Surprisingly, five independent LMtk- clones containing pSV2neo DNA were unstable at the neo locus. LMtk- clones containing origin deletion mutants were more stable but were not as stable as the X1 clones containing the same plasmid DNA. We conclude that the SV40 origin of replication and early control region are sufficient viral components for the genomic instability at sites of SV40 integration and that SV40 T Ag is not required.

Animals↗