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PubMed1986

Scrapie and cellular PrP isoforms are encoded by the same chromosomal gene.

PrP 27-30 is the major protein in purified preparations of scrapie agent. An almost complete PrP cDNA was used to select PrP-related genomic clones from normal hamster DNA. The gene contains a noncoding exon of 56 to 82 bp and a 2 kb coding exon, separated by a 10 kb intron. Transcription initiates at the same multiple sites in vivo and in vitro. The promoter lacks a TATA box and contains three repeats of the sequence GCCCCGCCC, which resembles the Sp1 binding site found in "housekeeping" genes. The PrP coding sequence encodes a presumptive amino-terminal signal peptide. The primary structure of PrP encoded by the gene of a healthy animal does not differ from that encoded by a cDNA from a scrapie-infected animal, suggesting that the different properties of PrP from normal and scrapie-infected brains are due to post-translational events.

Animals↗
PubMed1996

X chromosome imprinting and inactivation in the early mammalian embryo.

Quantitative differences in X-linked gene expression between androgenetic (two paternal genomes), gynogenetic (two maternal genomes) and normal embryos provide clues into the roles of genomic imprinting and the X:autosome ratio in controlling X chromosome function during development. These data and many others can be accounted for by a new model of X-chromosome-inactivation (XCI). Expression of the Xist RNA from all paternal X chromosomes during development preimplantation leads to repression of genes near the X-chromosome-inactivation center (Xic). Other genes are repressed as a result of spreading of the inactivation, but only in embryos with at least two X chromosomes. XY androgenones are only deficient in expression of genes near the Xic and can form blastocysts, whereas XX androgenones completely inactivate both X chromosomes and die before the blastocyst stage. The X:autosome ratio regulates XCI solely by promoting the spread of inactivation away from the Xic on chromosomes that express Xist. Methylation of the maternal Xist gene is retained in extraembryonic tissues, so that gynogenones and parthenogenones cannot express Xist, do not undergo XCI in those tissues, and so have extraembryonic defects. This model should be relevant to understanding how aberrant X chromosome regulation might occur and how this might contribute to distortion of the X-chromosome-transmission ratio, sex ratio distortion, and disease.

Animals↗
PubMed2004

Genomic organization and characterization of the promoter for the E2A gene.

Although E2A gene products are ubiquitously expressed, E2A-deficient mice display selective abnormalities in lymphocyte development, suggesting a certain requirement of the E2A gene products during lymphocyte development. To gain insights into the mechanisms of E2A transcriptional regulation, we isolated the genomic clones which are composed of four exons and one noncoding exon and span approximately 16 kb. The promoter region of E2A gene lacks a TATA box, and primer extension analysis showed several transcription initiation sites, a feature that characterizes TATA-less promoters. The transient transfection assay using the 5'-flanking region (positions -2994/+62) revealed that both positive (-357/-158) and negative (-831/-358) regulatory segments control E2A transcription in B-cell (WEHI-231) and T-cell (DO11.10) lines. However, contribution of a certain segment to promoter activity was different between lymphocytes and fibroblasts (NIH-3T3). Sequential deletion analysis of the constructs spanning the positive regulatory segments showed that the segment -257/-238 played a critical role in the basal promoter activity of the E2A gene, although other segments within -337 to -158 also appeared to be involved. Mutational analysis using the -257/-238 fragment failed to demonstrate a single cis-element responsible for the basal promoter activity, suggesting that E2A promoter requires the interaction of multiple regulatory elements. Electrophoretic mobility shift assay (EMSA) demonstrated a highly specific complex comprised of a positive regulatory segment (-267/-238) and putative transcription factor(s), which might be necessary for the basal promoter activity of the E2A gene.

5' Flanking Region↗
PubMed2003

Imprinted X-chromosome inactivation: enlightenment from embryos in vivo.

There are two forms of X chromosome inactivation (XCI) in the laboratory mouse, random XCI in the fetus and imprinted paternal XCI limited to the extraembryonic tissues supporting the fetal life in utero. Imprinted XCI has been studied extensively because it takes place first in embryogenesis and it may hold clues to the mechanism of control of XCI in general and to the evolution of random' XCI. Classical microscopic and biochemical studies of embryos in vivo provide a basis for interpreting the multifaceted information yielded by various inventive approaches and for planning further experiments.

Animals↗
PubMed1998

Xist and X chromosome inactivation.

X inactivation acts in female mammals to equalise X-linked gene dosage between XX females and XY males. X inactivation is controlled by a single X-linked cis-acting locus called the X inactivation centre (Xic). In 1991 the Xist gene was identified as a candidate for the Xic. Xist is expressed in all adult female tissues, but only from the allele on the inactive X. The Xist transcript does not encode a protein but remains sequestered within the nucleus and co-localises with the inactive X chromosome. Transgenic and knockout studies have shown that a genomic region covering only a few kilobases either side of Xist carries all of the functions attributed to the Xic. The major questions currently occupying researchers studying X inactivation are: how do cells count their number of X chromosomes to determine whether X inactivation is necessary, and how does the Xist transcript inactivate all genes on the X chromosome?

Dosage Compensation, Genetic↗
PubMedDate not supplied

X inactivation: Tsix and Xist as yin and yang.

A new study shows that expression of Tsix, an antisense Xist gene, can be controlled by imprinting, and that high Tsix activity during X inactivation can protect the future active X chromosome from silencing by Xist. Tsix and Xist seem to have a yin and yang relationship, with opposite effects on X inactivation.

Animals↗
PubMed2006

Scale-invariant structure of strongly conserved sequence in genomic intersections and alignments.

A power-law distribution of the length of perfectly conserved sequence from mouse/human whole-genome intersection and alignment is exhibited. Spatial correlations of these elements within the mouse genome are studied. It is argued that these power-law distributions and correlations are comprised in part by functional noncoding sequence and ought to be accounted for in estimating the statistical significance of apparent sequence conservation. These inter-genomic correlations of conservation are placed in the context of previously observed intra-genomic correlations, and their possible origins and consequences are discussed.

Animals↗
PubMed1982

Polyoma mutants that productively infect F9 embryonal carcinoma cells do not rescue wild-type polyoma in F9 cells.

Mouse embryonal carcinoma cells are refractory to infection by wild-type polyoma virus, the infection process apparently being blocked at a stage after adsorption and penetration but before early protein synthesis. Polyoma virus mutants capable of productive infection of mouse embryonal carcinoma cells have been isolated and these mutants all have DNA sequence alterations in a noncoding region near the origin of replication of the viral genome. PyF101 and PyF441 are two mutants selected for their ability to infect the embryonal carcinoma cell line F9. Here we show that these PyF mutants do not rescue replication of wild-type polyoma during a mixed infection of F9 cells. The mutant and wild-type DNAs were distinguished on the basis of restriction fragments obtained by digestion with Msp I or BstNI, and no wild-type DNA was detected in F9 cells coinfected with wild-type polyoma and with either PyF101 or PyF441. The mutant viruses do not appear to inhibit wild-type replication during a mixed infection because both mutant and wild-type DNAs can replicate efficiently in coinfected 3T6 cells which are permissive for both mutant and wild-type viruses. A double mutant having the PyF101 mutation and the ts-25E temperature-sensitive mutation in polyoma large tumor antigen was constructed and found to be temperature-sensitive for replication in F9 cells. This double mutant, designated PyFts-1, can be rescued in F9 cells at the restrictive temperature by coinfection with PyF441. These results suggest that the PyF mutations affect two processes in F9 cells, one involving expression of polyoma early genes and a second involving viral DNA replication.

Animals↗
PubMed1995

Analysis of human papillomavirus type 16 variants indicates establishment of persistent infection.

Sequence differences in the noncoding region of the human papillomavirus type 16 (HPV-16) genome were displayed using single-stranded conformational polymorphism (SSCP) analysis of polymerase chain reaction (PCR)-amplified material. Two variants accounted for 50%-70% of all HPV-16 variants from 3 cohorts in Seattle. Seventy subjects who were repeatedly HPV-16 DNA-positive over 2-8 4-monthly visits showed an identical SSCP pattern at every visit. Only 10%-20% of the specimens showed evidence of infection by multiple variants when assessed by SSCP. However, cloning and sequencing of the PCR products revealed a substantially higher proportion of specimens with > 1 variant. Sequencing many clones from each specimen confirmed that 1 major variant seemed to predominate over time, whereas minor variants appeared more transient. These results suggest that HPV-16 establishes a persistent infection in which a single variant predominates: coinfection with addition HPV-16 variants results in a minor population of HPV-16 genomes.

Base Sequence↗
PubMed1988

Mono- through hexanucleotide composition of the sense strand of yeast DNA: a Markov chain analysis.

Here we compare several methods for predicting oligonucleotide frequencies in 392 kb of yeast DNA. As in previous work on E. coli, a relatively simple equation based on tetranucleotide frequencies can be used in predicting the frequencies of longer oligonucleotides. For example, the mean of observed/expected abundances of 4,096 hexamers was 1.00 with a sample standard deviation of .18. This simple predictor arises by considering each base on the sense strand of yeast to depend only on the three bases 5' to it (a 3rd order Markov chain) and is more accurate in estimating oligonucleotide frequencies than other statistical methods examined. This equation is useful in predicting restriction enzyme fragment sizes, selecting restriction enzymes that cut preferentially in coding vs noncoding regions, and in constructing detailed physical maps of whole genomes. When ranked highest to lowest abundance, the observed frequencies of oligomers of a given length (up to 6 bases) are closely tracked by the predicted abundances of a 3rd or 4th order Markov chain. These ordered abundance curves have a power curve shape with a broad linear range with a sharp break at the top end of the curve. There is also a strong disparity between the most and least abundant oligomer with for example a 79-fold variation between the most and least abundant hexamer. The curves reveal a strong dependence of oligomer frequencies on base composition. Unlike E. Coli, there is no sharp downturn at the low end of the curves and hence, no class of oligomers rare relative to other oligomers of the same length.

Base Composition↗
PubMed2003

Imprinting errors and developmental asymmetry.

There are, in the broadest sense, two mechanisms by which gene expression can be extinguished in vertebrates. The first of these is based on mass action effects of positive and negative regulatory factors and is termed activation and repression; the second is independent of positive regulatory factors but is based on the history of the affected gene and is termed silencing. It can be said, again in the broadest sense, that imprinted genes, genes subject to X inactivation, and transposon promoters are subject to silencing, while the promoters of tissue-specific genes in non-expressing tissues are controlled by activation and repression. The escape of imprinted genes from silencing through unknown mechanisms can cause developmental abnormalities and can predispose to the formation of embryonal tumours. One developmental disorder caused by loss of imprinting of genes on chromosome 11p15.5 is Beckwith-Wiedemann syndrome (BWS). This syndrome has long been known to be inexplicably common in monozygotic twins; the twins are nearly always discordant for BWS, and nearly all twins are female. A loss of imprinting model based on stochastic errors in the nucleocytoplasmic trafficking of the DNA methyltransferase DNMT1, or a paternally expressed function that opposes maintenance methylation of maternally repressed growth-enhancing genes, is proposed to explain the perplexing genetics of BWS in monozygotic twins.

Beckwith-Wiedemann Syndrome↗
PubMed1998

Nucleotides in the panhandle structure of the influenza B virus virion RNA are involved in the specificity between influenza A and B viruses.

Influenza A and B viruses share common sequences and potentially similar panhandle structures in the terminal noncoding regions of virion RNA (vRNA). Interesting differences exist, however, in the number of conserved nucleotides at the 5' and 3' ends of the vRNAs, in base pairs constituting the panhandle duplex, and the length of uridine stretch (U stretch) juxtaposed to the RNA duplex. To analyse the contribution of these signals to the specificity between the two viruses, a transient ribonucleoprotein transfection method was used for the expression of the chloramphenicol acetyltransferase (CAT) reporter gene flanked by the noncoding nucleotides derived from influenza B vRNA. While the base pairing in the RNA duplex was primarily important for template activity, mismatch mutations G11 x G12' and C12 x A13' in the terminal RNA duplex region were utilized by influenza B virus, whereas these mutations were detrimental for influenza A virus. Different activity profiles were observed in the length preference of the RNA duplexes: maximum template activity was observed with 11 base pairs for influenza B virus, and 8 base pairs for influenza A virus. When the mutants with various lengths of U stretch were tested, highest CAT activities were observed with 5 to 7 uridine residues in influenza A virus, whereas in influenza B virus the activity was drastically decreased with 7 uridine residues. We suggest that the specific interaction of influenza virus RNA polymerase with these noncoding cis-acting signals in transcription of the RNA genome, along with unique coding strategies adopted by influenza B virus, has contributed to the divergence of these two closely related viruses.

Animals↗
PubMedDate not supplied

Genetics in heart failure: where are we headed?

Heart failure is a complex disease with many precipitating factors. Novel insights into the genetic background of heart failure have boosted new areas of research that gave rise to the concept of genetic predisposition for heart failure. Various genetic defects and variances have been identified and subsequently linked to the onset of or progression to heart failure. Nevertheless, our understanding of the genetic basis for heart failure is incomplete because we lack knowledge of the functionality of genetic variances. We also do not understand the impact of genetic variances in noncoding DNA because of logistic problems in performing whole-genome scans and difficulties in statistical evaluation of large amounts of data generated by the genetic boom. It is expected that in the future we will be able to overcome these problems and apply the knowledge gained by genetic analyses to target and optimize treatment.

Genetic Predisposition to Disease↗
PubMed1987

Diagnosis of porcine and bovine enteric coronavirus infections using cloned cDNA probes.

Molecular clones representing the first 2,000 bases from the 3' end of the porcine transmissible gastroenteritis coronavirus genome and the first 2,160 bases from the 3' end of the bovine enteric coronavirus genome were used in dot blot hybridization assays to detect viral RNA from cell culture and from fecal specimens. In each case, the cloned DNA represents approximately 10% of the genome. The cloned sequence for each virus encompasses the 3' noncoding region, the nucleocapsid protein gene, and a large portion of the matrix protein gene. 32P-labeled cDNA probes prepared from these clones detected as little as 25 pg of RNA from the parental virus but did not detect RNA from the nonparental virus even when amounts of up to 10 ng per dot were used. This specificity reflects the antigenic diversity between these two coronaviruses. The hybridization assay could also detect coronaviruses antigenically closely related to the parental virus but not coronaviruses belonging to an antigenically unrelated subgroup. Dot blot hybridization for transmissible gastroenteritis coronavirus diagnosis was compared with the routine procedures of virus isolation and electron microscopy as a diagnostic test.

Animals↗
PubMed1985

Molecular cloning and nucleotide sequence of deer papillomavirus.

The genome of deer papillomavirus (DPV) isolated from American white-tailed deer was cloned into pBR322, and the entire nucleotide sequence of 8,374 base pairs was determined. The overall genetic organization of the DPV genome was similar to that of other papillomaviruses. All significant open reading frames were located on one strand, and the locations of putative promoters and polyadenylation signals were similar to those identified in the closely related bovine papillomavirus type 1 (BPV-1) genome. The DPV genome was approximately colinear with BPV-1 except for a noncoding region separating the early and late regions. The regions of highest nucleotide sequence homology between DPV and BPV-1 were found in the E1 open reading frame coding for BPV-1 DNA replication function and in the L1 open reading frame, which encodes the major capsid protein of BPV-1.

Animals↗
PubMed2005

Euchromatic and heterochromatic domains at Drosophila telomeres.

Noncoding repetitive sequences make up a large portion of eukaryotic genomes, but their function is not well understood. Large blocks of repetitive DNA-forming heterochromatin around the centromeres are required for this region to function properly, but are difficult to analyze. The smaller regions of heterochromatin at the telomeres provide an opportunity to study their DNA and protein composition. Drosophila telomere length is maintained through the targeted transposition of specific non-long terminal repeat retrotransposons to chromosome ends, where they form long tandem arrays. A subterminal telomere-associated sequence (TAS) lies immediately proximal to the terminal-retrotransposon array. Here, we review the experimental support for the heterochromatic features of Drosophila telomeres, and provide evidence that telomeric regions contain 2 distinct chromatin subdomains: TAS, which exhibits features that resemble beta heterochromatin; and the terminal array of retrotransposons, which appears euchromatic. This organization is significantly different from the telomeric organization of other eukaryotes, where the terminal telomerase-generated repeats are often folded in a t-loop structure and become part of the heterochromatin protein complex.

Animals↗
PubMed2006

Rapid and quantitative method of allele-specific DNA methylation analysis.

Several biological phenomena depend on differential methylation of chromosomal strands. While understanding the role of these processes requires information on allele-specific methylation, the available methodologies are not quantitative or labor-intensive. We describe a novel, rapid method to quantitate allele-specific DNA methylation based on the combination of bisulfite PCR and Pyrosequencing. In this method, DNA is first treated with sodium bisulfite, which converts cytosine but not 5-methylcytosine to uracil. Genes of interest are subsequently amplified using PCR. Allele-specific methylation can then be determined by pyrosequencing each allele individually using sequencing primers that incorporate single nucleotide polymorphisms (SNPs) that allow differentiation between the two parental alleles. This allele-specific methylation methodology can potentially afford quantitative analyses relevant to the regulation of X chromosome inactivation, allele-specific expression of genes in the immune system, repetitive elements, and genomic imprinting. As an illustration of our new method, we quantitated allele-specific methylation of the differentially methylated region of the H19 gene, which is imprinted. Although we could reliably determine allele-specific methylation with our technique, additional studies will be required to confirm the ability of our assay to measure loss of imprinting.

Alleles↗