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PubMed2002

Yfm1, a multicopy marker specific for the Y chromosome and beneficial for forensic, population, genetic, and spermatogenesis-related studies.

A recently developed microsatellite marker on the Y chromosome, Yfm1, which was originally cloned from a cosmid clone mapped near the DAZ (Deleted in AZoospermia) genes, was used to classify Y chromosomes using an automatic sequencer. Yfm1 could detect multicopies on Y chromosomes in a single polymerase chain reaction, showing four main classes, A, A*, B, and C, according to the number of copies and peak patterns. Compound haplotype analysis of the Y chromosome using the Yfm1 marker with three other biallelic markers on the Y chromosome, SRY, DXYS5Y, and YAP, resulted in nine different haplotypes among different populations, including Japanese. Haplotype II (defined by YAP insertion) observed in the Japanese population was consistently associated with Yfm1 class A or A*, which showed the lowest number of copies of Yfm1. Haplotypes III and IV were consistently associated with Yfm1 class B. On the other hand, haplotype I showed a variety of Yfm1 patterns that were dubbed class C when not appropriately classified as A, A*, or B. These relationships among Yfm1 microsatellite and Y-specific biallelic markers could supply useful population genetic information. Moreover, because we have already shown that men with haplotype II have significantly lower spermatogenic ability than those with other haplotypes, Yfm1 class A or A* with the least number of copies may be related to the haplotype II-specific structure of the Y chromosome, such as deletion of DAZ or DAZ repeats, reflecting the lower spermatogenic abilities of Japanese haplotype II men. Thus, Yfm1 represents a very useful marker for analysis of genetic structure in different populations and studies on Y chromosome lineage-specific genotype-phenotype correlations.

Alleles↗

PubMed1990

Structural diversity in the 45-kilodalton merozoite surface antigen of Plasmodium falciparum.

An integral membrane protein associated with the merozoite surface of Plasmodium falciparum termed merozoite surface antigen 2 (the 45-kDa merozoite surface antigen), occurs in antigenically diverse forms. Here we report the sequences of the MSA 2 gene from two other isolates of P. falciparum. The 43 N-terminal residues and the 74 C-terminal residues of all three MSA 2 sequences are highly conserved, but between these conserved regions there are dramatic differences among the alleles. Instead of the two copies of a 32-amino-acid repeat present in the MSA 2 of isolate FC27, MSA 2 from clone 3D7 and isolate Indochina 1 contain 5 and 12 copies respectively of the four amino acid sequence Gly Gly Ser Ala. The sequences flanking the repeats also differ among the three antigens. The repeats in MSA 2 appear to be immunodominant during natural infection, and antibodies to the repeat regions of different alleles react with a restricted number of parasite isolates.

Amino Acid Sequence↗

PubMedDate not supplied

Evidence of chromosomal instability in prostate cancer determined by spectral karyotyping (SKY) and interphase fish analysis.

The way in which cytogenetic aberrations develop in prostate cancer (CaP) is poorly understood. Spectral karyotype (SKY) analysis of CaP cell lines has shown that they have unstable karyotypes and also have features associated with chromosomal instability (CIN). To accurately determine the incidence of de novo structural and numerical aberrations in vitro in CaP, we performed SKY analysis of three independent clones derived from one representative cell line, DU145. The frequent generation of new chromosomal rearrangements and a wide variation in the number of structural aberrations within two to five passages suggested that this cell line exhibited some of the features associated with a CIN phenotype. To study numerical cell-to-cell variation, chromosome 8 aneusomy was assessed in the LNCaP, DU145, and PC-3 cell lines and a patient cohort of 15 CaP primary tumors by interphase fluorescence in situ hybridization (FISH). This analysis showed that a high frequency of numerical alteration affecting chromosome 8 was present in both in vitro and in CaP tissues. In comparison to normal controls, the patient cohort had a statistically significant (P<.05), greater frequency of cells with one and three centromere 8 copies. These data suggest that a CIN-like process may be contributing towards the generation of de novo numerical and structural chromosome abnormalities in CaP.

Chromosome Aberrations↗

PubMed1992

Molecular genetic studies of tumor suppressor gene regions on chromosomes 13 and 17 in colorectal tumors.

BACKGROUND: In the majority of colorectal carcinomas, both copies of the tumor suppressor gene TP53 (tumor protein 53) are known to be inactivated. In contrast to a loss of tumor suppressor function, it has been suggested that an increased copy number of the RB1 gene is involved in the progression of these tumors. PURPOSE: To determine genetic alterations at chromosomes 13 and 17 in colorectal tumors, we have studied several loci on these chromosomes, with special focus on the RB1 and TP53 genes at both the level of DNA sequence and the level of gene expression. METHODS: Restriction fragment length polymorphism analysis was performed after alkaline Southern blotting of the DNA fragments and hybridization (in 7% sodium dodecyl sulfate and 0.5 M NaPO4) of the nylon membranes with multiprimed, radioactively labeled probes. Total RNA was extracted from tissue biopsy specimens by homogenization of the samples in guanidinium thiocyanate followed by separation in a CsCl gradient. By use of an image-processing system, x-ray film signals were measured densitometrically. Point mutations within the TP53 gene were detected by use of polymerase chain reaction (PCR) in combination with constant denaturant gel electrophoresis. Direct sequencing of PCR products revealed the exact nature of the mutations. Protein expression of TP53 was seen by immunostaining of sections from paraffin-embedded material using a mouse monoclonal antibody. The two-sided Fisher's Exact Test was used for statistical analysis. RESULTS: An increase in allelic copy number at 13q loci was seen in 10 (32%) of 31 tumors. In the majority of the cases, this increase probably reflected a change in the diploid status of chromosome 13; in some cases, however, only part of the 13q seemed to be involved. The RB1 gene showed an elevated level of RNA compared with the beta-actin signal. Fourteen (48%) of 29 tumors showed loss of heterozygosity at loci on 17p, and base mutations within the TP53 gene were seen in 14 (42%) of 33 tumors. RNA and protein analyses of TP53 revealed an increased level of expression in the tumors compared with normal mucosa. Allelic variations seen at 13q and 17p were not associated (P = .7). CONCLUSIONS: Our results suggest that, in addition to aneuploidy, gain of specific chromosome 13 sequences is involved in the tumorigenesis of the colon and rectum. In addition, they confirm the importance of TP53 mutations for the progression of such tumors and support the view that accumulation of events is more important than the order of events. The genetic changes observed at chromosome arms 13q and 17p seem to be independent of each other.

Adolescent↗

PubMed1993

Telomere reduction in hematologic cells.

The broken ends of chromosomes are unstable, and tandem fusion of telomeres has been observed in some tumors. Using Southern blot analysis, we report here telomeric DNA changes in hematologic cells. There was some variation in the length of the telomeric DNA in normal peripheral blood mononuclear cells obtained from four different individuals, ranging from 10 to 12 kilobases (kb), but there was little difference in signal strength. In two cell lines tested, HL-60 and K562, there was a telomeric sequence reduction of 2-4 kb and there was also a diminution of signal intensity. Reduction of the telomeric DNA array was also observed in two leukemic cases tested. The peak telomere length of the leukemic cells was 5 and 4 kb before and 10 and 7 kb after treatment, respectively, and in one case there was also a reduction in copy numbers of about 50%. Since no remarkable changes were detected in the Alu and alphoid sequences in either normal or leukemic cells, it appeared that the DNA change was specific to telomeric regions. Assessment of telomeric DNA changes may aid in determining the biological significance of leukemic cells.

Adult↗

PubMed1995

Different evolutionary behaviour of P element subfamilies: M-type and O-type elements in Drosophila bifasciata and D. imaii.

Distribution and variation of two P-element subfamilies designated M-type and O-type elements were investigated in Drosophila bifasciata (Db) and its relatives. PCR screening revealed that full-sized and internally deleted elements of both types occur in three geographic Db strains and in the related species, D. imaii (Di). Molecular analyses indicate differences in the evolutionary behaviour of the two P-element types. Internally deleted M-type elements fall into two size classes present in all three Db strains. In contrast, internally deleted O-type elements vary between the strains in number and length. With respect to genomic location, M-type elements seem to be restricted to conserved euchromatic sites, whereas the positions of O-type elements appear to be geographically variable. In one strain of Db (Italy), O-type elements seem to accumulate in the heterochromatin. Sequencing of a 397-bp segment shows intra- and interspecific divergence of M-type elements. In a 452-bp segment of the O-type elements, no substitutions were found, neither within nor between species. This finding suggests recent introgression of O-type elements via hybridization between Db and Di. Sequence identity and variation in chromosomal locations among different copies imply that O-type elements are transpositionally active. For M-type elements, genomic mobility cannot be proved. In a survey of several other taxa, no O-type-related sequences were detected so far. Therefore, the origin of the O-type subfamily remains unknown, whereas the source of M-type elements can be traced back to the genus Scaptomyza.

Animals↗

PubMed2005

Bioluminescence regenerative cycle (BRC) system: theoretical considerations for nucleic acid quantification assays.

A novel application of bioluminescence for nucleic acid quantification, the bioluminescence regenerative cycle (BRC), is described in theoretical terms and supported by preliminary experimental data. In the BRC system, pyrophosphate (PPi) molecules are released during biopolymerization and are counted and correlated to DNA copy number. The enzymes ATP-sulfurylase and firefly luciferase are employed to generate photons quantitatively from PPi. Enzymatic unity-gain positive feedback is implemented to amplify photon generation and to compensate for decay in light intensity by self-regulation. The cumulative total of photons can be orders of magnitude higher than in typical chemiluminescent processes. A system level theoretical model is developed, taking into account the kinetics of the regenerative cycle, contamination, and detector noise. Data and simulations show that the photon generation process achieves steady state for the time range of experimental measurements. Based on chain reaction theory, computations show that BRC is very sensitive to variations in the efficiencies of the chemical reactions involved and less sensitive to variations in the quantum yield of the process. We show that BRC can detect attomolar quantities of DNA (10(-18) mol), and that the useful dynamic range is five orders of magnitude. Sensitivity is not constrained by detector performance but rather by background bioluminescence caused by contamination by either PPi or ATP (adenosine triphosphate).

Adenosine Triphosphate↗

PubMed1998

Factors contributing to the hybrid dysgenesis syndrome in Drosophila virilis.

A hybrid dysgenesis syndrome in Drosophila virilis is associated with the mobilization of at least four unrelated transposable elements designated Helena, Paris, Penelope and Ulysses. We carried out 42 crosses between eight strains differing in transposable element copy number in order to assess their contributions to hybrid dysgenesis. Linear regression and stepwise regression analysis was performed to estimate the correlation between the difference in euchromatic transposable element number between the parental flies of different strains involved in the crosses and the percentage, in the progeny of these crosses, of males with atrophic gonads. Male gonadal atrophy is a typical manifestation of the D. virilis hybrid dysgenesis syndrome. About half the variability in the level of male gonadal atrophy can be attributed to Penelope and Paris/Helena. Other factors also seem to play a significant role in hybrid dysgenesis in D. virilis, including maternally transmitted host factors and/or uncontrolled environmental variation. In the course of this work a novel transposable element named Telemac was found. Telemac is also mobilized in hybrid dysgenesis but does not appear to play a major causative role.

Animals↗

PubMed1997

Evaluation of Two Methods for Quantitation of Hepatitis C Virus RNA.

Background: Accurate quantitation of hepatitis C virus (HCV) RNA in serum may provide a means to predict disease course and response to interferon-alpha therapy. Several quantitative assays are commercially available, but none have been accepted as the gold standard. Methods and Results: The branched DNA quantitative hybridization assay (Quantiplex HCV 1.0, Chiron, Emeryville, CA) and a quantitative reverse transcription polymerase chain reaction (Amplicor HCV MONITOR, Roche Diagnostic Systems, Branchburg, NJ) were compared using a panel of 53 sera from patients with chronic hepatitis C. All sera contained HCV RNA of known genotype. Overall, there was a positive correlation between the results for the 41 sera that gave discrete values in both tests (r =.81, linear regression; P <.01, Kendall's rank test); however, the mean number of HCV copies per milliliter was 13.5-fold higher with Quantiplex (P <.01). A plot of the difference between methods against their means showed poor agreement between the methods. No correlation between the results of the two tests was observed for sera with MONITOR values greater than 5.0 x 10(5) copies/mL. Discrete MONITOR values were obtained for all 12 sera that were below the lower limit of quantitation of Quantiplex (mean, 1.78 x 10(5)). Parallel testing of serial dilutions of two sera showed that each method gave linear responses over the stated dynamic ranges; however, the proportional systematic error was greater with MONITOR. The mean coefficient of variation for replicate determinations was 23% for Quantiplex and 45% for MONITOR (P =.13). Conclusions: Despite a positive correlation, systematic differences exist between the two methods for quantitation of HCV RNA and they cannot be used interchangeably.

Journal Article↗

PubMed2026

Comparative analysis of distinct genomic landscapes in young-onset gBRCA1/2 breast cancer.

Carriers of germline BRCA1/2 pathogenic variants (gBRCA1/2 PVs) have elevated young-onset breast cancer risk. To define the pretreatment genomic landscapes of young-onset gBRCA-associated breast cancer, we evaluated 136 treatment-naive tumors diagnosed before age 50 in the prospective POSH study and 66 noncarriers from The Cancer Genome Atlas. Using whole-exome sequencing, we analyzed somatic variation, allele-specific loss of heterozygosity (asLOH), homologous recombination deficiency (HRD), and single-base substitution (SBS) signatures. gBRCA1 and gBRCA2 breast cancers had high rates of asLOH but differed significantly in average HRD scores and median SBS composition of signatures SBS1 (aging-associated), SBS18 (ROS-associated), and SBS3 (HRD-associated). Compared with gBRCA2 tumors, gBRCA1 tumors with asLOH were significantly enriched for alterations in hallmark ROS, DNA repair, and epithelial-mesenchymal transition pathways. In ER-positive, HER2-negative tumors from gBRCA1/2 carriers compared with noncarriers, we found significant enrichment of RB1, TP53, FAT1, and MYC single-nucleotide variants, indels, and copy number variants associated with CDK4/6 inhibitor (CDK4/6i) resistance. Together, these findings demonstrate significant differences between gBRCA1- and gBRCA2-associated breast cancers, and preexisting CDK4/6i resistance mechanisms, supporting prospective trials comparing individualized therapy for gBRCA1 versus gBRCA2 carriers and comparing poly(ADP-ribose) polymerase inhibitors versus CDK4/6i for ER-positive gBRCA1/2-associated breast cancer.

Humans↗

PubMed1984

Temperature as a determinative factor in the evolution of genetic systems.

Heat induces a number of premutational lesions (for example, the deamination of cytosine to uracil) in DNA and RNA. These kinds of errors occur in resting as well as replicating polynucleotides. However, an increase in temperature also raises the probability of copying error occurring in nucleic acids because of increased thermal noise in the replicative machinery. In most modern genetic systems, the majority of heat-induced lesions are efficiently repaired. It follows that the importance of heat-induced error increases as the effectiveness of repair declines. We show in this paper that the error rate of enzymatic polynucleotide copying is expected to increase monotonically with temperature. We also explore the effects of temperature variations on the early evolution of biological information transmission mechanisms.

Biological Evolution↗

PubMed1987

Isolation of polymorphic DNA fragments from human chromosome 4.

We have identified and characterized 40 DNA probes detecting restriction fragment length polymorphism (RFLP) on human chromosome 4. Single copy human clones were isolated from a bacteriophage library enriched for chromosome 4 sequences. Each clone was hybridized to somatic cell hybrid DNAs for verification of its species and chromosomal origin and for regional localization. Sequences specific for chromosome 4 were tested for their ability to detect RFLPs in human DNA and their potential utility as genetic markers was assessed. Approximately 263,000 base pairs or 0.13% of the chromosome was screened for sequence variation. The estimate of heterozygosity calculated from this large body of data, H = 0.0021, indicates that the degree of sequence variation on chromosome 4 is comparable to other autosomes. The characterization of these 40 markers has tripled the number of polymorphic loci available for linkage studies on chromosome 4, making it feasible to begin construction of a detailed linkage map that will span the entire chromosome.

Animals↗

PubMed2005

Assessing the fidelity of ancient DNA sequences amplified from nuclear genes.

To date, the field of ancient DNA has relied almost exclusively on mitochondrial DNA (mtDNA) sequences. However, a number of recent studies have reported the successful recovery of ancient nuclear DNA (nuDNA) sequences, thereby allowing the characterization of genetic loci directly involved in phenotypic traits of extinct taxa. It is well documented that postmortem damage in ancient mtDNA can lead to the generation of artifactual sequences. However, as yet no one has thoroughly investigated the damage spectrum in ancient nuDNA. By comparing clone sequences from 23 fossil specimens, recovered from environments ranging from permafrost to desert, we demonstrate the presence of miscoding lesion damage in both the mtDNA and nuDNA, resulting in insertion of erroneous bases during amplification. Interestingly, no significant differences in the frequency of miscoding lesion damage are recorded between mtDNA and nuDNA despite great differences in cellular copy numbers. For both mtDNA and nuDNA, we find significant positive correlations between total sequence heterogeneity and the rates of type 1 transitions (adenine --> guanine and thymine --> cytosine) and type 2 transitions (cytosine --> thymine and guanine --> adenine), respectively. Type 2 transitions are by far the most dominant and increase relative to those of type 1 with damage load. The results suggest that the deamination of cytosine (and 5-methyl cytosine) to uracil (and thymine) is the main cause of miscoding lesions in both ancient mtDNA and nuDNA sequences. We argue that the problems presented by postmortem damage, as well as problems with contamination from exogenous sources of conserved nuclear genes, allelic variation, and the reliance on single nucleotide polymorphisms, call for great caution in studies relying on ancient nuDNA sequences.

Animals↗

PubMed1995

Determination of 16S ribosomal RNA gene copy number in Streptococcus uberis, S. agalactiae, S. dysgalactiae and S. parauberis.

Species-specific oligonucleotide probes and a universal oligonucleotide probe derived from sequences of 16S rRNA were hybridised to chromosomal DNA from Streptococcus agalactiae, S. dysgalactiae, S. parauberis and S. uberis following digestion with EcoRI. Due to the presence of a unique EcoRI site in each 16S rRNA gene, the number of hybridised fragments was indicative of the number of 16S rRNA genes. Southern hybridisation indicated six 16S rRNA genes in ten isolates of S. agalactiae, five genes in ten isolates of S. uberis, five genes in six isolates and six in another isolate of S. dysgalactiae, and six genes in four isolates of S. parauberis. For a fifth isolate of S. parauberis, six 16S rRNA genes were indicated by the universal probe but only five when hybridised to the species-specific probe, indicating sequence variation (microheterogeneity) within the probe target region.

Base Sequence↗

PubMed2006

Doubling genome size without polyploidization: dynamics of retrotransposition-driven genomic expansions in Oryza australiensis, a wild relative of rice.

Retrotransposons are the main components of eukaryotic genomes, representing up to 80% of some large plant genomes. These mobile elements transpose via a "copy and paste" mechanism, thus increasing their copy number while active. Their accumulation is now accepted as the main factor of genome size increase in higher eukaryotes, besides polyploidy. However, the dynamics of this process are poorly understood. In this study, we show that Oryza australiensis, a wild relative of the Asian cultivated rice O. sativa, has undergone recent bursts of three LTR-retrotransposon families. This genome has accumulated more than 90,000 retrotransposon copies during the last three million years, leading to a rapid twofold increase of its size. In addition, phenetic analyses of these retrotransposons clearly confirm that the genomic bursts occurred posterior to the radiation of the species. This provides direct evidence of retrotransposon-mediated variation of genome size within a plant genus.

Base Sequence↗

PubMed2002

The transposable elements of the Drosophila melanogaster euchromatin: a genomics perspective.

BACKGROUND: Transposable elements are found in the genomes of nearly all eukaryotes. The recent completion of the Release 3 euchromatic genomic sequence of Drosophila melanogaster by the Berkeley Drosophila Genome Project has provided precise sequence for the repetitive elements in the Drosophila euchromatin. We have used this genomic sequence to describe the euchromatic transposable elements in the sequenced strain of this species. RESULTS: We identified 85 known and eight novel families of transposable element varying in copy number from one to 146. A total of 1,572 full and partial transposable elements were identified, comprising 3.86% of the sequence. More than two-thirds of the transposable elements are partial. The density of transposable elements increases an average of 4.7 times in the centromere-proximal regions of each of the major chromosome arms. We found that transposable elements are preferentially found outside genes; only 436 of 1,572 transposable elements are contained within the 61.4 Mb of sequence that is annotated as being transcribed. A large proportion of transposable elements is found nested within other elements of the same or different classes. Lastly, an analysis of structural variation from different families reveals distinct patterns of deletion for elements belonging to different classes. CONCLUSIONS: This analysis represents an initial characterization of the transposable elements in the Release 3 euchromatic genomic sequence of D. melanogaster for which comparison to the transposable elements of other organisms can begin to be made. These data have been made available on the Berkeley Drosophila Genome Project website for future analyses.

Animals↗

PubMed1990

Cardiopulmonary resuscitation policies and practices. A statewide nursing home study.

We determined the prevalence of written cardiopulmonary resuscitation policies in North Carolina nursing homes and evaluated their content according to predetermined criteria. Questionnaires were mailed to 236 state-registered facilities. Two hundred nine nursing homes (88.5%) responded to the questionnaire; 83% reported having a written policy, and half (86 nursing homes) provided copies. Nine of ten nursing homes reported that cardiopulmonary resuscitation was performed at their institution, and a similar number (92%) permitted physician orders restricting cardiopulmonary resuscitation. Written policies were systematically compared with 10 model criteria. Policy content varied substantially. More than half of the policies contained provisions for authorization, informed consent, documentation, competency, review, and applicability of do not resuscitate orders. Less than half contained criteria for autonomy, treatment alternatives, dignity and quality of care, and patient identification. Nursing homes that had written policies were newer, larger, and for-profit; had a greater proportion of skilled nursing care beds; and were more likely to have both Medicare and Medicaid certification. The variations in these policies place nursing home residents at risk for having important personal rights limited or ignored. Inclusion of these 10 policy criteria in a comprehensive cardiopulmonary resuscitation policy would represent an important step toward enhancing the quality of decision making by nursing home residents.

Aged↗

PubMed1993

Automated measurement of QT interval dispersion from hard-copy ECGs.

Increased "dispersion" of the QT interval of the electrocardiogram has been proposed as a marker for increased risk of cardiac arrhythmias, but definitive identification of its independent predictive value requires accurate and reproducible measurement in large numbers of cases. A personal computer-based technique for (1) converting hard-copy electrocardiograms to digital records and (2) automatically measuring QT interval dispersion from the digitized records has been developed and validated. Hand measurements of the RR interval from the original tracing and cursor or automated measurements from digitized waveforms correlated to within 1%. QT intervals measured by cursor on digitized waveforms were a mean of 14 ms (95% confidence interval, 10-19 ms) longer than manual measurements on original tracings. Automatic QT interval measurements were a mean of 5 ms longer than cursor measurements (95% confidence interval, 3-7 ms). Automated measurements were observer independent and repeatable (coefficient of variation for repeat measurements, 0.137% RR and 0.370% QT). Estimates of QT dispersion (expressed as coefficient of interlead QT variation) were made for 14 patients with documented recurrent ventricular and 15 control subjects. The median coefficient of interlead QT variation was 8.8% (range, 4.4-12.4%) for arrhythmia patients and 3.6% (range, 2.7-6.3%) for the control group (P < .001). The automatic measurements were more conservative and less likely to give spuriously large values for QT dispersion than manual measurements. Automated QT dispersion measurements should facilitate future studies on predicting the risk of ventricular arrhythmias.

Analog-Digital Conversion↗