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Evidence for the regulation of 3 beta-hydroxysteroid dehydrogenase messenger RNA by human chorionic gonadotrophin in luteinized porcine granulosa cells.
The effects of hCG on the abundance of messenger RNA for the steroidogenic enzyme 3 beta-hydroxysteroid dehydrogenase (3 beta-OHSD) were studied in luteinized porcine granulosa cells. There were dose-dependent increases in the mRNA for this enzyme after 8 h incubation with hCG or dibutyryl cAMP. The results suggest that LH-like hormones regulate the expression of the 3 beta-OHSD gene in luteinized tissue, and this genomic regulation is a component of the luteotrophic regulation of steroidogenesis in the ovary.
Evidence for widespread convergent evolution around human microsatellites.
Microsatellites are a major component of the human genome, and their evolution has been much studied. However, the evolution of microsatellite flanking sequences has received less attention, with reports of both high and low mutation rates and of a tendency for microsatellites to cluster. From the human genome we generated a database of many thousands of (AC)(n) flanking sequences within which we searched for common characteristics. Sequences flanking microsatellites of similar length show remarkable levels of convergent evolution, indicating shared mutational biases. These biases extend 25-50 bases either side of the microsatellite and may therefore affect more than 30% of the entire genome. To explore the extent and absolute strength of these effects, we quantified the observed convergence. We also compared homologous human and chimpanzee loci to look for evidence of changes in mutation rate around microsatellites. Most models of DNA sequence evolution assume that mutations are independent and occur randomly. Allowances may be made for sites mutating at different rates and for general mutation biases such as the faster rate of transitions over transversions. Our analysis suggests that these models may be inadequate, in that proximity to even very short microsatellites may alter the rate and distribution of mutations that occur. The elevated local mutation rate combined with sequence convergence, both of which we find evidence for, also provide a possible resolution for the apparently contradictory inferences of mutation rates in microsatellite flanking sequences.
An integrative network approach for longitudinal stratification in Parkinson's disease.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms resulting from the loss of dopamine-producing neurons in the brain. Currently, there is no cure for the disease which is in part due to the heterogeneity in patient symptoms, trajectories and manifestations. There is a known genetic component of PD and genomic datasets have helped to uncover some aspects of the disease. Understanding the longitudinal variability of PD is essential as it has been theorised that there are different triggers and underlying disease mechanisms at different points during disease progression. In this paper, we perform longitudinal and cross-sectional experiments to identify which data modalities or combinations of modalities are informative at different time points. We use clinical, genomic, and proteomic data from the Parkinson's Progression Markers Initiative. We validate the importance of flexible data integration by highlighting the varying combinations of data modalities for optimal stratification at different disease stages in idiopathic PD. We show there is a shared signal in the DNAm signatures of participants with a mutation in a causal gene of PD and participants with idiopathic PD. We also show that integration of SNPs and DNAm data modalities has potential for use as an early diagnostic tool for individuals with a genetic cause of PD.
Positive selection drives the evolution of rhino, a member of the heterochromatin protein 1 family in Drosophila.
Heterochromatin comprises a significant component of many eukaryotic genomes. In comparison to euchromatin, heterochromatin is gene poor, transposon rich, and late replicating. It serves many important biological roles, from gene silencing to accurate chromosome segregation, yet little is known about the evolutionary constraints that shape heterochromatin. A complementary approach to the traditional one of directly studying heterochromatic DNA sequence is to study the evolution of proteins that bind and define heterochromatin. One of the best markers for heterochromatin is the heterochromatin protein 1 (HP1), which is an essential, nonhistone chromosomal protein. Here we investigate the molecular evolution of five HP1 paralogs present in Drosophila melanogaster. Three of these paralogs have ubiquitous expression patterns in adult Drosophila tissues, whereas HP1D/rhino and HP1E are expressed predominantly in ovaries and testes respectively. The HP1 paralogs also have distinct localization preferences in Drosophila cells. Thus, Rhino localizes to the heterochromatic compartment in Drosophila tissue culture cells, but in a pattern distinct from HP1A and lysine-9 dimethylated H3. Using molecular evolution and population genetic analyses, we find that rhino has been subject to positive selection in all three domains of the protein: the N-terminal chromo domain, the C-terminal chromo-shadow domain, and the hinge region that connects these two modules. Maximum likelihood analysis of rhino sequences from 20 species of Drosophila reveals that a small number of residues of the chromo and shadow domains have been subject to repeated positive selection. The rapid and positive selection of rhino is highly unusual for a gene encoding a chromosomal protein and suggests that rhino is involved in a genetic conflict that affects the germline, belying the notion that heterochromatin is simply a passive recipient of "junk DNA" in eukaryotic genomes.
Proper 5'-3' cotranslational mRNA decay in yeast requires import of Xrn1 to the nucleus.
The budding yeast Xrn1 protein shuttles between the nucleus, where it stimulates transcription, and the cytoplasm, where it executes the major cytoplasmic mRNA decay. In the cytoplasm, apart from catalyzing 5'→3' decay onto non translated mRNAs, Xrn1 can follow the last translating ribosome to degrade the decapped mRNA template, a process known as "cotranslational mRNA decay". We have previously observed that the import of Xrn1 to the nucleus is required for efficient cytoplasmic mRNA decay. Here by using an Xrn1 mutant that cannot enter the nucleus, but is otherwise functional in ribonuclease activity, we show that nuclear import is necessary for proper global cotranslational decay of mRNAs along coding regions and also affects degradation in the of 5' region of a large group of mRNAs, which comprise about 20% of the transcriptome. Furthermore, a principal component analysis of the genomic datasets of this mutant and other Xrn1 mutants also shows that lack of a cytoplasmic 5'→3' exoribonuclease is the primary cause of the physiological defects seen in a xrn1Δ mutant, but also suggests that Xrn1 import into the nucleus is necessary for its full in vivo functions.
The application of LTR retrotransposons as molecular markers in plants.
Retrotransposons are major, dispersed components of most eukaryotic genomes. They replicate by a cycle of transcription, reverse transcription, and integration of new copies, without excising from the genome in the process. Because they represent a major share of the genome, cause easily detectable genetic changes having known ancestral and derived states, and contain conserved regions for which polymerase chain reaction (PCR) primers may be designed, retrotransposon insertions can be exploited as powerful molecular marker systems. Here, we describe the background and strategies, as well as give detailed laboratory protocols, for four key retrotransposon-based methods: SSAP, IRAP, REMAP, and RBIP. The SSAP, IRAP, and REMAP methods are multiplex and generate anonymous marker bands; RBIP scores individual loci, much as microsatellite-based marker systems do. The methods are variously suited to marker detection on agarose and polyacrylamide slab gels, slab and capillary sequencing devices, and arrays on solid supports. The different strengths and weaknesses of these approaches and their performance relative to conventional marker methods are discussed, together with their applicability to marker-assisted breeding, phylogenetic analyses, biodiversity determinations, and evolutionary studies.
Differential induction of glutathione transferases and glucosyltransferases in wheat, maize and Arabidopsis thaliana by herbicide safeners.
By learning lessons from weed science we have adopted three approaches to make plants more effective in phytoremediation: (1) The application of functional genomics to identify key components involved in the detoxification of, or tolerance to, xenobiotics for use in subsequent genetic engineering/breeding programmes. (2) The rational metabolic engineering of plants through the use of forced evolution of protective enzymes, or alternatively transgenesis of detoxification pathways. (3) The use of chemical treatments which protect plants from herbicide injury. In this paper we examine the regulation of the xenome by herbicide safeners, which are chemicals widely used in crop protection due to their ability to enhance herbicide selectivity in cereals. We demonstrate that these chemicals act to enhance two major groups of phase 2 detoxification enzymes, notably the glutathione transferases and glucosyltransferases, in both cereals and the model plant Arabidopsis thaliana, with the safeners acting in a chemical- and species-specific manner. Our results demonstrate that by choosing the right combination of safener and plant it should be possible to enhance the tolerance of diverse plants to a wide range of xenobiotics including pollutants.
The selective packaging and annealing of primer tRNALys3 in HIV-1.
In HIV-1, tRNA(Lys3) serves as the primer for reverse transcriptase, and during viral assembly, the tRNA(Lys) isoacceptors, tRNA(Lys1,2) and tRNA(Lys3), are selectively packaged into the virion. In this review, we shall first discuss the evidence for the formation of a tRNA(Lys) packaging complex, whose components include Gag, GagPol, genomic RNA, lysyl-tRNA synthetase (LysRS), and tRNA(Lys). Evidence suggests that the formation of this complex involves a Gag/GagPol/viral genomic RNA complex interacting with a tRNA(Lys)/ LysRS complex, with Gag interacting with both GagPol and LysRS, and GagPol interacting with the tRNA(Lys). The interaction of Gag with LysRS is quite specific, does not require the presence of tRNA(Lys), and LysRS is believed to be the target that allows the specific packaging of tRNA(Lys) into the virion. The parameters influencing these interactions, and the molecular sites of interaction, will be discussed. The selective packaging of tRNA(Lys3) into HIV-1 facilitates annealing of tRNA(Lys) to the 5' region of viral RNA genome. This region contains a series of stem loops, and there exists several regions in both the viral RNA and the tRNA(Lys) that are believed to be important for tRNA(Lys) annealing. The annealing is facilitated by viral proteins such as unprocessed Gag, nucleocapsid, and reverse transcriptase.
Genome-wide linkage analyses of type 2 diabetes in Mexican Americans: the San Antonio Family Diabetes/Gallbladder Study.
The San Antonio Family Diabetes/Gallbladder Study was initiated to identify susceptibility genes for type 2 diabetes. Evidence was previously reported of linkage to diabetes on 10q with suggestive evidence on 3p and 9p in a genome-wide scan of 440 individuals from 27 pedigrees ascertained through a single diabetic proband. Subsequently, the study was expanded to include 906 individuals from 39 extended Mexican-American pedigrees, two additional examination cycles approximately 5.3 and 7.6 years after baseline, and genotypes for a new set of genome-wide markers. Therefore, we completed a second genome-wide linkage scan. Using information from a participant's most recent exam, the prevalence of diabetes in nonprobands was 21.8%. We performed genome-wide variance components-based genetic analysis on the discrete trait diabetes using a liability model and on the quantitative Martingale residual obtained from modeling age of diabetes diagnosis using Cox proportional hazard models. Controlling for age and age(2), our strongest evidence for linkage to the trait diabetes and the quantitative Martingale residual was on chromosome 3p at marker D3S2406 with multipoint empirical logarithm of odds scores of 1.87 and 3.76, respectively. In summary, we report evidence for linkage to diabetes on chromosome 3p in a region previously identified in at least three independent populations.
Multiple sclerosis: multiple etiologies, multiple genes?
Multiple sclerosis is a chronic inflammatory disease characterized by multifocal damage of the central nervous system myelin. Both humoral and cell-mediated immune abnormalities have been observed in patients with multiple sclerosis, but their relation to the demyelination process is not understood. The etiology of the disease is still unknown; however, evidence exists for an interplay between environmental and genetic factors. Several genes are involved in determining the disease susceptibility, at least one of them encoded within human leukocyte antigen gene complex. Other genomic regions coding for components of the immune system or myelin have also been suggested. Clinical, immunological and genetic data suggest that multiple sclerosis may turn out to be a heterogeneous disease. Therefore, molecular genetic dissection of this complex disease should provide important clues to its pathogenesis as well as unravel metabolic pathways for potential therapeutic or preventive strategies. This review will give an overview of recent progress and future challenges in identifying susceptibility genes for multiple sclerosis.
Mycoplasmas: sophisticated, reemerging, and burdened by their notoriety.
Mycoplasmas are most unusual self-replicating bacteria, possessing very small genomes, lacking cell wall components, requiring cholesterol for membrane function and growth, using UGA codon for tryptophan, passing through "bacterial-retaining" filters, and displaying genetic economy that requires a strict dependence on the host for nutrients and refuge. In addition, many of the mycoplasmas pathogenic for humans and animals possess extraordinary specialized tip organelles that mediate their intimate interaction with eucaryotic cells. This host-adapted survival is achieved through surface parasitism of target cells, acquisition of essential biosynthetic precursors, and in some cases, subsequent entry and survival intracellularly. Misconceptions concerning the role of mycoplasmas in disease pathogenesis can be directly attributed to their biological subtleties and to fundamental deficits in understanding their virulence capabilities. In this review, we highlight the biology and pathogenesis of these procaryotes and provide new evidence that may lead to increased appreciation of their role as human pathogens.
Genetic Testing in Cystic Kidney Disease.
Genomic investigation is playing an increasing role in the management of cystic kidney diseases, reflecting a broader shift toward precision medicine in nephrology. Recent updates to the Kidney Disease Improving Global Outcomes Clinical Practice Guideline emphasize diagnostic genomics as a core component of autosomal dominant polycystic kidney disease care in particular, recognizing its utility across a range of clinical scenarios. Traditionally, diagnosis of autosomal dominant polycystic kidney disease has been clinical, using age-dependent imaging criteria for at-risk individuals via ultrasound and magnetic resonance imaging. Although these imaging modalities have good sensitivity, there are pitfalls in clinical diagnosis, particularly in patients with atypical clinical features, those without family history, or those at a young age. A confirmed genetic diagnosis can guide screening of at-risk family members, inform reproductive decisions, support safe selection of living related kidney donors, and provide the opportunity to use genotype-specific prognostication tools. In addition, as genotype-specific therapies enter the landscape, accurate genotyping will become essential for identifying which patients will benefit from treatment. This narrative review aims to provide a practical approach for the general nephrologist of when to offer genetic testing to patients with cystic kidney disease and outline the technical and genetic counseling considerations in the provision of patient-centered genetic investigation.
Expression analysis of the epigenetic methyltransferases and methyl-CpG binding protein families in the normal B-cell and B-cell chronic lymphocytic leukemia (CLL).
The importance of epigenetic modifications in carcinogenesis has been a source of controversy for some time. There is little doubt that changes in genomic hypermethylation contribute to the silencing of tumor suppressor genes. Furthermore, recent studies have also identified the significance of genomic hypomethylation associated with chromosomal instability and tumorigenesis. One of the most perplexing questions regarding epigenetic modifications and leukemogenesis is the relationship with DNA methyltransferases (DNMT's). The primary function of the DNMT enzymes is to methylate genomic DNA, whereas the methyl-CpG binding domain proteins (MBD) interpret this methylation signal and regulate gene expression and chromatin behavior. In this study we analyse these gene families by quantitative real-time PCR to investigate whether expression levels and the B-cell chronic lymphocytic leukemia (B-CLL) phenotype are associated. Furthermore, given the epigenetic crosstalk between genome stability and the histone chromatin code we have analysed eukaryotic histone methyltransferase (Eu-HMTaseI). Surprisingly, we did not observe significant changes in DNMT1 expression in B-CLL cases when compared to normal lymphocytes, regardless of whether we normalise against GAPDH or PCNA as reference standards. Indeed, expression of the maintenance and de novo methylases were independently regulated. Of particular note was the significant down regulation of DNMT3b. Furthermore, we observed a positive correlation between HMTaseI expression levels and stage of leukemia suggesting that changes in the methylation patterns in B-CLL may represent deregulation of the epigenetic repertoire that also include the methylation dependent binding proteins, MBD2 and MeCP2. We envisage changes in the epigenetic program are multifactorial in nature and postulate that the prevalent genomic methylases just one component of a larger epigenetic repertoire.
Human endogenous retrovirus-R (ERV 3) env-like antigens expressed in baboon testes and epididymides.
BACKGROUND: A substantial component of the vertebrate genome comprise of retrovirus-related sequences named as endogenous retroviruses (ERVs). The role of these ERV-related sequences in the biological processes of the host species is still unknown. However, they have been associated with tumourigenesis, autoimmune diseases and placental morphogenesis in primates. OBJECTIVE: To determine the expression of ERVs in male baboon reproductive tissues. DESIGN: The testes and other reproductive tissues from sexually immature and mature male olive baboons (Papio anubis) were investigated for the expression of endogenous retrovirus-related particles. Immunohistochemical staining was performed using antibodies raised against human immunodeficiency virus (HIV)-1/2, simian immunodeficiency virus (SIV) and human ERVs. Biochemical properties were determined by western blot, and reverse transcriptase (RTase) activity in epididymal spermatozoa, ejaculate spermatozoa and seminal fluid was evaluated. SETTING: Institute of Primate Research, Nairobi, Kenya. RESULTS: ERV3 env-like antigens were detected on spermatogenic cells in mature baboon testes and on epididymal spermatozoa. Similarly, antigens cross-reactive with antibodies to HIV structural and envelope glycoproteins were expressed in mature and juvenile baboon testes. In addition, reverse transcriptase activity was detected in ejaculate spermatozoa, seminal fluid and epididymal spermatozoa. CONCLUSION: These results indicate that retroviral-related genes were expressed in normal male baboon testes and spermatozoa, similar to humans. The functions of these ERVs in vertebrates remains unclear.
A public database for gene expression in human cancers.
A public database, SAGEmap, was created as a component of the Cancer Genome Anatomy Project to provide a central location for depositing, retrieving, and analyzing human gene expression data. This database uses serial analysis of gene expression to quantify transcript levels in both malignant and normal human tissues. By accessing SAGEmap (http://www.ncbi.nlm.nih.gov/SAGE) the user can compare transcript populations between any of the posted libraries. As an initial demonstration of the database's utility, gene expression in human glioblastomas was compared with that of normal brain white matter. Of the 47,174 unique transcripts expressed in these two tissues, 471 (1.0%) were differentially expressed by more than 5-fold (P<0.001). Classification of these genes revealed functions consistent with the biological properties of glioblastomas, in particular: angiogenesis, transcription, and cell cycle related genes.
A new world view of genetics service models.
Identification of the components of the Human Genome and their relevance to health and disease is revolutionizing the provision of genetic services and all areas of health care. New genetic tools to diagnose, manage, and treat common diseases, along with Web-based innovations are changing the shape of how genetic services will be accessed and delivered. These advances represent a "bionic convergence" that will fundamentally transform medicine during the next few decades. The convergence of biotechnology and electronics is creating an expanding array of health care opportunities for clients and offers innovative opportunities for health promotion, restoration and management. Families and communities will soon be able to participate more fully in the direction and design of their own genetic health. Nurses with their long history of providing holistic, family-centered care in all practice settings, can help to create new dimensions to their practice to support their clients as they meet these health care innovations. This article explores a New World view of genetics services, and describes futuristic models for their provision. Nursing participation in and preparation for future genetics services also is described.
[Mobile genetic element MDG4 (gypsy) in Drosophila melanogaster. Features of structure and regulation of transposition].
Distribution of two structural functional variants of the MDG4 (gypsy) mobile genetic element was examined in 44 strains of Drosophila melanogaster. The results obtained suggest that less transpositionally active MDG4 variant is more ancient component of the Drosophila genome. Using Southern blotting, five strains characterized by increased copy number of MDG4 with significant prevalence of the active variant over the less active one were selected for further analysis. Genetic analysis of these strains led to the suggestion that some of them carry factors that mobilize MDG4 independently from the cellular flamenco gene known to be responsible for transposition of this element. Other strains probably contained a suppressor of the flam- mutant allele causing active transpositions of the MDG4. Thus, the material for studying poorly examined relationships between the retrovirus and the host cell genome was obtained.