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At least 145 records · Page 8Linked to original sources
PubMed2006

Genetic variants predisposing to cardiovascular disease.

PURPOSE OF REVIEW: The goal of this review is to provide an update on the most recent and relevant findings in the area of genotype-phenotype associations as well as the relationships between genetic factors and cardiovascular disease risk markers and events. In addition, emphasis will be placed on the methodological problems associated with studying the genetics of complex disorders, specifically cardiovascular diseases. RECENT FINDINGS: Genes associated with cardiovascular disease predisposition have been examined, including traditional cardiovascular disease candidate genes, such as ACE, AGT, eNOS, PON and MTHFR, new loci that have recently been added to the growing list of cardiovascular disease candidate genes (i.e. MEF2A, ALOX5, LTA, APOM, PDE4D), and genes that have been shown to be at the intersection of several age-related disorders through interaction with one another or with environmental factors (i.e. APOA5, APOE, PPARgamma, LPL and LIPC). SUMMARY: During the last year, tremendous effort has been made in elucidating new genes associated with cardiovascular disease predisposition. For the most part, however, major breakthroughs have not been made, primarily due to the poor replication of results among studies, as a consequence of poor experimental design. Nevertheless, we have increased our understanding of the complexity of cardiovascular disease and the relevance of gene-environment interactions as the ultimate drivers of the individual predisposition to the disease. It is essential, therefore, that present and future genetic studies in this area take into consideration the inclusion of high-quality environmental data in the analytical process to test the clinical usefulness of a genetic marker as a risk predictor.

Cardiovascular Diseases↗
PubMed2006

Studies of threespine stickleback developmental evolution: progress and promise.

A promising route for understanding the origin and diversification of organismal form is through studies at the intersection of evolution and development (evo-devo). While much has been learned over the last two decades concerning macroevolutionary patterns of developmental change, a fundamental gap in the evo-devo synthesis is the integration of mathematical population and quantitative genetics with studies of how genetic variation in natural populations affects developmental processes. This micro-evo-devo synthesis requires model organisms with which to ask empirical questions. Threespine stickleback fish (Gasterosteus aculeatus), long a model for studying behavior, ecology and evolution, is emerging as a prominent model micro-evo-devo system. Research on stickleback over the last decade has begun to address the genetic basis of morphological variation and sex determination, and much of this work has important implications for understanding the genetics of speciation. In this paper we review recent threespine stickleback micro-evo-devo results, and outline the resources that have been developed to make this synthesis possible. The prospects for stickleback research to speed the micro-(and macro-) evo-devo syntheses are great, and this workhorse model system is well situated to continue contributing to our understanding of the generation of diversity in organismal form for many more decades.

Animals↗
PubMed2005

On the structural regularity in nucleobases and amino acids and relationship to the origin and evolution of the genetic code.

To explore how chemical structures of both nucleobases and amino acids may have played a role in shaping the genetic code, numbers of sp2 hybrid nitrogen atoms in nucleobases were taken as a determinative measure for empirical stereo-electronic property to analyze the genetic code. Results revealed that amino acid hydropathy correlates strongly with the sp2 nitrogen atom numbers in nucleobases rather than with the overall electronic property such as redox potentials of the bases, reflecting that stereo-electronic property of bases may play a role. In the rearranged code, five simple but stereo-structurally distinctive amino acids (Gly, Pro, Val, Thr and Ala) and their codon quartets form a crossed intersection "core". Secondly, a re-categorization of the amino acids according to their beta-carbon stereochemistry, verified by charge density (at beta-carbon) calculation, results in five groups of stereo-structurally distinctive amino acids, the group leaders of which are Gly, Pro, Val, Thr and Ala, remarkably overlapping the above "core". These two lines of independent observations provide empirical arguments for a contention that a seemingly "frozen" "core" could have formed at a certain evolutionary stage. The possible existence of this codon "core" is in conformity with a previous evolutionary model whereby stereochemical interactions may have shaped the code. Moreover, the genetic code listed in UCGA succession together with this codon "core" has recently facilitated an identification of the unprecedented icosikaioctagon symmetry and bi-pyramidal nature of the genetic code.

Amino Acids↗
PubMed2024

Molecular mechanisms of the specialization of human synapses in the neocortex.

Synapses of the neocortex specialized during human evolution to develop over extended timescales, process vast amounts of information and increase connectivity, which is thought to underlie our advanced social and cognitive abilities. These features reflect species-specific regulations of neuron and synapse cell biology. However, despite growing understanding of the human genome and the brain transcriptome at the single-cell level, linking human-specific genetic changes to the specialization of human synapses has remained experimentally challenging. In this review, we describe recent progress in characterizing divergent morphofunctional and developmental properties of human synapses, and we discuss new insights into the underlying molecular mechanisms. We also highlight intersections between evolutionary innovations and disorder-related dysfunctions at the synapse.

Humans↗
PubMed2001

The biological basis of epistasis between quantitative trait loci for flavone and 3-deoxyanthocyanin synthesis in maize (Zea mays L.).

A major weakness in our understanding of the genetic basis of complex traits has been that of defining the extent and biological basis of epistasis. Our research group has been studying the genetic control of the accumulation of maysin, a C-glycosyl flavone, in maize, Zea mays (L.), silks. Previously, we demonstrated the importance of the p1 locus as a QTL for maysin synthesis. The p1 locus often exhibits significant epistatic interactions with other loci. We developed a mapping population, (W23al x GT119)F2, specifically designed to test whether genes in an intersecting pathway might be detected as QTLs for maysin synthesis and result in epistatic interaction effects. The a1 gene is not required for the synthesis of flavones but is required for the synthesis of 3-deoxyanthocyanins, an intersecting pathway, in maize silks. The p1 locus (P < 0.0001) was a QTL for both flavones and 3-deoxyanthocyanins. The a1 locus was also highly significant (P < 0.0001) for both traits, as was the p1 x a1 epistatic interaction (P < 0.0001). Our results demonstrate that altering the flux of biochemical intermediates between pathways may be the biological basis of major QTL effects and epistatic interactions.

Alleles↗
PubMed2000

Bim1p/Yeb1p mediates the Kar9p-dependent cortical attachment of cytoplasmic microtubules.

In Saccharomyces cerevisiae, positioning of the mitotic spindle depends on the interaction of cytoplasmic microtubules with the cell cortex. In this process, cortical Kar9p in the bud acts as a link between the actin and microtubule cytoskeletons. To identify Kar9p-interacting proteins, a two-hybrid screen was conducted with the use of full-length Kar9p as bait, and three genes were identified: BIM1, STU2, and KAR9 itself. STU2 encodes a component of the spindle pole body. Bim1p is the yeast homologue of the human microtubule-binding protein EB1, which is a binding partner to the adenomatous polyposis coli protein involved in colon cancer. Eighty-nine amino acids within the third quarter of Bim1p was sufficient to confer interaction with Kar9p. The two-hybrid interactions were confirmed with the use of coimmunoprecipitation experiments. Genetic analysis placed Bim1p in the Kar9p pathway for nuclear migration. Bim1p was not required for Kar9p's cortical or spindle pole body localization. However, deletion of BIM1 eliminated Kar9p localization along cytoplasmic microtubules. Furthermore, in the bim1 mutants, the cytoplasmic microtubules no longer intersected the cortical dot of Green Fluorescent Protein-Kar9p. These experiments demonstrate that the interaction of cytoplasmic microtubules with the Kar9p cortical attachment site requires the microtubule-binding protein Bim1p.

Amino Acid Sequence↗
PubMed1999

Intersecting signalling and transcriptional pathways in Drosophila heart specification.

The Drosophila heart, also called the dorsal vessel, is a linear tube consisting of two major cell types, namely cardioblasts which serve as cardiomyocytes and pericardial cells which surround its outer surface. This organ is derived from segmental clusters of cells in the dorsal mesoderm during early embryonic development. During the past few years, genetic and molecular studies have led to significant advances in our understanding of the regulatory mechanisms that pattern the early mesoderm by defining these cell clusters and ultimately specifying individual cells within them as heart progenitors. These studies established that the patterning events involve specific combinations of localized inductive signals that act in concert with mesoderm-autonomous transcription factors to achieve a progressive subdivision of the mesoderm. Some of the synergistic interactions between mesodermal transcription factors and external signalling molecules have been defined at the molecular level. With respect to the pericardial cells, the final specification steps were found to employ cell-intrinsic lineage mechanisms. Because of the many striking similarities between Drosophila and early vertebrate heart development, which appear to extend to the molecular level, these insights will be of significant help in defining related events during vertebrate cardiogenesis.

Animals↗
PubMed2003

CYP72B1 inactivates brassinosteroid hormones: an intersection between photomorphogenesis and plant steroid signal transduction.

Active brassinosteroids, such as brassinolide (BL) and castasterone, are growth promoting plant hormones. An Arabidopsis cytochrome p450 monooxygenase encoded by CYP72B1 has been implicated in brassinosteroid catabolism as well as photomorphogenesis. We expressed CYP72B1 in yeast, coupled with brassinosteroid feeding, and established the biochemical function to be the hydroxylation of BL and castasterone, to give 26-hydroxybrassinolide and 26-hydroxycastasterone, respectively. Brassinosteroid feeding experiments with wild-type Arabidopsis, a CYP72B1 null mutant, and a CYP72B1 overexpression line demonstrated that carbon 26 hydroxylation of active brassinosteroids is an endogenous function of CYP72B1. Seedling growth assays demonstrated that 26-hydroxybrassinolide is an inactive brassinosteroid. Genetic and physiological analysis of the hypocotyl response to exogenous BL and varying intensities of white and monochromatic light suggested that CYP72B1 modulates photomorphogenesis primarily through far-red light and to a lesser extent through blue- and red-light pathways. CYP72B1 transcript accumulation in dark-grown seedlings was organ specific and down-regulated after 1 h of illumination in dim white, red, and blue light, but not far-red light. CYP72B1 translational fusions with the beta-glucuronidase reporter gene demonstrated that protein levels increased in the hypocotyl elongation zone when shifted from the dark to far-red light, but not blue or red light. We propose a model in which Arabidopsis seedling development switches from dark-grown development (skotomorphogenesis) to light-grown development (photomorphogenesis) in part by rapid modulation of brassinosteroid sensitivity and levels. CYP72B1 provides an intersection between the light and brassinosteroid pathways mainly by far-red-light-dependent modulation of brassinosteroid levels.

Arabidopsis↗
PubMed2006

Refined spatial manipulation of neuronal function by combinatorial restriction of transgene expression.

Selective genetic manipulation of neuronal function in vivo requires techniques for targeting gene expression to specific cells. Existing systems accomplish this using the promoters of endogenous genes to drive expression of transgenes directly in cells of interest or, in "binary" systems, to drive expression of a transcription factor or recombinase that subsequently activates the expression of other transgenes. All such techniques are constrained by the limited specificity of the available promoters. We introduce here a combinatorial system in which the DNA-binding (DBD) and transcription-activation (AD) domains of a transcription factor are independently targeted using two different promoters. The domains heterodimerize to become transcriptionally competent and thus drive transgene expression only at the intersection of the expression patterns of the two promoters. We use this system to dissect a neuronal network in Drosophila by selectively targeting expression of the cell death gene reaper to subsets of neurons within the network.

Animals↗
PubMed2004

Genomic research and data-mining technology: implications for personal privacy and informed consent.

This essay examines issues involving personal privacy and informed consent that arise at the intersection of information and communication technology (ICT) and population genomics research. I begin by briefly examining the ethical, legal, and social implications (ELSI) program requirements that were established to guide researchers working on the Human Genome Project (HGP). Next I consider a case illustration involving deCODE Genetics, a privately owned genetic company in Iceland, which raises some ethical concerns that are not clearly addressed in the current ELSI guidelines. The deCODE case also illustrates some ways in which an ICT technique known as data mining has both aided and posed special challenges for researchers working in the field of population genomics. On the one hand, data-mining tools have greatly assisted researchers in mapping the human genome and in identifying certain "disease genes" common in specific populations (which, in turn, has accelerated the process of finding cures for diseases tha affect those populations). On the other hand, this technology has significantly threatened the privacy of research subjects participating in population genomics studies, who may, unwittingly, contribute to the construction of new groups (based on arbitrary and non-obvious patterns and statistical correlations) that put those subjects at risk for discrimination and stigmatization. In the final section of this paper I examine some ways in which the use of data mining in the context of population genomics research poses a critical challenge for the principle of informed consent, which traditionally has played a central role in protecting the privacy interests of research subjects participating in epidemiological studies.

Computational Biology↗
PubMedDate not supplied

Sarcopenia: age-related skeletal muscle changes from determinants to physical disability.

Human aging is characterized by skeletal muscle wasting, a debilitating condition which sets the susceptibility for diseases that directly affect the quality of life and often limit life span. Sarcopenia, i.e. the reduction of muscle mass and/or function, is the consequence of a reduction of protein synthesis and an increase in muscle protein degradation. In addition, the capacity for muscle regeneration is severely impaired in aging and this can lead to disability, particularly in patients with other concomitant diseases or organ impairment. Immobility and lack of exercise, increased levels of proinflammatory cytokines, increased production of oxygen free radicals or impaired detoxification, low anabolic hormone output, malnutrition and reduced neurological drive have been advocated as being responsible for sarcopenia. It is intriguing to notice that multiple pathways converge on skeletal muscle dysfunction, but the factors involved sometimes diverge to different pathways, thus intersecting at critical points. It is reasonable to argue that the activity of these nodes results from the net balance of regulating mechanisms, as in the case of the GH/IGF-1 axis, the testosterone and cortisol functions, the pro- and anti-inflammatory cytokines and receptors. Both genetic and epigenetic mechanisms operate in regulating the final phenotype, the extent of muscle atrophy and reduction in strength and force generation. It is widely accepted that intervention on lifestyle habits represents an affordable and practical way to modify on a large scale some detrimental outcomes of aging, and particularly sarcopenia. The identification of the molecular chain able to reverse sarcopenia is a major goal of studies on human aging.

Aging↗
PubMed1995

RNA fingerprinting and differential display using arbitrarily primed PCR.

RNA fingerprinting by arbitrarily primed PCR can be used to detect and clone transcripts that are differentially expressed between cells that have been subject to different environments or developmental programs. The method also allows an estimate of the number of genes that are differentially expressed under various circumstances. When many experimental treatments are compared in parallel, intersecting regulatory pathways are reflected in genes that are perturbed by more than one treatment.

Animals↗
PubMed2026

Adaptive evolution of polyploid crops.

Crop evolution represents a fundamental biological process through which plants respond to selection in different environments. This encompasses mechanisms operating at multiple scales of biological organization, including genetic and epigenetic regulation and higher-order interactions among molecular complexes. This Review synthesizes how polyploidy shapes crop evolution by generating duplicated genes, driving genome reorganization, altering dosage relationships and promoting regulatory divergence, which together influence crop metabolism, physiology, development and environmental responses. We focus mainly on the mechanisms underlying adaptation in polyploid crops, including the consequences of gene and genome duplication, genome reorganization and subfunctionalization. We also examine how hybridization, phenotypic plasticity and crop-microbiome interactions intersect with polyploidy to expand or constrain adaptive potential. Together, these processes affect crop survival, fitness and breeding value under changing environments. We suggest that future research connect polyploid genome architecture with experimentally validated signatures of selection and field performance to make better use of polyploidy-derived variation in crop improvement.

Polyploidy↗
PubMed2004

Generalized Venn diagrams: a new method of visualizing complex genetic set relations.

MOTIVATION: Microarray experiments generate vast amounts of data. The unknown or only partially known functional context of differentially expressed genes may be assessed by querying the Gene Ontology database via GOMiner. Resulting tree representations are difficult to interpret and are not suited for visualization of this type of data. Methods are needed to effectively visualize these complex set relationships. RESULTS: We present a visualization approach for set relationships based on Venn diagrams. The proposed extension enhances the usual notion of Venn diagrams by incorporating set size information. The cardinality of the sets and intersection sets is represented by their corresponding circle (polygon) sizes. To avoid local minima, solutions to this problem are sought by evolutionary optimization. This generalized Venn diagram approach has been implemented as an interactive Java application (VennMaster) specifically designed for use with GOMiner in the context of the Gene Ontology database. AVAILABILITY: VennMaster is platform-independent (Java 1.4.2) and has been tested on Windows (XP, 2000), Mac OS X, and Linux. Supplementary information and the software (free for non-commercial use) are available at http://www.informatik.uni-ulm.de/ni/mitarbeiter/HKestler/vennm together with a user documentation. CONTACT: hans.kestler@medizin.uni-ulm.de.

Algorithms↗
PubMed2006

CancerGenes: a gene selection resource for cancer genome projects.

The genome sequence framework provided by the human genome project allows us to precisely map human genetic variations in order to study their association with disease and their direct effects on gene function. Since the description of tumor suppressor genes and oncogenes several decades ago, both germ-line variations and somatic mutations have been established to be important in cancer-in terms of risk, oncogenesis, prognosis and response to therapy. The Cancer Genome Atlas initiative proposed by the NIH is poised to elucidate the contribution of somatic mutations to cancer development and progression through the re-sequencing of a substantial fraction of the total collection of human genes-in hundreds of individual tumors and spanning several tumor types. We have developed the CancerGenes resource to simplify the process of gene selection and prioritization in large collaborative projects. CancerGenes combines gene lists annotated by experts with information from key public databases. Each gene is annotated with gene name(s), functional description, organism, chromosome number, location, Entrez Gene ID, GO terms, InterPro descriptions, gene structure, protein length, transcript count, and experimentally determined transcript control regions, as well as links to Entrez Gene, COSMIC, and iHOP gene pages and the UCSC and Ensembl genome browsers. The user-friendly interface provides for searching, sorting and intersection of gene lists. Users may view tabulated results through a web browser or may dynamically download them as a spreadsheet table. CancerGenes is available at http://cbio.mskcc.org/cancergenes.

Databases, Genetic↗
PubMed1993

Transformation of NIH3T3 cells with ras oncogenes abrogates the retinoic acid induction of tissue transglutaminase.

Retinoic acid greatly increases enzyme activity and mRNA expression of the tissue-type transglutaminase enzyme in NIH3T3 cells. This response is blocked in cells transformed with activated H-ras, K-ras or N-ras oncogenes, but not in pSVneo vector transfected cells. Lack of induction by RA of the tissue-type TGase in these ras-transformed fibroblasts suggests intersecting pathways between retinoid action and the ras oncogene.

3T3 Cells↗
PubMed2026

Cooperative care influences genome-wide levels of DNA methylation in nestling chestnut-crowned babblers.

Carers in cooperatively breeding vertebrates increase food acquisition for offspring; however, they also impact the developmental social environment. One means of linking early-life environments, such as nutrition and social structure, with later-life phenotypes is DNA methylation. Here, using whole-genome methylation sequencing, we measured how additional carers influence DNA methylation in nestlings of the cooperatively breeding chestnut-crowned babbler (Pomatostomus ruficeps). A comparison of nestlings raised by their parents (two carers) and those raised by parents plus additional helpers ('three plus' carers; mean = 4.3 &#xb1; 1.4 s.d.) revealed that additional care is associated with genome-wide differences in DNA methylation. Overall, 570 cytosine-phosphate-guanine sites from the regulatory regions of 487 genes were differentially methylated, with 85% being more methylated in nestlings reared by groups. Specifially, sites associated with genes that are integral for metabolism, growth, the regulation and promotion of sociality, the ability to cope with stressors, and cell communication were differentially methylated between the groups. Furthermore, gene ontology-term analysis revealed that differentially methylated sites were over-represented in multiple pathways, including those important for protein binding, metabolism and cell-to-cell and environment-to-cell communication. Our results suggest that the effects of being reared by groups as opposed to pairs in cooperative breeders can extend beyond those typically attributed to nutritional benefits and that these effects are molecularly mediated. This article is part of the theme issue 'Ecological epigenetics at the intersection of behaviour and life history variation in non-model animals'.

Animals↗
PubMed2004

A vision for the National Cancer Program in the United States.

The intersection of two noble endeavors - the scientists' quest to understand life itself and the physicians' dedication to relieve suffering and prolong life - came into sharp focus in 1971 with the United States National Cancer Act. This focus has led to an exponential expansion of our understanding of cancer at the genetic, molecular and cellular levels, and concomitant advances in our ability to disrupt the disease process through prevention, early detection and successful treatment. At the National Cancer Institute we are committed to capitalize on these achievements. A new era is now within our grasp, a time when no one suffers or dies as a result of cancer.

Animals↗