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PubMed2001

A history of plant virology. Mendelian genetics and resistance of plants to viruses.

Virology was borne at the end of the nineteenth century, some years before the re-discovery of the so-called "Mendel's Laws". The rapid development of genetics was helpful to horticulturists and plant pathologists to produce hybrids of important cropping species resistant to several virus diseases. The concepts of Mendelian genetics were applied to plant virology by Francis Oliver Holmes, an American scientist who must be considered a pioneer in several fields of modern plant virology. During the Thirties, Holmes studied in particular the hypersensitive response of solanaceous plants to TMV and discovered the N dominant gene of tobacco hypersensitive to this virus. After the Second World War, the theoretic and practical support given by geneticists assisted plant virologists in better understanding the mechanism of inheritance of the character "resistance". The major problems posed by breeding for plant resistance were detected and critically discussed in several reviews published between the Fifties and the Sixties. These results, together with the discovery of the genetic functions of RNA virus raised interest on the possible relations between viral and plant genes. This fundamental subject saw the entry into the virological scene of molecular genetics, and in 1970 the Russian virologist Joseph Atabekov introduced host specificity to viruses as a central point of plant virology. From the mid 1980s, this point attracted the interest of several virologists, and many results led to several theoretic models of genetic interactions between plant and virus products. In the last fifteen years, the introduction of transgenic plants has given a remarkable contribution to the question of host specificity, which, however, still awaits a general explanation.

Botany↗
PubMed1998

Clinical importance of non-genetic and genetic cytochrome P450 function tests in liver disease.

Liver disease is associated with reduced metabolic capacity for drugs that are metabolized by oxidative biotransformation. Three cytochrome P450 (P450 or CYP) gene families in liver microsomes (CYP 1, CYP2 and CYP3) appear to be responsible for much of the drug metabolism that takes place. The genetic polymorphism of the CYPs responsible for debrisoquine/ sparteine (CYP2D6) metabolism and S-mephenytoin (CYP2C19) metabolism has been well documented, but information on the impairment of each isoform in liver disease is still limited. There are two types of hepatic P450 function tests. One type consists of non-genetic P450 function tests (CYP1A2, 2A6, 2C9/10, 2E1 and 3A3/4), and probe drugs include caffeine, catalysed by CYP1A2, coumarin by CYP2A6, phenytoin by CYP2C6, chlorzoxazone by CYP2E1, and nifedipine, erythromycin and lidocaine by CYP3A3/4. The second type of genetic P450 function tests (CYP2C19 and CYP2D6) involves probe drugs such as S-mephenytoin, catalysed by CYP2C19, and debrisoquine and sparteine, catalysed by CYP2D6. The metabolism of the probe drugs used in non-genetic P450 function tests in patients with liver disease falls into two categories: reduced (CYP1A2, CYP2C, 2E1 and 3A) and unchanged (CYP2C). In genetic P450 function tests there seems to be a lesser degree of inhibition in poor metabolizers (PMs) than extensive metabolizers (EMs) among patients with liver disease. There have been very few reports on changes in metabolism of the probe drugs used in genetic P450 function tests in liver disease. In this paper the subject is reviewed.

Biotransformation↗
PubMed2005

CCR5, RANTES and CX3CR1 polymorphisms: possible genetic links with acute heart rejection.

BACKGROUND: The inflammation response is modulated by the elaborated chemokine-chemokine receptor system, which also plays an important role in the development of acute rejection (AR). In this study, we hypothesized that functional genetic variants of some of these modulatory proteins might influence the outcome of AR. METHODS: In a retrospective analysis of a cohort of heart transplanted patients (n=158), we examined eight polymorphisms in four genes implicated in this inflammatory process: RANTES, CCR5, CCR2 and CX3CR1. On the basis of timing occurrence, AR episodes (grade>or= 3A) were classified in "early" (0-3 months posttransplantation; EAR) or "late" outcomes (4-12 months posttransplantation; LAR). RESULTS: The incidences of EAR and LAR were 57.6% and 41%, respectively. Number of LAR episodes was significantly higher in subjects that have already experienced one or more EAR episodes, as compared to subjects that had no EAR (median [25%-75%]: 4 () vs. 1 [1-2.5] respectively; P<0.0001). Statistical univariate analysis showed that none of the mentioned polymorphisms were correlated with EAR or LAR. However, allele-allele association analysis showed that subjects carrying both the CX3CR1 249I allele and CCR5 No-E haplotypes were significantly at lower risk of experiencing EAR (OR=0.2 [95%-CI=0.1-0.5], P=0.001). In contrast subjects carrying both the CCR5 E haplotype and the RANTES -403A allele were significantly at higher risk to develop LAR (OR=8.1 [95%-CI=2.3-28.7], P=0.002). CONCLUSIONS: This exploratory study in heart transplantation suggests that the outcomes of EAR and LAR episodes may be influenced by genetic variant interactions such as "CX3CR1 249I*CCR5 No-E" and "CCR5 E*RANTES -403A."

Acute Disease↗
PubMed2003

The PUF family of RNA-binding proteins: does evolutionarily conserved structure equal conserved function?

Drosophila Pumilio (Pum) protein is a founder member of a novel family of RNA-binding proteins, known as the PUF family. The PUF proteins constitute an evolutionarily highly conserved family of proteins present from yeast to humans and plants, and are characterized by a highly conserved C-terminal RNA-binding domain, composed of eight tandem repeats. The conserved biochemical features and genetic function of PUF family members have emerged from studies of model organisms. PUF proteins bind to related sequence motifs in the 3' untranslated region (3'UTR) of specific target mRNAs and repress their translation. Frequently, PUF proteins function asymmetrically to create protein gradients, thus causing asymmetric cell division and regulating cell fate specification. Thus, it was recently proposed that the primordial role of PUF proteins is to sustain mitotic proliferation of stem cells. Here we review the evolution, conserved genetic and biochemical properties of PUF family of proteins, and discuss protein interactions, upstream regulators and downstream targets of PUF proteins. We also suggest that a conserved mechanism of PUF function extends to the newly described mammalian members of the PUF family (human PUM1 and PUM2, and mouse Pum1 and Pum2), that show extensive homology to Drosophila Pum, and could have an important role in cell development, fate specification and differentiation.

3' Untranslated Regions↗
PubMed2004

Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway.

Eukaryotic cells catabolize their own cytoplasm by autophagy in response to amino acid starvation and inductive signals during programmed tissue remodeling and cell death. The Tor and PI3K signaling pathways have been shown to negatively control autophagy in eukaryotes, but the mechanisms that link these effectors to overall animal development and nutritional status in multicellular organisms remain poorly understood. Here, we reveal a complex regulation of programmed and starvation-induced autophagy in the Drosophila fat body. Gain-of-function genetic analysis indicated that ecdysone receptor signaling induces programmed autophagy whereas PI3K signaling represses programmed autophagy. Genetic interaction studies showed that ecdysone signaling downregulates PI3K signaling and that this represents the effector mechanism for induction of programmed autophagy. Hence, these studies link hormonal induction of autophagy to the regulatory function of the PI3K signaling pathway in vivo.

Amino Acids↗
PubMed1985

Growth analysis in clinical genetics.

The number of genetic and environmental determinants of human growth is very large and their interplay is responsible for the enormously complex phenomenon of prenatal and postnatal growth and simultaneous differentiation in function. Genetic factors participate substantially in determining size at birth, but become more and increasingly important in the realization of inherent potential after the age of two years. Thus, prenatal growth is determined by a greater number of environmental factors than postnatal growth, including parity, pregnancy spacing, maternal age, size, blood pressure, race, health, smoking, alcohol intake, twinning, intrauterine constraint, etc. Galilei's scale effect sets the upper limit of human size, and our surface area determines our metabolic rate and to some extent our life span. Age and rate of pubertal maturation varies with sex, race, and health of the individual, and may be dramatically influenced by numerous environmental and genetic disturbances. One of the most consistent and dramatic effects of autosomal aneuploidy on development is permanent reduction of growth rate, beginning very early in embryonic development. This effect on growth can be interpreted as an abnormality of developmental homeostasis or canalization. Reduced buffering or canalization of growth has been demonstrated in the DS and constitutes most elegant confirmation of the Waddington-Shapiro hypothesis; it ought to be demonstrable also in most if not all of the gonosomal aneuploidies. Thus, an ultrasonographic analysis of embryonic and fetal growth ought to be normal practice in all, not just high--risk pregnancies, and serve as valuable indicator of fetal developmental abnormality if IUGR is found. Because of difference in prognosis and possible difference in obstetric management, ultrasonographers ought to make a distinction in practice between (proportionate) IUGR and (disproportionate) CSOS. Depending on age of onset and severity, reduced prenatal movement can lead to the fetal akinesia sequence including growth retardation of all or part of the fetus. Neurohypotrophy shows that normal innervation is required for normal growth and function of limbs.

Aneuploidy↗
PubMedDate not supplied

On being an individual, or: the man in the red hat.

If health is a state of equilibrium between intrinsic (genetic) functions and extrinsic (environmental) factors, then disease can be defined as a state of disequilibrium. Medicine has traditionally emphasized extrinsic factors in the origin of human diseases; medical genetics is concerned with the intrinsic factors (mutations) that either yield disease in the universal environment or constitute states of risk for individuals in particular (or universal) enviroments. Genetic screening is a process that defines specific risks for particular individuals. Screening is an ineffective activity if there is no participation by clients. Newborn (and homozygote) screening, on the basis of an experience involving 35 million infants, is usually considered as a 'successful' enterprise. But adult screening, usually for heterozygosity, is quantitatively a much more important activity in its execution, judging from current experience. Comprehension of risk and perceived importance of biological individuality by potential participants and advocates are part of the problem. A major revision in the education of medical personnel and citizens is indicated if medical genetics is to achieve its goals.

Disease↗
PubMed2004

Determinants of endometrial receptivity.

Understanding the molecular changes that occur during the window of implantation is fundamental to our knowledge of human reproduction. Lately, the development of microarray technology has allowed this process to be studied from a global molecular perspective. In the last 2 years, researchers have focused their efforts on throwing light on the gene expression profile of the receptive endometrium. The genes hold the key to the development of the endometrium at any stage, and we have focused our work on the window of implantation. The four most recently published works in this field have revealed a long list of genes that are up- or downregulated at the time of implantation. Although these studies have been conducted using varying approaches, collectively these studies identify new candidate markers that can be used to accurately diagnose the receptive state of the endometrium. The next step is to perform functional analysis for confirming the importance of these genes. In this article, we gather together these recent findings to provide an overview of the current knowledge regarding the genetic functioning of human endometrial receptivity and related processes.

Embryo Implantation↗
PubMed2006

Tung tree DGAT1 and DGAT2 have nonredundant functions in triacylglycerol biosynthesis and are localized to different subdomains of the endoplasmic reticulum.

Seeds of the tung tree (Vernicia fordii) produce large quantities of triacylglycerols (TAGs) containing approximately 80% eleostearic acid, an unusual conjugated fatty acid. We present a comparative analysis of the genetic, functional, and cellular properties of tung type 1 and type 2 diacylglycerol acyltransferases (DGAT1 and DGAT2), two unrelated enzymes that catalyze the committed step in TAG biosynthesis. We show that both enzymes are encoded by single genes and that DGAT1 is expressed at similar levels in various organs, whereas DGAT2 is strongly induced in developing seeds at the onset of oil biosynthesis. Expression of DGAT1 and DGAT2 in yeast produced different types and proportions of TAGs containing eleostearic acid, with DGAT2 possessing an enhanced propensity for the synthesis of trieleostearin, the main component of tung oil. Both DGAT1 and DGAT2 are located in distinct, dynamic regions of the endoplasmic reticulum (ER), and surprisingly, these regions do not overlap. Furthermore, although both DGAT1 and DGAT2 contain a similar C-terminal pentapeptide ER retrieval motif, this motif alone is not sufficient for their localization to specific regions of the ER. These data suggest that DGAT1 and DGAT2 have nonredundant functions in plants and that the production of storage oils, including those containing unusual fatty acids, occurs in distinct ER subdomains.

Amino Acid Motifs↗
PubMed2007

Improved embryonic stem cell technologies.

Murine embryonic stem (ES) cells have become an indispensable tool for investigating genetic function both in vitro and, importantly, in vivo. Recent advances, including tetraploid aggregation, new site-specific recombinases and RNAi, have enabled more sophisticated manipulation of the ES cell genome. For instance, it is now possible to control gene expression in both a temporally and spatially restricted manner. Such new technologies are answering complex questions surrounding the function and interaction of an increasing number of genes. This chapter will review both the history and recent technological progress that has been made in mouse ES cell derivation, genetic manipulation and the generation of ES cell-derived chimaeric animals.

Animals↗
PubMed1991

The kalilo linear senescence-inducing plasmid of Neurospora is an invertron and encodes DNA and RNA polymerases.

The nucleotide sequence of kalilo, a linear plasmid that induces senescence in Neurospora by integrating into the mitochondrial chromosome, reveals structural and genetic features germane to the unique properties of this element. Prominent features include: (1) very long perfect terminal inverted repeats of nucleotide sequences which are devoid of obvious genetic functions, but are unusually GC-rich near both ends of the linear DNA; (2) small imperfect palindromes that are situated at the termini of the plasmid and are cognate with the active sites for plasmid integration into mtDNA; (3) two large, non-overlapping open-reading frames, ORF-1 and ORF-2, which are located on opposite strands of the plasmid and potentially encode RNA and DNA polymerases, respectively, and (4) a set of imperfect palindromes that coincide with similar structures that have been detected at more or less identical locations in the nucleotide sequences of other linear mitochondrial plasmids. The nucleotide sequence does not reveal a distinct gene that codes for the protein that is attached to the ends of the plasmid. However, a 335-amino acid, cryptic, N-terminal domain of the putative DNA polymerase might function as the terminal protein. Although the plasmid has been co-purified with nuclei and mitochondria, its nucleotide composition and codon usage indicate that it is a mitochondrial genetic element.

Amino Acid Sequence↗
PubMed1997

No association between bipolar disorder and alleles at a functional polymorphism in the COMT gene. Biomed European Bipolar Collaborative Group.

BACKGROUND: There is compelling evidence for the existence of susceptibility genes for bipolar disorder. Association studies using functional DNA variations are an important approach for identifying these genes. The enzyme catechol-O-methyltransferase (COMT) plays a key role in the degradation of catecholamine neurotransmitters and is a candidate for involvement in bipolar disorder. Recently a common functional genetic polymorphism that underlies population variation in COMT activity has been elucidated and a simple assay developed. METHOD: In a collaboration involving seven European centres, we have undertaken an association study of this functional polymorphism in 412 unrelated West European caucasian DSM-III-R bipolar patients and 368 ethnically matched controls. RESULTS: We found no evidence of allelic or genotypic association. CONCLUSIONS: We can conclude that variation at this functional polymorphism does not make an important contribution to bipolar disorder in the Western European population. Future studies using this powerful experimental approach can be expected to contribute to identification of bipolar susceptibility genes.

Adult↗
PubMed2006

Association study of genetic variants of pro-inflammatory chemokine and cytokine genes in systemic lupus erythematosus.

BACKGROUND: Several lines of evidence suggest that chemokines and cytokines play an important role in the inflammatory development and progression of systemic lupus erythematosus. The aim of this study was to evaluate the relevance of functional genetic variations of RANTES, IL-8, IL-1alpha, and MCP-1 for systemic lupus erythematosus. METHODS: The study was conducted on 500 SLE patients and 481 ethnically matched healthy controls. Genotyping of polymorphisms in the RANTES, IL-8, IL-1alpha, and MCP-1 genes were performed using a real-time polymerase chain reaction (PCR) system with pre-developed TaqMan allelic discrimination assay. RESULTS: No significant differences between SLE patients and healthy controls were observed when comparing genotype, allele or haplotype frequencies of the RANTES, IL-8, IL-1alpha, and MCP-1 polymorphisms. In addition, no evidence for association with clinical sub-features of SLE was found. CONCLUSION: These results suggest that the tested functional variation of RANTES, IL-8, IL-1alpha, and MCP-1 genes do not confer a relevant role in the susceptibility or severity of SLE in the Spanish population.

Adult↗
PubMed1961

Enzymatic expression of genetic units of function concerned with galactose metabolism in Escherichia coli.

Soffer, Richard L. (Stanford University, Palo Alto, Calif.). Enzymatic expression of genetic units of function concerned with galactose metabolism in Escherichia coli. J. Bacteriol. 82:471-478. 1961.-A series of genetically characterized galactose-negative mutants of Escherichia coli strain K12 were studied with respect to the enzymes of the Leloir pathway for utilization of this sugar. The functions pertaining to the three genetically defined cistrons were found to relate, respectively, to the expression of galactokinase, galactose 1-phosphate uridyl transferase, and uridine diphosphate galactose 4-epimerase. Mutants defective in the latter enzyme represent a new biochemical class in this strain of E. coli. Most of the mutants defective in galactokinase were found to exhibit significantly elevated levels of galactose 1-phosphate uridyl transferase as compared with the wild type when grown under conditions of induction. A suppressed transferase-deficient mutant was found to have regained this enzymatic activity.

Carbohydrate Metabolism↗
PubMed1988

Constitutive transcription and regulation of gene expression in non-photosynthetic plastids of higher plants.

The plastid genome in higher plants contains >50 genes for rRNAs, tRNAs and proteins for transcriptional and translational functions, besides the genes encoding photosynthetic proteins. Considering the totipotency of most higher plant cells and the differentiation capacity of plastids, it can be inferred that at least the genes for genetic functions must be constitutively expressed in all plant organs, including non-photosynthetic roots, to maintain a basal level of transcriptional and translational activities. To test this hypothesis, transcription, RNA accumulation and polysome formation were analyzed in root amyloplasts, and in plastids from hypocotyls and cotyledons of dark-grown spinach seedlings. The results for 10 representative genes show that they are constitutively transcribed at relative rates which are similar in root amyloplasts and leaf chloroplasts. The differential accumulation of their mRNAs in roots and other non-photosynthetic plant organs is controlled at the post-transcriptional level by a developmental program. Although mRNAs for photosynthetic proteins are detectable in root amyloplasts, some of them are specifically depleted from polysomes relative to mRNAs for ribosomal proteins. This translational discrimination does not result from modifications in splicing or 5'- and 3' -end processing of mRNAs for photosynthetic proteins, since processing is identical in root amyloplasts and leaf chloroplasts. The results support the model of constitutive transcription of the plastid genome, and indicate that the expression of most plastid genes in spinach plants is controlled primarily by post-transcriptional and translational mechanisms.

Journal Article↗
PubMed1999

Genetically modified organisms and monitoring.

The genetic modification of organisms for food use has raised serious concern about the potential for adverse effects on the environment, ecosystems and on the health of humans and animals. As a relatively new technology, its impacts remain uncertain but could range from disturbances to the genetic functioning of individual organisms to a reduction in the biodiversity of farmland. As a result, the question of how to monitor for potential impacts is beset with problems. The fact that genetic modification can be used on a range of organisms for a variety of purposes means that those developing monitoring systems will need to be as imaginative as those developing GMOs. In the case of genetically modified organisms (GMOs) for food use, concern has focussed on the transfer of genes to other organisms, the potential for effects on non-target organisms, or on the health of humans and animals, and the likelihood of adverse effects on wildlife due to changes in farming practice. As with other new and unfamiliar technologies, genetic modification is also plagued by the problem of uncertainty. Novel genes are inserted randomly into the genome of the host organisms, and this leads to the possibility of unexpected effects. Unanticipated environmental disasters, such as the concentration of persistent organic pollutants in ecosystems at high latitudes, have highlighted the need for monitoring despite the obvious difficulties inherent in monitoring for unexpected effects.

Agriculture↗
PubMed2002

Upregulation of IL-13 concentration in vivo by the IL13 variant associated with bronchial asthma.

BACKGROUND: A substantial body of evidence exists to support the pivotal role of IL-13 in the pathogenesis of bronchial asthma. We recently found that a variant of the IL13 gene (Arg110Gln) is genetically associated with bronchial asthma, which is concordant with animal experiments using IL-13 in the development of asthma. OBJECTIVE: To address whether the Gln110 variant of IL13 influences IL-13 function, contributing to the pathogenesis of bronchial asthma, we studied the functional properties of the variant. METHODS: We generated 2 types of recombinant IL-13 proteins, the amino acids of which at 110 were arginine or glutamine, and analyzed the binding affinities with the IL-13 receptors, as well as the stability of the proteins. We further compared the relationship between the genotype and serum levels of IL-13. RESULTS: The variant showed a lower affinity with the IL-13 receptor alpha2 chain, a decoy receptor, causing less clearance. The variant also demonstrated an enhanced stability in both human and mouse plasma. We further identified that asthmatic patients homozygous for the Gln110 variant have higher serum levels of IL-13 than those without the variant. CONCLUSION: These results suggested that the variant might act as a functional genetic factor of bronchial asthma with a unique mechanism to upregulate local and systemic IL-13 concentration in vivo.

Amino Acid Substitution↗