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PubMed1986

Primordial reading of genetic information.

From the consideration of general features of the anticodon loop and stem in tRNA and the properties of present-day translation, we put forward a plausible scenario to explain the evolution of the genetic code from a highly ambiguous triplet code to the present refined decoding system. Our model based on the reading of the code suggests that the anticodon of primordial tRNA could adopt either the 3' or the 5' stacked conformation permitting the formation of the "best two out of three" base pairs, either the first and second codon position or the second and third. Progressive acquisition of precise structural constraint and the modification of bases in the anticodon loop would give way eventually to the less ambiguous "two out of three" reading mechanism having only the 3' stacked conformation. Further adjustments of base composition and modification leads inevitably to the present generalized code. In this way the primordial code encoding 4-8 amino acids or related derivates evolves smoothly to the present code having 20 amino acids.

Biological Evolution↗
PubMed1990

[Lupus erythematosus disseminatus, lesional mechanisms, pathogenesis and genetics].

Systemic lupus erythematosus (SLE) is a model of autoimmune disease. Its study, and that of spontaneous murine models, have benefited from new immunological and molecular biology techniques. New hypotheses have been put forward to explain the mechanisms of SLE lesions. The genetic origin of autoantibodies begins to be better known. Auxiliary CD4+ lymphocytes seem to play a capital role in the occurrence of lymphocyte abnormalities. The disease is multigenic. Much work is currently devoted to the identification and characterization of genetic factors.

Autoantibodies↗
PubMed1999

Organic: What's in a name?

The organic foods industry is booming: by one estimate, the market for organic foods is worth $4 billion annually and is expected to grow at a rate of more than 24% per year. Faced with the threat of pesticide exposures and other food safety problems, many consumers are turning to organic foods in hopes of finding a healthy alternative, but there is currently no consistency in organic food labeling and no guarantee that foods labeled as organic are actually grown and processed in a purely organic fashion. There is also controversy about whether the label "organic" covers such new technologies as irradiation and genetic engineering. As part of the 1990 Farm Bill, the U.S. Department of Agriculture (USDA) is working to develop a proposed rule on organic foods. The rule would regulate the allowable methods, practices, and substances used in producing and handling crops and their processed products. The first draft of the proposed rule, released in December 1997, met with unprecedented opposition, which centered around the fact that the proposal appeared to virtually ignore the recommendations of a standards board formed to assist in the rule's development. Other criticism opposed three practices put forward for comment by the USDA: irradiation, genetic engineering, and the use of sewage sludge in farming. Due to the vehemence of the opposition to its original proposal, the USDA has decided to rewrite the proposed rule. In preparation for that proposal, the USDA Agricultural Marketing Service released three issue papers in October 1998 for public comment. The 10,000-plus comments received in response to those papers will be incorporated into the second draft proposal, due out later this year.

Agriculture↗
PubMedDate not supplied

Causes of insulin resistance in childhood.

The increasing incidence of type 2 diabetes worldwide is causing concern. Genetic and environmental influences have been put forward to explain the origins of this disease, but perhaps the most convincing contributory factor is high body weight. The authors review the literature on the subject to identify some of the predisposing factors influencing healthcare practitioners' concerns about the issue.

Birth Weight↗
PubMed2003

DNA databanks and consent: a suggested policy option involving an authorization model.

BACKGROUND: Genetic databases are becoming increasingly common as a means of determining the relationship between lifestyle, environmental exposures and genetic diseases. These databases rely on large numbers of research subjects contributing their genetic material to successfully explore the genetic basis of disease. However, as all possible research questions that can be posed of the data are unknown, an unresolved ethical issue is the status of informed consent for future research uses of genetic material. DISCUSSION: In this paper, we discuss the difficulties of an informed consent model for future ineffable uses of genetic data. We argue that variations on consent, such as presumed consent, blanket consent or constructed consent fail to meet the standards required by current informed consent doctrine and are distortions of the original concept. In this paper, we propose the concept of an authorization model whereby participants in genetic data banks are able to exercise a certain amount of control over future uses of genetic data. We argue this preserves the autonomy of individuals at the same time as allowing them to give permission and discretion to researchers for certain types of research. SUMMARY: The authorization model represents a step forward in the debate about informed consent in genetic databases. The move towards an authorization model would require changes in the regulatory and legislative environments. Additionally, empirical support of the utility and acceptability of authorization is required.

Advance Directives↗
PubMed1992

Random genetic drift and selection in a triallelic locus: a continuous diffusion model.

The Kolmogorov forward diffusion equation is used to examine the evolution of three alleles at one locus under viability selection and random genetic drift. Separation of variables and Chebyschev approximations are employed to solve this equation for long times. As an example, one artificial viability set is examined in detail; its general implications for the evolution at a triallelic locus are discussed.

Alleles↗
PubMed2006

Ephrin-B2 forward signaling regulates somite patterning and neural crest cell development.

Genetic studies in the mouse have implicated ephrin-B2 (encoded by the gene Efnb2) in blood vessel formation, cardiac development and remodeling of the lymphatic vasculature. Here we report that loss of ephrin-B2 leads to defects in populations of cranial and trunk neural crest cells (NCC) and to defective somite development. In addition, we show that Efnb1/Efnb2 double heterozygous embryos exhibit phenotypes in a number of NCC derivatives. Expression of one copy of a mutant version of Efnb2 that lacks tyrosine phosphorylation sites was sufficient to rescue the embryonic phenotypes associated with loss of Efnb2. Our results uncover an important role for ephrin-B2 in NCC and somites during embryogenesis and suggest that ephrin-B2 exerts many of its embryonic function via activation of forward signaling.

Animals↗
PubMed1998

Twisting the ladder of science: pure and practical goals in twentieth-century studies of inheritance.

In the twentieth century studies of inheritance have been driven by both practical and theoretical concerns. The metaphor of a ladder helps to illustrate how applied and pure interests have worked together in scientific development. This 'ladder' has significant 'twists' in it due to the unique nature of genetics, entwining the science of heredity with powerful and possibly compromising personal, social and commercial agendas. These implications are manifest in the history of agricultural research, eugenics, and the business of science. Today, as in the past, genetics is a prestigious science that requires cautious movement forward as human beings face its tremendous challenges and potential dangers.

Agriculture↗
PubMed2004

Rethinking the 'right not to know'.

The idea that an individual has a 'right not to know' genetic information about himself or herself is entrenched in both the policy sphere and the genetic counselling ethos. In this paper, I interrogate this idea of a 'right not to know', questioning particularly its status as a right. I identify the conception of rights that seems to underlie the posited 'right not to know' as a conception of rights in which they are prioritised non-outweighable interests. Turning to a series of hypothetical situations in which the 'right not to know' is invoked, I argue that the 'right not to know' is not a right consistent with such a conception. The 'right not to know' can only exist in a framework of rights in which they lack significant moral weight. Thus, considering the gravity of rights in popular understanding, I suggest caution in continuing use of the phrase 'right not to know' in the context of genetic testing. This investigation suggests that structuring the debate around genetic ignorance in terms of the 'right not to know' is not conducive to moving forward ethical thinking in this area.

Genetic Counseling↗
PubMed1988

[The role of environmental factors in the etiology of epilepsy (based on data from epidemiological genetic research)].

Genetic-epidemiological analysis of the role of ante-, peri- and postnatal exogenous adversities in the development of epilepsy was performed on the representative sample of 365 families using the multifactor and single locus models. The relationship was established of the genetic factors with ante- and perinatal factors on the one hand, and with postnatal ones on the other. An ecogenetic hypothesis of the epilepsy etiology was put forward.

Ecology↗
PubMed1996

Genetic pathways in colorectal cancer.

The model of colorectal tumorigenesis put forward by Fearon and Vogelstein has had great influence on molecular oncology. They proposed that a series of mutations occur in the progression from normal cells to colorectal cancer and that these mutations are associated with the histological features of such tumours. Several postulates of the model appear to be correct, particularly its emphasis on the stepwise accumulation of genetic changes and the inclusion of mutations at the adenomatous polyposis coli (APC) and TP53 loci. Since the publication of the original model, however, mutations at other loci have been identified which may be alternatives or additions. There is also evidence to suggest that some colorectal cancers develop along a different genetic pathway. In this review, we discuss how tumour development can occur as Darwinian evolution through selection of advantageous somatic mutations. The non-random nature of mutation selection gives rise to genetic pathways of tumorigenesis. In addition, we consider the Fearon and Vogelstein model, its shortcomings and possible additions to it. The evidence suggests that not all colorectal cancers follow the same genetic pathway during carcinogenesis.

Carcinoma↗
PubMed1996

Dynamics of repeat polymorphisms under a forward-backward mutation model: within- and between-population variability at microsatellite loci.

Suggested molecular mechanisms for the generation of new tandem repeats of simple sequences indicate that the microsatellite loci evolve via some of forward-backward mutation. We provide a mathematical basis for suggesting a measure of genetic distance between populations based on microsatellite variation. Our results indicate that such a genetic distance measure can remain proportional to the divergence time of populations even when the forward-backward mutations produce variable and/or directionally biased alleles size changes. If the population size and the rate of mutation remain constant, then the measure will be proportional to the time of divergence of populations. This genetic distance is expressed in terms of a ratio of components of variance of allele sizes, based on expressions developed for studying population dynamics of quantitative traits. Application of this measure to data on 18 microsatellite loci in the nine human populations leads to evolutionary trees consistent with the known ethnohistory of the populations.

Alleles↗
PubMed1998

The strategy of Myxococcus xanthus for group cooperative behavior.

New evidence has been presented from our laboratory that the gliding bacterium, Myxococcus xanthus, does not home by chemotaxis toward a nutrient source. Our experiments, those of others, and the theory presented here combine to suggest a model, called the 'Pied Piper' model. It hypothesizes a gene that has a high mutation rate forward and back (say something in excess 10(-4) mutations per cell generation) which leads to switching between two motility states. Occasionally rare organisms become genetically, but reversibly, changed so that they move unidirectionally instead of mostly forward and back as do the bulk of the cells. When such a 'leader' cell arises, it continues to move in its original orientation, and causes a cohort of cells to move together away from the bulk of the cells. That is, in the less common mutational state it counteracts the usual tendency to just move forward and backward achieving little net movement. The assumption of a genetic element that mutates in a reversible way is suggested by numerous cases of reversible switches now known in a wide range of bacteria serving a variety of functions. A second aspect of the model is that mechanisms exist that cause cells to move in the same direction as their nearby neighbors. This process results in a regular spacing of bands of cells to form mounds in the absence of a leader. The action of C-factor, a factor-secreted by the cells which has been largely studied in the laboratory of Dale Kaiser, and extracellular fibrils, (rod-shaped protein and carbohydrate bodies) largely studied in the laboratory of Martin Dworkin, may be key elements in coordinating (or linking) the movements of neighboring cells. Based on the assumption of the absence of chemotaxis, computer simulations of pattern formation for gliding bacterial swarms and flares are consistent with observed behaviors and thus are additional evidence that chemotactic motility of the type exhibited by Escherichia coli, is not necessary for the group movements of M. xanthus. Some tests for this model are suggested.

Computer Simulation↗
PubMed1994

International Commission for Protection Against Environmental Mutagens and Carcinogens. The subtlety of alkylating agents in reactions with biological macromolecules.

Genotoxic agents known to modify DNA by alkylation reactions (alkylating agents, AAs), either directly or after metabolic conversion to ultimately reactive intermediates, by no means represent a homogeneous class. For instance, their effectiveness for genotoxic damage, when expressed as the number of events (e.g., mutations) per unit exposure dose, varies over a more than 1-million-fold range in dose. Despite the multiplicity of chemical and biological processes involved between DNA adduct formation and expression of genotoxic damage, the principal aims of studies on structure-activity relationships (SARs) are to (a) dissect the multi-step process of genetic damage formation into its most essential components, (b) use SARs for making predictions and, at a later step (c) as a basis for regulatory measures. The analytical tools available for such a comprehensive analysis in eukaryotic systems include determination of multiple genetic endpoints: molecular mutation spectra, relative clastogenicity (clastogenic events in relation to forward mutation induction) and the quantitative measure of enhanced mutagenicity in repair-deficient conditions. The genetic activity profiles obtained in this way can then be compared with fundamental physico-chemical properties of the AAs under consideration (such as Swain-Scott's s value, a useful indicator of the selectivity of an AA in its reactions with nucleophiles of distinct nucleophilic strength n in DNA, RNA and proteins), their functionality (monofunctional versus cross-linking) and their tumorigenic potency (TD50s compared with measures of initial DNA interaction, i.e., O6-/N7-alkylguanine ratios, s values or the covalent binding index determined in the liver in vivo). The combination of these different methods revealed that carcinogenic potencies of AAs in rodents vary over a 10,000-fold range in dose, with the extremes having the following characteristics: (i) Chemicals of a relatively "high carcinogenic potency", as indicated by a low TD50 in rodents, either have low nucleophilic selectivity (and therefore mainly act through O-alkylation in DNA) or are capable of cross-linking DNA. The monofunctional members of this group, typified by N-ethyl-N-nitrosourea, are active in both spermatogonia and post-spermatogonial stages in the mouse and in Drosophila. Cross-linking agents also have a low TD50 value in rodents but are expected generally not to display genetic action in premeiotic stages (exceptions mitomycin C and chlorambucil). (ii) A relatively low carcinogenic potential is associated with AAs of high Swain-Scott s values, typified by trimethyl phosphate, epichlorohydrin or methyl methanesulphonate.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkylating Agents↗
PubMed2003

The role of the enterohepatic circulation of bile salts and nuclear hormone receptors in the regulation of cholesterol homeostasis: Bile salts as ligands for nuclear hormone receptors.

The coordinated effect of lipid activated nuclear hormone receptors; liver X receptor (LXR), bound by oxysterol ligands and farnesoid X receptor (FXR), bound by bile acid ligands, act as genetic transcription factors to cause feed-forward cholesterol catabolism to bile acids and feedback repression of bile acid synthesis, respectively. It is the coordinated action of LXR and FXR, each dimerized to retinoid X receptor, that signal nuclear DNA response elements to encode proteins that prevent excessive cholesterol accumulation and bile salt toxicity, respectively. LXR helps prevent hypercholesterolemia by enhancing transporters for cholesterol efflux that enhance reverse cholesterol transport, while FXR enhances intestinal reabsorption and preservation of bile salts by increasing the ileal bile acid binding protein. FXR also targets sodium taurocholate cotransport peptide and bile salt export pump (protein) genes to limit bile salt uptake and enhance export, respectively, which prevents bile salt toxicity. Other nuclear hormone receptors such as pregnan X receptor, which share the obligate partner, retinoid X receptor, and vitamin D receptor also function as bile acid sensors to signal detoxification by hydroxylation of toxic bile acids. Pharmacologically targeted receptor agonists (or antagonists) may be developed that alter cholesterol and bile salt concentrations by modulating nuclear hormone receptors and/or their coactivators or corepressors to positively affect cholesterol homeostasis and bile salt metabolism. It is the coordinated transcription factor action of LXR, which responds to ligand binding of circulating oxysterols in both liver and peripheral tissues, and FXR responding to bile salts within the enterohepatic circulation that make possible the regulation of cholesterol and bile acid homeostasis.

Bile Acids and Salts↗
PubMed2000

The interplay of genetic influences and social processes in developmental theory: specific mechanisms are coming into view.

In the coming years we can look forward to research that clarifies specific mechanisms that account for the interplay between genetic and environmental influences on psychological development. Certain misconceptions, arising from research traditions initiated by Francis Galton on the one hand and G. Stanley Hall on the other, may now be set aside in the light of new evidence. Three important findings promise a new synthesis. First, while each of us is born with about 100,000 genes that, under ordinary circumstances, do not change, the expression of these genes on behavior is dynamic. Some genetic influences are expressed early in development, but others are manifest many years later. Second, genetic factors often account not only for some of the individual differences in the measures of adjustments we typically use to monitor development but also for individual differences in environmental experiences that covary with those measures of adjustment. Indeed, genetic factors have been found to account for a surprising amount of covariance between measures of the social environment and of adjustment in young children, adolescents, and adults. Third, the expression of genetic influences are very malleable and responsive to the social environment. These new findings are revealing specific mechanisms for the interplay of genetic and social environmental factors in four domains. First, the social environment may play both a necessary and specific role in the expression of particular genetic influences on a range of behaviors from depression to social responsibility. Second, an understanding of the interplay between the social environment and genetics may lead to a clearer definition of the phenotypic manifestations of particular genetic influences. Third, we will-as a result of these studies-have a clearer fix on the timing of important events and their sequence in development. Fourth, this new genre of work promises to illumine more completely mechanisms by which the social environment influences development independent of genetic influence.

Adult↗
PubMed2005

Serotonin deficiency shortens the duration of forward movement in Caenorhabditis elegans.

Serotonin has been implicated in numerous behaviors in a wide variety of animals. We examined the effect of serotonin deficiency, induced by genetic perturbations and cell ablations, on the duration of Caenorhabditis elegans forward movement. Mutants with defective serotonin biosynthesis or worms with ablated serotonergic neurons showed a markedly decreased duration of forward movement, suggesting involvement of this neuromodulator in the regulation of the duration of worm locomotion.

Animals↗
PubMed1998

A genetic testing code of practice for insurers.

The Association of British Insurers has issued a Genetic Testing Code of Practice. The document consists of a forward and six parts, namely; Code of Practice, Statement of Duties of our Insurance Company's Chief Medical Director, Statement of the ABI Genetics advisors responsibilities, Principals of the adjudication system, the legal and ethical framework and confidentiality guidelines.

Genetic Testing↗