The frame of non-canonical theory of heredity: from genes to epigenes

Particular theory of heredity that exceeds the limits of mendelian genetics is suggested. The model based on five sufficiently obvious assumptions (accepted as axioms) As consequence of these axioms the strict statements concerningfunctional heredity memory were formulated in mathematical terms. Molecular-genetic realization of the memory cells appears as new class of heredity units--epigenes. In the epigenes part f hereditary information is contained, encoded and transmitted beyond the primary structure of DNA molecules of genome. Epigenes capable to conserve sequences of genes functional states in the course of ontogenesis and provide transmission of information contained in this states throw consequent generations. It was shown that epigenes differ from genes at least by encoding method of heredity information. There are three functional-equivalent classes of really existing epigenes mechanisms: dynamic, modificational and transpositional; and there is one hypothetical class--invertional. It was shown that a lot of experimental data concerning epigenetic mechanism of heredity is in accord with theoretical conclusions concerning epigenes existence. Moreover, we constructed an artificial epigenes by genetic engineering methods. The existence of epigenes means that obtaining complete genome sequence, its physical and genetic maps, as well as distinguishing the rules of genes function encoding by its primary structure do not provide complete decoding of hereditary information. The role of epigenes in ontogenesis and phylogenesis was examined. It was shown that even elementary epigenetic systems could determine key ontogenesis events. Epigenetic system could serve as the basis of non-darwinian evolutionary strategies by means of "memorization of rather unsuccessfully steps of evolution" and conservation of alternative variants of ontogenesis. Teleonomic hypothesis on functional heredity memory was formulated. This theory provides explanation of phenomena of acquired features inheritance and molecular mechanisms of stress-induced evolution.     

Abstract representations of biological systems in supercategories

An abstract representation of biological systems from the standpoint of the theory of supercategories is presented. The relevance of such representations forG-relational biologies is suggested. In section A the basic concepts of our representation, that is class, system, supercategory and measure are introduced. Section B is concerned with the mathematical representation starting with some axioms and principles which are natural extensions of the current abstract representations in biology. Likewise, some extensions of the principle of adequate design are introduced in section C. Two theorems which present the connection between categories and supercategories are proved. Two other theorems concerning the dynamical behavior of biological and biophysical systems are derived on the basis of the previous considerations. Section D is devoted to a general study of oscillatory behavior in enzymic systems, some general quantitative relations being derived from our representation. Finally, the relevance of these results for a quantum theoretic approach to biology is discussed.     

Convergence of one-dimensional diffusion processes to a jump process related to population genetics

A conjecture on the convergence of diffusion models in population genetics to a simple Markov chain model is proved. The notion of bi-generalized diffusion processes and their limit theorems are used systematically to prove the conjecture. Three limits; strong selection-weak mutation limit, moderate selection-weak mutation limit, weak selection-weak mutation limit are considered for typical diffusion models in population genetics.Supported in part by Research Grant from the Ministry of Education, Science and Culture of JapanSupported by the Air Force Office of Scientific Research Contract No. F49620 85C 0144     

IMGT-Kaleidoscope, the formal IMGT-ONTOLOGY paradigm

IMGT, the international ImMunoGeneTics information system (http://imgt.cines.fr), is the reference in immunogenetics and immunoinformatics. IMGT standardizes and manages the complex immunogenetic data which include the immunoglobulins (IG) or antibodies, the T cell receptors (TR), the major histocompatibility complex (MHC) and the related proteins of the immune system (RPI) which belong to the immunoglobulin superfamily (IgSF) and the MHC superfamily (MhcSF). The accuracy and consistency of IMGT data and the coherence between the different IMGT components (databases, tools and Web resources) are based on IMGT-ONTOLOGY, the first ontology for immunogenetics and immunoinformatics. IMGT-ONTOLOGY manages the immunogenetics knowledge through diverse facets relying on seven axioms, "IDENTIFICATION", "DESCRIPTION", "CLASSIFICATION", "NUMEROTATION", "LOCALIZATION", "ORIENTATION" and "OBTENTION", that postulate that objects, processes and relations have to be identified, described, classified, numerotated, localized, orientated, and that the way they are obtained has to be determined. These axioms constitute the Formal IMGT-ONTOLOGY, also designated as IMGT-Kaleidoscope. Through the example of the IG molecular synthesis, the concepts generated from the "IDENTIFICATION", "DESCRIPTION", "CLASSIFICATION" and "NUMEROTATION" axioms are detailed with their main instances and semantic relations. The axioms have been essential for the conceptualization of the molecular immunogenetics knowledge and can be used to generate concepts for multi scale approaches at the molecule, cell, tissue, organ, organism or population level, emphasizing the generalization of the application domain. In that way the Formal IMGT-ONTOLOGY represents a paradigm for the elaboration of ontologies in system biology.     

The economics of clinical genetics services. IV. Financial impact of outpatient genetic services on an academic institution.

Those clinical genetic services that do not involve laboratory tests or procedures--i.e., the "cognitive" services such as diagnosis, management, and counseling--are labor-intensive, time-consuming, and not self-supporting. However, as a result of an evaluation at a genetics clinics, a patient will often receive other services at the same medical center. The full economic impact of the genetics clinic may be underappreciated. Therefore, at one medical center we examined (a) three settings that delivered genetics services and (b) two specialty clinics providing services to children with genetics conditions; and we calculated charges and payments for an unselected, consecutive group of outpatients. The results showed that cognitive genetics services accounted for a variable, but generally low, percentage of both the professional (generally physicians') and total charges accumulated by patients as a consequence of their visit to the genetics clinic. With laboratory and procedural charges included, patients seen in general genetics clinics (or their insurance plans) paid up to three times as much to the medical center and to its health professionals as to the genetics professional. These data confirm that clinical genetics services, while not generating enough income to cover their own costs, bring considerable revenue to the medical center. This fact alone should prove useful to the director of clinical genetics programs when they are negotiating finances with institutional administrators.     

Simulating properties of in vitro epithelial cell morphogenesis

How do individual epithelial cells (ECs) organize into multicellular structures? ECs are studied in vitro to help answer that question. Characteristic growth features include stable cyst formation in embedded culture, inverted cyst formation in suspension culture, and lumen formation in overlay culture. Formation of these characteristic structures is believed to be a consequence of an intrinsic program of differentiation and de-differentiation. To help discover how such a program may function, we developed an in silico analogue in which space, events, and time are discretized. Software agents and objects represent cells and components of the environment. "Cells" act independently. The "program" governing their behavior is embedded within each in the form of axioms and an inflexible decisional process. Relationships between the axioms and recognized cell functions are specified. Interactions between "cells" and environment components during simulation give rise to a complex in silico phenotype characterized by context-dependent structures that mimic counterparts observed in four different in vitro culture conditions: a targeted set of in vitro phenotypic attributes was matched by in silico attributes. However, for a particular growth condition, the analogue failed to exhibit behaviors characteristic of functionally polarized ECs. We solved this problem by following an iterative refinement method that improved the first analogue and led to a second: it exhibited characteristic differentiation and growth properties in all simulated growth conditions. It is the first model to simultaneously provide a representation of nonpolarized and structurally polarized cell types, and a mechanism for their interconversion. The second analogue also uses an inflexible axiomatic program. When specific axioms are relaxed, growths strikingly characteristic of cancerous and precancerous lesions are observed. In one case, the simulated cause is aberrant matrix production. Analogue design facilitates gaining deeper insight into such phenomena by making it easy to replace low-resolution components with increasingly detailed and realistic components.     

Toward a unified theory of sexual mixing and pair formation.

Sexually transmitted diseases such as gonorrhea, syphilis, herpes, and AIDS are driven and maintained in populations by epidemiological and sociological factors that are not completely understood. One such factor is the way in which people mix sexually. In this paper, we outline a unified approach to modeling sexual mixing structures, where such structures are defined in terms of a set of axioms for a finite number of distinct groups of people. Theorems for homosexual, heterosexual, and arbitrary group mixing are presented, leading to a representation of all mixing structures defined by the axioms. The representation and its parameters are interpreted in terms of intergroup affinities for sexual mixing. The use of the approach in sexually transmitted disease modeling is discussed.     

Innovations in human genetics education. Incorporation of genetics into a problem-based medical school curriculum.

There has been recent interest in the development of problem-based human genetics curricula in U.S. medical schools. The College of Human Medicine at Michigan State University has had a problem-based curriculum since 1974. The vertical integration of genetics within the problem-based curriculum, called "Track II," has recently been revised. On first inspection, the curriculum appeared to lack a significant genetics component; however, on further analysis it was found that many genetics concepts were covered in the biochemistry, microbiology, pathology, and clinical science components. Both basic science concepts and clinical applications of genetics are covered in the curriculum by providing appropriate references for basic concepts and including inherited conditions within the differential diagnosis in the cases studied. Evaluations consist of a multiple-choice content exam and a modified essay exam based on a clinical case, allowing evaluation of both basic concepts and problem-solving ability. This curriculum prepares students to use genetics in a clinical context in their future careers.     

Ancestral processes in population genetics-the coalescent

A special stochastic process, called the coalescent, is of fundamental interest in population genetics. For a large class of population models this process is the appropriate tool to analyse the ancestral structure of a sample of n individuals or genes, if the total number of individuals in the population is sufficiently large. A corresponding convergence theorem was first proved by Kingman in 1982 for the Wright-Fisher model and the Moran model. Generalizations to a large class of exchangeable population models and to models with overlying mutation processes followed shortly later. One speaks of the "robustness of the coalescent, as this process appears in many models as the total population size tends to infinity. This publication can be considered as an introduction to the theory of the coalescent as well as a review of the most important "convergence-to-the-coalescent-theorems. Convergence theorems are not only presented for the classical exchangeable haploid case but also for larger classes of population models, for example for diploid, two-sex or non-exchangeable models. A review-like summary of further examples and applications of convergence to the coalescent is given including the most important biological forces like mutation, recombination and selection. The general coalescent process allows for simultaneous multiple mergers of ancestral lines.     

Evolution: geometrical and dynamical aspects.

We develop a possible axiomatic approach to the evolution theory that has been previously discussed in Freguglia [2002]. The axioms synthesize the fundamental ideas of evolution theory and allow a geometrical and dynamical interpretation of the generation law. Using the axioms we derive a simple reaction-diffusion model which introduces the species as self-organized stationary distribution of a finite population and simulates the evolution of a phenotypic character under the effect of an external perturbing action. The dynamical properties of the model are briefly presented using numerical simulations.     

Australian genetics: A brief history

Although Australia has a productive history in plant and animal breeding, fundamental genetics was late in becoming established. Before the 1950s there was no separate department of genetics in any university in the country. Reasons for the delay include geographical isolation, Australian and British colonial science policy, and the lack of a critical mass of researchers. Through the efforts of Ian Clunies Ross and the CSIR several prominent scientists were induced to come from overseas to set up the framework for an Australian-based genetics community. Since that time fundamental genetics in Australia has flourished with high quality graduates in genetics being produced at a number of universities, and many local research programs being initiated. This period has seen the gradual internationalisation of Australian genetics and increased collaboration with overseas researchers taking place. This paper provides an historical overview of the origins and progress of genetics in Australia beginning with plant breeding in the first decades of this century to the present era of molecular genetics. Significant personalities, institutions, policies, reports and publications are discussed in order to make sense of the current structures.     

R. Goldschmidt and J. Huxley: creative parallelisms

The comparative analysis of scientific heritage of Richard Goldschmidt and Julian Huxley shows convincingly the resemblance of these two scientists' views over the core problems of evolutionary theory, genetics and development biology. They both contributed to developing a triad "genetics--development--evolution". The problem of a relative growth of animals was the central point in both Goldschmidt's and Huxley's works. Huxley developed a formula of the allometric growth (law of constant differential growth) while Goldschmidt was the first to draw up the broad interpretation of the consequences of that phenomenon. Both scientists belonged to initiators of development genetics and used the "non-morganian" genetics in their efforts of solving problems of macroevolution. Goldschmidt tended toward an idea of an important role of macromutation in the process of macroevolution, though Huxley adhered to more moderate views. But at the same time the concept of preadaptive mutations proposed by Huxley was close to Goldschmidt's idea of macromutants. It is shown that both scientists analyzed profoundly the changes in early stages of embryogenesis in respect to macroevolution. It is not likely to be reasonable to oppose firmly Goldschmidt's saltationism to the evolutionary synthesis of Huxley. They developed the larger biological problems in a similar way, and undoubtedly their works in the field helped to enrich the development of the views over genetics and evolution. The open-minded analysis of Goldschmidt's and Huxley's concepts leads to creating modern and up-to-date views over the theory of evolution where seemingly incompatible things go together rather well and supplement each other. Evo-Devo rediscovered Goldshmidt's Biology and Huxley's Synthesis.     

Rapid enzyme kinetic assays of individualDrosophila and comparisons of field-caughtD. melanogaster andD. simulans

Techniques for performing numerous enzyme kinetic assays with minimum time and effort would be valuable to studies of the evolutionary genetics of metabolic control and the quantitative genetics of determinants of kinetic parameters. Microtiter plate readers have been used for a variety of repetitious analytical techniques, and instruments are available that can take repetitive readings with sufficient speed to perform kinetic assays. The ability of these instruments to assay rapidly the kinetic properties of small samples makes them potentially useful for a number of problems in population genetics. While the ability to handle large numbers of samples is very attractive, the small sample volumes and optical imprecision of microtiter plates result in some sacrifice in accuracy. This paper presents methods for performing kinetic assays on individual field-caughtDrosophila, quantifies the precision of these methods, and characterizes differences amongDrosophila melanogaster andD. simulans from samples caught in California and Pennsylvania. Comparisons between field-caught and laboratory rearedD. melanogaster show that most of the characters are very similar, with the exception of GPDH, which has a threefold higher mean activity among field-caught flies. The phenotypic correlations are presented with a brief discussion of their relevance to assessing the evolution of metabolic control of these enzymes.This work was supported by Grant BSR 8717495 from the National Science Foundation and by Grants HD 18379 and HD 00743 from the U.S. Public Health Service.     

Behaviour and the concept of “Heritability” axioms of an ethological refutation

This paper discusses the widespread use of heritability calculations in recent behaviour research including behaviour genetics. In the sequel, a radical criticism concerning the basic axioms of the underlying, more general concept itself is presented. The starting point for testing the proclaimed universal validity of this concept stems from a fictitious yet realistic example taken from learning research. The theoretical result, based on the application of the conventional reasoning in this field, states that developmental processes — and learning is only one specific case out of an immense number of similar behavioural mechanisms — can neither be adequately described nor causally explained with sufficient reliability within the context of the heredity paradigm. On the contrary, an inherent inconsistency of the concept itself when applied to behaviour processes is demonstrated. Finally, a conceptual alternative involving a systems-theoretical approach to the problem is presented: In such a perspective it is the concept of cognition which represents the adequate explanatory theorem - a theorem in which quantitative processing of information from the environment is clearly revealed to belong to a subordinate level of living organization.     

Axiomatization of genetics 2. Formal development

When certain assumptions are claimed to "found" a scientific theory, two kinds of controls are needed: it must be proved that every assertion of the theory is derived from the assumptions and that no assumption depends on (that is, derives from) the other ones. The formal approach (when possible) is the best method of achieving these results. In this paper the axiomatization of the elementary laws of genetics considered in Rizzotti & Zanardo (1986) is translated into a formal language and an axiomatic theory is defined in which the (translated) laws are deducible. Independence results are also considered.     

Education of nurses in genetics.

The need for education of nurses in genetics was articulated more than 25 years ago. This article reviews the knowledge of practicing nurses about genetics as well as the content of genetics in nursing curricula. Implementation of federal legislation that mandated increased availability of genetic services and genetics education provided support for the examination of genetics content in curricula for health professionals, including nurses, and for the development of model programs to expand this content. Recent efforts to begin to develop a pool of nurse faculty who are well prepared in genetics will be described, as well as programs to provide the necessary content through continuing-education efforts. These efforts are expected to substantially improve the capability of nurses to contribute more effectively in the delivery of genetic services.     

The population genetics of alleles affecting enzyme activity.

It is possible to predict the population genetics of allozymes by assuming that fitness is proportional to flux through a biochemical pathway. The model presented here extends previous work by incorporating two additional features of biological realism. Firstly, that more than one biochemical route may exist between any two metabolites. The major routes have been identified as the classical biochemical pathways but in the event of a mutation blocking a major route, minor routes become significant. These minor routes are named "bypass fluxes" and have profound effects on the population genetics of allozymes. Secondly, recent work has suggested that a metabolic cost is associated with enzyme synthesis; this will constitute an additional selective pressure on alleles which affect the amount of enzyme synthesized. The model generates a fitness curve which predicts the fitness associated with any level of enzyme activity. It can utilize data on null or near-null, structural or regulatory, mutations in the presence or absence of bypass fluxes. When data from natural populations of Drosophila are investigated, it is concluded that selection pressures acting on enzyme variants may be much higher than previously thought.     

Mathematical analysis of multienzyme systems. II. Steady state and transient control.

The control theory of steady states, previously presented for linear enzymatic systems (Heinrich and Rapoport, 1974) is extended to nonlinear systems. On the basis of three theorems a new procedure for the calculation of the control strength and of the control matrix is developed. The theory is applied to the extended model of glycolysis of erythrocytes, which includes also ATP-consuming processes. Also in this model the glycolytic flux is mainly controlled by the hexokinase-phosphofructokinase-system. The control strengths of the pyruvate kinase and of the enzymes of the 2.3 P2G-bypass are negligibly small. The control strength of the ATPase is negative, i.e. an activation of this enzyme leads to a decrease of the flux. For transition states of multienzyme systems definitions are given for the mean time required for the transition of the metabolites and for the "transient control" of enzymes. Enzymes with a pronounced influence on the transition time are called time-limiting enzymes. Enzymes which excert strong control on the time-dependent processes may have little influence under steady state conditions and vice versa. The transition times of ATP have been calculated for transient states of glycolysis.     

Uncovering the biodiversity of genetic and reproductive systems: time for a more open approach. American Society of Naturalists E. O. Wilson Award winner address

Important scientific findings frequently arise from serendipitous findings. Unfortunately, many scientists are not prepared to take advantage of unexpected results and to question established paradigms, and this prevents them from capitalizing on their good fortune. In this essay, I first explain how pure serendipity led us to discover unusual modes of reproduction such as clonal reproduction by males and a green-beard gene. Next, I argue that the reproductive systems of ants and other organisms are probably much more diverse than is generally appreciated. This leads me to advocate for a new "molecular naturalist" approach to reproductive systems and a more "naturalistic" approach in population and evolutionary genetics. Finally, I make two further points. The first is that our current funding and education systems tend to hinder originality and curiosity. The other is that the field of ecology and evolution, and more generally all of science, would benefit from a shift in values from scientific productivity to scientific creativity. A few suggestions are made to this effect.