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ISSN 1022-7954, Russian Journal of Genetics, 2006, Vol. 42, No. 9, pp. 10531065. Pleiades Publishing, Inc., 2006.

. Original Russian Text B.F. Chadov, 2006, published in Genetika, 2006, Vol. 42, No. 9, pp. 12611275.

THEORETICAL PAPERS AND REVIEWS

A New Stage in the Development of Genetics and Term Epigenetics1


B. F. Chadov
Institute of Cytology and Genetics, Russian Academy of Sciences, Novosibirsk, 630090 Russia; fax: (383)333-12-78; e-mail: chadov@bionet.nsc.ru
Received March 22, 2006

AbstractGenetics requires verication of the notion of gene. In this article, DNA and DNA parts are proposed to be named progenes, while the term gene refers to the informational products produced on DNA. These are RNA genes, protein genes, and DNA genes (transposable elements). The focus of genetics is switched today from characters of intraspecies difference to characters of intraspecies similarity. Regulatory genes controlling ontogeny (ontogenes) become the main object of research. These genes can be isolated by methods of both reverse and direct genetics. The properties of ontogene mutations, isolated by methods of direct genetics, are described. The problematic of epigenetics is related to the expression of ontogenes. The term epigenetics is not correct because of its ambiguity. DOI: 10.1134/S1022795406090110

INTRODUCTION As a rule, the appearance of a novel science or a eld of science is related to the development of a new method, generating abundant new data. Intellectual resources of researchers are then spent on processing of this information, while no attention is paid to relating it to the previously existing evidence. The new knowledge at rst seems alien and poorly connected to the neighboring areas of knowledge. It becomes necessary to specically dene the boundaries of the new led and to name this eld. The name should describe the eld (i.e., be unique) and be in logical connection with the names of related elds of science. It is clear that the process of the initial development of a new eld of science is complex both in essence and in a formal sense. The word epigenetics has been only recently introduced to genetics. The response of the scientic community has been ambiguous [13]. For some researchers, this was a long-awaited signal for parting with not working (for an unknown reason) statements of classical genetics; for others, it was simply nonsense. Indeed, the introduction of this term may be regarded as a formal recognition of the existence of a system of a higher order (prex epi means above, higher) above the generally known genetic system. The genetic system, which we though governing, turns out to be governed, while the governing system is the one, of which we know virtually nothing. For most researchers, who equate gene and DNA, epigenetics encompasses all that is above and
1The

higher than DNA, i.e., probably, the informational products, formed on DNA. The issue of dening epigenetics is further complicated by the existence of term epigenesis, which appeared long before genetics as a science [4, 5]. The meaning of epigenesis is not related to epigenetics, but in terms of syntax epigenetics is a derivative of epigenesis. To clarify the essence of epigenetic, we should sequentially consider the following issues: (1) did a new branch of genetics, deserving a special name, in fact emerged; (2) to what extent is the term epigenetics unique; and (3) how this term is connected with the names of the neighboring elds of science. FOUR STAGES IN THE DEVELOPMENT OF THE NOTION OF ELEMENTARY HEREDITARY UNIT, OR FOUR STAGES OF DEVELOPMENT OF GENETICS The rst stage is related to the name of Mendel and the idea on the existence of discrete material units of heredity, transmitted from parents to the offspring. The idea was based on experimentally found rules of inheritance of characters. The unit of heredity was termed by Mendel factor [6]. Later, Bateson and Iohannsen [7, 8] coined for it the term gene. The word gene, derived from the Greek genos (kinship, origin) adequately reects the essence of the hereditary unit, namely, its ability to be implemented in a character, give birth to a character. Methodologically, the rst stage of genetics was hybrid analysis. The second stage in the development of genetics consisted in an attempt to materialize the gene. According to the chromosomal theory of heredity,

terminology and statements made by the author in this article are of a debatable character.

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the process of realizing the genetic information, informational products, e.g., RNA, are formed on DNA. These are indeed discrete units. However, they do not satisfy the second part of the denition of the gene: they are not transmitted from parents to the progeny (the exceptions will be discussed below). Thus, materialization of the gene is not as perfect as seemed earlier. As in the case of chromosomes, in the case of DNA we only approached the understanding what is the material basis of the gene. The history of the appearance and change of the gene notion in the 20th century was discussed in detail by Ratner [10]. MOLECULAR GENETICS CREATED ALL PREREQUISITES FOR REVISING THE NOTION OF GENE The ingredients that serve to build living organisms are organic substances: proteins (structural proteins and enzymes), fats, carbohydrates, and the cell as a structural entity. Organic compounds are the chemical material of an organism, while enzymes catalyze biochemical transformations of substances. The cell is a special entity, which is not synthesized as an organic compound, but is completed during cell division. All of the above must be built as a result of realizing genetic information, received by the new individual from the parents (Fig. 1). Genetic information is contained in the parental DNA, but it cannot be realized without mediators. The mediators form the information ow, which starts with DNA and ends with the production of the nal ingredients (Fig. 1). A role of elementary units that realize the information transfer is played by RNA, regulatory proteins, and mobile DNA. They share two common properties: the presence of information and independent behavior. In the full sense of the word, exactly these products are genes. They are discrete, contain information, and transfer it for realization. Hereafter, the original DNA and its parts are called respectively progenome and progenies. The phrase hereditary substance is also appropriate in this respect. Thus, heredity is transmitted via progenies and realized via genes. This renaming makes the notion of hereditary units more precise. Let us group genes into three categories: RNA genes, protein genes, and DNA genes. The category of RNA genes includes iRNA, rRNA, microRNA, and tRNA. The category of protein genes includes regulatory proteins and transcriptional factors. DNA genes include DNA of transposable (mobile) elements (Fig. 2). In this new interpretation, genes are not universal in their structure, as was thought before. Universality is now a property of progenes. However, as shown later, gene diversity opens new perspectives for solving genetic problems. From the viewpoint of epigenetics, the information products termed here genes are epigenes, while DNA
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Fig. 1. Pathway from the integral hereditary substance through discrete informational products to nal constituents of the living matter.

advanced by Morgan and his coworkers [9], gene is part of a chromosome. Methodologically, the second stage of genetics was cytogenetics (cytological investigation of chromosomes as carriers of genetic information). The third stage is related to the discovery of DNA as a chemical substance, responsible for heredity. This stage involved the discovery of the DNS structure, the genetic code, and many other processes, involving DNA. At this stage, gene was equated to a DNA region [10]. Genetics proceeded to the molecular level. A large eld of science, molecular genetics, has appeared. The fourth stage. It seems that the third stage of the development of genetics as a science is coming to a close, with genetics entering the fourth stage. At this stage, informational products, synthesized on DNA, rather than DNA and its parts, will be regarded as genes. This issue is directly related to the topic of this article and thus will be considered in detail. DNA MOLECULE AND ITS PARTS ARE THE SUBSTANCE OF HEREDITY BUT NOT GENES Historically, the search for the material substrate of genes was successful twice. The rst time the sought substance was chromosome; the second time, DNA. These achievements were so signicant that some discrepancies and inaccuracies were disregarded. However, they exist and are the same in both cases. According to the genetic doctrine, genes are discrete material units (1), which are transmitted from parents to offspring via gametes (2). It has been demonstrated that chromosomes and DNA molecules are transmitted with gametes, but they are materially integral and, strictly speaking, cannot be called discrete. Certainly, the continuous DNA molecule can be divided into parts, as any other material body, but this does not allow to consider neither DNA not this body as discrete. In

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Fig. 3. Two schemes of inheritance of hereditary factors. (a) classical scheme: genes are inherited; (b) proposed scheme: progenes and genes are inherited.

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Fig. 2. Spaces of genetics and epigenetics at different meanings of the term gene. (a) Traditional notion of gene as a DNA region: genetics is shown as the inner circle, epigenetics, as the outer circle; (b) notion of gene as a discrete informational product: genetics operates with progenes and genes, epigenetics as an area does not exist.

and its regions are still genes. The modern molecular genetics showed that tens and hundreds of products with different functional roles could be produced on the same DNA region. Since in genetics, gene is a product with a certain function, neither the total DNA molecule nor its segments do not conform to the term of gene. In addition to the statement on non-discreteness of the DNA molecule, this is another argument against the regard as genes the DNA molecule or its regions. ADVANTAGES OF RENAMING DNA IN PROGENES AND INFORMATIONAL DNA PRODUCTS, IN GENES The above renaming does not leave place for epigenetics, since the events occurring with genes must be termed genetic rather than epigenetic (Fig. 2). The division of a hereditary unit into the progene and the gene claries the process of information transmission from a parent to the progeny, from a dividing cell to the daughter cells. In each case, a complete number of progenes (DNA) and a certain gene set are transmitted (Fig. 3). Transmission of genes along with the hereditary substance assumes the character of a rule. The maternal and paternal effects in character inheritance [11, 12] and the basic rules of the ontogenetic process [13] are explained. Progenes cannot be switched without genes. Depending of the transmitted genes, the development may follow different programs. Punctually following the rule of transmission of genes along with progenes, as discussed further, removes the cover of mystery from the emergence and the transmission to the progeny of the functional states of genetic material. In the classical sense, the gene combines two functions: transmission of information (passing it to the progeny) and its realization (the formation of a characRUSSIAN JOURNAL OF GENETICS Vol. 42 No. 9

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ter). It is reasonable to assume that these functions are fullled by two different, albeit mutually connected carriers: progenies transmit the information and genes realize it. In the case of classical interpretation of the term gene, information transmission automatically implies its realization. Modern genetics cannot assume such oversimplication. It is known that the activity of most genes is timed to the particular ontogenetic stages, while at the other stages these genes are inactive. There are genes that are active in one individual and inactive in another. The function of a signicant part of transmitted DNA remains unknown. The above term revision cardinally changes the concept of genetic system. Instead of the classical DNA protein chain, a cycle similar to the Eigens model is proposed: DNAproteinDNA [14, 15]. According to Eigens model, a set of progenes (DNA) cannot independently develop into an organism. It can be realized only in the presence of preliminarily acted genes and a morphological structure in form of a cell. In each interval of the life, progenes produce structural and regulatory proteins. The former build an organism, the latter determine the activities of some progenes in the following life stage. In the case of ontogeny, one of the cycle stages was named producing a regulatory product for export [13]. The genetic system after Eigen in our case is a constant interaction between progenes and genes. This interaction can stop at some life stage, but is always resumed. Its beginning dates back to the time of the appearance of life (the initial jolt). The concept of the interaction, of hypercycles at different scales, allows us to expand the horizons of genetics. To date, genetics is not the science on genes giving birth to characters, as it was seen at the previous stage of the development of genetics, but a science on the mode of existence of the living matter. Interaction between genes and progenes for the rst time provides a possibility to recognize the working genetic system of an organism simultaneously as part of the global biological life and as part of the ontogeny of the given species, and its phylogeny. In the 20th century, genetics has stimulated the development of the information theory [10, 16], the theory of dynamic systems [17], and synergetics [18]. However, the theoretical basis of genetics itself was not considerably changed by the development of these the2006

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ories. The subdivision of the informational genetic unit, the gene, into two units, the gene and the progene, lies foundation for devising a cyclic geneprogene model. Based on this model, the modern static genetics can develop into the dynamic genetics, which would have all attributes of the dynamic system: connection with ows of energy, development, generation of information, etc. [17]. Recognition of the existence of different gene categories opens an avenue for studying features of the action of these genes. Geneticists working with homeotic genes and other signal genes note low penetrance and high lethality of their mutations, as well as unexpected effects of mutation interactions [19]. In these aspects, these mutations strikingly differ from mutations of Mendelian genes. We will not understand these differences, if we restrict ourselves by studying differences between primary gene sequences. However, if we compare the set of genes (in the new meaning) controlling a Mendelian character, with the set of genes controlling the formation of a so-called normal character, they will be different. Identical as progenes, they are implemented by different genes. Structural genes obey the dominance-recessivity rule. This rule holds owing to the mode of interaction between the nal productsstructural genes, but not owing to a particular DNA structure of these progenes. Mutations of regulatory genes governing development (ontogenes) are characterized by a different rule, dominant lethality or the absence of expression [20]. This rule is ensured by a special mode of interaction of homologous protein genes, rather than the nal structural proteins, forming the character at the last stages. The rules for DNA genes, known as transposable elements, are strikingly different from that. MODERN GENETICS HAS STARTED TO STUDY CHARACTERS OF INTRASPECIES SIMILARITY, NEGLECTED IN CLASSICAL GENETICS The revision of the term gene is relevant in context of the event that has already occurred in genetics, but has not been adequately appreciated. The contemporary genetics focuses on biological characters alien to classical genetics. These are characters of intraspecies similarity or, according to the accepted terminology, normal characters. Their formation does not require defects in the primary DNA structure. It starts earlier and looks far more complicated than the formation of Mendelian characters. The formation of a Mendelian character begins with transcription of a changed DNA sequence of particular genes. These are structural genes, activated at the nal stages of the normal character formation. The formation of the interspecies similarity character commences at the zygotic stage and earlier. Character is all in which objects and phenomena are similar or in which they differ from one another; an aspect of an object or phenomenon, by which we can

identify the object or the phenomenon. This is the denition of the character in formal logics [21]. Characters inherent only to the given object are called differentiating and inherent to many objects, shared or non-differentiating [21]. In terms of biological objects, individuals within a species have both shared and differentiating characters. The shared characters form intraspecies similarity, while differentiating characters, intraspecies difference(s) [22, 23]. To analyze inheritance of characters, Mendel used characters of intraspecies difference. These were well inherited in breeding intra se and represented clearly distinct character pairs: white and red ower color, yellow and green pea color, smooth and wrinkled pea surface, etc. The use of characters of intraspecies difference was Mendels brilliant discovery. Many of his predecessors crossed members of different species to study inheritance (in some interspecies crosses, rst-generation progeny is viable). Interspecies crosses proved unsuccessful [24]. Mendels choice provided a possibility to observe the inheritance of a character pair in any number of generations, while the fact that the bearers of these characters belonged to the same species removed all problems connected to crossing. The inheritance of characters of similarity (at least as an experimental task) was not studied by Mendel and long time after him. To trace characters shared by parent in hybrid generation is meaningless, since they are identical in all past, present, and future members of the species by denition. Thus, at its birth genetic virtually was genetics of characters of intraspecies difference. After the famous works by Muller, documenting the appearance of genetic mutations induced by ionizing radiation [25], the mutational period in the development of genetics has started. Many authors generated numerous mutations in diverse living organisms [26]. Working with mutations has not changed the character of genetics stated above. Mutant characters were characters of intraspecies difference. Researchers still worked with pairs of characters, one character being mutant, and the other, normal. To be more precise, the normal character was the one that had not been changed by mutation. In classical genetics, it was thought that the norm in the mutationnorm pair is the element constituting the great norm, i.e., the organism. Geneticists aimed at obtaining as many mutations as possible. It was supposed that the issue of the genetic structure of the organism would be thus resolved automatically. Until very recently, there was no distinction between characters of similarity and difference in genetic literature. Because of this approach, the purpose of the bulk of genetic material was not understood. This situation has continued until the present. Classication of biological characters into two categories has been made rather recently [22, 23]. It was supposed that variability of characters of one of the catVol. 42 No. 9 2006

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egories and the absence of variability in the other category masked their different genetic bases. This assumption proved to be true. CHARACTERS OF INTRASPECIES SIMILARITY AND AN APPROACH TO THEIR INVESTIGATION It was supposed that the sought genes constitute the invariant part of the genome of the species. Altukhov [27] was the rst to advance the concept of the invariant genome part, developing it at the population level. Our initial statements were as follows: (1) the genome of the species has an invariant part; (2) mutations of invariant genes are dominant lethals; but (3) dominant lethality of the mutations is not obligate: such mutation can be lethal in some organisms, but not lethal in other organisms. To put it differently, these dominant lethals exhibit conditional lethality [28, 29]. The experimental work was aimed at searching for conditional dominant lethal mutations. Using methods devised for this purpose [2830], about 100 mutations were found, but this number can be easily increased. A rule for choosing a character for genetic work, introduced by Mendel, was taking characters with stable expression (expressivity) and stable inheritance in a pure line (penetrance). Characters that do not vary in all individuals of the species are thought the best. This rule is based on an idea that gene is a stable elementary unit of heredity that is not affected by variation in external and internal factors. The protocol for character selection, formulated by Mendel, was aimed at separating true (genetically based) characters from unstable (not genetically based), externally determined ones. The above procedure of selecting conditional dominant lethals rejects this attitude, introducing another one: there is a category of genes that do not necessarily manifest in all members of the species. ONTOGENES AND THEIR PROPERTIES The uniqueness of the genetic basis of characters of intraspecies similarity followed from the unusual properties of the obtained mutations. Morphoses in the progeny of the mutants; introducing the term ontogen. In the progeny of mutant individuals, individuals with visual defects (morphoses) usually appear at frequencies ranging from several percent to several tens percent [13, 31]. Morphoses can affect any parts of an individual, but usually at one side, right or left. They include defects of type plus tissue (protrusions, additional legs, wings, thoracic parts, etc.) or minus tissue (absent leg, wing, eye, part of the head, etc.) (Fig. 4). Such examples of pronounced morphoses as two heads, an additional leg, three wings suggest that morphoses are caused by a switch of a subprogram of the normal development in an inadequate cell group. As the mutated genes clearly are related to the process of ontogeny control, they were named ontogenes. In develRUSSIAN JOURNAL OF GENETICS Vol. 42 No. 9

opmental genetics, they seem to be close to newly appeared notions of signal genes and key genes [32, 33]. A mutation in an ontogene change its manifestation depending on the genetic background (sex of the mutation donor, genotype of the partner, sex of the mutation recipient, genotype of the mutation recipient). According to conditions of isolation, the mutations were expressed as lethal in one genotype and lacked this expression in another one. All genetic conditions listed in the heading of this section were present in the mutation isolation procedure [28, 30]. A mutation in an ontogene changes its expression depending on the spatial position of the genetic material in the cell. Mutations dealt with in genetics are usually indifferent to the position of the mutant region in the nucleus as well as to the positions of other regions. These mutations are maintained in lines, carrying diverse chromosomal rearrangements, and do not lose their standard expression. The lethal mutations described above proved to be sensitive to chromosomal rearrangements in the genome [12, 34]. In genotypes with rearrangements, they ceased to be lethal. The rearrangements preserved their effect in the progeny even in the cases when the rearrangement was carried by the mother rather than the progeny (the maternal effect of a chromosomal rearrangement) [12]. A mutation in an ontogene results in genetic instability. The above mutations manifested another property that distinguished them from Mendelian genes. A mutation in an ontogene induced instability in the genome. We described seven different manifestations of such instability [35], some of which are considered below. While maintained in laboratory cultures, ontogene mutations lose their lethal expression in the genetic background, in which they manifested it previously. The presence of an ontogene mutation disturbs the process of cell division, both mitotic and meiotic. In meiosis, nondisjunction and loss of X chromosomes occur. The rate of chromosome loss reach tens percent. In somatic cells (mitosis), the chromosome loss is manifested in the appearance of mosaic individuals and gynandromorphs (individuals having traits of both sexes). Instability is also expressed in secondary mutagenesis. Periodically, in the mutant progeny, visible mutations appear singly, in groups, or sometimes sequentially in consecutive generations. Another characteristic feature of ontogene mutant cultures is the presence of modications. Modication is an exterior defect, which, in contrast to mutation, is not preserved over generations. The formation of morphoses discussed above can also be considered as a manifestation of instability. The phenomenon of genetic instability has been known [36]. In the present work, it was found that this phenomenon is caused by mutation in a special gene, ontogene.
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Fig. 4. Morphoses in Drosophila melanogaster. Top row (from left to right): additional thorax with wing, laments in place of right wing, additional wing at left (directed forward); bottom row (from left to right): additional wing as a haltere, hanging eye, absence of several tergites.

Manifold manifestation of the ontogene mutation. Mendel classied genes into dominant and recessive. The currently existing genetic mutations are also subdivided into recessive and dominant. Mutations of ontogenes are recessive and dominant simultaneously. In some crosses, they behave as dominant lethals. In laboratory cultures, they are maintained in heterozygotes as typical recessive lethals. Some of them have visible recessive expression in homozygotes. These are dimorphic mutations with different expression in males and females [31]. Presumably, ontogenes are DNA sequences, from which several genes with different functions are transcribed. Some of these genes are structural, others are regulatory. The former are recessive, and the latter, dominant. Figure 5 schematically shows that ontogenes are regulatory genes connected by their signal function in regulatory networks. Structural genes, albeit transcribed from the same DNA sequences, does not form such networks. DNA damage, depending on its position in the gene locus, may cause: (1) a structural gene

defect only, (2) a regulatory ontogene defect only, and (3) a defect in both genes. In the rst case, the defect will be expressed as a typical Mendelian mutation; in the second, as an ontogene mutation (conditional dominant lethal); in the third, as a Mendelian mutation with abnormal inheritance, conditional lethal effect, interaction with other genes. The listed above mutation properties are strikingly exotic, although the mutations were generated by means of a traditional irradiation procedure and are inherited as defects of the primary DNA structure. They combine many of enigmatic phenomena that sporadically appear in genetic experiments. These include incomplete penetrance, modications, morphoses, and instability. These phenomena are often interpreted as cases of epigenetic [1, 37], dynamic variation [38] and attributed to noncanonical heredity [39]. However, in our experiments, they were all caused by trivial radiation damage of DNA.
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GENETIC BASES OF MENDELIAN CHARACTER AND CHARACTER OF INTRASPECIES SIMILARITY ARE DIFFERENT Based on the evidence of the existence of two gene categories, one of which is ontogenes (regulatory genes controlling ontogeny), the course of ontogeny is schematically presented in Fig. 6. Ontogenes form a multilevel network. Structural genes are located at the ends of the regulatory chains. The process of ontogeny is based on the principle of relay. An activity signal, arisen in a zygote, passes through the ontogene chains to the structural genes. After transmission of the signal, the ontogene switches off, but the activity of the structural genes is preserved (Fig. 6, right) [31]. The signal transmission is connected to cell division, ensuring the formation of differentiated groups of cells in a multicellular organism [13]. According to this scheme, characters of intraspecies differences appear as a result of mutations of the structural genes at the chain ends. The characters, as a rule, are monogenic. These are characters of intraspecies differences, existing in nature, and numerous articially produced characters (mutations). Only to date we can understand that the fundamental Mendelian principle of discrete heredity could be formulated only by analysis of characters of intraspecies differences. Genes controlling these characters are located at the ends of the functional gene chains, and therefore are mutually independent. The genetic nature of the characters of intraspecies similarity is different: these are total blocks of hierarchically connected ontogenes, ending by many structural genes. Thus, although the characters are controlled by genes, the genetic bases of these characters are different. The above scheme shows that every gene is not matched by a phene (visible manifestation). A mutation in a structural gene probably will produce a denite and heritable phenotypic change. A mutation in an ontogene, which is an element of a regulatory chain, will disrupt the development (lethal action). The organism simply will not exist. A mutation in an ontogene can lack manifestation, because this mutation is a conditional lethal. The above scheme evidently does not reect ontogeny in all its complexity. Even small stages of this process, studied experimentally, look far more intricate [33]. However, even this simple scheme clearly shows that the character in Mendelian and classical sense is a defect of development, caused by a defect in the DNA sequence. Rimane was right when he ironically referred to collections of genetic mutations as a real home for disabled [40]. The characters of intraspecies similarity appear as a result of realization of long gene chains. To form such a character, no defect in the DNA sequence is required. In connection with the chain process of formation of a normal character, including operation of regulatory ontogenes, features of the genetic system that could not be found by classic hybrid analysis
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Fig. 5. Polygenic effect of a mutation, disrupting the DNA sequence, which undergoes alternative splicing. Changes in the sites of initiation and termination of transcription (arrows) of progenes A and B, four proteins appear for each gene. Progene C produces three proteins. One protein of each set (top) is structural, the remaining ones are regulatory. The regulatory proteins are involved in regulatory pathways. The functional associations between them are shown as lines. If the DNA is damaged (progene A sequences), all four proteins (structural and three regulatory ones) are changed, which results in complex phenotypic expression and unusual inheritance of the mutation.

appear. They become accessible only as a result of the development of methods of reverse genetics and novel methods of hybrid analysis, devised only recently (see above). Figure 7 presents pathways of realization of hereditary information in the case of a Mendelian character and a character of intraspecies similarity. In the rst case, it is a short chain: progeneRNA genestructural protein; in the second, a cascade, consisting of many chains: progeneRNA geneprotein gene (transcription factor), connected by the bond protein geneprogene (numerals 1, 4, 7). Complex variants involving microRNA and DNA genes (transposable elements) are not presented in the scheme. In the case of a Mendelian gene, the features of its inheritance are explained by the relationships between two nal structural genes: the normal and the defective one. These relationships, known as recessivedominant, were described by Mendel. In the case of the character of intraspecies similarity, a protein geneprogene (=transcription factorDNA) stage is multiply wedged in between. The relationships between two protein genes, one of which is normal and the other, defective, are still unclear. Experiments with conditional dominant lethals suggest that these relationships are different from the classical recessivitydominance scheme. In most cases studied, the presence of a defective product even in one dose is lethal. Not considering more complex cases of the cascade chain, it is clear that genetics of similarity characters must be full of surprises.
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Fig. 6. Genetic model of ontogeny [31]. (a) Genes and signaling pathways. The genome of an individual consists of structural genes (dark circles) and ontogenes of various ranks (open circles, squares, and triangles). The ontogene is represented by a number of cisalleles (signs divided into sectors). t0t4 are ontogenetic stages. The genome activation proceeds by system of signaling pathways (lines connecting genes, arrows). The signal pathways are terminated by inclusion of structural genes. Ontogeny is the process of sequential switching of regulatory genes of different ranks according to the relay principle. In transition from the previous to the subsequent ontogenetic stage, the ontogenes acting at the previous stage, as well as structural genes providing the appearance of presumptive structures (hatched circles) are switched off. (b) Ontogeny at one of the last stages (t4). Switched off genes are shown by hatched lines. Most of the structural genes and some ontogenes with similar time of switching (regulatory genes of stem cells) remain switched.

GENETIC SYSTEM AND THE IMPACT OF THE EXTERNAL AND THE INTERNAL ENVIRONMENT Variability of structural genes and variation of ontogenes are provided by different mechanisms. The former is based on the existence of viable variants of the primary DNA structure, known as alleles. In Fig. 8, they are shown as dashed circles. A diploid organism has two alleles of each gene, one in the maternal, and the other in the paternal chromosome. The remaining alleles are carried by other individuals of the same species. Variability of such a species is of the populational nature. Variability of ontogenes is genomic rather than population one. Each ontogene is represented by a cassette of alleles. Variation emerges, because the regulatory pathway of several ontogenes may pass through different cis-alleles of these genes. With many ontogenes and many cis-alleles of each ontogene, the number of variants is enormous. This type of variation is not connected with changes in the primary DNA sequence. It is likely that variation of this type causes the so-called ontogenetic variability [41, 42], in particular, bilateral asymmetry [43].

This type of variation by meaning coincides with epigenetic variation, related to gene activity/inactivity. In our case, we focus on the possibility of this variation type, rather than on the activity of the target genes. This variation is caused by the existence of cis-alleles, each of which is capable of performing the function. The cis-allelic organization of ontogenes creates conditions in the organism for ontogenetic variants, i.e., programs and subprograms of different levels of complexity. The most grandiose of them is the sexual program, which operates in two variants, male and female. With practically identical sets of operating structural genes, the difference between the male and the female organisms, caused by different ensembles of regulatory genes, is striking. Analysis of operation of an ontogene system (gene network, in Kolchanovs terminology) allows us to approach the geneenvironment problem, which repeatedly caused confrontation between biologists and geneticists. In the work of a regulatory system, the notion of signal is signicant. In genetics, this is a material product activating a gene. In the case of sex determination, the signal for switching the male or the female developmental pathway is genetic. It is either the presence of the Y chromosome, or the ration
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between the number of sex chromosomes and autosomes. It was repeatedly suggested that factors of internal (positional ontogenetic information) and external environments might serve as signals. In plants, striking examples of external signals changing developmental programs are known. For instance, in water buttercup, the aerial environment results in the development of arrow-shaped leaves, while in the water environment the leaves are stripe-like. For cultured plants, the theory of alteration of limiting ontogenetic factors is supported by experimental facts. According to this theory, the ontogeny may take different pathways, i.e., involve different genes, depending on the signal from the environment, received at a particular time [44, 45]. If we take a suddenly arisen variant of ontogeny for an acquired character, it may prove to be inherited, which in fact is not surprising. However, this character will be expressed only under conditions that led to its expression in the parent. The phenomenon of morphoses in the progeny of ontogene mutants is very instructive for understanding inheritance of acquired characters. First, the entity that we call the acquired character has an intricate structure. Protrusions in the form of a leg, arista, tergite part, etc., are doubtlessly a result of realization of part of the genetic program of ontogeny, albeit they are realized in inappropriate places. Their repeated manifestation cannot be excluded, since the program itself is heritable. Generally speaking, the acquired character (if it is not a deformity) cannot be without a genetic basis. If so, a progeny, receiving from a parent its genome, theoretically inherits the possibility of expressing this character. This absolutely does not require transmission of information from somatic to germline cells, as is sometimes supposed [2]. In my opinion, there is also a channel for direct effect of the environment on the genetic structure of an organism. This occurs in the period of genome destruction and reorganization [35]. In these periods, such variants of the developmental programs and subprograms must be used, which ensure maximum possible adaptation of the organism in the given environment. If the system rearrangement proves to be successful, then clearly adaptive variants, during which it occurred, will be incorporated into the new system as an obligatory element. Thus, the impact of the environment will be retained by the genetic system, though this process is more complex than seemed to biologists in the 17th 18th centuries. This suggestion can be experimentally tested on mutant lines expressing genetic instability. A NEW FIELD HAS INDEED APPEARED IN GENETICS, BUT THE TERM EPIGENETICS IS INAPPROPRIATE FOR IT The key idea of the above is as follows: to date genetics is investigation of production of genes on the progene template before, after, and during the process of ontogeny. All processes here are genetic. Referring to them as epigenetic is incorrect from all viewRUSSIAN JOURNAL OF GENETICS Vol. 42 No. 9

Structural protein 1

Structural protein 2

RNA-gene 1

RNA-gene 3

RNA-gene 5

Progene A 2 1 RNA-gene 2 3 Protein gene 1 4

Progene B 5 7 RNA-gene 4 6 Protein gene 2

Progene C

Fig. 7. Two pathways of realizing the hereditary information of the progenome: short (progeneRNA-genestructural protein) and long (regulatory cascade). The cascade involves protein genes. The regulatory cascade transmits information by stages from 1 to 7. Boxed are the stable cell components: DNA (progenes) and structural proteins; in ovals, short-lived components: RNA-genes and protein genes.

points, and primarily because the meaning of the term epigenesis is, strange as it may seem, rather antigenetic. In Antiquity, the scientic formulation of the idea of development was represented by two concepts: Platos (development after a pattern) and Aristotles (epigenesis). In the rst concept, the development is implementation of a preexisting plan (thing in itself); in the second, as a self-realization process, i.e., the appearance from unorganized matter (chaos), reorganization and complication via making a superstructure (epigenesis) [5]. In the 18th-century biology, these concepts were retained in form of preformism and Wolfs epigenesis(cited from [4]). Thus, the word epigenesis with a quite distinct meaning has appeared and existed long before the foundation of genetics and coining the genetic terminology. Mendelian genetics, classical genetics, and modern genetics continue the preformism line in the issues of individual development. The organism is a result of realization of a hereditary program, consisting of elementary stable units, genes. At its birth, the ideology of genetics was straightforwardly preformistic: a phene for each gene. As the science of genetics developed, the issue of the origin of the character tilted toward epigenesis. Morgan [46] admitted change and development of genes during ontogeny; Goldschmidt [47] suggested interactions among gene products not controlled by genes. In 1963, Mayr [48] wrote that our notions of the connection between the gene and the character had been thoroughly revised, with phenotype increasingly regarded not as a mosaic of separate characters con2006

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C D E E6 E5 C8 Maternal homolog C7 a b Paternal homolog A1 A2 A3 A4 A5 B1 B2 B3 B4 B5 B6 C2 C3 C4 C5 C6 D1 D2 D3 D4 E2 E7 E8 F2 F3 F4 F5 F6 G1 G2 G3 A1 A2 A3 A4 A5 B1 B2 B3 B4 B5 B6 C1 D1 D2 D3 D4 E4 E3 E1 F8 F7 F1 G1 G2 G3 F G

Fig. 8. Scheme of organization and action of ontogenes [34]. C, E, F (dots) are unique structural genes; there are alleles of these genes in the population (e.g., 16), but the diploid genome has only two alleles. Ontogenes A, B, D, G consist of cassettes of cisalleles (e.g., 15). In a concrete organism, only one cis-allele of an ontogene and only in one of the homologs (hatched) is working. Depending on switching of a cis-allele, a concrete variant is realized. a (hatched line) and b (solid line) are variants of the ontogeny. Instead of operating in norm cis-allele 1, cis-allele 5 may be activated. Mutation in cis-allele D4 upon development by variant b is lethal, but is not expressed in development by variant a.

trolled by genes, but as a nal product of a complex interacting system, an epigenotype. Waddington [49, 50] aimed at uniting genetics and developmental biology, but according to him, ontogeny was not a process entirely controlled by genes [50, p. 17]. This motivated this author to look for a term to dene the process of individual development without referring to the term developmental genetics, which implies genetic basis of ontogeny. Several years ago, writes Waddington, I have introduced the term epigenetics, deriving it from Aristotles epigenesis, the word that is almost obsolete, and proposed to name epigenetics the branch of biology studying causal relationships between genes and their products, which form the phenotype. This term is currently rather often used exactly in this sense, but unfortunately, it turned out to be very appealing, so some authors employ it to denote very different notions [] in my view, we may escape much misunderstanding, if we reserve this term for the science studying causal relationships in development, as was suggested from the very beginning [51]. The author speaks of phenotype as an epigenetic phenomenon; he considers cell differentiation and morphogenesis as elementary processes of epigenetics [51]. In other words, for Waddington epigenetics is the science on the implementation of the phenotype as the integral realization of the genotype (in modern terms, the genome) as opposed to the simplistic notion genotype is the sum of genes and phenotype is the sum of their phenes. In modern terms, epigenetics deals with genetic of individual development. Criticisms considered in Introductions can be applied to Waddingtons term epigenetics, notwith-

standing insights into the meaning that this author put into it. By denition, genetics is the science that studies inheritance of characters. It deals also with the development of characters from the hereditary substance. It was not for nothing that the elementary units of heredity were named genes. Because of the prex epi, the term epigenetics seem to imply something beyond genes and characters. As noted Waddington [50, p. 38] himself, a term should not be ambiguous. This is very true. Exactly for this reason, the term epigenetics is not acceptable. Aristotles notion of epigenesis proved to be unsuitable for describing the process of individual development. Neither Wolf in the pre-genetic stage of biology, nor Waddington in the golden age of genetics could make this description. According to the contemporary evidence, the ontogeny strictly follows a genetic plan. Wolf could not know it; even Waddington was not fully aware of it. In his time, genetics operated only with structural genes; studies of regulatory genes, at that only in prokaryotes, have just started. From the beginning, epigenesis stood against preformism. After the appearance of genetics, which continued the ideology of preformism, the term epigenetics emerged in the cases, when researchers encountered phenomen that could not be explained genetically, i.e., on the basis of existence of governing (genetic) units. In the 1970s, Tchuraev has developed the notion of epigene. According to Tchuraev, epigene is a hereditary unit (cyclic system of genes) that has at least two regimes of functioning of the genes governed by it and capable of preserve each of the regimes in consecutive generations [52, 53]. DNA molecules, consisting of genes, store information in the structural way, whereas epigenes do it in the dynamic way [52]. Epigene is a supergene structure, united by an integral functional state.
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Genes in the epigene are DNA segments, whose activity is maintained by the gene products [54]. Epigene consists at least of two genes. In our terminology, this concerns interaction of genes and progenes. This interaction is a typical phenomenon occurring in the living organism, which has the form of a cycle of a certain size [15]. The development of the ides of gene systems with account of their functional state (activity and inactivity) by Tchuraev as early as in the 1970s was certainly a great achievement. The author has introduced the notion on a dynamic way of storing information and the possibility of inheritance of such information. Based on epigenes, the noncanonical theory of heredity was constructed [39, 52]. Tchuraev argues that the functional state of a genetic system can be transmitted to the progeny. Hereditary transmission of the functional states of the parental genome may serve as a basis for serious consideration of the idea of inheritance of acquired characters [38, 39]. I believe that the issue on the existence of dynamic inheritance was inuenced by the aforementioned drawback of classical genetics. Classical genetics is concerned with genes, but not their products. If, in the case of Tchuraevs epigene, we fail to take into account that the maintenance of the functional state requires corresponding gene products, the coincidence of the functional gene state in the parent and the progeny could be taken for inheritance of dynamic information. In reality, the functional state is restore, rather than inherited. The restoration results from the transmission of a regulatory product. Switching the activity of the corresponding gene, together with the maternal DNA. The author himself states so in one of his latest studies [54]. The renaming of the informational gene products into genes allows one not to overlook gene products when considering a functioning genetic system, and thus to describe the system clearly and comprehensively. If this is done, the number of cases of transmission of functional states from parents to the progeny must drastically drop. The word epigenetics is spreading in scientic literature with an astounding speed, demonstrating an example of reproduction of replicators of the mem type (mem is an abbreviation of the Greek word mimos, which means imitation) (cited from [55, p. 66]). To date, the bulk of experimental data, ascribed to epigenetics, should be separated from the term (or candidate term) itself. If the experimental data on epigenetics are reliable to the same extent as other data, then the term epigenetics is debatable. The main objection against the introduction of the word epigenetics to genetic usage was formulated in Introduction. It is Waddington, the author of the term epigenetics, who said: A term should not introduce to science any unwanted, additional meanings, which it might contain in its daily use, its biological signicance should strictly correspond to
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the properties that are found in the phenomenon examined, and to nothing else [50]. Epigenetics, which was formerly employed as a term for genetics of ontogeny, is currently assuming another meaning. Epigenetics begins to include phenomena and processes that classical genetics does not know of, cannot explain or have not dealt with. The range of these phenomena and processes is broad, but they all concern a new class of genes, regulatory genes controlling development (ontogenes, in our terminology). The properties of these genes were discussed in the rst part of this paper. The fundamental to epigenetics is the term epigenetic variation. In contrast to genetic variation, based on alteration of the primary DNA sequence, epigenetic variation is a change in the genome activity pattern. It is related to gene activation and deactivation, but not to a change in the DNA sequence. The activity pattern changed during ontogeny (which has long been known), and varies among the individuals within the species, which are at the same developmental stage (see above about the activity of cis-alleles of ontogenes). Two aspects of the activity are of particular interest. One of them lies in the fact that the transcriptional activity of a given DNA region does not mean production of the same product (see section Manifold Manifestations of Ontogene Mutations"); the second, that there are pattern variants (see section Genetic System and the Impact of the External and Internal Environments). It can be seen that within genetics of development, an area of general genetic interest emerges, which is above the concrete problems of ontogeny, i.e., morphogenesis, determination, differentiation, etc. I think that epigenetic is ultimately investigation of ontogenes. Even now, it is clear that ontogenes are related to (1) characters of intraspecies similarity (i.e., normal characters); (2) the process of ontogeny; (3) switching on and off the gene activity; (4) gene silencing; (5) parental effects; (6) incomplete penetrance; (7) dependence of the activity on the location within the genome; (8) alternative developmental programs; (9) association of the gene activity with external and internal environments; (10) speciation [29, 35, 56, 57]. In my view, instead of employing the term epigenetics, one should use the term genetics of within-species similarity and the term gene in its new meaning. The revision of the gene notion is inevitable, but will occur slowly because of clinging to tradition. Instead, we should develop a more logically formulated genetic doctrine and a larger eld of science named genetics. Aristotles epigenesis, which is in focus of interest of theoreticians [58, 59], has its place also in traditional biology. It lies in the eld, in biology referred to as phylogeny. This issue is beyond the scope of the present article and will be considered in forthcoming studies.
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ACKNOWLEDGMENTS I thank S.I. Maletskii and E.V. Levites for stimulating discussion on the issue of epigenetics, as well as E.V. Razin and I.F. Zhimulev for invitation to collective discussions of this problem in the framework of the Russian Academy of Natural Sciences and Vavilov Society of Geneticists and Breeders. The work was supported by the Russian Foundation for Fundamental Research (grant no. 04-04-48100) and by the Program of the Russian Academy of Sciences The Origin and Evolution of the Biosphere. REFERENCES
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